JP5243274B2 - Piperidinoylpyrrolidine, a type 4 melanocortin receptor agonist - Google Patents

Description

  The present invention relates to a specific class of compounds that are agonists of the melanocortin 4 (MC4) receptor and pharmaceutically acceptable salts, solvates and prodrugs thereof, particularly selective MC4 agonist compounds, their use in medicine, The present invention relates to compositions containing it, methods for its preparation, and intermediates used in the methods. In particular, the present invention relates to piperidinoylpyrrolidine compounds that are a class of MCR4 agonists useful for the treatment of sexual dysfunction, obesity, diabetes, and other disorders. [Terms such as “MC4”, “MC4 receptor”, “MCR4”, “MC4-R” are used interchangeably herein. ]

  Melanocortin is a peptide derived from pro-opiomelanocortin (POMC) that binds to and activates G protein-coupled receptors (GPCRs) of the melanocortin receptor family. Melanocortin regulates several diverse physiological processes including sexual function and behavior, food intake, and metabolism. The cloned melanocortin receptors are MCR1, MCR2, MCR3, MCR4, and MCR5, and are expressed in various tissues. MCR1 is specifically expressed in melanocytes and melanoma cells, MCR2 is an ACTH receptor, expressed in adrenal tissues, MCR3 is predominantly expressed in the brain and limbic system, and MCR4 is widely expressed in the brain and spinal cord Expressed, MCR5 is expressed in the brain and many peripheral tissues including skin, adipose tissue, skeletal muscle, and lymphoid tissue. MCR3 may also be involved in the control of sexual function, food intake, and heat production.

  MC4-R is a G protein-coupled seven-transmembrane receptor that is mainly expressed in the hypothalamus, hippocampus, and thalamus (Gantz et al., 1993, J Biol Chem 268: 15174-15179). This receptor is involved in central regulation of body weight. That is, MC4-R is activated by α-melanocyte stimulating hormone (MSH) derived from pro-opiomelanocortin and inactivated by agouti gene-related protein (AGRP). α-MSH induces weight loss, whereas ectopic expression of agouti protein leads to obesity in agouti mice (Fan et al., 1993, Nature 385: 165-168, Lu et al., 1994, Nature 371: 799-802). Additional evidence for the role of MC4-R in body weight regulation includes mouse knockout models (Huszar et al., 1997, Cell 88: 131-141) and human haploinsufficient mutations (Vaisse et al., 1998, Nat Genet 20: 113-114; Yeo et al., 1998, Nat Genet 20: 111-112, Hinney et al; 1999, J Clin Endocrinol Metab 84: 1483-1486). . In MC4-R knockout mice, an increase in body weight became distinguishable by 5 weeks of age. By 15 weeks of age, homozygous females averaged twice as heavy as their wild-type littermates, whereas homozygous males were approximately 50% heavier than wild-type controls. It was. Mice heterozygous for MC4-R knockout showed an intermediate weight gain compared to that seen in wild-type and homozygous littermates, thus showing a gene dosage effect due to MC4-R loss on body weight regulation. Homo mutant food intake increased by approximately 50% compared to wild-type siblings (Huszar et al., 1997, Cell 88: 131-141). [From Am. J. et al. Hum. Genet. 65: 1501-1507, since 1999]. Activation of MCR4 has been shown to induce penile erection in rodents, and inactivation of MCR4 has been shown to cause obesity (Hadley, 1999, Ann N Y Acad Sci 885: 1-21, Wikberg et al., 2000, Pharmacol Res., 42 (5), pages 393-420).

  Chaki and Nakazato, in Drugs Of The Future, 2004, 29 (10): 1065-1074, mention potential therapeutic uses for ligands that act at the MC4 receptor. International Patent Application Publication Nos. WO2005 / 077935, WO02 / 068387, and WO02 / 068388, and International Patent Application PCT / IB2006 / 002151 are useful in the treatment of sexual dysfunction, obesity, diabetes, and other disorders. Mentions certain piperidinylcarbonylpyrrolidines as potent MC4 agonists. The foregoing publication is incorporated by reference in its entirety with respect to the therapeutic aspects of MC4 agonists of the present invention.

The compounds of the present invention
Male and female sexual dysfunction, male erectile dysfunction, including hyposexual desire disorder, sexual arousal disorder, orgasmic disorder, and / or female sexual pain disorder;
Obesity (by reducing appetite, increasing metabolic rate, decreasing fat intake, or reducing craving for carbohydrates); and diabetes mellitus (increased glucose tolerance and / or reduced insulin resistance) )
Are useful in the treatment of diseases, disorders, or conditions that respond to MC4 receptor activation.

  The compounds of the present invention include hypertension, hyperlipidemia, osteoarthritis, cancer, gallbladder disease, sleep apnea, depression, anxiety, obsession, neurosis, insomnia / sleep disorder, substance abuse, pain, fever, inflammation, Immune modulation, rheumatoid arthritis; sunburn, acne, and other skin disorders; neuroprotection, cognitive and memory enhancement [treatment of Alzheimer's disease; lower urinary tract dysfunction (urinary incontinence, overactive bladder, daytime urination, nocturia, Urinary urgency; urinary incontinence (including any involuntary urinary incontinence) including stress urinary incontinence, urge incontinence, and mixed urinary incontinence, overactive bladder with urinary incontinence, enuresis, nocturia, persistent Urinary incontinence, urinary incontinence due to circumstances such as incontinence during intercourse, and treatment of lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)], and mentioned in the patent application cited above The Including any other symptoms are but this shall not apply, it is potentially useful another disease, disorder or in the treatment of conditions,.

  The compounds of the invention are particularly suitable for the treatment of female sexual dysfunction, male erectile dysfunction, obesity, diabetes, and lower urinary tract dysfunction conditions.

  The terms “treating”, “treating” or “treatment” are intended herein to include both prevention and control, ie, prophylactic and palliative treatment of the indicated condition.

  Desirable properties for the MCR4 agonist compounds of the present invention include desirable MCR4 agonist potency detailed below; selection for higher MCR4 agonistic action than described below for MCR1 and / or MCR5 and / or MCR3 Both; desirable MC4R agonist potency and selectivity to MCR4 higher than MCR1 and / or MCR5 and / or MCR3; good biopharmaceutical properties such as physical stability; solubility; Applicability; adequate metabolic stability; ability to remove AGRP from MC4 receptor.

  The present invention relates to a compound of formula (I)

[Where:
One of X and Y is N, the other is CH,
R is F, Cl, CN, CF ₃ , or methoxy, provided that when Y is N, R is not F or Cl;
R ¹ is phenyl, 2-pyridyl, C ₃ -C ₆ , wherein the ring portion may be substituted with one or more substituents each independently selected from F, Cl, CN, methyl, and methoxy. cycloalkyl, or a _CH 2 _(C 3 _{~C 6} cycloalkyl),
R ² is H, F, or Cl, provided that when Y is N, R ² is not F or Cl;
Het is a 6-membered ring containing 1 or 2 N atoms, which ring is aromatic or contains two double bonds in the ring and a ═O substituent, F , Cl, OH, CN, methyl, ethyl, NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , and methoxy, each independently substituted with one or more substituents,
Or alternatively, Het contains 1 or 2 N atoms fused to a 5-membered aromatic ring containing 1 or 2 other N atoms in the 3, 4 position relative to the bond to the pyrrolidine ring. And the 5-membered ring may be substituted with OH]
Alternatively, a pharmaceutically acceptable salt, solvate (including hydrate), or prodrug thereof is provided.

  Non-limiting examples of suitable “Het” groups are shown below.

  X is preferably N and Y is preferably CH.

  R is preferably chloro.

R ¹ is preferably phenyl optionally substituted with one or more substituents independently selected from F, Cl, CN, methyl, and methoxy.

More preferably, R ¹ is phenyl, 4-chlorophenyl, or 4-fluorophenyl.

In another embodiment, R ¹ is preferably C ₃ -C ₆ cycloalkyl, more preferably cyclopropyl or cyclohexyl.

R ² is preferably H or F.

R ² is more preferably H.

  Het is pyridin-2-yl, pyridin-3-yl, optionally substituted with one or more substituents independently selected from F, Cl, OH, CN, methyl, ethyl, and methoxy. Pyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihydropyridin-3-yl, 2-oxo-1,2-dihydropyrimidin-4-yl, 6-oxo-1,6-dihydropyrimidin-4-yl, 2-oxo-1,2-dihydropyridin-4-yl, imidazo [1,2-b] pyridazin-6-yl, [1,2,4] Triazolo [4,3-b] pyridazin-6-yl or 6-oxo-1,6-dihydropyridin-2-yl is preferred.

  Het is pyridin-2-yl, pyridin-3-yl, pyridazine-3- optionally substituted with one or more substituents independently selected from OH, CN, F, methyl, and methoxy. More preferably, it is yl or 6-oxo-1,6-dihydropyridazin-3-yl.

  Even more preferably, Het is pyridin-2-yl or pyridazin-3-yl substituted in the para position with OH, CN, or methoxy, respectively, for the bond linking to the pyrrolidine moiety.

  Most preferably, Het is pyridazin-3-yl substituted in the para position with OH, CN, or methoxy with respect to the bond linked to the pyrrolidine moiety.

Preferred groups of compounds, salts, solvates and prodrugs include those where R ¹ has the meaning associated with the following specific compounds.

  Preferred groups of compounds, salts, solvates and prodrugs include those where R has the meaning associated with the specific compounds below.

Preferred groups of compounds, salts, solvates and prodrugs include those where R ² has the meaning associated with the following specific compounds.

  Preferred groups of compounds, salts, solvates, and prodrugs include those where Het has the meaning associated with the following specific compounds.

Another preferred group of compounds, salts, solvates, and prodrugs includes those where R, R ¹ , R ² , and Het have the meanings associated with the following specific compounds.

The compound is preferably selected from:
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-pyridine-2- Ylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (5-chloropyridin-2-yl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-4- (4-methoxyphenyl) -3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-cyclohexyl-4-hydroxy-3,5-dimethylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -1- (6-chloropyridazin-3-yl) -4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (6-methoxypyridazin-3-yl) pyrrolidin-3-yl] carbonyl } -4-cyclopropyl-3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (5-fluoropyridin-3-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] nicotinonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- (5-fluoropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-fluoropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-fluoropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-cyanopyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4R) -3-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- (6-methoxypyridin-3-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- (5-methoxypyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
(3R, 4R, 5S) -4- (4-Fluorophenyl) -1-{[(3S, 4R) -1- (5-fluoropyridin-3-yl) -4- (6-methoxypyridine-3- Yl) pyrrolidin-3-yl] carbonyl} -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-pyridazin-3-ylpyrrolidin-3-yl] carbonyl} -4- ( 4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- [1,2,4] triazolo [4,3-b] pyridazine- 6-ylpyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-imidazo [1,2-b] pyridazin-6-ylpyrrolidin-3- Yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyrimidin-2 (1H) -one,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -1-methylpyrimidin-2 (1H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (6-methoxypyridazin-3-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
Or a pharmaceutically acceptable salt, solvate (including hydrate) or prodrug thereof.

The compound is more preferably selected from:
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (5-chloropyridin-2-yl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-pyridazin-3-ylpyrrolidin-3-yl] carbonyl} -4- ( 4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- [1,2,4] triazolo [4,3-b] pyridazine- 6-ylpyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-imidazo [1,2-b] pyridazin-6-ylpyrrolidin-3- Yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyrimidin-2 (1H) -one,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -1-methylpyrimidin-2 (1H) -one,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
Or a pharmaceutically acceptable salt, solvate (including hydrate) or prodrug thereof.

The compound is most preferably selected from:
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (5-chloropyridin-2-yl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
Pharmaceutically acceptable salts, solvates (including hydrates) or prodrugs thereof.

  Pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts thereof. Suitable acid addition salts are those formed from acids that produce non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, cansylate, citrate, cyclamine Acid salt, edicylate, esylate, formate, fumarate, gluconate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromic acid Salt / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulfate, naphthylate, 2-naphthylate, Nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphoric acid / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, sugar salt, stearate, succinic acid Salt, tannate, tartrate, Sill salts include trifluoroacetate and Kishinoho salts, (xinofoate) is. Acid hemi-salts such as hemisulfate may be produced. For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002).

  The compounds, salts, solvates and prodrugs of the present invention may exist in the form of tautomers, zwitterions, polymorphs, crystals, liquid crystals and the like. All such forms are included within the scope of the present invention. As an example illustrating the relationship of tautomers, for example, in a compound of formula (I) where the “Het” group is as shown below, both the following “keto” and “enol” tautomers are “ It is included within the range of “Het”.

  Also included within the scope of the invention are multi-component complexes (other than salts and solvates) in which the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. . This type of complex includes clathrates (drug-host inclusion complexes) and co-crystals. The latter is usually defined as a crystalline complex of neutral molecular components joined together by non-covalent interactions, but could also be a complex of neutral molecule and salt.

For example, isotope-labelled compounds of formula (I) incorporating ² H, ³ H, ¹³ C, ¹⁵ N, ¹⁸ O, or other isotopes are also included within the scope of the invention. Such compounds can be produced by appropriate variations of the synthetic methods described herein using methods and reagents known in the art or routine variations thereof.

  As indicated, so-called “prodrugs” of the compounds of formula (I) are within the scope of the invention. Thus, certain derivatives of compounds of formula (I), which may have little or no pharmacological activity per se, exhibit the desired activity when administered in or on the body, for example by cleavage by hydrolysis. Can be converted to a compound of formula (I). Such derivatives are referred to as “prodrugs”. More information on the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems”, Volume 14, ACS Symposium Series (T Higuchi and W Stella), and “Bioreversible Carriers in Drugs 198,” Year (E B Roche, American Pharmacists Association).

  Certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).

  Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from optically pure appropriate precursors, or racemates using, for example, chiral high pressure liquid chromatography (HPLC) (Or salt or derivative racemates) are included.

  Alternatively, the racemic compound (or racemic precursor) can be converted to a suitable optically active compound, such as an alcohol, or tartaric acid or 1--1 in the case where the compound of formula (I) contains an acidic or basic moiety. It can also be reacted with an acid or base such as phenylethylamine. The resulting diastereoisomeric mixture is separated by chromatography and / or fractional recrystallization, and one or both of the diastereoisomers are converted to the corresponding pure enantiomers by means well known to those skilled in the art. Can be converted.

  The chiral compounds of the present invention (and their chiral precursors) contain 0-50% by volume, usually 2-20% isopropanol, and may contain 0-5% by volume alkylamines. Enantiomerically enriched forms can also be obtained using chromatography on asymmetric resins, usually using a mobile phase consisting of heptane or hexane, usually HPLC. Concentration of the eluate provides a concentrated mixture. The absolute composition of the mobile phase depends on the chiral stationary phase (asymmetric resin) selected.

The following pathways, including those described in the Examples and Preparation Examples, illustrate methods for synthesizing compounds of Formula (I). Those skilled in the art will appreciate that the compounds of the invention and intermediates thereof are described in detail herein, for example by adapting the methods described herein, for example, by methods known in the art. It will be appreciated that it can be generated by other methods. Suitable guides for synthesis, functional group interconversion, use of protecting groups etc. are for example:
“Comprehensive Organic Transformations” by RC Larock, VCH Publishers Inc. (1989); According to the March, "Advanced Organic Chemistry", Wiley Interscience (1985 years); S According to Warren, "Designing Organic Synthesis", Wiley Interscience (1978 years); S According to Warren, "Organic Synthesis-The Disconnection Approach", Wiley Inetrscience (1982); RK “Guidebook to Organic Synthesis” by Mackie and DM Smith, Longman (1982); “Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, ohn Wiley and Sons, Inc. (1999); and “Protecting Groups” by PJ, Kocienski, Georg Thiem Verlag (1994); and the latest version of the standard work, if any.

In the following general synthetic methods, unless otherwise specified, the substituents R, R ¹ , R ² , X, Y, and Het are as defined above for compounds of formula (I) above.

  The following pathways exemplify methods for synthesizing compounds of formula (I). One skilled in the art will recognize that other methods may be feasible as well.

  Scheme 1 is a formula by peptide coupling of intermediates (II) and (III) where appropriate bases and / or additives (such as 1-hydroxybenzotriazole hydrate or 4-dimethylaminopyridine) are added if necessary. It illustrates the preparation of the compound (I).

Another condition used is a solution of piperidine of general formula (II) and an acid of general formula (III) with 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (EDCI), triethylamine or N -Stir at room temperature in dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM), or ethyl acetate (EtOAc) with methylmorpholine and 1-hydroxybenzotriazole hydrate (HOBt) . Yet another suitable procedure is to prepare a solution of intermediate compounds of general formula (II) and general formula (III) from O-benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium. Stir in CH ₂ Cl ₂ or EtOAc with hexafluorophosphate (HBTU) or 1-propylphosphonic acid cyclic anhydride. Any suitable inert solvent may be used in place of those described above, but an inert solvent means a solvent that does not contain a carboxylic acid or primary or secondary amine. At least one equivalent of each coupling reagent should be used, and either one or both may be used in excess if desired.

  According to another embodiment, the present invention provides a novel intermediate compound of general formula (III).

  Scheme 2 illustrates another route for preparing compounds of general formula (I) with a range of Het groups, utilizing a protecting group strategy.

  PG is a suitable nitrogen protecting group.

  Novel compounds of formula (IV), (V), and (VI) are another embodiment of the present invention.

  In Scheme 2, the standard peptide coupling method previously described in Scheme 1 is used to combine the amine intermediate of general formula (II) with the protected acid pyrrolidine intermediate of general formula (IV) to form the general formula Obtaining the bound and protected intermediate of (V) from which the nitrogen protecting group is removed using standard deprotection strategies can give compounds of general formula (VI). Any suitable nitrogen protecting group may be used (as described in “Protecting Groups in Organic Synthesis” 3rd edition, TW Greene and PG Wuts, Wiley-Interscience, 1999). . Common nitrogen protecting groups (PG) suitable for use herein are easily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane or 1,4-dioxane. T-butoxycarbonyl (t-Boc), as well as benzyl, which is easily removed by hydrogenation in the presence of a suitable catalyst or by treatment with 1-chloroethyl chloroformate.

  A “Het” group (where “Het” is a heteroaryl group) removes a suitable leaving group from, for example, a heteroaromatic precursor of the formula “Het-L” (L is a suitable leaving group). Can be introduced. Suitable leaving groups include halogen. In certain cases, transition metal catalysis that may be combined with phosphine ligands such as 1,1′-binaphthalene-2,2′-diylbisdiphenylphosphine (eg, palladium, copper) may result in the required coupling formation. It may be necessary to get things.

Alternatively, compounds of general formula (I) having a specific Het group can be converted to other compounds of general formula (I) having different Het groups. For example:
i) A compound of formula (Ia) in which Het contains a suitable leaving group L such as methoxy or chlorine as shown in Scheme 3 can be hydrolyzed under acidic or basic conditions as shown in Scheme 3. It can be converted to a compound of formula (Ib) by decomposition. Acidic conditions are preferred, particularly preferred is treatment of the compound of formula (Ia) with acetic acid at reflux temperature. Alternatively, L is a compound of formula (Ia) is chloro, wherein Z-O ^- is reacted with alkoxide (Z is a suitable oxygen protecting group), L is Formula (Ia) and OZ Intermediates can also be obtained. Subsequent deprotection then provides the compound of formula (Ib). For example, when Z = benzyl, Z can be easily removed by hydrogenation in the presence of a suitable catalyst.

ii) Compounds of formula Ic where Het is as shown in Scheme 4 and R ³ is H are treated with base and alkylating agent in a suitable solvent as shown in Scheme 4 to give R ³ Can be converted to a compound of Formula Id where is methyl or ethyl. Suitable bases include sodium hydride, lithium diisopropylamide, and sodium hexamethyldisilazide, and suitable alkylating agents include methyl iodide, methyl tosylate, dimethyl sulfate, and ethyl iodide. Suitable solvents include tetrahydrofuran, dimethylformamide, and N-methyl-2-pyrrolidinone. Optional additives such as lithium salts such as lithium bromide may be present in the reaction mixture.

  Scheme 5 illustrates a route for preparing acid pyrrolidine intermediates of general formula (IV) from unsaturated intermediates of general formula (VII).

PG is a suitable nitrogen protecting group. PG ² is a suitable carboxylic acid protecting group. Compounds of formula (VIII), (IX), (X), (XI), and (XII) are either commercially available, or one of ordinary skill in the art with reference to literature precedents and / or preparations herein. Become familiar with.

  The compound of general formula (VII) is a compound of the general formula (XI) using a suitable ylide such as methyl (triphenylphosphoranylidene) acetate, or a phosphonate anion obtained, for example, by deprotonation of trimethylphosphonoacetate. It can be produced primarily as the desired trans isomer by Wittig or similar olefination of the aldehyde intermediate.

  For the production of unsaturated intermediates of general formula (VII), protection of the precursor cinnamic acid derivative (VIII) using standard methods, or in the presence of a palladium catalyst and a suitable base such as triethylamine, Many alternatives exist in the literature, including Heck reactions of aromatic halides (IX) with appropriate acrylic acid derivatives (X) such as t-butyl acrylate.

  The resulting E olefin intermediate of general formula (VII) undergoes [3 + 2] -azomethine ylide cycloaddition by reaction with an ylide precursor of general formula (XII) to almost exclusively pyrrolidine, which is trans-stereochemistry. . This reaction may include one or more of an inert solvent such as dichloromethane, toluene, tetrahydrofuran, and (1) an acid catalyst such as TFA, (2) a desilylating agent such as silver fluoride, and (3) heating. Activation by is required.

  The compound of the general formula (XIII) obtained from the cycloaddition reaction is a racemate and may need to be resolved into its component enantiomers. Can be achieved by preparative HPLC. Alternatively, the acid intermediate of general formula (IV) can be converted to standard methods (eg, the production of diastereoisomeric derivatives by reaction with enantiomerically pure reagents, the physical properties of the resulting diastereoisomers). Separation by method and cleavage to acid (IV)).

Intermediate compounds of general formula (XIII) may be converted to compounds of general formula (IV) by deprotection of the protecting group PG ^2. Many methods can be used to realize this conversion ("Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4th edition, March, Jerry, 1992, pages 378-383, Publisher: Wiley, New York, NY, USA). See). In particular, with a base-labile protecting group, when the compound of the general formula (XIII) is treated with an aqueous alkali metal hydroxide solution such as lithium hydroxide, sodium hydroxide, potassium hydroxide in a suitable organic solvent, The corresponding compound of general formula (IV) is obtained. In such a reaction, it is preferable to use an organic co-solvent (1,4-dioxane, tetrahydrofuran or the like) miscible with water. If necessary, the reaction may be heated to aid hydrolysis. Certain protecting groups are more conveniently hydrolyzed under acidic conditions, such as in t-butyl or benzhydryl esters. Such esters can be cleaved by treatment with an anhydrous acid such as trifluoroacetic acid or hydrogen chloride in an inert organic solvent such as dichloromethane.

  The novel compound of formula (XIII) is another embodiment of the present invention.

Scheme 6 shows another route using oxazolidinone as a chiral auxiliary to prepare a single enantiomer of an acid pyrrolidine intermediate of general formula (IV) from an unsaturated intermediate of general formula (VII). This is just an example. The acid of formula (VIII) is obtained by deprotection of (VII) and then converted to a mixed anhydride and coupled to oxazolidinone (R ⁴ is preferably phenyl, t-butyl, or i-propyl). And an intermediate of formula (XIV). Alternatively, reaction of a compound of formula (VII) with a lithium salt of oxazolidinone (for example when PG ² = OCOt-Bu) in a suitable solvent (eg THF) may be of formula (XIV) A compound can be obtained.

The compound of formula (XIV) undergoes [3 + 2] -azomethine ylide cycloaddition by reaction with a compound of general formula (XII) to give diastereoisomers (XV) and (XVI), which are chromatographed or crystallized. And hydrolyzed to give the pyrrolidine of formula (IV). Alternatively, the compound of general formula (XVI) can be converted to the compound of general formula (XIII), for example by treatment with sodium methoxide in dimethyl carbonate (when PG ² = OMe).

PG is selected from suitable nitrogen protecting groups. PG ² is selected from the appropriate carboxylic acid protecting groups and may use different groups for compounds (VII) and (XIII).

  The novel compound of formula (XVI) is another embodiment of the present invention.

Scheme 7 illustrates a route for preparing an acid pyrrolidine intermediate of general formula (III) from an intermediate of general formula (XIII). Once the protecting group PG has been removed using any suitable conventional technique, the Het group can be introduced by the appropriate method described above for Scheme 2. Removal of the acid protecting group PG ² as described in Scheme 4 provides the acid of general formula (III).

PG is selected from suitable nitrogen protecting groups. PG ² is selected from suitable carboxylic acid protecting groups.

  The novel compounds of formula (XVII) and (XVIII) are another embodiment of the present invention.

As illustrated in Scheme 8, the piperidine intermediate of general formula (II) can be obtained by adding an organometallic nucleophile to a ketone of general formula (XIX) containing a suitable nitrogen protecting group (PG). It can be prepared by obtaining an intermediate of formula (XX). Addition stereochemistry is preferred such that the hydroxyl group in the product is cis to two methyl groups. Such controlled addition to the carbonyl system is described in the literature (eg, “Journal of Medicinal Chemistry” (1964), Volume 7 (6), pages 726-8). Such nucleophilic addition is generally performed at low temperature using Grignard, organolithium, or other suitable organometallic reagent in anhydrous ether or other non-polar solvent. These organometallic reagents can be generated by halogen-metal exchange using the appropriate halide precursors R ¹ -Br or R ¹ -I and n-butyl lithium or t-butyl lithium. Suitable protecting groups for obtaining the desired piperidine intermediate of general formula (II) include benzyl, which can be removed by hydrogenation, or Boc, which can be removed by treatment with an acid such as TFA, or DDQ, Included are CAN or p-methoxybenzyl (PMB) which can be removed by treatment with 1-chloroethyl chloroformate. Because certain protecting groups and under certain conditions, protecting groups can become unstable upon treatment with organometallic reagents, both transformations can also be realized in one step. For example, when PG = Boc, the protecting group may sometimes be cleaved upon treatment of the intermediate of formula (XIX) with an organometallic reagent.

  PG is selected from suitable nitrogen protecting groups.

  Those of ordinary skill in the art will, as discussed above, in addition to protecting the nitrogen or acid group at various points during the synthesis of the compound of formula I, another group such as a hydroxy group may be substituted with a suitable protecting group. It will be appreciated that it may be necessary to protect with and then remove the protecting group. The method of deprotection of any particular group depends on the protecting group. See "Protective groups in Organic synthesis", TW Greene and PGM Wutz for examples of protection / deprotection methods. For example, in the case of protecting the hydroxy group as methyl ether, the deprotection conditions could include, for example, refluxing in 48% aqueous HBr or stirring with borane tribromide in dichloromethane. Alternatively, when protecting the hydroxy group as a benzyl ether, the deprotection conditions could include hydrogenation using, for example, a palladium catalyst in a hydrogen atmosphere.

  All of the above reactions and the preparation of the new starting materials used in the above-described methods are conventional and the reaction conditions suitable for their performance or preparation, as well as the procedures for isolating the desired product, are described in literature precedents and in this document. Those skilled in the art will be familiar with the examples and preparations in the specification.

  The pharmaceutically acceptable salt of the compound of formula (I) can be easily prepared by appropriately mixing a solution of the compound of formula (I) and a solution of the desired acid. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Pharmaceutically acceptable salts of the compounds of formula (I) can be prepared by one or more of the following three methods.
(I) a method by reacting a compound of formula (I) with a desired acid;
(Ii) removing an acid or base labile protecting group from a suitable precursor of the compound of formula (I), or opening a suitable cyclic precursor, such as a lactone or lactam, using the desired acid. Or (iii) by converting one salt of a compound of formula (I) to another by reaction with a suitable acid or by a suitable ion exchange column.

  All three reactions are usually carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to hardly ionized.

The compounds of formula (I) of the present invention are useful as MCR4 agonists in the treatment of various disease states. Preferably, the MCR4 agonist exhibits a functional potency at the MC4 receptor indicated as an EC ₅₀ of less than about 1000 nM, more preferably less than 500 nM, even more preferably less than about 100 nM, and even more preferably less than about 50 nM; The EC ₅₀ value measurement of MCR4 functional efficacy can be performed using Protocol E described in International Patent Application Publication No. WO2005 / 077935. Using this assay, the compounds according to the invention show a functional potency at the MC4 receptor, indicated as an EC ₅₀ of less than 1000 nM.

  Preferred compounds herein show functional potency at the MCR4 receptor as previously defined herein and are selective for MCR4 over MCR1. Preferably, the MCR4 agonist has selectivity for MCR4 over MCR1, and the MCR4 receptor agonist has a functional selectivity for the MCR4 receptor of at least about 10 times that of the MCR1 receptor, preferably Is at least about 20 times, more preferably at least about 30 times, even more preferably at least about 100 times, even more preferably at least about 300 times, even more preferably at least about 500 times, especially at least about 1000 times, The relative selectivity assessment is based on a measurement of the functional potency of MCR1 and MCR4, which can be performed using an assay as described herein.

  Preferably, the MCR4 agonist has selectivity for MCR4 over MCR3, and the MCR4 receptor agonist has a functional selectivity for the MCR4 receptor of at least about 10 times that of the MCR3 receptor, preferably Is at least about 30 times, more preferably at least about 100 times, even more preferably at least about 300 times, even more preferably at least about 500 times, in particular at least about 1000 times, and the relative selectivity evaluation is Based on measuring the functional efficacy of MCR3 and MCR4, which can be performed using an assay as described herein.

  Preferred compounds herein show functional efficacy at the MCR4 receptor as previously defined herein and are selective for MCR4 over MCR5. Preferably, the MCR4 agonist has selectivity for MCR4 over MCR5, and the MCR4 receptor agonist has a functional selectivity for the MCR4 receptor of at least about 10 times, preferably compared to the MCR5 receptor, At least about 30 times, more preferably at least about 100 times, even more preferably at least about 300 times, even more preferably at least about 500 times, especially about 1000 times, the relative selectivity evaluation being Based on the measurement of functional efficacy of MCR5 and MCR4, which can be performed using an assay as described in the literature.

  The MCR4 agonist preferably has selectivity for MCR4 over MCR1 and MCR3, and the MCR4 receptor agonist is functionally selective for the MCR4 receptor at least about 10 compared to the MCR1 and MCR3 receptors. Times, preferably at least about 30 times, more preferably at least about 100 times, even more preferably at least about 300 times, even more preferably at least about 1000 times.

  Preferred compounds herein show functional potency at the MCR4 receptor as previously defined herein and are selective for MCR4 over MCR1 and MCR5. Preferably, the MCR4 agonist has selectivity for MCR4 over MCR1 and MCR5, and the MCR4 receptor agonist has a functional selectivity for the MCR4 receptor of at least about MCR1 and MCR5 receptors. 10 times, preferably at least about 30 times, more preferably at least about 100 times, even more preferably at least about 300 times, even more preferably at least about 500 times, especially at least about 1000 times.

  The MCR4 agonist preferably has selectivity for MCR4 over MCR3 and MCR5, and the MCR4 receptor agonist has a functional selectivity for the MCR4 receptor of at least about 10 compared to the MCR3 and MCR5 receptors. Times, preferably at least about 30 times, more preferably at least about 100 times, even more preferably at least about 300 times, and most preferably at least about 1000 times.

Combination Therapy The compounds of formula (I) of the present invention, or salts, solvates, or prodrugs thereof, are effective in the treatment of problematic conditions such as sexual dysfunction, lower urinary tract disorders, obesity, and / or diabetes. It can also be beneficially delivered in combination with supplementary active agents. Furthermore, the compounds of formula (I) of the present invention, or salts, solvates or prodrugs thereof, may also be beneficially delivered, optionally in combination with auxiliary active agents effective in reducing emesis. Some suitable auxiliary active agents that may be useful in the combinations of the present invention include the following.
1) Natriuretic factors, especially compounds that modulate the action of atrial natriuretic factor (also known as atrial natriuretic peptide), B-type and C-type natriuretic factor, eg inhibitors of neutral endopeptidase In particular, the compounds described and claimed in WO 02/02513, WO 02/03995, WO 02/079143, and EP-A-1258474, in particular the compound (2S) -2 {[1 of WO 02/079143 -{3-4 (-chlorophenyl) propyl] amino} carbonyl) -cyclopentyl] methyl} -4-methoxybutanoic acid,
2) Compounds that inhibit angiotensin converting enzyme, such as enalapril, as well as combined inhibitors of angiotensin converting enzyme and neutral endopeptidase, such as omapatrilat,
3) a substrate for NO synthase, such as L-arginine,
4) cholesterol-lowering drugs such as statins (eg atorvastatin / Lipitor ™) and fibrates,
5) Estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists, preferably raloxifene or lasofoxifene ((-)-cis-6-phenyl-5, whose preparation is detailed in WO 96/21656) [4- (2-Pyrrolidin-1-yl-ethoxy) -phenyl] -5,6,7,8-tetrahydronaphthalen-2-ol and pharmaceutically acceptable salts thereof),
6) PDE inhibitors that preferably have an IC50 for the respective enzyme of less than 100 nM, more particularly PDE2, 3, 4, 5, 7, or 8 inhibitors, preferably PDE2 or PDE5 inhibitors, most preferably PDE5 Inhibitors (see below) (however, PDE3 and 4 inhibitors are administered locally to the penis or only by injection for the treatment of male erectile dysfunction),
7) More specifically, vasoactive intestinal protein (VIP) mediated by one or more of VIP receptor subtypes VPAC1, VPAC, or PACAP (pituitary adenylate cyclase activating peptide), VIP mimetics, VIP An analog; VIP receptor agonist, VIP analog (eg, Ro-125-1553), one or more of a VIP fragment; one or more of a combination of an alpha adrenergic receptor antagonist and VIP (eg, Invicorp, Aviptadil),
8) Serotonin receptor agonists, antagonists or modulators, more particularly 5HT1A receptors (including VML670 [WO02 / 074288] and flibanserin [US2003 / 0104980]), WO-09902159, WO-0000002550, and / or WO -Agonists, antagonists or modulators of 5HT2A, 5HT2C, 5HT3, and / or 5HT6 receptors, including those described in -00028993
9) Testosterone replacement drugs (including dehydroandrostenedione), testosterone (eg Tostelle ™, LibiGel ™), dihydrotestosterone, or testosterone implants,
10) Selective androgen receptor modulators such as LGD-2226,
11) Estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA) (ie as a combination), or estrogen and methyltestosterone hormone replacement therapy (eg HRT, in particular premarin, cenestine, oestrofeminal) ), Equin, Estrace, Estrofem, Eleste Solo, Estring, East Raderm TTS, East Raderm Matrix, Del Mestril D, Mestril Der Premphase, preemp (Preempro), Puremupaku (Prempak), Puremiku (Premique), S. Tiger test (Estratest), es tiger test HS (EstratestHS, tibolone (Tibolone)),
12) Transporter modulators of noradrenaline, dopamine, and / or serotonin, such as bupropion, GW-320659,
13) Oxytocin / vasopressin receptor agonists or modulators, preferably selective oxytocin agonists or modulators,
14) Agonists or modulators of dopamine receptors, preferably D3 or D4 selective agonists or modulators such as apomorphine, and 15) antiemetics such as 5-HT ₃ antagonists or neurokinin 1 (NK-1) antagonists.

Suitable 5-HT ₃ antagonists include, but are not limited to, granisetron, ondansetron, tropisetron, ramosetron, palonsetron, indisetron, dolasetron, alosetron, and azasetron.

  Suitable NK-1 antagonists include aprepitant, casopitant, ezropitant, cripitant, netupitant, vestitant (vestitant), bophopitant (vofopitant) ) -3,5-bis (trifluoromethyl) phenyl) ethoxy-4- (5- (dimethylamino) methyl-1,2,3-triazol-4-yl) methyl-3- (S)-(4- Fluorophenyl) morpholine is included, but not limited to. See, for example, International Patent Application Publication No. WO 2006/049933.

With particular reference to the use of the compounds of the invention for the treatment of lower urinary tract dysfunction, combinations with other agents include, but are not limited to:
Muscarinic acetylcholine receptor antagonists such as tolterodine,
An alpha adrenergic receptor antagonist, in particular an alpha 1 adrenergic receptor antagonist or an alpha 2 adrenergic receptor antagonist,
An α-adrenergic receptor agonist or partial agonist, in particular an α1-adrenergic receptor agonist or partial agonist, or an α2-adrenergic receptor agonist or partial agonist,
5HT2C agonist (see WO 2004/096196),
Serotonin and noradrenaline reuptake inhibitors (SNRI),
A noradrenaline reuptake inhibitor (NRI), eg reboxetine in the form of its racemate or (S, S) -enantiomer,
A vanilloid receptor (VR) antagonist, such as capsaicin,
An α2δ ligand, such as gabapentin or pregabalin,
Β3-adrenergic receptor agonists,
A 5HT1a receptor antagonist or a 5HT1a receptor inverse agonist,
Prostanoid receptor antagonists, such as EP1 receptor antagonists.

For the use of compounds of formula (I) in the treatment of obesity and related disorders, the compounds can also be used with other antiobesity agents. Suitable anti-obesity drugs include cannabinoid 1 (CB-1) receptor antagonists (such as rimonabant), apolipoprotein B secretion / microsomal triglyceride transfer protein (apo-B / MTP) inhibitors (especially edipatapide or zirlotapide) Intestinal selective MTP inhibitors), 11β-hydroxysteroid dehydrogenase 1 (11β-HSD type 1) inhibitors, peptide YY _3-36 and analogs thereof, cholecystokinin A (CCK-A) agonists, monoamines reuptake inhibitors (such as sibutramine), sympathomimetic agents, beta ₃ adrenergic receptor agonists, dopamine receptor agonists (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT2c receptor agonists, melanin concentrating hormone Antagonists, leptin (OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin or orlistat), anorectic agents (such as bombesin agonists), neuropeptide Y receptor antagonists (such as In particular, NPY-5 receptor antagonists), thyroid mimetic drugs, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide 1 receptor agonists, ciliary neurotrophic factor ( Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA and Procter & Gamble Company, Ohio, USA Cincinnati available from Axokine (TM), etc.), human agouti-related protein (AGRP) inhibitors, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and the like neuromedin U receptor agonist. Other anti-obesity agents, including the preferred agents described below, are well known to those skilled in the art or will be readily apparent in light of this disclosure. The compounds of the present invention can also be administered in combination with natural compounds that serve to lower plasma cholesterol levels. Such natural compounds are usually considered dietary supplements and include, for example, garlic extract, hoodia plant extract, and niacin. Particularly preferred are anti-obesity selected from the group consisting of CB-1 antagonists, intestinal selective MTP inhibitors, orlistat, sibutramine, bromocriptine, ephedrine, leptin, peptide YY _3-36 and analogs thereof, and pseudoephedrine It is a medicine. For the treatment of obesity and related conditions, the compounds of the present invention and combination therapies are preferably administered in conjunction with exercise and a sensible diet. Preferred CB-1 antagonists include rimonabant as described in US Pat. No. 5,624,941 (SR141716A, also available from Sanofi-Synthelabo, also known under the trade name of Acomplia ™), and US Pat. Nos. 5,747,524, 6432984. , And 6518264, US Patent Publication Nos. US 2004/0092520, US 2004/0157839, US 2004/0214855, and US 2004/0214838, US Patent Application No. 10/971599, filed October 22, 2004, and PCT Patents. Compounds described in published WO 02/076949, WO 03/075666, WO 04/048317, WO 04/013120, and WO 04/012671 are included. Preferred intestinal selective MTP inhibitors include zirlotapid as described in US Pat. No. 6,720,351, and 4- (4- (4- (4-((2-((4 -Methyl-4H-1,2,4-triazol-3-ylthio) methyl) -2- (4-chlorophenyl) -1,3-dioxolan-4-yl) methoxy) phenyl) piperazin-1-yl) phenyl) -2-s-butyl-2H-1,2,4-triazol-3 (4H) -one (R103757), as well as impritapide (BAY 13-9952) described in US Pat. No. 6,265,431. Other representative antiobesity agents used in the combinations, pharmaceutical compositions, and methods of the invention can be prepared using methods known to those skilled in the art, for example, sibutramine is described in US Patents. No. 4,929,629 can be prepared, bromocriptine can be prepared as described in US Pat. Nos. 3,752,814 and 3,758,888, and orlistat is prepared in US Pat. Nos. 5,274,143, 5,420,305, 554017. And PYY _3-36 (including analogs) can be prepared as described in US 2002/0141985 and WO 03/027637. .

  As used herein, a preferred group includes compounds of the invention and PDE5 inhibitors; NEP inhibitors; D3 or D4 selective agonists or modulators; estrogen receptor modulators and / or estrogen agonists and / or estrogen antagonists; testosterone supplements , Testosterone, or testosterone implants; estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA), or estrogen and one or more additional therapeutic agents selected from methyltestosterone hormone replacement therapy It is.

  A preferred combination for the treatment of MED is a combination of a compound of the invention with one or more PDE5 inhibitors and / or NEP inhibitors.

  Preferred combinations for the treatment of FSD include compounds of the invention and PDE5 inhibitors; and / or NEP inhibitors; and / or D3 or D4 selective agonists or modulators; and / or estrogen receptor modulators, estrogen agonists, estrogens Antagonists; and / or testosterone replacement drugs, testosterone, testosterone implants; and / or a combination of estrogen, estrogen and medroxyprogesterone or medroxyprogesterone acetate (MPA), estrogen and methyltestosterone hormone replacement therapy.

Particularly preferred PDE5 inhibitors for combination products for MED or FSD treatment are:
5- [2-Ethoxy-5- (4-methyl-1-piperazinylsulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] Pyrimidin-7-one (sildenafil, especially present as citrate), (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylene Dioxyphenyl) -pyrazino [2 ′, 1 ′: 6,1] pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- ( 4-Ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one (Vardenafil) ), 5- (5-A Til-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5 -(5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -One, 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl) amino] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidine- 2-ylmethyl) pyrimidine-5-carboxamide (TA-1790), 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidine-5 Yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide (DA8159), and pharmaceutically acceptable salts thereof.

  Particularly preferred NEP inhibitors for combination products for MED or FSD treatment are the compounds exemplified in WO 02/079143.

  As used herein, therapeutically active as defined in the claims (especially claim 1) and specific examples by cross-reference to compounds included in patents and patent applications that can be used in accordance with the invention Compounds are described (all of which are hereby incorporated by reference).

  If a combination of active agents is administered, the agents can be in the same or different formulations and can be administered simultaneously, separately or sequentially.

Biological Assays Melanocortin Receptor Agonist Activity, Selectivity Measurement of In Vitro Agonist Efficacy (EC ₅₀ ) of Compounds against Melanocortin Receptors Type 1 and 3 (MC1 and MC3) Melanocortin (MC) receptor is activated by agonists This activates the intracellular adenylate cyclase enzyme that synthesizes the second messenger signaling molecule adenosine 3 ′, 5′-cyclic monophosphate (cAMP). Changes in cAMP levels after treatment of recombinant MC1 and MC3 cell lines with test compounds were measured, and MC1 and MC3 potency estimates (EC ₅₀ ) were calculated as follows.

Human embryonic kidney (HEK) cells or Chinese hamster ovary cell lines stably transfected with full-length cDNAs encoding human MC1 or MC3 receptors, respectively, were established using standard molecular biology methods. The test compound was dissolved in dimethyl sulfoxide (DMSO) at 4 mM. An 11-point semilog unit increasing serial dilution of the test compound, usually starting from 50 uM, is buffered with phosphate buffered saline (PBS), 2.5% DMSO, and 0.05% pluronic F-127 surfactant. Prepared in liquid. Freshly cultured cells at 80-90% confluency were collected and resuspended in Dulbecco's Modified Eagle Medium (DMEM). Cells (10000 for MC3, 20000 for MC1) were added to serial dilutions of test compounds in 384 well assay plates and incubated at 37 ° C. for 1 hour. The relative cAMP concentration in each well was then determined using the β-galactosidase enzyme fragment complementation method purchased in kit form as a Discoverx cAMP II kit from GE Healthcare / Amersham Biosciences UK. In the case of MC1, 3-isobutyl-1-methylxanthine (IBMX) was included in DMEM at a concentration of 750 μM when cells were resuspended for the assay. The fluorescence reading taken from each assay well was converted to the effect (%) relative to the maximum control well corresponding to the alpha melanocyte stimulating hormone concentration shown to give the maximum effect. Using a custom software application called SIGHTS, the sigmoid curve was fitted to a plot of log ₁₀ inhibitor concentration versus effect (%), which allows the EC ₅₀ estimate to be calculated at the bottom of the sigmoidal dose response curve. And measured as the concentration of the test compound giving an intermediate effect of the upper asymptote. Each experiment included a measurement of EC ₅₀ for alpha melanocyte stimulating hormone, which was used as a standard to track the consistency of the assay and provide a fair amount of EC ₅₀ estimates obtained in various experiments. Enabled comparison.

MC5 and MC4 EC ₅₀ activity was measured as described in US 2005/0176772 (pages 28-30) in assay protocols D and E, respectively.

Inhibition of Nle4, D-Phe7-α-MSH at the MC4 receptor Nle4, D-Phe7-α-MSH is a stable analog of melanocyte stimulating hormone (MSH) that acts as an agonist at the MC4 receptor (MC4R). is there. Can competitive binding assay with [ ¹²⁵ I] Nle4, D-Phe7-α-MSH be used to inhibit Nle4, D-Phe7-α-MSH binding to MC4R-expressing cell-derived membranes? I can evaluate the compound.

Cells expressing MC4R were homogenized and membrane fragments were isolated by differential centrifugation. CHO-CRE MC4R cell membranes were bound to PVT-PEI-WGA SPA Beads type A over 2 hours, spun at 1000 RPM for 5 minutes and suspended at a concentration of 300 ug beads / ml (0.15 ug membrane per well). , 15 ug beads). Bead / membrane mixture in a total volume of 50 μl buffer per well (25 mM HEPES, 1 mM MgCl ₂ , 2.5 mM CaCl ₂ , 1% Pluronic F68, 1 tablet of complete EDTA protease inhibitor / 50 ml pH 7) Incubated in duplicate with 0.06 nM [ ¹²⁵ I] Nle4, D-Phe7-α-MSH and 11 steps of half-log concentration of competitor ligand. Nonspecific binding was determined by including 100 nM SHU9119. Beads / membranes were added to initiate the reaction and the plates were incubated at room temperature for 12 hours (the first hour on a plate shaker), after which the amount of radioactivity present was measured using a Wallac plate counter. Ki values were determined by data analysis using appropriate software.

  The compounds of the present invention have a binding constant for Nle4, D-Phe7-α-MSH at the MC4 receptor, expressed as a Ki value, of less than about 1000 nM, more preferably less than 500 nM, even more preferably less than about 100 nM, More preferably, it is preferably less than about 50 nM and the Ki value is measured using the assay described above.

Inhibition of Nle4, D-Phe7-α-MSH at the MC3 receptor Nle4, D-Phe7-α-MSH is a stable analog of melanocyte stimulating hormone (MSH) that acts as an agonist at the MC3 receptor (MC3R). is there. Can competitive binding assays with [ ¹²⁵ I] Nle4, D-Phe7-α-MSH be used to inhibit Nle4, D-Phe7-α-MSH binding to MC3R-expressing cell-derived membranes? I can evaluate the compound.

Cells expressing MC3R were homogenized and membrane fragments were isolated by differential centrifugation. CHO-CRE MC3R cell membranes were bound to PVT-PEI-WGA SPA beads type A for 2 hours, spun at 1000 RPM for 5 minutes and suspended at a final assay concentration of 800 ug beads / ml (1.2 ug per well). Membrane, 40 ug beads). The bead / membrane mixture was placed in a total volume of 50 μl buffer per well (25 mM HEPES, 1 mM MgCl ₂ , 2.5 mM CaCl ₂ , 1% Pluronic F68, 1 tablet of complete EDTA protease inhibitor / 50 ml pH 7). , 0.06 nM [ ¹²⁵ I] Nle4, D-Phe7-α-MSH and 11 steps of half-logarithmic concentrations of competitor ligands in duplicate. Nonspecific binding was determined by including 100 nM SHU9119. Beads / membranes were added to initiate the reaction and the plates were incubated at room temperature for 12 hours (the first hour on a plate shaker), after which the amount of radioactivity present was measured using a Wallac plate counter. Ki values were determined by data analysis using appropriate software.

Dense drug interaction (DDI) 3 μM cocktail screen Drug interaction is the effect of a substance on the activity of another drug, ie its effect increases or decreases, or as a whole, both alone It is a situation that creates new effects that do not occur. While drug-drug interactions can be said to be the result of various processes, it is relatively common that one drug affects the pharmacokinetics of another drug by inhibiting the cytochrome P450 that metabolizes it. Is. Since these phenomena are important, the assessment of the DDI potential of a new chemical (NCE) is considered important early in the drug discovery process.

  The DDI cocktail screen in human liver microsomes (HLM) was performed in a fully automated manner, and the goal of this screen was to develop new chemicals for the four major cytochrome P450 enzymes 1A2, 2D6, 2C9, and 3A4 ( NCE, tested at 3 μM) to obtain a one-point evaluation for DDI potential.

  The substrate cocktail approach for P450 DDI utilizes an isoform-specific clinical drug probe along with human liver microsomes to simultaneously measure inhibition of P450 1A2, 2C9, 2D6, and 3A4 activity in a single incubation Is possible. This approach is performed at high throughput while simultaneously detecting metabolites by LC-MS / MS. This method has been thoroughly tested and evaluated using standard compounds. The probe substrates used are shown in the table below.

  The appearance of each substrate metabolite is measured over time in the presence and absence of a concentration of 3 μM NCE (test compound / inhibitor). The inhibitory potential of the compound is evaluated as a percentage value and is interpreted using the following scheme. These data are then used in conjunction with other measurements to assess NCE suitability and aid in compound design and advancement.

AGRP Inhibition Agouti-related protein (AGRP) is a high affinity endogenous antagonist / inverse agonist for the MC4 receptor (Lu et al., 1994, Nature 371: 799-802; Ollman et al., 1997, Science 278: 135-138). AGRP levels are up-regulated by fasting (Mizuno and Mobbs, 1999, Endocrinology, 140: 4551-4557), and therefore can anti-obesity drugs acting through the MC4 receptor inhibit AGRP binding? It is important to evaluate whether. The C-terminal fragment of AGRP (87-132) has been determined to contain determinants of MC4R binding (Yang et al., 1999, Mol Endocrinol 13: 148-155), and thus [ A competitive binding assay for < ¹²⁵ > I] AGRP (87-132) can be used to assess compounds that can inhibit AGRP binding to membranes from cells expressing MC4R. For this, cells expressing MC4R were homogenized and membrane fragments were isolated by differential centrifugation. CHO-CRE MC4R cell membranes (12 μg protein) were added to a total volume of 100 μl of buffer (25 mM HEPES, 1 mM MgCl ₂ , 2.5 mM CaCl ₂ , 0.5% BSA pH 7.0) in 0.001. Incubated in duplicate with 3 nM [ ¹²⁵ I] AGRP (87-132) and 11 half-log concentrations of competitor ligand. Nonspecific binding was determined by including 1 μM SHU9119. Membrane was added to initiate the reaction and the plate was incubated for 2 hours at room temperature. By rapid filtration through a GF / C filter (pre-soaked in 1% PEI) using a suction harvester, by washing 5 times with 200 μl of ice-cold wash buffer (binding buffer containing 500 mM NaCl) The reaction was terminated. The filter was immersed in 50 μl scintillation fluid and the amount of radioactivity present was measured by liquid scintillation counting. Ki values were determined by data analysis using appropriate software.

  The compounds of the invention have a binding constant for AGRP at the MC4 receptor, expressed as a Ki value, of less than about 1000 nM, more preferably less than 500 nM, even more preferably less than about 100 nM, even more preferably less than about 50 nM. Preferably, the Ki value is measured using the assay described above. Using this assay, the compounds according to the invention have a binding constant for AGRP at the MC4 receptor, expressed as Ki value, of less than 1000 nM.

Food intake study: To assess the efficacy of MC4 agonists on food intake and body weight over 24 hours in male rats. Rats were housed in one animal over approximately 2 weeks and reversed lighting conditions (9.30 am to 9.30 pm). ) And then start the survey. Rats are acclimated to the Technical Scientific Equipment * (TSE) cage approximately 24 hours prior to the study date. On the morning of the study, rats are randomly assigned to treatment groups based on their body weight (n = 5 / treatment). Each rat is given MC4 agonist or vehicle orally just before the light goes out. After dosing, rats are immediately returned to the TSE cage and monitored for food intake and water consumption throughout the course of the study (24 hours). Monitor athletic activity in the form of light breaks.

  At the end of the study, the rats are sacrificed by total blood collection under terminal anesthesia with isoflurane. Blood is removed from the rat by cardiac puncture and analyzed for drug concentration levels and biomarkers.

  Data are shown as mean ± SEM and control and treatment comparisons were analyzed by ANOVA. Statistical significance has been observed at a level of p <0.05.

In vitro metabolic rate measurement (human liver microsome (HLM), rat liver microsome (RLM) assay)
Many drugs are metabolized by the cytochrome P450 monooxygenase system. This enzyme is found in high concentration in the liver and is bound to the endoplasmic reticulum of liver parenchymal cells. This enzyme system can be obtained in a semi-purified state by preparing a liver microsomal fraction. Determining the in vitro half-life of a compound in such a system provides a useful indicator of metabolic stability.

Materials and Reagents All reagents are ANALAR grade.
1. 200 mM phosphate buffer (Sigma)-100 ml 1M phosphate buffer pH 7.4 is dissolved in 400 ml MilliQ water. If necessary, the pH should be adjusted with concentrated orthophosphoric acid to pH 7.4, prepared monthly and stored refrigerated (2-8 ° C.).
2. 0.1M MgCl ₂ . 6H ₂ O (BDH)-2.032 g dissolved in 100 ml MilliQ water and stored refrigerated (2-8 ° C.).
3. 0.02M NADP (Sigma) —15.3 mg dissolved in 1000 μl MilliQ water and then refrigerated (2-8 ° C.) for further use.
4). 0.1 M DL isocitrate (Sigma)-129 mg dissolved in 5 ml MilliQ water and then refrigerated (2-8 ° C) for further use.
5. Isocitrate dehydrogenase type IV (Sigma)-stored refrigerated (2-8 ° C).
6). A substrate preservation solution (about 1 mg / ml) in a miscible organic solvent such as methanol or ethanol or in water, and stored refrigerated (2-8 ° C.)
7. 50 mM p-nitroanisole (PNA) (Aldrich)-7.65 mg dissolved in 1 ml methanol and refrigerated (2-8 ° C) until ready for use.
8). 50 μM p-nitrophenol (PNP) (Sigma) —0.69 mg dissolved in 100 ml water and stored refrigerated (2-8 ° C.).
9. 20% trichloroacetic acid (TCA) (BDH)-20 g dissolved in 100 ml MilliQ water, prepared in amber glassware and stored at room temperature.
10. 40 g of 10M sodium hydroxide (BDH) —dissolved in 100 ml of MilliQ water (the reaction is exothermic and care should be taken when preparing this solution) and prepared in a “safebreak” glassware And stored at room temperature.
11. Liver or Supermix microsomes stored at −80 ° C. should be thawed immediately prior to use, stored on ice and dispensed.
12 MilliQ water.
13. Thermostatically controlled shaking water bath set at an incubation temperature of about 37 ° C.
14 Reagent for termination of incubation (usually organic solvent, acid, or base).

In Vitro Metabolic Rate Measurement Using Liver Microsomes and Supermix Microsomes The method outlined below is for a total incubation volume of 1.5 ml.
1. Prepare the following mixture in a test tube.

2. Sufficient microsomes are added to thaw the microsomes at room temperature to obtain a final concentration of cytochrome P450 of 0.5 nmol per ml of incubation, for example, in a 1.5 ml incubation, the microsome volume added is as follows:

3. Sufficient MilliQ water is added to obtain a total incubation volume of 1.425 ml.

4). Remove 237.5 μl of incubation mixture and place in test tube for PNA positive control. Add 2.5 μl of PNA solution, stir and plug the tube into a rack in a thermostatically controlled shaking water bath.

5. Remove 100 μl for substrate-free control and dispense into tubes. Place the test tube in a rack in a thermostatically controlled shaking water bath.

6). Add substrate to incubation. The substrate should be at an initial concentration of 1 μM. The substrate volume required for the remaining 1.162.5 ml of incubate is calculated as follows:

Note: The volume of organic solvent added should not exceed 0.1% of the total incubation volume.

7). Transfer 100 μl of the incubation mixture to a test tube for a cofactor free control. Stir and plug into a rack in a thermostatically controlled shaking water bath.

8). Tubes containing the incubation mixture, as well as positive control and non-cofactor tubes, are preincubated for approximately 5 minutes in a thermostatically controlled shaking water bath set at 37 ° C.

9. NADP is added to initiate the reaction (75 μl for each 1.162.5 ml incubation mixture, 12.5 μl for positive control tubes, 5 μl for substrate-free tubes) and immediately take the first time point. PNA positive controls, cofactor free controls, and substrate free tubes are incubated for a total incubation time.

10. 100 μl aliquots are removed at 9 different sampling points from 0 to 60 minutes (usually 0, 3, 5, 10, 15, 20, 30, 45, and 60 minutes) to complete the reaction. Longer incubation times can be used, but after 120 minutes the microsomes are altered. The reaction can be terminated by adding an organic solvent, an acid, or a base. At the end of the incubation process, the cofactor free and substrate free controls are terminated in the same way, ie with the same reagents.

11. PNA positive control procedure:
After taking the final sample, the positive control is removed and 1 ml of 20% TCA is added to the tube. A tube containing 250 μl of PNP standard at 50 μM is also prepared and 1 ml of 20% TCA is added. Stir both tubes and leave for about 5 minutes to precipitate the protein.

  Centrifuge both tubes with an instrument set at 3500 rpm for about 5 minutes. Remove 1 ml of supernatant and place in a clean test tube and discard the rest.

  Add 1 ml of 10M NaOH to the supernatant, stir, and let stand for about 5 minutes. A spectrophotometer containing distilled water is measured blank at 400 nm, and then the absorbance of the PNP standard is measured using distilled water as a control. Microsomal 4-nitroanisole O-demethylase activity is calculated as follows.

  Result calculation

  The activity value from this incubation should be at least 85% of the average value of the batch used for a valid incubation. If this criterion is not met, the incubation must be repeated.

11. Samples (including no cofactors and no substrate controls) are analyzed by substrate specific assays to determine extinction kinetics.

Data analysis The data obtained using the procedure described above can be quantified in terms of substrate in vitro intrinsic clearance (Clint). If the substrate concentration is lower than Km, metabolism should be first order and give a log-linear plot where the substrate disappears over time.

  The in vitro half-life of the substrate is determined by plotting the natural logarithm (ln) of the measured relative substrate concentration (eg drug / internal standard ratio) against time and fitting the best fit line to this data. Can be determined. The slope of this line is the first order rate constant (k) of substrate extinction and is determined by regression analysis. This rate constant can be converted to a half-life according to the following equation:

Alternatively, the rate constant can be converted to intrinsic clearance (Clint) according to the following equation:
Clint (μl / min / mg) = (k / protein concentration in incubation (mg / ml)) * 1000

  The compounds of the present invention have a clearance as measured by the above assay of less than about 200 μL / min / mg, more preferably less than 100 μL / min / mg, even more preferably less than about 50 μL / min / mg, even more preferably about It is preferably indicated as a value of less than 20 μL / min / mg. Using this assay, the tested compounds according to the invention exhibit a clearance of less than 200 μL / min / mg.

Method of Administration The compounds of the present invention are intended for use as a medicament that can be administered as a crystalline or amorphous product. The compound of the present invention can be obtained as a solid filling, powder, or film by a method such as precipitation, crystallization, freeze drying, spray drying, and evaporation drying. Microwave or radio frequency drying may be used for this purpose.

  The compounds of the present invention may be administered alone, or in combination with one or more other compounds of the present invention, or in combination with one or more other drugs (or any combination thereof). it can. Generally, the compounds of this invention are administered as a formulation in conjunction with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

  It goes without saying to those skilled in the art that pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation. Such compositions and methods for their preparation can be found, for example, in "Remington's Pharmaceutical Sciences" 19th Edition (Mack Publishing Company, 1995).

  Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable diluent or carrier.

  Any suitable route of administration that provides an effective dosage of a compound of the present invention to a mammal, particularly a human, may be used. For example, oral (including buccal and sublingual administration), rectal, topical, parenteral, eye, lung, nasal, and the like can be used. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. The compound of formula (I) is preferably administered orally or intranasally.

  The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the characteristics of the mammal being treated (eg, body weight), the condition being treated, and the severity of the condition being treated. Such dosages can be readily ascertained by those skilled in the art.

  For the treatment of sexual dysfunction, the compounds of the present invention may have from about 0.001 milligram (mg) to about 1000 mg, preferably from about 0.001 mg to about 500 mg, more preferably from about 0.001 mg to about 100 mg per kilogram body weight, More preferably, it is administered in a dose range of about 0.001 mg to about 50 mg, especially about 0.002 mg to about 25 mg, preferably orally as a single dose or as a nasal drop. For example, oral administration may require a total daily dose of from about 0.1 mg to about 1000 mg, whereas an intravenous dose may only require from about 0.001 mg to about 100 mg. The total daily dose can be administered in a single dose or in several divided doses, and may deviate from the typical ranges shown herein at the physician's discretion.

  When treating obesity with diabetes and / or hyperglycemia or alone, the compound of the present invention is about 0.0001 mg to about 1000 mg, preferably about 0.001 mg to about 500 mg, more preferably about 1 kg / kg animal body weight. When administered in a daily dose of about 0.005 mg to about 100 mg, especially about 0.005 mg to about 50 mg, preferably once, or divided into 2 to 6 times a day, or in sustained release form, In general, satisfactory results are obtained. For a 70 kg adult, the total daily dose will generally be from about 0.7 mg to about 3500 mg. This dosage regimen may also be adjusted to provide the optimal therapeutic response.

  When treating diabetes mellitus and / or hyperglycemia, and other diseases or disorders for which compounds of formula I are useful, the compounds of the invention may be administered at a daily dose of from about 0.001 mg to about 100 mg per kilogram of animal body weight. Satisfactory results are generally obtained when administered in dosages, preferably once, or in divided doses 2-6 times a day, or in sustained release form. For a 70 kg adult, the total daily dose will generally be from about 0.07 mg to about 350 mg. This dosage regimen may also be adjusted to provide the optimal therapeutic response.

  These dosages are based on an average human subject having a weight of about 65kg to 70kg. A physician will readily be able to determine doses for subjects whose weight falls outside this range, such as children, the elderly and obese.

  The compounds of the present invention can be administered orally. Oral administration may be swallowed so that the compound enters the gastrointestinal tract and / or may include buccal, lingual, or sublingual administration where the compound enters the bloodstream directly from the mouth.

  Formulations suitable for oral administration include tablets; soft or hard capsules containing multiparticulate or nanoparticulates, liquids or powders; lozenges (including liquid-filled forms), chewing agents, gels, rapidly dispersible dosage forms, Included are solid, semi-solid, and liquid systems such as films, vaginal suppositories, sprays, buccal / mucoadhesive patches and the like.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules (eg made of gelatin or hydroxypropyl methylcellulose) and are usually carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or Contains a suitable oil and one or more emulsifiers and / or suspending agents. A liquid formulation can also be prepared, for example, by reforming a solid from a sachet. For example, it can be prepared by reforming a solid from a sachet.

  The compounds of the present invention can be used in rapidly dissolving and rapidly disintegrating dosage forms such as those described in “Expert Opinion in Therapeutic Patents”, Volume 11 (6), pages 981-986 (2001) by Liang and Chen. You can also

  In tablet dosage forms, depending on dose, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropylcellulose, starch, pregelatinized Starch and sodium alginate are included. Generally, the disintegrant will comprise 1% to 25% by weight of the dosage form, preferably 5% to 20%.

  Binders are commonly used to impart adhesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. Tablets include diluents such as lactose (monohydrate, spray-dried monohydrate, anhydride, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dicalcium phosphate dihydrate It may contain.

  Tablets may also optionally contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and lubricants such as silicon dioxide and talc. When present, the surfactant may comprise from 0.2% to 5% by weight of the tablet and the lubricant may comprise from 0.2% to 1% by weight of the tablet.

  Tablets generally also contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise 0.25% to 10%, preferably 0.5% to 3% by weight of the tablet.

  Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and flavoring agents.

  Exemplary tablets are up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegration. And about 0.25 wt% to about 10 wt% lubricant.

  Tablet blends can be produced by compressing the tablet blend directly or by roller. Alternatively, the tablet blend or a portion of the blend may be tableted after being subjected to wet, dry, or melt granulation, melt coagulation, or extrusion processing. The final formulation may include one or more layers, may or may not be coated, and may be encapsulated.

  For tablet formulations, see H.C. Lieberman and L.L. Discussed in Lachman, “Pharmaceutical Dosage Forms: Tablets”, Volume 1 (Marcel Dekker, New York, USA, 1980).

  Ingestible oral films for human or veterinary use are usually water-soluble or water-swellable flexible thin film dosage forms, which can be fast dissolving or mucoadhesive, and are usually compounds of the formula I Includes film forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Some components of the formulation may perform multiple functions.

  The compound of formula I may be water-soluble or insoluble. Water-soluble compounds usually comprise 1% to 80% by weight of the solute, more typically 20% to 50% by weight. Less soluble compounds may make up a higher percentage of the composition, usually up to 88% by weight of the solute. Alternatively, the compound of formula I may be in the form of multiparticulate beads.

  The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids, usually in the range of 0.01 to 99% by weight, more typically in the range of 30 to 80% by weight. Exists.

  Other possible ingredients include antioxidants, colorants, flavoring and flavoring agents, preservatives, salivary gland stimulants, cooling agents, co-solvents (including oils), relaxation agents, bulking agents, antifoaming agents, Surfactants and flavoring agents are included.

  Films according to the present invention are usually prepared by evaporating and drying a thin water-soluble film coated on a strippable support carrier or paper. This can be done in a drying oven or drying tunnel, usually a composite coating dryer, or by freeze drying or vacuum.

  Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  A modified release formulation suitable for the purposes of the present invention is described in US Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersion and osmotic and coated particles can be found in “Pharmaceutical Technology On-line” by Verma et al., Volume 25 (2), pages 1-14 (2001). . The use of chewing gum to achieve controlled release is described in WO 00/35298.

  The compounds of the present invention can also be administered directly into the bloodstream, muscle, or viscera. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracerebral, intramuscular, intrasynovial and subcutaneous. Devices suitable for parenteral administration include needle syringes (including fine needles), needleless syringes, and infusion techniques.

  Parenteral formulations are usually aqueous solutions that may contain salts, carbohydrates, and excipients such as buffers (preferably to achieve a pH of 3-9), but for some applications are sterile, non-aqueous It can also be more suitably formulated as a solution or as a dry form for use with a suitable medium such as pyrogen-free sterile water.

  Preparation of parenteral preparations under aseptic conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

  The solubility of the compounds of formula (I) used in the preparation of parenteral solutions can also be increased using appropriate formulation techniques such as mixing solubility improvers.

  Formulations for parenteral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compounds of the present invention can also be formulated as solids, semisolids, or thixotropic liquids for administration as suspensions or as implantable depots that provide modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions containing dl-lactic acid-glycolic acid copolymer (PGLA) microspheres loaded with drug.

  The compounds of the invention can also be administered to the skin or mucosa, topically, intradermally (intradermally) or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and Microemulsions are included. Liposomes may be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. A permeability improver may be mixed. See, for example, J Pharm Sci by Finnin and Morgan, Volume 88 (10), pages 955-958 (October 1999).

  Other means of local administration include electroporation, iontophoresis, sonophoresis, ultrasound introduction, and delivery by microneedle or needle-free injection (eg Powderject ™, Bioject ™, etc.) .

  Formulations for topical administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of the invention are usually dry powder inhalers in the form of dry powders (alone or as a dry blend with eg lactose or as mixed component particles eg with phospholipids such as phosphatidylcholine). Or as an aerosol spray, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane It can also be administered intranasally or by inhalation from a pressurized container, pump, spray, atomizer (preferably an atomizer that produces a fine mist using electrohydraulics), or a nebulizer, or as a nasal solution. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, atomizers, or nebulizers are, for example, ethanol, aqueous ethanol or other substances suitable for dispersing, solubilizing or extending the release of active substances, propellants as solvents, As well as solutions or suspensions of the compounds of the present invention, including optional surfactants such as sorbitan trioleate, oleic acid, oligolactic acid.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminuting method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, spray drying and the like.

  Capsules, blisters, and cartridges (eg, made of gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator are compounds of the invention, suitable powder bases such as lactose and starch, and l-leucine, mannitol It can be formulated to contain a powder mixture of performance modifiers, such as magnesium stearate. Lactose may be anhydrous or in the monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

  A solution formulation suitable for use in an atomizer that uses electrohydraulics to generate a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation, with a working volume varying from 1 μl to 100 μl. Good. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Other solvents that may be used in place of propylene glycol include glycerol and polyethylene glycol.

  A suitable flavoring agent such as menthol or l-menthol, or a sweetening agent such as saccharin or sodium saccharin may be added to the formulations of the invention intended for inhalation / intranasal administration.

  Formulations for inhalation / intranasal administration can be formulated for immediate and / or modified release, for example using PGLA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. Units according to the invention are usually arranged to administer a metered dose or “puff” containing 0.001 mg to 10 mg of a compound of formula (I). The overall daily dose is usually in the range of 0.001 mg to 40 mg, and the amount can be administered once, or more usually in several divided portions throughout the day.

  The compounds of the invention can be administered rectally or vaginally, for example, in the form of a suppository, vaginal suppository, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

  Formulations for rectal / vaginal administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

  The compounds of the present invention may also be administered directly to the eye or ear, usually in the form of a finely divided suspension or solution droplet in isotonic sterile saline, pH adjusted. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable (eg absorbable gel sponges, collagen) and non-biodegradable (eg silicon resin) implants, wafers, lenses, As well as particulate or vesicle systems such as niosomes and liposomes. Crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid; cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose, or methylcellulose; heteropolysaccharide polymers such as gellan gum polymers may be mixed with preservatives such as benzalkonium chloride. . Such formulations can also be delivered by iontophoresis.

  Formulations for ocular / ear administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, or programmed release.

  The compounds of the present invention may be cyclodextrin and suitable derivatives thereof to improve its solubility, dissolution rate, taste masking, bioavailability, and / or stability for use in any of the above-described modes of administration. Alternatively, it can be combined with a soluble polymer such as a polyethylene glycol-containing polymer.

  For example, drug-cyclodextrin complexes have generally been found useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can also be used as auxiliary additives, ie carriers, diluents, or solubilizers. Most commonly used for these purposes are α, β, and γ cyclodextrins, examples of which can be found in international patent applications WO 91/11172, WO 94/02518, and WO 98/55148.

  Since it may be desirable to administer a combination of active compounds, eg, for the purpose of treating a particular disease or condition, two or more pharmaceutical compositions, at least one of which contains a compound according to the present invention, It is within the scope of the present invention that they may be conveniently combined in the form of a kit suitable for co-administration.

  Accordingly, the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) according to the invention, and a container, a divided bottle, or a divided foil bag. And means for holding the compositions separately. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.

  The kits of the invention are particularly suitable for administering different dosage forms, for example oral and parenteral, for administering separate compositions at different dosing intervals, or for titrating separate compositions against each other. To assist compliance, kits typically include directions for administration and may be provided with a so-called memory aid.

  Other aspects of the invention are listed in the claims.

  Biological data

  The effect of 3 mg / kg and 10 mg / kg of the compound of Example 2 on cumulative food intake over 24 hours and body weight change over 24 hours compared to vehicle is shown in FIGS.

The invention is illustrated by the following non-limiting examples in which the following abbreviations and definitions are used.
APCI Atmospheric pressure chemical ionization mass spectrum [α] _D Specific rotation br at 589 nm Broad Celite® filter agent δ Chemical shift d Double line dd Double double line EI Electrospray ionization Ex Example LRMS Low resolution mass Spectrum m Multiplet m / z Mass spectral peak NMR Nuclear magnetic resonance Prec Precursor Prep Preparation psi Pounds per square inch q Quadruple s Singlet t Triplet tlc Thin layer chromatography

  For convenience of synthesis, a compound is often first isolated in its free base form, but is often converted to its corresponding hydrochloride salt for analytical identification purposes. For the avoidance of doubt, both the free base and HCl salt forms are considered provided herein.

  For the avoidance of doubt, the named compounds used herein are named using ACD Labs Name Software v7.11 ™.

Example 1
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] nicotinonitrile

To a solution of pyrrolidine of Preparation Example 10 (200 mg, 0.46 mmol) and N-ethyldiisopropylamine (0.32 mL, 1.8 mmol) in acetonitrile (10 mL) was added 2-chloro-5-cyanopyridine (96 mg, 0.69 mmol). And the mixture was heated at 70 ° C. overnight in nitrogen. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane and increasing in polarity to 5% methanol in dichloromethane to give the title compound (191 mg, 77%) as white Obtained as a solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.4 to 0.6 (6H, 4xd), 0.78 to 0.82, 1.60 to 1.68, and 1.97 to 2.05 (2H, 3xm), 2.73-2.80 (1H, m), 3.00-3.20 (1H, m), 3.68-4.37 (8H, m), 6.62 (1H, m) 7.01 to 7.08 and 7.37 to 7.48 (5H, 2xm), 7.74 (1H, m), 7.80 and 7.95 (1H, 2xdd), 8.40 (1H, m), 8.57 and ^{8.60 (1H, 2xd); LRMS} (EI +) 534 [MH +]; [α] D 25 = -47.0 (c = 0.215, MeOH).

(Example 2)
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile

To a solution of pyrrolidine of Preparation Example 10 (40 mg, 0.09 mmol) and N-ethyldiisopropylamine (0.06 mL, 0.37 mmol) in acetonitrile (10 mL), 3-chloro-6-cyanopyridazine (prepared according to US Pat. No. 3,636,691) (20 mg, 0.14 mmol) was added and the mixture was heated at 70 ° C. overnight in nitrogen. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane and increasing in polarity to 5% methanol in dichloromethane to give the title compound (41 mg, 83%) as white Obtained as a solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.4 to 0.6 (6H, 4xd), 0.78 to 0.85, 1.60 to 1.69, and 1.97 to 2.10 (2H, 3xm), 2.72 to 2.80 (1H, m), 3.00 to 3.23 (1H, m), 3.68 to 4.38 (8H, m), 6.99 to 7.08 and 7.38-7.50 (6H, 2xm), 7.70 (1H, d), 7.80 and 7.94 (1H, 2xdd), 8.58 and 8.61 (1H, 2xd); LRMS ( EI ^<+> ) 535 [MH ^<+ >].

(Example 3)
(3R, 4R, 5S) -1-{[(3S, 4S) -1- (6-chloropyridazin-3-yl) -4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol

1,6-Dichloropyridazine (173 mg, 1.2 mmol) was added to a solution of pyrrolidine of Preparation Example 10 (100 mg, 0.23 mmol) and N-ethyldiisopropylamine (0.16 mL, 0.93 mmol) in acetonitrile (5 mL). The mixture was heated in nitrogen at 70 ° C. overnight. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane and increasing in polarity to 5% methanol in dichloromethane to give the title compound (52 mg, 42%) as white Obtained as a solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.4 to 0.6 (6H, 4xd), 0.78 to 0.85, 1.60 to 1.69, and 1.97 to 2.10 (2H, 3xm), 2.72 to 2.80 (1H, m), 3.00 to 3.23 (1H, m), 3.68 to 4.38 (8H, m), 6.99 to 7.08 and 7.38-7.50 (6H, 2xm), 7.70 (1H, d), 7.80 and 7.94 (1H, 2xdd), 8.58 and 8.61 (1H, 2xd); LRMS ( EI ^<+> ) 544 [MH ^<+ >].

Example 4
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (6-methoxypyridazin-3-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol

Sodium t-butoxide (31 mg, 0.32 mmol), 3-chloro-6-methoxypyridazine (34 mg, 0.23 mmol), tris (dibenzylideneacetone) dipalladium (0) (8.5 mg, 0.009 mmol), and 2,2′-bis (diphenylphosphino) -1,1′-binaphthalene (11.5 mg, 0.0185 mmol) was added to a solution of pyrrolidine (100 mg, 0.23 mmol) in Preparation Example 10 in toluene (10 mL). The mixture was heated in nitrogen at 80 ° C. overnight. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (25 mL), washed with water, dried (MgSO ₄ ) and evaporated. Purification by column chromatography (silica) eluting with dichloromethane and increasing polarity to 5% methanol in dichloromethane gave the title compound (48 mg, 40%) as a yellow foam. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.4 to 0.62 (d + t + t, 6H), 0.86 (m, 1H), 1.65 (m, 1H), 1.93 to 2.08 (br , 1H), 2.75 (m, 1H), 3.17 (t, 1H), 3.74 (m, 3H), 3.95 (s, 3H), 3.96 to 4.21 (m, 3H), 4.32 (d, 1H), 6.98 to 7.1 (m, 5H), 7.38 to 7.48 (m, 2H), 7.79 + 7.48 (2xdd, 1H), 8 .56 (d, 1H); LRMS (EI ⁺ ) 540 [MH ⁺ ].

(Example 5)
(3R, 4R, 5S) -4- (4-Chlorophenyl) -1-{[(3S, 4S) -1- (6-chloropyridazin-3-yl) -4- (5-fluoropyridin-2-yl) ) Pyrrolidin-3-yl] carbonyl} -3,5-dimethylpiperidin-4-ol

(3R, 4R, 5S) -4- (4-Chlorophenyl) -1-{[(3S, 4S) -4- (5-fluoropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -3,5 -Dimethylpiperidin-4-ol (aldehyde of Preparation 17 and (3R, 4s, 5S) -4- (4-chlorophenyl) -3,5-dimethylpiperidine-4 prepared according to International Patent Application Publication No. WO2005 / 077935 -Prepared by the same method used for the amine of Preparation 10 starting from the ol) (120 mg, 0.28 mmol) in dimethyl sulfoxide (2 mL) in 3,6-dichloropyridazine (98 mg, 0 .56 mmol), triethylamine (0.12 mL, 0.84 mmol), and cesium fluoride (13 mg, 0.084). mol) was added. The mixture was stirred in nitrogen at 110 ° C. for 3 hours. The reaction mixture was diluted with methanol (5 mL) and loaded onto an SCX column to remove non-basic material and dimethyl sulfoxide using methanol as the eluent, followed by 2M NH ₃ in methanol as the eluent. Eluted. The solvent was removed in vacuo to give the title compound (74 mg, 49%) as a colorless gum. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.44 to 0.60 (6H, 4xd), 0.95 to 1.02, 1.64 to 1.73, and 1.94 to 2.09 (2H, 3xm), 2.69-2.79 (1H, m), 2.99-3.06, and 3.16-3.22 (1H, 2xm), 3.74-3.79 (3H, m) 4.01 to 4.24 (4H, m), 4.32 to 4.36 (1H, m), 7.02 to 7.07 (1H, m), 7.29 to 7.70 (7H, m), 8.45-8.49 (1H, m); LRMS (EI +) 544 [MH +].

(Example 6)
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-fluoropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one

A solution of chloropyridazine of Example 5 (70 mg, 0.13 mmol) was dissolved in degassed acetic acid and stirred overnight at reflux temperature in nitrogen. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane / methanol / aqueous ammonia 95/5 / 0.5. This gave the title compound as an off-white solid (37 mg, 55%). ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.43 to 0.59 (6H, 4xd), 0.94 to 1.03, 1.64 to 1.73, and 1.93 to 2.03 (2H, 3xm), 2.65 to 2.78 (1H, m), 2.97 to 3.03 and 3.14 to 3.20 (1H, 2xm), 3.62 to 3.79 (3H, m), 3.86 to 4.17 (4H, m), 4.31 to 4.35 (1H, m), 6.88 to 6.91 (1H, m), 7.30 to 7.42 (5H, m) ), 7.47-7.57 (1H, m), 7.63-7.68 (1H, m), 8.44-8.48 (1H, m); LRMS (EI +) 526 [MH +].

(Example 7)
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-fluoropyridin-2-yl) pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one

To a solution of pyridazinone (30 mg, 0.057 mmol) in Example 6 in dimethylformamide (2 mL) was added 1 M sodium hexamethyldisilazide (0.07 mL, 0.07 mmol) and lithium bromide (6 mg, 0.07 mmol) in tetrahydrofuran. Was added. The mixture was stirred at room temperature for 30 minutes under nitrogen, then methyl iodide (0.004 mL, 0.07 mmol) was added and the mixture was stirred at room temperature for 2 hours under nitrogen. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with dichloromethane / methanol / aqueous ammonia 95/5 / 0.5. This gave the title compound as a yellow solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.44 to 0.59 (6H, 4xd), 0.94 to 1.03, 1.64 to 1.73, and 1.95 to 2.04 (2H, 3xm), 2.68 to 2.78 (1H, m), 2.95 to 3.01, and 3.14 to 3.21 (1H, 2xm), 3.62 to 3.81 (6H, m) 3.87-4.17 (4H, m), 4.31-4.35 (1H, m), 6.87-6.90 (1H, m), 7.25-7.34 (4H, m), 7.38-7.42 (1H, m), 7.48-7.58 (1H, m), 7.64-7.69 (1H, m), 8.44-8.48 ( 1H, m), LRMS (EI +) 540 [MH +].

(Example 8)
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (5-fluoropyridin-3-yl) pyrrolidin-3-yl] carbonyl } -3,5-Dimethyl-4-pyridin-2-ylpiperidin-4-ol

(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-pyridine-2 -Ilpiperidin-4-ol (starting from (3R, 4s, 5S) -3,5-dimethyl-4-pyridin-2-ylpiperidin-4-ol prepared according to WO 2005/077935 (Prepared by the same method used for the amine of Preparation Example 10) (50 mg, 0.12 mmol) in toluene (5 mL) was added 3-bromo, 5-fluoropyridine (25 mg, 0.14 mmol), tris (Dibenzilidineacetone) dipalladium (4.4 mg, 0.0048 mmol), BINAP (6 mg, 0.0096 mmol), and sodium t- butoxide (26mg, 0.27mmol) was added. The mixture was stirred overnight at 80 ° C. under nitrogen. The solvent is removed in vacuo and the residue is purified by column chromatography (silica), eluting with dichloromethane / methanol / aqueous ammonia 99/1 / 0.1 and increasing in polarity to 95/5 / 0.5. did. This gave the title compound (11 mg, 18%) as a yellow gum. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.33 to 0.53 (6H, 4xd), 0.81 to 0.93, 1.81 to 1.92, and 2.08 to 2.28 (2H, 3xm), 2.69 to 2.78 (1H, m), 2.99 to 3.20 (1H, m), 3.61 to 3.94 (5H, m), 4.01 to 4.23 ( 2H, m), 4.34 to 4.42 (1H, m), 6.81 to 6.90 (1H, m), 7.26 to 7.50 (3H, m), 7.70 to 7. 94 (4H, m), 8.51-8.62 (2H, m); LRMS (EI +) 510 [MH +].

Example 9
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-pyridazin-3-ylpyrrolidin-3-yl] carbonyl} -3,5 -Dimethyl-4-pyridin-2-ylpiperidin-4-ol

(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -3,5-dimethyl-4-pyridine-2 -Ylpiperidin-4-ol (starting from (3R, 4s, 5S) -3,5-dimethyl-4-pyridin-2-ylpiperidin-4-ol prepared according to International Patent Application Publication No. WO 2005/077935; Prepared by the same method used for the amine of Preparation Example 10) (50 mg, 0.12 mmol) in DMSO (2 mL) was added 3-chloropyridazine (28 mg, 0.24 mmol), cesium fluoride (18 mg, 0.12 mmol), and triethylamine (0.05 mL, 0.36 mmol) were added. The mixture was stirred overnight at 100 ° C. under nitrogen. The reaction mixture was diluted with 10 mL ethyl acetate and washed with 3 × 20 mL water. The combined aqueous extracts were extracted with 10 mL ethyl acetate, the combined organic extracts were washed with 10 mL brine, dried (MgSO ₄ ) and the solvent removed in vacuo. The residue was purified by column chromatography (silica) increasing in polarity to 95/5 / 0.5, eluting with dichloromethane / methanol / aqueous ammonia 99/1 / 0.1. This gave the title compound (16 mg, 27%) as a yellow gum. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.20 to 0.37 (6H, 4xd), 0.91 to 1.13, 1.67 to 1.76, and 1.94 to 2.09 (2H, 3xm), 2.54 to 2.62 (1H, m), 2.87 to 2.93, and 2.99 to 3.05 (1H, 2xm), 3.61 to 3.74 (3H, m) 3.86 to 4.08 (4H, m), 4.20 to 4.26 (1H, m), 6.83 to 6.88 (1H, m), 7.11 to 7.44 (4H, m), 7.63-7.78 (2H, m), 8.30-8.46 (3H, m), LRMS (EI +) 493 [MH +].

(Example 10)
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (5-chloropyridin-2-yl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one

To a solution of the carboxylic acid of Preparation 15 (42 mg, 0.08 mmol) in dichloromethane (3 mL), N-ethyldiisopropylamine (0.04 mL, 0.25 mmol), 1-hydroxybenzotriazole (15 mg, 0.095 mmol), and 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide was added and the mixture was stirred in nitrogen for 30 minutes. The amine of Preparation 16 was added and the mixture was stirred overnight under nitrogen. The reaction mixture was diluted with dichloromethane (20 mL) and washed with saturated NaHCO ₃ (20 mL) and brine (20 mL). The organic layer was dried over MgSO ₄ , filtered and evaporated to give a yellow oily solid. This was purified by column chromatography (silica) eluting with dichloromethane and increasing in polarity to 95/5 dichloromethane / methanol to give the title compound as a yellow solid (31 mg, 67%). ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.36 to 0.6 (m, 6H), 1.18 (br, 1H), 1.89 (br, 1H), 2.16 (br, 1H), 2.71 (m, 1H), 3.13 (m, 1H), 3.6-4.2 (s + m, 9H), 4.33 (d, 1H), 6.89 (d, 1H), 7 .2-7.5 (m, 3H), 7.78-7.92 (m, 2H), 8.56 (d, 2H), LRMS (EI ^{< +} >) 558 [MH ^<+ >].

(Examples 11 to 46)
Examples 11-46 were prepared according to the method described above for Examples 1-10 starting from the appropriate pyridine aldehyde ¹ and the appropriate 4-substituted 3,5-dimethylpiperidin-4-ol ² .
1. 2-methoxypyridine-5-carbaldehyde is commercially available. Other aldehydes are described in Preparative Examples 2, 17, 18, and 22.
2. (3R, 4s, 5S) -4- (5-chloropyridin-2-yl) -3,5-dimethylpiperidin-4-ol is described in Preparation Example 16. Another necessary piperidinol synthesis is described in International Patent Application Publication No. WO 2005/077935.

Preparation Example Preparation Example 1
5-Chloro-2-iodopyridine

To a solution of 2-bromo-5-chloropyridine (20.0 g, 0.103 mol) in acetonitrile (120 mL) was added acetyl chloride (11.05 mL, 0.155 mol), followed by sodium iodide (23.3 g, 0 .155 mol) was added and a drying tube was fitted for 3 hours to heat the mixture to reflux. The reaction was cooled in an ice bath, carefully basified with saturated aqueous potassium carbonate and then extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with saturated aqueous sodium sulfite (200 mL), dried (MgSO ₄ ) and evaporated. The residue was then subjected to the same reaction and workup conditions to ensure complete reaction, which gave the title compound (18.71 g, 75%) as a brown solid. _{^{1 H NMR (CDCl 3, 400MHz}} ) δ7.30 (1H, dd), 7.65 (1H, d), 8.35 (1H, d); LRMS (APCI +) 240 [MH +].

Preparation Example 2
5-chloropyridine-2-carbaldehyde

The iodide of Preparation Example 2 (18.71 g, 78.1 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to −15 ° C. in nitrogen. Then, a solution of isopropylmagnesium chloride in tetrahydrofuran (2M, 42.2 mL, 84.4 mmol) was added dropwise, ensuring that the temperature remained below 0 ° C. The reaction mixture was cooled to −15 ° C., stirred for 1 hour, and dimethylformamide (9.0 mL, 116 mmol) was added dropwise while keeping the temperature below 0 ° C. The reaction mixture was warmed to room temperature and stirred for 1 hour, then cooled back to 0 ° C. and carefully quenched with 2M HCl (100 mL) added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, and then a saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 6-7. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 200 mL). The combined organic layers were washed with water (200 mL), dried (MgSO ₄ ) and concentrated on a rotary evaporator keeping the temperature below 30 ° C. to give the crude product (13.7 g) as a brown oil. This was used without further purification. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.35 (1H, d), 7.95 (1H, d), 8.73 (1H, s), 10.02 (1H, s); LRMS (APCI ⁺ ) 142 [MH ⁺ ].

Preparation Example 3
(2E) -3- (5-Chloropyridin-2-yl) t-butyl acrylate

To a solution of t-butyl diethylphosphonoacetate (19.1 mL, 81 mmol) in diethyl ether (80 mL) was added dropwise n-butyllithium (2.5 M in hexane, 34 mL, 85 mmol) at −78 ° C. under nitrogen. Stirring was continued for 30 minutes. A solution of the crude aldehyde of Preparation Example 2 (from 78.1 mmol of iodide of Preparation Example 1) in diethyl ether (20 mL) was then added dropwise and the temperature kept below -65 ° C. When the addition was complete, the mixture was allowed to warm to room temperature over 2 hours and then carefully quenched by the addition of saturated aqueous ammonium chloride (200 mL). The mixture was extracted with diethyl ether (2 × 150 mL) and the combined organic extracts were washed with brine (200 mL), dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (silica) eluting with pentane and increasing in polarity to 8: 2 pentane / ethyl acetate to give the title compound (13.34 g, 74% over 2 steps) as an oil Got as. ¹ H NMR (CDCl ₃ , 400 MHz) δ 1.51, (9H, s), 6.79 (1H, d), 7.35 (1H, d), 7.52 (1H, d), 7.66 ( 1H, dd), 8.55 (1H, d); LRMS (APCI ⁺ ) 240 [MH ⁺ ].

(Preparation Example 4)
(2E) -3- (5-Chloropyridin-2-yl) acrylic acid trifluoroacetate

To an ice-cooled solution of the ester of Preparation Example 3 (2.09 g, 8.7 mmol) in dichloromethane (10 mL) was added dropwise a solution of trifluoroacetic acid (10 mL) in dichloromethane (10 mL), and the resulting mixture was stirred at room temperature overnight. Stir. Remove the solvent in vacuo, add toluene (10 mL), remove in vacuo, add dichloromethane (10 mL) and remove in vacuo to give the title compound (2.44 g, 94%) as a red solid. It was. ¹ H NMR (CD ₃ OD, 400 MHz) δ 6.86 (1H, d), 7.64 (2H, m), 7.87 (1H, dd), 8.59 (1H, d); LRMS (APCI ⁺ ) 184 [MH ⁺ ].

Preparation Example 5
(4S) -4-Benzyl-3-[(2E) -3- (5-chloropyridin-2-yl) prop-2-enoyl] -1,3-oxazolidine-2-one

A solution of the acid of Preparation Example 4 (2.44 g, 8.2 mmol) in tetrahydrofuran (15 mL) was cooled to −78 ° C. in nitrogen. Triethylamine (2.85 mL, 20 mmol) was added dropwise while controlling the dropping rate so that the temperature remained lower than −65 ° C., and then trimethylacetyl chloride (1.11 mL, 9.0 mmol) was added dropwise. The mixture was then stirred at −78 ° C. for 2 hours. To a solution of (4S) -4-benzyl-1,3-oxazolidine-2-one (1.74 g, 9.8 mmol) in tetrahydrofuran (15 mL) at −78 ° C. in nitrogen while the temperature remains below −65 ° C. ^N BuLi (2.5 M in hexane, 4.26 mL, 10.7 mmol) was added dropwise while controlling the dropping rate to be. After stirring at −78 ° C. for 20 minutes, a solution of the oxazolidinone anion was added via cannula to the mixed −78 ° C. anhydrous solution. The reaction mixture was then stirred at −78 ° C. for 20 minutes before slowly warming to room temperature overnight. The reaction was quenched by the addition of saturated aqueous ammonium chloride (30 mL) and then concentrated in vacuo to remove tetrahydrofuran. The solid precipitate was filtered and washed with diethyl ether to give the title compound (1.52 g, 54%) as a buff solid. The ether wash was evaporated to dryness, slurried in diethyl ether and filtered to give additional product (0.42 g, 15%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 2.84 (1H, t), 3.37 (1H, d), 4.22 (2H, m), 4.78 (1H, m), 7.2-7 .4 (5H, m), 7.51 (1H, d), 7.69 (1H, d), 7.86 (1H, d), 8.23 (1H, d), 8.62 (1H, s); LRMS (APCI ⁺ ) 343 [MH ⁺ ].

(Preparation Example 6)
(4S) -4-benzyl-3-{[(3S, 4S) -1-benzyl-4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidine-2 -ON

To a suspension of oxazolidinone of Preparation 5 (1.93 g, 5.6 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (90 μL, 1.2 mmol), followed by N-benzyl-N- (methoxymethyl) trimethylsilylamine. (2.3 mL, 9.0 mmol) was added dropwise over 10 minutes. After the addition was complete, the reaction was stirred at room temperature overnight. The reaction mixture was treated with saturated aqueous sodium bicarbonate (20 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2 × 20 mL) and the combined organic layers were dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (silica) eluting with 2: 8 ethyl acetate / pentane and increasing in polarity to 2: 3 to give the undesired (4S) -4-benzyl-3-{[ (3R, 4R) -1-benzyl-4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidine-2-one (1.16 g, 44%) As the eluting component of 1, the desired (4S) -4-benzyl-3-{[(3S, 4S) -1-benzyl-4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -1,3-oxazolidine-2-one (1.18 g, 45%) was obtained as the second eluting component. ¹ H NMR (CDCl ₃ , 400 MHz) δ 2.75 (2H, m), 2.92 (1H, m), 3.20 (3H, m), 3.27 (1H, br), 3.68 (2H , Br), 4.14 (2H, m), 4.23 (1H, m), 4.50 (1H, m), 4.67 (1H, m), 7.10 to 7.40 (11H, m), 7.58 (1H, dd), 8.50 (1H, d); LRMS (APCI ⁺ ) 476 [MH ⁺ ].

Preparation Example 7
(3S, 4S) -1-Benzyl-4- (5-chloropyridin-2-yl) pyrrolidine-3-carboxylate methyl

Sodium methoxide (664 mg, 12 mmol) was added to a solution of oxazolidinone of Preparation Example 6 (1.17 g, 2.5 mmol) and dimethyl carbonate (1.03 mL, 12 mmol) in dichloromethane (15 mL), and the reaction was stirred at room temperature overnight. did. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (50 mL) and water (30 mL). 2M HCl (˜6 mL) was added to neutralize the aqueous layer and then concentrated in vacuo. The residue was triturated with acetonitrile (25 mL) and then filtered. The filtrate was concentrated to give (3S, 4S) -1-benzyl-4- (5-chloropyridin-2-yl) pyrrolidine-3-carboxylic acid (123 mg, 16%) as a yellow solid (spectroscopic). See Preparation Example 8 for experimental data). The ethyl acetate layer was dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (silica) eluting with 2: 8 ethyl acetate / pentane and increasing in polarity to 2: 3 to give the title compound (371 mg, 45%) as a colorless oil. It was. ¹ H NMR (CDCl ₃ , 400 MHz) δ 2.71 (1H, t), 2.97 (1H, t), 3.05 (2H, m), 3.23 (1H, m), 3.63 (5H , M), 3.82 (1H, q), 7.15 to 7.35 (6H, m), 7.55 (1H, d), 8.46 (1H, s); LRMS (APCI ⁺ ) 331 [MH ⁺ ].

Preparation Example 8
(3S, 4S) -1-Benzyl-4- (5-chloropyridin-2-yl) pyrrolidine-3-carboxylic acid bishydrochloride

To a solution of the ester of Preparation 7 (371 mg, 1.1 mmol) in dioxane (10 mL) was added a solution of NaOH (135 mg, 3.3 mmol) in water (5 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL) and neutralized with 2M HCl (ca. 1.7 mL). The mixture was then concentrated in vacuo, triturated with acetonitrile (20 mL) and filtered. The filtrate was acidified with 2M HCl ether solution and concentrated in vacuo to give the title compound (290 mg, 68%) as a solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.40 to 4.20 (6H, m), 4.53 (2H, m), 7.40 to 7.60 (6H, m), 7.81 (1H , D), 8.60 (1H, br); LRMS (APCI ⁺ ) 317 [MH ⁺ ].

Preparation Example 9
(3R, 4R, 5S) -1-{[(3S, 4S) -1-benzyl-4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl ) -3,5-dimethylpiperidin-4-ol

To a solution of the acid of Preparation Example 8 (522 mg, 1.5 mmol) in dichloromethane (10 mL) and triethylamine (1.03 mL, 7.4 mmol) was added 1-hydroxybenzotriazole (230 mg, 1.7 mmol) and 1- ( 3-Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride (354 mg, 1.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes before (3R, 4s, 5S) -4- (4-fluorophenyl). -3,5-Dimethylpiperidin-4-ol hydrochloride (prepared according to US 2005/176772) (384 mg, 1.5 mmol) was added. The mixture was stirred at room temperature overnight, the solvent was removed in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO ₄ ) and evaporated. The residue was purified by column chromatography (silica) eluting with dichloromethane and increasing in polarity to 5% methanol in dichloromethane to give the title compound (546 mg, 71%) as an oil. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.3 to 0.6 (6H, 4xd), 1.23 (1H, m), 1.75 to 1.95 (2H, m), 2.72 (1H , T), 2.85 (1H, m), 2.90-3.20 (3H, m), 3.45-4.05 (5H, m), 4.32 (1H, d), 7. 02 (3H, m), 7.20-7.50 (7H, m), 7.80, (1H, dd), 8.50 (1H, d); LRMS (APCI ⁺ ) 522 [MH ⁺ ].

Preparation Example 10
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3, 5-Dimethylpiperidin-4-ol

To a solution of the amide of Preparation Example 9 (370 mg, 0.7 mmol) and N-ethyldiisopropylamine (0.27 mL, 1.6 mmol) in dichloromethane (10 mL) was added 1-chloroethyl chloroformate (0.3 mL, 2.8 mmol). In addition, the mixture was heated to reflux for 3 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between 10% aqueous citric acid (30 mL) and dichloromethane (30 mL). The organic layer was washed with water (30 mL), dried (MgSO ₄ ) and evaporated. The resulting dark oil was dissolved in methanol (10 mL) and heated to reflux for 3 hours. The solvent was removed in vacuo and the residue was purified by column chromatography (silica) eluting with 5% methanol in dichloromethane and increasing in polarity to 10% methanol in dichloromethane to give the title compound (305 mg, 100%) as an oil. ¹ H NMR (CD ₃ OD, 400 MHz) δ 0.4 to 0.6 (6H, 4xd), 1.00 to 1.06, 1.77 to 1.82, and 1.98 to 2.05 (2H, 3xm), 2.76 to 2.82 (1H, m), 3.00 to 3.20 (2H, m), 3.40 to 4.10 (6H, m), 4.36 (1H, m) 7.00-7.50 (5H, m), 7.85 and 7.95 (1H, 2xdd), 8.61 and 8.63 (1H, 2xd); LRMS (APCI ⁺ ) 432 [MH ⁺ ].

Preparation Example 11
(3S, 4S) -4- (5-Chloropyridin-2-yl) pyrrolidine-3-carboxylate methyl

To a solution of the ester of Preparation Example 7 (1.77 g, 5.35 mmol) and N-ethyldiisopropylamine (2.1 mL, 12 mmol) in dichloromethane (10 mL) was added 1-chloroethyl chloroformate (2.33 mL, 21.4 mmol). In addition, the mixture was heated to reflux for 3 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was dissolved in methanol (10 mL) and heated to reflux for 16 hours. The solvent is removed in vacuo and the residue is purified by column chromatography (silica) eluting with dichloromethane and increasing in polarity to 10% methanol in dichloromethane to give the desired product and N-ethyldiisopropylamine. Was obtained as an oil. The oil was dissolved in ethyl acetate (30 mL) and the resulting precipitate was filtered. The filtrate was concentrated in vacuo and the residue was dissolved in acetonitrile (25 mL). The resulting precipitate was filtered to give the title compound (619 mg, 48%) as a white solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.46 (m, 1H), 3.61 to 3.77 (m, 7H), 3.74 (s, 3H), 3.98 (m, 1H), 7.42 (d, 1H), 7.82 (dd, 1H), 8.57 (d, 1H); LRMS (APCI ⁺ ) 241 [MH ⁺ ].

Preparation Example 12
(3S, 4S) -1- (6-Chloropyridazin-3-yl) -4- (5-chloropyridin-2-yl) pyrrolidine-3-carboxylate methyl

To a solution of pyrrolidine (350 mg, 1.50 mmol) in Preparation Example 11 in dimethyl sulfoxide (10 mL) was added 3,6-dichloropyridazine (330 mg, 2.20 mmol), triethylamine (0.61 mL, 4.40 mmol), and cesium fluoride. (220 mg, 1.45 mmol) was added. The mixture was stirred overnight at 80 ° C. under nitrogen. The reaction mixture was dissolved in 25 mL ethyl acetate and washed with 20 mL water. The organic layer was separated and the aqueous layer was re-extracted with another 25 mL of ethyl acetate. The combined ethyl acetate extracts were dried over MgSO ₄ , filtered and evaporated to give a pale orange oily solid which was eluted with dichloromethane and increased in polarity to 95/5 dichloromethane / methanol. Purified by chromatography. This gave the title compound as a yellow solid. ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.66 (s, 1H), 3.72 (m, 1H), 3.78 (t, 1H), 3.96 to 4.12 (m, 4H), 7.04 (d, 1H), 7.42 (m, 2H), 7.79 (d, 1H), 8.52 (s, 1H); LRMS (EI ⁺ ) 353 [MH ⁺ ].

Preparation Example 13
(3S, 4S) -4- (5-Chloropyridin-2-yl) -1- (6-oxo-1,6-dihydropyridazin-3-yl) pyrrolidine-3-carboxylate methyl

A solution of the chloropyridazine of Preparation Example 12 (803 mg, 2.27 mmol) was dissolved in deoxygenated acetic acid and heated to reflux in nitrogen for 44 hours. The solvent was removed in vacuo and 15 mL of methanol was added. HCl gas was then bubbled into the reaction mixture until saturation and the mixture was stirred overnight under a drying tube. Methanol was removed in vacuo and the residue was partitioned between DCM and 10% K ₂ CO ₃ . The organic layer was separated, dried over MgSO ₄ , filtered and evaporated to give the title compound as a light brown solid (577 mg, 76%). ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.58-3.76 and 3.83-3.97 (6H, 2 × m), 3.65 (3H, s), 6.89 (1H, d), 7 .31 (1H, d), 7.39 (1H, d), 7.79 (1H, dd), 8.52 (1H, d); LRMS (EI ⁺ ) 335 [MH ⁺ ].

Preparation Example 14
(3S, 4S) -4- (5-Chloropyridin-2-yl) -1- (1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) pyrrolidine-3-carboxylate methyl

To a solution of pyridazinone (557 mg, 1.66 mmol) in Preparation Example 13 in dimethylformamide (10 mL) was added sodium hexamethidisilazide (1M in tetrahydrofuran, 2.00 mL, 2.00 mmol) and lithium bromide (173 mg, 2.00 mmol). ) Was added. The reaction was stirred in nitrogen for 10 minutes before iodomethane (0.083 mL, 1.30 mmol) was added. The reaction was stirred in nitrogen for 4 hours and then partitioned between ethyl acetate (30 mL) and water (30 mL). The organic layer is separated, dried over MgSO ₄ , filtered and evaporated to give a brown oil which is eluted with 100% dichloromethane and increased in polarity to 95/5 dichloromethane / methanol. Purified using column chromatography (silica). This gave the title compound as a yellow oil (500 mg, 90%). ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.64 (m, 9H), 3.92 (m, 3H), 6.87 (d, 1H), 7.26 (d, 1H), 7.37 ( d, 1H), 7.79 (dd, 1H), 8.51 (s, 1H); LRMS (EI ^{< +} >) 349 [MH ^<+ >].

Preparation Example 15
(3S, 4S) -4- (5-Chloropyridin-2-yl) -1- (1-methyl-6-oxo-1,6-dihydropyridazin-3-yl) pyrrolidine-3-carboxylic acid

To a solution of the ester of Preparation Example 14 (500 mg, 1.43 mmol) in dioxane (10 mL) was added sodium hydroxide (172 mg, 4.30 mmol) as a solution in 5 mL of water. The reaction was stirred overnight under a drying tube. The solvent was removed in vacuo and the residue was dissolved in water, neutralized with 4 equivalents of 2M HCl and evaporated. The residue was stirred with 20 mL acetonitrile and filtered to give a buff solid (512 mg-338 mg product +174 mg NaCl containing 3 eq NaCl). ¹ H NMR (CD ₃ OD, 400 MHz) δ 3.6 (m, 2H), 3.64 (s, 3H), 3.7 (t, 1H), 3.9 (m, 3H), 6.88 ( d, 1H), 7.27 (d, 1H), 7.41 (d, 1H), 7.79 (dd, 1H), 8.52 (s, 1H); LRMS (EI ⁺ ) 335 [MH ⁺ ].

Preparation Example 16
(3R, 4s, 5S) -4- (5-chloropyridin-2-yl) -3,5-dimethylpiperidin-4-ol

Step A: (3R, 4s, 5S) -4- (5-chloropyridin-2-yl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol 2-bromo-5-chloro A solution of pyridine (6.0 g, 31.2 mmol) in toluene (90 mL) was cooled to −78 ° C. in nitrogen. n-Butyllithium (2.5 M in hexane) (15 mL, 37.5 mmol) was added dropwise over 12 minutes and the mixture was stirred at -78 ° C. for 1 hour. (3R, 5S) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-one (prepared according to International Patent Application Publication No. WO 2005/077935) (6.93 g, 28.1 mmol) ) In toluene (15 mL) was added dropwise over 10 minutes and the mixture was stirred at −78 ° C. for an additional 3 hours before warming to room temperature. The mixture was quenched by pouring into saturated ammonium chloride (100 mL) and after stirring for 5 minutes, the mixture was partitioned between water (50 mL) and ethyl acetate (300 mL). The organic phase was separated and the aqueous phase was extracted with another ethyl acetate (2 × 300 mL). The combined organic extracts were dried over magnesium sulfate, filtered and then evaporated to dryness to give the crude intermediate. Purification by column chromatography (silica) with 2% methanol in dichloromethane as eluent and increasing polarity to 10% (10: 1 methanol: 880 ammonia) in dichloromethane gave (3R, 4s, 5S) -4- (5-Chloropyridin-2-yl) -1- (4-methoxybenzyl) -3,5-dimethylpiperidin-4-ol was obtained as an orange oil (8.48 g, 83%).

Step B: (3R, 4s, 5S) -4- (5-Chloropyridin-2-yl) -3,5-dimethylpiperidin-4-ol The product of Step A (6.56 g, 18.2 mmol) was anhydrous. Dissolved in dichloromethane (100 mL), triethylamine (2.02 g, 20.0 mmol) was added and the solution was cooled to 5 ° C. under nitrogen. To the stirred solution, 1-chloroethylchloroformic acid (3.1 g, 21.9 mmol) was added dropwise and when the addition was complete, the mixture was stirred at room temperature for an additional 2.5 hours. The mixture was then washed with 10% aqueous potassium carbonate solution (3 × 50 mL), dried over magnesium sulfate and evaporated to dryness. The crude oil was heated to reflux in methanol (100 mL) for 2.5 hours and the solvent removed in vacuo. The residue was dissolved in dichloromethane (100 mL) and methanol (10 mL), solid potassium carbonate (10 g) was added and the heterogeneous mixture was stirred for 30 minutes. Solid potassium carbonate was filtered off and the filtrate was evaporated to dryness. The crude product is then purified by column chromatography (silica), eluting with 10% methanol in dichloromethane and increasing in polarity to 20% in dichloromethane (10: 1 methanol: 880 ammonia) to give the title compound (3.37 g, 77%) was obtained as a yellowish solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.53 (3H, s), 0.57 (s, 3H), 2.60 to 2.71 (m, 2H), 3.13 (q, 2H), 3 .32 (d, 2H), 7.43 (d, 1H), 7.78 (dd, 1H), 8.50 (1H, d), 9.58 (br, 1H), 9.84 (br, 1H); LRMS (APCI +) 241 and 243 [MH ⁺ ].

Preparation Example 17
5-Fluoropyridine-2-carbaldehyde

The title compound was prepared according to the methods of Preparation Examples 1 and 2, starting from 2-bromo-5-fluoropyridine. This gave a crude material containing tetrahydrofuran and diethyl ether, which was used without further purification. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.57 (1H, dt), 8.03 (1H, dd), 8.62 (1H, d), 10.04 (1H, s); LRMS (APCI ⁺ ) 126 [MH ⁺ ].

Preparation Example 18
6-Formylnicotinonitrile

A mixture of 6-methylnicotinonitrile (10.0 g, 84.6 mmol) and iodine (20.0 g, 78.8 mmol) in dimethyl sulfoxide (150 mL) was heated in nitrogen at 150 ° C. for 20 minutes (reaction exhaust). Was rubbed with bleach to remove dimethyl sulfide). After cooling to room temperature, saturated aqueous sodium bicarbonate (200 mL) was carefully added and the resulting mixture was extracted with toluene (3 × 100 mL). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and evaporated to give the desired product as an orange oil (5.65 g, 50%) that was used without further purification. ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.06 (1H, d), 8.17 (1H, dd), 9.05 (1H, d), 10.12 (1H, s).

Preparation Example 19
5-Methoxy-2-methylpyridine

To a suspension of powdered KOH (103 g, 1.83 mol) in dimethyl sulfoxide (750 mL), 6-methylpyridin-3-ol (50.0 g, 0.458 mol) was added and the mixture was 1. Stir for 5 hours. Then, methyl iodide (30 mL, 68.3 g, 0.481 mol) was added dropwise to the dark brown mixture over 1 hour (exothermic). After stirring at room temperature for 1.5 hours, water (1.0 L) was added and the mixture was extracted with ethyl acetate (2 × 300 mL). The combined organic extracts were washed with brine, dried (MgSO ₄ ) and evaporated on a rotary evaporator at 40 ° C. The residue is purified by column chromatography (silica) eluting with pentane and increasing in polarity to ethyl acetate, and the volatile product is obtained in an approximately 1: 1 mixture with ethyl acetate (40 g, approximately 23.3 g). Product, 41%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 2.45 (3H, s), 3.79 (3H, s), 7.02 (1H, d), 7.08 (1H, dd), 8.16 (1H , D).

Preparation Example 20
5-methoxy-2-methylpyridine 1-oxide

M-Chloroperbenzoic acid (51.3 g, 0.297 mol) was added in small portions to a solution of the compound of Preparation Example 19 (40 g, 1: 1 mixture with ethyl acetate, 23.3 g, 189 mmol) in dichloromethane (1500 mL). The mixture was stirred at room temperature for 2 hours. A solution of sodium sulfite (45 g) in water (250 mL) was then added to the reaction and the mixture was stirred for 15 minutes, at which point KI starch paper showed a negative test result for the presence of oxidizing agent. The organic layer was separated, dried over MgSO ₄ and evaporated to give a pale yellow solid (54 g) which was an approximately 1: 1 mixture of the desired product and m-chlorobenzoic acid (mCBA). Met. This was taken to the next step without further purification. ¹ H NMR (CDCl ₃ , 400 MHz) δ 3.84 (3H, s), 6.97 (1H, dd), 7.19 (1H, d), 7.34 (1H, t, mCBA), 7.48 (1H, d, mCBA), 7.94 (1H, d, mCBA), 8.04 (1H, s, mCBA), 8.36 (1H, d).

Preparation Example 21
(5-Methoxypyridin-2-yl) methanol

To a solution of the product of Preparation 20 (about 135 mmol) in ice-cold dichloromethane (500 mL) was added trifluoroacetic anhydride (28.2 mL, 203 mmol) dropwise and the mixture was allowed to warm to room temperature and stirred overnight. Tlc analysis still indicated that most was starting material, so an additional portion of trifluoroacetic anhydride (15 mL, 108 mmol) was added dropwise and the mixture was stirred for an additional 27 hours. Methanol (250 mL) was carefully added to quench the reaction, stirred for 30 minutes, and then concentrated in vacuo. Then 2.5M sodium hydroxide (100 mL) was added carefully and the mixture was extracted with dichloromethane (4 × 100 mL). The combined organic extracts were dried (MgSO ₄ ) and evaporated to give the desired product (12 g, 64%) contaminated with recovered starting material (about 15 mol%). ¹ H NMR (CDCl ₃ , 400 MHz) δ 3.80 (3H, s), 4.40 (1H, br), 4.66 (2H, s), 7.16 (1H, dd), 7.20 (1H , D), 8.17 (1H, d).

Preparation Example 22
5-methoxypyridine-2-carbaldehyde

To a solution of the alcohol of Preparation Example 21 (12 g, 86 mmol) in dichloromethane (500 mL) was added MnO ₂ (97.0 g, 360 mmol) in one portion and the resulting suspension was stirred at room temperature for 64 hours. The reaction mixture was filtered through Celite®, the solvent was removed in vacuo, and the desired product (8.6 g, 73%) contaminated with 5-methoxy-2-methylpyridine 1-oxide (15 mol%). ) Was obtained as an orange oil. ¹ H NMR (CDCl ₃ , 400 MHz) δ 3.93 (3H, s), 7.26 (1H, dd), 7.91 (1H, d), 8.37 (1H, d), 9.94 (1H , S).

Effect of 3 mg / kg and 10 mg / kg of the compound of Example 2 on cumulative food intake over 24 hours.

Effect of 3 mg / kg and 10 mg / kg of the compound of Example 2 on body weight change over 24 hours.

Claims (19)

Compound of formula (I)
[Where:
One of X and Y is N, the other is CH,
R is F, Cl, CN, CF ₃ , or methoxy, provided that when Y is N, R is not F or Cl;
R ¹ is phenyl, 2-pyridyl, C ₃ -C ₆ , wherein the ring portion may be substituted with one or more substituents each independently selected from F, Cl, CN, methyl, and methoxy. cycloalkyl, or a _CH 2 _(C 3 _{~C 6} cycloalkyl),
R ² is H, F, or Cl, provided that when Y is N, R ² is not F or Cl;
Het is a 6-membered ring containing 1 or 2 N atoms, which ring is aromatic or contains double bonds and ═O substituents in the two rings, May be substituted with one or more substituents each independently selected from F, Cl, OH, CN, methyl, ethyl, NH ₂ , NHCH ₃ , N (CH ₃ ) ₂ , and methoxy;
Or alternatively, Het may be substituted with 1 or 2 N atoms fused to a 5-membered aromatic ring containing 1 or 2 other N atoms at positions 3, 4 with respect to the bond to the pyrrolidine ring. A 6-membered ring, which may be substituted with OH],
Or a pharmaceutically acceptable salt or solvate thereof (including hydrates).   2. The compound according to claim 1, wherein X is N and Y is CH, or a pharmaceutically acceptable salt or solvate thereof (including hydrates).   3. A compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt or solvate thereof (including hydrates), wherein R is chloro. R ¹ is phenyl optionally substituted by one or more substituents each independently selected from F, Cl, CN, methyl, and methoxy.
4. The compound according to any one of claims 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof (including a hydrate). R ¹ is phenyl, 4-chlorophenyl or 4-fluorophenyl, (including hydrates) compound or a pharmaceutically acceptable salt or solvate thereof, as claimed in claim 4. R ¹ is C ₃ -C ₆ cycloalkyl,
4. The compound according to any one of claims 1, 2, or 3, or a pharmaceutically acceptable salt or solvate thereof (including a hydrate). R ¹ is cyclopropyl or cyclohexyl,
The compound according to any one of claims 6 or a pharmaceutically acceptable salt or solvate (including hydrate). R ² is H or F, a compound according to any one of claims 3, 4, 5, 6 or 7, or a pharmaceutically acceptable salt, or solvate thereof, (water Including Japanese). The compound according to claim 8, wherein R ² is H, or a pharmaceutically acceptable salt or solvate thereof (including hydrate). Het may be substituted with one or more substituents independently selected from F, Cl, OH, CN, methyl, ethyl, and methoxy, pyridin-2-yl, pyridin-3-yl, Pyridazin-3-yl, 6-oxo-1,6-dihydropyridazin-3-yl, 6-oxo-1,6-dihydropyridin-3-yl, 2-oxo-1,2-dihydropyrimidin-4-yl, 6-oxo-1,6-dihydropyrimidin-4-yl, 2-oxo-1,2-dihydropyridin-4-yl, imidazo [1,2-b] pyridazin-6-yl, [1,2,4] Triazolo [4,3-b] pyridazin-6-yl, or 6-oxo-1,6-dihydropyridin-2-yl,
The compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, or 9, or a pharmaceutically acceptable salt or solvate thereof (including a hydrate). .   Het may be substituted with one or more substituents each independently selected from OH, CN, F, methyl, and methoxy. Pyridin-2-yl, pyridin-3-yl, pyridazine-3- 11. The compound according to claim 10, which is yl, or 6-oxo-1,6-dihydropyridazin-3-yl, or a pharmaceutically acceptable salt or solvate thereof (including hydrate).   12. A compound according to claim 11 or a pharmaceutical, wherein Het is pyridin-2-yl or pyridazin-3-yl substituted in the para position with OH, CN or methoxy, respectively, with respect to the bond linking to the pyrrolidine moiety Acceptable salts or solvates thereof (including hydrates).   13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein Het is pyridazin-3-yl substituted at the para position with OH, CN, or methoxy with respect to the bond linking to the pyrrolidine moiety, or Solvates (including hydrates). 6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-pyridine-2- Ylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (5-chloropyridin-2-yl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-4- (4-methoxyphenyl) -3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-cyclohexyl-4-hydroxy-3,5-dimethylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -1- (6-chloropyridazin-3-yl) -4- (5-chloropyridin-2-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (6-methoxypyridazin-3-yl) pyrrolidin-3-yl] carbonyl } -4-cyclopropyl-3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (5-fluoropyridin-3-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] nicotinonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- (5-fluoropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-fluoropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-fluoropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-cyanopyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4R) -3-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- (6-methoxypyridin-3-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- (5-methoxypyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
(3R, 4R, 5S) -4- (4-Fluorophenyl) -1-{[(3S, 4R) -1- (5-fluoropyridin-3-yl) -4- (6-methoxypyridine-3- Yl) pyrrolidin-3-yl] carbonyl} -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-pyridazin-3-ylpyrrolidin-3-yl] carbonyl} -4- ( 4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- [1,2,4] triazolo [4,3-b] pyridazine- 6-ylpyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-imidazo [1,2-b] pyridazin-6-ylpyrrolidin-3- Yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyrimidin-2 (1H) -one,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -1-methylpyrimidin-2 (1H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- (6-methoxypyridazin-3-yl) pyrrolidin-3-yl] carbonyl } -4- (4-Fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof (including hydrates) selected from: 6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4-hydroxy-3,5-dimethyl-4-phenylpiperidine-1 -Yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (5-chloropyridin-2-yl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-pyridazin-3-ylpyrrolidin-3-yl] carbonyl} -4- ( 4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1- [1,2,4] triazolo [4,3-b] pyridazine- 6-ylpyrrolidin-3-yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
(3R, 4R, 5S) -1-{[(3S, 4S) -4- (5-chloropyridin-2-yl) -1-imidazo [1,2-b] pyridazin-6-ylpyrrolidin-3- Yl] carbonyl} -4- (4-fluorophenyl) -3,5-dimethylpiperidin-4-ol,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyrimidin-2 (1H) -one,
4-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -1-methylpyrimidin-2 (1H) -one,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-Chloro-3-fluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (3,5-difluoropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
15. A compound according to claim 14, or a pharmaceutically acceptable salt or solvate thereof (including hydrates) selected from: 6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (5-chloropyridin-2-yl) -4-hydroxy -3,5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (4-fluorophenyl) -4-hydroxy-3,5 -Dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] -2-methylpyridazin-3 (2H) -one,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazine-3-carbonitrile,
6-[(3S, 4S) -3-{[(3R, 4R, 5S) -4- (4-chlorophenyl) -4-hydroxy-3,5-dimethylpiperidin-1-yl] carbonyl} -4- ( 5-chloropyridin-2-yl) pyrrolidin-1-yl] pyridazin-3 (2H) -one,
6-[(3S, 4S) -3- (5-chloropyridin-2-yl) -4-{[(3R, 4R, 5S) -4- (3,4-difluorophenyl) -4-hydroxy-3 , 5-dimethylpiperidin-1-yl] carbonyl} pyrrolidin-1-yl] pyridazin-3 (2H) -one,
16. A compound according to claim 15, or a pharmaceutically acceptable salt or solvate thereof (including hydrates) selected from:   17. A compound according to any one of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16, or a pharmaceutically acceptable A pharmaceutical composition comprising a salt or solvate (including hydrate) and a pharmaceutically acceptable diluent, carrier or adjuvant. The pharmaceutical composition according to claim 17, for treating a disorder for which MC4 agonist action is effective. Sexual dysfunction, obesity, for treating diabetes or urological state, The pharmaceutical composition according to claim 17.