# US 2017/0304277 A1 · Tetrahydropyrazolopyridine derivatives as ghrelin receptor agonists

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2017/0304277 A1
- Document ID: US20170304277A1
- Status: Published application
- Kind: A1
- Application number: 15/520,491
- Filed: 2015-11-02
- Published: 2017-10-26
- Earliest claimed: 2014-10-31
- Assignees: RaQualia Pharma Inc.
- Applicants: RaQualia Pharma Inc.
- Inventors: Yasuhiro IWATA; Kiyoshi KAWAMURA; Masaki SUDO; Kaoru SHIMADA; Shinichi KOIZUMI; Nobuyuki TAKAHASHI; Keiko OBATA; Makiko KURODA
- Web page: https://patentgrep.com/patent/US20170304277A1

## CPC

- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 25/16: Anti-Parkinson drugs
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/04: Ortho-condensed systems
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to novel compounds of a formula (I) or a pharmaceutically acceptable salt or solvate thereof, processes for their preparation, pharmaceutical compositions comprising them and their use in therapy, for example as modulators of the growth hormone secretagogue receptor (also referred to as the ghrelin receptor or GHSR-1a receptor) and/or for the treatment and/or prophylaxis of a disorder mediated by the ghrelin receptor.

## Claims

### Claim 1

A compound of the following formula (I):
Wherein:
R1 is C1-6 alkyl, where the alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen;
R2 is selected from the group consisting of (1) phenyl, (2) CH2-phenyl(CH2OH), and (3) CH2-pyridyl; where the benzene ring or the pyridine ring is unsubstituted or substituted with one to two substituents independently selected from (1) halogen, (2) C1-6 alkyl, which may have substituents selected from halogen, and hydroxyl, and (3) C1-6 alkylsulfonyl;
R3 is (1) benzyl, or (2) CH2-(2-pyridyl); where the benzene ring or the pyridine ring is unsubstituted or substituted with one to two substituents independently selected from (1) halogen and (2) C1-6 alkyl, which may have substituents selected from halogen, hydroxyl, and C1-6 alkylsulfonyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound represented by the above formula (I) according to claim 1,
wherein:
R1 is methyl or trifluoroethyl;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound represented by the above formula (I) according to claim 1,
wherein:
R1 is methyl or trifluoroethyl;
R2 is selected from the group consisting of (1) phenyl, (2) CH2-phenyl(CH2OH), and (3) CH2-pyridyl; where the benzene ring or the pyridine ring is unsubstituted or substituted with one to two substituents independently selected from (1) halogen, (2) methyl, (3) difluoromethyl, (4) trifluoromethyl, (5) hydroxymethyl, and (6) methanesulfonyl;
R3 is (1) benzyl or (2) CH2-(2-pyridyl), where the benzene ring or the pyridine ring is unsubstituted;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound represented by the above formula (I) according to claim 1,
wherein:
R1 is methyl or trifluoroethyl;
when R2 is (1) phenyl, a compound where the benzene ring is unsubstituted or substituted with one to two substituents independently selected from halogen and hydroxymethyl; when R2 is (2) CH2-phenyl(CH2OH), a compound where the benzene ring is unsubstituted; when R2 is (3) CH2-pyridyl, a compound where the pyridine ring is unsubstituted or substituted with one to two substituents independently selected from difluoromethyl and trifluoromethyl;
R3 is (1) benzyl or (2) CH2-(2-pyridyl) where the benzene ring or the pyridine ring is unsubstituted;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound represented by the above formula (I) according to claim 1,
wherein HLM CLint of the compound is lower than 65 mL/min/kg
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, which is selected from the group consisting of:
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-(methylsulfonyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-1-oxo-4-phenylbutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-chloro-4-(hydroxymethyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-fluoro-4-(hydroxymethyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-fluoro-5-(hydroxymethyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-(hydroxymethyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(3-(hydroxymethyl)phenyl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(2-(hydroxymethyl)phenyl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-1-oxo-5-(pyridin-2-yl)pentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-1-oxo-5-(6-(trifluoromethyl)pyridin-2-yl)pentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(5-fluoropyridin-2-yl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(6-methylpyridin-2-yl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(6-(difluoromethyl)pyridin-2-yl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-2-methyl-N-((R)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-phenylbutan-2-yl)propanamide;
2-amino-2-methyl-N-((R)-4-(2-(methylsulfonyl)phenyl)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)butan-2-yl)propanamide;
2-amino-N-((R)-4-(4-(hydroxymethyl)phenyl)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)butan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-4-(4-(fluoromethyl)-2-(hydroxymethyl)phenyl)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)butan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-4-(3-fluoro-4-(hydroxymethyl)phenyl)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)butan-2-yl)-2-methylpropanamide; and
2-amino-N4R)-4-(5-fluoro-2-(hydroxymethyl)phenyl)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)butan-2-yl)-2-methylpropanamide;
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, which is selected from the group consisting of:
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-1-oxo-4-phenylbutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-chloro-4-(hydroxymethyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-fluoro-4-(hydroxym ethyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-(2-fluoro-5-(hydroxym ethyl)phenyl)-1-oxobutan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(3-(hydroxymethyl)phenyl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(2-(hydroxymethyl)phenyl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-1-oxo-5-(pyridin-2-yl)pentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-1-oxo-5-(6-(trifluoromethyl)pyridin-2-yl)pentan-2-yl)-2-methylpropanamide;
2-amino-N-((R)-1-((R)-3a-benzyl-2-methyl-3-oxo-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-5-(6-(difluoromethyl)pyridin-2-yl)-1-oxopentan-2-yl)-2-methylpropanamide;
2-amino-2-methyl-N-((R)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)-4-phenylbutan-2-yl)propanamide; and
2-amino-N-((R)-4-(4-(fluoromethyl)-2-(hydroxymethyl)phenyl)-1-oxo-1-((R)-3-oxo-3a-(pyridin-2-ylmethyl)-2-(2,2,2-trifluoroethyl)-3a,4,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-5(3H)-yl)butan-2-yl)-2-methylpropanamide;
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, as described in claim 1, and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 8)

The pharmaceutical composition as described in claim 8, further comprising another pharmacologically active agent.

### Claim 10 (depends on 1)

A method of treatment of an animal including human suffering from a condition or disorder mediated by the ghrelin receptor, which comprises administering to the said subject an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt according to claim 1.

### Claim 11 (depends on 10)

The method as described in claim 10, wherein the said condition or disorder is selected from the group consisting of: cancer anorexia/cachexia; cachexia and anorexia by anti-cancer drugs; hyperalgesia by anti-cancer drugs; COPD/COPD cachexia; sarcopenia; eating disorders and neurological eating disorders; weight loss suppression; early postoperative recovery of cancer patients; chronic respiratory tract infection; inflammation; IBD; FD; constipation; diabetic gastroparesis and gastroparesis; heart failure; myocardial infarction; diabetic neuropathy; Parkinson's disease; multiple sclerosis; diagnosis and treatment of growth hormone deficiency; elderly QOL improvement; bowel movement disturbance of spinal cord injury patients; postoperative ileus; and morphine induced ileus. and combinations thereof.

### Claim at position 12

12-14. (canceled)

### Claim 15 (depends on 1)

A process for preparing a pharmaceutical composition comprising mixing a compound described in claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, diluent or excipient.