# US 10,501,411 B2 · Substituted benzamides

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- Number: US 10,501,411 B2
- Document ID: US10501411B2
- Status: Granted
- Kind: B2
- Application number: 15/157,734
- Filed: 2016-05-18
- Published: 2016-09-15
- Granted: 2019-12-10
- Earliest claimed: 2009-12-22
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Katrin Groebke Zbinden; Roger Norcross; Philippe Pflieger
- Web page: https://patentgrep.com/patent/US10501411B2

## CPC

- C07D 207/09: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 25/36: Opioid-abuse
- C07D 207/10: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 207/12: Oxygen or sulfur atoms
- C07D 211/26: with hydrocarbon radicals, substituted by nitrogen atoms
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 265/30: not condensed with other rings
- C07D 267/08: having the hetero atoms in positions 1 and 4
- C07D 267/10: not condensed with other rings
- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 495/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

The invention relates to compounds of formula wherein R, R1, R2, X, and Y are as defined herein and to a pharmaceutically suitable acid addition salt thereof. Compounds of formula I have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1. The compounds can be used for the treatment of depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD), stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.

## Claims

### Claim 1

A compound of formula I
wherein
R is hydrogen or lower alkyl;
R1 is heterocycloslky having 1 or 2 ring heteroatoms independently selected from N, O and S, wherein two of said ring heteroatoms are not both O, said heterocycloalkyl optionally substituted by hydroxyl, halogen by —(CH2)p-aryl;
P is 1 or 2;
R2 is a 5 or 6-member heteroaryl, optionally mono- or bi-substituted indepently with lower alkyl;
X is a bond, —NR′—, —CH2NH—, —CHR″—, —(CHR″)q—O—, —O—(CHR″)q— or —(CH2)2—;
Y is a bond or —CH2—;
R′ is hydrogen or lower alkyl;
R″ is hydrogen, lower alkyl, CF3, lower alkoxy; and
q is 0, 1, 2 or 3;
or a pharmaceutically suitable acid addition salt thereof,
wherein R1 is attached to the phenyl moiety in formula I via a carbon atom in the heterocycloalkyl ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X is NR′ and R′ is hydrogen.

### Claim 3 (depends on 1)

The compound of claim 1, wherein X is a bond.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X is —(CH2)q—O—.

### Claim 5 (depends on 1)

The compound of claim 1, wherein X is —O(CHR″)q—.

### Claim 6 (depends on 1)

The compound of claim 1, wherein X is —CHR″—.

### Claim 7 (depends on 1)

The compound of claim 1, wherein X is —CH2CH2—.

### Claim 8 (depends on 1)

A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically suitable acid addition salt thereof, and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein said compound is:
(RS)-2-Methyl-N-(4-(morpholin-2-yl)phenyl)thiazole-4-carboxamide hydrochloride;
(S)-6-Methyl-N-(4-(piperidin-3-yl)phenyl)nicotinamide hydrochloride;
(S)-5-Methyl-N-(4-(piperidin-3-yl)phenyl)pyrazine-2-carboxamide hydrochloride;
(R)-6-Methyl-N-(4-(piperidin-3-yl)phenyl)nicotinamide hydrochloride;
(S)-5-Ethyl-N-(4-(piperidin-3-yl)phenyl)pyrazine-2-carboxamide hydrochloride;
(S)—N-(4-(Piperidin-3-yl)phenyl)-5-propylpyrazine-2-carboxamide hydrochloride;
(S)—N-(4-(Piperidin-3-yl)phenyl)-6-propylnicotinamide;
(RS)-2-Methyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide dihydrochloride;
(RS)-2,6-Dimethyl-N-(4-(morpholin-2-yl)phenyl)isonicotinamide dihydrochloride; or
(S)-6-Ethyl-N-(4-(piperidin-3-yl)phenyl)nicotinamide,
or a pharmaceutically suitable acid addition salt thereof.

### Claim 10 (depends on 9)

A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 9, or a pharmaceutically suitable acid addition salt thereof, and a pharmaceutically acceptable carrier.