US20190135800A1 – May 9, 2019 – HALO-SUBSTITUTED PIPERIDINES AS OREXIN RECEPTOR MODULATORS

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Inventors :

Theodore M. Kamenecka; Jörg Holenz; Steven Wesolowski; Yuanjun He; Roland Bürli

Owner :

EOLAS THERAPEUTICS INC. ASTRAZENECA AB ASTRAZENECA UK LIMITED EOLAS THERAPEUTICS INC.

Application Number :

US16076818

Document Number :

US20190135800A1

Priority Date :

February 10, 2017

Filing Date :

February 10, 2017

Date of Grant/ Publication :

May 9, 2019

Class :

; C07D417 / 14; C07D401 / 14; A61P25 / 34

Abstract

The present application relates to certain halo-substituted piperidine compounds, pharmaceutical compositions containing them, and methods of using them, including methods for treating substance addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, or hypertension.

Claim(s)

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is halogen; X? is H or halogen; Z is NR 2 or O; A is aryl, aroyl, heteroaryl, or heteroaroyl, wherein A is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR a R b , —N(R a )C(O) alkyl, —N(R a )CO 2 alkyl, —N(R a )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR a R b , —SO 2 alkyl, and —SO 2 NR a R b ; wherein R a and R b are independently for each occurrence H or alkyl; B is aryl or heteroaryl, wherein B is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR c R d , —N(R c )C(O) alkyl, —N(R c )CO 2 alkyl, —N(R c )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR c R d , —SO 2 alkyl, and —SO 2 NR c R d ; wherein R c and R d are independently for each occurrence H or alkyl; E is aryl or heteroaryl, wherein E is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR e R f , —N(R e )C(O) alkyl, —N(R e )CO 2 alkyl, —N(R e )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR e R f , —SO 2 alkyl, and —SO 2 NR e R f ; wherein R e and R f are independently for each occurrence H or alkyl; n=1, 2, or 3; R 1 is alkyl; and R 2 is H or alkyl.;
2 . The compound of claim 1 , wherein A is optionally substituted aryl or heteroaryl, or a pharmaceutically acceptable salt thereof.;
3 . The compound of claim 1 , wherein the compound has the structure of formula (Ia): or a pharmaceutically acceptable salt thereof.;
4 . The compound of claim 1 , wherein Z is NR 2 , or a pharmaceutically acceptable salt thereof.;
5 . The compound of claim 1 , wherein R 2 is hydrogen, or a pharmaceutically acceptable salt thereof.;
6 . (canceled);
7 . The compound of claim 1 , wherein X is —F, or a pharmaceutically acceptable salt thereof.;
8 . The compound of claim 1 , wherein X? is —F, or a pharmaceutically acceptable salt thereof.;
9 . (canceled);
10 . The compound of claim 1 , wherein R 1 is methyl, or a pharmaceutically acceptable salt thereof.;
11 . (canceled);
12 . The compound of claim 1 , wherein A is selected from the list consisting of optionally substituted pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and benzoxazolyl, or a pharmaceutically acceptable salt thereof.;
13 – 17 . (canceled);
18 . The compound of claim 1 , wherein A is optionally substituted with one or more substituents independently selected from the list consisting of alkyl, alkoxy, and halo, or a pharmaceutically acceptable salt thereof.;
19 – 22 . (canceled);
23 . The compound of claim 1 , wherein A is substituted with —CF 3 , or a pharmaceutically acceptable salt thereof.;
24 . The compound of claim 1 , wherein B is an optionally substituted aryl, or a pharmaceutically acceptable salt thereof.;
25 – 27 . (canceled);
28 . The compound of claim 1 , wherein B is selected from the list consisting of optionally substituted pyridinyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, and benzoimidazolyl, or a pharmaceutically acceptable salt thereof.;
29 – 35 . (canceled);
claim 21: 36 . The compound of claim 1 , wherein B is optionally substituted with one or more substituents independently selected from the group consisting of an alkyl, halo, alkoxy, and —CN, or a pharmaceutically acceptable salt thereof.;
claim 22: 37 . (canceled);
claim 23: 38 . The compound of claim 36 , wherein B is substituted with one or more methyl, or a pharmaceutically acceptable salt thereof.;
claim 24: 39 – 40 . (canceled);
claim 25: 41 . The compound of claim 1 , wherein E is an optionally substituted phenyl, or a pharmaceutically acceptable salt thereof.;
claim 26: 42 . (canceled);
claim 27: 43 . The compound of claim 1 , wherein E is selected from the group consisting of optionally substituted triazolyl, tetrazolyl, pyrazolyl, pyridinyl, oxadiazolyl, pyrazinyl, and pyrimidinyl, or a pharmaceutically acceptable salt thereof.;
claim 28: 44 – 49 . (canceled);
claim 29: 50 . The compound of claim 1 , wherein E is optionally substituted with one or more substituents independently selected from the group consisting of alkyl, halo, and alkoxy, or a pharmaceutically acceptable salt thereof.;
claim 30: 51 – 52 . (canceled);
claim 31: 53 . The compound of claim 1 , wherein E is optionally substituted with one or more methyl or —F, or a pharmaceutically acceptable salt thereof.;
claim 32: 54 – 69 . (canceled);
claim 33: 70 . The compound of claim 1 , wherein Z is O, or a pharmaceutically acceptable salt thereof.;
claim 34: 71 . The compound of claim 1 , wherein n=1 or a pharmaceutically acceptable salt thereof.;
claim 35: 72 . The compound of claim 1 , wherein the compound has a structure of formula (II), or a pharmaceutically acceptable salt thereof; wherein: m is 1, 2, or 3; R 5 represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR j R k , —N(RJ)C(O) alkyl, —N(R j )CO 2 alkyl, —N(R j )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR j R k , —SO 2 alkyl, or —SO 2 NR j R k ; wherein R j and R k are independently for each occurrence H or alkyl; and X, X?, Z, B, E, n, R 1 and R 2 are as defined in claim 1 .;
claim 36: 73 . The compound of claim 1 , wherein the compound has a structure of formula (III): or a pharmaceutically acceptable salt thereof; wherein: m is 1, 2, 3 or 4; R 5 represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR j R k , —N(RJ)C(O) alkyl, —N(R j )CO 2 alkyl, —N(R j )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR j R k , —SO 2 alkyl, or —SO 2 NR j R k ; wherein R j and R k are independently for each occurrence H or alkyl; and X, X?, Z, B, E, n, R 1 and R 2 are as defined in claim 1 .;
claim 37: 74 . The compound of claim 1 , wherein the compound has a structure of formula (IV): or a pharmaceutically acceptable salt thereof; wherein: R 6 represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR o R p , —N(R o )C(O) alkyl, —N(R p )CO 2 alkyl, —N(R o )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR o R p , —SO 2 alkyl, or —SO 2 NR c R p ; wherein R o and R p are independently for each occurrence H or alkyl; and X, X?, Z, A, E, n, R 1 and R 2 are as defined in claim 1 .;
claim 38: 75 . The compound of claim 1 , wherein the compound has a structure of formula (V): or a pharmaceutically acceptable salt thereof, wherein: R 6 represents alkyl, cycloalkyl, halo, —OH, alkoxy, —CN, —NR o R p , —N(R o )C(O) alkyl, —N(R p )CO 2 alkyl, —N(R o )SO 2 alkyl, —C(O)alkyl, —CO 2 H, —CO 2 alkyl, —CONR o R p , —SO 2 alkyl, or —SO 2 NR c R p ; wherein R o and R p are independently for each occurrence H or alkyl; and X, X?, Z, A, E, n, R 1 and R 2 are as defined in claim 1 .;
claim 39: 76 . The compound of claim 1 , wherein the compound is compound 185, or a pharmaceutically acceptable salt thereof.;
claim 40: 77 . The compound of claim 1 , wherein the compound is compound 129, or a pharmaceutically acceptable salt thereof.;
claim 41: 78 . The compound of claim 1 , wherein the compound is compound 217, or a pharmaceutically acceptable salt thereof.;
claim 42: 79 . The compound of claim 1 , wherein the compound is compound 264, or a pharmaceutically acceptable salt thereof.;
claim 43: 80 . The compound of claim 1 , wherein the compound is compound 66, or a pharmaceutically acceptable salt thereof.;
claim 44: 81 . The compound of claim 1 , wherein the compound is compound 211, or a pharmaceutically acceptable salt thereof.;
claim 45: 82 . A compound selected from the group consisting of compounds as shown in Table 1, and pharmaceutically acceptable salts thereof.;
claim 46: 83 . A pharmaceutical composition comprising (a) a compound of claim 1 ; and (b) a pharmaceutically acceptable excipient.;
claim 47: 84 . (canceled);
claim 48: 85 . A method of treating a disease or disorder mediated by orexin receptor activity, comprising administering to a subject in need of such treatment an effective amount of at least one compound of claim 1 .;
claim 49: 86 – 96 . (canceled);
claim 50: 97 . A method of modulating the activity of an orexin receptor OX 1 , OX 2 , or both, comprising contacting a cell comprising the orexin receptor with an effective amount of at least one compound of claim 1 .;
claim 51: 98 . (canceled);
claim 52: 99 . A method of treating a disease or disorder in a patient in need thereof, comprising administering a compound of claim 1 .;
claim 53: 100 . The method of claim 99 , wherein the disease or disorder is selected from the group consisting of drug abuse or addiction, a sleep disorder, a cognitive dysfunction in a psychiatric or neurologic disorder, depression, anxiety, panic disorder, post-traumatic stress disorder, seasonal affective disorder, schizophrenia, Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea, pain, behavior disorder, mood disorder, manic depression, dementia, sex disorder, and psychosexual disorder.;
claim 54: 101 . The method of claim 99 , wherein the disease or disorder is selected from the group consisting of an eating disorder, obesity, alcoholism or an alcohol-related disorder, headache, migraine, gastrointestinal diseases, inflammations, immune-related diseases, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, endocrine-related diseases, cancer, hypertension, and renal disease.;
claim 55: 102 . The method of claim 99 , wherein the disease or disorder is selected from the group consisting of drug abuse or addiction, panic disorder, anxiety, post-traumatic stress disorder, pain, depression, seasonal affective disorder, an eating disorder, and hypertension.;
claim 56: 103 . The method of claim 100 , wherein the drug abuse or addiction is selected from abuse of or addiction to cocaine, opiates, amphetamines, ethanol, cannabis/marijuana, or nicotine.

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