TRPM8 antagonists and their use in treatments

Patent metadata

Field	Value
Publication number	US-9096527-B2
Application number	US-201414187677-A
Country	US
Kind code	B2
Filing date	Feb 24, 2014
Priority date	Jun 24, 2011
Publication date	Aug 4, 2015
Grant date	Aug 4, 2015

Abstract

Compounds of Formula I are useful as antagonists of TRPM8. Such compounds are useful in treating a number of TRPM8 mediated disorders and conditions and may be used to prepare medicaments and pharmaceutical compositions useful for treating such disorders and conditions. Examples of such disorders include, but are not limited to, migraines and neuropathic pain. Compounds of Formula I have the following structure:

where the definitions of the variables are provided herein.

First claim

What is claimed is:

1. A compound of Formula I having the structure:

a pharmaceutically-acceptable salt thereof, a tautomer thereof, a pharmaceutically-acceptable salt of the tautomer, a stereoisomer thereof, or a mixture thereof, wherein:
m is 0, 1, 2 or 3;
n is 0 or 1;
X 1 is C(R 4 );
X 2 is N;
R 1 is C 1-6 alk or a direct-bonded, C 1-2 alk-linked, C 1-2 alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one 0 or S atom, the C 1-6 alk and ring being substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, C 1-6 alk, C 1-6 alkOH, C 1-6 alk-C(═O)R a , C 1-6 alk-C(═O)OR a , C 1-4 haloalk, cyano, nitro, —C(═O)R a , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R a , —OC(═O)NR a R a , —OC(═O)N(R a )S(═O) 2 R a , —OC 2-6 alkNR a R a , —OC 2-6 alkOR a , —SR a , ═S, —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R a , —S(═O) 2 N(R a )C(═O)R a , —S(═O) 2 N(R a )C(═O)OR a , —S(═O) 2 N(R a )C(═O)NR a R a , —NR a R a , —N(R a )C(═O)R a , —N(R a )C(═O)OR a , —N(R a )C(═O)NR a R a , —N(R a )C(═NR a )NR a R a , —N(R a )S(═O) 2 R a , —N(R a )S(═O) 2 NR a R a , —NR a C 2-6 alkNR a R a and —NR a C 2-6 alkOR a , wherein the ring is additionally substituted by 0 or 1 directly bonded, SO 2 linked, C(═O) linked or CH 2 linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one 0 or S atom, and substituted by 0, 1, 2 or 3 groups selected from halo, oxo, C 1-6 alk, C 1-4 haloalk, cyano, nitro, —C(═O)R a , —C(═O)OR a , —C(═O)NR a R a , —C(═NR a )NR a R a , —OR a , —OC(═O)R a , —SR a , —S(═O)R a , —S(═O) 2 R a , —S(═O) 2 NR a R a , —NR a R a , and —N(R a )C(═O)R a ;
R 2 is —F or —CF 3 ;
R 3 is —OCF 3 or —CF 3 ;
R 4 is independently, at each instance, H, C 1-6 alk, —C 1-3 haloalk, —OC 1-6 alk, —OC 1-3 haloalk, —N(C 1-6 alk)C 1-6 alk, —NHC 1-6 alk, —NC(═O)C 1-6 alk, —N(C 1-6 alk)C 1-6 alk, F, Cl, Br, CN, OH or NH 2 ; or R 3 and R 4 together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R 5 substituents;
R 5 is independently, in each instance, halo, OR a , CH 3 or CF 3 ;
R 6 is F, C 1-6 alk, or OR a ;
R a is independently, at each instance, H or R b ; and
R b is independently, at each instance, phenyl, benzyl or C 1-6 alk, the phenyl, benzyl and C 1-6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, C 1-4 alk, C 1-3 haloalk, —OC 1-4 alk, —OH, —NH 2 , —OC 1-4 alk, —OC 1-4 haloalk, —NHC 1-4 alk, and —N(C 1-4 alk)C 1-4 alk.

2. The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein the compound of Formula I has the Formula IA:

3. The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R 1 is the saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring and the monocyclic or bicyclic ring is substituted by 0, 1, 2, or 3 substituents, wherein the substituents are selected from F, Cl, Br, I, oxo, cyano, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —C(H)(CH 3 ) 2 , —CH 2 C(H)(CH 3 ) 2 , —CH 2 C(H)═CH 2 , —CH 2 CO 2 H, —CH 2 CF 3 , —C(OH)(CH 3 ) 2 , —SO 2 N(H)CH 3 , —N(H)SO 2 CH 3 , —OCH 3 , —OCF 3 , —OH, —OCH 2 CO 2 H, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 C(H)(CH 3 )OH, —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —CO 2 C(CH 3 ) 3 , —CO 2 NH 2 , —CO 2 N(H)CH 3 , —SO 2 CH 3 , —OC(═O)CH 3 , —NH 2 , —NHC(═O)CH 3 , —N(CH 3 ) 2 , —N(H)CH 2 CH 3 , —CF 3 , —CHF 2 , —CH 2 C(H)(CF 3 )OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 -phenyl, —C(═O)-phenyl, tetrazolyl, oxadiazolonyl, pyridyl, oxetanyl,

4. The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R 1 is a phenyl, pyridyl, pyridinonyl, piperidinonyl, pyridazinonyl, pyrazinonyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetradyrofuranyl, tetrahydropyranyl, thiazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, triazolyl, oxazolyl, imidazolyl, pyrrolidinonyl, piperidinyl, cyclohexyl, cyclohexanonyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, benzothiophenyl, pyrazolopyrimidinyl, triazolopyrimidinyl, indazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydropyrazolooxazinyl, indolinonyl, isoindolinonyl, benzooxazolonyl, oxazolopyridinonyl, benzoimidazolonyl, isoindolindionyl, tetrahydroquinolinyl, dihydroquinolinonyl, benzooxazinonyl, dihydrobenzooxazinonyl, dihydroindenonyl, benzothiazolyl, benzimidazolyl, imidazopyridinyl, tetrazolopyridinyl, quinolinonyl, quinoxalinyl, or quinoxalindionyl substituted by 0, 1, 2, or 3 substituents.

5. The compound of claim 4 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R 1 is a pyridinonyl substituted by 0, or 1 substituent.

6. The compound of claim 4 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R 1 is a pyridyl substituted by 0, or 1 substituent.

7. The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R 1 is a group of formula

and the symbol , when drawn across a bond, indicates the point of attachment to the rest of the molecule.

8. The compound of claim 1 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof, wherein R 1 is

Assignees

• Amgen Inc

Inventors

• Biswas Kaustav
• Brown James
• Chen Jian J
• Gore Vijay Keshav
• Harried Scott
• Horne Daniel B
• Kaller Matthew R
• Liu Qingyian
• Ma Vu Van
• Monenschein Holger
• Nguyen Thomas T
• St Jean Jr David J
• Yuan Chester Chenguang
• Zhong Wenge

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P31/22

  for herpes viruses · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title