Glucosylceramide synthase inhibitors for the treatment of diseases

Patent metadata

Field	Value
Publication number	US-10927092-B2
Application number	US-201916264505-A
Country	US
Kind code	B2
Filing date	Jan 31, 2019
Priority date	Sep 20, 2013
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

Described herein are compounds of Formula I, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds to treat or prevent diseases or conditions associated with the enzyme glucosylceramide synthase (GCS).

First claim

We claim:

1. A compound of Formula I:

wherein
R 1 is —C(O)C(R 6 )(R 6a )R 1a or —C(O)C(R 6 )(R 6a )—X 1 —R 1a ;
X 1 is alkylene, alkenylene, or cycloalkylene;
R 1a is
(a) benzofuranyl, optionally substituted with 1, 2, or 3 R 7 groups, or
(b) phenyl substituted with one substituent selected from pyridinyl, indazolyl, benzothiophenyl, benzoisoxazolyl, benzothiazolyl, pyrazolyl, and triazolyl, wherein the substituent is optionally further substituted with 1, 2 or 3 R 7a groups;

R 2 and R 3 together with the nitrogen to which they are attached form a 3-10 membered heterocycloalkyl ring, optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R 8 ;
R 4 is aryl or heteroaryl each of which is optionally substituted with 1, 2, 3, or 4 R 9 groups;
R 5 is —OH, and R 5a is hydrogen;
R 6 and R 6a are halo; R 6 and R 6a are deuterium; or R 6 and R 6a together with the carbon to which they are attached form C(═NOH) or C(O);
each R 7 , when present, is independently nitro, cyano, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, alkenyl, alkynyl, hydroxy, alkoxy, haloalkoxy, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R 7a ;
each R 7a , when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;
each R 8 , when present, is independently deuterium, amino, alkylamino, dialkylamino, alkyl, hydroxy, alkoxy, halo, haloalkyl, or cycloalkyl; or two R 8 together with the carbon to which they are attached form C(O);
each R 9 , when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and the phenyl, either alone or as part of another group, are independently optionally substituted with 1 or 2 R 9a ;
each R 9a , when present, is independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, and dialkylamino; and
R 12 is hydrogen or C 1-5 alkyl;
optionally a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound of Formula I is according to Formula I(b) or Formula I(c):

optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein R 2 and R 3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; each of which is optionally substituted with 1 or 2 R 8 ; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 4 is aryl which is optionally substituted with 1, 2, or 3 R 9 groups; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , wherein each R 9 , when present, is independently halo, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyloxy, or heterocycloalkylalkyloxy; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 4 is heteroaryl which is optionally substituted with 1, 2, or 3 R 9 groups; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , wherein R 4 is 2,3-dihydrobenzo[b][1,4]dioxin-6-yl optionally substituted with a halo; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein X 1 is C 1-3 alkylene; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein R 6 and R 6a together with the carbon to which they are attached form C(O) or C(═NOH); optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein R 6 and R 6a are halo; optionally as a tautomer, a single stereoisomer or mixture of stereoisomers thereof and additionally optionally as a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 wherein:
R 1 is —C(O)C(R 6 )(R 6a )R 1a or —C(O)C(R 6 )(R 6a )—X 1 —R 1a ;
X 1 is alkylene, alkenylene, or cycloalkylene;
R 1a is
(a) benzofuranyl, optionally substituted with 1, 2, or 3 R 7 groups, or
(b) phenyl substituted with one substituent selected from pyridinyl, indazolyl, benzothiophenyl, benzoisoxazolyl, benzothiazolyl, pyrazolyl, and triazolyl, wherein the substituent is optionally further substituted with 1, 2 or 3 R 7a groups;

R 2 and R 3 together with the nitrogen to which they are attached form a 4-5 membered monocyclic heterocycloalkyl ring or a 7-8 membered bicyclic heterocycloalkyl; each of which is optionally substituted with 1 or 2 R 8 ;
R 4 is aryl or heteroaryl each of which is optionally substituted with 1, 2, or 3 R 9 groups;
R 5 is —OH, and R 5a is hydrogen;
R 6 and R 6a are halo; or R 6 and R 6a together with the carbon to which they are attached form C(═NOH) or C(O);
each R 7 , when present, is independently nitro, cyano, halo, haloalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl, phenyloxy, heteroaryl, heteroarylalkyl, or heteroaryloxy; where the phenyl and the heteroaryl, either alone or as part of another group, are independently optionally substituted with 1, 2 or 3 R 7a ;
each R 7a , when present, is independently selected from cyano, halo, alkyl, alkenyl, haloalkyl, hydroxyalkyl, and cycloalkyl;
each R 8 , when present, is independently amino, alkylamino, dialkylamino, alkyl, halo, or cycloalkyl; or two R 8 together with the carbon to which they are attached form C(O);
each R 9 , when present, is independently cyano, nitro, amino, alkylamino, dialkylamino, halo, haloalkyl, alkyl, hydroxy, alkoxy, alkenyloxy, hydroxyalkyloxy, haloalkoxy, cycloalkylthio, cycloalkyloxy, cycloalkylalkyloxy, heterocycloalkyl, heterocycloalkyloxy, heterocycloalkylalkyloxy, or phenyl; where the heterocycloalkyl and the phenyl, either alone or as part of another group, are independently optionally substituted with 1 or 2 R 9a ;
each R 9a , when present, is independently selected from alkyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, a

Assignees

• Biomarin Pharm Inc

Inventors

• Wang Bing
• Chu Daniel
• Bridges Alexander James

Classifications

• C07D277/22

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D215/06

  having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom · CPC title

• C07D471/08

  Bridged systems · CPC title

• C07D333/60

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title