Substituted 4-phenyl pyridine compounds as non-systemic TGR5 agonists

Patent metadata

Field	Value
Publication number	US-12084472-B2
Application number	US-202117185653-A
Country	US
Kind code	B2
Filing date	Feb 25, 2021
Priority date	Dec 18, 2015
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

Abstract

The invention relates to non-systemic TGR5 agonist useful in the treatment of chemotherapy-induced diarrhea, diabetes, Type II diabetes, gestational diabetes, impaired fasting glucose, impaired glucose tolerance, insulin resistance, hyperglycemia, obesity, metabolic syndrome, ulcerative colitis, Crohn's disease, disorders associated with parenteral nutrition especially during short bowel syndrome, and irritable bowel syndrome (IBS), and other TGR5 associated diseases and disorders, having the Formula:where R1, R2, R2′, R3, R4, X1, X2, X3, X4, Q, and n are described herein.

First claim

The invention claimed is:

1. A compound of Formula (I′):

or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:
Q is C═(O), and Q 1 is —NR 5 —;
or Q is —NR 5 — or —O—, and Q 1 is —CH 2 —;
or Q is —CH 2 —, and Q 1 is —O(CH 2 ) 0-1 — or —NR 5 —;
or Q is —SO 2 —, and Q 1 is —NR 5′ —, —CH 2 —, or O(CH 2 ) 0-1 ;
X 1 is CR 6 or N;
X 2 is CR 7 or N;
X 3 is CR 8 or N;
X 4 is CR 9 or N;
Y is CR b or N;
R a and R b are each independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, or halogen; or
R 1 and R a together with the carbon atoms to which they are attached form a heterocycloalkyl;
R 1 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —S(O) p (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O—(C 3 -C 8 ) cycloalkyl, or —O— heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents independently selected from halogen, (C 1 -C 4 ) alkoxy, —OH, —NH 2 , —NH(C 1 -C 4 ) alkyl, and —N((C 1 -C 4 ) alkyl) 2 ; or
R 1 and R 3 , when on adjacent atoms, together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and halogen;
R 2 is (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 ) haloalkoxy, and R 2 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, or (C 1 -C 6 ) haloalkoxy; or
R 2 and R 2′ together with the carbon atom to which they are attached form (C 3 -C 8 ) cycloalkyl or heterocycloalkyl;
each R 3 is independently, at each occurrence, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, —S(O) p (C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O—(C 3 -C 8 ) cycloalkyl, or —O-heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more substituents independently selected from halogen, (C 1 -C 4 ) alkoxy, —OH, —NH 2 , —NH(C 1 -C 4 ) alkyl, and —N((C 1 -C 4 ) alkyl) 2 ; or
R 1 and R 3 together with the carbon atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more substituents independently selected from (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, and halogen;
R 4 is H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —OH, —NH 2 , CN, —S(O) m (C 1 -C 6 ) alkyl, —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
R 5 is H, (C 1 -C 6 ) alkyl, —C(O)NR 10 R 11 , —C(O)(C 1 -C 6 ) alkyl, or —C(O)O(C 1 -C 6 ) alkyl;
each R 6 and R 9 is independently H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, halogen, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —OH, —NH 2 , CN, —S(O) o (C 1 -C 6 ) alkyl, —NH(C 1 -C 4 ) alkyl, or —N((C 1 -C 4 ) alkyl) 2 ;
each R 7 and R 8 is independently H, (C 1 -C 8 ) alkenyl, (C 1 -C 8 ) alkynyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, (C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, halogen, (C 3 -C 8 ) cycloalkyl, (C 3 -C 8 ) cycloalkenyl, heterocycloalkyl, —OH, —NH 2 , —S(O) q NH 2 , —S(O) q OH, CN, or (C 1 -C 18 ) alkyl, wherein 0 to 7 methylene of the (C 1 -C 18 ) alkyl is optionally replaced by a moiety selected from the group consisting of —O—, —NR 13 —, —S(O) q —, —C(O)—, —C(CH 2 )—, and —C(NH)—, provided that when any two methylene in the alkyl is replaced, then two —O—, two —S(O) q —, or two —NR 13 — and —O— and —NR 13 — are not contiguous, wherein the alkyl is optionally substituted with one or more R 12 , and wherein the cycloalkyl and cycloalkenyl are optionally substituted with one or more R 13 ;
R 10 and R 11 are each independently H or (C 1 -C 6 ) alkyl optionally substituted with one or more substituent independently selected from —NH 2 and OH;
R 12 is D, —OH, halogen, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , —C(O)OH, —OC(O)(C 1 -C 6 ) alkyl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 10 ) aryl, heteroaryl, or R 17 , wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , halogen, and R 10 ;
R 13 is H, —OH, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 10 ) aryl, heteroaryl, or (C 1 -C 12 ) alkyl, wherein 0 to 7 methylene of the (C 1 -C 12 ) alkyl is optionally replaced by a moiety selected from the group consisting of —O—, —NR 13 —, —S(O) r —, —C(O)—, and —C(NH)—, provided that when any two methylene in the alkyl is replaced, then O and N are not contiguous and wherein the alkyl is optionally substituted with one or more R 15 , and wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more substituents independently selected from —OH, —C(O)OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, and —N((C 1 -C 6 ) alkyl) 2 ;
R 14 is (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O—(C 3 -C 8 ) cycloalkyl, —O-heterocycloalkyl, (C 1 -C 12 ) alkyl or (C 2 -C 12 ) alkenyl, wherein 0 to 7 methylene of the (C 1 -C 12 ) alkyl and the
(C 2 -C 12 ) alkenyl are optionally replaced by a moiety selected from the group consisting of —O—, —NR 13 —, —S(O) r —, —C(O)—, and —C(NH)—, provided that when any two methylene in the alkyl or alkenyl is replaced, then O and N are not contiguous and wherein the alkyl and alkenyl are optionally substituted with one or more R 15 , and the cycloalkyl and heterocycloalkyl are optionally substituted with one or more R 16 ; or
when R 12 is cycloalkyl or heterocycloalkyl, two R 14 together with the atom to which they are attached form C═(O); or when R 12 is cycloalkyl or heterocycloalkyl, two R 14 together with the atoms to which they are attached form a (C 3 -C 8 ) cycloalkyl or heterocycloalkyl optionally substituted with one or more R 13 ; or when R 12 is cycloalkyl or heterocycloalkyl, two R 14 together with the atom to which they are attached form a (C 3 -C 8 ) spirocycloalkyl or a spiroheterocycloalkyl optionally substituted with one or more R 13 ; or when R 12 is cycloalkyl or heterocycloalkyl, two R 10 together with the atom to which they are attached form a (C 6 -C 10 ) aryl or heteroaryl optionally substituted with one or more R 13 ;
R 15 is —OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, (C 6 -C 10 ) aryl or heteroaryl, wherein the (C 3 -C 8 ) cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from
(C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, —C(O)OH, —OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , and oxo;
R 16 is —OH, —C(O)OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) hydroxyalkyl, (C 3 -C 8 ) cycloalkyl, heterocycloalkyl, —O—(C 3 -C 8 ) cycloalkyl, —O— heterocycloalkyl, (C 6 -C 10 ) aryl or heteroaryl, wherein the (C 3 -C 8 ) cycloalkyl and heterocycloalkyl are optionally substituted with one or more substituents independently selected from
(C 1 -C 6 ) hydroxyalkyl, (C 1 -C 6 ) aminoalkyl, —C(O)OH, —OH, —NH 2 , —NH(C 1 -C 6 ) alkyl, —N((C 1 -C 6 ) alkyl) 2 , and oxo;
R 17 is (C 1 -C 18 ) alkyl or (C 2 -C 18 ) alkenyl, wherein 0 to 8 methylene of the (C 1 -C 18 ) alkyl and the (C 2 -C 18 ) alkenyl

Assignees

• Ardelyx Inc

Inventors

• Lewis Jason G
• Leadbetter Michael Robert
• Caldwell Jeremy
• Dragoli Dean
• Bell Noah
• Jacobs Jeffrey W
• Finn Patricia
• Jain Rakesh
• Chen Tao
• Siegel Matthew

Classifications

• C07C409/12

  with two alpha,alpha-dialkylmethyl hydroperoxy groups bound to carbon atoms of the same six-membered aromatic ring · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D213/80

  in position 3 · CPC title