Metabolites of glp1r agonists

Patent metadata

Field	Value
Publication number	US-2024391908-A1
Application number	US-202418789977-A
Country	US
Kind code	A1
Filing date	Jul 31, 2024
Priority date	Dec 15, 2020
Publication date	Nov 28, 2024
Grant date	—

Abstract

The present invention provides compounds of Formula XA-1, XA-2, XA-3, XA-4, XA-5, or XA-6, or metabolites of Compound 1 or metabolites of a compound of Formula I, PA-I, or PA-III, including compositions and salts thereof, which are useful in the prevention and/or treatment of a disease or disorder such as T2DM, obesity, or NASH, as well as analytical methods related to the administration of Compound 1 or a compound of Formula I, PA-1, or PA-III.

First claim

What is claimed is:

1 . A compound of Formula XA-3 or XA-4:

or a pharmaceutically acceptable salt thereof, wherein:
Ring T 1 is phenyl or pyridinyl, wherein each of the phenyl or pyridinyl is substituted with 1, 2, 3, or 4 independently selected R 500 , wherein each R 500 is independently F, Cl, —CN, or —OR 501 , or two adjacent R 500 together form a moiety of —O—CR 502 R 503 —O— that is fused to the phenyl or pyridinyl of Ring T 1 , and wherein when the phenyl or pyridinyl of ring T 1 is not substituted with a moiety of —O—CR 502 R 503 —O—, then it is at least substituted with one —OR 501 ;
each R 501 is independently —C(R 504 R 505 )R 506 ;
R 502 is H or —C 1-3 alkyl, wherein the —C 1-3 alkyl is substituted with 0 to 1 OH;
R 503 is independently phenyl or a 6-membered heteroaryl, wherein each of the phenyl or pyridinyl is substituted with 0, 1, 2, or 3 independently selected R 50 7;
each of R 504 and R 505 is H or —C 1-3 alkyl, wherein the —C 1-3 alkyl is substituted with 0 to 1 OH;
each R 506 is independently phenyl or a 6-membered heteroaryl, wherein each of the phenyl or pyridinyl is substituted with 0, 1, 2, or 3 independently selected R 508 ;
each R 507 is independently halogen, —CN, —C 1-3 alkyl, or —OC 1-3 alkyl, wherein each of the C 1-3 alkyl and OC 1-3 alkyl is substituted with 0 to 3 F atoms;
each R 508 is independently halogen, —CN, —C 1-3 alkyl, or —OC 1-3 alkyl, wherein each of the C 1-3 alkyl and OC 1-3 alkyl is substituted with 0 to 3 F atoms;
each R 3 is independently F, —OH, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, or —C 3-4 cycloalkyl, or 2 R 3 s may together cyclize to form —C 3 -4spirocycloalkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl, or spirocycloalkyl may be substituted as valency allows with 0 to 3 F atoms and with 0 to 1 —OH;
q is 0, 1, or 2;
R 4 is —C 1-3 alkyl, —C 0-3 alkylene-C 3-6 cycloalkyl, —C 0-3 alkylene-R 5 , or —C 1-3 alkylene-R 6 , wherein said alkyl may be substituted as valency allows with 0 to 3 substituents independently selected from 0 to 3 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 , and

wherein said alkylene and cycloalkyl may be independently substituted as valency allows with 0 to 2 substituents independently selected from 0 to 2 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 ;
R 5 is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 1 oxo (═O),
0 to 1 —CN,
0 to 2 F atoms, and
0 to 2 substituents independently selected from —C 1-3 alkyl and —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms,
0 to 1 —CN, and
0 to 1 —OR O ;

R 6 is a 5- to 6-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 halogens,
0 to 1 substituent selected from —OR O and —N(R N ) 2 , and
0 to 2 —C 1-3 alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms, and
0 to 1 —OR O ;

each R O is independently H, or —C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
each R N is independently H, or —C 1-3 alkyl;
Z 1 is CH or N;
Z 2 and Z 3 are each independently —CR Z or N, provided that when Z 1 or Z 3 is N, Z 2 is —CR Z ; and
each R Z is independently H, F, Cl, or —CH 3 .

2 . A compound that is selected from:
a compound of Formula Mtblt-4

a compound of Formula Mtblt-5

and
a compound of Formula Mtblt-6

or a pharmaceutically acceptable salt thereof, wherein
each R 1 is independently halogen, —CN, —C 1-3 alkyl, or —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl is substituted with 0 to 3 F atoms;
m is 0, 1, 2, or 3;
each R 2 is independently F, Cl, or —CN;
p is 0, 1 or 2;
each R 3 is independently F, —OH, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, or —C 3-4 cycloalkyl, or 2 R 3 s may together cyclize to form —C 3-4 spirocycloalkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl, cycloalkyl, or spirocycloalkyl may be substituted as valency allows with 0 to 3 F atoms and with 0 to 1 —OH;
q is 0, 1, or 2;
R 4 is —C 1-3 alkyl, —C 0-3 alkylene-C 3-6 cycloalkyl, —C 0-3 alkylene-R 5 , or —C 1-3 alkylene-R 6 , wherein said alkyl may be substituted as valency allows with 0 to 3 substituents independently selected from 0 to 3 F atoms and 0 to 1 substituent selected

from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 , and
wherein said alkylene and cycloalkyl may be independently substituted as valency allows with 0 to 2 substituents independently selected from 0 to 2 F atoms and 0 to 1 substituent selected from —C 0-1 alkylene-CN, —C 0-1 alkylene-OR O , and —N(R N ) 2 ;
R 5 is a 4- to 6-membered heterocycloalkyl, wherein said heterocycloalkyl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 1 oxo (═O),
0 to 1 —CN,
0 to 2 F atoms, and
0 to 2 substituents independently selected from —C 1-3 alkyl and —OC 1-3 alkyl, wherein the alkyl of C 1-3 alkyl and OC 1-3 alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms,
0 to 1 —CN, and
0 to 1 —OR O ;

R 6 is a 5- to 6-membered heteroaryl, wherein said heteroaryl may be substituted with 0 to 2 substituents as valency allows independently selected from:
0 to 2 halogens,
0 to 1 substituent selected from —OR O and —N(R N ) 2 , and
0 to 2 —C 1-3 alkyl, wherein the alkyl may be substituted with 0 to 3 substituents as valency allows independently selected from:
0 to 3 F atoms, and
0 to 1 —OR O ;

each R O is independently H, or —C 1-3 alkyl, wherein C 1-3 alkyl may be substituted with 0 to 3 F atoms;
each R N is independently H, or —C 1-3 alkyl;
Z 1 is CH or N;
Z 2 and Z 3 are each independently —CR Z or N, provided that when Z 1 or Z 3 is N, Z 2 is —CR Z ;
each R Z is independently H, F, Cl, or —CH 3 ; and
R 31 is —OH, —O—S(═O) 2 OH, or —O-glucuronidation.

3 . The compound of claim 1 wherein the compound is a compound of Formula XA-4, or a pharmaceutically acceptable salt thereof.

4 . A composition comprising the compound or pharmaceutically acceptable salt of claim 1 , wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 25% by weight.

5 . The composition of claim 4 wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 50% by weight.

6 . The composition of claim 4 wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 75% by weight.

7 . A preparation of the compound or pharmaceutically acceptable salt of claim 1 , which has greater than about 95% purity.

8 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of claim 1 , and a least

Assignees

• Pfizer

Inventors

• Bessire Andrew John
• Edmonds David James
• Griffith David Andrew
• Kalgutkar Amit Sumant
• Ryder Timothy Frank

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K45/06

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07H17/02

  Heterocyclic radicals containing only nitrogen as ring hetero atoms · CPC title

• C07H17/04

  Heterocyclic radicals containing only oxygen as ring hetero atoms · CPC title