Metabolites of GLP1R agonists

1. A compound of Formula XA-1, XA-2, XA-3, XA-4, XA-5, or XA-6:

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 507 ;

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 3-4 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 21 is glucuronidation,

wherein the compound of Formula XA-1, XA-2, XA-3, XA-4, XA-5, or XA-6, or pharmaceutically acceptable salt is substantially isolated.

2. A compound that is selected from:

a compound of Formula Mtblt-1

a compound of Formula Mtblt-2

a compound of Formula Mtblt-3

a compound of Formula Mtblt-4

a compound of Formula Mtblt-5

a compound of Formula Mtblt-6

a compound of Formula Mtblt-7

a compound of Formula Mtblt-8

 and

a compound of Formula Mtblt-9

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 ;

R 21 is glucuronidation; and

R 31 is —OH, —O—S(═O) 2 OH, or —O-glucuronidation,

wherein the compound of Formula Mtblt-1, Mtblt-2, Mtblt-3, Mtblt-4, Mtblt-5, Mtblt-6, Mtblt-7, Mtblt-8, or Mtblt-9, or pharmaceutically acceptable salt is substantially isolated.

3. A composition comprising the compound or pharmaceutically acceptable salt of claim 2 , wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 25% by weight.

4. The composition of claim 3 wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 50% by weight.

5. The composition of claim 3 wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 75% by weight.

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

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

8. The pharmaceutical composition of claim 7 , wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 0.1% by weight.

9. A pharmaceutical combination comprising (1) the compound or pharmaceutically acceptable salt of claim 1 , and (2) an additional therapeutic agent.

10. A compound selected from Compound M2, Compound 574a, Compound 574b, Compound M1, a compound of Formula X, and Compound M4:

a compound of Formula X

wherein R 11 is

and wherein R 1 is substituted at the phenyl ring, the pyridine ring, or the part of the piperidine ring within the dotted oval shape; and

or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is substantially isolated.

11. The compound or pharmaceutically acceptable salt of claim 10 , wherein the compound or pharmaceutically acceptable salt is Compound M1, Compound M4, Compound 574a, Compound 574b, or a compound of Formula X, or a pharmaceutically acceptable salt thereof, and wherein the compound or pharmaceutically acceptable salt is substantially isolated.

12. A composition comprising a compound or pharmaceutically acceptable salt of claim 10 , wherein the compound or pharmaceutically acceptable salt is selected from Compound M1, Compound M4, Compound 574a, Compound 574b, and a compound of Formula X, or a pharmaceutically acceptable salt thereof, wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 25% by weight.

13. The composition of claim 12 wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 50% by weight.

14. The composition of claim 12 wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 75% by weight.

15. A preparation comprising a compound or pharmaceutically acceptable salt of claim 10 , wherein the compound or pharmaceutically acceptable salt is selected from Compound M2, Compound M4, Compound 574a, Compound 574b, and a compound of Formula X, or a pharmaceutically acceptable salt thereof, which has greater than about 95% purity.

16. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of claim 10 and a least one pharmaceutically acceptable carrier, wherein the compound or pharmaceutically acceptable salt is selected from Compound M1, Compound M4, Compound 574a, Compound 574b, and a compound of Formula X.

17. The pharmaceutical composition of claim 16 , wherein the compound or pharmaceutically acceptable salt thereof is present in the composition in an amount greater than about 0.1% by weight.

18. A pharmaceutical combination comprising (1) a compound or pharmaceutically acceptable salt of claim 10 , wherein the compound or pharmaceutically acceptable salt is selected from Compound M1, Compound M4, Compound 574a, Compound 574b, and a compound of Formula X, or a pharmaceutically acceptable salt thereof, and (2) an additional therapeutic agent.

19. The pharmaceutical combination of claim 9 , wherein the additional therapeutic agent is a diacylglyceryl acyltransferase 2 inhibitor.

20. The pharmaceutical combination of claim 9 , wherein the additional therapeutic agent is selected from:

(S)-2-(5-((3-Ethoxy-5-fluoropyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide;

N-(2-cyanopropan-2-yl)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxamide;

2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)pyrimidine-5-carboxamide;

2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrimidine-5-carboxamide;

(S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide;

(S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(3-(hydroxymethyl)tetrahydrofuran-3-yl)pyrimidine-5-carboxamide;

(R)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(3-(hydroxymethyl)tetrahydrofuran-3-yl)pyrimidine-5-carboxamide;

2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(2-methyl-1-(methylsulfonyl)propan-2-yl)pyrimidine-5-carboxamide;

(S)-2-(5-((3-(2-fluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide;

3-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-triazine-6-carboxamide;

N-(1,3-dihydroxy-2-methylpropan-2-yl)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxamide;

(S)-3-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)-1,2,4-triazine-6-carboxamide;

N-(1,1-dioxidotetrahydrothiophen-3-yl)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)pyrimidine-5-carboxamide;

(R)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide; and

2-(5-((3-ethoxypyrazin-2-yl)oxy)pyridin-3-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrimidine-5-carboxamide,

or a pharmaceutically acceptable salt thereof.

21. The pharmaceutical combination of claim 9 , wherein the additional therapeutic agent is (S)-2-(5-((3-ethoxypyridin-2-yl)oxy)pyridin-3-yl)-N-(tetrahydrofuran-3-yl)pyrimidine-5-carboxamide, or a pharmaceutically acceptable salt thereof.