IP Library › Granted Patent US 12,448,396
Granted Patent B2
US 12,448,396 · App. 18/056,863 · Granted Oct 21, 2025

Methods of using heterocyclic compounds as Delta-5 Desaturase inhibitors

Inventors: Jennifer R. Allen (Newbury Park, CA); Michela Beltrani (Verona, IT); Matthew P. Bourbeau (Woodland Hills, CA); Teodora P. Damyanova (Verona, IT); Iain Lingard (Verona, IT); Ana E. Minatti (Los Angeles, CA); Paolo Vincetti (Verona, IT)
Assignee: AMGEN INC.
C07D513/04A61P3/04C07D487/04C07D498/04
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Quick Facts
Patent No.
US 12,448,396
App. No.
18/056,863
Granted
Oct 21, 2025
Kind
B2
Abstract

The present disclosure provides compounds useful for the inhibition of Delta-5 Desaturase (“D5D”). The compounds have a general Formula I. wherein the variables of Formula I are defined herein. This disclosure also provides pharmaceutical compositions comprising the compounds, uses of the compounds, and compositions for treatment of, for example, a metabolic or cardiovascular disorder. Further, the disclosure provides intermediates useful in the synthesis of compounds of Formula I.

Claims (299)

1. A method of reducing the body weight or the body-mass-index of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer,

wherein

each instance of R is independently selected from H, halogen, —OH, —CN, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COOH, —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, —NH(COC 1-4 alkyl), —N(C 1-4 alkyl)C(═O)F, C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

wherein the C 1-4 alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

wherein the —CH 2 (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and

wherein R of a first CR group and R of a second CR group, if present, may, together with the atoms to which they are attached, form a C 3-5 carbocycle;

each R″, if present, is independently selected from H, —OH, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and

wherein the —(CH 2 ) m (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

R 1 is O, S, or NH;

R 2 is

 wherein

Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein

i) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via an N atom; or

ii) Ring A is attached via an N atom to the bicyclic core and R 3 is attached via a C atom; or

iii) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via a C atom;

and wherein the

 portion of R 2 is further optionally substituted with one or two independently selected substituents R 3′ ;

R 3 is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), —S(O) n CH 2 (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), or phenyl; wherein the C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), and —S(O) n CH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 3′ , if present, is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 4 is C 1-3 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-5 cycloalkyl, or C 3-5 cyclohaloalkyl;

n is 0, 1, or 2; and

m is 1 or 2.

2. The method according to claim 1 , wherein

each R is independently selected from H, halogen, —COO(C 1-4 alkyl), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, C 1-4 alkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, C 1-4 alkylamino, and diC 1-4 alkylamino; and

wherein the —(CH 2 ) m (C 3-5 cycloalkyl), 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, and C 1-4 alkyl.

3. The method according to claim 1 , wherein

each R is independently selected from H, halogen, —COO(C 1-4 alkyl), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, C 1-4 alkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, and C 1-4 alkoxy.

4. The method according to claim 1 , wherein

each R is independently selected from H, C 1-4 alkyl, C 1-4 deuteroalkyl, and C 1-4 alkoxy; wherein the C 1-4 alkyl group is optionally substituted with a substituent selected from —OH and —CN.

5. The method according to claim 1 , wherein each R is independently selected from H and methyl.

6. The method according to claim 1 , wherein

each R″, if present, is independently selected from H, —COO(C 1-4 alkyl), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkynyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, C 1-4 alkylamino, and diC 1-4 alkylamino; and

wherein the —(CH 2 ) m (C 3-5 cycloalkyl), 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, and C 1-4 alkyl.

7. The method according to claim 1 , wherein

each R″, if present, is independently selected from H, —COOMe, methyl, ethyl, isopropyl, fluoromethyl, trifluoromethyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, —CH 2 CN, 2-hydroxypropyl, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , dimethylaminomethyl, 2-(dimethylamino)ethyl, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, (1-hydroxycyclopropyl)ethyl, —CD 3 , cyclopropyl, (oxetan-3-yl)methyl, oxetan-3-yl, prop-2-yn-1-yl, pyrazolyl, 1-methyl-pyrazol-4-yl, pyridinyl, pyrazinyl, pyrimidinyl, 6-methylpyridin-2-yl, and 6-chloropyridin-2-yl.

8. The method according to claim 1 , wherein R 1 is O.

9. The method according to claim 1 , wherein

R 2 is

10. The method according to claim 1 , wherein

R 2 is

11. The method according to claim 1 , wherein

R 2 is

 wherein A is a 5-membered heteroaryl containing two N atoms.

12. The method according to claim 1 , wherein

R 2 is

13. The method according to claim 1 , wherein

R 2 is

14. The method according to claim 1 , wherein

R 3 is C 1-6 alkyl, C 2-6 alkoxy, —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), or phenyl; wherein the C 1-6 alkyl, C 2-6 alkoxy, —CH 2 (C 3-5 cycloalkyl), and —OCH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with one halogen substituent.

15. The method according to claim 1 , wherein

R 3 is 2,2,2-trifluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, 2,2,3,3,3-pentafluoropropyl, —OCH 2 CN, —OC(CH 3 ) 2 CN, difluoromethoxy, trifluoromethoxy, —OCH(CN)CH 3 , 2-fluoroethoxy, 2,2,-difluoroethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoropropoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,3-pentafluoropropoxy, cyclopropylmethyl, (2,2-difluorocyclopropyl)methyl, (3,3-difluorocyclobutyl)methyl, cyclopropylmethoxy, (2,2-difluorocyclopropyl)methoxy, (oxetan-3-yl)methyl, phenyl, 3-fluorophenyl, or 4-fluorophenyl.

16. The method according to claim 1 , wherein

R 3 is C 1-6 alkyl, C 2-6 alkoxy, —CH 2 (C 3-5 cycloalkyl), or —CH 2 (C 3-5 heterocycloalkyl); wherein the C 1-6 alkyl, C 2-6 alkoxy, and —CH 2 (C 3-5 cycloalkyl) groups are substituted with 2-5 halogen atoms.

17. The method according to claim 1 , wherein

R 4 is C 1-3 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-5 cycloalkyl.

18. The method according to claim 1 , wherein R 4 is C 1-4 haloalkyl.

19. The method according to claim 1 , wherein

R 4 is methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or cyclopropyl.

20. The method according to claim 1 , wherein the compound is

1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

3-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-chloro-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-chloro-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-cyclopropyl-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-chloro-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1,2-dimethyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1,2-dimethyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-(methoxymethyl)-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(2-methoxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(propan-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(cyclopropylmethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-(methoxymethyl)-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(2-hydroxypropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1,2-dimethyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(cyclopropylmethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-[2-(dimethylamino)ethyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(cyclopropylmethyl)-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-[2-(dimethylamino)ethyl]-2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methoxy-1-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methoxy-1-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-( 2 H 3 )methyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(2H 3 )methyl-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(2-hydroxyethyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

methyl 2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-1-carboxylate;

1-[(2,2-difluorocyclopropyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-[(3,3-difluorocyclobutyl)methyl]-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(2-hydroxyethyl)-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-[2-(dimethylamino)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(prop-2-yn-1-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-{2-methyl-5-oxo-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-1-yl}acetonitrile;

2-[2-methyl-5-oxo-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-1-yl]acetonitrile;

1-(2-hydroxy-2-methylpropyl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-[2-(1-hydroxycyclopropyl)ethyl]-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-1-[(oxetan-3-yl)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-1-(oxetan-3-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1,2-dimethyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidine-5-thione;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-1-(pyridin-2-yl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyrazin-2-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-1-(6-methylpyridin-2-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-1-(1-methyl-1H-pyrazol-4-yl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-3-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-(6-chloropyridin-2-yl)-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(pyridin-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-1-(1H-pyrazol-4-yl)-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-1,2-dimethyl-7-(trifluoromethyl)-1H,5H-imidazo[1,2-a]pyrimidin-5-one;

1-{[(1R)-2,2-difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one; or

1-{[(1S)-2,2-difluorocyclopropyl]methyl}-2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-1H,5H-imidazo[1,2-a]pyrimidin-5-one.

21. The method according to claim 1 , wherein the compound is

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-(methoxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-cyclopropyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-cyclopropyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

7-ethyl-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-methyl-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

6-{1-[(2,2-difluorocyclopropyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

6-{1-[(3,3-difluorocyclobutyl)methyl]-1H-pyrazol-4-yl}-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-methyl-6-{1-[(oxetan-3-yl)methyl]-1H-pyrazol-4-yl}-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-3-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-methyl-6-[4-(2,2,2-trifluoroethoxy)phenyl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

7-ethoxy-2-methyl-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-(methoxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-methoxy-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-(hydroxymethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-(hydroxymethyl)-7-(trifluoromethyl)-6-[1-(3,3,3-trifluoropropyl)-1H-pyrazol-4-yl]-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-(fluoromethyl)-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

2-[(dimethylamino)methyl]-6-[1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazol-4-yl]-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one;

6-(1-{[(1R)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one; or

6-(1-{[(1S)-2,2-difluorocyclopropyl]methyl}-1H-pyrazol-4-yl)-2-methyl-7-(trifluoromethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one.

22. The method according to claim 1 , wherein the compound is

23. The method according to claim 1 , wherein the compound is

24. The method according to claim 1 , wherein the compound is

25. The method according to claim 1 , wherein the compound is

26. The method according to claim 1 , wherein the compound is

27. The method according to claim 1 , wherein the compound is

28. The method according to claim 1 , wherein the compound is

29. The method according to claim 1 , wherein the compound is

30. The method according to claim 1 , wherein the compound is

31. The method according to claim 1 , wherein the compound is

32. The method according to claim 1 , wherein the compound is

33. The method according to claim 1 , wherein the compound is

34. The method according to claim 1 , wherein the compound is

35. The method according to claim 1 , wherein the compound is

36. The method according to claim 1 , wherein the compound is

37. The method according to claim 1 , wherein the compound is

38. A method of treating a metabolic or cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer,

wherein

each instance of R is independently selected from H, halogen, —OH, —CN, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COOH, —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, —NH(COC 1-4 alkyl), —N(C 1-4 alkyl)C(═O)F, C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

wherein the C 1-4 alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

wherein the —CH 2 (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and

wherein R of a first CR group and R of a second CR group, if present, may, together with the atoms to which they are attached, form a C 3-5 carbocycle;

each R″, if present, is independently selected from H, —OH, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and

wherein the —(CH 2 ) m (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

R is O, S, or NH;

R 2 is

 wherein

Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein

iv) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via an N atom; or

v) Ring A is attached via an N atom to the bicyclic core and R 3 is attached via a C atom; or

vi) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via a C atom;

and wherein the

portion of R 2 is further optionally substituted with one or two independently selected substituents R 3′ ;

R is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), —S(O) n CH 2 (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), or phenyl; wherein the C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), and —S(O) n CH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 3′ , if present, is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 4 is C 1-3 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-5 cycloalkyl, or C 3-5 cyclohaloalkyl;

n is 0, 1, or 2; and

m is 1 or 2.

39. A method of treating diabetes, obesity, dyslipidemia, or non-alcoholic steatohepatitis (NASH) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer,

wherein

each instance of R is independently selected from H, halogen, —OH, —CN, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COOH, —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, —NH(COC 1-4 alkyl), —N(C 1-4 alkyl)C(═O)F, C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 deuteroalkoxy, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

wherein the C 1-4 alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

wherein the —CH 2 (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and

wherein R of a first CR group and R of a second CR group, if present, may, together with the atoms to which they are attached, form a C 3-5 carbocycle;

each R″, if present, is independently selected from H, —OH, —CO(C 1-4 alkyl), —S(O) n (C 1-4 alkyl), —COO(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CO(diC 1-4 alkylamino), C 1-4 alkyl, —(CH 2 ) m (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), C 1-4 deuteroalkyl, C 3-5 cycloalkyl, C 3-4 heterocycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1-4 alkyl group is optionally substituted with 1 to 4 F atoms or is optionally substituted with a substituent selected from —OH, —CN, C 1-4 alkoxy, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl); and

wherein the —(CH 2 ) m (C 3-5 cycloalkyl), C 3-4 heterocycloalkyl, 5-membered heteroaryl, or 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1-4 alkoxy, C 1-4 alkyl, —NH 2 , C 1-4 alkylamino, diC 1-4 alkylamino, and —S(O) n (C 1-4 alkyl);

R 1 is O, S, or NH;

R 2 is

 wherein

Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein

vii) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via an N atom; or

viii) Ring A is attached via an N atom to the bicyclic core and R 3 is attached via a C atom; or

ix) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via a C atom;

and wherein the

 portion of R 2 is further optionally substituted with one or two independently selected substituents R 3′ ;

R 3 is C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), —S(O) n CH 2 (C 3-5 cycloalkyl), —CH 2 (C 3-5 heterocycloalkyl), or phenyl; wherein the C 1-6 alkyl, C 3-5 cycloalkyl, C 2-6 alkoxy, C 1-6 alkylamino, diC 1-6 alkylamino, —S(O) n (C 1-6 alkyl), —CH 2 (C 3-5 cycloalkyl), —OCH 2 (C 3-5 cycloalkyl), —NHCH 2 (C 3-5 cycloalkyl), and —S(O) n CH 2 (C 3-5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 3′ , if present, is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;

R 4 is C 1-3 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-5 cycloalkyl, or C 3-5 cyclohaloalkyl;

n is 0, 1, or 2; and

m is 1 or 2.

40. A method of reducing the body weight or the body-mass-index of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the

group together with the N atom and the C atom to which it is attached forms a 5 membered ring, wherein the ring is aromatic, unsaturated, partially saturated, or saturated;

x, y, and z are independently selected from CR, CRR′, N, NR″, O, S(O) n , C═O, C═S, and C═NH;

each R and R′ are independently selected from H, halogen, —OH, —CN, —CO(C 1−4 alkyl), —S(O) n (C 1−4 alkyl), —COOH, —COO(C 1−4 alkyl), —CONH 2 , —CONH(C 1−4 alkyl), —CO(diC 1−4 alkylamino), —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, —NH(COC 1−4 alkyl), —N(C 1−4 alkyl)C(═O)F, C 1−4 alkyl, —(CH 2 ) m (C 3−5 cycloalkyl), —CH 2 (C 3−5 heterocycloalkyl), C 1−4 deuteroalkyl, C 3−5 cycloalkyl, C 3−4 heterocycloalkyl, C 2−4 alkenyl, C 2−4 alkynyl, C 1−4 alkoxy, C 1−4 deuteroalkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1−4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1−4 alkoxy, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl);

wherein the C 1−4 alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C 1−4 alkoxy, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl);

wherein the —CH 2 (C 3−5 cycloalkyl), C 3−4 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1−4 alkoxy, C 1−4 alkyl, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl); and

wherein R of a first CR or CRR′ group and R of a second CR or CRR′ group, if present, together with the atoms to which they are attached, forrn a C 3−5 carbocycle;

each R″ is independently selected from H, —OH, —CO(C 1−4 alkyl), —S(O) n (C 1−4 alkyl), —COO(C 1−4 alkyl), —CONH 2 , —CONH(C 1−4 alkyl), —CO(diC 1−4 alkylamino), C 1−4 alkyl, —(CH 2 ) m (C 3−5 cycloalkyl), —CH 2 (C 3−5 heterocycloalkyl), C 1−4 deuteroalkyl, C 3−5 cycloalkyl, C 3−4 heterocycloalkyl, C 2−4 alkenyl, C 2−4 alkynyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1−4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1−4 alkoxy, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl); and

wherein the —(CH 2 ) m (C 3−5 cycloalkyl), C 3−4 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1−4 alkoxy, C 1−4 alkyl, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl);

R 1 is O, S, or NH;

R 2 is

 wherein

Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein

x) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via an N atom, or

xi) Ring A is attached via an N atom to the bicyclic core and R 3 is attached via a C atom, or

xii) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via a C atom,

and wherein the

 portion of R 2 is further

optionally substituted with one or two independently selected substituents R 3′ ,

R 3 is C 1−6 alkyl, C 2−6 alkoxy, C 1−6 alkylamino, diC 1−6 alkylamino, —S(O) n (C 1−6 alkyl), —CH 2 (C 3−5 cycloalkyl), —OCH 2 (C 3−5 cycloalkyl), —NHCH 2 (C 3−5 cycloalkyl), —S(O) n CH 2 (C 3−5 cycloalkyl), —CH 2 (C 3−5 heterocycloalkyl), or phenyl, wherein the C 1−6 alkyl, C 3−5 cycloalkyl, C 2−6 alkoxy, C 1−6 alkylamino, diC 1−6 alkylamino, —S(O) n (C 1−6 alkyl), —CH 2 (C 3−5 cycloalkyl), —OCH 2 (C 3−5 cycloalkyl), —NHCH 2 (C 3−5 cycloalkyl), and —S(O) n CH 2 (C 3−5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C 1−4 alkyl, C 1−4 haloalkyl, C 1−4 alkoxy, and C 1−4 haloalkoxy,

R 3 is independently halogen, C 1−4 alkyl, C 1−4 haloalkyl, C 1−4 alkoxy, or C 1−4 haloalkoxy,

R 4 is C 1−3 alkyl, C 1−4 haloalkyl, C 1−4 alkoxy, C 1−4 haloalkoxy, C 3−5 cycloalkyl, or C 3−5 cyclohaloalkyl,

n is 0,1, or 2; and

m is 1 or 2; provided that

then R 2 is not

then R 2 is not

then R 2 is not

and

( 4 ) if any of R, R′ or R″ is phenyl then R 3 is not an unsubstituted C 1−6 alkyl and R 3 is not C 1−2 alkoxy.

41. The method of Claim 40 , wherein

42. The method according to claim 40 , wherein the compound is

43. The method according to claim 40 , wherein the compound is

44. The method according to claim 40 , wherein the compound is

45. The method according to claim 40 , wherein the compound is

46. The method according to claim 40 , wherein the compound is

47. The method according to claim 40 , wherein the compound is

48. The method according to claim 40 , wherein the compound is

49. The method according to claim 40 , wherein the compound is

50. The method according to claim 39 , wherein the compound is

51. The method according to claim 39 , wherein the compound is

52. The method according to claim 39 , wherein the compound is

53. The method according to claim 39 , wherein the compound is

54. The method according to claim 39 , wherein the compound is

55. The method according to claim 39 , wherein the compound is

56. The method according to claim 39 , wherein the compound is

57. The method according to claim 39 , wherein the compound is

58. A method of treating a metabolic or cardiovascular disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein the

group together with the N atom and the C atom to which it is attached forms a 5 membered ring, wherein the ring is aromatic, unsaturated, partially saturated, or saturated;

x, y, and z are independently selected from CR, CRR′, N, NR″, O, S(O) n , C═O, C═S, and C═NH;

each R and R′ are independently selected from H, halogen, —OH, —CN, —CO(C 1−4 alkyl), —S(O) n (C 1−4 alkyl), —COOH, —COO(C 1−4 alkyl), —CONH 2 , —CONH(C 1−4 alkyl), —CO(diC 1−4 alkylamino), —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, —NH(COC 1−4 alkyl), —N(C 1−4 alkyl)C(═O)F, C 1−4 alkyl, —(CH 2 ) m (C 3−5 cycloalkyl), —CH 2 (C 3−5 heterocycloalkyl), C 1−4 deuteroalkyl, C 3−5 cycloalkyl, C 3−4 heterocycloalkyl, C 2−4 alkenyl, C 2−4 alkynyl, C 1−4 alkoxy, C 1−4 deuteroalkoxy, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1−4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1−4 alkoxy, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl);

wherein the C 1−4 alkoxy group is optionally substituted with 1 to 4 independently selected halogens or optionally substituted with a substituent selected from —OH, —CN, C 1−4 alkoxy, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl);

wherein the —CH 2 (C 3−5 cycloalkyl), C 3−4 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1−4 alkoxy, C 1−4 alkyl, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl); and

wherein R of a first CR or CRR′ group and R of a second CR or CRR′ group, if present, together with the atoms to which they are attached, forrn a C 3−5 carbocycle;

each R″ is independently selected from H, —OH, —CO(C 1−4 alkyl), —S(O) n (C 1−4 alkyl), —COO(C 1−4 alkyl), —CONH 2 , —CONH(C 1−4 alkyl), —CO(diC 1−4 alkylamino), C 1−4 alkyl, —(CH 2 ) m (C 3−5 cycloalkyl), —CH 2 (C 3−5 heterocycloalkyl), C 1−4 deuteroalkyl, C 3−5 cycloalkyl, C 3−4 heterocycloalkyl, C 2−4 alkenyl, C 2−4 alkynyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl;

wherein the C 1−4 alkyl group is optionally substituted with 1 to 4 F or optionally substituted with a substituent selected from —OH, —CN, C 1−4 alkoxy, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl); and

wherein the —(CH 2 ) m (C 3−5 cycloalkyl), C 3−4 heterocycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl groups are optionally substituted with 1 to 4 substituents independently selected from halogen, —OH, —CN, C 1−4 alkoxy, C 1−4 alkyl, —NH 2 , C 1−4 alkylamino, diC 1−4 alkylamino, and —S(O) n (C 1−4 alkyl);

R 1 is O, S, or NH;

R 2 is

 wherein

Ring A is a 5-membered heteroaryl containing one heteroatom selected from N, S, and O and optionally one or two further N atoms with the remaining ring atoms of the 5-membered heteroaryl being carbon, wherein

xiii) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via an N atom, or

xiv) Ring A is attached via an N atom to the bicyclic core and R 3 is attached via a C atom, or

xv) Ring A is attached via a C atom to the bicyclic core and R 3 is attached via a C atom,

and wherein the

 portion of R 2 is further

optionally substituted with one or two independently selected substituents R 3′ ,

R 3 is C 1−6 alkyl, C 2−6 alkoxy, C 1−6 alkylamino, diC 1−6 alkylamino, —S(O) n (C 1−6 alkyl), —CH 2 (C 3−5 cycloalkyl), —OCH 2 (C 3−5 cycloalkyl), —NHCH 2 (C 3−5 cycloalkyl), —S(O) n CH 2 (C 3−5 cycloalkyl), —CH 2 (C 3−5 heterocycloalkyl), or phenyl, wherein the C 1−6 alkyl, C 3−5 cycloalkyl, C 2−6 alkoxy, C 1−6 alkylamino, diC 1−6 alkylamino, —S(O) n (C 1−6 alkyl), —CH 2 (C 3−5 cycloalkyl), —OCH 2 (C 3−5 cycloalkyl), —NHCH 2 (C 3−5 cycloalkyl), and —S(O) n CH 2 (C 3−5 cycloalkyl) groups are optionally substituted with 1-9 halogen atoms and are optionally substituted with —CN and wherein the phenyl is optionally substituted with 1-3 substituents selected from halogen, C 1−4 alkyl, C 1−4 haloalkyl, C 1−4 alkoxy, and C 1−4 haloalkoxy,

R 3 is independently halogen, C 1−4 alkyl, C 1−4 haloalkyl, C 1−4 alkoxy, or C 1−4 haloalkoxy,

R 4 is C 1−3 alkyl, C 1−4 haloalkyl, C 1−4 alkoxy, C 1−4 haloalkoxy, C 3−5 cycloalkyl, or C 3−5 cyclohaloalkyl,

n is 0,1, or 2; and

m is 1 or 2; provided that

(5) if

 then R 2 is not

(6) if

 then R 2 is not

(7) if

 then R 2 is not

 and

(8) if any of R, R′ or R″ is phenyl then R 3 is not an unsubstituted C 1−6 alkyl and R 3 is not C 1−2 alkoxy.

59. The method of claim 58 , wherein

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2023
From: ALLEN, JENNIFER R.; MINATTI, ANA E; BOURBEAU, MATTHEW P
To: AMGEN INC.
Reel/Frame 062550/0308 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2023
From: APTUIT (VERONA) SRL, AN EVOTEC COMPANY
To: AMGEN INC.
Reel/Frame 062551/0572 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2023
From: BELTRANI, MICHELA; DAMYANOVA, TEODORA P; VINCETTI, PAOLO; LINGARD, IAIN
To: APTUIT (VERONA) SRL, AN EVOTEC COMPANY
Reel/Frame 062551/0592 →
Continuity (3)
Division 17103389 · Nov 24, 2020
Provisional Application 62939821 · Nov 25, 2019
Related Publication 20230159560A1 · May 25, 2023
References Cited (98)
US 4567263A · Eicken · 1986 [cited by applicant]
US 6096753A · Spohr · 2000 [cited by applicant]
US 8211828B2 · Dietz · 2012 [cited by applicant]
US 8952012B2 · Chicco · 2015 [cited by applicant]
US 9108984B2 · Combs · 2015 [cited by applicant]
US 10065972B2 · Okuyama · 2018 [cited by applicant]
US 20030073704A1 · Spohr · 2003 [cited by applicant]
US 20030216411A1 · Zhu et al. · 2003 [cited by applicant]
US 20050222171A1 · Bold · 2005 [cited by applicant]
US 20070082900A1 · Guzi · 2007 [cited by applicant]
US 20080139570A1 · Chisholm et al. · 2008 [cited by applicant]
US 20080200480A1 · Dietz · 2008 [cited by applicant]
US 20080214395A1 · Dietz · 2008 [cited by applicant]
US 20080312078A1 · Dietz · 2008 [cited by applicant]
US 20090163545A1 · Goldfarb · 2009 [cited by applicant]
US 20090253704A1 · Koltun · 2009 [cited by applicant]
US 20090286811A1 · Lingham · 2009 [cited by applicant]
US 20100029636A1 · Buehlmayer · 2010 [cited by applicant]
US 20100099561A1 · Selby et al. · 2010 [cited by applicant]
US 20100105557A1 · Habicher · 2010 [cited by applicant]
US 20100150913A1 · Blue · 2010 [cited by applicant]
US 20100190747A1 · Suzuki · 2010 [cited by applicant]
US 20110015212A1 · Li · 2011 [cited by applicant]
US 20140066448A1 · Combs · 2014 [cited by applicant]
US 20140275092A1 · Albrecht · 2014 [cited by applicant]
US 20150065522A1 · Albrecht · 2015 [cited by applicant]
US 20160362425A1 · Li · 2016 [cited by applicant]
US 20160376289A1 · Okuyama · 2016 [cited by applicant]
US 20180079753A1 · Konteatis · 2018 [cited by applicant]
US 20210221824A1 · Allen · 2021 [cited by applicant]
CN 106749271B · 2019 [cited by applicant]
EP 242690A · 1987 [cited by applicant]
JP 2004107228A · 2004 [cited by applicant]
JP 2017081908A · 2017 [cited by applicant]
JP 2017091808A · 2017 [cited by applicant]
WO 9824780A · 1998 [cited by applicant]
WO 2001029044A1 · 2001 [cited by applicant]
WO 2003106435A1 · 2003 [cited by applicant]
WO 2005070431A1 · 2005 [cited by applicant]
WO 2006067401A1 · 2006 [cited by applicant]
WO 2007002701A2 · 2007 [cited by applicant]
WO 2008089307A2 · 2008 [cited by applicant]
WO 2008089310A2 · 2008 [cited by applicant]
WO 2008092836A2 · 2008 [cited by applicant]
WO 2009130560A1 · 2009 [cited by applicant]
WO 2010087467A1 · 2010 [cited by applicant]
WO 2011114148A1 · 2011 [cited by applicant]
WO 2012011592A1 · 2012 [cited by applicant]
WO 2015064714A1 · 2015 [cited by applicant]
WO 2015135094A1 · 2015 [cited by applicant]
WO 2017112678A1 · 2017 [cited by applicant]
WO 2018045071A1 · 2018 [cited by applicant]
WO WO2018039972A1 · 2018 [cited by applicant]
WO 2018213365A1 · 2018 [cited by applicant]
WO 2018229683A1 · 2018 [cited by applicant]
WO 2019055750A1 · 2019 [cited by applicant]
WO 2021108408A1 · 2021 [cited by applicant]
Alnajjar, Abdulaziz et al., Synthesis of New [1,2,4]Triazolo[1,5-a]pyrimidine Derivatives: Reactivity of 3-Amino [1,2,4]triazole towards Enaminonitriles and Enaminones, Journal of Heterocyclic Chemistry, 2018, 55 (7) 18… [cited by applicant]
Aretz, et al., Allosteric Inhibition of a Mammalian Lectin, J. Am. Chem. Soc., 2018, 140, 14915-14925. [cited by applicant]
Badawey, E. Synthesis of Some New Imidazo[1,2-a]pyrimidin-5_1H-ones as Potential Antineoplastic Agents, J. Heterocyclic Chem. 32:1003-1006 (1995). [cited by applicant]
Baugh, SD. et al.,“Design, synthesis, and in vivo activity of novel inhibitors of delta-5 desaturase for the treatment of metabolic syndrome”, Bioorg. Med. Chem. Lett. 25(18):3836-3839 (2015). [cited by applicant]
Bellec, C. et al. Deaminative electrochemical reduction of pyrazolo[1,5-a]pyrimidine-7-amines Canadian journal of chemistry, 1981, 59(19), 2826-2832. [cited by applicant]
Bueno, J. et al. The molecular and supramolecular structures of the isomeric compounds 5,7-dimethoxyimidazo[1,2-c]pyrimidine and 7-methoxy-1-methylimidazo[1,2-a]pyrimidin-5(1H)-one, Crystal Structure Communications, 200… [cited by applicant]
Chopra, M. et al., “A global response to a global problem: the epidemic of overnutrition”, Bull. World Health Organ. 80:952-958 (2002). [cited by applicant]
Di Marzo V and Matias I, “Endocannabinoid control of food intake and energy balance”, Nat. Neurosci. 8(5):585-589 (2005). [cited by applicant]
Djerrari, et al., “L'acide déhydracétique, précurseur de nouvelles pyridopyrimidines”, thiazolopyrimidines et pyridones; vol. 5, No. 3., p. 177-183, 2002. [cited by applicant]
Dupuis, J., New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk, Nat. Genet. 42(2):105-116 (2010). [cited by applicant]
Eliel, Stereochemistry of Carbon 5 Compounds (McGraw-Hill, NY, 1962). [cited by applicant]
Frey, R. 7-Aminopyrazolo[1,5-a]pyrimidines as Potent Multitargeted Receptor Tyrosine Kinase Inhibitors, J. Med. Chem. 2008, 51, 13, 3777-3787. [cited by applicant]
Fumagalli, M. et al., Greenlandic Inuit show genetic signatures of diet and climate adaptation, Science 349(6254):1343-1347 (2015). [cited by applicant]
Gommerman, N.,et al., New pyrazolo[1,5a]pyrimidines as orally active inhibitors of Lck Bioorganic, Medicinal Chemistry Letters, 2010, 20(12), 3628-3631. [cited by applicant]
Haidar, Y.M. and Cosman B.C., Obesity epidemiology, Clin. Colon Rectal Surg. 24:205-210 (2011). [cited by applicant]
Harizi, H. et al., Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology, Trends Mol. Med. 14(10):461-469 (2008). [cited by applicant]
International Search Report for PCT/2020/062020 dated Mar. 4, 2021. [cited by applicant]
Jacques et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981). [cited by applicant]
Jadhav, Sunil B., et al., Antitubercular Activity and Synergistic Study of Novel Pyrazole Derivatives, Journal of Heterocyclic Chemistry, 2018, 55(7), 1634-1644. [cited by applicant]
Jafari, B. et al. Synthesis and anticancer activity of novel water soluble benzimidazole carbamates, European Journal of Medicinal Chemistry, 2018, 144, 372-385. [cited by applicant]
Khalymbadzha, Igor, et al., Synthesis of acyclic nucleoside analogs based on 1,2,4-triazolo[1,5-a]pyrimidin-7-ones by one-step Vorbrueggen glycosylation, Tetrahedron, 2014, 70(6), 1298-1305. [cited by applicant]
Kibbe, Arthur H., Handbook of Pharmaceutical Excipients (3rd Ed.), American Pharmaceutical Association, 20 Washington, 2000. [cited by applicant]
Kroger J. and Schulze M.B., Recent insights Into the relation of delta5 desaturase and delta6 desaturase activity to the development of type 2 diabetes, Curr. Opin. Lipidol. 23(1):4-10 (2012). [cited by applicant]
Liberman et al., Eds., Pharmaceutical Dosage Forms (vol. 1-3), Marcel Dekker, New York, NY, 1992. [cited by applicant]
Mendis S. et al., World Health Organization (WHO) and International Society of Hypertension (ISH) risk prediction charts: assessment of cardiovascular risk for prevention and control of cardiovascular disease in low and… [cited by applicant]
Merino, D.M. et al., Genetic variation in lipid desaturases and its impact on the development of human disease, Lipids Health Dis. 9:63 (2010). [cited by applicant]
Merino, D.M. et al., Polymorphisms in FADS1 and FADS2 alter desaturase activity in young Caucasian and Asian adults, Mol. Genet. Metab. 103(2):171-178 (2011). [cited by applicant]
Miyahisa, I. et al., T-3364366 Targets the Desaturase Domain of Delta-5 Desaturase with Nanomolar Potency and a Multihour Residence Time, ACS Med. Chem. Lett. 7(9):868-872 (2016). [cited by applicant]
Monteiro, C.A. et al., Socioeconomic status and obesity in adult populations of developing countries: a review. Bull. World Health Organ. 82:940-946 (2004). [cited by applicant]
Nagender, P., et al., Synthesis of Novel Imidazo[1,2-a]pyrimidin-5(1H)-one Derivatives by Intramolecular Cycloisomerisation of 2-Amino-3-N-alkyl Pyrimidine-4_3H-one in Presence of Aqueous Base, Chemistry Letters, 2013, … [cited by applicant]
Obukowicz, M.G. et al., Novel, selective delta6 or delta5 fatty acid desaturase inhibitors as antiinflammatory agents in mice, J. Pharmacol. Exp. Ther. 287(1):157-166 (1998). [cited by applicant]
Powell, D.R. et al., Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque, Diabetes Metab. Syndr. Obes. 9:185-199 (2016). [cited by applicant]
Remington: The Science and Practice of Pharmacy, vol. I and vol. II, twenty-second edition, edited by Loyd V. Allen Jr., Philadelphia, PA, Pharmaceutical Press, 2012. [cited by applicant]
Shukurov, S., et al., Interaction of 2-bromo-7-methyl-5-oxo-5H-1,3,4-thiadiazolo[3,2-α]pyrimidine with methylene-active compounds and acid hydrolysis of its products, Russian Chemical Bulletin, 1993, 42, 1874-1878. [cited by applicant]
Tosi, F. et al., Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease, Adv. Exp. Med. Biol. 824:61-81 (2014). [cited by applicant]
Tovey, Pharmaceutical Formulation: The Science and Technology of Dosage Forms (Drug Discovery), first edition, Royal Society of Chemistry, 2018. [cited by applicant]
Wilen, et al., Strategies in optical resolutions, Tetrahedron 33:2725-2769, 1977. [cited by applicant]
Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). [cited by applicant]
Willer, C.J. et al., Discovery and refinement of loci associated with lipid levels, Nat. Genet. 45(11):1274-1283 (2013). [cited by applicant]
Yashiro, H. et al., A Novel Selective Inhibitor of Delta-5 Desaturase Lowers Insulin Resistance and Reduces Body Weight in Diet-Induced Obese C57BL/6J Mice, PLoS One 11(11):e0166198 (2016). [cited by applicant]
CAS Resistry, Registry No. 1339559-73-7, STN Nov. 2, 2011. [cited by applicant]