Methods for antagonizing a melanocortin 4 receptor

1. A method for treating an MC4R-related condition, disease, or disorder in a human, where the method comprises administering to the human in need thereof a compound of Formula I or a pharmaceutically acceptable salt thereof, and wherein the condition, disease, or disorder is selected from cachexia; anorexia or anorexia nervosa; weight loss; failure to thrive; sarcopenia; muscle wasting; muscle weakness; frailty; and malnutrition;

wherein the compound of Formula I is:

wherein:

R 1 is H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or R 1a , wherein each of the C 3-6 cycloalkyl and 4- to 7-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C 1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected R B , wherein each R B is halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-4 cycloalkyl, or R B1 ; or two adjacent R B together with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R 1a is 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R A , wherein each R A is halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-4 cycloalkyl, —N(C 1-4 alkyl) 2 , R A1 , or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein each of the C 1-4 alkyl, C 3-4 cycloalkyl, and (C 3-4 cycloalkyl)-C 1-4 alkyl-is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or two adjacent R A together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6-membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R A1 is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

R B1 is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

X 1 is C (R X ) 2 , wherein each R X is independently H or C 1-4 alkyl;

each of R 2 and R 3 is independently H, halogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, (C 1-4 alkoxy)-C 1-4 alkyl-, C 3-4 cycloalkyl, or (C 3-4 cycloalkyl)-C 1-4 alkyl, wherein each of C 3-4 cycloalkyl and (C 3-4 cycloalkyl)-C 1-4 alkyl-is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

or R 2 and R 3 together with the carbon atom to which they are attached form C 3-6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;

each of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 is independently CR 4 or N, provided that no more than 3 of Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are N; and

each R 4 is independently H, halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, —N(C 1-2 alkyl) 2 , C 3-4 cycloalkyl, or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein each of the C 1-4 alkyl, C 3-4 cycloalkyl, and (C 3-4 cycloalkyl)-C 1-4 alkyl-is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

2. The method of claim 1 , wherein the administering comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. The method of claim 1 , wherein the condition, disease, or disorder is cachexia; wherein the cachexia is associated with a chronic illness or with a treatment of the chronic illness.

4. The method of claim 3 , wherein the chronic illness is cancer, acquired immunodeficiency syndrome (AIDS), heart failure, or chronic kidney disease (CKD).

5. The method of claim 1 , wherein the condition, disease, or disorder is weight loss, failure to thrive, sarcopenia, muscle wasting, frailty, or malnutrition.

6. The method of claim 1 , wherein the condition, disease, or disorder is malnutrition.

7. The method of claim 1 , wherein the compound is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein:

R 1 is R 1a ; and

R 1a is 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R A , wherein each R A is halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-4 cycloalkyl, or (C 3-4 cycloalkyl)-C 1-4 alkyl-, wherein each of the C 1-4 alkyl, C 3-4 cycloalkyl, and (C 3-4 cycloalkyl)-C 1-4 alkyl-is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or two adjacent R A together with the two ring-atoms of the 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, —OH, —CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy.

9. The method of claim 1 , wherein X 1 is CH 2 , and wherein each of R 2 and R 3 is independently H, F, or C 1-4 alkyl.

10. The method of claim 1 , wherein Y 3 is N, and each of Y 1 , Y 2 , Y 4 , and Y 5 is independently CR 4 .

11. The method of claim 1 , wherein each R 4 is independently H, halogen, or C 1-2 alkoxy.

12. The method of claim 1 , wherein the compound is selected from:

(2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one, DIAST-1;

2-(6-methoxy-2-methylpyrimidin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one, DIAST-1;

2-[6-(difluoromethoxy) pyridin-3-yl]-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one, DIAST-2;

1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]-2-[4-(trifluoromethyl)phenyl]propan-1-one, DIAST-1;

1-(4,7-dimethyl-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl)-2-(4-fluorophenyl) ethan-1-one, DIAST-1;

(2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(2-methyl-2H-tetrazol-5-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one;

(2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one;

(2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one;

(2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[7-methyl-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one, DIAST-1; and

(2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-[(4,6- 2 H 2 ) pyrimidin-2-yl]-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl}propan-1-one,

or the pharmaceutically acceptable salt thereof.

13. The method of claim 1 , wherein the compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro [1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one, or the pharmaceutically acceptable salt thereof.

14. The method of claim 13 , wherein the compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro [1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one.

15. The method of claim 13 , wherein the administering comprises administering a pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. The method of claim 13 , wherein the condition, disease, or disorder is cachexia; wherein the cachexia is associated with a chronic illness or with a treatment of the chronic illness.

17. The method of claim 16 , wherein the chronic illness is cancer, acquired immunodeficiency syndrome (AIDS), heart failure, or chronic kidney disease (CKD).

18. The method of claim 13 , wherein the condition, disease, or disorder is weight loss, failure to thrive, sarcopenia, muscle wasting, frailty, or malnutrition.

19. The method of claim 13 , wherein the condition, disease, or disorder is malnutrition.

20. A method for antagonizing a melanocortin-4 receptor (MC4R) comprising contacting the MC4R with (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-[(2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro[1,8-naphthyridine-2,3′-pyrrolidin]-1′-yl]propan-1-one, or a pharmaceutically acceptable salt thereof.