Substituted 3-azabicyclo[3.1.0]hexanes as ketohexokinase inhibitors

1. A compound of Formula I

or a pharmaceutically salt thereof, wherein

Y is N or C—CN;

Z is N or CH;

X is N or CR 3 ;

provided that at least one of Y, Z, or X is N;

R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cycloalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent; or

N(C 1-3 alkyl) 2 , NH(C 1-3 alkyl), or NH(C 3-4 cycloalkyl), wherein each C 1-3 alkyl is substituted with 0 to 1 OH;

R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L -(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , -L-(CH 2 ) n SO 2 NHCONH 2 , or -L-(CH 2 ) n tetrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

R N is H or —C 1-3 alkyl;

R s is H or —C 1-3 alkyl;

L is CH 2 , CHF, or CF 2 ;

R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;

R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and

R 4 is cyclopropyl, cyclobutyl, or —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

Y is N or C—CN;

Z is N or CH;

X is CR 3 ;

provided that at least one of Y or Z is N;

R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cycloalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent; or

N(C 1-3 alkyl) 2 , NH(C 1-3 alkyl), or NH(C 3-4 cycloalkyl), wherein each C 1-3 alkyl is substituted with 0 to 1 OH;

R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L -(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , -L-(CH 2 ) n SO 2 NHCONH 2 , or -L-(CH 2 ) n tetrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

R N is H or _ 13 C 1-3 alkyl;

R s is H or —C 1-3 alkyl;

L is CH 2 , CHF, or CF 2 ;

R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;

R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and

R 4 is —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

3. The compound of claim 1 , or a pharmaceutically salt thereof, wherein Y is C—CN;

Z is N;

X is CR 3 ;

R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cycloalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent;

R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L -(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , or -L-(CH 2 ) n tetrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

R N is H or —C 1-3 alkyl;

R s is H or —C 1-3 alkyl;

L is CH 2 , CHF, or CF 2 ;

R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;

R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and

R 4 is —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein

Y is N;

Z is N;

X is CR 3 ;

R 1 is C 3-7 cycloalkyl or a 4- to 7-membered heterocyclic moiety, wherein the heterocyclic moiety contains 1 to 2 atoms independently selected from nitrogen, oxygen and sulfur, and wherein the cyclalkyl or heterocyclic moiety has 0 to 3 substitutuents independently selected from —C 1-3 alkyl, and —OH, provided that there is no more than one —OH substituent;

R 2 is -(L) m -CON(R N ) 2 , -(L) m -SO 2 R s , -L-(CH 2 ) n SO 2 R s , -L-(CH 2 ) n CO 2 H, -L-(CH 2 ) n C(O)R c , -L-(CH 2 ) n CONHSO 2 R s , -L-(CH 2 ) n SO 2 NHCOR s , or -L-(CH 2 ) n tetrazol-5-yl;

m is 0 or 1;

n is 0 or 1;

R N is H or —C 1-3 alkyl;

R s is H or —C 1-3 alkyl;

L is CH 2 , CHF, or CF 2 ;

R c is —C 1-4 alkyloxy, —C 1-4 alkyloxycarbonyloxy-C 1-4 alkyloxy, or —C 1-4 alkylcarbonyloxy-C 1-4 alkyloxy;

R 3 is H, halogen, —CN, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl substituted with 1 to 3 halogen atoms, or —C 3-4 cycloalkyl; and

R 4 is —C 1-3 alkyl substituted with 0 to 5 halogen atoms as valency allows.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R s is H or —CH 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , or —CH 2 CO 2 CH 2 CH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H, —Cl, —CH 3 , —CH 2 CH 3 , —O—CH 3 , cyclopropyl, or CN.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is —CF 3 , —CHF 2 , or —CF 2 CH 3 .

9. The compound of claim 1 , or a pharmaceutically salt thereof, wherein R 1 is the 4- to 7-membered heterocyclic moiety selected from azetidin-1-yl, pyrrolidin-1-yl, and piperidin-1-yl having 0 to 3 substitutuents independently selected from —CH 3 and —OH, provided that there is no more than one —OH substituent.

10. The compound of claim 1 , or a pharmaceutically salt thereof, wherein R 1 is azetidin-1-yl, having 1 to 2 —CH 3 substituents and having 0 to 1 —OH substituent, and wherein Y is C—CN and Z is N, or Y and Z are each N.

11. The compound of claim 1 , or a pharmaceutically salt thereof, wherein R 1 is cyclobutyl having 0 to 3 substitutuents independently selected from —CH 3 and —OH, provided that there is no more than one —OH substituent.

12. The compound of claim 1 , or pharmacuetically acceptable salt thereof, wherein the compound is selected from [(1R,5S,6R)-3-{5-cyano-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(1R,5S,6R)-3-{3-chloro-5-cyano-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

Methyl [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetate;

[(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(1R,5S,6R)-3-{5-cyclopropyl-2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(1R,5S,6R)-3-{5-ethyl-2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(1R,5S,6R)-3-{3-chloro-2-(1,1-difluoroethyl)-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]pyridin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid; and

[(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-5-methoxy-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

13. The compound of claim 1 , or pharmacuetically acceptable salt thereof, wherein the compound is selected from

14. The compound of claim 1 , or pharmacuetically acceptable salt thereof, wherein the compound is selected from

(2S,3R)-2,3-dimethyl-1[4-{(1R,5S,6S)-6-[(methylsulfonyl)methyl]-3-azabicyclo[3.1.0]hex-3-yl}-6-(trifluoromethyl)pyrimidin-2-yl]azetidin-3-ol;

2-[(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]-N-(methylsulfonyl)acetamide; and

(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-6-(1H -tetrazol-5-ylmethyl)-3-azabicyclo[3.1.0]hexane.

15. The compound of claim 1 , or pharmacuetically acceptable salt thereof, wherein the compound is selected from

[(1R,5S,6R)-3-{5-cyano-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(R1R,5S,6R)-3-{3-chloro-5-cyano-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-4-(trifluoromethyl)pyridin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(R1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(R1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid;

[(R1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-5-methyl-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid; and

[(R1R,5S,6R)-3-{5-cyano-4-(1,1-difluoroethyl)-3-fluoro-6-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]pyridin-2-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

16. The compound of claim 13 , or pharmacuetically acceptable salt thereof, wherein the compound is selected from

17. A compound, which is [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid, or pharmaceutically acceptable salt thereof.

18. The compound of claim 16 , wherein the compound is [(1R,5S,6R)-3-{2-[(2S) -2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

19. The compound of claim 16 , wherein the compound is a crystalline form of [(1R,5S,6R)-3-{2-[(2S)-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

20. The compound of claim 19 , wherein the crystalline form is characterized substantially by the following principal powder x-ray diffraction pattern peaks expressed in terms of 2θ as measured with a copper radiation chosen from 9.0, 10.4, 15.0, and 21.4+/−0.2°.

21. A compound, which is [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid, or pharmaceutically acceptable salt thereof.

22. The compound of claim 21 , wherein the compound is [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

23. The compound of claim 21 , wherein the compound is a sodium salt form of [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

24. The compound of claim 21 , wherein the compound is a crystalline sodium salt form of [(1R,5S,6R)-3-{2-[(2S,3R)-3-hydroxy-2-methylazetidin-1-yl]-6-(trifluoromethyl)pyrimidin-4-yl}-3-azabicyclo[3.1.0]hex-6-yl]acetic acid.

25. The compound of claim 24 , wherein the crystalline form is characterized substantially by the following principal powder x-ray diffraction pattern peaks expressed in terms of 2θ as measured with a copper radiation chosen from 5.9, 11.5, 11.8, 13.3, and 21.5+/−0.2°.

26. A pharmaceutical composition comprising the compound of Formula I of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.