2′-chloro aminopyrimidinone and pyrimidine dione nucleosides

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:

R 1 is selected from NH and N;

the dashed line (- - - -), in conjunction with the solid line to which it is parallel, represents an optional double bond;

R 2 is selected from oxo or NH 2 , with the proviso that, when R 2 is oxo, R 1 and the bond represented by the dashed line (- - - -), in conjunction with the solid line to which it is parallel, is a single bond; and with the proviso that, when R 2 is NH 2 , R 1 is N and the bond represented by the dashed line (- - - -), in conjunction with the solid line to which it is parallel, is a double bond;

R 3 is selected from the group of H, F, CH 2 F, CHF 2 , and CF 3 ;

R 5 is selected from the group of CN; unsubstituted C 1 -C 4 alkyl; C 1 -C 4 alkyl substituted with 1, 2, or 3 halogens; C 1 -C 4 alkyl substituted with 1 substituent selected from —S—CH 3 and —O—CH 3 ; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; unsubstituted C 3 -C 6 cycloalkyl; and C 3 -C 6 cycloalkyl substituted by 1, 2, or 3 substituents selected from F and CH 3 ;

R 4 ′ is selected from the group of H, —C(═O)R 6 , —C(═O)OR 6 , and —C(═O)NR 6 R 7 ;

R 4 is selected from the group of H, —C(═O)R 6 , —C(═O)OR 6 , and —C(═O)NR 6 R 7 ; or

a) R 4 is a group of the formula:

wherein:

each Y is O, S, NR, + N(O)(R), N(OR), + N(O)(OR), or N—NR 2 ; and

W 1 and W 2 , when taken together, are —Y 3 (C(R y ) 2 ) 3 Y 3 —;

or one of W 1 or W 2 together with R 4 ′ is —Y 3 — and the other of W 1 or W 2 is Formula Ia;

or W 1 and W 2 are each, independently, a group of the Formula Ia:

wherein:

each Y 1 is, independently, O, S, NR, + N(O)(R), N(OR), + (N)(O)(OR), or N—NR 2 ;

each Y 2 is independently a bond, O, CR 2 , —O—CR 2 —, NR, + N(O)(R), N(OR), + N(O)(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ;

each Y 3 is a single bond;

M1 is 0, 1, 2, or 3;

each R x is independently R y or the formula:

wherein:

each M2a, M2b, and M2c is independently 0 or 1;

M2d is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R y is independently H, F, Cl, Br, I, OH, R, —C(═Y 1 )R, —C(═Y 1 )OR, —C(═Y 1 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC(═Y 1 )R, —OC(═Y 1 )OR, —OC(═Y 1 )(N(R) 2 ), —SC(═Y 1 )R, —SC(═Y 1 )OR, —SC(═Y 1 )(N(R) 2 ), —N(R)C(═Y 1 )R, —N(R)C(═Y 1 )OR, —N(R)C(═Y 1 )N(R) 2 , —SO 2 NR 2 , —CN, —N 3 , —NO 2 , —OR, or W 3 ;

or when taken together, two R y on the same carbon atom form a carbocyclic ring having 3, 4, 5, 6, or 7 carbon ring atoms;

or when taken together, two R y on the same carbon atom form along with the carbon atom a heterocycle having 3, 4, 5, 6, or 7 ring atoms wherein one ring atom is selected from O or N and all other ring atoms are carbon;

each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 10 aryl, C 6 -C 10 substituted aryl, a 3- to 10-membered heterocycle, a substituted 3- to 10-membered heterocycle, a 5- to 12-membered heteroaryl, a substituted 5- to 12-membered heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl; and

W 3 is W 4 or W 5 ;

W 4 is R, —C(Y 1 )R y , —C(Y 1 )W 5 , —SO 2 R y , or —SO 2 W 5 ;

W 5 is selected from phenyl, naphthyl, a C 3 -C 8 carbocycle, or a 3- to 10-membered heterocycle, wherein W 5 is independently substituted with 0, 1, 2, 3, 4, 5, or 6 R y groups;

each R 6 and R 7 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, C 6 -C 10 aryl, C 6 -C 10 substituted aryl, 5- to 10-membered heteroaryl, substituted 5- to 10-membered heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or aryl(C 1 -C 8 )alkyl;

or R 6 and R 7 taken together with a nitrogen to which they are both attached form a 3- to 7-membered heterocycle wherein any one ring carbon atom of said heterocycle can optionally be replaced with —O—, —S—or —NR a —;

and wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl of each R 6 or R 7 is, independently, optionally substituted with one, two, three, or four substituents selected from halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one, two, or three of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —; or

b) R 4 is a group selected from:

wherein:

R 8 is selected from phenyl, 1-naphthyl, 2-naphthyl,

R 9 is selected from H and CH 3 ;

R 10 is selected from H or C 1 -C 6 alkyl;

R 10 ′ is selected from H or C 1 -C 6 alkyl;

or R 10 and R 10 ′, together with the carbon atom to which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle wherein all ring atoms of the spirocycle are carbon;

or R l0 and R 10 ′, together with the carbon atom to which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle wherein 1 or 2 of the ring atoms of the spirocycle are selected from the group of O, S, and N, and all other ring atoms of the spirocycle are carbon;

R 11 is selected from H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, —CH 2 —C 3 -C 6 cycloalkyl, —CH 2 CH 2 —S—C(O)—C 3 -C 6 alkyl,

R 7 ′ is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 —C 3 -C 6 cycloalkyl, and CF 3 ; or

c) R 4 and R 4 ′ combine to form the structure selected from:

2. A compound according to claim 1 of Formula (II), or a pharmaceutically acceptable salt thereof:

wherein R 3 , R 4 , R 4 ′, and R 5 are as defined in claim 1 .

3. A compound according to claim 1 of Formula (III), or a pharmaceutically acceptable salt thereof:

wherein R 3 , R 4 , R 4 ′, and R 5 are as defined in claim 1 .

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 ′ is hydrogen.

5. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group of CN; unsubstituted C 1 -C 3 alkyl; C 1 -C 3 alkyl substituted with 1, 2, or 3 halogens selected from F and Cl; C 1 -C 3 alkyl substituted with 1 substituent selected from —S—CH 3 and —O—CH 3 ; C 2 -C 3 alkenyl; C 2 -C 3 alkynyl; unsubstituted C 3 -C 5 cycloalkyl; and C 3 -C 5 cycloalkyl substituted by 1, 2, or 3 substituents selected from F and CH 3 .

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

7. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F.

8. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are both hydrogen.

9. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 , R 4 , and R 4 ′ are each hydrogen.

10. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is F and R 4 and R 4 ′ are each hydrogen.

11. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group of H and F; R 5 is selected from the group of CN, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, CH 2 F, CHF 2 , CH 2 Cl, CH 2 SMe, —CH 2 OMe, and cyclopropyl; R 4 is H; and R 4 ′ is hydrogen.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

wherein:

n′ is selected from 1, 2, 3, and 4;

R 7 is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 —C 3 -C 6 cycloalkyl, —O—CH 2 —C 3 -C 6 cycloalkyl, and CF 3 ;

R 7 ′ is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 —C 3 -C 6 cycloalkyl, and CF 3 ;

R 8 is selected from phenyl, 1-naphthyl, 2-naphthyl,

R 9 is selected from H and CH 3 ;

R 10 is selected from H or C 1 -C 6 alkyl;

R 11 is selected from H, C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.

13. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

wherein:

R 7 is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, and —CH 2 —C 3 -C 6 cycloalkyl;

R 7 ′ is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, —O-benzyl, —CH 2 —C 3 -C 6 cycloalkyl, and CF 3 ;

R 10 is selected from H or C 1 -C 6 alkyl;

R 10 ′ is selected from H or C 1 -C 6 alkyl;

or R 10 and R 10 ′, together with the carbon atom to which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle wherein all ring atoms of the spirocycle are carbon;

or R 10 and R 10 ′, together with the carbon atom to which they are bound, form a 3-, 4-, 5-, or 6-membered spirocycle wherein 1 or 2 of the ring atoms of the spirocycle are selected from the group of O, S, and N, and all other ring atoms of the spirocycle are carbon; and

R 11 is selected from C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.

14. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is selected from the group of H and F;

R 4 ′ is hydrogen;

R 5 is selected from the group of CN, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, CH 2 F, CHF 2 , CH 2 Cl, CH 2 SMe, —CH 2 OMe, and cyclopropyl; and

R 4 is selected from the group of:

wherein:

R 7 is selected from C 1 -C 8 alkyl, —O—C 1 -C 8 alkyl, benzyl, and —CH 2 —C 3 -C 6 cycloalkyl; and

R 11 is selected from C 1 -C 8 alkyl, benzyl, C 3 -C 6 cycloalkyl, and —CH 2 —C 3 -C 6 cycloalkyl.

15. A compound according to claim 14 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

16. A compound of claim 1 selected from the group of:

or a pharmaceutically acceptable salt thereof.

17. A compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.

18. A compound of claim 1 of the formula:

or a pharmaceutically acceptable salt thereof.

19. A method of treating Pneumovirinae virus infection in a human, the method comprising administering to the human a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. A method of treating human respiratory syncytial virus infection in a human, the method comprising administering to the human a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.