IP Library › Granted Patent US 12,173,026
Granted Patent B2
US 12,173,026 · App. 17/266,521 · Granted Dec 24, 2024

PRMT5 inhibitors

Inventors: Michelle Machacek (Belmont, MA); David Witter (Norfolk, MA); Craig Gibeau (Northborough, MA); Chunhui Huang (Arlington, MA); Shuhei Kawamura (Cambridge, MA); David L. Sloman (Brookline, MA); Phieng Siliphaivanh (Newton, MA); Ryan Quiroz (Boston, MA); Murray Wan (Watertown, MA); Sebastian Schneider (Boston, MA); Charles S. Yeung (Dedham, MA); Michael H. Reutershan (Brighton, MA); Timothy J. Henderson (Beaulieu, MA); Jean-Laurent Paparin (Vendemian, FR); Houcine Rahali (Beaulieu, FR); Jonathan M. E. Hughes (Hoboken, NJ); Sulagna Sanyal (Belmont, MA); Yingchun Ye (Belmont, MA); David A. Candito (Wrentham, MA); Patrick S. Fier (Monroe Township, NJ); Steven M. Silverman (Jersey City, NJ)
Assignees: Merck Sharp & Dohme LLC; MSD International GmbH
C07H19/14A61P35/00C07D487/04
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Quick Facts
Patent No.
US 12,173,026
App. No.
17/266,521
Granted
Dec 24, 2024
Kind
B2
Abstract

The present invention provides a compound of Formula (I) and the pharmaceutically acceptable salts, esters, and prodrugs thereof, which are PRMT5 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat cancer, sickle cell, and hereditary persistence of foetal hemoglobin (HPFH) mutations.

Claims (209)

1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein

X is CH 2 or O;

Y is CH 2 , NH, or O;

Z 1 is CR 4 or N;

Z 2 , Z 3 , Z 4 , and Z 5 are independently selected from N and CR 9 ;

A 1 is CH or N;

A 2 is CR 10 or N

A 3 is CH or N;

A 4 is CR 8 or N;

R 1 and R 7 taken together to form a five membered carbon ring optionally substituted with 1-3 halogens or a five membered heterocycloalkyl ring comprising one O atom;

R 2 is H, OH, CH 3 , CHF 2 , or F;

R 3 is H, halogen, NH 2 , NHCH 3 , CN, OH, OCH 3 , C 1-4 alkyl optionally substituted with 1-3 halogen or OH, or C 3-5 cycloalkyl optionally substituted with 1-3 halogens or OH;

R 5 is H, NH 2 , or NHR 6 ; and R 4 , when present, is H, halogen, CH 3 , CHF 2 , or CF 3 ; or

R 4 and R 5 taken together with the carbon atoms to which they are attached, join to form a 5 membered heterocycloalkyl comprising one N atom, wherein the heterocycloalkyl is optionally substituted with one to four substituents independently selected from halogen, CH 3 , CF 3 , and CF 2 H;

R 6 , when present, is CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CHF 2 , CH 2 CF 3 , or CH 2 -cyclopropyl;

R 8 , when present, is H, halogen, C 1-4 alkyl optionally substituted with 1-3 halogens, C 3-5 cycloalkyl optionally substituted with 1-3 halogens, or aryl optionally substituted with 1-3 halogens;

each R 9 , when present, is independently selected from H and halogen; and

R 10 , when present, is H, C 1-6 alkyl, NH 2 , or halogen.

2. A compound of claim 1 , thereof, of formula Ib:

or a pharmaceutically acceptable salt thereof, wherein

X is CH 2 or O;

Y is CH 2 , NH, or O;

W is CR 11 R 11 or O;

72, Z 3 , Z 4 , and Z 5 are independently selected from N and CR 9 ;

A 2 is CR 10 or N;

R 2 is H, OH, CH 3 , CHF 2 , or F;

R 3 is H, halogen, OH, NH 2 , NHCH 3 , CN, OCH 3 , C 1-4 alkyl optionally substituted with 1-3 halogen or OH, or C 3-5 cycloalkyl optionally substituted with 1-3 halogens or OH;

R 4 is H, halogen, CH 3 , CHF 2 , or CF 3 ;

R 5 is H, NH 2 , or NHR 6 ;

R 8 is H, halogen, C 1-4 alkyl optionally substituted with 1-3 halogens, C 3-5 cycloalkyl optionally substituted with 1-3 halogens, or aryl optionally substituted with 1-3 halogens;

each R 9 , when present, is independently selected from H and halogen;

R 10 , when present, is H, C 1-6 alkyl, NH 2 , or halogen; and

each R 11 , when present, is independently selected from H and halogen.

3. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, F, Cl, Br, CF 3 , CHF 2 , or CH 3 .

4. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 9 , when present, is independently selected from F, Cl and H.

5. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein A 2 is N, CH, CNH 2 , CF, CCI or C (CH 3 ).

6. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is NH 2 , Cl, OCH 3 , CH 2 OH, CHF 2 , C (CH 3 ) 2 OH, CH 2 CH 3 , CH (CH 3 ) 2 , cyclopropyl, NHCH 3 , or CH 3 .

7. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H, CH 3 , CH 2 CH 3 , cyclopropyl, CHF 2 , or F.

8. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 , NHCH 2 CF 3 or NCH 2 cyclopropyl.

9. A compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein W is O, CHF, CF 2 , or CH 2 .

10. A compound of claim 1 of formula Ic:

or a pharmaceutically acceptable salt thereof, wherein

X is CH 2 or O;

Y is CH 2 , NH, or O;

W is CH 2 or O;

R 2 is H, halogen, OH, CH 3 , NH 2 , NHCH 3 , CH 2 OH, CH 2 F, or CHF 2 ;

R 3 is H, halogen, CH 3 , C 2 H 5 , cyclopropyl, NH 2 , NHCH 3 , CN, CF 3 , OH, OCH 3 or CHF 2 , CH 2 OH, C (CH 3 ) 2 OH CH 2 CH 3 or CH (CH 3 ) 2 ;

R 4 is H, halogen, CH 3 , CHF 2 , or CF 3 ;

R 5 is H, NH 2 , or NHR 6 ; or

R 4 and R 5 taken together with the carbon atoms to which they are attached, join to form a 5 membered heterocycloalkyl comprising one N atom, wherein the heterocycloalkyl is optionally substituted with one to four substituents independently selected from halogen, CH 3 , CF 3 , and CF 2 H;

R 6 , when present, is CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CHF 2 , CH 2 CF 3 , or CH 2 -cyclopropyl; and

R 8 is H, C 1-4 alkyl, or halogen.

11. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

12. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 3 is CH 3 , Cl, OCH 3 , CH 2 OH, C (CH 3 ) 2 OH, CHF 2 , CH 2 CH 3 , CH (CH 3 ) 2 , cyclopropyl or NH 2 .

13. A compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H, Cl, F, CH 3 , CHF 2 , CF 3 or Br.

14. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 5 is NH 2 , NHCH 2 CF 3 or NHCH 2 cyclopropyl.

15. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 8 is H.

16. A compound of claim 1 , or a pharmaceutically acceptable salt thereof,

which is:

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-chloro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4R,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3,8-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl]-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl) quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3,5-difluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((6-amino-7-fluoro-1,5-naphthyridin-3-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloro-8-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3,6-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((7-amino-6-chloro-1,8-naphthyridin-2-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-4-((2-amino-3-chloroquinolin-7-yl)methyl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-4-((2-amino-3-fluoroquinolin-7-yl)methyl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-[(2-amino-3,5-difluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-[(2-amino-3-chloro-5-fluoroquinolin-7-yl)methyl]-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-4-((2-amino-3-bromoquinolin-7-yl)methyl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl)methyl]-2-[4-amino-5-(difluoromethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl] hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-2-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-((2-amino-3-fluoroquinolin-7-yl)methyl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(2-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol dihydrochloride,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-chloro-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-[(2-amino-3-chloroquinolin-7-yl)methyl] hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-chloro-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl] hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl) oxy]-2-(4-amino-5-phenyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-5-cyclopropyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl] hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-[4-amino-5-(difluoromethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl]-6-[(2-amino-3-fluoroquinolin-7-yl)methyl] hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl) oxy]-2-(4-amino-5-cyclopropyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-5,5-difluorohexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,5S,6S,6aR)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-5-fluorohexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,5S,6S,6aR)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-[(2-amino-3-fluoroquinolin-7-yl)methyl]-5-fluorohexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-((2-((2,2,2-trifluoroethyl)amino) quinolin-7-yl) oxy) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-((2-((cyclopropylmethyl)amino) quinolin-7-yl) oxy) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-((2-amino-3-bromoquinolin-7-yl)methyl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-2-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-((2-amino-3-bromoquinolin-7-yl) oxy) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl) oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl) oxy)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl) oxy)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl) oxy)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl) oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl) oxy)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-((2,3-dihydro-1H-pyrrolo[2,3-b] quinolin-7-yl) oxy) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl) quinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl) oxy]-2-[4-(hydroxymethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl] hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-[(2-amino-3-bromoquinolin-7-yl) oxy]-2-[4-(2-hydroxypropan-2-yl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl] hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-(difluoromethyl)-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-amino-5-ethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-isopropyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl) oxy)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-cyclopropyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(trifluoromethyl) quinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2,3-dihydro-1H-pyrrolo[2,3-b] quinolin-7-yl) oxy)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(2,4-dimethyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(5-fluoro-4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(2R,3R,3aS,6S,6aR)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6-((2-aminoquinolin-7-yl) oxy) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl) oxy)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-aminoquinolin-7-yl) oxy)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(2-amino-4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl) quinolin-7-yl) oxy)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(1S,2R,3aR,4S,6aR)-4-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydropentalene-1,6a (1H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)amino)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-6a-methylhexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-fluoroquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-methylquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(2-amino-4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl) quinolin-7-yl) oxy)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl) oxy)-2-(2-amino-5-fluoro-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-chloroquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-3aH-cyclopenta[b] furan-3,3a-diol,

(3aS,4S,5R)-1-((2-amino-3-bromoquinolin-7-yl)methyl)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) tetrahydro-1H-cyclopenta[c] furan-3a,4 (3H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) tetrahydrofuro[3,4-b] furan-3,3a (4H)-diol,

(2R,3R,3aS,6R,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) tetrahydrofuro[3,4-b] furan-3,3a (4H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-5-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl) tetrahydrofuro[3,4-b] furan-3,3a (4H)-diol,

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-bromoquinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) tetrahydrofuro[3,4-b] furan-3,3a (4H)-diol, or

(2R,3R,3aS,6S,6aR)-6-((2-amino-3-(difluoromethyl) quinolin-7-yl)methyl)-2-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl) hexahydro-2H-cyclopenta[b] furan-3,3a-diol.

17. A composition for treating cancer comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.

18. A method for treating cancer comprising administering to a patient in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. A compound of formula Ia,

or a pharmaceutically acceptable salt thereof, wherein

X is CH 2 or O;

Y is CH 2 , NH, or O;

Z 1 is CR 4 or N;

Z 2 is CH or N;

Z 3 is CH or N;

Z 4 is CH or N;

A 1 is CH or N;

A 2 is CH, N, CNH 2 or CCH 3 ;

A 3 is CH or N;

A 4 is CR 8 or N;

R 1 and R 7 taken together to form a five membered ring;

R 2 is H, OH, CH 3 , CHF 2 , or F;

R 3 is H, halogen, CH 3 , C 2 H 5 , cyclopropyl, NH 2 , NHCH 3 , CN, CF 3 , OH, OCH 3 , or CHF 2 ;

R 4 , when present, is H, halogen, CH 3 , CHF 2 , or CF 3 ; and R 5 is H, NH 2 , or NHR 6 ; or

R 4 and R 5 taken together with the carbon atoms to which they are attached, join to form a 5 membered heterocycloalkyl comprising one N atom, wherein the heterocycloalkyl is optionally substituted with one to four substituents independently selected from halogen, CH 3 , CF 3 , and CF 2 H;

R 6 , when present, is CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CHF 2 , CH 2 CF 3 , or CH 2 -cyclopropyl; and

R 8 , when present, is H, C 1-4 alkyl, or halogen.

20. A compound, or a pharmaceutically acceptable salt thereof,

which is:

(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-2,3-dimethyltetrahydrofuran-3,4-diol,

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl) oxy) methyl)-5-(4-methoxy-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-2-methyltetrahydrofuran-3,4-diol,

(2R,3S,4R,5R)-2-(((2-amino-3-bromoquinolin-7-yl) oxy) methyl)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-2-methyltetrahydrofuran-3,4-diol,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-3-methyl-1,2-cyclopentanediol,

(1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl) oxy) methyl)-1-methyl-3-(4-(methylamino)-7H-pyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol,

(2R,3S,4R,5R)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-2-methyl-2-((quinolin-7-yloxy) methyl) tetrahydrofuran-3,4-diol,

(1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl) oxy) methyl)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-3-methylcyclopentane-1,2-diol,

(1S,2R,3R,5R)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-3-(((2-aminoquinolin-7-yl) oxy) methyl)-3-methylcyclopentane-1,2-diol,

(1S,2R,5R)-3-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-3-(fluoromethyl)cyclopentane-1,2-diol,

(1R,2S,3R,5R)-5-(((2-aminoquinolin-7-yl) oxy) methyl)-1-methyl-3-(7H-pyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol,

(1S,2R,3S,5R)-3-(2-(2,3-dihydro-1H-pyrrolo[2,3-b] quinolin-7-yl)ethyl)-3-methyl-5-(4-methyl-7H-pyrrolo[2,3-d] pyrimidin-7-yl)cyclopentane-1,2-diol,

(1S,2R,3R,5R)-3-(2-(2-amino-3-fluoroquinolin-7-yl)ethyl)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-3-methylcyclopentane-1,2-diol,

(1R,2S,3R,5S)-5-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-3-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-1,5-dimethylcyclopentane-1,2-diol,

(1R,2S,3S,4R)-1-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-4-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-2-methylcyclopentane-1,2,3-triol,

(1R,2S,3R,5R)-5-(((2-amino-3-bromoquinolin-7-yl) oxy) methyl)-3-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-1,5-dimethylcyclopentane-1,2-diol, or

(1S,2R,3S,5R)-5-(4-amino-7H-pyrrolo[2,3-d] pyrimidin-7-yl)-3-(2-(2,3-dihydro-1H-pyrrolo[2,3-b] quinolin-7-yl)ethyl)-3-methylcyclopentane-1,2-diol.

Assignments (6)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 5, 2021
From: PAPARIN, JEAN-LAURENT; RAHALI, HOUCINE
To: IDENIX SARL
Reel/Frame 055168/0949 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 5, 2021
From: IDENIX SARL
To: IDENIX PHARMACEUTICALS LLC.
Reel/Frame 055168/0985 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 5, 2021
From: IDENIX PHARMACEUTICALS LLC
To: MERCK GLOBAL RESEARCH LLC
Reel/Frame 055169/0103 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 5, 2021
From: MERCK GLOBAL REARCH LLC
To: MSD INTERNATIONAL GMBH
Reel/Frame 055169/0135 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 5, 2021
From: MACHACEK, MICHELLE; WITTER, DAVID; GIBEAU, CRAIG; HUANG, CHUNHUI; KAWAMURA, SHUHEI; SLOMAN, DAVID L.; SILIPHAIVANH, PHIENG; QUIROZ, RYAN; WAN, MURRAY; SCHNEIDER, SEBASTIAN; YEUNG, CHARLES S.; REUTERSHAN, MICHAEL H.; HENDERSON, TIMOTHY J.; SANYAL, SULAGNA; YE, YINGCHUN; CANDITO, DAVID A.; HUGHES, JONATHAN M.E.; FIER, PATRICK S.; SILVERMAN, STEVEN M.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 055231/0370 →