IP Library › Granted Patent US 11,993,602
Granted Patent B2
US 11,993,602 · App. 17/266,474 · Granted May 28, 2024

PRMT5 inhibitors

Inventors: David Witter (Norfolk, MA); Shuhei Kawamura (Cambridge, MA); Michelle Machacek (Belmont, MA); Ryan Quiroz (Boston, MA); Michael H. Reutershan (Brighton, MA); Sebastian Schneider (Boston, MA); Phieng Siliphaivanh (Newton, MA); Yingchun Ye (Belmont, MA); Charles S. Yeung (Dedham, MA)
Assignee: Merck Sharp & Dohme LLC
C07D487/04C07D519/00
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Quick Facts
Patent No.
US 11,993,602
App. No.
17/266,474
Granted
May 28, 2024
Kind
B2
Abstract

The present invention provides a compound of Formula (I) Formula (I) or the pharmaceutically acceptable salts thereof, which are PRMT5 inhibitors.

Claims (85)

1. A compound having formula I

or a pharmaceutically acceptable salt thereof, wherein

A is O or CH 2 ;

R 1 is halogen, NH 2 , OC 1-6 alkyl, NHCH 3 , CHF 2 , C 1-6 alkyl, cyclopropyl, CH 2 OH, or C(CH 3 ) 2 OH;

R 2 is H, C 1-6 alkyl, CF 3 or CHF 2 ;

R 3 is H, halogen, CH 3 , CF 3 , or CHF 2 , and R 4 is H or NHR 5 , or R 3 and R 4 together with the atom to which they are attached form a 5-membered saturated ring containing zero or one N atom, wherein the ring is unsubstituted or substituted with CH 3 ;

R 5 is H, 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 —C 3-8 cycloalkyl;

R 6 is H, C 1-4 alkyl, or halogen;

R 7 is H, NH 2 , or C 1-6 alkyl;

Z 1 is CH or N;

Z 2 is CH or N;

Z 3 is CH or N;

Z 4 is CH or N; and

Z 5 is CR 3 or N.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is NH 2 , Cl, NHCH 3 , OCH 3 , or CH 3 .

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

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is NH 2 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is NHCH 2 CHF 2 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is CH 2 CHF 2 .

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

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is CH 3 or NH 2 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the formula

or a pharmaceutically acceptable salt thereof, wherein

A is O or CH 2 ;

R 1 is halogen, NH 2 , or OC 1-6 alkyl;

R 2 is H or C 1-6 alkyl;

R 3 is H, CH 3 , or halogen;

R 4 is H or NHR 5 ; and

R 5 is H or CH 2 —C 3-8 cycloalkyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, having the formula

12. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, having the formula

13. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein

A is 0 or CH 2 ;

R 1 is C 1 , NH 2 , or OCH 3 ;

R 2 is H or CH 3 ;

R 3 is H, Br, F, CH 3 , or Cl; and

R 4 is NH 2 or NH—CH 2 -cyclopropyl.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is

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

7-[5-O-(2-amino-3-chloroquinolin-7-yl)-4-thio-beta-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-[5-O-(2-amino-3-fluoroquinolin-7-yl)-4-thio-beta-D-ribofuranosyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

7-(5-O-{2-[(cyclopropylmethyl)amino]quinolin-7-yl}-4-thio-beta-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine,

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

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

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

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

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

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

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

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

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

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

(2S,3S,4R,5R)-2-[2-(2-aminoquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,

(2R,3S,4R,5R)-2-[2-(2-aminoquinolin-7-yl)ethyl]-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,

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

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

(2R,3S,4R,5R)-2-{2-[2-amino-3-(trifluoromethyl)quinolin-7-yl]ethyl}-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,

(2S,3S,4R,5R)-2-{2-[2-amino-3-(trifluoromethyl)quinolin-7-yl]ethyl}-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,

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

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

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

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

(2R,3S,4R,5R)-2-(2-{2-[(2,2-difluoroethyl)amino] quinolin-7-yl}ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,

(2S,3S,4R,5R)-2-(2-{2-[(2,2-difluoroethyl)amino] quinolin-7-yl}ethyl)-5-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrothiophene-3,4-diol,

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

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

(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-methyltetrahydrothiophene-3,4-diol,

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

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

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

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

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

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

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

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

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

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

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

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

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

15. A composition for treating cancer ameliorated by inhibition of PRMT5 comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A method for treating cancer ameliorated by inhibition of PRMT5 comprising administering to a patient in need thereof a composition of claim 15 .

17. A method for treating cancer ameliorated by inhibition of PRMT5 comprising administering to a patient in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignments (2)
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: WITTER, DAVID; KAWAMURA, SHUHEI; MACHACEK, MICHELLE; QUIROZ, RYAN; REUTERSHAN, MICHAEL H.; SCHNEIDER, SEBASTIAN; SILIPHAIVANH, PHIENG; YE, YINGCHUN; YEUNG, CHARLES S.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 055231/0161 →