Antiproliferation compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10815225-B2
Application number	US-201916391419-A
Country	US
Kind code	B2
Filing date	Apr 23, 2019
Priority date	Apr 24, 2018
Publication date	Oct 27, 2020
Grant date	Oct 27, 2020

Abstract

The present invention provides compounds of Formula I′, or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof for treating cellular proliferative disorders (e.g., cancer).

First claim

The invention claimed is:

1. A compound of formula I′:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is ring selected from phenyl, a 5-7 membered saturated or partially unsaturated carbocyclic ring, a 8-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R 1 is independently hydrogen, or C 1-3 aliphatic optionally substituted by 1-6 halogen; or
two R 1 groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring;

each of R 2 is independently hydrogen, halogen, —CN, —NO 2 , —C(O)OR, —C(O)NR 2 , —NR 2 , —NRC(O)R, —NRC(O)OR, —NRS(O) 2 R, —OR, —P(O)R 2 , —SR, —S(O)R, —S(O) 2 R, —S(O)(NH)R, —S(O) 2 NR 2 , or R; or
two R 2 groups are optionally taken together to form ═O; or
two R 2 groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R 3 is independently hydrogen, —OH, or C 1-3 aliphatic; or
two R 3 groups are optionally taken together to form ═O; or
two R 3 groups are optionally taken together to form ═CH 2 ; or
two R 3 groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or
two R 3 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 7-10 membered saturated spirobicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or:
two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups;

is a single bond or a double bond;
X is —O—;
m is 0, 1, or 2;
n is 0, 1, 2, 3, 4 or 5; and
p is 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 is C 1-3 aliphatic.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 is —CH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 1 is attached to position 6 of the pyrimidine.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is C 1-6 aliphatic, optionally substituted 1-4 times by halogen, —OH, NH 2 , —OCH 3 , —NHC(O)CH 3 , —S(O) 2 CH 3 , —COOH, —CO 2 CH 3 , —CO 2 C2H 5 , or —N(CH 3 )C(O)CH 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is a 3-6 membered saturated monocyclic carbocyclic ring.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is a 7-10 membered saturated spirobicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is a 7-10 membered saturated fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is a 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-4 times by halogen, —OH, —CH 3 , —OCH 3 , ═O, 0 , or

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is —C(O)OR, wherein R is hydrogen or C 1-6 aliphatic.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is —C(O)NR 2 , wherein each of R is independently hydrogen, C 1-6 aliphatic which is optionally substituted by a —N(CH 3 ) 2 , unsubstituted 3-6 membered saturated monocyclic carbocyclic ring, or unsubstituted 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen, or two R taken together with their intervening atoms to form a 4-7 membered saturated and unsubstituted ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is —NR 2 , wherein each of R is independently:
hydrogen;
C 1-6 aliphatic which is optionally substituted 1-2 times by —OH,

unsubstituted 3-6 membered saturated monocyclic carbocyclic ring;
4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen, which is optionally substituted 1-2 times by CH 3 , —OH, —C(O)OC(CH 3 ) 3 , or —C(O)CH 3 ; or
6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur which is optionally substituted 1-2 times by —CH 3 or —NH 2 .

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is —NHC(O)R, wherein R is C 1-6 aliphatic optionally substituted 1-3 times by halogen, —OCH 3 , —N(CH 3 ) 2 , or —OH, 3-6 membered saturated monocyclic carbocyclic ring optionally substituted 1-2 times by halogen or —OH, or 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur optionally substituted 1-2 times by halogen, —OH, or —CH 3 .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is —NHC(O)OR,

Assignees

• Merck Patent Gmbh
• Vertex Pharma

Inventors

• Yu Henry
• Clark Michael
• Bemis Guy
• Boyd Michael
• Chandupatla Kishan
• Collier Philip
• Deng Hongbo
• Dong Huijun
• Dorsch Warren
• Hoover Russell R
• Johnson Jr Mac Arthur
• Kukarni Shashank
• Penney Marina
• Ronkin Steven
• Takemoto Darin
• Tang Qing
• Waal Nathan D
• Wang Tiansheng
• Lauffer David J
• Li Pan

Classifications

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title