Antiproliferation compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-12195453-B2
Application number	US-202217930352-A
Country	US
Kind code	B2
Filing date	Sep 7, 2022
Priority date	Apr 24, 2018
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

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 ═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;
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 C 2 H 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 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-4times by halogen, —OH, —CH 3 , —OCH 3 , ═O,

8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 is selected from

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

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 1.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, 4, or 5.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula VII

or a pharmaceutically acceptable salt thereof, wherein:
n′ is 1; and
R 2′ is halogen or —OC 1-3 aliphatic.

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2′ is Cl.

15. A compound selected from:

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
• Kulkarni Shashank
• Penney Marina
• Ronkin Steven
• Takemoto Darin
• Tang Qing
• Waal Nathan D
• Wang Tiansheng
• Lauffer David J
• Li Pan

Classifications

• C07D403/04

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

• C07D491/113

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• C07D413/04 Primary

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title