Pteridinone compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-11059826-B2
Application number	US-201916391407-A
Country	US
Kind code	B2
Filing date	Apr 23, 2019
Priority date	Apr 24, 2018
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

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

We claim:

1. A compound of formula IV′:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, indanyl, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 8-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-8 membered saturated or partially unsaturated bridged bicyclic carbocyclic ring, a 5-6 membered monocyclic 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;
L is a covalent bond or a C 1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein one to three methylene units of the chain are independently and optionally replaced with -Cy-, —O—, —C(R) 2 —, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D) 2 -, —C(F) 2 —, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)—, —S(O) 2 —, or —Si(R) 2 —, wherein -Cy- is an optionally substituted bivalent group selected from phenylenyl, cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, cyclohexylenyl, furylenyl, tetrahydrofurylenyl, azetidylenyl, pyrrolidylenyl, piperidylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolylenyl, or thiazolylenyl;
R 2 is R D , or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, 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;
R 3 is hydrogen, R D , or an optionally substituted C 1-6 aliphatic group; or
each of R 6 is independently halogen, —CN, —NO 2 , —C(O)R, —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, —SF 5 , —S(CF 3 ) 5 , —S(O)R, —S(O) 2 R, —S(O)(NH)R, —C(═NR)—OR, —O—C(═NR)—R, or R; or
two R 6 groups are optionally taken together to form ═O;

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 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;
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;
R D is a C 1-4 aliphatic group wherein one or more hydrogens are replaced by deuterium;
and
n is 0, 1, 2, 3, 4 or 5.

2. The compound of claim 1 , wherein Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.

3. The compound of claim 1 , wherein Ring A is phenyl.

4. The compound of claim 1 , wherein Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

5. The compound of claim 1 , wherein Ring A is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

6. The compound of claim 1 , wherein Ring A is

7. The compound of claim 1 , wherein Lisa C 1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein one to three methylene units of the chain are independently and optionally replaced with -Cy-, —O—, —C(R) 2 —, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D) 2 -, —C(F) 2 —, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)N(R)—, —N(R)C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O), —S(O) 2 —, or —Si(R) 2 —.

8. The compound of claim 1 , wherein L is a covalent bond.

9. The compound of claim 1 , wherein L is a C 1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein one to three methylene units of the chain are independently and optionally replaced with -Cy-, —O—, —C(R) 2 —, —CH(R)—, —CH(OR)—, —CR(OR)—, —C(D) 2 -, —C(F) 2 —, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —C(O)—, —OC(O)—, —C(O)O—.

10. The compound of claim 9 , wherein -Cy- is an optionally substituted bivalent group selected from cyclopropylenyl, cyclobutylenyl, cyclopentylenyl, or cyclohexylenyl.

11. The compound of claim 9 , wherein -Cy- is an optionally substituted bivalent group selected from furylenyl, triazolylenyl, pyrrolylenyl, pyrazolylenyl, pyridylenyl, or thiazolylenyl.

12. The compound of claim 1 , wherein R 2 is R D .

13. The compound of claim 1 , wherein R 2 is an optionally substituted C 1-6 aliphatic.

14. The compound of claim 13 , wherein R 2 is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring.

15. The compound of claim 14 , wherein R 2 is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

16. The compound of claim 1 , wherein R 2 is an optionally substituted 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

17. The compound of claim 1 , wherein R 2 is C 1-6 aliphatic substituted by 1-3 halogen, —OH, —OCH 3 , or —OC(CH 3 ) 3 .

18. The compound of claim 1 , wherein R 2 is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring substituted by 1-3 halogen, —OH, —OCH 3 , or —OC(CH 3 ) 3 .

19. The compound of claim 1 , wherein R 2 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, substituted by 1-3 halogen, —OH, —OCH 3 , or —OC(CH 3 ) 3 .

20. The compound of claim 1 , wherein R 2 is unsubstituted C 1-6 aliphatic.

21. The compound of claim 1 , wherein R 3 is hydrogen or an optionally substituted C 1-6 aliphatic group.

22. The compound of claim 1 , wherein R 3 is C 1-6 aliphatic substituted by

or —OCH 3 .

23. The compound of claim 1 , wherein each of R 6 is independently halogen, —CN, —NO 2 , —C(O)R, —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, or R.

24. The compound of claim 1 , wherein one or more

Assignees

• Vertex Pharma

Inventors

• Lauffer David J
• Bemis Guy
• Boyd Michael
• DEININGER David
• Deng Hongbo
• Dorsch Warren
• Gu Wenxin
• Hoover Russell R
• Johnson Jr Mac Arthur
• Ledeboer Mark Willem
• Ledford Brian
• Maltais Francois
• Penney Marina
• Takemoto Darin
• Waal Nathan D
• Wang Tiansheng
• Li Pan

Classifications

• C07D487/14

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D491/20

  Spiro-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title