Compounds and compositions for inhibition of FASN

• US 10,399,951 B2
• Filed: 08/31/2018
• Issued: 09/03/2019
• Est. Priority Date: 03/13/2013
• Status: Expired due to Fees

• Current Assignee: Forma Therapeutics, Inc. (Novo Nordisk A/S)
• Original Assignee: Forma Therapeutics, Inc. (Novo Nordisk A/S)
• Inventors: Bair, Kenneth W., Lancia, Jr., David R., Li, Hongbin, Loch, James, Lu, Wei, Martin, Matthew W., Millan, David S., Schiller, Shawn E. R., Tebbe, Mark J.
• Primary Examiner(s): Balasubramanian, Venkataraman
• Application Number:
  US16/119,962
• Publication Number:
  US 20180370933A1
• Time in Patent Office: 368 Days
• Field of Search: 544359, 544387, 51425202, 51425213
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/5025 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/18 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/56 Amides
• CPC Class Codes: C07D 213/65 attached in position 3 or 5
• CPC Class Codes: C07D 213/69 Two or more oxygen atoms
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 217/16 substituted by oxygen atoms
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 235/08 Radicals containing only hydrogen and carbon atoms
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 263/57 : Aryl or substituted aryl radicals
• CPC Class Codes: C07D 271/12 : condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 277/62 : Benzothiazoles
• CPC Class Codes: C07D 277/66 : with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 305/08 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds and compositions for inhibition of FASN, their synthesis, applications, and antidotes.

Claims

1. A fatty acid synthase inhibitor compound of formula (I):

2. The compound of claim 1, wherein

(a) A and B are O;

and

(b) R₁ is a 3 or 4 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of —

R_a, —

OR_a, —

NHR_a, and —

NR_aR_a1.

3. The compound of claim 2, wherein R₂ is a substituted or unsubstituted monocyclic or bicyclic 5-10 membered aryl or heteroaryl.

4. The compound of claim 2, wherein R₂ is a substituted or unsubstituted form of:

14. The compound of claim 1, wherein R₁ is selected from the group consisting of:

5. A fatty acid synthase inhibitor compound of formula (I):

6. The compound of claim 5, wherein A and B are independently O.

7. The compound of claim 6, wherein L is a 6-membered monocyclic substituted heteroalkyl wherein the heteroatom ring members comprise two N.

8. The compound of claim 7, wherein Ar₁ is a substituted or unsubstituted 6-membered monocyclic aryl.

9. The compound of claim 8, wherein each R_b is methyl.

10. The compound of claim 8, wherein R_b is halo or C₁-C₃ alkyl.

11. The compound of claim 9, wherein R₂ is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N.

12. The compound of claim 10, wherein R₂ is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N.

13. The compound of claim 12, wherein R₁ is selected from the group consisting of:

15. A fatty acid synthase inhibitor compound of formula (I):

16. The compound of claim 15, wherein R₁ is selected from the group consisting of:

17. The compound of claim 15, wherein L is a 6-membered monocyclic substituted heteroalkyl wherein the heteroatom ring members consist of two N, and L is substituted with one or two R_b.

18. The compound of claim 16, wherein L is a 6-membered monocyclic substituted heteroalkyl wherein the heteroatom ring members consist of two N, and L is substituted with one R_b.

19. The compound of claim 16, wherein Ar₁ is a substituted or unsubstituted 6-membered monocyclic aryl.

20. The compound of claim 18, wherein Ar₁ is a substituted or unsubstituted 6-membered monocyclic aryl.

21. The compound of claim 15, wherein R₂ is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N.

22. The compound of claim 16, wherein R₂ is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N.

23. The compound of claim 17, wherein R₂ is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N.

24. The compound of claim 18, wherein R₂ is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N.

25. A fatty acid synthase inhibitor compound of formula (I):

26. The compound of claim 25, wherein R₁ is selected from the group consisting of:

27. The compound of claim 26, wherein L is a 6-membered monocyclic substituted heteroalkyl wherein the heteroatom ring members consist of two N and L is substituted with one or two R_b.