Compounds and compositions for inhibition of FASN

• US 10,472,342 B2
• Filed: 04/12/2019
• Issued: 11/12/2019
• 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:
  US16/383,296
• Publication Number:
  US 20190241532A1
• Time in Patent Office: 214 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 composition for inhibition of FASN, their synthesis, applications, and antidotes. An illustrative compound of the invention is shown below:

Claims

1. A compound of formula (I-B)

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar₁ is

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Ph₁ is phenyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R_e is halogen.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar₁ is

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R_e is halogen.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ar₁ is

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, 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.

9. The compound of claim 2, or a pharmaceutically acceptable salt thereof, 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.

10. The compound of claim 3, or a pharmaceutically acceptable salt thereof, 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.

11. The compound of claim 5, or a pharmaceutically acceptable salt thereof, 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 1, or a pharmaceutically acceptable salt thereof, wherein R₂ is elected from the group consisting of:

13. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R₂ is selected from the group consisting of:

14. A compound of formula (I-B)

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R₂ is selected from the group consisting of:

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R₂ is selected from the group consisting of:

17. The compound of claim 14, selected from the group consisting of:

1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol;

1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol;

1-[(4-{[4-(6-chloro-1,3-benzoxazol-2-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol;

1-{4-[2-fluoro-4-(6-fluoro-1,3,-benzoxazol-2yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol; and

1-[(4-{[4-(1-methyl-1H-1,3-benzodiazol-5-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol;

or a pharmaceutically acceptable salt thereof.

18. A compound of formula (I-B)

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R_e is hydrogen.

20. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R_e is fluoro.

21. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R₂ is selected from the group consisting of:

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R_e is hydrogen.

23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein R_e is fluoro.

24. The compound of claim 18, wherein the compound is 1-{4-[2-fluoro-4-(1-methyl-1H-1,3-benzodiazol-5-yl)benzoyl]piperazine-1-carbonyl}cyclopropan-1-ol, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 18, wherein the compound is 1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol, or a pharmaceutically acceptable salt thereof.