Tetrazolones as inhibitors of fatty acid synthase

• US 9,346,769 B2
• Filed: 08/23/2013
• Issued: 05/24/2016
• Est. Priority Date: 05/05/2010
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Bahadoor, Adilah, Castro, Alfredo C., Chan, Lawrence K., Keaney, Gregg F., Nevalainen, Marta, Nevalainen, Vesa, Peluso, Stephane, Snyder, Daniel A., Tibbitts, Thomas T.
• Primary Examiner(s): Otton, Alicia L
• Application Number:
  US13/975,236
• Publication Number:
  US 20140079667A1
• Time in Patent Office: 1,005 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/428 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/217 IFN-gamma
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: C07D 257/04 : Five-membered rings
• CPC Class Codes: C07D 295/185 : from aliphatic carboxylic acids
• CPC Class Codes: C07D 295/205 : Radicals derived from carbonic acid
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• 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 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided herein are tetrazolone FASN inhibitors of the formula (I):

or a pharmaceutically acceptable form thereof; wherein the variables R^A, R^B and R^C are defined herein.

Also provided herein are pharmaceutical compositions of the compounds provided herein as well as methods of their use for the treatment of various disorders such as hyperproliferative disorders, inflammatory disorders, obesity-related disorders and microbial infections.

Claims

1. A method of inhibiting fatty acid synthase (FASN) in a subject, wherein the subject has a FASN-mediated disorder selected from hyperproliferative disorders, inflammatory disorders, obesity related disorders, Type II diabetes mellitus, fatty liver disease, microbial infections, viral infections, bacterial infections, fungal infections, parasitic infections, and protozoal infections comprising administering to a subject a therapeutically effective amount of a compound of formula (I):

2. The method of claim 1, wherein the hyperproliferative disorder is selected from prostate cancer and hepatocellular cancer.

3. A method of inhibiting fatty acid synthase (FASN) in a subject, wherein the subject has a FASN-mediated disorder selected from hyperproliferative disorders, inflammatory disorders, obesity related disorders, Type II diabetes mellitus, fatty liver disease, microbial infections, viral infections, bacterial infections, fungal infections, parasitic infections, and protozoal infections comprising administering to &

the subject a therapeutically effective amount of a compound of formula (I);

4. The method of claim 3, wherein L is a covalent bond.

5. The method of claim 3, wherein L is a divalent C_1-10 hydrocarbon chain, wherein one methylene unit of L is optionally and independently replaced with a divalent carbocyclyl, divalent heterocyclyl, divalent aryl or divalent heteroaryl group.

6. The method of claim 3, wherein R^D is selected from —

CN, —

NO₂, —

SO₂H, —

SO₃H, —

C(═

O)R^B7, —

CO₂H, —

CHO, —

CO₂R^B7, —

C(═

O)N(R^B8)₂, —

C(═

NR^B8)OR^B7, —

C(═

NR^B8)N(R^B8)₂, —

C(═

O)NR^B8SO₂R^B7, —

SO₂N(R^B8)₂, —

SO₂R^B7, —

SO₂OR^B7, —

S(═

O)R^B7, —

C(═

S)N(R^B8)₂, —

C(═

O)SR^B7, —

C(═

S)SR^B7, —

P(═

O)₂R^B7, —

P(═

O)(R^B7)₂, —

P(═

O)₂N(R^B8)₂, —

P(═

O)(NR^B8)₂, —

B(OR^B9)₂, —

BR^B7(OR^B9) and tetrazolyl.

7. The method of claim 6, wherein R^D is selected from —

C(═

O)R^B7, —

CO₂H, —

CHO, —

CO₂R^B7, —

C(═

O)N(R^B8)₂, —

C(═

NR^B8)OR^B7, —

C(═

NR^B8)N(R^B8)₂, —

C(═

O)NR^B8SO₂R^B7, —

C(═

S)N(R^B8)₂, —

C(═

O)SR^B7 and —

C(═

S)SR^B7.

8. The method of claim 7, wherein R^D is selected from —

C(═

O)R^B7, —

CO₂H, —

CHO, and —

CO₂R^B7.

9. The method of claim 8, wherein R^D is —

CO₂H.

10. The method of claim 3, wherein R^B is further substituted with the group:

—

R^E

wherein;

R^E is selected from halogen, —

OH, —

OR^B10, —

ON(R^B11)₂, —

N(R^B11)₂, —

N(OR^B12)R^B12, —

SH, —

SR^B10, —

SSR^B12, —

OC(═

O)R^B10, —

OCO₂R^B10, —

OC(═

O)N(R^B11)₂, —

NR^B11C(═

O)R^B10, —

NR^B11CO₂R^B10, —

NR^B11C(═

O)N(R^B11)₂, —

OC(═

NR^B11)R^B10, —

OC(═

NR^B11)OR^B10, —

OC(═

NR^B11)N(R^B11)₂, —

NR^B11(═

NR^B11)N(R^B11)₂, —

NR^B11SO₂R^B10, —

OSO₂R^B10, —

OS(═

O)R^B10, —

Si(R^B10)₃, —

OSi(R^B10)₃, —

SC(S)SR^B10, —

OP(═

O)₂R^B10, —

OP(═

O)(R^B10)₂, —

OP(═

O)(OR^B12)₂, —

OP(═

O)₂N(R^B11)₂, —

OP(═

O)(NR^B11)₂, —

NR^B11P(═

O)(OR^B12)₂, —

NR^B11P(═

O)(NR^B11)₂, —

P(R^B12)₂, —

P(R^B12)₃, —

OP(R^B12)₂, —

OP(R^B12)₃, 3-14 membered heterocyclyl and 5-14 membered heteroaryl, wherein the point of attachment of the 3-14 membered heterocyclyl or 5-14 membered heteroaryl group is on a nitrogen atom;

each instance of R^B10 is, independently, selected from C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, 3-14 membered heteroaliphatic, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl;

each instance of R^B11 is, independently, selected from hydrogen, —

OH, —

OR^B10, —

N(R^B12)₂, —

CN, —

C(═

O)R^B10, —

C(═

O)N(R^B12)₂, —

CO₂R^B10, —

SO₂R^B10, —

C(═

NR^B12)OR^B10, —

C(═

NR^B12)N(R^B12)₂, —

SO₂N(R^B12)₂, —

SO₂R^B12, —

SO₂OR^B12, —

SOR^B10, —

C(═

S)N(R^B12)₂, —

C(═

O)SR^B12, —

C(═

S)SR^B12, —

P(═

O)₂R^B10, —

P(═

O)(R^B10)₂, —

P(═

O)₂N(R^B12)₂, —

P(═

O)(NR^B12)₂, C_1-10alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, 3-14 membered heteroaliphatic, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^B11 groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and

each instance of R^B12 is, independently, selected from hydrogen, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, 3-14 membered heteroaliphatic, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^B12 groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

11. The method of claim 10, wherein R^E is selected from halogen, —

OH, —

OR^B10, —

ON(R^B11)₂, —

N(R^B11)₂, —

N(OR^B12)R^B12, —

SH, —

SR^B10, —

SSR^B12, —

Si(R^B10)₃, —

OSi(R^B10)₃, —

P(R^B12)₂, —

P(R^B12)₃, —

OP(R^B12)₂, —

OP(R^B12)₃, 3-14 membered heterocyclyl and 5-14 membered heteroaryl, wherein the point of attachment of the 3-14 membered heterocyclyl or 5-14 membered heteroaryl group is on a nitrogen atom.

12. The method of claim 11, wherein R^E is selected from halogen, —

OR^B10 and —

N(R^B11)₂.

13. The method of claim 3, wherein R^C is selected from C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, 3-14 membered heteroaliphatic, C_3-10 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl.

14. The method of claim 13, wherein R^C is C_3-10 alkyl.

15. The method of claim 13, wherein R^C is C_3-10 carbocyclyl.

16. The method of claim 3, wherein R^A is C_6-14 aryl or 5-14 membered heteroaryl, and R^B is C_6-14 aryl.

17. The method of claim 16, wherein R^A is C_6-14 aryl and R^B is C_6-14 aryl.

18. The method of claim 16, wherein R^A is 5-14 membered heteroaryl and R^B is C_6-14 aryl.

19. The method of claim 3, wherein the compound is of the formula (II):

20. The method of claim 19, wherein at least one of R⁶, R⁷, R⁸, R⁹ and R¹⁰ is the group —

R^E.

21. The method of claim 3, wherein the FASN-mediated disorder is a microbial infection.

22. The method of claim 21, wherein the microbial infection is a viral infection.

23. The method of claim 22, wherein the viral infection is an infection with an enveloped virus or a picornavirus.

24. The method of claim 22, wherein the viral infection is selected from HSV-1, HSV-2, VZV, EBV, CMV, HHV-6, HHV-8, HMCV, CVB3, influenza type A, influenza type B, RSV, PIV, measles virus, rhinovirus, adenovirus, HMPV, SARS virus, vaccinia virus, cowpox virus, ectomelia virus, monkeypox virus, rabbitpox virus, HBV, HCV, papillomavirus, BK virus, VEE virus, Rift Valley fever virus, Tavaribe virus, Yellow fever virus, West Nile virus, dengue virus, PTV or Pichinde virus.

25. The method of claim 24, wherein the viral infection is infection with HCV or dengue virus.

26. The method of claim 22, which further comprises administration of one or more additional anti-viral agents.

27. The method of claim 26, wherein the additional anti-viral agent is an interferon, a protease inhibitor, an integrase inhibitor, a reverse transciptase inhibitor, or a combination thereof.

28. The method of claim 26, wherein the additional anti-viral agent is an interferon, ribavirin or a combination thereof.

29. The method of claim 28, wherein the interferon is interferon type III, interferon type II, interferon type I, peginterferon alfa-2a, peginterferon alfa-2b, standard interferon alfa-2a, standard interferon alfa-2b, consensus interferon, interferon alfacon-1, ALBUFERON, omega interferon, interferon gamma-1b, lymphoblastoid interferon tau, or a combination thereof.

30. The method of claim 21, wherein the microbial infection is a bacterial infection.

31. The method of claim 30, wherein the bacterial infection is selected from Helicobacter pyloris, Borelia burgdorferi, Legionella pneumophilia, Mycobacteria tuberculosis, M. avium, M. intracellulare, M. kansaii, M. gordonae, Staphylococcus aureus, Neisseria gonorrhoeae, Neisseria meningitidis, Listeria monocytogenes, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, Streptococcus faecalis, Streptococcus bovis, Streptococcus pneumoniae, Haemophilus influenzae, Bacillus antracis, corynebacterium diphtheriae, Erysipelothrix rhusiopathiae, Clostridium perfringers, Clostridium tetani, Enterobacter aerogenes, Klebsiella pneumoniae, Pasturella multocida, Fusobacterium nucleatum, Streptobacillus moniliformis, Treponema pallidium, Treponema pertenue, Leptospira, Rickettsia, Actinomyces israelli or a combination thereof.

32. The method of claim 31, wherein the bacterial infection is Mycobacteria tuberculosis.

33. The method of claim 30, wherein the compound is:

34. The method of claim 21, wherein the microbial infection is a fungal infection.

35. The method of claim 34, wherein the fungal infection is an infection with aspergilliosis, crytococcosis, sporotrichosis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, blastomycosis, zygomycosis or candidiasis.

36. The method of claim 21, wherein the microbial infection is a parasitic or protozoal infection.

37. The method of claim 36, wherein the parasitic or protozoal infection is an infection with P. falcifarium, P. ovale, P. vivax, P. malariae, L. donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana, L. braziliensis, T. Gondii, B. microti. B. divergens, B. coli, B. hominis, C. parvum, C. cayetanensis, D. fragilis, E. histolytica, I. belli, S. mansonii, S. haematobium, Trypanosoma ssp. Toxoplasma ssp., O. volvulus, Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp., T. canis, Cestoda, Theileria ssp. or a combination thereof.

38. The method of claim 36, wherein the parasitic or protozoal infection causes malaria, babesiosis, trypanosomiasis, American trypanosomiasis, leishmaniasis, toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis, cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis, ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis, toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis, filariasis, schistosomiasis or dermatitis caused by animal schistosomes.

39. The method of claim 38, wherein the parasitic or protozoal infection causes malaria.

40. The method of claim 38, wherein the parasitic or protozoal infection causes leishmaniasis, babesiosis, toxoplasmosis or trypanosomiasis.

41. The method of claim 3, wherein the FASN-mediated disorder is a hyperproliferative disorder.

42. The method of claim 41, wherein the hyperproliferative disorder is cancer.

43. The method of claim 42, wherein the cancer is selected from bladder cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, endometrial cancer, gastric cancer, gastrointestinal stromal tumor, kidney cancer, liver cancer, lung cancer, mesothelioma, multiple myeloma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, Paget'"'"'s disease of the vulva, retinoblastoma, soft tissue sarcoma, skin cancer or thyroid cancer.

44. The method of claim 42, wherein the cancer is pancreatic cancer.

45. The method of claim 42, wherein the cancer is selected from mesothelioma, multiple myeloma, neuroblastoma, Paget'"'"'s disease, retinoblastoma, leukemia, myelodisplastic syndrome, and soft tissue sarcoma.

46. The method of claim 42, which further comprises administration of one or more anti-cancer agents.

47. The method of claim 3, wherein the FASN-mediated disorder is an inflammatory disorder.

48. The method of claim 47, wherein the inflammatory disorder is selected from anemia, asthma, arteritis, arthritis, chronic obstructive pulmonary disease, dermatitis, gastroesophageal reflux disease, Crohn'"'"'s disease, inflammatory bowel syndrome, multiple sclerosis, psoriasis and an autoimmune disease.

49. The method of claim 3, wherein the FASN-mediated disorder is an obesity related disorder.

50. The method of claim 49, wherein the obesity related disorder is selected from Type II diabetes mellitus, elevated blood pressure, elevated cholesterol levels, ischemic heart disease, arterial vascular disease, angina, myocardial infarction, stroke, migraines, congestive heart failure, deep vein thrombosis, pulmonary embolism, gall stones, gastroesophagael reflux disease, obstructive sleep apnea, obesity hypoventilation syndrome, asthma, gout, poor mobility, back pain, erectile dysfunction, urinary incontinence, liver injury, fatty liver, and chronic renal failure.

51. The method of claim 3, wherein the FASN-mediated disorder is Type II diabetes mellitus.

52. The method of claim 3, wherein the FASN-mediated disorder is fatty liver disease.

53. The method of claim 3, wherein the compound is:

54. The method of claim 3, wherein the compound is:

55. The method of claim 3, wherein the hyperproliferative disorder is selected from prostate cancer and hepatocellular cancer.

56. The method of claim 55, wherein the compound is

57. A method of treating pancreatic cancer in a subject comprising administering to the subject a therapeutically effective amount of compound: