Heterocyclic compounds and uses thereof

• US 9,775,844 B2
• Filed: 03/18/2015
• Issued: 10/03/2017
• Est. Priority Date: 03/19/2014
• Status: Active Grant

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Kutok, Jeffery L., Winkler, David G., Palombella, Vito J., Castro, Alfredo C., Evans, Catherine A., Janardanannair, Somarajannair, Lescarbeau, Andre, Liu, Tao, Tremblay, Martin R.
• Primary Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US14/661,656
• Publication Number:
  US 20150290207A1
• Time in Patent Office: 930 Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• 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 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• 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 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 39/0005 Vertebrate antigens from snakes A61K39/38
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 39/39566 against immunoglobulins, e.g. anti-idiotypic antibodies
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• 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 3/12 : for electrolyte homeostasis
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07K 16/2827 : against B7 molecules, e.g. CD80, CD86
• 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

Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.

Claims

1. A method of treating a PI3K-gamma mediated disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the formula:

2. The method of claim 1, wherein the subject has a PI3K-gamma mediated disorder selected from cancer, an inflammatory disease, or an autoimmune disease.

3. The method of claim 2, wherein the disorder is cancer and the cancer is a solid tumor.

4. The method of claim 2, wherein the disorder is a cancer selected from one or more of:

a cancer of the pulmonary system, a brain cancer, a cancer of the gastrointestinal tract, a skin cancer, a genitourinary cancer, head and neck cancer, a sarcoma, a carcinoma, and a neuroendocrine cancer.

5. The method of claim 1, wherein the subject is a human.

6. The method of claim 1, wherein the therapeutically effective amount of the compound is about 2 mg per day, about 1-3 mg per day, about 1-5 mg per day, about 1-10 mg per day, about 0.5-20 mg per day, about 0.1-50 mg per day, about 0.1-75 mg per day, about 0.1-100 mg per day, about 0.1-250 mg per day, about 0.1-500 mg per day, about 0.1-1000 mg per day, about 1-50 mg per day, about 1-75 mg per day, about 1-100 mg per day, about 1-250 mg per day, about 1-500 mg per day, about 1-1000 mg per day, about 10-50 mg per day, about 10-75 mg per day, about 10-100 mg per day, about 10-250 mg per day, about 10-500 mg per day, about 10-1000 mg per day, about 100-500 mg per day, or about 100-1000 mg per day.

7. The method of claim 1, wherein the therapeutically effective amount of the compound is about 0.029 mg/kg, about 0.014-0.14 mg/kg, about 0.02-0.04 mg/kg, about 0.01-0.05 mg/kg, about 0.01-0.1 mg/kg, or about 0.01-0.5 mg/kg.

8. The method of claim 1, wherein the compound is administered once every two days.

9. The method of claim 1, wherein the compound is administered once per day.

10. The method of claim 1, wherein the compound is administered twice per day.

11. The method of claim 1, wherein the compound is administered at a dose such that the level of the compound in the subject is higher than the compound'"'"'s IC₅₀ of PI3K-gamma inhibition during at least 70%, 80%, 90%, 95%, 97%, 98%, or 99% of 6 hours, 12 hours, 24 hours, or 48 hours immediately following the administration.

12. The method of claim 1, wherein the compound is administered at a dose such that the level of the compound in the subject is higher than the compound'"'"'s IC₉₀ of PI3K-gamma inhibition during at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% of 6 hours, 12 hours, 24 hours, or 48 hours immediately following the administration.

13. The method of claim 1, wherein the compound is administered at a dose such that the level of the compound in the subject does not rise higher than the compound'"'"'s IC₂₀ or IC₅₀ of PI3K-delta inhibition within 6 hours, 12 hours, 24 hours, or 48 hours immediately following the administration.

14. The method of claim 1, wherein the compound is administered at a dose such that it provides at least 50% inhibition of PI3K-gamma in the subject but less than 10% or 20% inhibition of PI3K-delta in the subject.

15. The method of claim 1, wherein the subject is a human and the compound has a half life of about 10-13 hours in the subject.

16. The method of claim 2, wherein the disorder is a cancer selected from one or more of:

a pancreatic cancer, a lung cancer, a breast cancer, a prostate cancer, a testicular cancer, an esophageal cancer, a liver cancer, a gastric cancer, a colon cancer, a colorectal cancer, an ovarian cancer, a cervical cancer, a uterine cancer, an endometrial cancer, a bladder cancer, a kidney cancer, and a viral-induced cancer.

17. The method of claim 2, wherein the disorder is a cancer selected from one or more of:

a medullobastoma, a basal cell carcinoma, a glioma, a hepatocellular cancer, a gastrointestinal stromal tumor (GIST), a melanoma, a neuroectodermal tumor, a soft-tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, a leiomyosarcoma, a bladder carcinoma, an epithelial carcinoma, a squamous cell carcinoma, an adenocarcinoma, a bronchogenic carcinoma, a renal cell carcinoma, a hepatoma, a bile duct carcinoma, a carcinoid tumor, diffuse type giant cell tumor, and glioblastoma.

18. The method of claim 3, wherein the solid tumor is melanoma, lung cancer, head and neck cancer, renal cell carcinoma, bladder cancer, breast cancer, colon cancer, or glioblastoma.

19. The method of claim 18, wherein the solid tumor is non-small cell lung cancer.

20. The method of claim 2, wherein the cancer is metastatic.

21. The method of claim 1, wherein the compound is administered at a dose of about 10, about 15, about 20, about 25, about 30, about 35, or about 40 mg once daily.

22. The method of claim 3, which further comprises administering to the subject a second therapeutic agent that is a P-gp substrate.

23. The method of claim 3, which further comprises administering a PI3K-delta inhibitor to the subject.

24. The method of claim 3, which further comprises administering an immunomodulator to the subject.

25. The method of claim 24, wherein the immunomodulator is a NKG2C ligand, a NKG2D ligand, a CTLA-4 inhibitor, a PD-1 inhibitor, a PDL-1 inhibitor, a LAG3 inhibitor, a TIM-3 inhibitor, a BTLA inhibitor, a VISTA inhibitor, a TIGIT inhibitor, a HDAC inhibitor, a proteasome inhibitor, an IDO inhibitor, a CSF1 inhibitor, a CCL2 antibdoy, an ARG1 inhibitor, a CD28 agonist, an ICOS agonist, a CD137 agonist, an OX40 agonist, a GITR agonist, a CD27 agonist, a CD30 agonist, a HVEM agonist, a CD28 agonist, a TLF ligand, GMCSF, a CD40 agonist, or a B7-H3 antibody.

26. The method of claim 24, wherein the immunomodulator is a PDL-1 inhibitor or an anti-PDL-1 antibody.

27. The method of claim 26, wherein the PD-L1 inhibitor or the anti-PDL-1 antibody is YW243.55.S70, MDPL3280A, MSB0010718C, MDX-1105, or MEDI-4736.

28. The method of claim 24, wherein the immunomodulator is a PD-1 inhibitor or an anti-PD-1 antibody.

29. The method of claim 28, wherein the PD-1 inhibitor or the anti-PD-1 antibody is nivolumab, pembrolizumab, pidilizumab, AMP-244, or AMP-514.

30. The method of claim 29, wherein the PD-1 inhibitor or the anti-PD-1 antibody is nivolumab.

31. The method of claim 29, wherein the PD-1 inhibitor or the anti-PD-1 antibody is pembrolizumab.

32. The method of claim 24, wherein the immunomodulator is a CTLA-4 inhibitor or an anti-CTLA4 antibody.

33. The method of claim 32, wherein the CTLA-4 inhibitor or the anti-CTLA4 antibody is tremelimumab or ipilimumab.

34. The method of claim 24, wherein the immunomodulator is a combination of a PD-1 inhibitor or an anti-PD-1 antibody and a CTLA-4 inhibitor or an anti-CTLA-4 antibody.

35. The method of claim 34, wherein the PD-1 inhibitor or the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, AMP-244, and AMP-514, and the CTLA-4 inhibitor or the anti-CTLA-4 antibody is selected from the group consisting of tremelimumab and ipilimumab.

36. The method of claim 35, wherein the PD-1 inhibitor or the anti-PD-1 antibody is nivolumab.

37. The method of claim 35, wherein the PD-1 inhibitor or the anti-PD-1 antibody is pembrolizumab.

38. The method of claim 24, wherein the immunomodulator is a combination of a PD-1 inhibitor or an anti-PD-1 antibody, a PDL-1 inhibitor or an anti-PDL-1 antibody, and a CTLA-4 inhibitor or an anti-CTLA-4 antibody.

39. The method of claim 24, wherein the immunomodulator is a combination of an antibody or fragment thereof, an inhibitory nucleic acid, a soluble ligand, or a fusion of PD-1 with a Fc region of an immunoglobulin;

an antibody or fragment thereof, an inhibitory nucleic acid, a soluble ligand, or a fusion of PD-L1 with a Fc region of an immunoglobulin; and

an antibody or fragment thereof, an inhibitory nucleic acid, a soluble ligand, or a fusion of a CTLA-4 ligand with a Fc region of an immunoglobulin.

40. The method of claim 24, wherein the immunomodulator is a costimulatory ligand, a MCSF/CSF-1R inhibitor, an immunostimulant, a CXCR4/CXCL12 inhibitor, a CCL2 inhibitor, or a CCR2 inhibitor.

41. The method of claim 40, wherein the immunostimulant is GMCSF.

42. The method of claim 24, wherein the immunomodulator is cyclophosphamide, docetaxel, paclitaxel, 5-FU, or temozolomide.

43. The method of claim 3, which further comprises administering gemcitabine to the subject.

44. The method of claim 3, wherein the compound is administered in combination with a radiation therapy or a chemotherapy.

45. The method of claim 44, wherein the compound is administered after the administration of the radiation therapy or the chemotherapy.

46. The method of claim 6, wherein the therapeutically effective amount of the compound is about 1-100 mg per day.

47. The method of claim 24, wherein the immunomodulator is an IDO inhibitor.

48. The method of claim 47, wherein the IDO inhibitor is indoximod, NLG919, INCB024360, F001287, norharmane, rosmarinic acid, or alpha-methyl-tryptophan.