INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA

• US 20100152211A1
• Filed: 10/07/2009
• Published: 06/17/2010
• Est. Priority Date: 04/25/2000
• Status: Active Grant

• Current Assignee: ICOS Corporation (Eli Lilly and Company)
• Original Assignee: ICOS Corporation (Eli Lilly and Company)
• Inventors: Treiberg, Jennifer, Dick, Ken, SADHU, Chanchal, Sowell, C. Gregory, Kesicki, Edward A., Oliver, Amy
• Granted Patent: US 8,492,389 B2
• Time in Patent Office: Days
• US Class Current: 514/263.210
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/04 Antipruritics
• 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 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/08 Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/66 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
• CPC Class Codes: C07D 233/66 : 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 carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/00 : Heterocyclic compounds containing purine ring systems
• CPC Class Codes: C07D 473/16 : two nitrogen atoms
• CPC Class Codes: C07D 473/24 : one nitrogen and one sulfur atom
• CPC Class Codes: C07D 473/30 : attached in position 6, e.g. hypoxanthine
• CPC Class Codes: C07D 473/32 : Nitrogen atom
• CPC Class Codes: C07D 473/34 : attached in position 6, e.g. adenine
• CPC Class Codes: C07D 473/38 : attached in position 6
• CPC Class Codes: C07D 473/40 : with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C12N 9/1205 : Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases
• CPC Class Codes: C12N 9/99 : Enzyme inactivation by chemical treatment
• CPC Class Codes: C12Y 207/01137 : Phosphatidylinositol 3-kinase (2.7.1.137)

Abstract

Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3Kδ) activity, and methods of treating diseases, such as disorders of immunity and inflammation, in which PI3Kδ plays a role in leukocyte function are disclosed. Preferably, the methods employ active agents that selectively inhibit PI3Kδ, while not significantly inhibiting activity of other PI3K isoforms. Compounds are provided that inhibit PI3Kδ activity, including compounds that selectively inhibit PI3Kδ activity. Methods of using PI3Kδ inhibitory compounds to inhibit cancer cell growth or proliferation are also provided. Accordingly, the invention provides methods of using PI3Kδ inhibitory compounds to inhibit PI3Kδ-mediated processes in vitro and in vivo.

Claims

1-17. -17. (canceled)

18. A compound of formula I

19. The compound of claim 18, wherein R³ is optionally substituted phenyl.

20. The compound of claim 19, wherein R³ is unsubstituted phenyl.

21. The compound of claim 19, wherein phenyl is substituted with one to three groups selected from the group consisting of halo, OR^a, C_1-6alkyl, aryl, heteroaryl, NO₂, N(R^a)₂, NR^aSO₂CF₃, NR^aC(═

O)R^a, C(═

O)OR^a, N(R^a)C_1-4alkylene(R^a)₂, SO₂N(R^a)₂, CN, C(═

O)R^a, C_1-4alkyleN(R^a)₂, OC_1-4alkyleneC≡

CR^a, OC_1-4alkyleneC(═

O)N(R^a)₂, OC_1-4alkylenearyl, OC_1-4-alkyleneheteroaryl, OC_1-4alkyleneHet, OC_1-4alkyleneN(R^a)₂, and N(R^a)C_1-4alkyleneN(R^a)₂;

wherein Het is a 5- or 6-membered heterocyclic ring, saturated or partially or fully unsaturated, containing at least one heteroatom selected from the group consisting of oxygen, nitrogen and sulfur, and optionally substituted with C_1-4alkyl or C(═

O)OR^a.

22. The compound of claim 19, wherein R³ is phenyl substituted with one to three substitutents selected from the group consisting of Cl, F, CH₃, CH(CH₃)₂, OH, OCH₃, O(CH₂)₃N(CH₃)₂, OCH₂C≡

CH, OCH₂C(═

O)NH₂, C₆H₅, NO₂, NH₂, NHC(═

O)CH₃, CO₂H, N(CH₃)CH₂CH₂N(CH₃)₂.

23. The compound of claim 18, wherein R¹ and R², independently, are selected from the group consisting of hydrogen, C_1-6 alkyl, halo, NO₂, OR^a, OCF₃, N(R^a)₂, and CN;

and

R^a is selected from the group consisting of hydrogen and C_1-6 alkyl.

24. The compound of claim 18, wherein R¹ and R², independently, are selected from the group consisting of hydrogen, OCH₃, Cl, Br, F, CH₃, CF₃, NO₂, OH and N(CH₃)₂.

25. The compound of claim 18, wherein A is optionally substituted with one to two substitutents selected from the group consisting of N(R^a)₂, halo, C_1-3alkyl, S(C_1-3alkyl), and OR^a.

26. The compound of claim 18, wherein A is optionally substituted with one to two substitutents selected from the group consisting of NH₂, NH(CH₃), N(CH₃)₂, NHCH₂C₆H₅, NH(C₂H₅), Cl, F, CH₃, SCH₃, and OH.

27. The compound of claim 18 selected from the group consisting of

2-[1-(2-fluoro-9H-purin-6-ylamino)ethyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-[1-(9H-purin-6-ylamino)ethyl]-3-o-tolyl-3H-quinazolin-4-one;

2-(1-(2-amino-9H-purin-6-ylamino)ethyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

5-methyl-2-(1-(9H-purin-6-ylamino)propyl)-3-o-tolyl-3H-quinazolin-4-one;

2-(1-(2-fluoro-9H-purin-6-ylamino)propyl)-5-methyl-3-o-tolyl-3H-quinazolin-4-one; and

2-[1-(2-amino-9H-purin-6-ylamino)propyl]-5-methyl-3-o-tolyl-3H-quinazolin-4-one;

or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising an effective amount of a compound of claim 18 or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable excipient.

29. A method to treat an arthritic disorder, which comprises administering to a subject in need thereof an effective amount of a compound of claim 18.

30. The method of claim 29, wherein the arthritic disorder is selected from the group consisting of rheumatoid arthritis, monoarticular arthritis, osteoarthritis, and gouty arthritis.

31. A method to treat a condition selected from the group consisting of asthma, allergic rhinitis, chronic obstructive pulmonary disease, diabetes, and multiple sclerosis;

which comprises administering to a subject in need thereof an effective amount of a compound of claim 18.

32. A method to treat leukemia, which comprises administering to a subject in need thereof an effective amount of a compound of claim 18.

33. The method of claim 32, wherein leukemia is chronic myeloid leukemia (CML) or lymphocytic leukemia.