THIENOPYRIMIDIONES FOR TREATMENT OF INFLAMMATORY DISORDERS AND CANCERS

• US 20100216820A1
• Filed: 11/13/2007
• Published: 08/26/2010
• Est. Priority Date: 11/13/2006
• Status: Abandoned Application

• Current Assignee: ICOS Corporation (Eli Lilly and Company)
• Original Assignee: ICOS Corporation (Eli Lilly and Company)
• Inventors: Farouz, Francine, Thorsett, Eugene, Ruan, Fuqiang, White, Stephen L., Kesicki, Edward A.
• Application Number:
  US12/514,779
• Publication Number:
  US 20100216820A1
• Time in Patent Office: Days
• US Class Current: 514/260.100
• 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 11/02 Nasal agents, e.g. decongestants
• 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 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 519/00 : Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The current invention provides compounds of formula (1): wherein: one of Q¹, Q² and Q³ is S, and the other of two of Q¹, Q² and Q³ are —CR¹—, which are inhibitors of PI3K-delta. These compounds are useful for treatment of conditions mediated by PI3K-delta, such as hematopoietic cancers, immune disorders, and bone resorption disorders. The invention further provides pharmaceutical compositions comprising a compound of formula (1) and methods of using these compounds and compositions to treat conditions mediated by PI3K-delta.

Claims

1. A compound of the formula (1):

2. The compound of claim 1, wherein Q¹ is S.

3. The compound of claim 1, wherein Q² is S.

4. The compound of claim 1, wherein Q³ is S.

5. The compound of claim 1, wherein Z is a bond and R³ is optionally substituted aryl.

6. The compound of claim 5, wherein Het is an optionally substituted bicyclic group consisting of two aromatic rings fused together, wherein each of the two aromatic rings contains at least one N as a ring member.

7. The compound of claim 6, wherein Het represents a purine ring system.

8. The compound of claim 6, wherein Het represents a pyrazolopyrimidine ring system.

9. The compound of claim 6, wherein Het represents a pyrrolopyrimidine ring system.

10. The compound of claim 6, wherein L is CHR².

11. The compound of claim 6, wherein L is —

CHR²—

NR²—

.

12. The compound of claim 6, wherein L is —

CHR²—

S(O)_n—

, and n is 0 or 2.

13. The compound of claim 10, wherein L contains a chiral center that is in the S stereochemical configuration.

14. The compound of claim 1, which is a compound of formula (2a), (2b), or (2c):

15. A method to treat a hematologic cancer, comprising administering to a subject diagnosed with a hematologic cancer an effective amount of a compound of claim 1.

16. The method of claim 15, wherein the hematologic cancer is leukemia.

17. The method of claim 16, wherein the leukemia is acute lymphoblastic leukemia;

acute myeloid leukemia;

chronic lymphocytic leukemia;

chronic myelogenous leukemia;

or hairy cell leukemia.

18. A method to treat an inflammatory disorder or immune disorder, comprising administering to a subject diagnosed with an inflammatory disorder or immune disorder an effective amount of a compound of claim 1.

19. The method of claim 18, wherein the inflammatory disorder or immune disorder is rheumatoid arthritis, multiple sclerosis, asthma, systemic lupus erythematosus, scleroderma, Sjö

gren'"'"'s syndrome, myasthenia gravis, Guillain-Barré

syndrome, Hashimoto'"'"'s thyroiditis, Graves'"'"' disease, inflammatory bowel disease (IBD), Crohn'"'"'s disease, ulcerative colitis, vasculitis, hemolytic anemia, thrombocytopenia, psoriasis, type I (insulin dependent) diabetes, or allergic rhinitis.

20. A method to treat hypertension, comprising administering to a subject diagnosed with hypertension an effective amount of a compound of claim 1.

21. A pharmaceutical composition comprising a compound of claim 1, admixed with at least one pharmaceutically acceptable excipient.

22. The pharmaceutical composition of claim 21, which is a solid dosage form for oral administration.

25. The compound of claim 11, wherein L contains a chiral center that is in the S stereochemical configuration.

26. The compound of claim 12, wherein L contains a chiral center that is in the S stereochemical configuration.

27. The compound of claim 1, which is selected from:

6-Bromo-3-phenyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-thieno[2,3-d]pyrimidin-4-one;

2-(6-Amino-purin-9-ylmethyl)-6-bromo-3-phenyl-3H-thieno-[2,3-d]pyrimidin-4-one;

2-[1-(4-Amino-benzoimidazol-1-yl)-ethyl]-3-phenyl-3H-thieno[3,2-d]pyrimidin-4-one;

3-Phenyl-2-[1-(9H-purin-6-ylsulfanyl)-ethyl]-3H-thieno[3,2-d]pyrimidin-4-one;

3-Phenyl-2-[1-(9H-purin-6-ylamino)-ethyl]-3H-thieno[3,2-d]pyrimidin-4-one;

3-Phenyl-2-(9H-purin-6-ylsulfanylmethyl)-3H-thieno[3,2-d]pyrimidin-4-one;

3-Phenyl-2-[1-(9H-purin-6-ylamino)propyl]thieno-[3,2-d]pyrimidin-4(3H)-one;

3-(2-Methylphenyl)-2-[1-(9H-purin-6-ylamino)propyl]thieno[3,2-d]pyrimidin-4(3H)-one;

3-(3-Methylphenyl)-2-[1-(9H-purin-6-ylamino)propyl]thieno[3,2-d]pyrimidin-4(3H)-one;

3-(4-methylphenyl)-2-[1-(9H-purin-6-ylamino)propyl]thieno[3,2-d]pyrimidin-4(3H)-one;

3-(3,5-Difluorophenyl)-2-[1-(9H-purin-6-ylamino)propyl]thieno[3,2-d]pyrimidin-4(3H)-one;

3-(3-Methoxyphenyl)-2-[1-(9H-purin-6-ylamino)propyl]thieno[3,2-d]pyrimidin-4(3H)-one;

2-{1-[(2-Amino-9H-purin-6-yl)amino]propyl}-3-phenylthieno[3,2-d]pyrimidin-4(3H)-one;

2-{1-[(2-Fluoro-9H-purin-6-yl)amino]propyl}-3-phenylthieno[3,2-d]pyrimidin-4(3H)-one;

2-[(6-Amino-9H-purin-9-yl)methyl]-3-(2-methylphenyl)thieno[3,2-d]pyrimidin-4(3H)-one;

2-[1-(4-Amino-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propyl]-3-phenylthieno[3,2-d]pyrimidin-4(3H)-one;

2-[(6-Amino-9H-purin-9-yl)methyl]-3-(2-methylphenyl)thieno[2,3-d]pyrimidin-4(3H)-one;

and the pharmaceutically acceptable salts thereof.

28. The compound of claim 1, which is selected from

23-24. -24. (canceled)