BICYCLIC INDOLE-PYRIMIDINE PI3K INHIBITOR COMPOUNDS SELECTIVE FOR P110 DELTA, AND METHODS OF USE

• US 20100305084A1
• Filed: 05/26/2010
• Published: 12/02/2010
• Est. Priority Date: 05/27/2009
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG), Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Lucas, Matthew, Kondru, Rama, Savy, Pascal Pierre Alexandre, Goldstein, David, Sweeney, Zachary K., Palmer, Wylie, Seward, Eileen Mary, Price, Stephen, Sutherlin, Daniel P., Castanedo, Georgette, Safina, Brian
• Granted Patent: US 8,158,625 B2
• Time in Patent Office: Days
• US Class Current: 514/186
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Formula I (Ia and Ib) compounds wherein (i) X¹ is N and X² is S, (ii) X¹ is CR⁷ and X² is S, (iii) X¹ is N and X² is NR², (iv) X¹ is CR⁷ and X² is O, or (v) X¹ is CR⁷ and X² is NR², including stereoisomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Claims

1. A compound selected from Formulas Ia and Ib:

2. The compound of claim 1 selected from the structures:

3. The compound of claim 1 selected from the structures:

4. The compound of claim 1 selected from the structures:

5. The compound of claim 1 selected from the structures:

6. The compound of claim 1 selected from the structures:

7. The compound of claim 1 wherein R¹ is selected from the structures

8. The compound of claim 1 wherein R² is C₁-C₁₂ alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, —

CH₃, —

CH₂OH, —

CN, —

CF₃, —

CO₂H, —

COCH₃, —

CO₂CH₃, —

CONH₂, —

CONHCH₃, —

CON(CH₃)₂, —

NO₂, —

NH₂, —

NHCH₃, —

NHCOCH₃, —

NHS(O)₂CH₃, —

OH, —

OCH₃, —

S(O)₂N(CH₃)₂, —

SCH₃, —

CH₂OCH₃, and —

S(O)₂CH₃.

9. The compound of claim 8 wherein R² is CH₃.

10. The compound of claim 1 wherein R⁷ is H.

11. The compound of claim 1 wherein R⁷ is C₁-C₁₂ alkyl optionally substituted with one or more groups independently selected from F, Cl, Br, I, —

CH₃, —

CH₂OH, —

CN, —

CF₃, —

CO₂H, —

COCH₃, —

CO₂CH₃, —

CONH₂, —

CONHCH₃, —

CON(CH₃)₂, —

NO₂, —

NH₂, —

NHCH₃, —

NHCOCH₃, —

NHS(O)₂CH₃, —

OH, —

OCH₃, —

S(O)₂N(CH₃)₂, —

SCH₃, —

CH₂OCH₃, and —

S(O)₂CH₃.

12. The compound of claim 1 selected from:

1-((2-(1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine;

1-((2-(indolin-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine;

1-((2-(1H-indol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine;

4-(1-((2-(1H-indol-3-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine;

N,N-dimethyl-1-((2-(2-methyl-1H-indol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine;

(S)-2-(4-((2-(1H-indol-3-yl)-7-methyl-4-(3-methylmorpholino)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide;

2-(1-((9-(2-hydroxyethyl)-2-(1H-indol-3-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol;

4-(2-(1H-indol-3-yl)-9-methyl-8-(4-(tetrahydro-2H-1,1-dioxo-thiopyran-4-yl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine;

1-(1-((9-ethyl-2-(5-fluoro-1H-indol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)pyrrolidin-2-one;

1-((2-(1H-indol-3-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-N,N-dimethylpiperidin-4-amine;

4-(2-(1H-indol-3-yl)-9-methyl-8-((4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine;

N,N-dimethyl-1-((2-(5-methyl-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-amine;

1-((2-(5-fluoro-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine;

2-(4-((2-(1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide;

2-(1-((2-(1H-indol-3-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol;

9-((2-(1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one;

4-(5-(1H-indol-3-yl)-2-(3-morpholinoazetidin-1-yl)methyl)thiazolo[5,4-d]pyrimidin-7-yl)morpholine;

1-((2-(7-fluoro-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine;

1-((2-(5-fluoro-2-methyl-1H-indol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine;

1-((2-(5-fluoro-1H-indol-1-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-N,N-dimethylpiperidin-4-amine;

2-(2-(2-(1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)propan-2-yloxy)-1-(pyrrolidin-1-yl)ethanone;

(3S,4R)-1-((2-(1H-indol-3-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine;

(3R,4S)-1-((2-(1H-indol-3-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine;

2-(1-((2-(6-fluoro-1H-indol-3-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol;

4-(2-(1H-indol-3-yl)-6-(2-(2-(pyrrolidin-1-yl)ethoxy)propan-2-yl)thieno[3,2-d]pyrimidin-4-yl)morpholine;

2-(4-((2-(2-(methoxymethyl)-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide;

2-(1-((2-(2-(methoxymethyl)-1H-indol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol;

2-(1-((9-methyl-2-(2-methyl-1H-indol-1-yl)-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol;

2-(4-((2-(2-cyano-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide;

4-(2-(1H-indol-3-yl)-8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-9H-purin-6-yl)morpholine;

4-(8-((4-(2-methoxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-2-(2-methyl-1H-indol-1-yl)-9H-purin-6-yl)morpholine;

1-(6-((4-(dimethylamino)piperidin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidin-2-yl)-1H-indol-5-ol;

2-methyl-2-(4-((2-(2-methyl-1H-indol-3-yl)-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide;

2-(1-((5-(1H-indol-3-yl)-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)methyl)piperidin-4-yl)propan-2-ol;

3-(8-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)-1H-indole-2-carbonitrile; and

1-(8-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-9-methyl-6-morpholino-9H-purin-2-yl)-1H-indole-2-carbonitrile.

13. A pharmaceutical composition comprised of a compound of claim 1, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

14. The pharmaceutical composition according to claim 13, further comprising a second chemotherapeutic agent.

15. A process for making a pharmaceutical composition which comprises combining a compound of claim 1 with a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

16. A method of treating a disease or disorder which method comprises administering a therapeutically effective amount of a compound of claim 1 to a patient with a disease or disorder selected from immune disorders, cancer, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by the p110 delta isoform of PI3 kinase.

17. The method of claim 16 wherein the disease or disorder is an immune disorder selected from systemic and local inflammation, arthritis, inflammation related to rheumatoid arthritis, immune suppression, organ transplant rejection, allergies, ulcerative colitis, Crohn'"'"'s disease, dermatitis, asthma, systemic lupus erythematosus, Sjö

gren'"'"'s Syndrome, multiple sclerosis, scleroderma/systemic sclerosis, idiopathic thrombocytopenic purpura (ITP), anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis, chronic obstructive pulmonary disease (COPD), and psoriasis.

18. A kit for treating a condition mediated by the p110 delta isoform of PI3 kinase, comprising:

a) a first pharmaceutical composition comprising a compound of claim 1; and

b) instructions for use.