# US 8,569,296 B2 · PI3K (delta) selective inhibitors

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- Number: US 8,569,296 B2
- Document ID: US8569296B2
- Status: Granted
- Kind: B2
- Application number: 13/498,770
- Filed: 2010-09-29
- Published: 2012-08-09
- Granted: 2013-10-29
- Earliest claimed: 2009-09-29
- Assignees: Xcovery Holding Company, LLC
- Applicants: Congxin Liang
- Inventors: Congxin Liang
- Web page: https://patentgrep.com/patent/US8569296B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 473/16: two nitrogen atoms
- C07D 495/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Novel PI3K, especially PI3K delta isoform, selective inhibitors are disclosed. The compounds are useful in treating disorders related to abnormal PI3K or PI3Kδ activities such as cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorders and neurological disorders.

## Claims

### Claim 1

A compound that is
4-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl}piperidyl 4-methylpiperazinyl ketone.

### Claim 2

A compound that is
1-(2-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl}ethyl)-4-(methylsulfonyl)piperazine;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;
[4-[6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(4-fluorophenyl)methanone;
[4-[6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(4-pyridyl)methanone;
[4-[6-[2-(difluoromethyl)benzimidazol-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(3-pyridyl)methanone;
(4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-N,N-dimethylcarboxamide;
methyl 4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidinecarboxylate;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;
(2R)-1-(4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-2-hydroxypropan-1-one;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl pyrrolidinyl ketone;
4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;
4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;
1-(9-(2H-3,4,5,6-tetrahydropyran-4-yl)-2-morpholin-4-ylpurin-6-yl)-2-(difluoromethyl)-4-methoxybenzimidazole;
(3-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}pyrrolidinyl)-N,N-dimethylcarboxamide; or
4-{3-(2H-3,4,5,6-tetrahydropyran-4-yl)-7-[2-(difluoromethyl)benzimidazolyl]-1,2,3-triazolo[5,4-d]pyrimidin-5-yl}morpholine.

### Claim 3

A method of treating a PI-3 kinase mediated disease in a subject having said disease comprising administering to the subject a compound selected from:
4-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl}piperidyl 4-methylpiperazinyl ketone;
1-(2-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo[5,4-d]pyrimidinyl}ethyl)-4-(methylsulfonyl)piperazine;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;
[4-[6-[2-(difluoromethyl)benzimidazolyl-1-yl]-2-morpholin-purin-9-yl]-1-piperidyl]-(4-fluorophenyl)methanone;
[4-[6-[2-(difluoromethyl)benzimidazolyl-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(4-pyridyl)methanone;
[4-[6-[2-(difluoromethyl)benzimidazolyl-1-yl]-2-morpholino-purin-9-yl]-1-piperidyl]-(3-pyridyl)methanone;
(4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-N,N-dimethylcarboxamide;
methyl 4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidinecarboxylate;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;
(2R)-1-(4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-2-hydroxypropan-1-one;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl pyrrolidinyl ketone;
4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;
4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;
1-(9-(2H-3,4,5,6-tetrahydropyran-4-yl)-2-morpholin-4-ylpurin-6-yl)-2-(difluoromethyl)-4-methoxybenzimidazole;
(3-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-pyrrolidinyl)-N,N-dimethylcarboxamide; and
4-{3-(2H-3,4,5,6-tetrahydropyran-4-yl)-7-[2-(difluoromethyl)benzimidazolyl]-1,2,3-triazolo[5,4-d]pyrimidin-5-yl}morpholine.

### Claim 4

A method of treating a PI-3 kinase mediated disease in a subject having said disease comprising administering to the subject a composition comprising a compound selected from:
4-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo-[5,4-d]pyrimidinyl}piperidyl 4-methylpiperazinyl ketone;
1-(2-{4-[2-(difluoromethyl)benzimidazolyl]-6-morpholin-4-ylpyrazolo-[5,4-d]pyrimidinyl}ethyl)-4-methylsulfonyl)piperazine;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;
[4-[6-[2-(difluoromethyl)benzimidazolyl-1-yl]-2-morpholin-purin-9-yl]-1-piperidyl]-(4-fluorophenyl)methanone;
[4-[6-[2-(difluoromethyl)benzimidazolyl-1-yl]-2-morpholin-purin-9-yl]-1-piperidyl]-(4-pyridyl)methanone;
[4-[6-[2-(difluoromethyl)benzimidazolyl-1-yl]-2-morpholin-purin-9-yl]-1-piperidyl]-(3-pyridyl)methanone;
(4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-N,N-dimethylcarboxamide;
methyl 4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidinecarboxylate;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;
(2R)-1-(4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl)-2-hydroxypropan-1-one;
4-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl pyrrolidinyl ketone;
4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}piperidyl 4-methylpiperazinyl ketone;
4-{6-[2-(difluoromethyl)-4-methoxybenzimidazolyl]-2-morpholin-4-ylpurin-9-yl}-1-(methylsulfonyl)piperidine;
1-(9-(2H-3,4,5,6-tetrahydropyran-4-yl)-2-morpholin-4-ylpurin-6-yl)-2-(difluoromethyl)-4-methoxybenzimidazole;
(3-{6-[2-(difluoromethyl)benzimidazolyl]-2-morpholin-4-ylpurin-9-yl}pyrrolidinyl)-N,N-dimethylcarboxamide; and
4-{3-(2H-3,4,5,6-tetrahydropyran-4-yl)-7-[2-(difluoromethyl)benzimidazolyl]-1,2,3-triazolo[5,5-d]pyrimidin-5-yl}morpholine.

### Claim 5 (depends on 4)

The method of claim 4, wherein the disease is mediated by the PI3Kδ.

### Claim 6 (depends on 4)

The method of claim 4, wherein the disease is mediated by one or more of the PI3K isoforms.

### Claim 7 (depends on 4)

The method of claim 4, wherein the disease is cancer, immune disorder, cardiovascular disease, viral infection, inflammation, metabolism/endocrine disorder or neurological disorder.