# US 2013/0157977 A1 · Benzimidazole Boronic Acid Derivatives As PI3 Kinase Inhibitors

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- Number: US 2013/0157977 A1
- Document ID: US20130157977A1
- Status: Published application
- Kind: A1
- Application number: 13/674,202
- Filed: 2012-11-12
- Published: 2013-06-20
- Earliest claimed: 2011-12-20
- Assignees: GlaxoSmithKline LLC
- Inventors: Ralph A. Rivero; Rosanna Tedesco; Juan Ignacio Luengo
- Web page: https://patentgrep.com/patent/US20130157977A1

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

This invention relates to the use of benzimidazole boronic acid derivatives for the modulation, notably the inhibition of the activity or function of the phosphoinositide 3′ OH kinase family (hereinafter PI3 kinases), suitably, PI3Kα, PI3Kδ, PI3Kβ, and/or PI3Kγ. Suitably, the present invention relates to the use of benzimidazole boronic acids in the treatment of one or more disease states selected from: autoimmune disorders, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergy, asthma, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, cancer, sperm motility, transplantation rejection, graft rejection and lung injuries. More suitably, the present invention relates to PI3Kβ selective benzimidazole boronic acid compounds for treating cancer.

## Claims

### Claim 1

A compound of formula (I):
wherein
R2 is selected from H, —NHRa, alkoxy, halogen, —CF3, —CHF2, and C1-6alkyl;
R3 is selected from aryl and heteroaryl, wherein said aryl or heteroaryl may be substituted by one to three Rc;
R4 is selected from H or Ra;
each R5 is independently selected from C1-6alkyl;
each Ra is independently selected from C1-3alkyl;
each Rc is independently selected from C1-3alkyl, halogen, —CF3, and hydroxy; and
n is 0-2,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compounds of claim 1, having the formula (I)(A)
wherein
R2 is selected from H, —NHRa, alkoxy, —CH2Rc, —CH(Rc)2, —CF3, or C1-6alkyl;
each of R6, R7, and R8 is independently selected from C1-3alkyl, halogen, —CF3, and hydroxyl, or R6 and R7 combine to form a bi-cyclic aryl or heteroaryl, or R7 and R8 combine to form a bi-cyclic aryl or heteroaryl;
each Ra is independently selected from C1-3alkyl; and
each Rc is selected from CH3 and F;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compounds of claim 1, having the Formula (I)(B)
wherein
R2 is selected from H, —CH2Rc, —CH(Rc)2, —CF3, or C1-6alkyl;
each of R6 and R7 is independently selected from C1-3alkyl, halogen, and —CF3, or R6 and R7 combine to form a bi-cyclic aryl or heteroaryl; and
each Rc is selected from CH3 and F;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compounds of claim 3, wherein R6 and R7 combine to form a naphthal or an indole.

### Claim 5 (depends on 3)

The compounds of claim 3, wherein R6 and R7 are independently selected from C1-3alkyl, halogen, and —CF3.

### Claim 6

A compound selected from
4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;
4-(4-bromo-1-(3-chloro-2-methylbenzyl)-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;
4-(4-bromo-2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-1H-benzo[d]imidazol-6-yl)morpholine;
(2-methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(3-chloro-2-methylbenzyl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(2-methyl-6-morpholino-1-(naphthalen-1-ylmethyl)-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(2,3-dimethylbenzyl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(2,3-dichlorobenzyl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
4-(1-(benzo[b]thiophen-7-ylmethyl)-4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine;
(2-methyl-1-(3-methylbenzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(2-methyl-1-(2-methylbenzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(2-chlorobenzyl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(3-chlorobenzyl)-2-methyl-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(3-chloro-2-methylbenzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(2-(fluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(3-chloro-2-methylbenzyl)-2-(fluoromethyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(2-(hydroxymethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(3-chloro-2-methylbenzyl)-2-(difluoromethyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(2-(difluoromethyl)-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid;
(1-(3-chloro-2-methylbenzyl)-6-morpholino-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)boronic acid;
(2-isopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid; and
(2-cyclopropyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazol-4-yl)boronic acid,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A method for treating a susceptible neoplasm in a mammal in need thereof, said method comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1.

### Claim 8 (depends on 7)

The method according to claim 7, wherein said susceptible neoplasm is a PTEN-deficient neoplasm selected from brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, cancer, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T cell, leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma, Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), and testicular cancer.

### Claim 9 (depends on 8)

The method according to claim 8, wherein said PTEN-deficient neoplasm is selected from hormone refractory prostate cancer, non-small-cell lung cancer, endometrial cancer, gastric cancer, melanoma, head and neck cancer, breast cancer, including trip-negative breast cancer, and glioma.

### Claim 10 (depends on 8)

The method according to claim 8, wherein said mammal is a human.

### Claim 11 (depends on 1)

A compound according to claim 1 for use in therapy.

### Claim 12 (depends on 1)

A compound according to claim 1 for use in the treatment of a PTEN-deficient susceptible neoplasm selected from brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, cancer, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T cell, leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma, Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), and testicular cancer.

### Claim 13 (depends on 1)

The use of a compound according to claim 1 for the preparation of a medicament for the treatment of a PTEN-deficient susceptible neoplasm selected from brain (gliomas), glioblastomas, leukemias, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, inflammatory breast cancer, colorectal cancer, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, squamous cell carcinoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, cancer, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T cell, leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, Plasmacytoma, Immunoblastic large cell leukemia, Mantle cell leukemia, Multiple myeloma, Megakaryoblastic leukemia, multiple myeloma, Acute megakaryocytic leukemia, promyelocytic leukemia, Erythroleukemia, malignant lymphoma, hodgkins lymphoma, non-hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), and testicular cancer in a mammal (e.g., human) in need thereof.