KRAS G12C INHIBITORS

• US 20180072723A1
• Filed: 11/15/2017
• Published: 03/15/2018
• Est. Priority Date: 05/18/2016
• Status: Active Grant

• Current Assignee: Mirati Therapeutics Inc., Array Biopharma Incorporated (Pfizer Inc.)
• Original Assignee: Mirati Therapeutics Inc., Array Biopharma Incorporated (Pfizer Inc.)
• Inventors: Blake, James F., Burgess, Laurence E., Chicarelli, Mark Joseph, Christensen, James Gail, Fell, Jay Bradford, Fischer, John P., Gaudino, John J., Hicken, Erik James, Hinklin, Ronald Jay, Lee, Matthew Randolf, Marx, Matthew Arnold, Mejia, Macedonio J., Rodriguez, Martha E., Savechenkov, Pavel, Tang, Tony P., Vigers, Guy P.A., Zecca, Henry J.
• Granted Patent: US 10,125,134 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• 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
• CPC Class Codes: H05K 999/99 dummy group

Abstract

The present invention relates to compounds that inhibit KRas G12C. In particular, the present invention relates to compounds that irreversibly inhibit the activity of KRas G12C, pharmaceutical compositions comprising the compounds and methods of use therefor.

Claims

1. A compound, wherein the compound is selected from the group consisting of:

2. A pharmaceutical composition, comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable excipient.

3. A method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a compound of claim 1, pharmaceutically acceptable salts thereof or pharmaceutical compositions containing the compound of claim 1, or pharmaceutically acceptable salt thereof.

4. A method for treating cancer comprising administering to a patient having cancer a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt of a compound claim 1, alone or combined with a pharmaceutically acceptable carrier, excipient or diluents.

5. The method of claim 4, wherein the therapeutically effective amount of the compound is between about 0.01 to 100 mg/kg per day.

6. The method of claim 5, wherein the therapeutically effective amount of the compound is between about 0.1 to 50 mg/kg per day.

7. The method of claim 6, wherein the cancer is selected from the group consisting of Cardiac:

sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;

Lung;

bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

Gastrointestinal;

esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi'"'"'s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

Genitourinary tract;

kidney (adenocarcinoma, Wilm'"'"'s tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);

Liver;

hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

Biliary tract;

gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma;

Bone;

osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'"'"'s sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;

Nervous system;

skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);

Gynecological;

uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);

Hematologic;

blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'"'"'s disease, non-Hodgkin'"'"'s lymphoma (malignant lymphoma);

Skin;

malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi'"'"'s sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and

Adrenal glands;

neuroblastoma.

8. The method of claim 7, wherein the cancer wherein the cancer is a KRas G12C-associated cancer.

9. The method of claim 8, wherein the cancer is non-small cell lung cancer.

10. A method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer);

and (b) administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof of a compound of claim 1, or a pharmaceutical composition thereof.