COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR

• US 20120245174A1
• Filed: 06/07/2012
• Published: 09/27/2012
• Est. Priority Date: 05/06/2009
• Status: Abandoned Application

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Ibrahim, Prabha N., Spevak, Wayne, Cho, Hanna, Shi, Songyuan, Wu, Guoxian
• Application Number:
  US13/491,480
• Publication Number:
  US 20120245174A1
• Time in Patent Office: Days
• US Class Current: 514/234.5
• CPC Class Codes: A61P 13/12 of the kidneys
• 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 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

Abstract

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, and forms thereof are active on each of BRaf and c-Raf-1 protein kinase, and may also be active on either or both of A-Raf and B-Raf V600E protein kinase. Also described are methods of use thereof to treat diseases and conditions, including melanoma, colorectal cancer, thyroid cancer, ovarian cancer, and biliary tract cancer.

Claims

1. A compound having the chemical structure of Formula I,

2. A composition comprising a pharmaceutically acceptable carrier;

and a compound according to claim 1.

3. A kit comprising a compound according to claim 1.

4. A kit comprising a composition according to claim 2.

5. A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a compound according to claim 1, wherein the disease or condition is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, and biliary tract cancer.

6. A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a compound according to claim 1, wherein the disease or condition is selected from the group consisting of melanoma, liver cancer, biliary tract cancer, colorectal cancer, lung cancer, bladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, and acute myeloid leukemia.

7. A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a compound according to claim 1, wherein the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer and biliary tract cancer.

8. A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a composition according to claim 2, wherein the disease or condition is selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, and biliary tract cancer.

9. A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a composition according to claim 2, wherein the disease or condition is selected from the group consisting of melanoma, liver cancer, biliary tract cancer, colorectal cancer, lung cancer, bladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial cancer, and acute myeloid leukemia.

10. A method for treating a subject suffering from or at risk of a disease or condition, comprising administering to the subject in need thereof an effective amount of a composition according to claim 2, wherein the disease or condition is selected from the group consisting of melanoma, colorectal cancer, thyroid cancer, ovarian cancer and biliary tract cancer.

11. The compound according to claim 1, wherein the compound is selected from the group consisting of:

N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2002),

N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2003),

N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2009),

N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2010),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2011),

N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2014),

N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2015),

N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2016),

N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2017),

N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2018),

N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2019),

N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2020),

N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-fluoro-benzenesulfonamide (P-2021),

N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-2022),

N-[2,4-Difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-fluoro-benzenesulfonamide (P-2023),

N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,6-difluoro-benzenesulfonamide (P-2024),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2029),

N-[3-(4-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2033),

N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2036),

N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2037),

N-[3-(4-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2039),

N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2-fluoro-benzenesulfonamide (P-2041),

N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-2042),

N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,6-difluoro-benzenesulfonamide (P-2043),

N-{2,4-Difluoro-3-[5-(2-methoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide (P-2045),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-2046),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2-fluoro-benzenesulfonamide (P-2051),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,5-difluoro-benzenesulfonamide (P-2052),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-3-fluoro-benzenesulfonamide (P-2053),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-2,6-difluoro-benzenesulfonamide (P-2054),

N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-benzenesulfonamide (P-2056),

Pyridine-3-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2069),

Pyridine-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2071),

Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2072),

Pyridine-3-sulfonic acid [2,4-difluoro-3-(4-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-2073),

Pyridine-3-sulfonic acid [3-(4-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2074),

Pyridine-3-sulfonic acid [3-(4-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-2077),

Pyridine-3-sulfonic acid [3-(5-cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide (P-2086), and any salt, prodrug, or tautomer thereof.