Tyrosine kinase inhibitors

• US 8,673,925 B1
• Filed: 06/27/2013
• Issued: 03/18/2014
• Est. Priority Date: 04/09/2013
• Status: Active Grant

• Current Assignee: Principia Biopharma Inc. (Sanofi )
• Original Assignee: Principia Biopharma Inc. (Sanofi )
• Inventors: Goldstein, David Michael
• Primary Examiner(s): Murray, Jeffrey H
• Application Number:
  US13/929,004
• Time in Patent Office: 264 Days
• Field of Search: None
• US Class Current: 514/262.1
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/00 Medicinal preparations characterised by special physical form nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/10 Spiro-condensed systems

Abstract

The present disclosure provides compounds such as pyrazolpyrimidine compounds, and pharmaceutically acceptable salts thereof, that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, TEC, BTK, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts thereof and processes for preparing such compounds and pharmaceutically acceptable salts thereof.

Claims

1. An (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof wherein the compound is:

2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure;

2. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is a mixture of (R) and (S) isomers of -(2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

3. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

4. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (S,E)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

5. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (S,Z)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

6. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

7. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

8. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (R,Z)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure;

9. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is a mixture of (R) and (S) isomers of 2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

10. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

11. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (R,E)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

12. The (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 wherein the compound is (R,Z)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

13. A pharmaceutical composition comprising an (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers or an (E) or (Z) isomer, or a mixture of (E) and (Z) isomers of a compound or a pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable excipient.

14. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is a mixture of (R) and (S) isomers of -(2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

15. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

16. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is (S,E)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

17. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof of is (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

18. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is (R,E)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

19. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is (R,Z)-2-(3-(4-amino-3-(2-fluoro-4-phenoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

20. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is (R)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

21. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is (R,E)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure:

22. The pharmaceutical composition of claim 13 wherein the (R) isomer, (S) isomer, or a mixture of (R) and (S) isomers of a compound or a pharmaceutically acceptable salt thereof is (R,Z)-2-(3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carbonyl)-4,4-dimethylpent-2-enenitrile having the structure: