Claims for Patent: 9,284,307

Summary for Patent: 9,284,307

Title:	Macrocyclic serine protease inhibitors
Abstract:	Provided herein are macrocyclic serine protease inhibitor compounds, for example, of Formula Ia or Ib, pharmaceutical compositions comprising the compounds, and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof. ##STR00001##
Inventor(s):	Parsy; Christophe Claude (Jacou, FR), Alexandre; Francois-Rene (Montpellier, FR), Leroy; Frederic (Montarnaud, FR), Convard; Thierry (Sathonay-Camp, FR), Surleraux; Dominique (Wauthier-Braine, BE)
Assignee:	Idenix Pharmaceuticals LLC (Cambridge, MA)
Application Number:	12/850,534
Patent Claims:	1. A compound of Formula Ia or Ib: ##STR00174## or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt thereof; wherein: R.sup.5 is --NHS(O).sub.2R.sup.8; wherein R.sup.8 is 1-methylcyclopropyl or 1-ethynylcyclopropyl; L is --O-- or --OC(O)NH--; R.sup.6 is methoxy-fluoro-(isopropylthiazolyl)quinolinyl, methoxy-chloro-(isopropyl-thiazolyl)quinolinyl, methoxy-bromo-(isopropylthiazolyl)quinolinyl, methoxy-methyl-(isopropylthiazolyl)quinolinyl, dimethoxy-(isopropylthiazolyl)quinolinyl, difluoromethyl-chloro-(isopropylthiazolyl)quinolinyl, difluoromethyl-methyl-(isopropylthiazolyl)quinolinyl, trifluoromethyl-methyl-(isopropyl-thiazolyl)quinolinyl, methanesulfonamido-chloro-(isopropylthiazolyl)quinolinyl, methane-sulfonamido-methyl-(isopropylthiazolyl)quinolinyl, methoxy-fluoro-(trifluoromethylthiazolyl)-quinolinyl, methoxy-chloro-(trifluoro-methylthiazolyl)quinolinyl, methoxy-bromo-(trifluoromethylthiazolyl)quinolinyl, methoxy-methyl-(trifluoromethylthiazolyl)quinolinyl, dimethoxy-(trifluoromethylthiazolyl)quinolinyl, methanesulfonamido-methyl-(trifluoromethylthiazolyl)quinolinyl, methoxy-chloro-(ethenyl-thiazolyl)quinolinyl, methoxy-chloro-(ethynylthiazolyl)quinolinyl, methoxy-methyl-(ethynyl-thiazolyl)quinolinyl, methoxy-chloro-(cyanothiazolyl)quinolinyl, methoxy-chloro-(methyl-thiazolyl)quinolinyl, methoxy-chloro-(cyclopropylthiazolyl)quinolinyl, methoxy-chloro-(cyclobutylthiazolyl)quinolinyl, chloro-methoxy-(isopropyl-1H-pyrazolyl)quinolinyl, methyl-methoxy-(isopropyl-1H-pyrazolyl)quinolinyl, chloro-methoxy-(trifluoromethyl-1H-pyrazolyl)-quinolinyl, methyl-methoxy-(trifluoromethyl-1H-pyrazolyl)quinolinyl, methoxy-fluoro-(isopropylisoxazolyl)quinolinyl, methoxy-chloro-(isopropyl-isoxazolyl)quinolinyl, methoxy-bromo-(isopropylisoxazolyl)quinolinyl, methoxy-methyl-(isopropylisoxazolyl)quinolinyl, dimethoxy-(isopropylisoxazolyl)quinolinyl; and Q.sup.1 is --N(R.sup.17)--; wherein R.sup.17 is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; Q.sup.2 has the structure of: ##STR00175## wherein: Y is a bond, --O--, --S--, --S(O)--, --S(O).sub.2--, or --N(R.sup.Y)--, wherein R.sup.Y is hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, --C(O)R.sup.Ya, --C(O)OR.sup.Ya, --C(O)NR.sup.YbR.sup.Yc, --S(O).sub.2NR.sup.YbR.sup.Yc, or --S(O).sub.2R.sup.Ya; where each R.sup.Ya, R.sup.Yb, and R.sup.Yc is independently hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; q is an integer of 0, 1, 2, 3, or 4; r is an integer of 0, 1, 2, 3, or 4; and m is an integer of 0 or 1; and n is an integer of 1 or 2; with the proviso that the sum of m and n is 2. 2. The compound of claim 1, wherein R.sup.17 is hydrogen or methyl. 3. The compound of claim 1, wherein R.sup.6 is 7-methoxy-8-fluoro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 5,7-dimethoxy-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-chloro-7-methoxy-2-(4-isopropyl-thiazol-2-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-methoxy-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-methoxy-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-difluoromethyl-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-difluoromethyl-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-trifluoromethyl-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-trifluoromethyl-8-methyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-trifluoromethyl-8-chloro-2-(4-isopropyl-thiazol-2-yl)quinolin-4-yl, 7-methanesulfonamido-8-methyl-2-(4-isopropylthiazol-2-yl)-quinolin-4-yl, 7-methanesulfonamido-8-chloro-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 6-methyl-8-difluoromethyl-2-(4-isopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-fluoro-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(4-trifluoromethyl-thiazol-2-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 5,7-dimethoxy-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 6-methoxy-8-methyl-2-(4-trifluoromethylthiazol-2-yl)quinolin-4-yl, 7-methanesulfonamido-8-methyl-2-(4-trifluoromethylthiazol-2-yl)quinolin-4- -yl, 7-methoxy-8-chloro-2-(4-ethenylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-ethynylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(4-ethynylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-cyanothiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-methylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-cyclopropylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(4-cyclobutylthiazol-2-yl)quinolin-4-yl, 7-methoxy-8-fluoro-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 5,7-dimethoxy-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 6-methoxy-8-methyl-2-(2-isopropylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-chloro-2-(2-trifluoromethylthiazol-4-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(2-trifluoromethylthiazol-4-yl)quinolin-4-yl, 8-chloro-7-methoxy-2-(3-isopropyl-1H-pyrazol-1-yl)quinolin-4-yl, 8-methyl-7-methoxy-2-(3-isopropyl-1H-pyrazol-1-yl)-quinolin-4-yl, 8-chloro-7-methoxy-2-(3-trifluoromethyl-1H-pyrazol-1-yl)quinolin-4-yl, 8-methyl-7-methoxy-2-(3-trifluoromethyl-1H-pyrazol-1-yl)quinolin-4-yl, 7-methoxy-8-fluoro-2-(5-isopropylisoxazol-3-yl)-quinolin-4-yl, 7-methoxy-8-chloro-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, 7-methoxy-8-bromo-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, 7-methoxy-8-methyl-2-(5-isopropyl-isoxazol-3-yl)quinolin-4-yl, 5,7-dimethoxy-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, 6-methoxy-7-chloro-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl, or 6-methoxy-8-methyl-2-(5-isopropylisoxazol-3-yl)quinolin-4-yl. 4. The compound of claim 1, wherein m is 0. 5. The compound of claim 1, wherein m is 1. 6. The compound of claim 1, wherein n is 1. 7. The compound of claim 1, wherein n is 2. 8. The compound of claim 1, wherein R.sup.8 is 1-methylcyclopropyl. 9. The compound of claim 1, wherein the compound is: ##STR00176## or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition comprising the compound of claim 1, and one or more pharmaceutically acceptable carriers. 11. The pharmaceutical composition of claim 10, further comprising a second antiviral agent. 12. The pharmaceutical composition of claim 11, wherein the second antiviral agent is selected from an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, or a ribozyme. 13. The pharmaceutical composition of claim 11, wherein the second antiviral agent is an interferon. 14. The pharmaceutical composition of claim 13, wherein the interferon is selected from pegylated interferon alpha 2a, interferon alfahcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, or interferon gamma-1b. 15. The pharmaceutical composition of claim 10, wherein the composition is formulated for single dose administration. 16. The pharmaceutical composition of claim 10, wherein the composition is formulated as oral, parenteral, or intravenous dosage form. 17. The pharmaceutical composition of claim 16, wherein the oral dosage form is a tablet or capsule. 18. The pharmaceutical composition of claim 10, wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram daily.

Details for Patent 9,284,307

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Biogen Inc.	AVONEX	interferon beta-1a	For Injection	103628	05/17/1996		2029-08-05
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	05/28/2003		2029-08-05
Biogen Inc.	AVONEX	interferon beta-1a	Injection	103628	02/27/2012		2029-08-05
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	03/07/2002		2029-08-05
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	12/17/2004		2029-08-05
Emd Serono, Inc.	REBIF	interferon beta-1a	Injection	103780	12/21/2012		2029-08-05
Horizon Therapeutics Ireland Dac	ACTIMMUNE	interferon gamma-1b	Injection	103836	02/25/1999		2029-08-05