Claims for Patent: 8,415,345

Summary for Patent: 8,415,345

Title:	Benzene sulfonamide thiazole and oxazole compounds
Abstract:	The present invention provides thiazole sulfonamide and oxazole sulfonamide compounds, compositions containing the same, as well as processes for the preparation and methods for their use as pharmaceutical agents.
Inventor(s):	George Adjabeng, Jerry Leroy Adams, Scott Howard Dickerson, Keith Hornberger, Neil W. Johnson, Kevin Kuntz, Kimberly Petrov, Jeffrey M. Ralph, Tara Renae Rheault, Gregory Schaaf, John Stellwagen, Xinrong Tian, David E. Uehling, Alex G. Waterson, Brian Wilson
Assignee:	Novartis AG, Novartis Pharma AG
Application Number:	US12/991,004
Patent Claims:	1. A compound of formula (I) wherein: a is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from halo, alkyl, haloalkyl, —OR6, —CO2R6, —NR6R7, and —CN; Ring A is selected from C3-6cycloalkyl, phenyl, 5-6 membered heterocycle and 5-6 membered heteroaryl, said heterocycle and said heteroaryl each having 1 or 2 heteroatoms selected from N, O and S; each of Q1, Q2, Q3 and Q4 is CH, C—R2 or N, wherein not more than one of Q1, Q2, Q3, and Q4 is N; each R2 is the same or different and is independently selected from halo, alkyl, haloalkyl, and —OR6; W is selected from —O— and —S—; R3 is selected from H, alkyl, haloalkyl-, -alkylene-OH, —NR6R7, —C3-6cycloalkyl, -alkylene-C(O)—OH, -alkylene-NH2, and Het; wherein said R3C3-6cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo, C1-3alkyl, haloC1-3alkyl, OH, O—C1-3alkyl, oxo, S(C1-3alkyl), SO2, NH2, N(H)C1-3alkyl and N(C1-3alkyl)2; Het is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1 or 2 substituents which are the same or different and are each independently selected from halo, C1-3alkyl, haloC1-3alkyl, O—C1-3alkyl, C1-3alkylene-O—C1-3alkyl, OH, C1-3alkylene-OH, oxo, SO2(C1-3alkyl), C1-3alkylene-SO2(C1-3alkyl), NH2, N(H)C1-3alkyl, N(C1-3alkyl)2, CN, and —CH2CN; R4 is selected from H, alkyl, haloalkyl, alkenyl, —OR6, —R5—OR6, —R5—CO2R6, —R5—SO2R6, —R5—Het, —R5—C(O)—Het, —N(H)R8, —N(CH3)R8, and —R5—NR6R7; each R5 is the same or different and is independently C1-4olkylene; each R6 and each R7 is the same or different and is independently selected from H, alkyl, haloalkyl, —C(O)-alkyl, and —C(O)-cycloalkyl; R8 is selected from H, alkyl (optionally substituted by —OH), haloalkyl, C3-6cycloalkyl, —R5—C3-6cycloalkyl, Het2, —R5—Het2, —R5—OR6, —R5—O—R5—OR6, —R5—C(O)2R6, —R5—C(O)NR6R7, —R5—N(H)C(O)—R6, —R5—N(H)C(O)—R5—OR6, —R5—N(H)C(O)2—R6, —R5—NR6R7, —R5—S(O)2R6, —R5—CN, and —R5—N(H)S(O)2R6; wherein said R8C3-6cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo, C1-3alkyl, haloC1-3alkyl, OH, O—C1-3alkyl, oxo, S(C1-3alkyl), SO2(C1-3alkyl), NH2, N(H)C1-3alkyl and N(C1-3alkyl)2, and N(H)SO2C1-3alkyl; and Het2 is a 4-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1, 2, 3, 4 or 5 C1-3alkyl or 1 or 2 substituents which are the same or different and are each independently selected from halo, C1-3alkyl, haloC1-3alkyl, O—C1-3alkyl, C1-3alkylene-O—C1-3alkyl, OH, C1-3alkylene-OH, oxo, SO2(C1-3alkyl), C1-3alkylene-SO2(C1-3alkyl), NH2, N(H)C1-3alkyl, N(C1-3alkyl)2, N(H)SO2C1-3alkyl, C(O)(C1-3alkyl), CO2(C1-4alkyl), CN, and —CH2CN; and pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, wherein each R1 is the same or different and is independently selected from halo, alkyl, haloalkyl, and —OR6. 3. The compound according to claim 1, wherein Ring A is phenyl, 5-6 membered heterocycle or 5-6 membered heteroaryl. 4. The compound according to claim 1, wherein each of Q1, Q2, Q3, and Q4 is CH or C—R2, wherein at least two of Q1, Q2, Q3, and Q4 are CH. 5. The compound according to claim 1, wherein each R2 is the same or different and is independently halo or C1-3alkyl. 6. The compound according to claim 1 wherein each of Q1, Q2, and Q3 is CH and Q4 is C—F or C—Cl. 7. A compound of formula (I): wherein: a is 0, 1, 2 or 3; each R1 is the same or different and is independently selected from halo, alkyl, haloalkyl, —OR6, —CO2R6, —NR6R7, and —CN; Ring A is selected from C3-6cycloalkyl, phenyl, 5-6 membered heterocycle and 5-6 membered heteroaryl, said heterocycle and said heteroaryl each having 1 or 2 heteroatoms selected from N, O and S; each of Q1, Q2, Q3 and Q4 is CH, C—R2 or N, wherein not more than one of Q1, Q2, Q3, and Q4 is N; each R2 is the same or different and is independently halo, alkyl, haloalkyl, or —OR6; W is —O— or —S—; R3 is H, alkyl, haloalkyl, alkylene-OH, NR6R7, C3-6cycloalkyl, or Het; wherein said R3C3-6cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo, C1-3alkyl, haloC1-3alkyl, OH, O—C1-3alkyl, oxo, S(C1-3alkyl), SO2, NH2, N(H)C1-3alkyl and N(C1-3alkyl)2; Het is a 5-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1 or 2 substituents which are the same or different and are each independently selected from halo, C1-3alkyl, haloC1-3alkyl, O—C1-3alkyl, C1-3alkylene-O—C1-3alkyl, OH, C1-3alkylene-OH, oxo, SO2(C1-3alkyl), C1-3alkylene-SO2(C1-3alkyl), NH2, N(H)C1-3alkyl, N(C1-3alkyl)2, CN, and —CH2CN; R4 is H, alkyl, haloalkyl, alkenyl, —OR6, —R5—OR6, —R5—CO2R6, —R5—SO2R6, —R5—Het, —N(H)R8, —N(CH3)R8, or —R5—NR6R7; each R5 is the same or different and is independently C1-4alkylene; each R6 and each R7 is the same or different and is independently H, alkyl or haloalkyl; and R8 is selected from H, alkyl, haloalkyl, C3-6cycloalkyl, —R5—C3-6cycloalkyl, Het2, —R5—Het2, —R5—OR6, —R5—O—R5—OR6, —R5—C(O)2R6, —R5—C(O)NR6R7, —R5—N(H)C(O)—R6, —R5—N(H)C(O)—R5—OR6, —R5—N(H)C(O)2—R6, —R5—NR6R7, —R5—S(O)2R6, and —R5—N(H)S(O)2R6; wherein said R8C3-6cycloalkyl is optionally substituted with 1 or 2 substituents which are the same or different and are independently selected from halo, C1-3alkyl, haloC1-3alkyl, OH, O—C1-3alkyl, oxo, S(C1-3alkyl), SO2(C1-3alkyl), NH2, N(H)C1-3alkyl and N(C1-3alkyl)2, and N(H)SO2C1-3alkyl; and Het2 is a 4-6 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S and optionally substituted with 1, 2, 3, 4 or 5 C1-3alkyl or 1 or 2 substituents which are the same or different and are each independently selected from halo, C1-3alkyl, haloC1-3alkyl, O—C1-3alkyl, C1-3alkylene-O—C1-3alkyl, OH, C1-3alkylene-OH, oxo, SO2(C1-3alkyl), C1-3alkylene-SO2(C1-3alkyl), NH2, N(H)C1-3alkyl, N(C1-3alkyl)2, N(H)SO2C1-3alkyl, C(O)(C1-3alkyl), CO2(C1-4-alkyl), CN, and —CH2CN; or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 7, wherein the compound of formula (I) is a compound of formula (I-iii-a): wherein Q4 is CH or C—R2. 9. The compound according to claim 7, wherein the compound of formula (I) is a compound of formula (I-iii-b): wherein Q4 is CH or C—R2. 10. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient. 11. A method for treating melanoma in a human in need thereof, said method comprising administering to the human a therapeutically effective amount of a compound according to claim 1. 12. A process for preparing a compound according to claim 1, said process comprising reacting a compound of formula (VIII): wherein R10 is halo or thiomethyl; with one of: i) molecular hydrogen ii) an alkyl metal reagent or alkenyl metal reagent iii) an alcohol, or iv) a compound of formula (IX): N(Ra)—R8, wherein Ra is H or CH3, to prepare a compound of formula (I). 13. A process for preparing a compound according to claim 1 comprising reacting a compound of formula (XVIII): with a compound of formula (VII): to prepare a compound of formula (I). 14. The method according to claim 11, wherein said melanoma is metastatic melanoma having a mutation encoding a V600E amino acid substitution.