Claims for Patent: 9,090,562

Summary for Patent: 9,090,562

Title:	Aryl- or heteroaryl-substituted benzene compounds
Abstract:	The present invention relates to aryl- or heteroaryl-substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.
Inventor(s):	Kevin Wayne Kuntz, Richard Chesworth, Kenneth William Duncan, Heike Keilhack, Natalie Warholic, Christine Klaus, Sarah Kathleen Knutson, Timothy James Nelson Wigle, Masashi Seki, Syuji Shirotori, Satoshi Kawano
Assignee:	Eisai R&D Management Co Ltd, Epizyme Inc
Application Number:	US14/275,667
Patent Claims:	1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein X1 is N or CR11; X2 is N or CR13; Z is NR7R8, OR7, S(O)nR7, or CR7R8R14, in which n is 0, 1, or 2; each of R1, R5, R9, and R10, independently, is H or C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; each of R2, R3, and R4, independently, is -Q1-T1, in which Q1 is a bond or C1-C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T1 is H, halo, hydroxyl, COOH, cyano, or RS1, in which RS1 is C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxyl, C(O)O—C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and RS1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, COOH, C(O)O—C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; R6 is C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q2-T2, wherein Q2 is a bond or C1-C3 alkyl linker optionally substituted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T2 is H, halo, cyano, —ORa, —NRaRb, —(NRaRbRc)+A−, —C(O)Ra, —C(O)ORa, —C(O)NRaRb, —NRbC(O)Ra, —NRbC(O)ORa, —S(O)2Ra, —S(O)2NRaRb, or RS2, in which each of Ra, Rb, and Rc, independently is H or RS3, A− is a pharmaceutically acceptable anion, each of RS2 and RS3, independently, is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or Ra and Rb, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of RS2, RS3, and the 4 to 12-membered heterocycloalkyl ring formed by Ra and Rb, is optionally substituted with one or more -Q3-T3, wherein Q3 is a bond or C1-C3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T3 is selected from the group consisting of halo, cyano, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, ORd, COORd, —S(O)2Rd, —NRdRe, and —C(O)NRdRe, each of Rd and Re independently being H or C1-C6 alkyl, or -Q3-T3 is oxo; or any two neighboring -Q2-T2, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S and optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl; R7 is -Q4-T4, in which Q4 is a bond, C1-C4 alkyl linker, or C2-C4 alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C1-C6 alkoxy, and T4 is H, halo, cyano, NRfRg, —ORf, —C(O)Rf, —C(O)ORf, —C(O)NRfRg, —C(O)NRfORg, —NRfC(O)Rg, —S(O)2Rf, or RS4, in which each of Rf and Rg, independently is H or RS5, each of RS4 and RS5, independently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of RS4 and RS5 is optionally substituted with one or more -Q5-T5, wherein Q5 is a bond, C(O), C(O)NRk, NRkC(O), S(O)2, or C1-C3 alkyl linker, Rk being H or C1-C6 alkyl, and T5 is H, halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O)qRq in which q is 0, 1, or 2 and Rq is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T5 is optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T5 is H, halo, hydroxyl, or cyano; or -Q5-T5 is oxo; each of R8, R11, and R13, independently, is H, halo, hydroxyl, COOH, cyano, RS6, ORS6, or COORS6, in which RS6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino, and RS6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, and di-C1-C6 alkylamino; or R7 and R8, together with the N atom to which they are attached, form a 4 to 11-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, or R7 and R8, together with the C atom to which they are attached, form C3-C8 cycloalkyl or a 4 to 11-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 11-membered heterocycloalkyl rings or C3-C8 cycloalkyl formed by R7 and R8 is optionally substituted with one or more Q6-T6, wherein Q6 is a bond, C(O), C(O)NRm, NRmC(O), S(O)2, or C1-C3 alkyl linker, Rm being H or C1-C6 alkyl, and T6 is H, halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O)pRp in which p is 0, 1, or 2 and Rp is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T6 is optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, hydroxyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T6 is H, halo, hydroxyl, or cyano; or -Q6-T6 is oxo; R12 is halo, hydroxyl, COOH, cyano, RS6, ORS6, or COORS6, in which RS6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C1-C6 alkylamino, or di-C1-C6 alkylamino, and RS6 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, and di-C1-C6 alkylamino; and R14 is absent, H, or C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—C1-C6 alkyl, cyano, C1-C6 alkoxyl, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, C3-C8 cycloalkyl, C6-C10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl. 2. The compound of claim 1, wherein R6 is phenyl substituted with one or more -Q2-T2. 3. The compound of claim 1, wherein R6 is 5- or 6-membered heteroaryl containing 1-3 additional heteroatoms selected from N, O, and S and optionally substituted with one or more -Q2-T2. 4. The compound of claim 1, wherein R7 is C1-C6 alkyl, C3-C8 cycloalkyl or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q5-T5. 5. The compound of claim 1, wherein each of R1 and R11 is H and each of R2 and R4, independently is H or C1-C6 alkyl optionally substituted with amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, or C6-C10 aryl. 6. The compound of claim 1, wherein R12 is methyl, ethyl, ethenyl, or halo; and R8 is H, methyl, or ethyl. 7. The compound of claim 1, wherein X1 is CR11 and X2 is CR13. 8. The compound of claim 1, wherein X1 is CR11 and X2 is N. 9. The compound of claim 1, wherein X1 is N and X2 is CR13. 10. The compound of claim 1, wherein X1 is N and X2 is N. 11. The compound of claim 1, wherein Z is NR7R8. 12. The compound of claim 1, wherein Z is CR7R8R14. 13. The compound of claim 1, wherein Z is OR7. 14. The compound of claim 1, wherein Z is SR7. 15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 16. The compound of claim 1, wherein R6 is C6-C10 aryl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q2-T2, in which Q2 is a bond or methyl or ethyl linker and T2 is H, halo, —ORa, —NRaRb, —(NRaRbRc)+A−, —S(O)2Ra, or —S(O)2NRaRb. 17. The compound of claim 1, wherein the compound is of Formula (Ig) or a pharmaceutically acceptable salt thereof: in which R6 is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q2-T2, in which Q2 is a bond or C1-C3 alkyl linker optionally substituted with halo or hydroxyl, and T2 is H, halo, —ORa, —NRaRb, —(NRaRbRc)+A−, —S(O)2Ra, or —S(O)2NRaRb, and R7 is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q5-T5. 18. The compound of claim 17, wherein R6 is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q2-T2, in which Q2 is a bond or methyl linker, and T2 is —ORa, —NRaRb, —(NRaRbRc)+A−, or —S(O)2Ra. 19. The compound of claim 17, wherein Q5 is a bond and T5 is amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino. 20. The compound of claim 17, wherein R6 is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q2-T2, in which Q2 is a bond or methyl linker, and T2 is —ORa or —S(O)2Ra, in which Ra is H or C1-C6 alkyl optionally substituted with one or more -Q3-T3.