US 11,052,093 B2
Aryl-or heteroaryl-substituted benzene compounds
Kevin W. Kuntz, Woburn, MA (US); Richard Chesworth, Concord, MA (US); Kenneth W. Duncan, Westwood, MA (US); Heike Keilhack, Belmont, MA (US); Natalie Warholic, Cambridge, MA (US); Christine Klaus, Waban, MA (US); Sarah K. Knutson, Lincoln, MA (US); Timothy J. N. Wigle, Waltham, MA (US); Masashi Seki, Tsukuba (JP); Syuji Shirotori, Tsukuba (JP); and Satoshi Kawano, Tsukuba (JP)
Assigned to Epizyme, Inc., Cambridge, MA (US)
Filed by Epizyme, Inc., Cambridge, MA (US)
Filed on Oct. 22, 2019, as Appl. No. 16/660,339.
Application 16/660,339 is a continuation of application No. 16/291,800, filed on Mar. 4, 2019, abandoned.
Application 16/291,800 is a continuation of application No. 15/816,907, filed on Nov. 17, 2017, granted, now 10,420,775, issued on Sep. 24, 2019.
Application 15/816,907 is a continuation of application No. 15/598,078, filed on May 17, 2017, granted, now 9,855,275, issued on Jan. 2, 2018.
Application 15/598,078 is a continuation of application No. 15/346,677, filed on Nov. 8, 2016, granted, now 10,155,002, issued on Dec. 18, 2018.
Application 15/346,677 is a continuation of application No. 14/876,658, filed on Oct. 6, 2015, granted, now 9,522,152, issued on Dec. 20, 2016.
Application 14/876,658 is a continuation of application No. 14/742,481, filed on Jun. 17, 2015, granted, now 9,549,931, issued on Jan. 24, 2017.
Application 14/742,481 is a continuation of application No. 14/275,667, filed on May 12, 2014, granted, now 9,090,562, issued on Jul. 28, 2015.
Application 14/275,667 is a continuation of application No. 13/722,807, filed on Dec. 20, 2012, granted, now 8,765,732, issued on Jul. 1, 2014.
Application 13/722,807 is a continuation of application No. 13/447,007, filed on Apr. 13, 2012, granted, now 8,410,088, issued on Apr. 2, 2013.
Claims priority of provisional application 61/499,595, filed on Jun. 21, 2011.
Claims priority of provisional application 61/474,821, filed on Apr. 13, 2011.
Prior Publication US 2020/0155562 A1, May 21, 2020
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/5377 (2006.01); A61K 31/444 (2006.01); A61K 31/506 (2006.01); A61K 31/4412 (2006.01); A61K 31/553 (2006.01); A61K 31/551 (2006.01); C07D 213/64 (2006.01); C07D 409/12 (2006.01); C07D 498/08 (2006.01); C07D 401/12 (2006.01); C07D 405/12 (2006.01); C07D 413/12 (2006.01); C07D 417/12 (2006.01); C07D 491/08 (2006.01); C07D 491/107 (2006.01); C07D 405/14 (2006.01); A61K 31/443 (2006.01); A61K 31/4433 (2006.01); A61K 31/4436 (2006.01); A61K 31/4439 (2006.01); A61K 31/4545 (2006.01); A61K 31/4709 (2006.01); A61K 31/496 (2006.01)
CPC A61K 31/5377 (2013.01) [A61K 31/443 (2013.01); A61K 31/444 (2013.01); A61K 31/4412 (2013.01); A61K 31/4433 (2013.01); A61K 31/4436 (2013.01); A61K 31/4439 (2013.01); A61K 31/4545 (2013.01); A61K 31/4709 (2013.01); A61K 31/496 (2013.01); A61K 31/506 (2013.01); A61K 31/551 (2013.01); A61K 31/553 (2013.01); C07D 213/64 (2013.01); C07D 401/12 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 409/12 (2013.01); C07D 413/12 (2013.01); C07D 417/12 (2013.01); C07D 491/08 (2013.01); C07D 491/107 (2013.01); C07D 498/08 (2013.01)] 20 Claims
 
1. A compound of Formula (Ia):

OG Complex Work Unit Chemistry
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 and R5, 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 Qi 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, R12, 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; 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.