US 12,312,359 B2
Inhibitors of the menin-MLL interaction
Salvacion Cacatian, Norristown, PA (US); David A. Claremon, Maple Glen, PA (US); Lawrence Wayne Dillard, Yardley, PA (US); Chengguo Dong, Staten Island, NY (US); Yi Fan, Doylestown, PA (US); Lanqi Jia, Horsham, PA (US); Stephen D. Lotesta, Burlington, NJ (US); Andrew Marcus, Media, PA (US); Angel Morales-Ramos, Blue Bell, PA (US); Suresh B. Singh, Kendall Park, NJ (US); Shankar Venkatraman, Lansdale, PA (US); Jing Yuan, Lansdale, PA (US); Yajun Zheng, Foster City, CA (US); Linghang Zhuang, Chalfont, PA (US); Stephan D. Parent, West Lafayette, IN (US); and Travis L. Houston, Lafayette, IN (US)
Assigned to Vitae Pharmaceuticals, LLC, North Chicago, IL (US)
Filed by Vitae Pharmaceuticals, LLC, Madison, NJ (US)
Filed on Sep. 2, 2022, as Appl. No. 17/902,432.
Application 17/902,432 is a continuation of application No. 16/837,421, filed on Apr. 1, 2020, granted, now 11,479,557.
Application 16/837,421 is a continuation of application No. 16/308,739, granted, now 10,683,302, issued on Jun. 16, 2020, previously published as PCT/US2017/036506, filed on Jun. 8, 2017.
Claims priority of provisional application 62/348,496, filed on Jun. 10, 2016.
Prior Publication US 2023/0174541 A1, Jun. 8, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 405/14 (2006.01); A61K 31/407 (2006.01); A61P 3/10 (2006.01); A61P 35/00 (2006.01); A61P 35/02 (2006.01); C07D 403/04 (2006.01); C07D 403/14 (2006.01); C07D 471/10 (2006.01); C07D 487/10 (2006.01); C07D 491/10 (2006.01); C07D 491/107 (2006.01); C07F 9/6561 (2006.01)
CPC C07D 487/10 (2013.01) [A61P 35/02 (2018.01); C07D 403/04 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 471/10 (2013.01); C07D 491/10 (2013.01); C07D 491/107 (2013.01); C07F 9/6561 (2013.01); C07B 2200/13 (2013.01)] 15 Claims
 
1. A Compound A having from the following formula:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein:
A, B, D, and E are each independently selected from —C(RA1)(RA2)—, —C(RA1)(RA2)—C(RA1)(RA2)—, —C(RA1)(RA2)—O—, —C(RA1)(RA2)—NRA3—, —C(═O)—, —C(RA1)(RA2)—C(═O)—, and —N═C(NH2)— wherein no more than one of A, B, D, and E is C(RA1)(RA2)—O—, —C(RA1)(RA2)—NRA3—, —C(RA1)(RA2)—C(═O)—, —C(═O)—, or —N═C(NH2)—;
U is N or CRU, wherein RU is H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkyl amino, or C2-8 dialkylamino;
W is N or CRW, wherein RW is H, halo, CN, OH, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkyl amino, or C2-8 dialkylamino;
X is NH;
Y is O, S, CRY1RY2 or NRY3, wherein RY1, RY2, and RY3 are each independently selected from H and C1-4 alkyl;
Z is Cy2, halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3,NRc3C(═NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, S(O)2NRc3Rd3, and P(O)Rc3Rd3 wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Cy2, halo, CN, NO2, CN, NO2, ORa3, SRa3, C(O)Rb3, C(O)NRc3Rd3, C(O)ORa3, OC(O)Rb3, OC(O)NRc3Rd3, C(═NRe3)NRc3Rd3, NRc3C(═NRe3)NRc3Rd3, NRc3Rd3, NRc3C(O)Rb3, NRc3C(O)ORa3, NRc3C(O)NRc3Rd3, NRc3S(O)Rb3, NRc3S(O)2Rb3, NRc3S(O)2NRc3Rd3, S(O)Rb3, S(O)NRc3Rd3, S(O)2Rb3, and S(O)2NRc3Rd3,
each R2 and R3 is independently selected from H, halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, CN, NO2, ORa4, SRa4, C(O)Rb4, C(O)NRc4Rd4, C(O)ORa4, OC(O)Rb4, OC(O)NRc4Rd4, C(═NRe4)NRc4Rd4, NRc4C(═NRe4)NRc4Rd4, NRc4Rd4, NRc4C(O)Rb4, NRc4C(O)ORa4, NRc4C(O)NRc4Rd4, NRc4S(O)Rb4, NRc4S(O)2Rb4, NRc4S(O)2NRc4Rd4, S(O)Rb4, S(O)NRc4Rd4, S(O)2Rb4, and S(O)2NRc4Rd4;
each RA1 is independently selected from H, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, CN, NO2, and OH;
each RA2 is independently selected from H, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, CN, NO2, and OH;
each RA3 is independently selected from H, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C(O)Rz, and C(O)ORz, wherein said C1-4 alkyl is optionally substituted by phenyl, C1-4 alkoxy, C1-4 haloalkoxy, CN, NO2, or OH;
Rz is H, C1-4 alkyl, or phenyl;
each Cy2 is independently selected from C6-14 aryl, C3-18 cycloalkyl, 5-16 membered heteroaryl, and 4-18 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RCy2;
each RCy2 is independently selected from halo, C1-6 alkyl, C1-4 haloalkyl, C1-4 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORa5, OC(O)Rb5, OC(O)NRc5Rd5, C(═NRe5)NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl, C3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from CN, NO2, ORa5, SRa5, C(O)Rb5, C(O)NRc5Rd5, C(O)ORc5, OC(O)Rb5, OC(O)NRc5Rd5, C(═NRe5) NRc5Rd5, NRc5C(═NRe5)NRc5Rd5, NRc5Rd5, NRc5C(O)Rb5, NRc5C(O)ORa5, NRc5C(O)NRc5Rd5, NRc5S(O)Rb5, NRc5S(O)2Rb5, NRc5S(O)2NRc5Rd5, S(O)Rb5, S(O)NRc5Rd5, S(O)2Rb5, and S(O)2NRc5Rd5;
each Ra3, Rb3, Rc3, Rd3, Ra4, Rb4, Rc4, Rd4, Ra5, Rb5, Rc5, and Rd5 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl, C3-10 cycloalkyl-C1-6 alkyl, (5-10 membered heteroaryl)-C1-6 alkyl, and (4-10 membered heterocycloalkyl)-C1-6 alkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-6 alkyl, C3-10 cycloalky-C1-6 alkyl, (5-10 membered heteroaryl)-C1-6 alkyl, and (4-10 membered heterocycloalkyl)-C1-6 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Rg;
each Re3, Re4, and Re5 is independently selected from H, C1-4 alkyl, and CN;
each Rg is independently selected from the group consisting of OH, NO2, CN, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano-C1-3 alkyl, HO—C1-3 alkyl, amino, C1-6 alkylamino, di(C1-6 alkyl) amino, thiol, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, carboxy, aminocarbonyl, C1-6 alkylcarbonyl, and C1-6 alkoxycarbonyl;
p is 0, 1, 2, or 3; and
q is 0, 1, or 2,
wherein any cycloalkyl or heterocycloalkyl group is optionally further substituted by 1 or 2 oxo groups.