	US 11,739,085 B2
	Inhibitors of the menin-MLL interaction
Salvacion Cacatian, Conshohocken, PA (US); David A. Claremon, Maple Glen, PA (US); Chengguo Dong, Staten Island, NY (US); Yi Fan, Doylestown, PA (US); Lanqi Jia, Horsham, PA (US); Stephen D. Lotesta, Burlington, NJ (US); Suresh B. Singh, Kendall Park, NJ (US); Shankar Venkatraman, Lansdale, PA (US); Jing Yuan, Lansdale, PA (US); Yajun Zheng, Hockessin, DE (US); and Linghang Zhuang, Chalfont, PA (US)
Assigned to Vitae Pharmaceuticals, LLC, Madison, NJ (US)
Filed by Vitae Pharmaceuticals, LLC, Madison, NJ (US)
Filed on Aug. 11, 2020, as Appl. No. 16/990,657.
Application 16/990,657 is a continuation of application No. 16/333,852, granted, now 10,899,758, previously published as PCT/US2017/051780, filed on Sep. 15, 2017.
Claims priority of provisional application 62/395,618, filed on Sep. 16, 2016.
Prior Publication US 2021/0179611 A1, Jun. 17, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 471/04 (2006.01); C07D 487/04 (2006.01); A61P 35/00 (2006.01)

CPC C07D 471/04 (2013.01) [A61P 35/00 (2018.01); C07D 487/04 (2013.01)]

21 Claims

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a C_6-10aryl group, 5-14 membered heteroaryl group, C_3-14cycloalkyl group, or 4-14 membered heterocycloalkyl group;

U is N or CR^U, wherein R^Uis H, halo, CN, OH, C_1-4alkyl, C_1-4alkoxy, amino, C_1-4alkyl amino, or C_2-8dialkylamino;

the moiety

is selected from:

wherein R^Yis H, halo, CN, OH, C_1-4alkyl, C_1-4alkoxy, amino, C_1-4alkyl amino, or C_2-8dialkylamino;

X is F or C₁;

L is selected from —C_1-6alkylene- and —(C_1-4alkylene)_a-Q-(C_1-4alkylene)_b-, wherein the C_1-6alkylene group and any C_1-4alkylene group of the —(C_1-4alkylene)_a-Q-(C_1-4alkylene)_b- group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C_1-3alkyl, C_1-3alkoxy, C_1-3hydroxyalkyl, C_1-3haloalkyl, C_1-3haloalkoxy, amino, C_1-3alkylamino, and di(C_1-3alkyl)amino;

Q is —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—, —C(═O)NR^q1—, —C(═O)O—, —OC(═O)NR^q1—, —NR^q1—, —NR^q1C(═O)O—, —NR^q1C(═O)NR^q1—, —S(═O)₂NR^q1—, —C(═NR^q2)—, or —C(═NR^g2)—NR^q1—, wherein each R^qis independently selected from H, C_1-6alkyl, and C_1-3hydroxyalkyl, and wherein each R^qis independently selected from H, C_1-6alkyl, and CN;

Cy is a linking C_6-14aryl, linking C_3-18cycloalkyl, linking 5-16 membered heteroaryl, or linking 4-18 membered heterocycloalkyl group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^Cy;

each R^Cyis independently selected from halo, C_1-6alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from CN, NO₂, OR^a1, SR^a1, C(O)R^b1, C(O)NR^c1R^d1, C(O)OR^a1, OC(O)R^b1, OC(O)NR^c1R^d1, C(═NR^e1)NR^c1R^d1, NR^c1C(═NR^e1)NR^c1R^d1, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, NR^c1S(O)R^b1, NR^c1S(O)₂R^b1, NR^c1S(O)₂NR^c1R^d1, S(O)R^b1, S(O)NR^c1R^d1, S(O)₂R^b1, and S(O)₂NR^c1R^d1;

R¹is H, Cy¹, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2and S(O)₂NR^e2R^d2, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, CN, NO₂, OR^a2, SR^a2, C(O)R^b2, C(O)NR^c2R^d2, C(O)OR^a2, OC(O)R^b2, OC(O)NR^c2R^d2, C(═NR^e2)NR^c2R^d2, NR^c2C(═NR^e2)NR^c2R^d2, NR^c2R^d2, NR^c2C(O)R^b2, NR^c2C(O)OR^a2, NR^c2C(O)NR^c2R^d2, NR^c2S(O)R^b2, NR^c2S(O)₂R^b2, NR^c2S(O)₂NR^c2R^d2, S(O)R^b2, S(O)NR^c2R^d2, S(O)₂R^b2, and S(O)₂NR^c2R^d2;

Z is Cy², C_1-4haloalkyl, C_1-4cyanoalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(S)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, S(O)₂NR^c3R^d3, and P(O)R^c3R^d3wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from Cy², halo, CN, NO₂, CN, NO₂, OR^a3, SR^a3, C(O)R^b3, C(O)NR^c3R^d3, C(O)OR^a3, OC(O)R^b3, OC(O)NR^c3R^d3, C(═NR^e3)NR^c3R^d3, NR^c3C(═NR^e3)NR^c3R^d3, NR^c3R^d3, NR^c3C(O)R^b3, NR^c3C(O)OR^a3, NR^c3C(O)NR^c3R^d3, NR^c3S(O)R^b3, NR^c3S(O)₂R^b3, NR^c3S(O)₂NR^c3R^d3, S(O)R^b3, S(O)NR^c3R^d3, S(O)₂R^b3, and S(O)₂NR^c3R^d3;

each R², R³, R⁴, and R⁵is independently selected from H, halo, C_1-6alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, C_2-6alkenyl, C_2-6alkynyl, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4OC(O)R^b4, OC(O)NR^c4R^d4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted by 1, 2, 3, or 4 substituents independently selected from halo, CN, NO₂, OR^a4, SR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, OC(O)R^b4, OC(O)NR^c4R^d4, C(═NR^e4)NR^c4R^d4, NR^c4C(═NR^e4)NR^c4R^d4, NR^c4R^d4, NR^c4C(O)R^b4, NR^c4C(O)OR^a4, NR^c4C(O)NR^c4R^d4, NR^c4S(O)R^b4, NR^c4S(O)₂R^b4, NR^c4S(O)₂NR^c4R^d4, S(O)R^b4, S(O)NR^c4R^d4, S(O)₂R^b4, and S(O)₂NR^c4R^d4;

each Cy¹is independently selected from C_6-14aryl, C_3-18cycloalkyl, 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 R^Cy1;

each Cy²is independently selected from C_6-14aryl, C_3-18cycloalkyl, 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 R^Cy2;

each R^Cy1and R^Cy2is independently selected from halo, C_1-6alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, C_2-6alkenyl, C_2-6alkynyl, phenyl, C_3-7cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, CN, NO₂, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, C(═NR^e5)NR^c5R^d5, NR^c5C(═NR^e5)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5C(O)NR^c5R^d5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)RVs, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, phenyl, C_3-7cycloalkyl, 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, OR^a5, SR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, OC(O)R^b5, OC(O)NR^c5R^d5, C(═NR^e5)NR^c5R^d5, R5C(═NR^e5)NR^c5R^d5, NR^c5R^d5, NR^c5C(O)R^b5, NR^c5C(O)OR^a5, NR^c5C(O)NR^c5R^d5, NR^c5S(O)R^b5, NR^c5S(O)₂R^b5, NR^c5S(O)₂NR^c5R^d5, S(O)R^b5, S(O)NR^c5R^d5, S(O)₂R^b5, and S(O)₂NR^c5R^d5;

each R^a1, R^b1, R^c1, R^d1, R^a2, R^b2, R^c2, R^d2, R^a3, R^b3, R^c3, R^d3, R^a4, R^b4, R^c4, R^d4, R^a5, R^b5, R^c5, and R^d5is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-6alkyl, C_3-10cycloalkyl-C_1-6alkyl, (5-10 membered heteroaryl)-C_1-6alkyl, and (4-10 membered heterocycloalkyl)-C_1-6alkyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C_6-10aryl-C_1-6alkyl, C_3-10cycloalky-C_1-6alkyl, (5-10 membered heteroaryl)-C_1-6alkyl, and (4-10 membered heterocycloalkyl)-C_1-6alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R^g;

each R^e1, R^e2, R^e3, R^e4, and R^e5is independently selected from H, C_1-4alkyl, and CN;

each R^gis independently selected from the group consisting of OH, NO₂, CN, halo, C_1-20alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-4haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, cyano-C_1-3alkyl, HO—C_1-3alkyl, amino, C_1-6alkylamino, di(C_1-6alkyl)amino, thiol, C_1-6alkylthio, C_1-6alkylsulfinyl, C_1-6alkylsulfonyl, carboxy, C_1-6alkylcarbonyl, and C_1-6alkoxycarbonyl;

n is 0 or 1;

m is 0 or 1;

p is 0, 1, 2, or 3;

r is 0, 1, or 2;

a is 0 or 1; and

b is 0 or 1,

wherein any cycloalkyl or heterocycloalkyl group is optionally further substituted by 1 or 2 oxo groups.