Cyclopropylamines as LSD1 inhibitors
View Patent ↗The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
1. A compound of Formula IIIa:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl;
R Z is Cy 1 , CN, C(O)NR c R d , OR a , SR a , C(O)R b , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NR c R d ;
each R 1 is independently selected from halo or C 1-6 alkyl;
R N is H or R B ;
each R B is independently selected from Cy, halo, C 1-6 alkyl, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
wherein R B is substituted on any ring-forming atom of ring B except the ring-forming atom of ring B to which R Z is bonded;
R 3 and R 4 are each independently selected from H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, and —(C 1-4 alkyl)-OR a4 ;
R 5 and R 6 are each independently selected from H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, and —(C 1-4 alkyl)-OR a4 ;
each Cy is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
Cy 1 is phenyl, pyridinyl, pyrimidyl, cyclohexyl, or cyclobutyl, each of which is substituted with 1, 2, 3, or 4 substituents independently selected from Cy 2 , halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;
Cy 2 is C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(═NR e3 )NR c3 R d3 NR c3 C(═NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;
each R a , R b , R c , and R d is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
or any R c and R d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 and S(O) 2 NR c4 R d4 ;
each R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, and Cy, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
or any R c2 and R d2 is together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
each R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
or any R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
each R a4 , R b4 , R c4 , and R d4 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
each R e2 , R e3 , and R e4 is independently selected from H, C 1-4 alkyl, and CN;
n is 0, 1, 2, or 3;
p is 0, 1, 2, or 3;
q is 0, 1, or 2; and
s is 1, 2, 3, or 4.
2. A compound of Formula IIIa:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl;
R Z is Cy 1 , CN, C(O)NR c R d , OR a , SR a , C(O)R b , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O) 2 R b , S(O)R b , S(O)NR c R d , S(O) 2 R b , or S(O) 2 NR c R d ;
each R 1 is independently selected from halo or C 1-6 alkyl;
R N is H or R B ;
each R B is independently selected from Cy, halo, C 1-6 alkyl, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 ;
wherein R B is substituted on any ring-forming atom of ring B except the ring-forming atom of ring B to which R Z is bonded;
R 3 and R 4 are each independently selected from H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, and —(C 1-4 alkyl)-OR a4 ;
R 5 and R 6 are each independently selected from H, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, and —(C 1-4 alkyl)-OR a4 ;
each Cy is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl;
Cy 1 is phenyl, pyridinyl, pyrimidyl, cyclohexyl, or cyclobutyl, each of which is substituted with 1, 2, 3, or 4 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(═NR e3 )NR c3 R d3 , NR c3 C(═NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 ;
each R a , R b , R c , and R d is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
or any R c and R d together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
each R a2 , R b2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, and Cy, wherein said C 1-6 alkyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Cy, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
or any R c2 and R d2 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group;
each R a3 , R b3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
or any R c3 and R d3 together with the N atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, C 1-6 haloalkyl, halo, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl, C 3-7 cycloalkyl, 4-7 membered heterocycloalkyl, C 6-10 aryl, and 5-6 membered heteroaryl are optionally substituted by 1, 2, or 3 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, CN, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)NR c4 R d4 , NR c4 C(O)OR a4 , C(═NR e4 )NR c4 R d4 , NR c4 C(═NR e4 )NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , NR c4S (O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , and S(O) 2 NR c4 R d4 ;
each R a4 , R b4 , R c4 , and R d4 is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, and C 2-4 alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, di(C 1-4 alkyl)amino, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
each R e2 , R e3 , and R e4 is independently selected from H, C 1-4 alkyl, and CN;
n is 0, 1, 2, or 3;
p is 0, 1, 2, or 3;
q is 0, 1, or 2; and
s is 1, 2, 3, or 4.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein q is 0.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein q is 1.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein s is 1.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 5 and R 6 are H.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein both R 3 and R 4 are H.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is CN, OR a , or Cy 1 .
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is CN.
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is OR a .
12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is OR a and R a is selected from C 1-6 alkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl-C 1-4 alkyl-, and C 3-10 cycloalkyl-C 1-4 alkyl-, each of which is optionally substituted with halo or CN.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is methoxy.
14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is ethoxy.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is phenoxy substituted by 1 or 2 substituents independently selected from halo and CN.
16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is (C 6-10 aryl-C 1-4 alkyl)-O—.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is (pyridinyl)-O— or (pyrimidinyl)-O—, of which is substituted by 1 or 2 substituents independently selected from halo.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is (C 3-10 cycloalkyl-C 1-4 alkyl)-O—.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is (C 3-10 cycloalkyl)-O—.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is Cy 1 .
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is phenyl substituted by 1 or 2 substituents independently selected from Cy 2 , halo, CN, C 1-6 alkoxy, —C(O)NR c3 R d3 , —C(O)OR a3 , (4-10 membered heterocycloalkyl)-O—, and C 1-4 cyanoalkyl.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is phenyl substituted by 1 or 2 substituents independently selected from Cy 2 , halo, and C 1-4 cyanoalkyl.
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is phenyl substituted by 1 or 2 halo.
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is pyridinyl substituted by 1 or 2 substituents independently selected from halo and C 1-6 alkoxy.
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-(cyanomethyl)phenyl, 3-carboxyphenyl, 3-[(3S)-tetrahydrofuran-3-yloxy]phenyl, 3-(tetrahydropyran-4-yloxy)phenyl, 2-fluorophenoxy, 3-fluorophenoxy, 4-fluorophenoxy, benzyloxy, 4-cyanophenyl, 4-cyano-2-fluorophenyl, 3-cyanophenyl, 2-cyanophenoxy, (5-fluoropyridin-2-yl)oxy, (5-fluoropyrimidin-2-yl)oxy, 3-cyanophenoxy, 6-methoxypyridin-3-yl, 5-fluoropyridin-2-yl, ethoxy, cyclobutylmethoxy, cyclohexyloxy, 4-methoxyphenyl, 3-(aminocarbonyl)phenyl, 3-methoxyphenyl, 3-ethoxyphenyl,
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R Z is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 4-(cyanomethyl)phenyl,
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R N is H.
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R N is R B .
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R B is independently selected from C 1-6 alkyl, 4-10 membered heterocycloalkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and S(O) 2 R b2 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 NR c2 R d2 NR c2 C(O)R b2 NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c1 R d2 .
30. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R B is independently selected from C 1-6 alkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , and S(O) 2 R b2 , wherein said C 1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from Cy, halo, CN, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c1 R d2 .
31. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R B is a group of formula:
32. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0.
33. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 1.
34. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula IIIa.
35. The compound of claim 1 selected from:
(1-Acetyl-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile;
Methyl 4-(cyanomethyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidine-1-carboxylate,
4-(Cyanomethyl)-N,N-dimethyl-4-{[(trans-2-phenylcyclopropyl)amino]methyl}-piperidine-1-carboxamide;
(1-(Methylsulfonyl)-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile;
(1-Methyl-4-{[(trans-2-phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile;
(4-{[(trans-2-Phenylcyclopropyl)amino]methyl}piperidin-4-yl)acetonitrile; and
[4-{[(trans-2-Phenylcyclopropyl)amino]methyl}-1-(pyridin-3-ylmethyl)piperidin-4-yl]acetonitrile,
or a pharmaceutically acceptable salt of any of the aforementioned.
36. The compound of claim 1 selected from:
3-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N-methylpropanamide;
3-[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N,N-dimethylpropanamide;
(1R,2S)—N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;
(1S,2R)—N-{[4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;
[4-(4-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]acetic acid;
(1R,2S)—N-{[1-[(2S)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;
(1R,2S)—N-{[1-[(2R)-2-aminopropanoyl]-4-(4-fluorobenzyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;
3-[4-(2-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(3-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(2,4-difluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(2,3-difluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(3,4-difluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
(1R,2S)—N-{[4-(methoxymethyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;
3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N,N-dimethylpropanamide;
3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-N-methylpropanamide;
3-[4-[4-(cyanomethyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}-methyl)piperidin-1-yl]propanoic acid;
3-[4-[4-(1-cyanocyclopropyl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid; and
3-[4-[3-(1-methyl-1H-pyrazol-4-yl)benzyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
or a pharmaceutically acceptable malt of any of the aforementioned.
37. The compound of claim 1 selected from:
(1R,2S)—N-{[4-(methoxymethyl)-1-(morpholin-4-ylacetyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;
(1R,2S)—N-{[4-(methoxymethyl)-1-(morpholin-4-ylcarbonyl)piperidin-4-yl]methyl}-2-phenylcyclopropanamine;
3-(4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-{3-[(3R)-tetrahydrofuran-3-yloxy]benzyl}piperidin-1-yl)propanoic acid
3-[4-(3-ethoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(3-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(4-cyano-2-fluorobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(4-cyanobenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(4-methoxybenzyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(ethoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]-2,2-dimethylpropanoic acid;
3-[4-[(2-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(2-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(3-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(3-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(4-cyanophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(4-fluorophenoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(fluoropyridin-2-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(6-methoxypyridin-3-yl)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(benzyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(cyclobutylmethoxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-[(cyclohexyloxy)methyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-{[(fluoropyridin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-[4-{[(fluoropyrimidin-2-yl)oxy]methyl}-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]propanoic acid;
3-{[1-(2-cyanoethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid;
3-{[1-(cyclopropylmethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid;
3-{[1-[(dimethylamino)acetyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzamide;
3-{[1-[(dimethylamino)acetyl]-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzonitrile;
3-{[1-ethyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid;
3-{[1-isopropyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid;
3-{[1-methyl-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-4-yl]methyl}benzoic acid;
3-{[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-(pyridin-2-ylmethyl)piperidin-4-yl]methyl}benzoic acid;
3-{[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-(pyridin-3-ylmethyl)piperidin-4-yl]methyl}benzoic acid;
3-{[4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl]methyl}benzoic acid; and
3-{4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)-4-[3-(tetrahydro-2H-pyran-4-yloxy)benzyl]piperidin-1-yl}propanoic acid;
or a pharmaceutically acceptable salt of any of the aforementioned.
38. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable malt thereof, and at least one pharmaceutically acceptable carrier.
39. A method of inhibiting LSD1 comprising contacting a compound of claim 1 , or a pharmaceutically acceptable salt thereof with said LSD1.
40. A method of inhibiting LSD1 comprising contacting a pharmaceutical composition of claim 38 with said LSD1.
41. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof: wherein said disease is cancer.
42. The method of claim 41 , wherein said cancer is a hematological cancer.
43. The method of claim 42 , wherein said hematological cancer is selected from acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyelocytic leukemia (APL) chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma, Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), and multiple myeloma.
44. The method of claim 41 , wherein said cancer is a sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, or skin cancer.
45. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of claim 38 wherein said disease is cancer.
46. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein said disease is a viral disease or a beta-globinopathy.
47. A method of treating a disease comprising administering to a patient a therapeutically effective amount of a pharmaceutical composition of claim 38 wherein said disease is a viral disease or a beta-globinopathy.