Cyclopropylamines as LSD1 inhibitors
The present invention is directed to cyclopropylamine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.
1. A method of inhibiting LSD1 in a patient in need thereof, comprising administering to the patient a compound of formula:
or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl;
ring C is monocyclic C 3-7 cycloalkyl;
L is C 1-4 alkylene;
each R 1 is independently selected from halo and —O—(C 1-6 alkyl);
R Z is C 1-4 alkyl substituted by methoxy or CN;
R 4 is C(O)OR a3 ;
both R 5 and R 6 are H;
each R a3 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- are each 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 4 , 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, are each 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;
or any R c4 and R d4 together with the N atom to which they are attached form a 3-, 4-, 5-6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-6 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 e4 is independently selected from H, C 1-4 alkyl, and CN;
n is 0, 1, 2, or 3; and
q is 1.
2. The method of claim 1 , wherein n is 0.
3. The method of claim 1 , wherein n is 1.
4. The method of claim 1 , wherein n is 2.
5. The method of claim 1 , wherein each R 1 is independently selected from F and methoxy.
6. The method of claim 1 , wherein L is —CH 2 —.
7. The method of claim 1 , wherein ring C is cyclopentyl.
8. The method of claim 1 , wherein ring C is cyclobutyl.
9. The method of claim 1 , wherein ring C is cyclopropyl.
10. The method of claim 1 , wherein R Z is cyanomethyl.
11. The method of claim 1 , wherein R Z is methoxymethyl.
12. The method of claim 1 , wherein the compound or a pharmaceutically acceptable salt thereof has a trans configuration with respect to the di-substituted cyclopropyl group depicted in Formula I.
13. The method of claim 1 , wherein the compound is 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclopentanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the compound is 1-{[4-(methoxymethyl)-4-({[(1R,2S)-2-phenylcyclopropyl]amino}methyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the compound is 1-{[4-({[(1R,2S)-2-(4-fluorophenyl)cyclopropyl]amino}methyl)-4-(methoxymethyl)piperidin-1-yl]methyl}cyclobutanecarboxylic acid, or a pharmaceutically acceptable salt thereof.