LSD1 inhibitors and uses thereof
Provided are novel compounds of Formula (I): and pharmaceutically acceptable salts thereof, which are useful for treating a variety of diseases, disorders or conditions, associated with LSD1. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I), pharmaceutically acceptable salts thereof, and methods for their use in treating one or more diseases, disorders or conditions, associated with LSD1.
1. A compound represented by structural Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from C 3 -C 10 carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which being optionally substituted with up to 4 independently selected substituents;
each of R 2 and R 3 is independently selected from hydrogen, halo, —CN and optionally substituted C 1 -C 8 alkyl;
R 4 is selected from hydrogen, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted heterocyclyl, and —C(R 6 )(R 7 )(R 8 );
each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl;
R 6 is selected from hydrogen and —C 1 -C 4 alkyl,
R 7 is selected from hydrogen, halo, —CN, and optionally substituted C 1 -C 8 alkyl; and
R 8 is selected from hydrogen, halo, —C 1 -C 4 alkyl, —(C 0 -C 4 alkylene)-C 3 -C 10 carbocyclyl, —(C 0 -C 4 alkylene)-heterocyclyl, —(C 0 -C 4 alkylene)-aryl, and —(C 0 -C 4 alkylene)-heteroaryl, wherein any C 3 -C 10 carbocyclyl, heterocyclyl, aryl, heteroaryl, or alkyl portion of R 8 is optionally substituted;
wherein the substituents for an optionally substituted alkyl, carbocyclyl, heterocyclyl, aryl group and heteroaryl group as defined above are selected from halogen, ═O, —CN, —OR c , —NR a R b , —S(O) i R c , —NR d S(O) 2 R c , —S(O) 2 NR e R f , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR e R f , —NR d C(═O)R c , —C(═S)NR e R f , —NR d C(═S)R c , —NR d (C═O)OR c , —O(C═O)NR e R f , —NR d (C═S)OR c , —O(C═S)NR e R f , —NR d (C═O)NR e R f , —NR d (C═S)NR e R f , —C(═S)R c , —C(═O)R c , (C 1 -C 6 )alkyl, cycloalkyl, —(CH 2 ) 1- 4 -cycloalkyl, heterocyclyl, —(CH 2 ) 1-4 -heterocyclyl, aryl, —(CH 2 ) 1-4 -aryl, heteroaryl and —(CH 2 ) 1-4 -heteroaryl, wherein each of the (C 1 -C 6 )alkyl, cycloalkyl, —(CH 2 ) 1-4 -cycloalkyl, heterocyclyl, —(CH 2 ) 1-4 -heterocyclyl, aryl, —(CH 2 ) 1-4 -aryl, heteroaryl and —(CH 2 ) 1-4 -heteroaryl are optionally substituted with halogen, OR c , —NO 2 , —CN, —NR d C(═O)R c , —NR g R h , —S(O) i R c , —C(═O)OR c , —C(═O)NR e R f , —C(═O)R c , (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, and halo(C 1 -C 3 )alkoxy;
R a and R b are each independently selected from —H and (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, hydroxy, COOH, —NR g R h , and (C 1 -C 3 )alkoxy;
R c is —H or (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —NR g R h , hydroxyl, and (C 1 -C 3 )alkoxy;
R d is —H or (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —NR g R h , hydroxyl, and (C 1 -C 3 )alkoxy;
R e and R f are each independently selected from —H and (C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from halogen, —NR g R h , hydroxyl, and (C 1 -C 3 )alkoxy; or R e and R f , together with the nitrogen to which they are attached, form a 3-8 membered ring optionally substituted with 1 to 3 substituents independently selected from halogen, —NR g R h , —CN, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 3 )alkoxy, halo(C 1 -C 3 )alkoxy, and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl;
R g and R h are each independently selected from —H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, and (C 1 -C 3 )alkoxy(C 1 -C 6 )alkyl; and
i is 0, 1 or 2;
provided that the compound is other than
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 7 is hydrogen.
3. The compound of claim 1 , wherein
R 1 is selected from C 3 -C 10 carbocyclyl, heterocyclyl, aryl and heteroaryl, each of which being optionally substituted with up to 3 substituents independently selected from R X ;
each of R 2 and R 3 is independently selected from hydrogen, halo, and C 1 -C 4 alkyl;
each R 5 is independently selected from hydrogen and C 1 -C 4 alkyl;
R 6 is hydrogen;
R 8 is selected from —(C 0 -C 4 alkylene)-C 3 -C 10 carbocyclyl, —(C 0 -C 4 alkylene)-heterocyclyl, —(C 0 -C 4 alkylene)-aryl, and —(C 0 -C 4 alkylene)-heteroaryl, wherein said C 3 -C 10 carbocyclyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with up to 3 substituents independently selected from R Y ; and
R X and R Y are each independently selected from halogen, —CN, —OR c , —NR a R b , —S(O) i R c , —NR d S(O) 2 R c , —S(O) 2 NR e R f , —C(═O)OR c , —OC(═O)OR c , —OC(═O)R c , —OC(═S)OR c , —C(═S)OR c , —O(C═S)R c , —C(═O)NR e R f , —NR d C(═O)R c , —C(═S)NR e R f , —NR d C(═S)R c , —NR d (C═O)OR c , —O(C═O)NR e R f , —NR d (C═S)OR c , —O(C═S)NR e R f , —NR d (C═O)NR e R f , —NR d (C═S)NR e R f , —C(═S)R c , —C(═O)R c , (C 1 -C 6 )alkyl, cycloalkyl, —(CH 2 ) 1-4 -cycloalkyl, heterocyclyl, —(CH 2 ) 1-4 -heterocyclyl, aryl, —(CH 2 ) 1-4 -aryl, heteroaryl and —(CH 2 ) 1-4 -heteroaryl, wherein each of the (C 1 -C 6 )alkyl, cycloalkyl, —(CH 2 ) 1-4 -cycloalkyl, heterocyclyl, —(CH 2 ) 1-4 -heterocyclyl, aryl, —(CH 2 ) 1-4 -aryl, heteroaryl and —(CH 2 ) 1-4 -heteroaryl are optionally substituted with halogen, OR c , —NO 2 , —CN, —NR d C(═O)R c , —NR g R h , —S(O) i R c , —C(═O)OR c , —C(═O)NR e R f , —C(═O)R c , (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, and halo(C 1 -C 3 )alkoxy; or two R X bonded to the same carbon atom or two R Y bonded to the same carbon atom are taken together to form ═O.
4. The compound of claim 3 , wherein R 1 is aryl, heteroaryl, or heterocyclyl, each being optionally substituted with up to 3 substituents independently selected from R X .
5. The compound of claim 4 , wherein R 1 is phenyl, pyridinyl, pyrazolyl, pyridinonyl, imidazolyl, or pyrimidinyl, each being optionally substituted with up to 3 substituents independently selected from R X .
6. The compound of claim 3 , wherein R X and R Y are each independently selected from halogen, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, hydroxy(C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —(CH 2 ) 1-4 -aryl, —(CH 2 ) 1-4 -aryl-COOH, —(CH 2 ) 1-4 -aryl-C(═O)NR e R f , —NR d (C═O)OR c , —CN, —C(═O)NR e R f , —NR a R b , and (C 1 -C 4 )alkyl optionally substituted with —C(═O)NR e R f , —C(═O)OR c , or —S(O) i R c ; or two R X bonded to the same carbon atom or two R Y bonded to the same carbon atom are taken together to form ═O.
7. The compound of claim 3 , wherein R X is selected from halogen, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, hydroxy(C 1 -C 4 )alkyl, —CN, —C(═O)NR e R f , —NR a R b , and (C 1 -C 4 )alkyl optionally substituted with —C(═O)NR e R f ; or two R X bonded to the same carbon atom are taken together to form ═O.
8. The compound of claim 3 , wherein R X is halogen, —CN, —C(═O)NR e R f , or (C 1 -C 4 )alkyl; or two R X on the same carbon atom are taken together to form ═O.
9. The compound of claim 3 , wherein R X is halogen, —CN, (C 1 -C 4 )alkyl, —C(═O)NH 2 , or —C(═O)NH(C 1 -C 3 )alkyl; or two R X on the same carbon atom are taken together to form ═O.
10. The compound of claim 1 , wherein R 1 is selected from unsubstituted phenyl, 2-fluorophenyl, pyridin-3-yl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H-imidazol-4-yl, 1-methyl-6-oxopyridin-3-yl, 1-methyl-6-oxopyridin-4-yl, 4-cyanophenyl, pyrimidin-5-yl, 4-aminocarbonylphenyl, and 4-methylaminocarbonylphenyl.
11. The compound of claim 1 , wherein R 1 is selected from unsubstituted phenyl, 2-fluorophenyl and pyridin-3-yl.
12. The compound of claim 1 , wherein R 2 is hydrogen.
13. The compound of claim 1 , wherein R 3 is selected from hydrogen, halogen and C 1 -C 4 alkyl.
14. The compound of claim 1 , wherein R 3 is selected from hydrogen, fluoro, —CH 3 and —CH 2 CH 3 .
15. The compound of claim 1 , wherein R 3 is selected from hydrogen and —CH 3 .
16. The compound of claim 3 , wherein R 4 is hydrogen, —CH 2 — piperidinyl, —CH 2 -pyridinyl, —CH 2 -cyclopropyl, piperidinyl, 1-azaspiro[4.5]decane-8-yl, bicyclo[3.2.1]octan-8-amine-3-yl, or cyclohexyl, wherein each of said piperidinyl, pyridinyl, cyclopropyl, and cyclohexyl, is optionally substituted with up to 3 substituents independently selected from R Y .
17. The compound of claim 3 , wherein R Y is selected from halogen, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, halo(C 1 -C 4 )alkoxy, cyano(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkyl, hydroxy(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, —(CH 2 ) 1-4 -aryl, —(CH 2 ) 1-4 -aryl-COOH, —(CH 2 ) 1-4 -aryl-C(═O)NR e R f , —NR a R b , —NR d (C═O)OR c , —C(═O)NR e R f , and (C 1 -C 6 )alkyl optionally substituted with —C(═O)OR c , —C(═O)NR e R f , or —S(O) i R c ; or two R Y on the same carbon atom are taken together to form ═O.
18. The compound of claim 3 , wherein R Y is selected from —NH 2 , —NH(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, cyano(C 1 -C 4 )alkyl, —(CH 2 ) 1-4 -aryl, —NR d (C═O)OR c , —(CH 2 ) 1-4 -arylCOOH, —(CH 2 ) 1-4 -aryl-C(═O)NR e R f , hydroxy(C 1 -C 6 )alkyl, —C(═O)NR e R f , —NR a R b and (C 1 -C 6 )alkyl optionally substituted with —S(O) 2 R c , —C(═O)OR c , or —C(═O)NR e R f , where R a is (C 1 -C 6 )alkyl optionally substituted with COOH; R b is —H; R e is —H or (C 1 -C 6 )alkyl; R f is —H or (C 1 -C 6 )alkyl; and R c is —H or (C 1 -C 6 )alkyl optionally substituted with COOH.
19. The compound of claim 1 , wherein R 4 is selected from hydrogen, 1-((2-ethylsulfonyl)ethyl)piperidin-4-ylmethyl, 1-(2-cyanoethyl)piperidin-4-ylmethyl, 1-(2-hydroxy-2,2-dimethylethyl)piperidin-4-ylmethyl, 1-(3-carboxy-2,2-dimethylpropyl)piperidin-4-ylmethyl, 1-(3-carboxy-3,3-dimethylpropyl)piperidin-4-ylmethyl, 1-(4-aminocarbonylbenzyl)piperidin-4-ylmethyl, 1-(4-carboxybenzyl)piperidin-4-ylmethyl, 1-(4-dimethylaminocarbonylbenzyl)piperidin-4-ylmethyl, 1-(aminocarbonylethyl)piperidin-4-ylmethyl, 1-(carboxyethyl)piperidin-4-ylmethyl, 1-(carboxymethyl)piperidin-4-ylmethyl, 1-(dimethylaminoethyl)piperidin-4-ylmethyl, 1-(methoxyethyl)piperidin-4-ylmethyl, 1-benzylpiperidin-4-ylmethyl, 2-aminopyridin-3-ylmethyl, 4-amino-4-methylcyclohexyl, 4-aminocyclohexyl, 4-carbboxypropylaminocyclhexyl, 4-carboxyethylaminocyclohexyl, 4-ethylaminocyclohexyl, 4-fluoropiperidin-4-ylmethyl, 8-aminobicyclo[3.2.1]octan-3-yl, azaspiro[4.5]decan-8-yl, cyclopropylmethyl, piperidin-4-yl, and piperidin-4-ylmethyl.
20. The compound of claim 1 , wherein R 4 is selected from hydrogen 1-(4-carboxybenzyl)piperidin-4-ylmethyl, piperidin-4-ylmethyl, 1-(carboxyethyl)piperidin-4-ylmethyl, 1-benzylpiperidin-4-ylmethyl, 4-fluoropiperidin-4-ylmethyl, 4-aminocyclohexyl, 1-(carboxymethyl)piperidin-4-ylmethyl, 1-((2-ethylsulfonyl)ethyl)piperidin-4-ylmethyl, 2-aminopyridin-3-ylmethyl, 1-(2-hydroxy-2,2-dimethylethyl)piperidin-4-ylmethyl, cyclopropylmethyl, piperidin-4-ylmethyl, piperidin-4-yl, and 4-carboxyethylaminocyclohexyl.
21. The compound of claim 1 , wherein the compound is of the formula
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.