TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES AS LSD1 INHIBITORS

US 20190152976A1
Filed: 10/29/2018
Published: 05/23/2019
Est. Priority Date: 07/10/2014
Status: Abandoned Application

First Claim

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1. A compound of Formula IVb:

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Abstract

The present invention is directed to [1,2,4]triazolo[4,3-a]pyridine and [1,2,4]triazolo[4,3-a]pyrazine derivatives which are LSD1 inhibitors useful in the treatment of diseases such as cancer.

Citations

45 Claims

1. A compound of Formula IVb:
- View Dependent Claims (2, 3, 4, 5, 9, 10, 12, 13, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 38, 39, 40, 41, 42, 43, 44, 45)
- - 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
    - X is N or CR^X;
      
      R¹is halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, Cy¹, CN, 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, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═
      
      NR^e1)R^b1, C(═
      
      NR^e1)NR^c1R^d1, NR^c1C(═
      
      NR^e1)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, or S(O)₂NR^c1R^d1, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, halo, CN, 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, NR^c1R^d1, NR^c1C(O)R^b1, NR^c1C(O)OR^a1, NR^c1C(O)NR^c1R^d1, C(═
      
      NR^e1)R^b1, C(═
      
      NR^e1)NR^c1R^d1, NR^c1C(═
      
      NR^e1)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;
      
      each R^Ais independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, 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, or 3, substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, S(O)₂R^b4, and S(O)₂NR^c4R^d4;
      
      each R^Bis independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, S(O)₂R^b5, and S(O)₂NR^c5R^d5, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, S(O)₂R^b5, and S(O)₂NR^c5R^d5;
      
      R^Xis H;
      
      each Cy¹and Cy⁵is independently selected from C_6-10aryl, C_3-10cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R^Cy;
      
      each R^Cyis selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, C_2-6alkenyl, C_2-6alkynyl, phenyl, C_3-7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C_1-4alkyl-, C_3-7cycloalkyl-C_1-4alkyl-, (5-6 membered heteroaryl)-C_1-4alkyl-, (4-7 membered heterocycloalkyl)-C_1-4alkyl-, CN, NO₂, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, C(═
      
      NR^e6)NR^c6R^d6, NR^c6C(═
      
      NR^e6)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)OR^a6, NR^c6C(O)NR^c6R^d6, NR^c6S(O)R^b6, NR^c6S(O)₂R^b6NR^c6S(O)₂NR^c6R^d6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, and S(O)₂NR^c6R^d6, wherein said C_1-4alkyl, C_2-6alkenyl, C_2-6alkynyl, phenyl, C_3-7cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C_1-4alkyl-, C_3-7cycloalkyl-C_1-4alkyl-, (5-6 membered heteroaryl)-C_1-4alkyl-, and (4-7 membered heterocycloalkyl)-C_1-4alkyl- are each optionally substituted by 1, 2, or 3 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, NO₂, OR^a6, SR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, OC(O)R^b6, OC(O)NR^c6R^d6, C(═
      
      NR^e6)NR^c6R^d6, NR^c6C(═
      
      NR^e6)NR^c6R^d6, NR^c6R^d6, NR^c6C(O)R^b6, NR^c6C(O)OR^a6, NR^c6C(O)NR^c6R^d6, NR^c6S(O)R^b6, NR^c6S(O)₂R^b6, NR^c6S(O)₂NR^c6R^d6, S(O)R^b6, S(O)NR^c6R^d6, S(O)₂R^b6, and S(O)₂NR^c6R^d6;
      
      each R^a1is independently selected from H, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, and Cy⁵, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from Cy⁵, halo, CN, OR^a7, SR^a7, C(O)R^b7, C(O)NR^c7R^d7, C(O)OR^a7, OC(O)R^b7, OC(O)NR^c7R^d7, NR^c7R^d7, NR^c7C(O)R^b7, NR^c7C(O)OR^a7, NR^c7C(O)NR^c7R^d7, C(═
      
      NR^e7)R^b7, C(═
      
      NR^e7)NR^c7R^d7, NR^c7C(═
      
      NR^e7)NR^c7R^d7, NR^c7S(O)R^b7, NR^c7S(O)₂R^b7, NR^c7S(O)₂NR^c7R^d7, S(O)R^b7, S(O)NR^c7R^d7, S(O)₂R^b7, and S(O)₂NR^c7R^d7;
      
      each R^b1, R^c1, and R^d1is 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl-, 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e5)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      or any R^c1and R^d1together 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_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each R^a4, R^b4, R^c4, and R^d4is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      or any R^c4and R^d4together 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_1-6alkyl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl-, 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      or any R^c5and R^d5together 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_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each R^a6, R^b6, R^c6, and R^d6is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      or any R^c6and R^d6together 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_1-6alkyl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each R^a7, R^b7, R^c7, and R^d7is 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl-, 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      or any R^c7and R^d7together 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_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each R^a8, R^b8, R^e8, and R^d8is independently selected from H, C_1-4alkyl, C_1-4haloalkyl, C_2-4alkenyl, and C_2-4alkynyl, wherein said C_1-4alkyl, C_2-4alkenyl, and C_2-4alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylthio, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4haloalkyl, and C_1-4haloalkoxy; and
      
      each R^e1, R^e6, R^e7, and R^e8is independently selected from H, C_1-4alkyl, and CN;
      
      wherein when X is N, then n is at least 1 or m is at least 1.
  - 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:
    - X is N or CR^X;
      
      R¹is OR^a1;
      
      each R^Ais independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, 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, or 3, substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, S(O)₂R^b4, and S(O)₂NR^c4R^d4;
      
      each R^Bis independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, S(O)₂R^b5, and S(O)₂NR^c5R^d5, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, S(O)₂R^b5, and S(O)₂NR^c5R^d5;
      
      R^Xis H;
      
      each Cy⁵is independently selected from 4-7 membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R^Cy;
      
      each R^Cyis selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, CN, NO₂, OR^a6, C(O)R^b6, C(O)NR^c6R^d6, C(O)OR^a6, NR^c6R^d6, NR^c6C(O)R^b6, S(O)₂R^b6, and S(O)₂NR^c6R^d6;
      
      each R^a1is C_1-6alkyl optionally substituted with Cy⁵;
      
      each R^a4, R^b4, R^c4, and R^d4is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      or any R^c4and R^d4together 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_1-6alkyl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c5C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c5C(O)OR^a5, C(═
      
      NR^e8)NR^c8R^d8, NR^c5C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl-, 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_1-4alkyl-, C_3-10cycloalkyl-C_1-4alkyl-, (5-10 membered heteroaryl)-C_1-4alkyl-, and (4-10 membered heterocycloalkyl)-C_1-4alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      or any R^c5and R^d5together 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_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, 5-6 membered heteroaryl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8, wherein said C_1-6alkyl, C_3-7cycloalkyl, 4-7 membered heterocycloalkyl, C_6-10aryl, and 5-6 membered heteroaryl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each R^a6, R^b6, R^c6, and R^d6is independently selected from H, C_1-6alkyl, C_1-4haloalkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from C_1-4alkyl, C_1-4haloalkyl, C_1-4cyanoalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8and S(O)₂NR^c8R^d8;
      
      or any R^c6and R^d6together 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_1-6alkyl, C_1-6haloalkyl, halo, CN, OR^a8, SR^a8, C(O)R^b8, C(O)NR^c8R^d8, C(O)OR^a8, OC(O)R^b8, OC(O)NR^c8R^d8, NR^c8R^d8, NR^c8C(O)R^b8, NR^c8C(O)NR^c8R^d8, NR^c8C(O)OR^a8, C(═
      
      NR^e8)NR^c8R^d8, NR^c8C(═
      
      NR^e8)NR^c8R^d8, S(O)R^b8, S(O)NR^c8R^d8, S(O)₂R^b8, NR^c8S(O)₂R^b8, NR^c8S(O)₂NR^c8R^d8, and S(O)₂NR^c8R^d8;
      
      each R^a8, R^b8, R^c8, and R^d8is independently selected from H, C_1-4alkyl, C_1-4haloalkyl, C_2-4alkenyl, and C_2-4alkynyl, wherein said C_1-4alkyl, C_2-4alkenyl, and C_2-4alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4alkyl, C_1-4alkoxy, C_1-4alkylthio, C_1-4alkylamino, di(C_1-4alkyl)amino, C_1-4haloalkyl, and C_1-4haloalkoxy; and
      
      each R^e8is independently selected from H, C_1-4alkyl, and CN;
      
      wherein when X is N, then n is at least 1 or m is at least 1.
  - 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.
  - 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CR^X.
  - 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2.
  - 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R^Ais CN.
  - 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring B is m is 1 or 2.
  - 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 2 and R^Bis methyl.
  - 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^Xis H.
  - 19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^Ais independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, 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, or 3, substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a4, C(O)R^b4, C(O)NR^c4R^d4, C(O)OR^a4, NR^c4R^d4, NR^c4C(O)R^b4, S(O)₂R^b4, and S(O)₂NR^c4R^d4.
  - 20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^Ais CN.
  - 21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^Bis independently selected from halo, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, CN, NO₂, OR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, S(O)₂R^b5, and S(O)₂NR^c5R^d5, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are each optionally substituted by 1, 2, or 3 substituents independently selected from halo, C_1-6haloalkyl, CN, NO₂, OR^a5, C(O)R^b5, C(O)NR^c5R^d5, C(O)OR^a5, NR^c5R^d5, NR^c5C(O)R^b5, S(O)₂R^b5, and S(O)₂NR^c5R^d5.
  - 22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^Bis C_1-6alkyl.
  - 23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^Bis methyl.
  - 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^a1is C_1-6alkyl optionally substituted with Cy⁵.
  - 25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^a1is C_1-6alkyl optionally substituted with 4-7 membered heterocycloalkyl.
  - 26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R^a1is pyrrolidinylmethyl.
  - 29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy⁵is 4-7 heterocycloalkyl.
  - 30. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy⁵is pyrrolidinyl.
  - 38. The compound of claim 1 selected from:
    - 4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile;
      
      2-fluoro-4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyridin-6-yl}benzonitrile; and
      
      4-{5-(4-methylphenyl)-8-[(3R)-pyrrolidin-3-ylmethoxy][1,2,4]triazolo[4,3-a]pyrazin-6-yl}benzonitrile;
      
      or a pharmaceutically acceptable salt of any of the aforementioned.
  - 39. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  - 40. A method of inhibiting LSD1 comprising contacting a compound of claim 1, or a pharmaceutically acceptable salt thereof, 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 (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma, primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasia syndrome (MDS), or 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 compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein said disease is a viral disease or a beta-globinopathy.

6-8. -8. (canceled)

11. (canceled)

14-17. -17. (canceled)

27-28. -28. (canceled)

31-37. -37. (canceled)

Specification

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Litigation Campaign Assessment

Current Assignee
Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
Original Assignee
Incyte Corporation
Inventors
Wu, Liangxing, Sun, Yaping, Wang, Xiaozhao, Yao, Wenqing, Zhang, Colin

Application Number

US16/173,612
Publication Number

US 20190152976A1
Time in Patent Office

Days
Field of Search
US Class Current
CPC Class Codes

A61P 35/00   Antineoplastic agents

C07D 471/04   Ortho-condensed systems

C07D 487/04   Ortho-condensed systems

TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES AS LSD1 INHIBITORS

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TRIAZOLOPYRIDINES AND TRIAZOLOPYRAZINES AS LSD1 INHIBITORS

First Claim

2 Assignments

Subscription Required

Subscription Required

0 Petitions

Subscription Required

Accused Products

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Abstract

Citations

45 Claims

Specification

Subscription Required

Solutions

Use Cases

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