Substituted benzene compounds

• US 10,150,764 B2
• Filed: 07/18/2014
• Issued: 12/11/2018
• Est. Priority Date: 07/19/2013
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Campbell, John Emmerson
• Primary Examiner(s): Vajda, Kristin A
• Application Number:
  US14/904,801
• Publication Number:
  US 20160194316A1
• Time in Patent Office: 1,607 Days
• Field of Search: 544106
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 231/20 One oxygen atom attached in position 3 or 5
• CPC Class Codes: C07D 231/30 attached in positions 3 and 5
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein the compound is of Formula (Ia):

3. The compound of claim 1, wherein the compound is of Formula (Ib):

4. The compound of claim 1, wherein the compound is of Formula (Ic), (Id1) or (Id2):

5. The compound of claim 1, X is

6. The compound of claim 1, Z is NR₇R₈.

7. The compound of claim 1, wherein i) R₆ is C₆-C₁₀ aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q₂-T₂, wherein Q₂ is a bond or C₁-C₃ alkyl linker, and T₂ is H, halo, cyano, —

OR_c, —

NR_cR_d, —

C(O)NR_cR_d, —

NR_dC(O)R_c, —

S(O)₂R_c, —

S(O)₂NR_cR_d, or R_S4, in which each of R_c and R_d, independently is H or R_S5, each of R_S4 and R_S5, independently, is C₁-C₆ alkyl, or R_c and R_d, together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R_S4, R_S5, and the 4 to 7-membered heterocycloalkyl ring formed by R_c and R_d, is optionally, independently substituted with one or more -Q₃-T₃, wherein Q₃ is a bond or C₁-C₃ alkyl linker and T₃ is selected from the group consisting of H, halo, C₁-C₆ alkyl, 4 to 7-membered heterocycloalkyl, OR_e, —

S(O)₂R_e, and —

NR_eR_f, each of R_e and R_f independently being H or C₁-C₆ alkyl optionally substituted with OH, O—

C₁-C₆ alkyl, or NH—

C₁-C₆ alkyl, or -Q₃-T₃ is oxo;

or any two neighboring -Q₂-T₂, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S;

or ii) R₆ is halo, C₁-C₃ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkyl, C(O)H, or —

C(O)R_a, in which R_a is C₁-C₆ alkyl or 4 to 12-membered heterocycloalkyl;

or iii) R₆ is ethynyl substituted with one or more -Q₂-T₂, in which Q₂ is a bond or C₁-C₃ alkyl linker and T₂ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or 4 to 7-membered heterocycloalkyl optionally substituted with one or more -Q₃-T₃.

8. The compound of claim 7, wherein i) R₆ is phenyl or pyridyl, Q₂ is a bond or methyl linker, and T₂ is H, halo, —

OR_c, —

NR_cR_d, or —

S(O)₂NR_cR_d;

or ii) R₆ is F, Br, or Cl;

or iii) R₆ is

9. The compound of claim 1, wherein R₇ is C₃-C₈ cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q₅-T₅.

10. The compound of claim 9, wherein i) R₇ is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, piperazinyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q₅-T₅;

or ii) R₇ is tetrahydropyran,

11. The compound of claim 1, wherein R₈ is H or C₁-C₆ alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, C(O)OH, C(O)O—

C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, and di-C₁-C₆ alkylamino.

12. The compound of claim 1, wherein R₇ is piperidinyl, tetrahydropyran, cyclopentyl, or cyclohexyl, each optionally substituted with one -Q₅-T₅ and R₈ is ethyl.

13. The compound of claim 1, wherein n is 1 or 2.

14. The compound of claim 13, wherein n is 1.

15. The compound of claim 1, wherein the compound is selected from those in Tables 1-5, and pharmaceutically acceptable salts thereof.

16. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. A method of treating cancer wherein the cancer is lymphoma, leukemia or melanoma comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the cancer is diffuse large B-cell lymphoma (DLBCL), non-Hodgkin'"'"'s lymphoma (NHL), follicular lymphoma or diffuse large B-cell lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia, or myelodysplastic syndromes (MDS).

19. The method of claim 17, wherein the cancer is malignant rhabdoid tumor or INI1-defecient tumor.