Substituted Benzene Compounds

• US 20140142083A1
• Filed: 04/13/2012
• Published: 05/22/2014
• Est. Priority Date: 04/13/2011
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Kuntz, Kevin Wayne, Chesworth, Richard, Duncan, Kenneth William, Keilhack, Heike, Warholic, Natalie, Klaus, Christine, Knutson, Sarah K., Wigle, Timothy James Nelson, Seki, Masashi
• Granted Patent: US 9,376,422 B2
• Time in Patent Office: Days
• US Class Current: 514/210.2
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• 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 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• 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 491/048 the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/08 Bridged systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/113 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

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

X₁ is N or CR₁₁;

X₂ is N or CR₁₃;

X₃ is N or C, and when X₃ is N, R₆ is absent;

Z is NR₇R₈, OR₇, S(O)_aR₇, or CR₇R₈R₁₄, in which a is 0, 1, or 2;

each of R₁, R₅, R₉, and R₁₀, independently, is H or C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—

C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

each of R₂, R₃, and R₄, independently, is -Q₁-T₁, in which Q₁ is a bond or C₁-C₃ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₁ is H, halo, hydroxyl, COOH, cyano, azido, or R_S1, in which R_S1 is C₁-C₃ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxyl, C(O)O—

C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, amino, mono-C₁-C₆ alkylamino, C₆ alkylamino, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R_S1 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, oxo, COOH, C(O)O—

C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

R₆ is H, halo, cyano, azido, —

NR_aR_b, —

C(O)R_a, —

C(O)OR_a, —

C(O)NR_aR_b, —

NR_bC(O)R_a, —

S(O)_bR_a, —

S(O)_bNR_aR_b, or R_S2, in which R_S2 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, or 4 to 12-membered heterocycloalkyl, b is 0, 1, or 2, each of R_a and R_b, independently is H or R_S3, and R_S3 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl;

or R_a and R_b, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom; and

each of R_S2, R_S3, and the 4 to 12-membered heterocycloalkyl ring formed by R_a and R_b, is optionally substituted with one or more -Q₂-T₂, wherein Q₂ is a bond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₂ is H, halo, cyano, —

OR_c, —

NR_cR_d, —

C(O)R_c, —

C(O)OR_c, —

C(O)NR_cR_d, —

NR_dC(O)R_c, —

NR_dC(O)OR_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, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, or R_c and R_d, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R_S4, R_S5, and the 4 to 12-membered heterocycloalkyl ring formed by R_c and R_d, is optionally substituted with one or more -Q₃-T₃, wherein Q₃ is a bond or C₁-C₃ alkyl linker each optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₃ is selected from the group consisting of halo, cyano, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR_e, COOR_e, —

S(O)₂R_e, —

NR_eR_f, and —

C(O)NR_eR_f, each of R_e and R_f independently being H or C₁-C₆ alkyl, or -Q₃-T₃ is oxo;

or -Q₂-T₂ is oxo;

R₇ is -Q₄-T₄, in which Q₄ is a bond, C₁-C₄ alkyl linker, or C₂-C₄ alkenyl linker, each linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₄ is H, halo, cyano, NR_gR_h, —

OR_g, —

C(O)R_g, —

C(O)OR_g, —

C(O)NR_gR_h, —

C(O)NR_gOR_h, —

NR_gC(O)R_h, —

S(O)₂R_g, or R_S6, in which each of R_g and R_h, independently is H or R_S7, each of R_S6 and R_S7, independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 14-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R_S6 and R_S7 is optionally substituted with one or more -Q₅-T₅, wherein Q₅ is a bond, C(O), C(O)NR_k, NR_kC(O), S(O)₂, or C₁-C₃ alkyl linker, R_k being H or C₁-C₆ alkyl, and T₅ is H, halo, C₁-C₆ alkyl, hydroxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O)_qR_q in which q is 0, 1, or 2 and R_q is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T₅ is optionally substituted with one or more substituents selected from the group consisting of halo, C₁-C₆ alkyl, hydroxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T₅ is H, halo, hydroxyl, or cyano;

or -Q₅-T₅ is oxo;

provided that (i) R₇ is not C(O)R_g or —

S(O)₂R_g when Z is NR₇R₈;

(ii) R₇ is not C₁-C₆ alkyl when Z is OR₇, and (iii) R₇ is not H;

each of R₈, R₁₁, R₁₂, and R₁₃, independently, is H, halo, hydroxyl, COOH, cyano, R_S8, OR_S8, or COOR_S8, in which R_S8 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, 4 to 12-membered heterocycloalkyl, amino, mono-C₁-C₆ alkylamino, or di-C₁-C₆ alkylamino, and R_S8 is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—

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

or R₇ and R₈, together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, or R₇ and R₈, together with the C atom to which they are attached, form C₃-C₈ cycloalkyl or a 4 to 12-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 12-membered heterocycloalkyl rings or C₃-C₈ cycloalkyl formed by R₇ and R₈ is optionally substituted with one or more -Q₆-T₆, wherein Q₆ is a bond, C(O), C(O)NR_m, NR_mC(O), S(O)₂, or C₁-C₃ alkyl linker, R_m being H or C₁-C₆ alkyl, and T₆ is H, halo, C₁-C₆ alkyl, hydroxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O)_pR_p in which p is 0, 1, or 2 and R_p is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T₆ is optionally substituted with one or more substituents selected from the group consisting of halo, C₁-C₆ alkyl, hydroxyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T₆ is H, halo, hydroxyl, or cyano;

or -Q₆-T₆ is oxo; and

R₁₄ is absent, H, or C₁-C₆ alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—

C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.

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

8. The compound of claim 1, wherein Z is NR₇R₈.

12. The compound of claim 1, wherein 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.

13. The compound of claim 1, wherein R₆ is 4 to 12-membered heterocycloalkyl optionally substituted with one or more -Q₂-T₂, in which -Q₂-T₂ is oxo or Q₂ is a bond and T₂ is C₁-C₆ alkyl, —

OR_c, —

NR_cR_d, —

C(O)R_c, —

C(O)OR_c, —

S(O)₂R_c, or 4 to 12-membered heterocycloalkyl optionally substituted with one or more -Q₃-T₃.

14. The compound of claim 1, wherein Q₃ is a bond or C₁-C₃ alkyl linker and T₃ is selected from the group consisting of C₁-C₃ alkyl, OR_e, —

S(O)₂R_e, or —

NR_eR_f.

15. The compound of claim 1, wherein R₆ is piperidinyl, 2,2,6,6-tetramethyl-piperidinyl, 1,2,3,6-tetrahydropyridinyl, 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, tetrahydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, pyrrolidinyl, F, Br, or Cl.

17. The compound of claim 1, wherein R₇ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl or 4 to 14-membered heterocycloalkyl, each optionally substituted with one or more -Q₅-T₅.

25. The compound of claim 1, wherein R₇ is tetrahydrothiopyran, cyclopentyl or cyclohexyl, each optionally substituted with one or more -Q₅-T₅, or R₇ is isopropyl.

29. The compound of claim 1, wherein each of R₂ and R₄, independently is C₁-C₃ alkyl optionally substituted with C₁-C₆ alkoxyl.

31. The compound of claim 1, wherein R₁ is H and R₃ is H.

32. The compound of claim 1, wherein R₁₂ is H, methyl, ethyl, ethenyl, or halo.

36. The compound of claim 1, wherein R₈ is H, methyl, or ethyl.

40. The compound of claim 1, wherein R₁₃ is H or methyl and R₁₁ is H.

43. The compound of claim 1, wherein the compound is of Formula (Ie):

53. The compound of claim 1, wherein the compound is of Formula (II):

54. The compound of claim 1, wherein the compound is of Formula (IIA):

66. A pharmaceutical composition comprising a compound of claim 1, N-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)furan-2-carboxamide, N,N′

-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1,3-phenylene)diacetamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-pivalamidobenzamide, 3-(3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamido)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethoxybenzamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4,5-trimethoxybenzamide, 3-allyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4,5-dimethoxybenzamide, 4-(2-amino-2-oxoethoxy)-3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxybenzamide, 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-hydroxy-5-methoxybenzamide, or 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxy-4-propoxybenzamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

67. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, N-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)furan-2-carboxamide, N,N′

-(5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1,3-phenylene)diacetamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-pivalamidobenzamide, 3-(3,4-dihydro-2H-benzo[b][1,4]dioxepine-7-sulfonamido)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,5-dimethoxybenzamide, N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3,4,5-trimethoxybenzamide, 3-allyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4,5-dimethoxybenzamide, 4-(2-amino-2-oxoethoxy)-3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxybenzamide, 3-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-hydroxy-5-methoxybenzamide, or 3-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-methoxy-4-propoxybenzamide, or a pharmaceutically acceptable salt thereof.

4-7. -7. (canceled)

9-11. -11. (canceled)

16. (canceled)

18-24. -24. (canceled)

26-28. -28. (canceled)

30. (canceled)

33-35. -35. (canceled)

37-39. -39. (canceled)

41-42. -42. (canceled)

44-52. -52. (canceled)

55-65. -65. (canceled)

68. (canceled)