Aryl- or Heteroaryl-Substituted Benzene Compounds

• US 20120264734A1
• Filed: 04/13/2012
• Published: 10/18/2012
• Est. Priority Date: 04/13/2011
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: KUNTZ, KEVIN W., CHESWORTH, RICHARD, DUNCAN, KENNETH W., KEILHACK, HEIKE, WARHOLIC, NATALIE, KLAUS, CHRISTINE, ZHENG, WANJUN, SEKI, MASASHI, SHIROTORI, SYUJI, KAWANO, SATOSHI
• Granted Patent: US 8,410,088 B2
• Time in Patent Office: Days
• US Class Current: 514/210.18
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 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 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 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/08 : Bridged systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 498/08 : Bridged systems

Abstract

The present invention relates to aryl- or heteroaryl-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 or ester thereof:

2. A compound of claim 1, wherein

X₁ is CR₁₁;

X₂ is CR₁₃;

Z is NR₇R₈, OR₇, SR₇, or CR₇R₈R₁₄;

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 7-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, 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, di-C₁-C₆ alkylamino, 4 to 7-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 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

R₆ is C₆-C₁₀ aryl or 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more -Q₂-T₂, wherein Q₂ is a bond or C₁-C₃ alkyl linker optionally substituted with halo, cyano, hydroxyl or C₁-C₆ alkoxy, and T₂ is H, halo, cyano, —

OR_a, —

NR_aR_b, —

(NR_aR_bR_c)⁺A⁻

, —

C(O)R_a, —

C(O)OR_a, —

C(O)NR_aR_b, —

NR_bC(O)R_a, —

NR_bC(O)OR_a, —

S(O)₂R_a, —

S(O)₂NR_aR_b, or R_S2, in which each of R_a, R_b, and R_c, independently is H or R_S3, A⁻

is a pharmaceutically acceptable anion, each of R_S2 and R_S3, independently, is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-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 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R_S2, R_S3, and the 4 to 7-membered heterocycloalkyl ring formed by R_a and R_b, is optionally substituted with one or more 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 7-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR_d, COOR_d, —

S(O)₂R_d, —

NR_dR_e, and —

C(O)NR_dR_e, each of R_d and R_e independently being H or 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 and 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 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl;

provided that -Q₂-T₂ is not H;

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_fR_g, —

OR_f, —

C(O)R_f, —

C(O)OR_f, —

C(O)NR_fR_g, —

C(O)NR_fOR_g, —

NR_fC(O)R_g, —

S(O)₂R_f, or R_S4, in which each of R_f and R_g, independently is H or R_S5, each of R_S4 and R_S5, independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4 to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and each of R_S4 and R_S5 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 7-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 7-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 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T₅ is H, halo, hydroxyl, or cyano;

or -Q₅-T₅ is oxo;

provided that R₇ is not H;

each of R₈, R₁₁, R₁₂, and R₁₃, independently, is H, halo, hydroxyl, COOH, cyano, R_S6, OR_S6, or COOR_S6, in which R_S6 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, amino, mono-C₁-C₆ alkylamino, or di-C₁-C₆ alkylamino, and R_S6 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 11-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 11-membered heterocycloalkyl ring having 1 to 3 heteroatoms, and each of the 4 to 11-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 7-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 7-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 7-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 7-membered heterocycloalkyl, and 5- or 6-membered heteroaryl.

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

4. The compound of claim 1, wherein R₆ is phenyl substituted with one or more -Q₂-T₂.

5. The compound of claim 1, wherein R₆ is 5- or 6-membered heteroaryl containing 1-3 additional heteroatoms selected from N, O, and S and optionally substituted with one or more -Q₂-T₂.

6. The compound of claim 5, wherein R₆ is pyridinyl, pyrazolyl, pyrimidinyl, quinolinyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, or thienyl, each of which is optionally substituted with one or more -Q₂-T₂.

7. The compound of claim 1, wherein T₂ is —

NR_aR_b or —

C(O)NR_aR_b, in which each of R_a and R_b, independently is H or C₁-C₆ alkyl, 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, the C₁-C₆ alkyl and the 4 to 12-membered heterocycloalkyl ring being optionally substituted with one or more -Q₃-T₃.

8. The compound of claim 1, wherein Q₂ is C₁-C₃ alkyl linker optionally substituted with halo or hydroxyl.

9. The compound of claim 1, wherein R₇ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q₅-T₅.

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

13. The compound of claim 1, wherein each of R₂ and R₄, independently is H or C₁-C₆ alkyl optionally substituted with amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or C₆-C₁₀ aryl.

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

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

17. The compound of claim 1, wherein Z is NR₇R₈ or CR₇R₈R₁₄ wherein R₇ and R₈, together with the atom to which they are attached, form a ring selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, and cyclohexenyl, each optionally substituted with one -Q₆-T₆.

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

20. The compound of claim 1, wherein the compound is of Formula (Ig):

21. The compound of claim 20, wherein 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_a, —

NR_aR_b, —

(NR_aR_bR_c)⁺A⁻

, —

C(O)NR_aR_b, —

NR_bC(O)R_a, —

S(O)₂R_a, or R_S2, in which each of R_a and R_b, independently is H or R_S3, each of R_S2 and R_S3, independently, is C₁-C₆ alkyl, or R_a and R_b, 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_S2, R_S3, and the 4 to 7-membered heterocycloalkyl ring formed by R_a and R_b, 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 halo, C₁-C₆ alkyl, 4 to 7-membered heterocycloalkyl, OR_d, —

S(O)₂R_d, and —

NR_dR_e, each of R_d and R_e independently being H or 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.

22. The compound of claim 2, wherein the compound is of Formula (II):

28. The compound of claim 1, wherein the compound is selected from

29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier.

30. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof.

11. (canceled)

12. (canceled)

14. (canceled)

18. (canceled)

23. A compound of Formula (IIa) or a pharmaceutically acceptable salt or ester thereof:

24. The compound of claim 23, wherein R_a and R_b, together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom and the ring is optionally substituted with one or more -Q₃-T₃, wherein the heterocycloalkyl is azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl.

25. The compound of claim 24, wherein R₇ is C₃-C₈ cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q₅-T₅.

26. The compound of claim 25, wherein R₇ is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q₅-T₅.

27. The compound of claim 26, R₈ is H or C₁-C₆ alkyl which 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.

31. A compound selected from the group consisting of

32. The compound of claim 31, wherein the compound is

33. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 31 and a pharmaceutically acceptable carrier.

34. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 32 and a pharmaceutically acceptable carrier.