Dihidropyridin-2-one benzamine compounds

• US 9,376,422 B2
• Filed: 04/13/2012
• Issued: 06/28/2016
• 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
• Primary Examiner(s): Rodriguez-Garcia, Valerie
• Application Number:
  US14/110,873
• Publication Number:
  US 20140142083A1
• Time in Patent Office: 1,537 Days
• Field of Search: 549/429
• US Class Current: 1/1
• 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 (Ie) or a pharmaceutically acceptable salt thereof:

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

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

4. 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.

5. The compound of claim 1, wherein

R₁ is H or C₁-C₆ alkyl optionally substituted one or more times with a substituent selected from hydroxyl, C₁-C₆ alkoxyl and C₆-C₁₀ aryl;

R₇ is -Q₄-T₄, in which Q₄ is a bond or a C₁-C₄ alkyl linker, and T₄ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, C(O)—

C₁-C₆ alkyl, C(O)—

C₃-C₆ cycloalkyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl and oxetanyl, each optionally substituted with one or more substituents independently selected from oxo and -Q₅-T₅;

R₈ is H, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl or C₃-C₈ cycloalkyl; and

R₁₂ is halo, C₁-C₆ alkyl, C₁-C₆ haloalkyl or C₁-C₆ alkoxyl.

6. The compound of claim 1, wherein

Z is NR₇R₈ or SR₇;

R₆ is H, halo, cyano, OR_a, —

C(O)NR_aR_b, —

S(O)₂R_a, or R_S2;

wherein R_S2 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, or 4 to 12-membered heterocycloalkyl, and wherein 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; and

each of R_S2 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, and T₂ is H, halo, —

OR_c, —

NR_cR_d, —

C(O)OC₁-C₆ alkyl, or C₁-C₆ alkyl, in which each of R_c and R_d, independently is H or C₁-C₆ alkyl, 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 0 or 1 C₁-C₆ alkyl substituents;

R₇ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl and oxetanyl, each optionally substituted with one or more substituents independently selected from oxo and -Q₅-T₅; and

R₁₂ is halo or C₁-C₆ alkyl.

7. The compound of claim 1, wherein R₂, R₄ and R₁₂ are each independently C₁-C₆ alkyl and R₅ is H.

8. The compound of claim 1, wherein R₇ is cyclohexyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl oxetanyl, 1,4-dioxaspiro[4.5]decan-8-yl, 1-oxaspiro[4.5]decan-8-yl, 3′

H-spiro[cyclohexane-1,1′

-isobenzofuran]-4-yl, 7′

H-spiro[cyclohexane-1,5′

-furo[3,4-b]pyridin]-4-yl, 3′

H-spiro[cyclohexane-1,1′

-furo[3,4-c]pyridin]-4-yl, or 1-azaspiro[4.5]decan-8-yl, each substituted with one or more -Q₅-T₅.

9. The compound of claim 1, wherein Z is selected from the group consisting of piperidinyl, morpholinyl, piperazinyl, azetidinyl, pyrrolidinyl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and 1,4-dioxa-8-azaspiro[4.5]decan-8-yl, each optionally substituted with one -Q₆-T₆.

10. The compound of claim 1, wherein (i) R₆ is halo and Z is SR₇, in which R₇ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl or 4 to 7-membered heterocycloalkyl and R₇ is optionally substituted with one or more -Q₅-T₅;

or (ii) R₆ is —

S(O)_bR_a or azido, in which b is 0, 1, or 2 and R_a is C₁-C₆ alkyl; and

Z is NR₇R₈, in which R₇ is C₃-C₈ cycloalkyl or 4 to 14-membered heterocycloalkyl, each optionally substituted with one or more -Q₅-T₅; and

R₈ is H or C₁-C₆ alkyl.

11. The compound of claim 1, wherein (i) Q₅ is a bond and T₅ is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, amino, mono-C₁-C₆ alkylamino, or di-C₁-C₆ alkylamino, T₅ being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, C₁-C₆ alkoxyl, or C₃-C₈ cycloalkyl;

(ii) Q₅ is CO, S(O)₂, or NHC(O); and

T₅ is C₁-C₆ alkyl, C₁-C₆ alkoxyl, C₃-C₈ cycloalkyl, or 4 to 12-membered heterocycloalkyl;

or (iii) Q₅ is C₁-C₃ alkyl linker and T₅ is H, C₆-C₁₀ aryl, C₃-C₈ cycloalkyl, 4 to 12-membered heterocycloalkyl, or S(O)_qR_q.

12. The compound of claim 1, wherein one or more -Q₅-T₅ are oxo.

13. The compound of claim 3, wherein U is CH-Q₅-T₅ and n is 0.

14. The compound of claim 1, wherein (i) one or more -Q₆-T₆ are oxo;

or (ii) Q₆ is a bond or C(O) and T₆ is C₁-C₆ alkyl or C₁-C₆ alkoxy.

15. The compound of claim 1, wherein R₆ is halo or R₆ is C₂-C₆ alkynyl optionally substituted with one or more -Q₂-T₂.

16. The compound of claim 15, wherein R₁₂ is C₁-C₆ alkyl or halo.

17. The compound of claim 15, wherein -Q-T₂ is 4 to 12-membered heterocycloalkyl optionally substituted with one or more -Q₃-T₃.

18. The compound of claim 1, wherein one Z is NR₇R₈ in which R₈ is H and R₇ is C₁-C₆ alkyl optionally substituted with C₁-C₆ alkoxyl.

19. A compound selected from