Dihidropyridin-2-one benzamine compounds
View Patent ↗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.
1. A compound of Formula (Ie) or a pharmaceutically acceptable salt thereof:
wherein
Z is NR 7 R 8 or S(O) a R 7 , in which a is 0;
R 1 is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from hydroxyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 6 -C 10 aryl;
each of R 2 and R 4 independently, is -Q 1 -T 1 , in which Q 1 is a bond or C 1 -C 3 alkyl linker optionally substituted with one or more substituents selected from halo and hydroxyl, and T 1 is H, halo, or azido;
R 3 is H or halo;
R 5 is H or C 1 -C 6 alkyl;
R 6 is H, halo, cyano, azido, OR a , —NR a R b , —C(O)NR a R b , —S(O) b R a , or R S2 ; wherein R S2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 4 to 12-membered heterocycloalkyl, wherein b is 0, 1 , or 2, and wherein each of R a and R b , independently is H, C 1 -C 6 alkyl, or 4 to 12-membered heterocycloalkyl; 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 a , R S2 and the 4 to 12-membered heterocycloalkyl ring formed by R a and R b , is optionally substituted with one or more -Q 2 -T 2 ; wherein Q 2 is a bond or C 1 -C 3 alkyl linker, and T 2 is H, halo, —OR e , —NR c R d , —C(O)OR c , C 1 -C 6 alkyl, or R S4 , in which each of R c and R d , independently is H or C 1 -C 6 alkyl, R S4 is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and R S4 is optionally substituted with one or more -Q 3 -T 3 , wherein Q 3 is a bond or C 1 -C 3 alkyl linker each optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxy, and T 3 is selected from the group consisting of halo, cyano, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, OR e , COOR e , —S(O) 2 R e , —NR e R f , and
—C(O)NR e R f , each of R e and R f independently being H or C 1 -C 6 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 optionally substituted with C 1 -C 6 alkyl;
R 7 is -Q 4 -T 4 , in which Q 4 is a bond or C 1 -C 4 alkyl linker and T 4 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C(O)—C 1-6 alkyl, C(O)—C 3-6 cycloalkyl, or 4 to 14-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 , wherein Q 5 is a bond, C(O), C(O)NR k , NR k C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R k being H or C 1 -C 6 alkyl, and T 5 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) q R q in which q is 0, 1, or 2 and R q is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 5 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 5 is H, halo, hydroxyl, or cyano; or -Q 5 -T 5 is oxo;
R 8 is H, C 1 -C 6 alkyl optionally substituted with halo, hydroxyl or C 1 -C 6 alkoxyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, or 4 to 7-membered heterocycloalkyl; or R 7 and R 8 , together with the N atom to which they are attached, form a 4 to 12-membered heterocycloalkyl ring having 0 to 2 additional heteroatoms, and the 4 to 12-membered heterocycloalkyl ring formed by R 7 and R 8 is optionally substituted with one or more -Q 6 -T 6 , wherein Q 6 is a bond, C(O), C(O)NR m , NR m C(O), S(O) 2 , or C 1 -C 3 alkyl linker, R m being H or C 1 -C 6 alkyl, and T 6 is H, halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, or S(O) p R p in which p is 0, 1, or 2 and R p is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, or 5- or 6-membered heteroaryl, and T 6 is optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, hydroxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 12-membered heterocycloalkyl, and 5- or 6-membered heteroaryl except when T 6 is H, halo, hydroxyl, or cyano; or -Q 6 -T 6 is oxo; and
R 12 is halo, C 1 -C 6 alkoxyl, or C 1 -C 6 alkyl optionally substituted with halo or C 2 -C 6 alkenyl.
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):
wherein n is 0, 1, or 2; U is O, S, N-Q 5 -T 5 , or CH-Q 5 -T 5 ; and R 12 is Cl, Br, or methyl.
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
R 1 is H or C 1 -C 6 alkyl optionally substituted one or more times with a substituent selected from hydroxyl, C 1 -C 6 alkoxyl and C 6 -C 10 aryl;
R 7 is -Q 4 -T 4 , in which Q 4 is a bond or a C 1 -C 4 alkyl linker, and T 4 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, C(O)—C 1 -C 6 alkyl, C(O)—C 3 -C 6 cycloalkyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl and oxetanyl, each optionally substituted with one or more substituents independently selected from oxo and -Q 5 -T 5 ;
R 8 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl or C 3 -C 8 cycloalkyl; and
R 12 is halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 alkoxyl.
6. The compound of claim 1 , wherein
Z is NR 7 R 8 or SR 7 ;
R 6 is H, halo, cyano, OR a , —C(O)NR a R b , —S(O) 2 R a , or R S2 ; wherein R S2 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 4 to 12-membered heterocycloalkyl, and wherein each of R a and R b , independently is H or C 1 -C 6 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 -Q 2 -T 2 ; wherein Q 2 is a bond or C 1 -C 3 alkyl linker, and T 2 is H, halo, —OR c , —NR c R d , —C(O)OC 1 -C 6 alkyl, or C 1 -C 6 alkyl, in which each of R c and R d , independently is H or C 1 -C 6 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 C 1 -C 6 alkyl substituents;
R 7 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, azetidinyl and oxetanyl, each optionally substituted with one or more substituents independently selected from oxo and -Q 5 -T 5 ; and
R 12 is halo or C 1 -C 6 alkyl.
7. The compound of claim 1 , wherein R 2 , R 4 and R 12 are each independently C 1 -C 6 alkyl and R 5 is H.
8. The compound of claim 1 , wherein R 7 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 -Q 5 -T 5 .
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 -Q 6 -T 6 .
10. The compound of claim 1 , wherein (i) R 6 is halo and Z is SR 7 , in which R 7 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or 4 to 7-membered heterocycloalkyl and R 7 is optionally substituted with one or more -Q 5 -T 5 ; or (ii) R 6 is —S(O) b R a or azido, in which b is 0, 1, or 2 and R a is C 1 -C 6 alkyl; and Z is NR 7 R 8 , in which R 7 is C 3 -C 8 cycloalkyl or 4 to 14-membered heterocycloalkyl, each optionally substituted with one or more -Q 5 -T 5 ; and R 8 is H or C 1 -C 6 alkyl.
11. The compound of claim 1 , wherein (i) Q 5 is a bond and T 5 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 4 to 12-membered heterocycloalkyl, 5- or 6-membered heteroaryl, amino, mono-C 1 -C 6 alkylamino, or di-C 1 -C 6 alkylamino, T 5 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, C 1 -C 6 alkoxyl, or C 3 -C 8 cycloalkyl; (ii) Q 5 is CO, S(O) 2 , or NHC(O); and T 5 is C 1 -C 6 alkyl, C 1 -C 6 alkoxyl, C 3 -C 8 cycloalkyl, or 4 to 12-membered heterocycloalkyl; or (iii) Q 5 is C 1 -C 3 alkyl linker and T 5 is H, C 6 -C 10 aryl, C 3 -C 8 cycloalkyl, 4 to 12-membered heterocycloalkyl, or S(O) q R q .
12. The compound of claim 1 , wherein one or more -Q 5 -T 5 are oxo.
13. The compound of claim 3 , wherein U is CH-Q 5 -T 5 and n is 0.
14. The compound of claim 1 , wherein (i) one or more -Q 6 -T 6 are oxo; or (ii) Q 6 is a bond or C(O) and T 6 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
15. The compound of claim 1 , wherein R 6 is halo or R 6 is C 2 -C 6 alkynyl optionally substituted with one or more -Q 2 -T 2 .
16. The compound of claim 15 , wherein R 12 is C 1 -C 6 alkyl or halo.
17. The compound of claim 15 , wherein -Q-T 2 is 4 to 12-membered heterocycloalkyl optionally substituted with one or more -Q 3 -T 3 .
18. The compound of claim 1 , wherein one Z is NR 7 R 8 in which R 8 is H and R 7 is C 1 -C 6 alkyl optionally substituted with C 1 -C 6 alkoxyl.
19. A compound selected from
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and pharmaceutically acceptable salts thereof.