US 11,786,519 B2
Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
Le Wang, Vernon Hills, IL (US); George Doherty, Libertyville, IL (US); Xilu Wang, Libertyville, IL (US); Zhi-Fu Tao, Gurnee, IL (US); Milan Bruncko, Green Oaks, IL (US); Aaron R. Kunzer, Arlington Heights, IL (US); Michael D. Wendt, Vernon Hills, IL (US); Xiaohong Song, Grayslake, IL (US); Robin Frey, Libertyville, IL (US); Todd M. Hansen, Grayslake, IL (US); Gerard M. Sullivan, Lake Villa, IL (US); Andrew Judd, Grayslake, IL (US); and Andrew Souers, Evanston, IL (US)
Assigned to ABBVIE INC., North Chicago, IL (US)
Filed by AbbVie Inc., North Chicago, IL (US)
Filed on Sep. 16, 2020, as Appl. No. 17/22,693.
Application 14/961,748 is a division of application No. 14/543,817, filed on Nov. 17, 2014, granted, now 9,227,963, issued on Jan. 5, 2016.
Application 17/022,693 is a continuation of application No. 16/578,229, filed on Sep. 20, 2019, abandoned.
Application 16/578,229 is a continuation of application No. 15/803,568, filed on Nov. 3, 2017, abandoned.
Application 15/803,568 is a continuation of application No. 14/961,748, filed on Dec. 7, 2015, granted, now 9,844,547, issued on Dec. 19, 2017.
Application 14/543,817 is a continuation of application No. 13/649,900, filed on Oct. 11, 2012, granted, now 8,889,675, issued on Nov. 18, 2014.
Claims priority of provisional application 61/547,162, filed on Oct. 14, 2011.
Prior Publication US 2021/0228565 A1, Jul. 29, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/4725 (2006.01); C07D 401/04 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 493/08 (2006.01); C07D 513/04 (2006.01); A61K 31/4985 (2006.01); A61K 31/5025 (2006.01); A61K 31/5377 (2006.01); A61K 31/541 (2006.01)
CPC A61K 31/4725 (2013.01) [A61K 31/4985 (2013.01); A61K 31/5025 (2013.01); A61K 31/5377 (2013.01); A61K 31/541 (2013.01); C07D 401/04 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 493/08 (2013.01); C07D 513/04 (2013.01)] 5 Claims
 
1. A compound having Formula (V)

OG Complex Work Unit Chemistry
or a therapeutically acceptable salt thereof, wherein:
X is heteroaryl; wherein the heteroaryl represented by X is optionally substituted with one, two, three, or four R4;
Rx, at each occurrence, is independently selected from the group consisting of R5, OR5, SR5, S(O)R5, SO2R5, C(O)R5, CO(O)R5, OC(O)R5, OC(O)OR5, NH2, NHR5, N(R5)2, NHC(O)R5, NR5C(O)R5, NHS(O)2R5, NR5S(O)2R5, NHC(O)OR5, NR5C(O)OR5, NHC(O)NH2, NHC(O)NHR5, NHC(O)N(R5)2, NR5C(O)NHR5, NR5C(O)N(R5)2, C(O)NH2, C(O)NHR5, C(O)N(R5)2, C(O)NHOH, C(O)NHOR5, C(O)NHSO2R5, C(O)NR5SO2R5, SO2NH2, SO2NHR5, SO2N(R5)2, CO(O)H, C(O)H, OH, CN, N5, NO2, F, Cl, Br and I;
L1 is selected from the group consisting of (CR6R7)q, (CR6R7)s—O—(CR6R7)r, (CR6R7)s—C(O)—(CR6R7)r, (CR6R7)s—S—(CR6R7)r, (CR6R7)s—S(O)2—(CR6R7)r, (CR6R7)s—NR6AC(O)—(CR6R7)r, (CR6R7)s—C(O)NR6A—(CR6R7)r, (CR6R7)s—NR6A—(CR6R7)r, (CR6R7)s—S(O)2NR6A—(CR6R7)r, and (CR6R7)s—NR6AS(O)2—(CR6R7)r;
Y2 is C8-14 cycloalkyl, C8-14 cycloalkenyl, C8-14 heterocycloalkyl, or C8-14 heterocycloalkenyl; optionally fused to one or two rings selected from the group consisting of C3-8 cycloalkane, C3-8 cycloalkene, benzene, C5-6 heteroarene, C3-8 heterocycloalkane, and C3-8 heterocycloalkene; wherein Y2 is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of R8, OR8, SR8, S(O)R8, SO2R8, C(O)R8, CO(O)R8, OC(O)R8, OC(O)OR8, NH2, NHR8, N(R8)2, NHC(O)R8, NR8C(O)R8, NHS(O)2R8, NR8S(O)2R8, NHC(O)OR8, NR8C(O)OR8, NHC(O)NH2, NHC(O)NHR8, NHC(O)N(R8)2, NR8C(O)NHR8, NR8C(O)N(R8)2, C(O)NH2, C(O)NHR8, C(O)N(R8)2, C(O)NHOH, C(O)NHOR8, C(O)NHSO2R8, C(O)NR8SO2R8, SO2NH2, SO2NHR8, SO2N(R8)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
Z1 is selected from the group consisting of C(O)OR9, C(O)NR10R11, C(O)R11, NR10C(O)R11, NR10C(O)NR10R11, OC(O)NR10R11, NR10C(O)OR9, C(═NOR10)NR10R11, NR10C(═NCN)NR10R11, NR10S(O)2NR10R11, S(O)2R9, S(O)2NR10R11, N(R10)S(O)2R11, NR10C(═NR11)NR10R11, C(═S)NR10R11, C(═NR10)NR10R11, halogen, NO2, and CN; or
Z1 is selected from the group consisting of

OG Complex Work Unit Chemistry
R1, at each occurrence, is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R2, at each occurrence, is independently selected from the group consisting of deuterium, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
two R2 that are attached to the same carbon atom, together with said carbon atom, optionally form a ring selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;
R3, at each occurrence, is independently selected from the group consisting of halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R4, at each occurrence, is independently selected from the group consisting of NR12R13, OR12, CN, NO2, halogen, C(O)OR12, C(O)NR12R13, NR12C(O)R13, NR12S(O)2R14, NR12S(O)R14, S(O)2R14, S(O)R14 and R14;
R5, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;
R6A is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl;
R6 and R7, at each occurrence, are each independently selected from the group consisting of hydrogen, R15, OR15, SR15, S(O)R15, SO2R15, C(O)R15, CO(O)R15, OC(O)R15, OC(O)OR15, NH2, NHR15, N(R15)2, NHC(O)R15, NR15C(O)R15, NHS(O)2R15, NR15S(O)2R15, NHC(O)OR15, NR15C(O)OR15, NHC(O)NH2, NHC(O)NHR15, NHC(O)N(R15)2, NR15C(O)NHR15, NR15C(O)N(R15)2, C(O)NH2, C(O)NHR15, C(O)N(R15)2, C(O)NHOH, C(O)NHOR15, C(O)NHSO2R15, C(O)NR15SO2R15, SO2NH2, SO2NHR15, SO2N(R15)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I;
R8, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R8 C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 haloalkyl are optionally substituted with one, two, three, four, five, or six substituents independently selected from the group consisting of R16, OR16, SR16, S(O)R16, SO2R16, C(O)R16, CO(O)R16, OC(O)R16, OC(O)OR16, NH2, NHR16, N(R16)2, NHC(O)R16, NR16C(O)R16, NHS(O)2R16, NR16S(O)2R16, NHC(O)OR16, NR16C(O)OR16, NHC(O)NH2, NHC(O)NHR16, NHC(O)N(R16)2, NR16C(O)NHR16, NR16C(O)N(R16)2, C(O)NH2, C(O)NHR16, C(O)N(R16)2, C(O)NHOH, C(O)NHOR16, C(O)NHSO2R16, C(O)NR16SO2R16, SO2NH2, SO2NHR16, SO2N(R16)2, CO(O)H, C(O)H, OH, CN, N3, NO2, F, Cl, Br and I; wherein the R8 aryl, heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, NH2, C(O)NH2, SO2NH2, C(O)H, (O), OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R9 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, cycloalkyl, phenyl and (CH2)1-4 phenyl; and
R10 and R11, at each occurrence, are each independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-6 haloalkyl, phenyl and (CH2)1-4-phenyl; or
R10 and R11, or R10 and R9, together with the atom to which each is attached are combined to form a heterocyclyl;
Rk, at each occurrence, is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 heterocycloalkyl, C3-7 cycloalkyl and C1-6 haloalkyl;
R12 and R13, at each occurrence, are each independently selected from the group consisting of hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl and (CH2)1-4 phenyl;
R14, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl and C1-4 haloalkyl;
R12 and R13, or R12 and R14, at each occurrence, together with the atom to which each is attached, are optionally combined to form a heterocyclyl;
R15, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R15 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one, two, or three substituents independently selected from the group consisting of O—(C1-4 alkyl), NH2, C(O)NH2, SO2NH2, C(O)H, C(O)OH, (O), OH, CN, NO2, OCF3, OCF2CF3, F, Cl, Br and I;
R16, at each occurrence, is independently selected from the group consisting of C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R16 C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, and C1-4 hydroxyalkyl are optionally substituted with one substituent independently selected from the group consisting of OCH3, OCH2CH2OCH3, and OCH2CH2NHCH3;
q is 1, 2, or 3;
s is 0, 1, or 2;
r is 0, 1, or 2;
wherein the sum of s and r is 0, 1, or 2;
m is 0, 1, 2, or 3;
n is 0, 1, 2, 3, 4, 5, or 6;
o is 0, 1, 2, 3, or 4; and
p is 0, 1, or 2.