US 2023/0390404 A1 · TETRAHYDROISOQUINOLINE HETEROBIFUNCTIONAL BCL-XL DEGRADERS

A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is selected from the group consisting of:
(a) C3-15 cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of:
Ra and Rb;
and
(b) phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting of:
Ra and Rb,
R1 is selected from the group consisting of:
(a) C(O)OH,
(b) C(O)NRdRe, and
(c) C(O)OC1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1-3 Re;
each R2, R3, R4, and R5 is independently selected from the group consisting of:
halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, OH, and NRdRe;
m2 is 0, 1, or 2;
m3 and m4 are independently 0, 1, 2, or 3;
m5 is 0, 1, 2, 3, or 4;
L is -(LA)n1-, wherein LA and n1 are defined according to (AA) or (BB):
(AA)
n1 is an integer from 3 to 15;
and
each LA is independently selected from the group consisting of:
LA1 LA3, and LA4 provided that 1-3 occurrences of LA is LA4;
(BB)
n1 is an integer from 0 to 20;
and
each LA is independently selected from the group consisting of:
LA1 and LA3;
each LA1 is independently selected from the group consisting of:
—CH2—, —CHRL—, and —C(RL)2—;
each LA is independently selected from the group consisting of:
—N(Rd)—, —N(Rb)—, —O—, —S(O)0-2—, and C(═O);
each LA4 is independently selected from the group consisting of:
(a) C3-15 cycloalkylene or 3-15 membered heterocyclylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of:
Ra and Rb;
and
(b) C6-15 arylene or 5-15 membered heteroarylene, each of which is optionally substituted with 1-6 substituents independently selected from the group consisting of:
Ra and Rb,
provided that L does not contain any N—O, 0-0, N—N, N—S(O)o, or O—S(0)0-2 bonds;
wherein each RL is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NRdRe;
C(═O)N(R)2;
S(O)0-2(C1-6 alkyl);
S(O)0-2(C1-6 haloalkyl);
S(O)1-2N(Rf)2;
—Rb;
and C1-6 alkyl optionally substituted with 1-6 Rc;
Ring C is selected from the group consisting of:
c1 is 0, 1, 2, or 3;
each RY is independently selected from the group consisting of Ra and Rb,
RaN is H or C1-6 alkyl optionally substituted with 1-3 Rc;
Y1 and Y2 are independently N, CH, or CRY;
yy represents the point of attachment to L;
X is CH, C, or N;
the is a single bond or a double bond;
LC is selected from the group consisting of:
a bond, —CH2—, —CHRa—, —C(Ra)2—, —N(Rd)—, and O, provided that when X is N, then LC is other than O;
each Ra is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) —OH;
(d) oxo;
(e) —C1-6 alkoxy;
(f) —C1-6 haloalkoxy;
(g) —NRdRe;
(h) C(═O)C1-6 alkyl;
(i) C(═O)C1-6 haloalkyl;
(i) C(═O)OH;
(k) C(═O)OC1-6 alkyl;
(l) C(═O)OC1-6 haloalkyl;
(m) C(═O)N(Rf);
(n) S(O)0-2(C1-6 alkyl);
(o) S(O)0-2(C1-6 haloalkyl);
(p) S(O)1-2N(R′)2;
and
(q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Re;
each Rb is independently selected from the group consisting of:
-(Lb)b-Rb1 and —Rb1, wherein:
each b is independently 1, 2, or 3;
each -Lb is independently selected from the group consisting of:
—O—;
—N(H)—;
—N(C1-3 alkyl)-;
—S(O)0-2—;
C(═O);
and C1-3 alkylene;
and
each Rb1 is independently selected from the group consisting of:
C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;
each Re is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NRdRe;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl;
C(═O)OC1-6 alkyl;
C(═O)OC1-6 haloalkyl;
C(═O)OH;
C(═O)N(Rf)2;
S(O)0-2(C1-6 alkyl);
S(O)0-2(C1-6 haloalkyl);
and S(O)1-2N(Rf)2;
each Rd and Re is independently selected from the group consisting of:
H;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl;
C(═O)OC1-6 alkyl;
C(═O)OC1-6 haloalkyl;
C(═O)N(R)2;
S(O)1-2(C1-6 alkyl);
S(O)1-2(C1-6 haloalkyl);
S(O)1-2N(R′)2;
and C1-6 alkyl optionally substituted with 1-3 Rh,
each Rf is independently selected from the group consisting of:
H and C1-6 alkyl optionally substituted with 1-3 Rh;
each Rg is independently selected from the group consisting of:
Rh;
C1-3 alkyl;
and C1-3 haloalkyl;
and
each Rh is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NH2, —N(H)(C1-3 alkyl);
and —N(C1-3 alkyl)2.

132 more elements

A compound of Formula (SI-A):

or salts thereof, wherein:
each R2 and R4 is independently selected from:
halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, OH, and NRdRe;
m2 is 0, 1, or 2;
m4 is 0, 1, 2, or 3;
m6 is 0 or 1;
Re1 is H or C1-6 alkyl optionally substituted with 1-3-F;
Re2 is H or C1-6 alkyl optionally substituted with 1-3-F;
a3 is 0 or 1;
LA3 is selected from the group consisting of:
—O—, —N(H)—, and —N(C1-3 alkyl)-;
LA1a and LA1b are independently selected from the group consisting of:
—CH2—, —CHRL—, and —C(RL)2—;
LA4 is selected from the group consisting of:
a) C3-10 cycloalkylene or 4-10 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra;
and
b) phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Ra;
a1a and a1b are independently integers from 0 to 5, provided that a1a+a1b is from 1 to 5;
each RL is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NRdRe;
C(═O)N(Rf)2;
S(O)0-2(C1-6 alkyl);
S(O)0-2(C1-6 haloalkyl);
S(O)1-2N(Rf)2;
—Rb;
and C1-6 alkyl optionally substituted with 1-6 Rc;
each Ra is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) —OH;
(d) oxo;
(e) —C1-6 alkoxy;
(f) —C1-6 haloalkoxy;
(g) —NRdRe;
(h) C(═O)C1-6 alkyl;
(i) C(═O)C1-6 haloalkyl;
(j) C(═O)OH;
(k) C(═O)OC1-6 alkyl;
(l) C(═O)OC1-6 haloalkyl;
(m) C(═O)N(Rf)2;
(n) S(O)0-2(C1-6 alkyl);
(o) S(O)0-2(C1-6 haloalkyl);
(p) S(O)1-2N(Rf)2;
and
(q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc;
each Rb is independently selected from the group consisting of:
-(Lb)b-Rb1 and —Rb1, wherein:
each b is independently 1, 2, or 3;
each -Lb is independently selected from the group consisting of:
—O—;
—N(H)—;
—N(C1-3 alkyl)-;
—S(O)0-2—;
C(═O);
and C1-3 alkylene;
and
each Rb1 is independently selected from the group consisting of:
C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;
each Rc is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NRdRe;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl;
C(═O)OC1-6 alkyl;
C(═O)OC1-6 haloalkyl;
C(═O)OH;
C(═O)N(Rf)2;
S(O)0-2(C1-6 alkyl);
S(O)0-2(C1-6 haloalkyl);
and S(O)1-2N(Rf)2;
each Rd and Re is independently selected from the group consisting of:
H;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl;
C(═O)OC1-6 alkyl;
C(═O)OC1-6 haloalkyl;
C(═O)N(Rf)2;
S(O)1-2(C1-6 alkyl);
S(O)1-2(C1-6 haloalkyl);
S(O)1-2N(Rf)2;
and C1-6 alkyl optionally substituted with 1-3 Rh;
each Rf is independently selected from the group consisting of:
H and C1-6 alkyl optionally substituted with 1-3 Rh;
and
each Rh is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NH2, —N(H)(C1-3 alkyl);
and —N(C1-3 alkyl)2;
or
a compound of Formula (SI-E):
or a salt thereof, wherein:
each R2 and R4 is independently selected from:
H, C1-3 alkyl, and halo;
a3 is 0 or 1;
m2 is 0, 1, or 2;
m4 is 0, 1, 2, or 3;
m6 is 0 or 1;
Re1 is H or C1-6 alkyl optionally substituted with 1-3-F;
LA3 is selected from the group consisting of:
—O—, —N(H)—, and —N(C1-3 alkyl)-:
LA1a and LA1b are independently selected from the group consisting of:
—CH2—, —CHRL—, and —C(RL)2—;
LA4 is selected from the group consisting of:
a) C3-10 cycloalkylene or 4-10 membered heterocyclylene, each of which is optionally substituted with 1-3 Ra;
and
b) phenylene or 5-6 membered heteroarylene, each of which is optionally substituted with 1-3 Ra;
a1a is an integer from 0 to 5:
a1d is an integer from 0 to 4, provided that a1a+a1d is from 1 to 4:
each RL is independently selected from the group consisting of:
halo:
cyano:
—OH:
—C1-6 alkoxy;
—C1-6 haloalkoxy:
—NRdRe:
C(═O)N(Rf)2:
S(O)0-2(C1-6 alkyl):
S(O)0-2(C1-6 haloalkyl);
S(O)1-2N(Rf)2;
—Rb;
and C1-6 alkyl optionally substituted with 1-6 Rc;
each Ra is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) —OH:
(d) oxo;
(e) —C1-6 alkoxy:
(f) —C1-6 haloalkoxy;
(g) —NRdRe;
(h) C(═O)C1-6 alkyl;
(i) C(═O)C1-6 haloalkyl;
(j) C(═O)OH:
(k) C(═O)OC1-6 alkyl;
(l) C(═O)OC1-6 haloalkyl;
(m) C(═O)N(Rf)2;
(n) S(O)0-2(C1-6 alkyl);
(o) S(O)0-2(C1-6 haloalkyl):
(p) S(O)1-2N(Rf)2;
and
(q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Re,
each Rb is independently selected from the group consisting of:
-(Lb)b-Rb1 and —Rb1, wherein:
each b is independently 1, 2, or 3:
each -Lb is independently selected from the group consisting of:
—O—;
—N(H)—:
—N(C1-3 alkyl)-;
—S(O)0-2—;
C(═O);
and C1-3 alkylene:
each Rb1 is independently selected from the group consisting of:
C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;
each Rc is independently selected from the group consisting of:
halo:
cyano:
—OH:
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NRdRe;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl;
C(═O)OC1-6 alkyl;
C(═O)OC1-6 haloalkyl;
C(═O)OH;
C(═O)N(Rf)2;
S(O)0-2(C1-6 alkyl);
S(O)0-2(C1-6 haloalkyl);
and S(O)1-2N(Rf)2;
each Rd and Re is independently selected from the group consisting of:
H;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl:
C(═O)OC1-6 alkyl:
C(═O)OC1-6 haloalkyl:
C(═O)N(Rf)2:
S(O)1-2(C1-6 alkyl);
S(O)1-2(C1-6 haloalkyl):
S(O)1-2N(Rf)2;
and C1-6 alkyl optionally substituted with 1-3 Rh;
each Rf is independently selected from the group consisting of:
H and C1-6 alkyl optionally substituted with 1-3 Rh;
each Rg is independently selected from the group consisting of:
Rh;
C1-3 alkyl;
and C1-3 haloalkyl;
and
each Rh is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy:
—NH2, —N(H)(C1-3 alkyl);
and —N(C1-3 alkyl)2.

204 more elements

A compound of any one of Formulas (I-Ind-1), (I-Ind-2), or (I-Ind-3):

or salts thereof, wherein:
each RY is independently selected from the group consisting of Ra and Rb,
c1 is 0, 1, 2, or 3;
n2 and n3 are independently 0, 1, or 2;
RaN is H or C1-6 alkyl optionally substituted with 1-3 Rc;
m8 is 0 to 4;
each Ra is independently selected from the group consisting of:
(a) halo;
(b) cyano;
(c) —OH;
(d) oxo;
(e) —C1-6 alkoxy;
(f) —C1-6 haloalkoxy;
(g) —NRdRe;
(h) C(═O)C1-6 alkyl;
(i) C(═O)C1-6 haloalkyl;
(j) C(═O)OH;
(k) C(═O)OC1-6 alkyl;
(l) C(═O)OC1-6 haloalkyl;
(m) C(═O)N(Rf)2;
(n) S(O)0-2(C1-6 alkyl);
(o) S(O)0-2(C1-6 haloalkyl);
(p) S(O)1-2N(Rf)2;
and
(q) C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with 1-6 Rc;
each Rh is independently selected from the group consisting of:
-(Lb)b-Rb1 and —Rb1, wherein:
each b is independently 1, 2, or 3;
each -Lb is independently selected from the group consisting of:
—O—;
—N(H)—;
—N(C1-3 alkyl)-;
—S(O)0-2—;
C(═O);
and C1-3 alkylene;
each Rb1 is independently selected from the group consisting of:
C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, each of which is optionally substituted with 1-3 Rg;
each Rc is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NRdRe;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl;
C(═O)OC1-6 alkyl;
C(═O)OC1-6 haloalkyl;
C(═O)OH;
C(═O)N(Rf)2;
S(O)0-2(C1-6 alkyl);
S(O)0-2(C1-6 haloalkyl);
and S(O)1-2N(Rf)2;
each Rd and Re is independently selected from the group consisting of:
H;
C(═O)C1-6 alkyl;
C(═O)C1-6 haloalkyl;
C(═O)OC1-6 alkyl;
C(═O)OC1-6 haloalkyl;
C(═O)N(Rf)2;
S(O)1-2(C1-6 alkyl);
S(O)1-2(C1-6 haloalkyl);
S(O)1-2N(Rf)2;
and C1-6 alkyl optionally substituted with 1-3 Rh;
each Rf is independently selected from the group consisting of:
H and C1-6 alkyl optionally substituted with 1-3 Rh;
each R9 is independently selected from the group consisting of:
Rh;
C1-3 alkyl;
and C1-3 haloalkyl;
and
each Rh is independently selected from the group consisting of:
halo;
cyano;
—OH;
—C1-6 alkoxy;
—C1-6 haloalkoxy;
—NH2, —N(H)(C1-3 alkyl);
and —N(C1-3 alkyl)2.

76 more elements

Tetrahydroisoquinoline heterobifunctional bcl-xl degraders

Life of this patent

Tetrahydroisoquinoline heterobifunctional bcl-xl degraders

Life of this patent

Abstract

Claims58