RAS INHIBITORS
The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
1 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula I:
wherein:
Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, or an optionally substituted 7- to 12-membered bicyclic heterocyclylene, wherein a first ring in Q is bonded to X, and a second ring in Q is bonded to A;
X is a bond; a straight chain C 1 -C 3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, —CN, —C 1 -C 3 alkyl, and —O—C 1 -C 3 alkyl; —O—; —S(O) 0-2 —; *—CH 2 —O—; *—CH 2 —S(O) 0-2 —; *—O—CH 2 —; or *—CH 2 —S(O) 0-2 —, wherein “*” represents a portion of X bound to —C(R 7 )(R 8 )—;
Y is —O—, —NH— or —N(C 1 -C 3 alkyl)-;
R 3 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 6 -C 10 aryl, or optionally substituted 3- to 11-membered heterocyclyl;
W is:
wherein:
ring A1 is a 4- to 8-membered cycloalkyl or a 4- to 8-membered heterocyclyl;
W 1 is —N(R 20 )—, —O—, or —C(R 20a )(R 20b )—;
each R A is each independently halo, cyano, hydroxyl, optionally substituted amino, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 1 -C 3 alkyl;
r is 0, 1, 2, 3, or 4;
R 17 , if present, is optionally substituted C 1 -C 6 heteroalkylene or optionally substituted C 1 -C 6 alkylene;
R 18 , if present, is optionally substituted C 1 -C 4 alkylene;
R 19 is optionally substituted C 1 -C 6 heteroalkylene, optionally substituted C 1 -C 6 alkylene, —NH—, or —N(optionally substituted C 1 -C 6 alkyl) or a saturated, nitrogen-containing 3- to 8-membered heterocyclyl;
R 20 is hydrogen or —C 1 -C 3 alkyl;
R 20 is taken together with one R A , the atoms to which they are respectively attached and any intervening atoms, to form an optionally substituted, 5- to 8-membered heterocyclyl that is fused or spiro-fused to ring A, or
R 20 is taken together with any methylene unit in R 18 , or any methylene unit in R 19 , the atoms to which they are respectively attached and any intervening atoms, to form an optionally substituted, 5- to 8-membered heterocyclyl;
each of R 20a and R 20b is, independently, hydrogen, or —C 1 -C 3 alkyl, or R 20a and R 20b are taken together with the carbon atom to which they are bound to form a 3- to 6-membered cycloalkyl ring;
R 16 is O, S, N—CN, or N—O—C 1 -C 3 alkyl;
WH is
each R 22 is, independently, hydrogen, cyano, optionally substituted C 1 -C 3 alkyl, or an optionally substituted 4- to 7-membered saturated heterocyclyl; or R 22 is taken together with either of R 17 or R 19 , the atoms to which they are attached and any intervening atoms to form an optionally substituted 5- to 8-membered ring system;
R 23 is hydrogen, optionally substituted C 1 -C 3 alkyl, or an optionally substituted 4- to 7-membered saturated heterocyclyl;
R 24 is hydrogen, optionally substituted C 1 -C 3 alkyl, or an optionally substituted 4- to 7-membered saturated heterocyclyl; or R 24 is taken together with either of R 17 or R 19 , the atoms to which they are attached and any intervening atoms, to form an optionally substituted 5- to 8-membered ring system;
A is optionally substituted C 2 -C 4 alkylene, optionally substituted C 1 -C 4 heteroalkylene, or optionally substituted C 2 -C 4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 8 cycloalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
or
optionally, wherein L is not
R 3 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted C 6 aryl, or optionally substituted 3- to 7-membered heterocyclyl;
R 10 is hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or C 1 -C 3 optionally substituted heteroalkyl;
R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl;
R 8 is hydrogen, halogen, —OH, —CN, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl; or
R 7 and R 8 are taken together to form ═CH 2 , an optionally substituted C 3 -C 6 cycloalkyl, or a 3- to 7-membered saturated heterocyclyl; or
R 8 is taken together with a ring atom in Q, the carbon atom to which R 7 is bound and X to form a 4- to 9-membered saturated or unsaturated heterocyclyl that is fused to Q;
R 6 is hydrogen or —CH 3 ;
each R 5 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, or optionally substituted C 1 -C 3 haloalkyl; and
p is 0, 1, 2, or 3, wherein:
(i) the compound is not:
or
(ii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, two R L1 substituents taken together form spiro cyclopropyl, and W is
then, Q is not 1-ethyl-indole-2,5-diyl or indole-2,5-diyl substituted with C 1-4 alkyl; or
(iii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, two R L1 substituents taken together form spiro cyclopropyl, and W is
then, Q is not 1-ethyl-2,5-indol-diyl optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein the C 1-4 alkyl and C 1-4 alkoxy are each optionally substituted with 1, 2 or 3 substituents independently selected from halogen, OH, C 1-3 alkyl and C 1-3 alkoxy, wherein C 1-3 alkyl and C 1-3 alkoxy are each substituted with 1, 2 or 3 substituents independently selected from deuterium, halogen, OH, methyl, methoxy and OCF 3 ; or
(iv) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, and W is
then Q is not 1-ethyl-2,5-indol-diyl or 2,5-indol-diyl substituted with C 1-4 alkyl; or
(v) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, and W is
then Q is 1-ethyl-2,5-indol-diyl or 2,5-indol-diyl substituted with C 1-4 alkyl; or
(vi) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, and W is
then Q is not 1-ethyl-2,5-indol-diyl optionally substituted with 1, 2 or 3 substituents independently selected from halogen, C 1-4 alkyl and C 1-4 alkoxy, wherein the C 1-4 alkyl and C 1-4 alkoxy are each optionally substituted with 1, 2 or 3 substituents independently selected from halogen, OH, C 1-3 alkyl and C 1-3 alkoxy, wherein C 1-3 alkyl and C 1-3 alkoxy are each substituted with 1, 2 or 3 substituents independently selected from deuterium, halogen, OH, methyl, methoxy and OCF 3 ; or
(vii) when A is -hydroxy-benzene-3,5-diyl or optionally substituted phenylene and two R L1 substituents taken together form spiro cyclopropyl, then W is not
or
(viii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, then W is not
or
(ix) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, WH is
and two R L1 substituents taken together form spiro cyclopropyl or spiro cycloalkyl, then A1 is not 1,4-piperazin-diyl optionally substituted with methyl or C 1-4 alkyl; or
(x) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, WH is
and R L1 and R L2 taken together form fused cyclopropyl or fused cycloalkyl, then A1 is not is not 1,4-piperazin-diyl optionally substituted with methyl or C 1-4 alkyl.
2 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula IIa:
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is optionally substituted C 2 -C 4 alkylene, optionally substituted C 1 -C 4 heteroalkylene, optionally substituted C 2 -C 4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )—where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3- to 8-membered heteroarylene;
L 1 is a linker;
W is hydrogen, cyano, S(O) 2 R′, optionally substituted amino, optionally substituted amido, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 hydroxyalkyl, optionally substituted C 1 -C 4 aminoalkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 guanidinoalkyl, C 0 -C 4 alkyl optionally substituted 3- to 11-membered heterocycloalkyl, optionally substituted 3- to 8-membered cycloalkyl, or optionally substituted 3- to 8-membered heteroaryl;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 1 -C 6 heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
or
optionally, wherein L is not
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) q ;
X 2 is O or NH;
X 3 is N or CH;
q is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, hydrogen or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 13 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or
R 13 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- to 10-membered heteroaryl;
R 14 is absent or R 2 and R 14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl;
R 15 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 heteroalkyl, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl;
R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
R 9 is hydrogen, fluoro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ , combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl;
R 10 is hydrogen, halogen, hydroxy, optionally substituted C 1 -C 3 heteroalkyl, or optionally substituted C 1 -C 3 alkyl;
R 10a is hydrogen or halogen;
R 11 is hydrogen or optionally substituted C 1 -C 3 alkyl; and
R 21 is hydrogen or optionally substituted C 1 -C 3 alkyl wherein:
(i) the compound is not
or
(ii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, two R L1 substituents taken together form spiro cyclopropyl, L 1 is —N(CH 3 )C(O)— or —N(CH 3 )C(O)CH 2 N(CH 3 )— and B is —CH(R 9 )—, wherein R 9 is isopropyl or cyclopentyl, then W is not 3-cyclopropylaziridin-2-yl, 3-phenyltetrahydrofuran-2-yl, optionally substituted aziridin-2-yl or optionally substituted tetrahydrofuran-2-yl; or
(iii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, two R L1 substituents taken together form spiro cyclopropyl, L 1 is —N(CH 3 )C(O)— or —N(CH 3 )C(O)CH 2 N(CH 3 )— and B is —CH(R 9 )—, wherein R 9 is C 1-6 alkyl or 3- to 6-membered cycloalkyl, then W is not 3-cyclopropylaziridin-2-yl, 3-phenyltetrahydrofuran-2-yl, optionally substituted aziridin-2-yl or optionally substituted tetrahydrofuran-2-yl; or
(iv) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form optionally substituted fused cyclopropyl, L 1 is —N(CH 3 )C(O)— or —N(CH 3 )C(O)CH 2 N(CH 3 )— and B is —CH(R 9 )—, wherein R 9 is isopropyl or cyclopentyl, then W is not 3-cyclopropylaziridin-2-yl, 3-phenyltetrahydrofuran-2-yl, optionally substituted aziridin-2-yl or optionally substituted tetrahydrofuran-2-yl; or
(v) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form optionally substituted fused cyclopropyl, L 1 is —N(CH 3 )C(O)— or —N(CH 3 )C(O)CH 2 N(CH 3 )— and B is —CH(R 9 )—, wherein R 9 is C 1-6 alkyl or 3- to 6-membered cycloalkyl, then W is not 3-cyclopropylaziridin-2-yl, 3-phenyltetrahydrofuran-2-yl, optionally substituted aziridin-2-yl or optionally substituted tetrahydrofuran-2-yl; or
(vi) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, two R L1 substituents taken together form optionally substituted spiro cyclopropyl, L 1 is —N(CH 3 )C(O)— or —N(CH 3 )C(O)CH 2 N(CH 3 )—, R 14 is absent and B is —CH(R 9 )—, wherein R 9 is isopropyl or cyclopentyl, then R 2 is not ethyl or optionally substituted C 1-6 alkyl; or
(vii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form optionally substituted fused cyclopropyl, L 1 is —N(CH 3 )C(O)— or —N(CH 3 )C(O)CH 2 N(CH 3 )—, R 14 is absent and B is —CH(R 9 )—, wherein R 9 is isopropyl or cyclopentyl, then R 2 is not ethyl or optionally substituted C 1-6 alkyl; or
(viii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene and two R L1 substituents taken together form optionally substituted spiro cyclopropyl, then R 2 is optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- to 10-membered heteroaryl; or
(ix) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form optionally substituted fused cyclopropyl, then R 2 is optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- to 10-membered heteroaryl; or
(x) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene and two R L1 substituents taken together form optionally substituted spiro cyclopropyl, then R 2 and R 14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl; or
(xi) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form optionally substituted fused cyclopropyl, then R 2 is optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- to 10-membered heteroaryl.
3 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula IIb:
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is optionally substituted C 2 -C 4 alkylene, optionally substituted C 1 -C 4 heteroalkylene, optionally substituted C 2 -C 4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )—where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3- to 8-membered heteroarylene;
L 1 is a linker;
W is a cross-linking group comprising a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, an aziridine, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an epoxide, an oxazolium, or a glycal;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 1 -C 6 heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
or
optionally, wherein L is not
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) q ;
X 2 is O or NH;
X 3 is N or CH;
q is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, hydrogen or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 13 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or
R 13 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 14 is absent or R 2 and R 14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl;
R 15 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 heteroalkyl, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
R 9 is hydrogen, fluoro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ , combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl;
R 10 is hydrogen, halogen, hydroxy, optionally substituted C 1 -C 3 heteroalkyl, or optionally substituted C 1 -C 3 alkyl;
R 10a is hydrogen or halogen;
R 11 is hydrogen or optionally substituted C 1 -C 3 alkyl; and
R 21 is hydrogen or optionally substituted C 1 -C 3 alkyl wherein:
(i) the compound is not
or
(ii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is 3-cyclopropylaziridin-2-yl or optionally substituted aziridine and two R L1 substituents taken together form spiro cyclopropyl, then R 2 is not ethyl or C 1-6 alkyl; or
(iii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is 3-cyclopropylaziridin-2-yl or optionally substituted aziridine and R L1 and R L2 taken together form fused cyclopropyl, then R 2 is not ethyl or C 1-6 alkyl; or
(iv) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene and two R L1 substituents taken together form spiro cyclopropyl, then W is not 3-cyclopropylaziridin-2-yl or optionally substituted aziridine; or
(v) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene and R L1 and R L2 taken together form fused cyclopropyl, then W is not 3-cyclopropylaziridin-2-yl or optionally substituted aziridine; or
(vi) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is 3-cyclopropylaziridin-2-yl or optionally substituted aziridine and two R L1 substituents taken together form spiro cyclopropyl, then L 1 is not —N(CH 3 )C(O)CH 2 N(CH 3 )C(O)—; or
(vii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is 3-cyclopropylaziridin-2-yl or optionally substituted aziridine and R L1 and R L2 taken together form fused cyclopropyl, then L 1 is not —N(CH 3 )C(O)CH 2 N(CH 3 )C(O)—.
4 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula IIc:
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is optionally substituted C 2 -C 4 alkylene, optionally substituted C 1 -C 4 heteroalkylene, optionally substituted C 2 -C 4 alkenylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )—where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3- to 8-membered heteroarylene;
L 1 is a linker;
W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, a haloacetyl, or an alkynyl sulfone;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 1 -C 6 heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
or
optionally, wherein L is not
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) q ;
X 2 is O or NH;
X 3 is N or CH;
q is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, hydrogen or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 13 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 6-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, or
R 13 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl; R 14 is absent or R 2 and R 14 combine with the atom to which they are attached to form an optionally substituted 3- to 8-membered cycloalkyl or optionally substituted 3- to 14-membered heterocycloalkyl;
R 15 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 heteroalkyl, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 8-membered cycloalkyl, optionally substituted 3- to 14-membered heterocycloalkyl, optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 6- to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3- to 6-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
R 9 is hydrogen, fluoro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl; or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ , combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl;
R 10 is hydrogen, halogen, hydroxy, optionally substituted C 1 -C 3 heteroalkyl, or optionally substituted C 1 -C 3 alkyl;
R 10a is hydrogen or halogen;
R 11 is hydrogen or optionally substituted C 1 -C 3 alkyl; and
R 21 is hydrogen or optionally substituted C 1 -C 3 alkyl; wherein:
(i) the compound is not:
or
(ii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, two R L1 substituents taken together form spiro cyclopropyl, and W is vinyl ketone, then R 2 is not ethyl or C 1-6 alkyl; or
(iii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, and W is vinyl ketone, then R 2 is not ethyl or C 1-6 alkyl; or
(iv) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene and two R L1 substituents taken together form spiro cyclopropyl, then W is not vinyl ketone; or
(v) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, then W is not vinyl ketone; or
(vi) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and two R L1 substituents taken together form spiro cyclopropyl or spiro cycloalkyl, then L 1 is other than
or
(vii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and R L1 and R L2 taken together form fused cyclopropyl or fused cycloalkyl, then L 1 is other than
or
(vii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and two R L1 substituents taken together form spiro cycloalkyl, then L 1 is not
optionally substituted with 1, 2 or 3 independently selected C 1-6 alkyl; or
(ix) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and R L1 and R L2 taken together form fused cycloalkyl, then L 1 is not
optionally substituted with 1, 2 or 3 independently selected C 1-6 alkyl.
5 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula III:
wherein A is optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5- to 6-membered heteroarylene, optionally substituted C 2 -C 4 alkylene, optionally substituted C 1 -C 4 heteroalkylene or optionally substituted C 2 -C 4 alkenylene;
Y 8 is
W is hydrogen, C 1 -C 4 alkyl, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 1 -C 6 heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl; or R L1 and R L2 taken together form a bond;
wherein L does not have the structure of
or
optionally, wherein L is not
X 4 and X 5 are each, independently, CH 2 , CH(CH 3 ) or NH;
R 13 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl;
R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5- or 6-membered heteroaryl;
R 10 is hydrogen, hydroxy, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl; and
R 7 and R 8 are each, independently, selected from fluoro or CH 3 , or R 7 and R 8 combine with the atoms to which they are attached to make a 3-membered cycloalkyl; wherein:
(i) the compound is not E10 to E52 in Table 2 and those set forth in Table 5; or
(ii) when A is thiazole-2,4-diyl and two R L1 substituents taken together form spiro cyclopropyl, then R 2 is not optionally substituted C 1-6 alkyl; or
(iii) when A is thiazole-2,4-diyl and two R L2 substituents taken together form spiro cyclopropyl, then R 2 is not optionally substituted C 1-6 alkyl; or
(iv) when A is thiazole-2,4-diyl and R L1 and R L2 taken together form optionally substituted fused cyclopropyl, then R 2 is not optionally substituted C 1-6 alkyl; or
(v) when A is thiazole-2,4-diyl and R L1 and R L2 taken together form a bond, then R 2 is not optionally substituted C 1-6 alkyl; or
(vi) when A is thiazole-2,4-diyl and R L1 and R L2 taken together form fused cyclobutyl, then R 2 is not optionally substituted C 1-6 alkyl; or
(vii) when A is thiazole-2,4-diyl and R L1 and R L3 together with the atoms to which they are attached form bridged cyclobutyl, then R 2 is not optionally substituted C 1-6 alkyl; or
(viii) when A is thiazole-2,4-diyl and R L1 and R L3 together with the atoms to which they are attached form bridged cyclobutyl, then W is not optionally substituted cyclopropyl.
6 . A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula IV:
wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;
L 1 is a linker;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 1 -C 6 heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
or
optionally, wherein L is not
W is a cross-linking group comprising a vinyl ketone, vinyl sulfone, ynone, or an alkynyl sulfone;
R 1 is hydrogen, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C 1 -C 6 heteroalkyl;
R 2 is optionally substituted C 1 -C 6 alkyl; and
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl;
(i) the compound is not:
or
(ii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, two R L1 substituents taken together form spiro cyclopropyl, and W is vinyl ketone, then R 2 is not ethyl; or
(iii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, and W is vinyl ketone, then R 2 is not ethyl; or
(iv) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene and two R L1 substituents taken together form spiro cyclopropyl, then W is not vinyl ketone; or
(v) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, R L1 and R L2 taken together form fused cyclopropyl, then W is not vinyl ketone; or
(vi) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and two R L1 substituents taken together form spiro cyclopropyl or spiro cycloalkyl, then L 1 is other than
or
(vii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and R L1 and R L2 taken together form fused cyclopropyl or fused cycloalkyl, then L 1 is not
or
(viii) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and two R L1 substituents taken together form spiro cyclopropyl or spiro cycloalkyl, then L 1 is not
optionally substituted with 1, 2 or 3 independently selected C 1-6 alkyl; or
(ix) when A is 1-hydroxy-benzene-3,5-diyl or optionally substituted phenylene, W is vinyl ketone and two R L1 and R L2 taken together form fused cyclopropyl or fused cycloalkyl, then L 1 is not
optionally substituted with 1, 2 or 3 independently selected C 1-6 alkyl.
7 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula V:
wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 1 -C 6 heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
or
optionally, wherein L is not
W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
X 6 is CH 2 or O;
m is 1 or 2;
n is 0 or 1;
R 1 is hydrogen or optionally substituted 3- to 10-membered heterocycloalkyl; and
R 2 is optionally substituted C 1 -C 6 alkyl.
8 . A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula VI:
wherein A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 3- to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene;
L has the structure of Formula VIIa or VIIb:
optionally, wherein L is not
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, or optionally substituted C 1 -C 6 heteroalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
X 6 , X 7 , and X 8 are each independently selected from CH 2 , CHF, CF 2 , C═O, or O;
m is 1 or 2;
n is 0 or 1;
R 1 is hydrogen, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl;
R 2 is optionally substituted C 1 -C 6 alkyl; and
R 3 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted heterocycloalkyl,
and wherein each hydrogen is independently, optionally, isotopically enriched for deuterium.
9 . A compound having Formula VIIIa:
or a pharmaceutically acceptable salt thereof, wherein:
the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
L has the structure of Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 8 cycloalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
or
optionally, wherein L is not
A is optionally substituted C 2 -C 4 alkylene, optionally substituted C 1 -C 4 heteroalkylene, or optionally substituted C 2 -C 4 alkenylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )—where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3 to 8-membered heteroarylene;
swIp (Switch I/P-loop) is an organic moiety that non-covalently binds to both the Switch I binding pocket and residues 12 or 13 of the P-loop of a Ras protein;
X 3 is N or CH;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
R 3 is absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl; and
R 10a is hydrogen or halo.
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein the compound has formula VIIIb, VIIIc, VIIId, VIIIe, VIIIf or VIIIg:
wherein at each occurrence,
each L is independently having Formula VIIa or VIIb:
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —;
each of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 8 cycloalkyl; or any two of R L1 , R L2 , R L3 , R L4 , R L4 , R L5 , and R L6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C 3 -C 8 cycloalkyl or a 3- to 8-membered heterocyclyl;
wherein L does not have the structure of
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )—where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3 to 8-membered heteroarylene;
Z is —C(O)— or —S(O) 2 —;
each B is independently absent, —NH—, —N(CH 3 )—, —O—, —CH(R 9 )— or >C═CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
each L 1 is independently absent or a linker;
each W is independently hydrogen, cyano, optionally substituted amino, optionally substituted amido, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 hydroxyalkyl, optionally substituted C 1 -C 4 aminoalkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 1 -C 4 guanidinoalkyl, C 0 -C 4 alkyl optionally substituted 3 to 11-membered heterocycloalkyl, optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 3 to 10-membered heteroaryl;
each X 3 is independently N or CH;
X e is N, CH, or CR 17 ;
X f is N or CH;
R 12 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 6 heteroalkyl;
R 17 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl.
each Y 1 is independently C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
each Y 5 is independently CH, CH 2 , or N;
each Y 6 is independently C(O), CH, CH 2 , or N;
each R 1 is independently cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
each R 2 is independently absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
each R 3 is independently absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
each R 4 is independently absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
each R 6 is independently hydrogen or methyl; each R 7 is independently hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
each R 8 is independently hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7′ is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
each R 9 is independently hydrogen, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
each R 9′ is independently hydrogen or optionally substituted C 1 -C 6 alkyl;
each R 10 is independently hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl;
R 10a is hydrogen or halo;
R 11 is hydrogen or C 1 -C 3 alkyl.
11 . The compound of any one of claims 1 to 10 , or a pharmaceutically acceptable salt thereof, wherein L has the structure of Formula VIIa, Formula VIIa-1, Formula VIIa-2, Formula VIIa-3, Formula VIIa-4, Formula VIIa-5, Formula VIIa-6, Formula VIIb, Formula VIIb-1, Formula VIIb-2, or
wherein X 9 is —NR L6 —; or X 9 is —C(O)—; or X 9 is S(O) 2 —.
12 . The compound of any one of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, wherein z is 0; or z is 1; or z is 2.
13 . The compound of any one of claims 1 to 12 , or a pharmaceutically acceptable salt thereof, wherein R L1 is hydrogen; or R L1 is optionally substituted C 1 -C 6 alkyl; or R L1 is methyl, ethyl, or trifluoromethyl; or R L1 is optionally substituted C 1 -C 6 heteroalkyl; or R L1 is methoxy or ethoxy; R L1 is optionally substituted C 2 -C 6 alkynyl; or R L1 is ethynyl.
14 . The compound of any one of claims 1 to 13 , or a pharmaceutically acceptable salt thereof, wherein R L2 is hydrogen; or R L2 is halogen; or R L2 is fluoro.
15 . The compound of any one of claims 1 to 14 , or a pharmaceutically acceptable salt thereof, wherein R L3 is hydrogen; or R L3 is optionally substituted C 1 -C 6 alkyl; or R L3 is methyl.
16 . The compound of any one of claims 1 to 15 , or a pharmaceutically acceptable salt thereof, wherein:
R L4 is hydrogen; or
R L1 and R L4 combine to form an optionally substituted C 4 cycloalkyl; or
R L1 and R L3 combine to form an optionally substituted C 4 cycloalkyl; or
R L1 and R L3 combine to form an optionally substituted C 5 cycloalkyl; or
two R L1 combine to form an optionally substituted C 3 -C 6 cycloalkyl; or
R L1 and R L2 combine to form an optionally substituted C 3 -C 6 cycloalkyl.
17 . The compound of any one of claims 1 to 16 , or a pharmaceutically acceptable salt thereof, wherein L is:
or
L is:
18 . The compound of any one of claims 1 to 17 , or a pharmaceutically acceptable salt thereof, wherein R L6 is optionally substituted C 1 -C 6 alkyl; or R L6 is methyl.
19 . The compound of any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, wherein R L5 is hydrogen; or R L5 is optionally substituted C 1 -C 6 alkyl; or R L5 is optionally substituted C 3 -C 8 cycloalkyl; or two R L5 combine to form an optionally substituted C 3 -C 8 cycloalkyl.
20 . The compound of any one of claims 1 to 19 , or a pharmaceutically acceptable salt thereof, wherein:
A is optionally substituted 3- to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5- to 10-membered heteroarylene; or
A is optionally substituted 6-membered arylene; or
A is
or
A is optionally substituted 3- to 6-membered heterocycloalkylene;
A is
or
A is optionally substituted 5- to 10-membered heteroarylene; or
A is
21 . The compound of any one of claims 2 to 20 , or a pharmaceutically acceptable salt thereof, wherein R 2 is ethyl or haloethyl.
22 . The compound of any one of claims 1 and 6 to 21 , or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted C 1 -C 6 alkyl.
23 . A compound, or a pharmaceutically acceptable salt thereof, of Table 1.
24 . A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 23 and a pharmaceutically acceptable excipient.
25 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 23 or a pharmaceutical composition of claim 24 ,
optionally wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, or endometrial cancer;
or optionally wherein the cancer comprises a Ras mutation; or
optionally wherein the method further comprises administering an additional anti-cancer therapy, optionally wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4/6 inhibitor, a HER2 inhibitor, or a combination thereof.
26 . A method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 23 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 24 , optionally wherein the Ras protein is K-Ras; or
optionally wherein the method further comprises administering an additional anti-cancer therapy, optionally wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4/6 inhibitor, a HER2 inhibitor, or a combination thereof.
27 . A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 23 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 24 ,
optionally wherein the Ras protein is K-Ras;
or optionally wherein the cell is a cancer cell, optionally wherein the cancer cell is a pancreatic cancer cell, a colorectal cancer cell, a non-small cell lung cancer cell, or an endometrial cancer cell; or
optionally wherein the method further comprises administering an additional anti-cancer therapy, optionally wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4/6 inhibitor, a HER2 inhibitor, or a combination thereof.