MACROCYCLIC 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 selected from Formula Ia, Formula Ib, Formula IIa, Formula IIb, Formula IIa-1, Formula IIIa, Formula IIIb, Formula IIIa-1, Formula IVa, Formula IVb, Formula Va, Formula Vb, Formula VIa, Formula VIb, Formula VIIa, Formula VIIb, or Formula XI, or a pharmaceutically acceptable salt thereof,
wherein Formula Ia has the structure of:
wherein:
Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, 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)-;
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 is a linker;
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, —O-(optionally substituted C 1 -C 3 alkyl), 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 together form ═CH 2 , an optionally substituted C 3 -C 6 cycloalkyl, or a 3- to 7-membered saturated heterocyclyl; or
R 8 and 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;
p is 0, 1, 2, or 3;
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —; and
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 Formula Ib has the structure of:
wherein:
Q is an optionally substituted 7- to 12-membered bicyclic arylene, an optionally substituted 7- to 12-membered bicyclic heteroarylene, 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)-;
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 is a linker;
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, —O-(optionally substituted C 1 -C 3 alkyl), 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 together form ═CH 2 , an optionally substituted C 3 -C 6 cycloalkyl, or a 3- to 7-membered saturated heterocyclyl; or
R 8 and 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;
p is 0, 1, 2, or 3;
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —; and
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 Formula IIa has the structure of:
or a pharmaceutically acceptable salt thereof, 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 is a linker;
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 CR x , CH, CH 2 , or N;
Y 6 is CR z , C(O), CH, CH 2 , or N;
R x is hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
R z is hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
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, 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; 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;
R 21 is hydrogen or optionally substituted C 1 -C 3 alkyl;
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —; and
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 Formula IIb has the structure of:
or a pharmaceutically acceptable salt thereof, 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 is a linker;
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 CR x , CH, CH 2 , or N;
Y 6 is CR z , C(O), CH, CH 2 , or N;
R x is hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
R z is hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
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, 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; 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;
R 21 is hydrogen or optionally substituted C 1 -C 3 alkyl;
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —; and
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 Formula IIa-1 has the structure of:
or a pharmaceutically acceptable salt thereof, 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 is a linker;
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 CR x , CH, CH 2 , or N;
Y 6 is CR z , C(O), CH, CH 2 , or N;
R x is hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
R z is hydrogen, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
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, 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; 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 Formula IIIa has the structure of:
or a pharmaceutically acceptable salt thereof, 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
L is a linker;
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 7-membered heterocycloalkyl;
R 7 and R 8 are each, independently, selected from F or CH 3 , or R 7 and R 8 combine with the atoms to which they are attached to make a 3-membered cycloalkyl;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
t is 0, 1, 2, or 3;
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —; and
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 Formula IIIb has the structure of:
or a pharmaceutically acceptable salt thereof, 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
L is a linker;
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 7-membered heterocycloalkyl;
R 7 and R 8 are each, independently, selected from F or CH 3 , or R 7 and R 8 combine with the atoms to which they are attached to make a 3-membered cycloalkyl;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
t is 0, 1, 2, or 3;
z is 0, 1, or 2;
X 9 is —NR L6 —, —C(O)—, or —S(O) 2 —; and
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 Formula IIIa-1 has the structure of:
or a pharmaceutically acceptable salt thereof, 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
L is a linker;
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 7-membered heterocycloalkyl;
R 7 and R 8 are each, independently, selected from F or CH 3 , or R 7 and R 8 combine with the atoms to which they are attached to make a 3-membered cycloalkyl;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula IVa has the structure of:
or pharmaceutically acceptable salt thereof, 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 is a linker;
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, 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;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula IVb has the structure of:
or pharmaceutically acceptable salt thereof, 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 is a linker;
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, 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;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula Va has the structure of:
or pharmaceutically acceptable salt thereof, 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 is a linker;
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, 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;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula Vb has the structure of:
or pharmaceutically acceptable salt thereof, 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 is a linker;
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, 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;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula VIa has the structure of:
or a pharmaceutically acceptable salt thereof, 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 is a linker;
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, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl;
R 2 is optionally substituted C 1 -C 6 alkyl;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula VIb has the structure of:
or a pharmaceutically acceptable salt thereof, 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 is a linker;
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, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl;
R 2 is optionally substituted C 1 -C 6 alkyl;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula VIIa has the structure of:
or a pharmaceutically acceptable salt thereof, 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 is a linker;
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 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, 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;
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;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3;
wherein Formula VIIb has the structure of:
or a pharmaceutically acceptable salt thereof, 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 is a linker;
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 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, 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;
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;
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;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3; and
wherein Formula XI has the structure of:
or pharmaceutically acceptable salt thereof, 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, or optionally substituted C 2 -C 4 alkenylene;
W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl;
X 4 is CH 2 or NH;
R 1 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, 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 1 -C 6 heteroalkyl, 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; and R 3 is hydrogen;
or R 2 and R 3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl;
each of R 4 , R 5 , R 6 , and R 7 are hydrogen; or R 4 and R 6 are hydrogen and R 5 and R 7 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R 5 and R 7 are hydrogen and R 4 and R 6 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl;
R 10 is —OR 11 or —NR 12 R 13 ;
R 11 , R 12 , and R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or R 12 and R 13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl;
each R 33 is, independently, halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 1 -C 3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; and
t is 0, 1, 2, or 3.
2 . A compound, or a pharmaceutically acceptable salt thereof, of Table 1.
3 . A pharmaceutical composition comprising a compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
4 . 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 of claim 1 or 2 , or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 3 .
5 . 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 claim 1 or 2 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3 .
6 . A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of claim 1 or 2 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 3 .