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 C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, —CN, —C1-C3 alkyl, and —O—C1-C3 alkyl;
- —O—;
- —S(O)0-2—;
- *—CH2—O—;
- *—CH2—S(O)0-2—;
- *—O—CH2—;
- or *—CH2—S(O)0-2—, wherein “*” represents a portion of X bound to —C(R7)(R8)—;
- Y is —O—, —NH— or —N(C1-C3 alkyl)-;
- A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 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;
- R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl;
- R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl, or C1-C3 optionally substituted heteroalkyl;
- R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl;
- R8 is hydrogen, halogen, —OH, —CN, —O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl;
- or
- R7 and R8 together form ═CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7-membered saturated heterocyclyl;
- or
- R8 and a ring atom in Q, the carbon atom to which R7 is bound, and X to form a 4- to 9-membered saturated or unsaturated heterocyclyl that is fused to Q;
- R6 is hydrogen or —CH3;
- each R5 is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted
- C1-C3 haloalkyl;
- p is 0, 1, 2, or 3;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- and
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 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 C1-C3 alkylene optionally substituted with 1 to 3 substituents independently selected from fluoro, —CN, —C1-C3 alkyl, and —O—C1-C3 alkyl;
- —O—;
- —S(O)0-2—;
- *—CH2—O—;
- *—CH2—S(O)0-2—;
- *—O—CH2—;
- or *—CH2—S(O)0-2—, wherein “*” represents a portion of X bound to —C(R7)(R8)—;
- Y is —O—, —NH— or —N(C1-C3 alkyl)-;
- A is optionally substituted C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted C2-C4 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;
- R3 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6 aryl, or optionally substituted 3- to 7-membered heterocyclyl;
- R10 is hydrogen, halogen, optionally substituted C1-C3 alkyl, or C1-C3 optionally substituted heteroalkyl;
- R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl;
- R8 is hydrogen, halogen, —OH, —CN, —O-(optionally substituted C1-C3 alkyl), optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C6-C10 aryl, optionally substituted 4- to 8-membered heteroaryl, optionally substituted C3-C6 cycloalkyl, or optionally substituted 3- to 7-membered heterocyclyl;
- or
- R7 and R8 together form ═CH2, an optionally substituted C3-C6 cycloalkyl, or a 3- to 7-membered saturated heterocyclyl;
- or
- R8 and a ring atom in Q, the carbon atom to which R7 is bound, and X to form a 4- to 9-membered saturated or unsaturated heterocyclyl that is fused to Q;
- R6 is hydrogen or —CH3;
- each R5 is independently halogen, optionally substituted C1-C3 alkyl, or optionally substituted
- C1-C3 haloalkyl;
- p is 0, 1, 2, or 3;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- and
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 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 C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 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(R9)—, >C═CR9R9′, or >CR9R9′ where the carbon is bound to the carbonyl carbon of —N(R11)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 C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, —C(O)O—CH(R6)— where C is bound to —C(R7R8)—, —C(O)NH—CH(R6)— where C is bound to —C(R7R8)—, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene;
- L is a linker;
- X3 is N or CH;
- q is 0, 1, or 2;
- R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′)2, S(O)R′, S(O)2R′, or S(O)2N(R′)2;
- each R′ is, independently, hydrogen or optionally substituted C1-C4 alkyl;
- Y1 is C, CH, or N;
- Y2, Y3, Y4, and Y7 are, independently, C or N;
- Y5 is CRx, CH, CH2, or N;
- Y6 is CRz, C(O), CH, CH2, or N;
- Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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
- R13 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
- R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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;
- R14 is absent, or R2 and R14 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;
- R15 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
- R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl;
- R6 is hydrogen or methyl;
- R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or
- R6 and R7 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;
- R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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
- R7 and R8 combine with the carbon atom to which they are attached to form C═CR7′R8′;
- C═N(OH), C═N(O—C1-C3 alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- R7a and R8a are, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
- R7′ is hydrogen, halogen, or optionally substituted C1-C3 alkyl;
- R8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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
- R7′ and R8′ 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;
- R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- or
- R9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
- R9′ is hydrogen or optionally substituted C1-C6 alkyl;
- or
- R9 and R9′, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl;
- R10 is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl;
- R10a is hydrogen or halogen;
- R11 is hydrogen or optionally substituted C1-C3 alkyl;
- R21 is hydrogen or optionally substituted C1-C3 alkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- and
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 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 C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 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(R9)—, >C═CR9R9′, or >CR9R9′ where the carbon is bound to the carbonyl carbon of —N(R11)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 C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, —C(O)O—CH(R6)— where C is bound to —C(R7R8)—, —C(O)NH—CH(R6)— where C is bound to —C(R7R8)—, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene;
- L is a linker;
- X3 is N or CH;
- q is 0, 1, or 2;
- R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′)2, S(O)R′, S(O)2R′, or S(O)2N(R′)2;
- each R′ is, independently, hydrogen or optionally substituted C1-C4 alkyl;
- Y1 is C, CH, or N;
- Y2, Y3, Y4, and Y7 are, independently, C or N;
- Y5 is CRx, CH, CH2, or N;
- Y6 is CRz, C(O), CH, CH2, or N;
- Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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
- R13 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
- R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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;
- R14 is absent, or R2 and R14 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;
- R15 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
- R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl;
- R6 is hydrogen or methyl;
- R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or
- R6 and R7 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;
- R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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
- R7 and R8 combine with the carbon atom to which they are attached to form C═CR7′R8′;
- C═N(OH), C═N(O—C1-C3 alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- R7a and R8a are, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
- R7′ is hydrogen, halogen, or optionally substituted C1-C3 alkyl;
- R8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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 R7′ and R8′ 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;
- R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- or
- R9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
- R9′ is hydrogen or optionally substituted C1-C6 alkyl;
- or
- R9 and R9′, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl;
- R10 is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl;
- R10a is hydrogen or halogen;
- R11 is hydrogen or optionally substituted C1-C3 alkyl;
- R21 is hydrogen or optionally substituted C1-C3 alkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- and
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 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 C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene, optionally substituted C2-C4 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(R9)—, >C═CR9R9′, or >CR9R9′ where the carbon is bound to the carbonyl carbon of —N(R11)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 C1-C4 alkylene, optionally substituted C1-C4 alkenylene, optionally substituted C1-C4 heteroalkylene, —C(O)O—CH(R6)— where C is bound to —C(R7R8)—, —C(O)NH—CH(R6)— where C is bound to —C(R7R8)—, optionally substituted C1-C4 heteroalkylene, or 3- to 8-membered heteroarylene;
- L is a linker;
- X1 is optionally substituted C1-C2 alkylene, NR, O, or S(O)q;
- X2 is O or NH;
- X3 is N or CH;
- q is 0, 1, or 2;
- R is hydrogen, cyano, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′)2, S(O)R′, S(O)2R′, or S(O)2N(R′)2;
- each R′ is, independently, hydrogen or optionally substituted C1-C4 alkyl;
- Y1 is C, CH, or N;
- Y2, Y3, Y4, and Y7 are, independently, C or N;
- Y5 is CRx, CH, CH2, or N;
- Y6 is CRz, C(O), CH, CH2, or N;
- Rx is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- Rz is hydrogen, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- R13 is cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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
- R13 and R2 combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
- R2 is absent, hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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;
- R14 is absent, or R2 and R14 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;
- R15 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
- R5 is hydrogen, C1-C4 alkyl optionally substituted with halogen, cyano, hydroxy, or C1-C4 heteroalkyl, cyclopropyl, or cyclobutyl;
- R6 is hydrogen or methyl;
- R7 is hydrogen, halogen, or optionally substituted C1-C3 alkyl, or
- R6 and R7 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;
- R8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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
- R7 and R8 combine with the carbon atom to which they are attached to form C═CR7′R8′;
- C═N(OH), C═N(O—C1-C3 alkyl), C═O, C═S, C═NH, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- R7a and R8a are, independently, hydrogen, halogen, optionally substituted C1-C3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
- R7′ is hydrogen, halogen, or optionally substituted C1-C3 alkyl;
- R8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C1-C3 heteroalkyl, optionally substituted C1-C3 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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
- R7′ and R8′ 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;
- R9 is hydrogen, F, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3- to 6-membered cycloalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- or
- R9 and L combine with the atoms to which they are attached to form an optionally substituted 3- to 14-membered heterocycloalkyl;
- R9′ is hydrogen or optionally substituted C1-C6 alkyl;
- or
- R9 and R9′, combined with the atoms to which they are attached, form a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocycloalkyl;
- R10 is hydrogen, halogen, hydroxy, optionally substituted C1-C3 heteroalkyl, or optionally substituted C1-C3 alkyl;
- R10a is hydrogen or halogen;
- R11 is hydrogen or optionally substituted C1-C3 alkyl;
- and
- R21 is hydrogen or optionally substituted C1-C3 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 C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;
- Y8 is
- L is a linker;
- R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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;
- R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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;
- R10 is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- R7 and R8 are each, independently, selected from F or CH3, or R7 and R8 combine with the atoms to which they are attached to make a 3-membered cycloalkyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- and
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 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 C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;
- Y8 is
- L is a linker;
- R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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;
- R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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;
- R10 is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- R7 and R8 are each, independently, selected from F or CH3, or R7 and R8 combine with the atoms to which they are attached to make a 3-membered cycloalkyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- and
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 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 C2-C4 alkylene, optionally substituted C1-C4 heteroalkylene or optionally substituted C2-C4 alkenylene;
- Y8 is
- L is a linker;
- X4 and X5 are each, independently, CH2, CH(CH3) or NH;
- R13 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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;
- R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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;
- R10 is hydrogen, hydroxy, optionally substituted C1-C6 alkoxy, optionally substituted C1-C3 alkyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 7-membered heterocycloalkyl;
- R7 and R8 are each, independently, selected from F or CH3, or R7 and R8 combine with the atoms to which they are attached to make a 3-membered cycloalkyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted 3- to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- X6 is CH2 or O;
- m is 1 or 2;
- n is 0 or 1;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)— or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- X6 is CH2 or O;
- m is 1 or 2;
- n is 0 or 1;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, or optionally substituted 3- to 10-membered heterocycloalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- z is 0, 1, or 2;
- X9 is —NRL6—, —C(O)— or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- X6, X7, and X8 are each independently selected from CH2, CHF, CF2, C═O, or O;
- m is 1 or 2;
- n is 0 or 1;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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;
- X6, X7, and X8 are each independently selected from CH2, CHF, CF2, C═O, or O;
- m is 1 or 2;
- n is 0 or 1;
- R1 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 heteroalkyl, or optionally substituted 3- to 10-membered heterocycloalkyl;
- R2 is optionally substituted C1-C6 alkyl;
- R3 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 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;
- X9 is —NRL6—, —C(O)—, or —S(O)2—;
- each of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 is, independently, hydrogen, halogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, or optionally substituted C1-C6 heteroalkyl;
- or any two of RL1, RL2, RL3, RL4, RL4, RL5, and RL6 together with the atoms to which they are attached and any intervening atoms to form an optionally substituted C3-C8 cycloalkyl or a 3- to 8-membered heterocyclyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 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 C2-C4 alkylene, or optionally substituted C2-C4 alkenylene;
- W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl;
- X4 is CH2 or NH;
- R1 is optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 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;
- R2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 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 R3 is hydrogen;
- or R2 and R3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl;
- each of R4, R5, R6, and R7 are hydrogen;
- or R4 and R6 are hydrogen and R5 and R7 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl;
- or R5 and R7 are hydrogen and R4 and R6 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl;
- R10 is —OR11 or —NR12R13;
- R11, R12, and R13 are each, independently, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, or R12 and R13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl;
- each R33 is, independently, halogen, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl;
- and
- t is 0, 1, 2, or 3.