Small-molecule-linker constructs and conjugates thereof

Abstract

The present disclosure relates generally to compounds of formulas (I) and (II) as defined herein, and methods of use thereof. More specifically, the disclosure relates to small-molecule-linker constructs comprising integrin-binding compounds, conjugates thereof, and methods of using any of the foregoing.

Description

Attorney Docket No.: 199C-436282-WOSMALL-MOLECULE-LINKER CONSTRUCTS AND CONJUGATES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Patent Application No. 63 / 777,974, filed March 26, 2025, the entire contents of which are incorporated by reference herein.FIELD

[0002] The present disclosure relates generally to small-molecule-linker constructs, conjugates thereof, and methods of using any of the foregoing. More specifically, the disclosure relates to small-molecule-linker constructs comprising integrin-binding compounds, conjugates thereof, and methods of using any of the foregoing.BACKGROUND

[0003] Therapeutic compounds (such as a drug molecule) or diagnostically useful compounds (such as a radiolabel or a dye) need to be delivered to their specific desired target cell or tissue in order to be most effective. In addition, non-specific delivery of compounds can often lead to undesired side effects (such as off-target toxicity). This is particularly the case when the delivery occurs in vivo.

[0004] One method to facilitate delivery of a therapeutic or diagnostic compound to its desired location in vivo is by linking or conjugating said compound (i.e., the payload) to a targeting ligand. Targeting ligands can enhance the delivery of therapeutic or diagnostic compounds to a specific site, such as a specific organ or tissue, within a subject such as a human.

[0005] Integrins are transmembrane receptor proteins that mediate cell-to-cell and cell-extracellular matrix (ECM) adhesion. Integrins are ubiquitously expressed across many cell types, including leukocytes, neurons, tumor cells, cardiac cells, skeletal muscle cells, and vascular cells. Furthermore, overexpression of specific integrin subunits is implicated in a variety of different diseases, including cancer, fibrotic disease, and inflammation.SUMMARY

[0006] In one aspect, provided is a compound of formula (I), or any variation thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein.

[0007] Further provided is a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable carrier or excipient.

[0008] Provided herein is a compound of formula (I):RA-RB-RC(I)or a pharmaceutically acceptable salt thereof, wherein:Attorney Docket No.: 199C-436282-WORAis a fragment of formula (RA-I) or (RA-II):IQ (RA-I) orIQ (RA-II),* denotes the point of attachment to RB;R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, 6-aminopyridin-2-yl optionally substituted by one or more R4, or (pyridin-2-yl)amino optionally substituted by one or more R4;Q is H or Ci-Ce alkyl;R3is C6-C14 arylene or 5- to 10-membered heteroarylene, wherein the Ce-Cu arylene or 5- to 10-membered heteroarylene are optionally substituted by one or more R4;R2is:(i) RB2, wherein:RB2is Ci-Ce alkyl optionally substituted by one or more RB2a, Cs-Cs cycloalkyl optionally substituted by one or more RD2b, 3- to 12- membered saturated heterocyclyl optionally substituted by one or more RB2cwherein a carbon atom of the 3- to 12-membered saturated heterocyclyl is bonded to the -C(O), or C2-CB alkenyl optionally substituted by one or more B2d.wherein each RB2a, RB2b, RB2c, and RB2dis independently oxo, deuterium, halogen, CI-CB alkyl, C2-CB alkenyl, C2-CB alkynyl, Cs- Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -SR5, -NR6R7, -NO2, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-Ce alkyl, C2-CB alkenyl, C2-Ce alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl of RB2a, RB2b, RB2c, and RB2dare independently optionally substituted by one or more R4a;(ii) RC2, wherein:Attorney Docket No.: 199C-436282-WORC2is C6-C12 aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, C3-C10 cycloalkenyl optionally substituted by one or more RC2c, 3- to 12- membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Ce alkyl substituted by one or more RC2e, Ci-Ce alkenyl substituted by one or more RC2f, C3-C s cycloalkyl substituted by one or more RC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h; whereinat least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2tgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2fare independently optionally substituted by one or more R4a; and each of the other RC2fgroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4; andeach RC2a, RC2b, RC2c, and RC2dis, where possible, independently oxo or R4;(iii) RD2, whereinAttorney Docket No.: 199C-436282-WORD2is -NRD3(CI-C6alkyl), -NRD3(C3-C8cycloalkyl), -NRD3(3- to 12- membered saturated heterocyclyl) such that a carbon atom of the 3- to 12- membered saturated heterocyclyl of -NRD3(3- to 12-membered saturated heterocyclyl) is bonded to tire N of -NRD3, 3- to 12-membered N-containing saturated heterocyclyl such that a nitrogen atom of the 3- to 12-membered N- containing saturated heterocyclyl is bonded to the carbon of -C(O)-, or 5- to 10-membered heteroaryl such that a nitrogen atom of the 5- to 10-membered heteroaryl is bonded to the carbon of -C(O)-,wherein the Ci-C6alkyl of the -NRD3(CI-C6alkyl) of RD2is optionally substituted by one or more RD2a, the': cycloalkyl of the - NRD3(C3-C8cycloalkyl) of RD2is optionally substituted by one or more RD2b, the 3- to 12-membered saturated heterocyclyl of the -NRD3(3- to 12- membered saturated heterocyclyl) of RD2is optionally substituted by one or more RD2c, the 3- to 12-membered N-containing saturated heterocyclyl of RD2is optionally substituted by one or more RD2d, and the 5- to 10-membered heteroaryl is optionally substituted by one or more RD2e;RD3is H, deuterium, Ci-Cg alkyl, C3-C8cycloalkyl, or 3- to 12- membered saturated heterocyclyl,wherein the Ci-Ce alkyl of RD3is optionally substituted by one or more RD3a, the C3-C8cycloalkyl of RD3is optionally substituted by one or more RD3b, and the 3- to 12-membered saturated heterocyclyl of RD3is optionally substituted by one or more RD3c‘; andeach RD2a, RD2b, RD2c, RD2d, RD2e, RD3a, RD3b, and RD3cis, where possible, independently oxo or R4; or(iv) RE2, whereinRE2is -O(Ci-Ce alkyl), -O(C3-C8cycloalkyl), -0(3- to 12-membered saturated heterocyclyl) such that a carbon atom of the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) is bonded to the -0C(0)-, -0(5- to 10-membered aryl) such that a carbon atom of the 5- to 10-membered aryl of -0(Ce-Ci4 aryl) is bonded to the -0C(0)-, or -0(5- to 10-membered heteroaryl) such that a carbon atom of the 5- to 10- membered heteroaryl of -0(5- to 10-membered heteroaryl) is bonded to the - 0C(0)-,wherein the Ci-Cg alkyl of -O(Ci-Ce alkyl) of RE2is optionally substituted by one or more RE2a, the C3-C8cycloalkyl -O(C3-C8cycloalkyf) of RE2is optionally substituted by one or more RE2b, the 3- to 12-memberedAttorney Docket No.: 199C-436282-WOsaturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) of RE2is optionally substituted by one or more RE2c, tire 5- to 10-membered heteroaryl of -0(Ce-Cu aryl) of RF2is optionally substituted by one or more RE2d, tire 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) of RE2eis optionally substituted by one or more RE2e; andeach RE2a, RE2b, RE2c, RE2d, and RE2eis, where possible, independently oxo or R4;Rxis unsubstituted C3-C s alkyl, Ci-Cs alkyl substituted by one or more K1, C3-Ce cycloalkyl optionally substituted by one or more Rxb, 3- to 12-membered heterocyclyl optionally substituted by one or more Rxc, Ce-C aryl optionally substituted by one or more Rxd, 5- to 10-membered heteroaryl optionally substituted by one or more Rxe, or -S(0)2Rxf;each Rxais independently halogen, C2-Ce alkenyl, C2-Ce alkynyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, oxo, -CN, -OR5, -SR5, -NR6R7, -NO2, -N3, -C=NH(0R5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the C2-Ce alkenyl, C2-Ce alkynyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of Rxaare independently optionally substituted by one or more R4a;Rxfis Ci-Ce alkyl optionally substituted by one or more Rxgor C3-C5 cycloalkyl optionally substituted by one or more Rxh;each Rxb, Rxc, Rxd, Rxe, Rxg, and Rxhis independently oxo or R4;L1is C2-C4 alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Ce alkylene optionally substituted by one or more R4;I? is C2-C4 alkylene optionally substituted by one or more R4;Y is a bond or C3-C5 cycloalkylene optionally substituted by one or more oxo or R4; each R4is independently deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -SR5, -NRfiR7, -NO2, -N3, -C=NH(0RS), -C(0)R5, -0C(0)R5, -C(0)0R5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -S(O)2OH, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NRSR7, or -P(0)(0Rs)(0R6), wherein tire Ci-Ce alkyl, C2-Cs alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently deuterium, halogen, oxo, -OR8, -NR8R9, -C(0)R8, -C(0)0R8, -NR8C(O)OR10, -CN, -S(O)R8, -S(O)2R8, -P(O)(OR8)(OR9), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-C aryl, or Ci-Ce alkyl, wherein tire 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-C aryl, and Ci-Ce alkyl of R4aare independently optionally substituted by one or more R4b;Attorney Docket No.: 199C-436282-WOeach R4bis independently deuterium, oxo, -OH, -O-Ci-Cg alkyl, -O(2H), halogen, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -Oil, -O(2II), or oxo;each R5is independently hydrogen, deuterium, Ci-Cg alkyl, Ci-Ce alkenyl, (C-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Cg alkyl, Ci-Cg alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, Cg-Ci4 aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of Rsare each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12, -P(O)(ORn)(OR12), Cs-Cg cycloalkyl, 3- to 12-membered heterocyclyl, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R6is independently hydrogen, deuterium, Ci-Cg alkyl, (C-G, alkenyl, -G, alkynyl, C3-G, cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Cg alkyl, Cj-Cg alkenyl, Ci-C alkynyl, Cs-C cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R7is independently hydrogen, deuterium, Ci-Cg alkyl, C2-C.6 alkenyl, Ci-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Cg alkyl, Cj-C alkenyl, Cj-Cg alkynyl, Cs-C cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;or R6and R7are taken together with tire atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, oxo, -OH, or -O(2H);each R8, R9, and R10is independently hydrogen, deuterium, Ci-Cg alkyl, Ci-Cg alkenyl, or C2-Cg alkynyl, wherein the Ci-Cg alkyl, C2-Cg alkenyl and C2-C alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andeach R11and R12is independently hydrogen, deuterium, Ci-Cg alkyl, C2-Cg alkenyl, or C2-Cg alkynyl, wherein the Ci-Cg alkyl, C2-Cg alkenyl and C2-Cg alkynyl are optionally substituted by one or more deuterium, halogen, or oxo;or R11and R12are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, or Ci-Cg alkyl optionally substituted by one or more deuterium, oxo, or halogen;RBis a linker; andRcis a conjugatable group.Attorney Docket No.: 199C-436282-WO

[0009] Further provided herein is a compound of formula (II):RA-RB-RD-RE(II)or a pharmaceutically acceptable salt thereof, wherein:RAis a fragment of formula (RA-I) or (RA-II):IQ (RA-I) orIQ (RA-II),* denotes the point of attachment to RB;R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, 6-aminopyridin-2-yl optionally substituted by one or more R4, or (pyridin-2-yl)amino optionally substituted by one or more R4;Q is H or Ci-Ce alkyl;R3is Ce-Cu arylene or 5- to 10-membered heteroarylene, wherein the Ce-Cu arylene or 5- to 10-membered heteroarylene are optionally substituted by one or more R4;R2is:(i) RB2, wherein:RB2is Ci-Ce alkyl optionally substituted by one or more RB2a, Cs-Cs cycloalkyl optionally substituted by one or more RB2b, 3- to 12- membered saturated heterocyclyl optionally substituted by one or more RB2cwherein a carbon atom of the 3- to 12-membered saturated heterocyclyl is bonded to the -C(O), or Ci-Ce alkenyl optionally substituted by one or more B2d.wherein each RB2a, RB2b, RB2c, and RB2dis independently oxo, deuterium, halogen, Ci-Ce alkyl, Ci-Ce alkenyl, C^-Ce alkynyl, C3- Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -SR5, -NR6R7, -NO2, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-Cs cycloalkyl, 3- toAttorney Docket No.: 199C-436282-WO12-membered saturated heterocyclyl of RB2a, RB2b, RB2c, and RB2dare independently optionally substituted by one or more R4a;(ii) RC2, wherein:RC2is C6-C12 aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, C3-C10 cycloalkenyl optionally substituted by one or more RC2c, 3- to 12- membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Ce alkyl substituted by one or more RC2e, Cz-Ce alkenyl substituted by one or more RC2f, Cs-Cg cycloalkyl substituted by one or more RC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h; whereinat least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2fgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- C aryl, and 5- to 10-membered heteroaryl of RC2fare independently optionally substituted by one or more R4a; and each of the other RC2fgroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- C aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4; andAttorney Docket No.: 199C-436282-WOeach RC2a, RC2b, RC2c, and RC2dis, where possible, independently oxo or R4;(iii) RD2, whereinRD2is -NRD3(CI-C6alkyl), -NRD3(C3-C8cycloalkyl), -NRD3(3- to 12- membered saturated heterocyclyl) such that a carbon atom of the 3- to 12- membered saturated heterocyclyl of -NRD3(3- to 12-membered saturated heterocyclyl) is bonded to the N of -NRD3, 3- to 12-membered N-containing saturated heterocyclyl such that a nitrogen atom of the 3- to 12-membered N- containing saturated heterocyclyl is bonded to the carbon of -C(O)-, or 5- to 10-membered heteroaryl such that a nitrogen atom of the 5- to 10-membered heteroaryl is bonded to the carbon of -C(O)-,wherein the Ci-C6alkyl of tire -NRD3(CI-C6alkyl) of RD2is optionally substituted by one or more RD2a, the C3-Cs cycloalkyl of the - NRD3(C3-Cs cycloalkyl) of RD2is optionally substituted by one or more RD2b, the 3- to 12-membered saturated heterocyclyl of the -NRD3(3- to 12- membered saturated heterocyclyl) of RD2is optionally substituted by one or more RD2c, the 3- to 12-membered N-containing saturated heterocyclyl of RD2is optionally substituted by one or more RD2d, and the 5- to 10-membered heteroaryl is optionally substituted by one or more RD2e;RD3is H, deuterium, Ci-Cg alkyl, Cs-Cs cycloalkyl, or 3- to 12- membered saturated heterocyclyl,wherein the Ci-Cg alkyl of RD3is optionally substituted by one or more RD3a, the C3-Cs cycloalkyl of RD3is optionally substituted by one or more RD3b, and tire 3- to 12-membered saturated heterocyclyl of RD3is optionally substituted by one or more RD3c'; andeach RD2a, RD2b, RD2c, RD2d, RD2e, RD3a, RD3b, and RD3cis, where possible, independently oxo or R4; or(iv) RE2, whereinRE2is -O(Ci-Ce alkyl), -O(C3-Cs cycloalkyl), -0(3- to 12-membered saturated heterocyclyl) such that a carbon atom of the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) is bonded to the -0C(0)-, -0(5- to 10-membered aryl) such that a carbon atom of the 5- to 10-membered aryl of -0(Ce-Ci4 aryl) is bonded to the -0C(0)-, or -0(5- to 10-membered heteroaryl) such that a carbon atom of the 5- to 10-Attorney Docket No.: 199C-436282-WOmembered heteroaryl of -0(5- to 10-membered heteroaryl) is bonded to the - 0C(0)-,wherein the Ci-Ce alkyl of -0(Ci-Ce alkyl) of RE2is optionally substituted by one or more RE2a, tire C3-Cg cycloalkyl -0(C3-Cg cycloalkyl) of RE2is optionally substituted by one or more RE2b, the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) of RE2is optionally substituted by one or more RE2c, the 5- to 10-membered heteroaryl of -0(Ce-Ci4 aryl) of RE2is optionally substituted by one or more RE2d, the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) of RE2eis optionally substituted by one or more RE2e; andeach RE2a, RE2b, RE2c, RE2d, and RE2eis, where possible, independently oxo or R4;Rxis unsubstituted Cs-Cg alkyl, Ci-Cs alkyl substituted by one or more Rxa, C3-Ce cycloalkyl optionally substituted by one or more Rxb, 3- to 12-membered heterocyclyl optionally substituted by one or more Rxc, Ce-Cu aryl optionally substituted by one or more Rxd, 5- to 10-membered heteroaryl optionally substituted by one or more Rxe, or -S(O)2Rxf;each Rxais independently halogen, Cu-Ce alkenyl, Cu-Ce alkynyl, C3-Cg cycloalky], 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, oxo, -CN, -OR5, -SR5, -NR6R7, -N02, -N3, -C=NH(0R5), -C(0)R5, -0C(0)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the C2-Ce alkenyl, C2-Ce alkynyl, C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of Rxaare independently optionally substituted by one or more R4a;Rxfis Ci-Ce alkyl optionally substituted by one or more Rxgor C3-C5 cycloalkyl optionally substituted by one or more Rxh;each Rxb, Rxc, Rxd, Rxe, Rxg, and Rxhis independently oxo or R4;L1is C2-C4 alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Ce alkylene optionally substituted by one or more R4;L3is C2-C4 alkylene optionally substituted by one or more R4;Y is a bond or C3-C5 cycloalkylene optionally substituted by one or more oxo or R4; each R4is independently deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -SR5, -NR6R7, -NO2, -N3, -C=NH(0R5), -C(0)R5, -0C(0)R5, -C(0)0R5, -C(0)NRSR7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -S(O)2OH, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-C6alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Cs-Cg cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;Attorney Docket No.; 199C-436282-WOeach R4ais independently deuterium, halogen, oxo, -OR8, -NR8R9, -C(O)R8, -C(O)OR8, -NR8C(O)OR10, -CN, -S(O)R8, -S(O)2R8, -P(O)(OR8)(OR9), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Cg-Cu aryl, or Ci-Cg alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Cg-Cu aryl, and Ci-Cg alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently deuterium, oxo, -OH, -O-Ci-Cg alkyl, -O(2H), halogen, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R5is independently hydrogen, deuterium, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Cz-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12, -P(O)(ORn)(OR12), C3-Cg cycloalkyl, 3- to 12-membered heterocyclyl, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R6is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-C aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R7is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-C aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Cj-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-Ci4 aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -Oil, -O(2II), or oxo;or Rfiand R7are taken together with the atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, oxo, -OH, or -O(2H);each R8, Rq, and R10is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, or Cz-Cg alkynyl, wherein the Ci-Cg alkyl, Cz-Cg alkenyl and Cz-Cg alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andeach R11and R12is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, or Cz-Cg alkynyl, wherein the Ci-Cg alkyl, Cz-Cg alkenyl and Cz-Cg alkynyl are optionally substituted by one or more deuterium, halogen, or oxo;Attorney Docket No.: 199C-436282-WOor R11and R12are taken together with tire atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, or Ci-Cg alkyl optionally substituted by one or more deuterium, oxo, or halogen;RBis a linker;RDis a conjugated group; andREis a payload.

[0010] In some embodiments, RBis a linker of formula (RB-I):O'Jn (RB-I)wherein * denotes the point of attachment to RA, ** denotes the point of attachment to Rcor RD, and n is an integer from 0 to 100.

[0011] In some embodiments, the compound is a compound of formula (I) and Rcis Cz-Cg alkynyl, an azide, or Ci-Cg alkyl substituted by an azide.

[0012] In some embodiments, the compound is a compound of formula (I) and Rcis Cz-Cg alkynyl.

[0013] In some embodiments, Rcis, wherein ** denotes the point of attachment to RB.

[0014] In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and Rcis a fragment of formula (Rc-I):M-NI N— L*cl_RC HN— LEND(Rc-I)wherein each LRCis independently a bond or Ci-Cg alkyl, LENDis selected from H and a protecting group, and wherein ** denotes the point of attachment to RB., ON=Nk N O

[0015] In some embodiments, Rcis:, wherein ** denotes the point of attachment to RB.

[0016] In some embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, and RDis a group comprising a cycloalkyl, a heterocycle, an aryl, a heteroaryl, a disulfide, a thioether, a hydrazone, an ester, a sulfonamide, a carbamate, or an amide.Attorney Docket No.: 199C-436282-WON — [ ***

[0017] In some embodiments, R1’ is'1, wherein ** denotes the point of attachment to RB, and *** denotes the point of attachment to RE.

[0018] In some embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, and RDis a fragment of formula (RD-I):(RD-I),wherein each LRCis independently a bond or Ci-Ce alkyl, wherein ** denotes the point of attachment to RBand *** denotes the point of attachment to RE.

[0019] In some embodiments, RDis:wherein ** denotes the point of attachment to RB, and *** denotes the point of attachment to RE.

[0020] In some embodiments, RDis a fragment of formula (RD-II):wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and m is an integer from 1 to 20.

[0021] In some embodiments, RDis a fragment of formula (RD-III):(RD-III) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and p is an integer from 1 to 20.

[0022] In some embodiments, RDis a fragment of formula (RD-IV):Attorney Docket No.: 199C-436282-WOwherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and qi and cp are each independently an integer from 1 to 20.

[0023] In some embodiments, RDis a fragment of formula (RD-V):wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and ri, n, and rr, are each independently an integer from 1 to 20.

[0024] In some embodiments, RDis a fragment of formula (RD-VI):(RD-VI) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and 2 is an integer from 1 to 20.

[0025] In some embodiments, REis a reporting group or a label.

[0026] In some embodiments, REis a fragment of formula (RE-A):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

[0027] In some embodiments, REis an antineoplastic agent optionally conjugated to a cleavable group and / or self-immolative group.

[0028] In some embodiments, REis a fragment of formula (RE-B):wherein *** denotes the point of attachment to RD.

[0029] In some embodiments, REis a fragment of formula (RE-E):wherein *** denotes the point of attachment to RD.

[0030] In some embodiments, REis a fragment of formula (RE-F):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

[0031] In some embodiments, REis a fragment of formula (RE-G):wherein *** denotes the point of attachment to RD.

[0032] In some embodiments, REis a fragment of formula (RE-H):wherein *** denotes the point of attachment to RD.

[0033] In some embodiments, REis a fragment of formula (RE-I):wherein *** denotes the point of attachment to RD.

[0034] In some embodiments, REis a fragment of formula (RE-J):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

[0035] In some embodiments, provided herein is a method of delivering a payload to a cell, comprising (a) contacting the cell with a compound as disclosed herein, and (b) incubating the cell wherein the is internalized into the cell.

[0036] In some embodiments, provided herein is a method of treating cancer in a subject in need thereof, comprising administering a compound as disclosed herein to the subject.

[0037] In some embodiments, the cancer is melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (e.g., Hodgkin's lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma.BRIEF DESCRIPTION OF THE FIGURES

[0038] FIG. 1A-1G are bar graphs showing the relative cell surface level of av e normalized to a control for Reference Compound 1, Reference Compound 2, or test articles for 60 min at 37°C, fixed and immunostained for ctv e.

[0039] FIG. 2 shows confocal images of H358 (FIG. 2 A) and SW48O-av0e (FIG. 2B) cells treated with 0.5 mM Compound C4 (probe) for an hour.

[0040] FIG. 3 shows the dose response curves plotted for average intracellular fluorescence intensity per cell for H358 (FIG. 3 A) and SW480-avf (FIG. 3B) at differing concentrations of Compound C4 (circles) and in the presence of 100-fold excess parent Compound S4 (squares).

[0041] FIG. 4 is a bar graph that shows the side-by-side comparison of fluorescence intensity between the two cell lines (N = 2 technical replicates).

[0042] FIG. 5 is a bar graph that shows (lie cell surface level of integrin |F, in cells treated with vehicle and test Compounds B, S4, C9, CIO, and C17.

[0043] FIG. 6A is a dose response curve that shows the observed cytotoxicity in wild-type (WT) and avp6highNCI-H358 clones treated with Compound C9.

[0044] FIG. 6B is a dose response curve that shows the observed cytotoxicity in wild-type (WT) and avp6highNCI-H358 clones treated with Compound C16.

[0045] FIG. 7 is a dose response curve that shows the observed cytotoxicity in avp6hlghNCI-H358 clones treated with Compound C16 and C21.Attorney Docket No.: 199C-436282-WO

[0046] FIG. 8 is a bar graph that shows the competitive binding assay between Compound A and Compounds Cl 6 and C21.DETAILED DESCRIPTION

[0047] The following description sets forth exemplary methods, parameters and the like. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.Definitions

[0048] For use herein, unless clearly indicated otherwise, use of the terms “a”, “an” and the like refers to one or more.

[0049] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. Likewise, reference to a value “X” also includes description of “about X”. In some embodiments, tire term “about,” when used in association with a measurement or to modify a parameter or a value or a range of values, refers to variations of that measurement, parameter, value, or range of values of + / - 10%, + / - 9%, + / - 8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / -1%. For example, in some embodiments, “about X” includes and describes X + / - 10%, + / - 9%, + / -8%, + / - 7%, + / - 6%, + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1% of X. In some embodiments, the term “about” refers to variations of + / - 5%, + / - 4%, + / - 3%, + / - 2%, or + / - 1%. In some embodiments, tire term “about” refers to variations of + / - 2% or + / - 1%. In some embodiments, the term “about” refers to variations of + / - 2%. In some embodiments, the term “about” refers to variations of + / - 1%.

[0050] “Alkyl” as used herein refers to and includes, unless otherwise stated, a saturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbon atoms). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”), having 1 to 10 carbon atoms (a “C1-C10 alkyl”), having 6 to 10 carbon atoms (a “Cs-Cio alkyl”), having 1 to 6 carbon atoms (a “Ci-Cs alkyl”), having 2 to 6 carbon atoms (a “C2-Ce alkyl”), or having 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0051] “Alkylene” as used herein refers to tire same residues as alkyl, but having bivalency.Particular alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20 alkylene”), having 1 to 10 carbon atoms (a “C1-C10 alkylene”), having 6 to 10 carbon atoms (a “Ce-Cw alkylene”), having 1 to 6 carbon atoms (a “Ci-Ce alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”). Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), isopropylene (-CH2CH(CH3)-), butylene (-CH2(CH2)2CH2-), isobutylene (-CH2CH(CH3)CH2-), pentylene (-CH2(CH2)3CH2-), hexylene (-CH2(CH2)4CH2-), heptylene (-CH2(CH2)5CH2-), octyleneAttorney Docket No.: 199C-436282-WO(-CI b(CI LhCI L-), and the like. It is understood that when alkylene is substituted (for example with a cycloalkyl group), the substituent is not one of the sites of bivalency. For example, propylenesubstitution with cyclopropyl may providebut does not provide, wherein the wavy line denotes a site of bi valency.

[0052] “n-Alkylene” as used herein refers to the same residues as alkylene, but having a straight chain of carbon atoms, wherein the two sites of bivalency are on the two ends of die straight chain of carbon atoms. For example, a “C3 n-alkylene” or “n-propylene” refers to -CH2CH2CH2-, wherein each of die -CH2- is optionally substituted, but “C3 n-alkylene” does not encompass -CH2-CH(CH3)- or -C(CH3)2-. For another example, a “C4 n-alkylene” or “n-butylene” refers to, wherein each of the -CH2- is optionally substituted, but does not encompass,;,or,wherein the wavy line denotes a site of bivalency. Particular n-alkylene groups are those having 1 to 20 carbon atoms (a “C1-C20 n-alkylene”), having 1 to 10 carbon atoms (a “C1-C10 n-alkylene”), having 6 to 10 carbon atoms (a “Ce-Cw n-alkylene”), having 1 to 6 carbon atoms (a “Ci-Cg n-alkylene”), 1 to 5 carbon atoms (a “C1-C5 n-alkylene”), 1 to 4 carbon atoms (a “C1-C4 n-alkylene”) or 1 to 3 carbon atoms (a “C1-C3 n-alkylene”). It is understood that when n-alkylene is substituted (for example with a cycloalkyl group), the substituent is not one of the sites of bivalency. For example, n-propylene substitution withcyclopropyl may providebLl( JoesnO| provide, wherein the wavy line denotes a site of bivalency.

[0053] “Alkenyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). An alkenyl group may have “cis” or “trans” configurations, or alternatively have “E” or “Z” configurations. Particular alkenyl groups arc those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 6 to 10 carbon atoms (a “Ce-Cio alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2-Attorney Docket No.: 199C-436282-WOenyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta- 1,3-dienyl, 2-methylbuta- 1,3-dienyl, pent-l-enyl, pent-2-enyl, hex-l-enyl, hex-2-enyl, hex-3-enyl, and the like.

[0054] “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency. Particular alkenylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenylene”), having 2 to 10 carbon atoms (a “C2-C10 alkenylene”), having 6 to 10 carbon atoms (a “Ce-Cio alkenylene”), having 2 to 6 carbon atoms (a “C2-C6 alkenylene”), 2 to 4 carbon atoms (a “C2-C4 alkenylene”) or 2 to 3 carbon atoms (a “C2-C3 alkenylene”). Examples of alkenylene include, but are not limited to, groups such as ethenylene (or vinylene) (-CH=CH-), propenylene (-CH=CHCH2-), 1,4-but-l-enylene (-CH=CH-CH2CH2-), 1,4-but-2-enylene (-CH2CH=CHCH2-), 1,6-hex-l-enylene (-CH=CH-(CH2)3CH2-), and the like.

[0055] “Alkynyl” as used herein refers to and includes, unless otherwise stated, an unsaturated linear (i.e., unbranched) or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of die formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 6 to 10 carbon atoms (a “Ce-Cio alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-G5 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl group include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2-ynyl (or propargyl), but-l-ynyl, but-2-ynyl, but-3-ynyl, and the like.

[0056] “Alkynylene” as used herein refers to the same residues as alkynyl, but having bivalency. Particular alkynylene groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynylene”), having 2 to 10 carbon atoms (a “C2-C10 alkynylene”), having 6 to 10 carbon atoms (a “Cg-Cio alkynylene”), having 2 to 6 carbon atoms (a “Ci-Cs alkynylene”), 2 to 4 carbon atoms (a “C2-C4 alkynylene”) or 2 to 3 carbon atoms (a “C2-C3 alkynylene”). Examples of alkynylene include, but are not limited to, groups such as ethynylene (or acetylenylene) (-C=C-), propynylene (-C=CCH2-), and the like.

[0057] “Cycloalkyl” as used herein refers to and includes, unless otherwise stated, saturated cyclic univalent hydrocarbon structures, having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. A cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. Particular cycloalkyl groups are those having from 3 to 12 annular carbon atoms. A preferred cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a " C3-C8 cycloalkyl''), having 3 to 6 annular carbon atoms (a “C3-C6 cycloalkyl”), or having from 3 to 4 annular carbon atoms (a " C3-C4 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0058] “Cycloalkylene” as used herein refers to the same residues as cycloalkyl, but having bivalency. Cycloalkylene can consist of one ring or multiple rings which may be fused, spiro or bridged, or combinations thereof. Particular cycloalkylene groups are those having from 3 to 12Attorney Docket No.: 199C-436282-WOannular carbon atoms. A preferred cycloalkylene is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a " Cs-Cg cycloalkylene"), having 3 to 6 carbon atoms (a “C3-C6 cycloalkylene”), or having from 3 to 4 annular carbon atoms (a " C3-C4 cycloalkylene"). Examples of cycloalkylene include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, norbornylene, and die like. A cycloalkylene may attach to die remaining structures via the same ring carbon atom (e.g., 1,1 -cyclopropylene) or different ring carbon atoms (e.g., 1,2-cyclopropylene). When a cycloalkylene attaches to the remaining structures via two different ring carbon atoms, the connecting bonds may be cis or trans to each other (e.g., cis-1,2-cyclopropylene or trans-1,2-cyclopropylene). If points of attachment are not specified, die moiety can include any chemically possible attachments. For example, cyclopropylene can indicate 1,1 -cyclopropylene or 1,2-cyclopropylene (e.g., cis-l,2-cyclopropylene, trans- 1,2-cyclopropylene, or a mixture thereof), or a mixture thereof.

[0059] “Cycloalkenyl” refers to and includes, unless otherwise stated, an unsaturated cyclic nonaromatic univalent hydrocarbon structure, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C3-C10 means three to ten carbon atoms). Cycloalkenyl can consist of one ring, such as cyclohexenyl, or multiple rings, such as norbomenyl. A preferred cycloalkenyl is an unsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “Cs-Cg cycloalkenyl”). Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, norbornenyl, and the like.

[0060] “Cycloalkenylene” as used herein refers to the same residues as cycloalkenyl, but having bivalency.

[0061] “Aryl” or “Ar” as used herein refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings are carbocyclic and may or may not be aromatic, provided at least one ring in the multiple condensed ring structure is aromatic. Particular aryl groups are those having from 6 to 14 annular carbon atoms (a “Ce-Cu aryl”). An aryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a nonaromatic ring position. In one variation, an aryl group having more than one ring where at least one ring is non-aromatic is connected to tire parent structure at an aromatic ring position.

[0062] “Arylene” as used herein refers to the same residues as aryl, but having bivalency. Particular arylene groups are those having from 6 to 14 annular carbon atoms (a “Ce-Cu arylene”).

[0063] “Heteroaryl” as used herein refers to an unsaturated aromatic cyclic group having from 1 to 14 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur. A heteroaryl group may have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzo thienyl) which condensed rings may be carbocyclic or may contain one or more annular heteroatom and which may or may not be aromatic, provided atAttorney Docket No.: 199C-436282-WOleast one ring in the multiple condensed ring structure is both aromatic and contains at least one annular heteroatom. Particular heteroaryl groups are 5 to 14-membered rings having 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 5 to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 5, 6 or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, particular heteroaryl groups are monocyclic aromatic 5-, 6- or 7-membered rings having from 1 to 6 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In another variation, particular heteroaryl groups are polycyclic aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. A heteroaryl group having more than one ring where at least one ring is non-aromatic may be connected to the parent structure at either an aromatic ring position or at a non-aromatic ring position. In one variation, a heteroaryl group having more than one ring where at least one ring is non-aromatic is connected to the parent structure at an aromatic ring position. A heteroaryl group may be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0064] “Heteroarylene” as used herein refers to the same residues as heteroaryl, but having bivalency.

[0065] “Heterocycle,” “heterocyclic,” or “heterocyclyl” as used herein refers to a saturated or an unsaturated non-aromatic cyclic group having from 1 to 14 annular carbon atoms and from 1 to 6 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like. A heterocyclic group may have a single ring (e.g., pyrrolidinyl) or multiple condensed rings (e.g., decahydroisoquinolin-1 -yl), which condensed rings which may be carbocyclic or contain one or more annular heteroatoms, but which excludes aryl and heteroaryl rings. A heterocycle comprising more than one ring may be fused, bridged or spiro, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl or aryl, but excludes heteroaryl groups. The heterocyclyl group may be optionally substituted independently with one or more substituents described herein. Particular heterocyclyl groups are 3 to 14-membered rings having 1 to 13 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 12-membered rings having 1 to 11 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 10-membered rings having 1 to 9 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, 3 to 8-membered rings having 1 to 7 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur, or 3 to 6-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- or 7-membered rings having from 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 annular carbon atoms and 1 to 2, 1 to 3, or 1 to 4 annular heteroatoms independently selectedAttorney Docket No.: 199C-436282-WOfrom nitrogen, oxygen and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having from 1 to 12 annular carbon atoms and 1 to 6 annular heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0066] “Heterocyclylene” as used herein refers to the same residues as heterocyclyl, but having bi valency.

[0067] ‘ ‘Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. Preferred halo groups include the radicals of fluorine, chlorine, bromine and iodine. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily the same halogen; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0068] “Carbonyl” refers to the group C=O.

[0069] ‘ ‘Oxo” refers to the moiety =0.

[0070] ‘ ‘D” refers to deuterium (2H).

[0071] ‘ ‘Boc” refers to tert-butyloxycarbonyl.

[0072] “Optionally substituted” unless otherwise specified means dial a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or 5) of the substituents listed for that group in which the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, or 2 to 5 substituents. In one embodiment, an optionally substituted group is unsubstituted.

[0073] Unless clearly indicated otherwise, “an individual” as used herein intends a mammal, including but not limited to a primate, human, bovine, horse, feline, canine, or rodent. In one variation, the individual is a human.

[0074] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. For purposes of this invention, beneficial or desired results include, but are not limited to, one or more of the following: decreasing one more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread of the disease, delaying the occurrence or recurrence of the disease, delay or slowing the progression of the disease, ameliorating tire disease state, providing a remission (whether partial or total) of the disease, decreasing the dose of one orAttorney Docket No.: 199C-436282-WOmore other medications required to treat the disease, enhancing effect of another medication, delaying tire progression of the disease, increasing the quality of life, and / or prolonging survival. Also encompassed by “treatment” is a reduction of pathological consequence of fibrosis. The methods of tire invention contemplate any one or more of these aspects of treatment.

[0075] As used herein, the term “effective amount” intends such amount of a compound of the invention which should be effective in a given therapeutic form. As is understood in the art, an effective amount may be in one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents (e.g., a compound, or pharmaceutically acceptable salt thereof), and a single agent may be considered to be given in ait effective amount if, in conjunction with one or more other agents, a desirable or beneficial result may be or is achieved. Suitable doses of any of the co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) of the compounds.

[0076] A “therapeutically effective amount” refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome.

[0077] As used herein, “unit dosage form” refers to physically discrete units, suitable as unit dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Unit dosage forms may contain a single or a combination therapy.

[0078] As used herein, the term “controlled release” refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool. The term encompasses depot formulations designed to gradually release the drug compound over an extended period of time. Controlled release formulations can include a wide variety of drug delivery systems, generally involving mixing the drug compound with carriers, polymers or other compounds having the desired release characteristics (e.g., pl [-dependent or non-pH-dependent solubility, different degrees of water solubility, and the like) and formulating the mixture according to the desired route of delivery (e.g., coated capsules, implantable reservoirs, injectable solutions containing biodegradable capsules, and the like).

[0079] As used herein, by “pharmaceutically acceptable” or “pharmacologically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U. S. Food and Drug Administration, herein incorporated by reference in its entirety.Attorney Docket No.: 199C-436282-WO

[0080] “Pharmaceutically acceptable salts” are those salts which retain at least some of the biological activity of the free (non-salt) compound and which can be administered as drugs or pharmaceuticals to an individual. Exemplary pharmaceutically acceptable salts are found in, e.g., Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 23rded. (2020), which is hereby incorporated by reference in its entirety. Such salts, for example, include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, and tire like; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine and the like. Acceptable inorganic bases which can be used to prepared salts include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like. Pharmaceutically acceptable salts can be prepared in situ in the manufacturing process, or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0081] The term “excipient” as used herein means an inert or inactive substance that may be used in the production of a drug or pharmaceutical, such as a tablet containing a compound of the invention as an active ingredient. Various substances may be embraced by the term excipient, including without limitation any substance used as a binder, disintegrant, coating, compression / encapsulation aid, cream or lotion, lubricant, solutions for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspending / gelling agent, or wet granulation agent. Exemplary excipients are found in, e.g., Handbook of Pharmaceutical Excipients, Pharmaceutical Press, 9thed. (2020), which is hereby incorporated by reference in its entirety. Binders include, e.g., carbomers, povidone, xanthan gum, etc.; coatings include, e.g., cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, e.g., calcium carbonate, dextrose, fructose de (de = “directly compressible”), honey de, lactose (anhydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch de, sucrose, etc.; disin tegrants include, e.g., croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, e.g., maltodextrin, carrageenans, etc.; lubricants include, e.g., magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, e.g., dextrose, fructose de, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, e.g., carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame, dextrose, fructose de, sorbitol, sucrose de, etc.; and wet granulation agents include, e.g., calcium carbonate, maltodextrin, microcrystalline cellulose, etc.Attorney Docket No.: 199C-436282-WO

[0082] Unless otherwise stated, "substantially pure" intends a composition that contains no more than 10% impurity, such as a composition comprising less than about 9%, 7%, 5%, 3%, 1%, 0.5% impurity.

[0083] It is understood that aspects and embodiments described herein as “comprising” include “consisting of’ and “consisting essentially of’ embodiments.

[0084] When a composition is described as “consisting essentially of’ the listed components, the composition contains the components expressly listed, and may contain other components which do not substantially affect the disease or condition being treated such as trace impurities. However, the composition either does not contain any other components which do substantially affect the disease or condition being treated other than those components expressly listed; or, if the composition does contain extra components other than those listed which substantially affect the disease or condition being treated, the composition does not contain a sufficient concentration or amount of those extra components to substantially affect the disease or condition being treated. When a method is described as “consisting essentially of” the listed steps, the method contains the steps listed, and may contain other steps that do not substantially affect the disease or condition being treated, but the method does not contain any other steps which substantially affect the disease or condition being treated other than those steps expressly listed.

[0085] When a moiety is indicated as substituted by “at least one” substituent, this also encompasses the disclosure of exactly one substituent.

[0086] When a moiety is indicated as substituted by “at least two” substituents, this also encompasses the disclosure of exactly two substituents.

[0087] When a moiety is indicated as substituted by “at least three” substituents, this also encompasses the disclosure of exactly three substituents.CompoundsI. Small-Molecule-Linker Constructs

[0088] In one embodiment, provided herein is a compound of formula (I):RA-RB-RC(I)or a pharmaceutically acceptable salt thereof, wherein:RAis a small molecule fragment;RBis a linker; andRcis a conjugatable group.

[0089] In one embodiment, the small molecule fragment of RAis an integrin-binding fragment.

[0090] In one embodiment, provided herein is a compound of formula (I):RA-RB-RC(IIAttorney Docket No.: 199C-436282-WOor a pharmaceutically acceptable salt thereof, wherein:RAis an in tegrin -binding fragment;RBis a linker; andRcis a conjugatable group.

[0091] In one embodiment, provided herein is a compound of formula (I):RA-RB-RC(I)or a pharmaceutically acceptable salt thereof, wherein:RAis a fragment of formula (RA-I) or (RA-II):IQ (RA-I) orIQ (RA-II),* denotes tire point of attachment to RB;R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, 6-aminopyridin-2-yl optionally substituted by one or more R4, or (pyridin-2-yl)amino optionally substituted by one or more R4;Q is H or Ci-Ce alkyl;R3is Ce-Cu arylene or 5- to 10-membered heteroarylene, wherein the Ce-Ci4 arylene or 5- to 10-membered heteroarylene are optionally substituted by one or more R4;R2is:(i) RB2, wherein:RB2is Ci-Ce alkyl optionally substituted by one or more RB2a, Cs-Cs cycloalkyl optionally substituted by one or more RB2b, 3- to 12- membered saturated heterocyclyl optionally substituted by one or more RB2cwherein a carbon atom of the 3- to 12-membered saturated heterocyclyl is bonded to the -C(O), or Cz-Cg alkenyl optionally substituted by one or more B2d.wherein each RB2a, RB2b, RB2c, and RB2dis independently oxo, deuterium, halogen, Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3- C8cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -SR5,Attorney Docket No.: 199C-436282-WO-NR6R7, -N02, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2Rfi, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-Ce alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C8 cycloalkyl, 3- to 12-membered saturated heterocyclyl of RB2a, RB2b, RB2c, and RB2dare independently optionally substituted by one or more R4a;(ii) RC2, wherein:RC2is Cg-Ci2aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, C3-C10 cycloalkenyl optionally substituted by one or more RC2c, 3- to 12- membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Cg alkyl substituted by one or more RC2e, C2-Cg alkenyl substituted by one or more RC2f, Cs-Cs cycloalkyl substituted by one or more RC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h; whereinat least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Ci4 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- C14 aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2fgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Ci4 aryl, and 5- to 10-membered heteroaryl of RC2fare independently optionally substituted by one or more R4a; and each of the other RC2fgroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Ci4 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Ci4 aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of die other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Ci4 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Og-Attorney Docket No.: 199C-436282-WOCu aryl, and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4; andeach RC2a, RC2b, RC2c, and RC2dis, where possible, independently oxo or R4;(iii) RD2, whereinRD2is -NRD3(CI-C6alkyl), -NRD3(C3-C8cycloalkyl), -NRD3(3- to 12- membered saturated heterocyclyl) such that a carbon atom of the 3- to 12- membered saturated heterocyclyl of -NRD3(3- to 12-membered saturated heterocyclyl) is bonded to the N of -NRD3, 3- to 12-membered N-containing saturated heterocyclyl such that a nitrogen atom of the 3- to 12-membered N- containing saturated heterocyclyl is bonded to the carbon of -C(O)-, or 5- to 10-membered heteroaryl such that a nitrogen atom of the 5- to 10-membered heteroaryl is bonded to the carbon of -C(O)-,wherein the Ci-C6alkyl of the -NRD3(CI-C6alkyl) of RD2is optionally substituted by one or more RD2a, the C3-C8cycloalkyl of the - NRD3(C3-C8cycloalkyl) of RD2is optionally substituted by one or more RD2b, the 3- to 12-membered saturated heterocyclyl of the -NRD3(3- to 12- membered saturated heterocyclyl) of RD2is optionally substituted by one or more RD2c, the 3- to 12-membered N-containing saturated heterocyclyl of RD2is optionally substituted by one or more RD2d, and the 5- to 10-membered heteroaryl is optionally substituted by one or more RD2e;RD3is H, deuterium, Ci-Cs alkyl, C3-Cs cycloalkyl, or 3- to 12- membered saturated heterocyclyl,wherein the Ci-Ce alkyl of RD3is optionally substituted by one or more RD3a, the C3-C8 cycloalkyl of RD3is optionally substituted by one or more RD3b, and tire 3- to 12-membered saturated heterocyclyl of RD3is optionally substituted by one or more RD3c'; andeach RD2a, RD2b, RD2c, RD2d, RD2e, RD3a, RD3b, and RD3cis, where possible, independently oxo or R4; or(iv) RE2, whereinRE2is -O(Ci-Ce alkyl), -O(C3-C8cycloalkyl), -0(3- to 12-membered saturated heterocyclyl) such that a carbon atom of the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) is bonded to the -0C(0)-, -0(5- to 10-membered aryl) such that a carbon atomAttorney Docket No.: 199C-436282-WOof the 5- to 10-membered aryl of -0(Ce-Ci4 aryl) is bonded to the -OC(O)-, or -0(5- to 10-membered heteroaryl) such that a carbon atom of the 5- to 10- membered heteroaryl of -0(5- to 10-membered heteroaryl) is bonded to die - 0C(0)-,wherein die Ci-Ce alkyl of -O(Ci-Ce alkyl) of RE2is optionally substituted by one or more RE2a, the C3-Cs cycloalkyl -0(C3-Cs cycloalkyl) of RE2is optionally substituted by one or more RE2b, the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) of RE2is optionally substituted by one or more RE2c, the 5- to 10-membered heteroaryl of -0(Ce-Ci4 aryl) of RE2is optionally substituted by one or more RE2d, the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) of RE2eis optionally substituted by one or more RE2e; andeach RE2a, RE2b, RE2c, RE2d, and RE2eis, where possible, independently oxo or R4;Rxis unsubstituted C3-Cs alkyl, Ci-Cs alkyl substituted by one or more Rxa, C3-Cs cycloalkyl optionally substituted by one or more Rxb, 3- to 12-membered heterocyclyl optionally substituted by one or more Rxc, Ce-C aryl optionally substituted by one or more Rxd, 5- to 10-membered heteroaryl optionally substituted by one or more Rxe, or -S(O)2Rxf;each Rxais independently halogen, C2-Ce alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-C aryl, 5- to 10-membered heteroaryl, oxo, -CN, -OR5, -SR5, -NR6R7, -N02, -N3, -C=NH(0R5), -C(0)R5, -0C(0)R5, -C(0)0R5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the C2-Ce alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-C aryl, and 5- to 10-membered heteroaryl of Rxaare independently optionally substituted by one or more R4a;Rxfis Ci-Ce alkyl optionally substituted by one or more Rxgor C3-Cs cycloalkyl optionally substituted by one or more Rxh;each Rxb, Rxc, Rxd, Rxe, Rxg, and Rxbis independently oxo or R4;L1is C2-C4alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Ce alkylene optionally substituted by one or more R4;L3is C2-C4alkylene optionally substituted by one or more R4;Y is a bond or C3-Cs cycloalkylene optionally substituted by one or more oxo or R4; each R4is independently deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Cs: cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -SR5, -NR6R7, -N02, -N3, -C=NH(0R5), -C(0)R5, -0C(0)R5, -C(0)0R5, -C(O)NR6R7, -NR5C(0)RG, -NR5C(0)0RG, -NR5C(O)NRGR7, -S(O)R5, -S(O)2R5, -S(O)2OH, -NR5S(O)RG, -NR5S(O)2RG, -S(O)NR6R7, -S(O)2NRGR7, or -P(O)(OR5)(OR6), wherein the Ci-C6alkyl, C2-Attorney Docket No.: 199C-436282-WOCe alkenyl, Cz-Ce alkynyl, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently deuterium, halogen, oxo, -OR8, -NR8R9, -C(O)R8, -C(O)OR8, -NR8C(O)OR10, -CN, -S(O)R8, -S(O)2R8, -P(O)(OR8)(OR9), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-Cu aryl, or Ci-Ce alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-C aryl, and Ci-Ce alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently deuterium, oxo, -OH, -O-Ci-Ce alkyl, -O(2H), halogen, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R5is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-Cg cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12, -P(O)(ORn)(OR12), Cs-Ce cycloalkyl, 3- to 12-membered heterocyclyl, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R6is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R7is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ca-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ca-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NR" R12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;or R6and R7are taken together with the atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, oxo, -OH, or -O(2H);each R8, R9, and R10is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz-Ce alkynyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andAttorney Docket No.: 199C-436282-WOeach R11and R12is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz- (>, alkynyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo;or R11and R12are taken together with die atom to which diey are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, or Ci-Ce alkyl optionally substituted by one or more deuterium, oxo, or halogen;RBis a linker; andRcis a conjugatable group.

[0092] In some embodiments, the compound of formula (I) is a compound selected from compounds S1-S45 of Table 1.

[0093] In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt thereof, RAis a fragment of formula (RA-I). In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt thereof, RAis a fragment of formula (RA-II).

[0094] In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt thereof, Rcis a Cz-Cs alkynyl or an azide.

[0095] In some embodiments of a compound of formula (I), or a pharmaceutically acceptable salt thereof, RBis a linker of formula (RB-I):L J n(RB-I)wherein * denotes the point of attachment to RA, ** denotes the point of attachment to Rc, and n is an integer from 0 to 100; andRcis Cz-Ce alkynyl, an azide, or Ci-Ce alkyl substituted by an azide.

[0096] It will be understood that, for all sub formulae of RA, * denotes the point of attachment to RB.

[0097] Any variation or embodiment of formula (I) provided herein can be combined with every other variation or embodiment of formula (I) provided herein. For example, any variation or embodiment of RA, RB, or Rcprovided herein can be combined with every other variation or embodiment of RA, RB, or Rc. Further, any variation or embodiment within any subformula of RA, RB, or Rccan be combined with every other variation or embodiment within the same subformula. For example, any variation or embodiment within subformula (RA-T) can be combined with every other variation or embodiment within subformula (RA-I).II. Conjugates

[0098] In another aspect, provided is a compound of formula (II)RA-RB-RD-RE([I)wherein:Attorney Docket No.: 199C-436282-WORAis a small molecule fragment;RBis a linker;RDis a conjugated group; andREis a payload.

[0099] In one embodiment, the small molecule fragment of RAis an integrin-binding fragment.

[0100] In another aspect, provided is a compound of formula (II):RA-RB-RD-RE(II)wherein:RAis an integrin-binding fragment;RDis a linker;RDis a conjugated group; andREis a payload.

[0101] In some embodiments, the compound of formula (II) is a compound selected from compounds C1-C7 of Table 2.

[0102] In some embodiments, REis a reporting group or a label.

[0103] In some embodiments, REis a dye, such as a fluorescent dye.

[0104] In some embodiments of a compound of formula (II), or a pharmaceutically acceptable salt thereof, RBis a linker of formula (RB-I):L J n(RB-I)wherein * denotes the point of attachment to RA, ** denotes the point of attachment to RD, and n is an integer from 0 to 100.

[0105] Any variation or embodiment of formula (II) provided herein can be combined with every other variation or embodiment of formula (II) provided herein. For example, any variation or embodiment of RA, RB, RD, or REprovided herein can be combined with every other variation or embodiment of RA, RB, RD, or RE. Further, any variation or embodiment within any subformula of RA, RB, RD, or REcan be combined with every other variation or embodiment within the same subformula. For example, any variation or embodiment within subformula (RA-I) can be combined with every other variation or embodiment within subformula (RA-I).III. Fragments of Formula (RA-I)

[0106] In some embodiments, RAis a fragment of formula (RA-I):Attorney Docket No.: 199C-436282-WOQ (RA-I) wherein:* denotes the point of attachment to RB;R1is 5,6,7,8-tctrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, 6-aminopyridin-2-yl optionally substituted by one or more R4, or (pyridin-2-yl)amino optionally substituted by one or more R4;Q is H or Ci-Ce alkyl;R2is:(i) RB2, wherein:RB2is Ci-C6alkyl optionally substituted by one or more RB2a, Cs-Cs cycloalkyl optionally substituted by one or more RB2b, 3- to 12- membered saturated heterocyclyl optionally substituted by one or more RB2cwherein a carbon atom of the 3- to 12-membered saturated heterocyclyl is bonded to the -C(O), or Cz-Ce alkenyl optionally substituted by one or more B2d.wherein each RB2a, RB2b, RB2c, and RB2dis independently oxo, deuterium, halogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cs- Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -SR5, -NR6R7, -NO2, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-Ce alkyl, C2-Cs alkenyl, C2-Ce alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl of RB2a, RB2b, RB2c, and RB2dare independently optionally substituted by one or more R4a;(ii) RC2, wherein:RC2is Ce-Ci2 aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, C3-C10 cycloalkcnyl optionally substituted by one or more RC2c, 3- to 12- membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Ce alkyl substituted by one or more Rr2e, C2-C6 alkenyl substituted by one or more RC2f, Cs-Cs cycloalkyl substituted by one or moreAttorney Docket No.: 199C-436282-WORC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h; whereinat least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2fgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2fare independently optionally substituted by one or more R4a; and each of the other RC2fgroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4; andeach RC2a, RC2b, RC2c, and RC2dis, where possible, independently oxo or R4;(iii) RD2, whereinRD2is -NRD3(CI-C6alkyl), -NRD3(C3-C8cycloalkyl), -NRD3(3- to 12- membered saturated heterocyclyl) such that a carbon atom of the 3- to 12- membered saturated heterocyclyl of -NRD3(3- to 12-membered saturated heterocyclyl) is bonded to the N of -NRD3, 3- to 12-membered N-containing saturated heterocyclyl such that a nitrogen atom of the 3- to 12-membered N- containing saturated heterocyclyl is bonded to the carbon of -C(O)-, or 5- toAttorney Docket No.: 199C-436282-WO10-membered heteroaryl such that a nitrogen atom of the 5- to 10-membered heteroaryl is bonded to the carbon of -C(O)-,wherein the Ci-C6alkyl of the -NRD3(CI-C6alkyl) of RD2is optionally substituted by one or more RD2a, the Cs-Cg cycloalkyl of the - NRD3(C3-CS cycloalkyl) of RD2is optionally substituted by one or more RD2b, Ute 3- to 12-membered saturated heterocyclyl of the -NRD3(3- to 12- membered saturated heterocyclyl) of RD2is optionally substituted by one or more RD2c, the 3- to 12-membered N-containing saturated heterocyclyl of RD2is optionally substituted by one or more RD2d, and tire 5- to 10-membered heteroaryl is optionally substituted by one or more RD2e;RD3is H, deuterium, Ci-Cs alkyl, Cs-Cg cycloalkyl, or 3- to 12- membered saturated heterocyclyl,wherein the Ci-Ce alkyl of RD3is optionally substituted by one or more RD3a, the Cs-Cg cycloalkyl of RD3is optionally substituted by one or more RD3b, and the 3- to 12-membered saturated heterocyclyl of RD3is optionally substituted by one or more RD3c'; andeach RD2a, RD2b, RD2c, RD2d, RD2e, RD3a, RD3b, and RD3cis, where possible, independently oxo or R4; or(iv) RE2, whereinRE2is -O(Ci-Ce alkyl), -CXCj-Cg cycloalkyl), -0(3- to 12-membered saturated heterocyclyl) such that a carbon atom of the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) is bonded to the -0C(0)-, -0(5- to 10-membered aryl) such that a carbon atom of the 5- to 10-membered aryl of -0(Ce-Ci4 aryl) is bonded to the -0C(0)-, or -0(5- to 10-membered heteroaryl) such that a carbon atom of tire 5- to 10- membered heteroaryl of -0(5- to 10-membered heteroaryl) is bonded to the - 0C(0)-,wherein the Ci-Ce alkyl of -O(Ci-Ce alkyl) of RE2is optionally substituted by one or more RE2a, the Cs-Cg cycloalkyl -0(C3-Cg cycloalkyl) of RE2is optionally substituted by one or more RE2b, the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) of RE2is optionally substituted by one or more RE2c, the 5- to 10-membered heteroaryl of -0(Ce-Ci4 aryl) of RE2is optionally substituted by one or more RE2d, the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) of RE2eis optionally substituted by one or more RE2e; andAttorney Docket No.: 199C-436282-WOeach RE2a, RE2b, RE2c, RE2d, and RE2eis, where possible, independently oxo or R4;L1is C2-C4 alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Cg alkylene optionally substituted by one or more R4;L3is C2-C4 alkylene optionally substituted by one or more R4;Y is a bond or C3-C5 cycloalkylene optionally substituted by one or more oxo or R4; each R4is independently deuterium, halogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-Cs: cycloalkyl, 3- to 12-membered heterocyclyl, Cg-C aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -SR5, -NR6R7, -NO2, -N3, -C=NH(0R5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)RG, -NR5C(O)ORG, -NR5C(O)NRGR7, -S(O)R5, -S(O)2R5, -S(0)20H, -NR5S(O)RG, -NR5S(O)2RG, -S(O)NR6R7, -S(O)2NRGR7, or -P(O)(OR5)(OR6), wherein the Ci-C6alkyl, C2-Cg alkenyl, C2-C6 alkynyl, Cs-Cg cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently deuterium, halogen, oxo, -OR8, -NR8R9, -C(O)R8, -C(O)OR8, -NR8C(O)OR10, -CN, -S(O)R8, -S(O)2R8, -P(O)(OR8)(OR9), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-Cu aryl, or Ci-Cg alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-Cu aryl, and Ci-Cg alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently deuterium, oxo, -OH, -O-Ci-Ce alkyl, -0(2H), halogen, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -0(2H), or oxo;each R5is independently hydrogen, deuterium, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Cs-Cg cycloalkyl, Cg-C aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12, -P(O)(OR11)(OR12), C3-Cg cycloalkyl, 3- to 12-membered heterocyclyl, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -0(2H), or oxo;each R6is independently hydrogen, deuterium, Ci-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-C6 cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -0(2H), or oxo;each R7is independently hydrogen, deuterium, Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, whereinAttorney Docket No.: 199C-436282-WOthe Ci-Cs alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Cz-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NR" R12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;or R6and R7are taken together with the atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, oxo, -OH, or -O(2H);each R8, R9, and R10is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz-Ce alkynyl, wherein the Ci-Ce alkyl, Cz-Cs alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andeach R11and R12is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz- Ce alkynyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andor R11and R12are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, or Ci-Ce alkyl optionally substituted by one or more deuterium, oxo, or halogen.

[0107] In some variations of formula (RA-I),R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4or l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4;Q is H;RZ jsRBZwhereinRB2is Ci-Ce alkyl, Cz-Cs cycloalkyl, or 3- to 12-membered saturated heterocyclyl, such that a carbon atom of tire 3- to 12-membered saturated heterocyclyl is bonded to the -C(O),wherein tire Ci-Ce alkyl is optionally substituted by one or more RB2a, tire Cz-Cs cycloalkyl is optionally substituted by one or more RB2b, and the 3- to 12 -membered saturated heterocyclyl is optionally substituted by one or more RB2c;L1is Cz-C4n-alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Cz n-alkylene optionally substituted by one or more by R4;L3is C2-C4 n-alkylene optionally substituted by one or more by R4;Y is a bond or C3-C5 cycloalkylene optionally substituted by one or more oxo or R4; each RB2ais, where possible, independently halogen, Ci-Ce alkyl, Cz-Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -NR6R7, or -NR5C(O)OR6, wherein the Ci-Ce alkyl, Cz-Cs cycloalkyl and 3- to 12-membered saturated heterocyclyl of RD2aare independently optionally substituted by one or more R4a;each RB2bis, where possible, independently halogen or Ci-Ce alkyl, wherein the Ci-Ce alkyl of RBZI, jsin(iepen(ientiy optionally substituted by one or more R4a;Attorney Docket No.: 199C-436282-WOeach RB2cis, where possible, independently halogen, Ci-Cg alkyl, -C(O)R5, or -C(O)OR5, wherein die Ci-Cg alkyl of RB2cis independendy optionally substituted by one or more R4a;each R4is independently Ci-Cg alkyl, wherein die Ci-Cg alkyl of R4is independently optionally substituted by one or more R4a;each R4ais independently halogen, oxo, -OR8, -NR8R9, -CN, C3-Cs cycloalkyl, 5- to 10-membered heteroaryl, or Ci-Cg alkyl, wherein the Cj-Cs cycloalkyl, 5- to 10-membered heteroaryl and Ci-Cg alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently halogen;each R5is independently hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-C6 cycloalkyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, -OR10, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R° is independently hydrogen or Ci-Cg alkyl, wherein the Ci-Cg alkyl of R6is independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R7is hydrogen;each R8is independently hydrogen or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, or oxo;each R9is hydrogen;each R10is independently Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, or oxo;each R11is independently hydrogen, deuterium, Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, or oxo, Cz-Cg alkenyl optionally substituted by one or more deuterium, halogen, or oxo, or Cz-Cg alkynyl optionally substituted by one or more deuterium, halogen, or oxo; andeach R12is independently hydrogen, deuterium, Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, or oxo, Cz-Cg alkenyl optionally substituted by one or more deuterium, halogen, or oxo, or Cz-Cg alkynyl optionally substituted by one or more deuterium, halogen, or oxo;or R11and R12are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo or Ci-Cg alkyl optionally substituted by one or more deuterium, oxo, or halogen.

[0108] In some variations of formula (RA-I),R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4or l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl;Q is H;Attorney Docket No.; 199C-436282-WOR2is RB2wherein RB2is Ci-Ce alkyl, Ca-Cs cycloalkyl, or 3- to 12-membered saturated heterocyclyl, such that a carbon atom of the 3- to 12-membered saturated heterocyclyl is bonded to tire -C(O),wherein tire Ci-Ce alkyl is optionally substituted by one or more RB2a, tire Ca-Cg cycloalkyl is optionally substituted by one or more RB2b, and the 3- to 12-membered saturated heterocyclyl is optionally substituted by one or more RB2c;L1is C2-C4 n-alkylene;L2is a bond or C1-C3 n-alkylene;L3is C2-C4 n-alkylene;Y is a bond or C3-C5 cycloalkylene;each RB2ais, where possible, independently halogen, Ci-Cg alkyl, Ca-Cg cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -NR6R7, or -NR5C(O)OR6, wherein the Ci-Cs alkyl, Ca-Cg cycloalkyl and 3- to 12-membered saturated heterocyclyl of RB2aare independently optionally substituted by one or more R4a;each RB2bis, where possible, independently halogen or Ci-Cs alkyl, wherein the Ci-Cs alkyl of RB2bis independently optionally substituted by one or more R4a;each RB2cis, where possible, independently halogen, Ci-Ce alkyl, -C(O)R5, or -C(O)OR5, wherein the Ci-Ce alkyl of RB2cis independently optionally substituted by one or more R4a;each R4is independently Ci-Cs alkyl, wherein the Ci-Ce alkyl of R4is independently optionally substituted by one or more R4a;each R4ais independently halogen, oxo, -OR8, -NR8R9, -CN, Ca-C3cycloalkyl, 5- to 10-membered heteroaryl, or Ci-Ce alkyl, wherein the Ci-Ce alkyl of R4ais independently optionally substituted by one or more R4b;each R4bis independently halogen;each R5is independently hydrogen, Ci-Ce alkyl, Ca-Cs cycloalkyl, CB-CU aryl, or 5- to 10-membered heteroaryl, wherein the CI-CB alkyl, Ca-Cs cycloalkyl, Cs-Cu aryl, and 5- to 10-membered heteroaryl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, -OR10, or Ci-Cs alkyl;each R6is independently hydrogen or Ci-Cs alkyl;each R7is hydrogen;each R8is independently hydrogen or Ci-Cs alkyl;each R9is hydrogen; andeach R10is independently Ci-Cs alkyl.

[0109] In some variations of formula (RA-I),R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4or l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl;Q is H;Attorney Docket No.; 199C-436282-WOR2is RB2wherein RB2is Ci-Ce alkyl, Ca-Cs cycloalkyl, or 4- to 6-membered saturated heterocyclyl, such that a carbon atom of the 4- to 6-membered saturated heterocyclyl is bonded to the -C(O),wherein tire Ci-Ce alkyl is optionally substituted by one or more RB2a, tire Ca-Cs cycloalkyl is optionally substituted by one or more RB2b, and tire 4- to 6-membered saturated heterocyclyl is optionally substituted by one or more RB2c;L1is Cz n-alkylene;L2is a bond or Ci-Ca n-alkylene;L3is C2-C4 n-alkylene;Y is a bond or C3-C5 cycloalkylene;each RB2ais, where possible, independently halogen, C1-C5 alkyl, C3-C6 cycloalkyl, 4- to 6-membered saturated heterocyclyl, -CN, -OR5, -NR6R7, or -NR5C(O)OR6, wherein the C1-C5 alkyl, Ca-Cg cycloalkyl, and 4- to 6-membered saturated heterocyclyl of RB2aare independently optionally substituted by one or more R4a;each RB2bis, where possible, independently halogen or Ci alkyl, wherein the Ci alkyl of RB2bis independently optionally substituted by one or more R4a;each RB2cis, where possible, independently halogen, C1-C5 alkyl, -C(O)R5, or -C(O)OR5, wherein the C1-C5 alkyl of RB2cis independently optionally substituted by one or more R4a;each R4is independently Ci alkyl, wherein the Ci alkyl of R4is independently optionally substituted by one or more R4a;each R4ais independently halogen, oxo, -OR8, -NR8R9, -CN, Ca cycloalkyl, 6-membered heteroaryl, or C1-C3 alkyl, wherein the C1-C3 alkyl of R4ais independently optionally substituted by one or more R4b;each R4bis independently halogen;each R5is independently hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, Ce aryl, or 5- to 6-membered heteroaryl, wherein the Ci-Ce alkyl, C3-C5 cycloalkyl, Ce aryl, and 5- to 6-membered heteroaryl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, -OR10, or Ci alkyl;each R6is independently hydrogen or Ci alkyl;each R7is hydrogen;each R8is independently hydrogen or Ci alkyl;each R9is hydrogen; andeach R10is Ci alkyl.

[0110] In some variations of formula (RA-I),R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4; Q is H;Attorney Docket No.: 199C-436282-WOR2is RC2wherein RC2is Ce-C aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, such that a carbon atom of the 5- to 12-membered heteroaryl is bonded to tire -C(O), 3- to 12-membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Cg alkyl substituted by one or more RC2e, Cs-Cs cycloalkyl substituted by one or more RC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h;L1is C2-C4 n-alkylene optionally substituted by one or more oxo or R4;L2is a bond or C1-C3 n-alkylene optionally substituted by one or more R4;L3is C2-C4 n-alkylene optionally substituted by one or more R4;Y is a bond or C3-C5 cycloalkylene optionally substituted by one or more oxo or R4;at least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, C6-Ci4 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg-Ci4 aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cs-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is Cg-Cu aryl or 5- to 10-membered heteroaryl, wherein the Cg-Cu aryl and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4;each RC2a, RC2b, and RC2dis where possible, independently oxo or R4;each R4is independently halogen, Ci-Cg alkyl, 5- to 10-membered heteroaryl, -CN, -OR5, -S(O)2R5, or -S(O)2OH, wherein the Ci-Cg alkyl and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently halogen, oxo, -OR8, -CN, -S(O)2R8, or Ci-Cg alkyl, wherein the Ci-Cg alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently halogen;each Rsis independently hydrogen, Ci-Cg alkyl, Cs-Cg cycloalkyl, C -Ci4 aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, Cs-Cg cycloalkyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl of R5are each independently optionally substituted by one or more RSa;each R5ais independently halogen, -OR10, Cs-C cycloalkyl, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R8is independently hydrogen or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, or oxo; andeach R10is independently Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, or oxo.Attorney Docket No.; 199C-436282-WO

[0111] In some variations of formula (RA-I),R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4; Q is H;R2 jsj^c2wiierejnRC2 jsC6_Q12aj-yi optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, such that a carbon atom of the 5- to 12-membered heteroaryl is bonded to the -C(O), 3- to 12-membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Ce alkyl substituted by one or more RC2e, Ci-C: cycloalkyl substituted by one or more RC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h;L1is C2-C4 n-alkylene;L2is a bond or C1-C3 n-alkylene;L3is C2-C4 n-alkylene;Y is a bond or C3-C5 cycloalkylene;at least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cfi-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is Ce-C aryl or 5- to 10-membered heteroaryl, wherein the Ce-Cu aryl and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4;each RC2a, RC2b, and RC2dis, where possible, independently oxo or R4;each R4is independently halogen, Ci-Ce alkyl, 5- to 10-membered heteroaryl, -CN, -OR5, -S(O)2R5, or -S(O)2OII, wherein the Ci-Ce alkyl and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently halogen, oxo, -OR8, -CN, -S(O R8, or Ci-Ce alkyl, wherein the Ci-Cs alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently halogen;each R5is independently hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Cg alkyl, C3-C6 cycloalkyl, and 5- to 10-membered heteroaryl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, -OR10, C3-C6 cycloalkyl, or Ci-Ce alkyl;each R8is independently hydrogen or Ci-Ce alkyl optionally substituted by one or more halogen; andAttorney Docket No.; 199C-436282-WOeach R1C1is independently Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, or oxo.

[0112] In some variations of formula (RA-I),R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4; Q is H;R2is RC2wherein RC2is Cg-C, aryl optionally substituted by one or more RC2a, 5- to 9-membered heteroaryl optionally substituted by one or more RC2b, such that a carbon atom of the 5- to 12-membered heteroaryl is bonded to the -C(O), 3- to 10-membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, C1-C4 alkyl substituted by one or more RC2e, C3-C4 cycloalkyl substituted by one or more RC2g, or 4- to 6-membered fully saturated heterocyclyl substituted by one or more RC2h;L1is C2 n-alkylene;L2is a bond or C1-C3 n-alkylene;L3is C2-C4 n-alkylene;Y is a bond or C3 cycloalkylene;at least one RC2egroup, when present, is 6- to 10-membered partially unsaturated heterocyclyl, Cg aryl, or 5- to 6-membered heteroaryl, wherein the 6- to 10-membered partially unsaturated heterocyclyl, Cg aryl, and 5- to 6-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2ggroup, when present, is 6-membered partially unsaturated heterocyclyl, Cg aryl, or 5- to 10-membered heteroaryl, wherein the 6-membered partially unsaturated heterocyclyl, Cg aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is Cg aryl or 5-membered heteroaryl, wherein the Cg aryl and 5-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4;each RC2a, RC2b, and RC2dis, where possible, independently oxo or R4;each R4is independently halogen, Ci-Cg alkyl, 5- to 10-membered heteroaryl, -CN, -OR5, -S(O)2R5, or -S(O)2OH, wherein the Ci-Cg alkyl and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently halogen, oxo, -OR8, -CN, -S(O R8, or Ci alkyl, wherein the Ci alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently halogen;each R5is independently hydrogen, C1-C4 alkyl, C3-C5 cycloalkyl, Cg aryl, or 6-membered heteroaryl, wherein the C1-C4 alkyl, C3-C5 cycloalkyl, and 6-membered heteroaryl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, -OR10, C3 cycloalkyl, or Ci alkyl;Attorney Docket No.: 199C-436282-WOeach R8is independently hydrogen or Ci alkyl optionally substituted by one or more halogen; andeach Rlnis independently Ci alkyl optionally substituted by one or more deuterium, halogen, or oxo.

[0113] In some variations of formula (RA-I),R2is RD2wherein each RD2ais independently halogen, Ci-Ce alkoxy, Cs-Cs cycloalkyl, 3- to 12-membered saturated or partially unsaturated heterocyclyl, Ce-Cu membered aryl, or 5- to 10-membered heteroaryl,wherein the 3- to 12-membered saturated or partially unsaturated heterocyclyl of RD2ais optionally substituted by halogen or Ci-Ce haloalkyl,wherein the Ca-Cs cycloalkyl of RD2ais optionally substituted by halogen, andwherein the Ce-Cu membered aryl of RD2ais optionally substituted by halogen, CN, Ci-Ce haloalkyl or Ci-Cg haloalkoxy;each RD2bis -OH; andeach RD2cis halogen, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl, or -C(O)OR5,wherein the Ci-Ce alkyl of RD2cis optionally substituted by halogen, -OH, or Ci-Os alkoxy.

[0114] In some variations of formula (RA-I),R2is RE2wherein each RE2ais independently halogen, Ci-Ce alkoxy, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu membered aryl, or 5- to 12-membered heteroaryl,wherein the 3- to 12-membered heterocyclyl of RE2ais optionally substituted by Ci-Ce alkyl, wherein the Ca-Cs cycloalkyl of RE2ais optionally substituted by halogen, andwherein the Ce-Cu membered aryl of RE2ais optionally substituted by halogen, CN, Ci-Ce haloalkyl or Ci-Ce haloalkoxy;each RE2bis halogen, Ci-Ce alkyl; andeach RE2dis halogen.

[0115] In some variations of formula (RA-I), the carbon bearing the C(O)OQ and N(H)C(0)R2moieties is in the “S" configuration. In some variations of formula (RA-I), tire carbon bearing tire C(O)OQ and N(H)C(0)R2moieties is in the “R” configuration. Mixtures of a compound of the formula (I) are also embraced, including racemic or non -racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulae.

[0116] In the descriptions herein, it is understood that every description, variation, embodiment or aspect of a moiety may be combined with every description, variation, embodiment or aspect of other moieties the same as if each and every combination of descriptions is specifically and individually listed. For example, every description, variation, embodiment or aspect provided herein with respect to R2of formula (RA-I) may be combined with every description, variation, embodiment or aspect of L1, Q, L2, Y, L3and / or R1the same as if each and every combination were specifically and individually listed. It is also understood that all descriptions, variations, embodiments or aspects ofAttorney Docket No.: 199C-436282-WOformula (RA-I), where applicable, apply equally to other formulae detailed herein, and are equally described, the same as if each and every description, variation, embodiment or aspect were separately and individually listed for all formulae.

[0117] In some variations of formula (RA-I), at least one of RB2a, RB2b, RB2c, RB2d, RC2a, RC2b, RC2c,deuterium.

[0118] In some variations of formula (RA-I), L1is unsubstituted C2-C4 n-alkylene. In a particular variation, L1is -CH2-CH2-, -CH2-CH2-CH2-, or -CH2-CH2-CH2-CH2-. In another variation, L1is -CH2-CH2-.

[0119] In some variations of formula (RA-I), L1is C2-C4 n-alkylene substituted by 1-3 R4groups. In one variation, each R4on L1is independently selected from halogen, deuterium, and Ci-Ce alkyl.

[0120] In some variations of formula (RA-1), L1is C2-C4 n-alkylene substituted by oxo. In one variation, L1is C3 n-alkylene substituted by oxo. In one variation, L1is -C(=O)-CH2-CH2-. In one variation, L1is -CH2-C(=O)-CH2-. In one variation, L1is -CH2-CH2-C(=O)-. In one variation, L1is C2 n-alkylene substituted by oxo. In one variation, L1is -C(=O)-CH2-. In one variation, L1is -CH2-C(=O)-.

[0121] In some variations of formula (RA-I), L2is a bond.

[0122] In some variations of formula (RA-I), L2is -CH2-.

[0123] In some variations of formula (RA-I), L2is C1-C3 n-alkylene substituted by 1-3 R4groups. In one variation, each R4group on L2is independently selected from the group consisting of halogen, deuterium, and Ci-Cg alkyl.

[0124] In some variations of formula (RA-I), L3is unsubstituted C2-C4 n-alkylene. In one variation, I is -(CH2)4-. In another variation, L3is -(CH2)2-.

[0125] In some variations of formula (RA-I), L3is C2-C4 n-alkylene substituted by 1-3 R4groups. In one variation, each R4group on L3is independently selected from the group consisting of halogen, deuterium, and Ci-Cg alkyl. In one variation, L3is -CH2-CF2-CH2-CH2-. In another variation, L3is -CII2-CIIF-CII2-CII2-. In another variation, L3is -CII2-CIIF-CII2-CIIF-. In another variation, L3is -CH2-CH2-CHF-CHF-.

[0126] In some variations of formula (RA-I), Y is a bond.

[0127] In some variations of formula (RA-I), Y is unsubstituted C3-C5 cycloalkylene. In one variation, Y is unsubstituted cyclopropylene. In another variation, Y is unsubstituted cyclobutylene.

[0128] In some variations of formula (RA-I), Y is C3-C5 cycloalkylene substituted by 1-3 R4groups. In one variation, each R4is independently selected from the group consisting of halogen, deuterium, and Ci-Ce alkyl.

[0129] In some variations of formula (RA-I), Y is a C3-C4 cycloalkylene. In one aspect, Y is a cyclopropylene. In another aspect, Y is a cyclobutylene. In one variation, the point of attachment of the C3-C4 cycloalkylene to L2and L3are via the same carbon atom. In another variation, the point ofAttorney Docket No.: 199C-436282-WOattachment of the C3-C4 cycloalkylene to L2and I are via two different carbon atoms. In another variation, when the point of attachment of the C3-C4 cycloalkylene to L2and L3are via two different carbon atoms, die stereochemistry introduced at the C3-C4 cycloalkylene is trans. In another variation, when die point of attachment of the C3-C4 cycloalkylene to L2and L3are via two different carbon atoms, the stereochemistry introduced at die C3-C4 cycloalkylene is cis.

[0130] In some variations of formula (RA-I), -U-Y-L3- are taken together to form a moiety selected from the group consisting of: -CH2CH2CH2-, -CH2CH2CH2CH2-,-CH2CH2CH2CH2CH2-, -CH2(CH2)2CH2-, -CH2(CH2)3CH2-, and.wjlerejn||le wavy ]jnesdenote attachment points to the parent molecule.

[0131] In some variations of formula (RA-I), -L1-(N-*)-L2-Y-L3- are taken together to form a moiety selected from the group consisting of:★C2-C4n-alkylene—N-C2-C7 n-alkylene-^wherein the C2-C4 n-alkylene is optionally substituted by one or more oxo or R4, and the C2-C7 n-alkylene is optionally substituted by one or more R4,I— C2-C4n-alkylene— N-CO-C3n-alkylene— A I — C2-C4n-alkylene— |(ii).wherein the C2-C4 n-alkylene to the left of the -N(-*)- moiety is optionally substituted by oneA'' or more R4, the C0-C3 n-alkylene is optionally substituted by one or more R4, the ' - -zmoiety is a C3-C5 cycloalkylene optionally substituted by one or more R4, and the C2-C4 n-alkylene to the right oftire ( 'A- - )zmoiety is optionally substituted by one or more R4; and1 A;C2-C4n-alkylene — N-C0-C3n-alkylene^^C2-C4n-iwherein the C2-C4 n-alkylene to die left of the -N(-*)- moiety is optionally substituted by one or more R4, the C0-C3 n-alkylene is optionally substituted by one or more R4, the N / moiety is a C3-C5 cycloalkylene optionally substituted by one or more R4, and the C2-C4 n-alkylene to the right of (Adie N / moiety is optionally substituted by one or more R4.Attorney Docket No.: 199C-436282-WO

[0132] In some variations of formula (RA-I), -L1-(N-*)-L2-Y-L3- are taken together to form amoiety selected from the group consisting of:are taken together to form a moiety selected from the group consisting of:variation, -L1-(N-*)-L2-Y-L3- are taken together to form a moiety selected from the group consisting

[0133] In some variations of formula (RA-I), -L1-(N-*)-L2-Y-L3- are taken together to form aNNmoiety with the formula of:0, orOAttorney Docket No.: 199C-436282-WO

[0134] In some variations of formula (RA-I), -L1-(N-*)-L2-Y-L3- are taken together to form amoiety with the formula of:

[0135] In some variations of formula (RA-I), -L1-(N-*)-L2-Y-L3- are taken together to form aNmoiety with the formula of:

[0136] In some variations of formula (RA-I), -L1-(N-*)-L2-Y-L3- are taken together to form aNmoiety with the formula of:

[0137] In some variations of formula (RA-I), Q is H. In some embodiments, Q is Ci-Cg alkyl. In some embodiments, Q is C1-C2 alkyl. In some embodiments, Q is methyl. In some embodiments, Q is ethyl.

[0138] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-1)HN / hk, NI J(RA-I-1) wherein R2is as defined for formula (RA-I).

[0139] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-2)H(RA-I-2) wherein R2is as defined for formula (RA-I).

[0140] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-2a)H(RA-I-2a) wherein R2is as defined for formula (RA-I).

[0141] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-2b)Attorney Docket No.: 199C-436282-WOwherein R2is as defined for formula (RA-I).

[0142] In some variations, tire fragment of formula (RA-I) is a fragment of the formula (RA-I-3):wherein R2is as defined for formula (RA-I).

[0143] In some variations, tire fragment of formula (RA-I) is a fragment of the formula (RA-I-4):wherein R2is as defined for formula (RA-I).

[0144] In some variations, the fragment of formula (RA-I) is a fragment of tire formula (RA-I-5):wherein R2is as defined for formula (RA-I).

[0145] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-6):wherein R2is as defined for formula (RA-I).

[0146] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-7):wherein R2is asdefined for formula (RA-I).

[0147] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-8):Attorney Docket No.: 199C-436282-WOwherein R2is as defined for formula (RA-I).

[0148] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-9):wherein R2is as defined for formula (RA-I).

[0149] In some variations, die fragment of formula (RA-I) is a fragment of the formula (RA-I-9a):wherein R2is as defined for formula (RA-I).

[0150] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-9b):(RA-I-9b) wherein R2is as defined for formula (RA-I).

[0151] In some variations, die fragment of formula (RA-I) is a fragment of the formula (RA-I-9c):wherein R2is as defined for formula (RA-I).

[0152] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I- 10):(RA-I-10)Attorney Docket No.: 199C-436282-WOwherein R2is as defined for formula (RA-I).

[0153] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-10a):wherein R2is as defined for formula (RA-I).

[0154] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-10b):wherein R2is as defined for formula (RA-I).

[0155] In some variations, the fragment of formula (RA-I) is a fragment of the formula (RA-I-10c):wherein R2is as defined for formula (RA-I).

[0156] In some variations, tlie fragment of formula (RA-I) is a fragment of the formula (RA-I- lOd):wherein R2is as defined for formula (RA-I).

[0157] In some variations, tlie fragment of formula (RA-I) is a fragment of the formula (RA-I- 11):wherein R2is as defined for formula (RA-I).

[0158] When R, S, or a mixture of R and S is indicated for the alpha-carbon of the amino acid, the structures are intended to encompass the following variations, which are illustrated forAttorney Docket No.: 199C-436282-WOand; or a pharmaceutically acceptable salt thereof, wherein R2is as defined for formula (RA-I), or any applicable variation thereof, wherein * denotes the point of attachment to RB, and the alpha-carbon of the amino acid or ester can have either R or S absolute stereochemistry as indicated. In one such embodiment, tire alpha-carbon of the amino acid or ester is in tire S absolute stereochemistry. When the alpha-carbon of the amino acid or ester is in the S absolute stereochemical configuration, in some embodiments such a compound is substantially isolated from the corresponding compound in which the amino acid or ester is in the R absolute stereochemical configmation, such as when a composition comprising the compound in the S absolute stereochemical configmation comprises no more than about 5% or about 3% or about 1% or about 0.5% or about 0.1% by weight of the corresponding compound having the R absolute stereochemical configmation. In another such embodiment, the alpha-carbon of the amino acid or ester is in the R absolute stereochemistry. When the alpha-carbon of the amino acid or ester is in the R absolute stereochemical configmation, in some embodiments such a compound is substantially isolated from the corresponding compound in which the amino acid or ester is in the 5 absolute stereochemical configmation, such as when a composition comprising the compound in the R absolute stereochemical configuration comprises no more than about 5% or about 3% or about 1% or about 0.5% or about 0.1% by weight of the corresponding compound having the S absolute stereochemical configuration.

[0159] In some embodiments of formula (RA-I), R1is selected from the group consisting of:Attorney Docket No.: 199C-436282-WO

[0160] In some embodiments of formula (RA-I), R2is RB2wherein RB2is Ci-Ce alkyl optionally substituted by 1-5 RB2agroups. In one aspect of the foregoing embodiment, RB2is unsubstituted Ci-Ce alkyl. In one aspect of the foregoing embodiment, the Ci-Ce alkyl of RB2is straight-chain alkyl. In another aspect of the foregoing embodiment, the Ci-Ce alkyl of RB2is branched alkyl. In anotheraspect of the foregoing embodiment, RB2is. In another aspect of die foregoing embodiment,the RB2isin another aspect of die foregoing embodiment, RB2is Ci-Ce alkyl substituted by 1-5 RB2agroups, wherein each RB2ais independently selected from of halogen, Ci-Ce alkyl, C3-Cg cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -NR6R7, -NR5C(O)OR6, and -S(ObR5. wherein the Ci-Ce alkyl, Cs-Cs cycloalkyl, and 3- to 12-membered saturated heterocyclyl of RB2aare independently optionally substituted by one or more R4a. In some embodiments, RB2is Ci-Ce alkyl substituted by 1-5 RB2agroups, wherein each RB2ais independently selected from the group consisting of halogen, Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -NR6R7, and -NR5C(O)OR6, wherein the Ci-Ce alkyl, C3-Cs cycloalkyl, and 3- to 12-membered saturated heterocyclyl of RB2aare independently optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, RB2is Ci-Ce alkyl substituted by 1-5 RB2agroups, wherein at least one of the RB2agroups is halogen or Ci-Ce alkyl optionally substituted with 1-3 -OH. In another aspect of tire foregoing embodiment, RB2isCi-Ce alkyl substituted by 1-5 RB2agroups, wherein at least one of the RB2agroups is Cs-C? cycloalkyl. In another aspect of the foregoing embodiment, RB2is C1-C3 alkyl substituted by Cs-Cs cycloalkyl, wherein die Cs-Ce cycloalkyl is optionally substituted by 1-5 groups selected from die group consisting of halogen and Ci-Cs alkyl optionally substituted with 1-3 halogen. In another aspect of the foregoing embodiment, RB2is C1-C3 alkyl substituted by 1-5 Cs-Ce cycloalkyl, wherein the C3-(>, cycloalkyl is unsubstituted. In another aspect of the foregoing embodiment, RB2is C1-C3 alkyl substituted by 1-5 C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is substituted by 1-5 C1-C3 alkyl groups. In another aspect of the foregoing embodiment, RB2is C1-C3 alkyl subsdtuted by 1-5 C3-Cs cycloalkyl, wherein the C3-C6 cycloalkyl is substituted with 1-5 C1-C3 alkyl optionally substituted with 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C3 alkyl substituted by C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is substituted widt 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C5 alkyl substituted by 1-5 RB2agroups, wherein at least one of the RB2agroups is 3- to 12-membered saturated heterocyclyl. In some embodiments, RB2isC1-C3 alkyl substituted by 1-54- to 6-membered saturated heterocyclyl. In another aspect of the foregoing embodiment, RB2is C1-C3 alkyl substituted by 1-54- to 6-membered saturated heterocyclyl, wherein the 4- to 6-membered saturated heterocyclyl is unsubstituted. In another aspect, RB2is C1-C3 alkyl substituted by 1-54- to 6-membered saturated heterocyclyl, wherein the 4- to 6-Attorney Docket No.: 199C-436282-WOmembered saturated heterocyclyl is substituted with one or more groups selected from die group consisting of C1-C& alkyl, halogen and oxo. In another aspect, RB2is C1-C3 alkyl substituted by 1-54-to 6-membered saturated heterocyclyl, wherein the 4- to 6-membered saturated heterocyclyl is substituted with one or more groups selected from die group consisting of Ci-Ce alkyl and oxo. In anodier aspect of die foregoing embodiment, RB2is C1-C5 alkyl substituted by 1-5 RB2agroups, wherein at least one of the RB2agroups is -OR5, wherein each R5is independendy selected from hydrogen, Ci-Ce alkyl, C3-C6 cycloalkyl, and Ce-Cu aryl. In anodier aspect of the foregoing embodiment, RB2is C1-C5 alkyl substituted by 1-5 RB2agroups, wherein at least one of the RB2agroups is -OR5, wherein each R5is independently selected from hydrogen, Ci-Ce alkyl and Ce-Cu aryl. In some embodiments, RB2is C1-C5 alkyl substituted by 1-5 RB2agroups, wherein at least one of die RB2agroups is -OR5, wherein each R5is independendy selected from hydrogen, Ci-Ce alkyl, and Ce-Cu aryl, wherein the Ci-Ce alkyl is optionally substituted with 1-5 halogen, and wherein die Ce-Cu aryl is optionally substituted with 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C5 alkyl substituted by -OR5, wherein R5is hydrogen or C1-C4 alkyl. In another aspect of the foregoing embodiment, RB2is C1-C4 alkyl substituted by -OR5, wherein R5is C1-C3 alkyl optionally substituted with 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C4 alkyl substituted 1 -5 by -OR5, wherein R5is unsubstituted C1-C3 alkyl. In another aspect of the foregoing embodiment, RB2is C1-C4 alkyl substituted by -OR5, wherein R5is unsubstituted C1-C3 alkyl. In another aspect of the foregoing embodiment, RB2is C1-C3 alkyl substituted by -OR5, wherein R5is Ce-C14 aryl optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C4 alkyl substituted by 1-5 -OR5, wherein R5is phenyl optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C5 alkyl substituted by 1-5 RB2agroups, wherein at least one of the RB2agroups is -ON, -NR6R7, -NR5C(O)OR6, or -S(O)2R5. In another aspect of the foregoing embodiment, RB2is C1-C5 alkyl substituted by 2-5 RB2agroups, wherein each RB2ais independendy selected from halogen, Ci-Cg alkyl, Cs-Cs cycloalkyl, 3- to 6-membered saturated heterocyclyl, -ON, -OR5, -NR6R7, and -NR5C(O)OR6. In another aspect of the foregoing embodiments, RB2is C1-C4 alkyl substituted by 2-5 RB2agroups, wherein at least one RB2agroup is selected from the group consisting of halogen and Ci-Ce alkyl, and at least one RB2agroup is -OR5, wherein each R5is independently selected from die group consisting of hydrogen and Ci-Ce alkyl optionally substituted with 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C5 alkyl substituted by 2-5 RB2agroups, wherein at least one RB2agroup is halogen and at least one RB2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl optionally substituted with 1-5 halogen. In another aspect of the foregoing embodiment, RB2is C1-C5 alkyl substituted by 2-5 RB2agroups, wherein at least one RB2agroup is C3-C6 cycloalkyl and at least one RB2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl optionally substituted witit 1-5 halogen. In some embodiments, RB2is C1-C4 alkyl substituted by 2-5 RB2agroups, wherein at least one RB2agroup is C3-C6 cycloalkyl, and at least one RB2agroup is -Attorney Docket No.: 199C-436282-WOOR5, wherein each R5is independently selected from the group consisting of hydrogen and Ci-Ce alkyl optionally substituted with 1-5 halogen. In another aspect of the foregoing embodiments, RB2isunsubstituted Ci-Ce alkyl. In another aspect of tire foregoing embodiments, RB2is.

[0161] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the group, and wherein each RB2ais independently as defined for formula (RA-I).pB2a

[0162] In some embodiments of formula (RA-I), R2is RB2wherein RB2is, wherein each RB2ais C2-C5 alkyl or Ca-Ce cycloalkyl, wherein the C2-C5 alkyl is optionally substituted by 1-5 halogen, and wherein the Cs-Cg cycloalkyl of RB2ais optionally substituted by C1-C3 alkyl or halogen.

[0163] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the groupAttorney Docket No.: 199C-436282-WO

[0164] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the group consisting of:

[0165] In some embodiments of formula (RA-I), R2is RB2wherein RB2is Ca-Cs cycloalky] optionally substituted by 1-5 RB2bgroups. In another aspect of the foregoing embodiment, the Ca-Cs cycloalkyl of RB2is monocyclic. In another aspect, the Ca-Cs cycloalkyl of RB2is bicyclic. In another aspect, RB2is unsubstituted Ca-Cs cycloalkyl. In another aspect of the foregoing embodiment, RB2is Ca-Cs cycloalkyl substituted by 1-5 RB2bgroups, wherein each RB2bis independently selected from halogen, Ci-Ce alkyl, 3- to 12-membered saturated heterocyclyl, and -OR5, wherein the Ci-Cg alkyl, and 3- to 12-membered saturated heterocyclyl of RB2bare optionally substituted by 1-5 R4agroups. In another aspect of the foregoing embodiment, RB2is Ca-Cs cycloalkyl substituted by 1-5 RB2bgroups, wherein each RB2bis independently selected from the group consisting of halogen and Ci-Ce alkyl, wherein the Ci-C alkyl of RB2bare optionally substituted by 1-5 R4agroups. In another aspect of the foregoing embodiment, RB2is Ca-C cycloalkyl substituted by 1-5 RB2bgroups, wherein at least one of tire RB2bgroups is halogen. In another aspect of the foregoing embodiment, RB2is Ca-CgAttorney Docket No.: 199C-436282-WOcycloalkyl substituted by 1-5 RB2bgroups, wherein at least one of the RB2bgroups is C1-C3 alkyl, wherein die C1-C3 alkyl of RB2bis optionally substituted by 1-5 R4agroups. In another aspect of the foregoing embodiment, RB2is C3-C6 cycloalkyl substituted by 1-5 RB2bgroups, wherein at least one of tire RB2bgroups is C1-C3 alkyl optionally substituted by 1-5 halogen or 5- to 6-membered heteroaryl. In another aspect of tire foregoing embodiment, RB2is C3-C6 cycloalkyl substituted by 1-5 RB2bgroups, wherein at least one of the RB2bgroups is unsubstituted C1-C3 alkyl. In another aspect of the foregoing embodiment, RB2is C3-C6 cycloalkyl substituted by 1-5 RB2bgroups, wherein at least one of the RB2bgroups is 3- to 12-membered saturated heterocyclyl. In another aspect of the foregoing embodiment, RB2is C3-C6 cycloalkyl substituted by 2-5 RB2bgroups, wherein each RB2bis independently selected from halogen, Ci-Ce alkyl, and -OR5. In another aspect of the foregoing embodiment, RB2is Cs-Ce cycloalkyl substituted by 2-5 RB2bgroups, wherein at least one RB2bgroup is halogen and at least one RB2bgroup is Ci-Ce alkyl. In another aspect of the foregoing embodiment, RB2is C3-C6 cycloalkyl substituted by 2-5 RB2bgroups, wherein at least one RB2bgroup is -OH and at least one RB2bgroup is Ci-Cg alkyl. In another aspect, RB2unsubstituted C3-C8 cycloalkyl.

[0166] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the group(RB2b)n^y(RB2b)n, and;wherein RB2bis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.

[0167] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the group consisting of:

[0168] In some embodiments of formula (RA-I), R2is RB2wherein RB2is 3- to 12-membered saturated heterocyclyl optionally substituted by 1-5 RB2cgroups, such that the atom of the 3- to 12-membered heterocyclyl that is bonded to the -C(O) is a carbon. In another aspect of the foregoingAttorney Docket No.: 199C-436282-WOembodiment, the 3- to 12-membered saturated heterocyclyl of RB2is monocyclic. In another aspect of the foregoing embodiment, the 3- to 12-membered saturated heterocyclyl of RB2is bicyclic. In another aspect of the foregoing embodiment, RB2is unsubslituted 3- to 12-membered saturated heterocyclyl. In another aspect of the foregoing embodiment, RB2is unsubstituted 4- to 10-membered saturated heterocyclyl. In another aspect of (lie foregoing embodiment, RB2is unsubslituted 4- to 6-membered saturated heterocyclyl. In another aspect of the foregoing embodiment, RB2is 3- to 12-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein each RB2cis independently selected from oxo, halogen, Ci-Ce alkyl, -CN, -OR5, -C(0)R5, -C(0)0R5, and -S(O)2R5. In another aspect of the foregoing embodiment, RD2is 3- to 12-membered saturated heterocyclyl substituted by 1-5 RD2cgroups, wherein each RB2cis independently selected from halogen, Ci-Ce alkyl, -C(0)R5, and -C(0)0R5, wherein the Ci-Ce alkyl is optionally substituted by 1-5 R4agroups. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one of the RB2cgroups is halogen. In another aspect of the foregoing embodiment, RB2cis C1-C2 alkyl substituted by 1-5 R4agroups, wherein each R4agroups is independently selected from halogen, phenyl, 6-membered heteroaryl, and -NR8C(O)OR10, wherein the phenyl and 6-membered heteroaryl of R4aare each independently optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one of the RB2cgroups is Ci-Ce alkyl optionally substituted by 1-5 R4agroups, wherein each R4ais selected from the group consisting of halogen and 5- to 6-membered heteroaryl groups. In another aspect of the foregoing embodiment, RB2cis C1-C2 alkyl substituted by 1-5 R4agroups, wherein each R4ais 6-membered heteroaryl optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one of the RB2cgroups is Ci-Cg alkyl, wherein the Ci-Cg alkyl of RB2cis optionally substituted by 1-5 R4agroups. In some embodiments, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one of the RB2cgroups is Ci-Ce alkyl, wherein the Ci-Cs alkyl of RB2cis substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one of the RB2cgroups is unsubstituted Ci-Cg alkyl. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one RB2cgroup is -OR5, -C(0)R5, or -C(0)0R5, wherein each R5is independently hydrogen or Ci-Ce alkyl. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one RB2cgroup is -C(O)RS, or -C(0)0R5, wherein each R5is Ci-Ce alkyl. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 1-5 RB2cgroups, wherein at least one RB2cgroup is oxo. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 2-5 RB2cgroups, wherein each RB2cis independently selected from halogen, Ci-Cg alkyl, -C(0)R5, and -C(0)0R5, wherein each R5isAttorney Docket No.: 199C-436282-WOindependently Ci-Ce alkyl. In some embodiments, RB2is 4- to 6-membered saturated heterocyclyl substituted by 2-5 RB2cgroups, wherein each RB2cis independently selected from halogen and -C(O)OR5, wherein each Rsis independently Ci-Ce alkyl. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered heterocyclyl substituted by 2-5 RB2cgroups, wherein at least one RB2cgroup is Ci-Ce alkyl optionally substituted by 1-5 halogen and at least one RB2cgroup is -C(O)R5or -C(O)OR5. In another aspect of the foregoing embodiment, RB2is 4- to 6-membered saturated heterocyclyl substituted by 2-5 RB2cgroups, wherein each RB2cis independently selected from halogen and -C(O)OR5, wherein each R5is independently Ci-Ce alkyl. In another aspect of the foregoing embodiment, RB2is azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxabicyclohexanyl, oxabicyclooctanyl, tetrahydro-2H-thiopyranyl, or morpholinyl, each of which is independently optionally substituted by 1-5 RB2cgroups. In another aspect of the foregoing embodiment, RB2is pyrrolidinyl, piperidinyl, oxetanyl, tetrahydropyranyl, or morpholinyl, each of which is independently and optionally substituted by 1-5 RB2cgroups. In another aspect of the foregoing embodiment, RB2is pyrrolidinyl, piperidinyl, oxetanyl, or tetrahydropyranyl, each of which is independently and optionally substituted by 1 -5 RB2cgroups.

[0169] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the groupwherein RB2cis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3. In the above structures that depict an -N(H)- moiety and n is 1, 2, or 3, it is understood that one of the RB2cgroups can replace the hydrogen atom of the -N(H)- moiety.Attorney Docket No.: 199C-436282-WO

[0170] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the groupconsisting of:,

[0171] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the groupAttorney Docket No.: 199C-436282-WO

[0172] In some embodiments of formula (RA-I), R2is RB2wherein RB2is selected from the groupAttorney Docket No.: 199C-436282-WO

[0173] In some embodiments of formula (RA-I), R2is RC2wherein RC2is Ci-Cg alkyl substituted by 1-5 RC2egroups. In one aspect of the foregoing embodiment, the Ci-Ce alkyl of RC2is straight-chain alkyl substituted by 1-5 RC2egroups. In another aspect of the foregoing embodiment, the Ci-Cs alkyl of RC2is branched alkyl substituted by 1-5 RC2egroups. In another aspect of the foregoing embodiment, RC2is C1-C5 alkyl substituted by 1 -5 RC2egroups, wherein at least one RC2egroup is 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, and each of the other RC2egroups, when present, is independently selected from halogen, Ci-Ce alkyl, C3-Attorney Docket No.: 199C-436282-WOCs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Ci4 aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -NR6R7, -NR5C(O)OR6, and -S(O)zR5, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RC2aare independently optionally substituted by one or more R4a. In some embodiments, RC2is C1-C5 alkyl substituted by 1-5 RC2egroups, wherein al least one RC2egroup is 3-to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, and each of the other RC2egroups, when present, is independently selected from the group consisting of halogen, Ci-Ce alkyl, -CN, and -OR5, and wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and Ci-Ce alkyl of RC2eare independently optionally substituted by one or more R4a. In another aspect of the foregoing embodiment, RC2is C1-C5 alkyl substituted by 1-5 RC2egroups, wherein at least one of the RC2egroups is Ce-Cu aryl, wherein the Ce-Ci4 aryl is independently optionally substituted by 1-5 R4agroups. In another aspect of the foregoing embodiment, RC2is C1-C4 alkyl substituted by 1-5 RC2egroups, and wherein at least one RC2egroup is unsubstituted phenyl. In another aspect of the foregoing embodiment, RC2is C1-C4 alkyl substituted by phenyl, wherein the phenyl is unsubstituted. In some embodiments, RC2is C1-C4 alkyl substituted by 1-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 1-5 R4agroups, and wherein at least one R4agroup is selected from the group consisting of halogen, -CN, -OR8, and Ci-Ce alkyl optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RC2is C1-C4 alkyl substituted by 1-5 RC2e, wherein at least one RC2egroup is phenyl substituted by 1-5 R4agroups, wherein at least one R4agroup is selected from halogen and Ci-Ce alkyl substituted by 0-5 halogen. In some embodiments, RC2is C1-C4 alkyl substituted by 1-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 2-5 R4agroups, wherein at least one R4agroup is halogen or -CN, and wherein at least one R4agroup is -OR8or Ci-Ce alkyl optionally substituted by 1-5 halogen. In some embodiments, RC2is C1-C4 alkyl substituted by 2-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 1-5 R4agroups, and wherein at least one RC2eis selected from the group consisting of halogen, -CN, and -OR5. In another aspect of the foregoing embodiment, RC2is C1-C4 alkyl substituted by 1-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 2-5 R4agroups, wherein at least two R4agroups are halogen. In another aspect of the foregoing embodiment, RC2is C1-C4 alkyl substituted by 1-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 2-5 R4agroups, wherein at least one R4agroup is halogen and at least one R4agroup is Ci-Ce alkyl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RC2is C1-C4 alkyl substituted by 2-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 1-5 R4agroups, and wherein at least one RC2eis selected from the group consisting of halogen, -CN, and -OR5.

[0174] In another aspect, RC2is C1-C5 alkyl substituted by 1-5 RC2egroups, wherein at least one of the RC2egroups is 5- to 10-membered heteroaryl, and wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-5 R4agroups. In some embodiments, RC2is C1-C5 alkyl substituted by 1-5Attorney Docket No.: 199C-436282-WORC2egroups, wherein at least one RC2egroup is 5- to 10-membered heteroaryl, and wherein the 5- to 10-membered heteroaryl is optionally substituted by 1-5 R4agroups. In some embodiments, RC2is C1-C5 alkyl substituted by 1-5 RC2egroups, wherein at least one RC2egroup is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is substituted by 1-5 R4agroups, and wherein at least one R4agroup is selected from the group consisting of halogen, -CN, -OR8, and Ci-Ce alkyl optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RC2is C1-C5 alkyl substituted by 1-5 RC2egroups, wherein at least one RC2egroup is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is substituted by 1-5 R4agroups, and wherein at least one R4agroup is selected from the group consisting of halogen, -CN, -OH, and Ci-Ce alkyl substituted by 0-5 halogen. In some embodiments, RC2eis pyridyl optionally substituted by 1-5 R4agroups, and wherein at least one R4agroup, when present, is selected from the group consisting of halogen, -CN, -OR8, and Ci-Cg alkyl optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RC2is pyridyl substituted by 0-5 R4agroups, and wherein at least one R4agroup, when present, is selected from the group consisting of halogen, -CN, -OH, and Ci-Cg alkyl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RC2is unsubstituted pyridyl. In another aspect of the foregoing embodiment, RC2is C1-C5 alkyl substituted by 2-5 RC2egroups, wherein at least one RC2egroup is 5- to 10-membered heteroaryl, and wherein at least one RC2eis selected from the group consisting of halogen, -CN, and -OR5.

[0175] In another aspect, RC2is C1-C5 alkyl substituted by 1-5 RC2egroups, wherein at least one RC2egroup is 5- to 10-membered partially unsaturated heterocyclyl, wherein the 5- to 10-membered partially unsaturated heterocyclyl is optionally substituted by 1-5 R4agroups, and wherein at least one R4agroup is oxo.

[0176] In another aspect, RC2is C1-C5 alkyl substituted by 2-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 0-5 halogen and at least one RC2egroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl. In another aspect of the foregoing embodiment, RC2is C1-C5 alkyl substituted by 2-5 RC2egroups, wherein at least one RC2egroup is phenyl substituted by 0-5 halogen and at least one RC2egroup is halogen.

[0177] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the groupformula (RA-I).Attorney Docket No.: 199C-436282-WO nC2e

[0178] In some embodiments of formula (RA-I), R2is RC2wherein RC2is, wherein each RC2eis Ce-Cu aryl or 5- to 10-membered heteroaryl, wherein the Ce-Cu aryl and 5- to 10-membered heteroaryl of RC2eis optionally substituted by C1-C3 alkyl, halogen, or -OR5.

[0179] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the groupconsisting of:, wherein n is 1, 2, or 3, m is 0, 1, or 2, and RC2eand R4are each independently defined as formula (RA-I).

[0180] In some embodiments of formula (RA-I), R2is RC2wherein RC2is Cs-Cs cycloalkyl substituted by 1-5 RC2ggroups. In another aspect of the foregoing embodiment, the C3-C8 cycloalkyl of RC2is monocyclic. In another aspect, the Cs-Cs cycloalkyl of RC2is bicyclic. In another aspect, In another aspect of the foregoing embodiment, RC2is C3-C8 cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is selected from the group consisting of Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 10 membered partially unsaturated heterocyclyl, wherein each of the other RC2ggroups, when present, is independently selected from the group consisting of halogen, Ci-Cg alkyl, and -OR5, and wherein the Ci-Ce alkyl, 3- to 10-membered partially unsaturated heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RC2gare substituted by 0-5 R4agroups. In some embodiments, RC2is Cs-Cs cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is selected from the group consisting of Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3-to 10 membered partially unsaturated heterocyclyl, and each of the other RC2ggroups, when present, is independently -OR5, and wherein the 3- to 10-membered partially unsaturated heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RC2gare optionally substituted by 1-5 R4agroups. In another aspect of the foregoing embodiment, RC2is C3-C4 cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one of the RC2ggroups is Ce-Cu aryl substituted by 0-5 R4agroups, wherein each R4ais independently selected from halogen, Ci-Cg alkyl, and -OR5. In some embodiments, RC2is Cs-Ce cycloalkyl substituted by 1-5 RC2ggroups, and wherein at least one RC2ggroup is Ce-C aryl. In some embodiments, RC2is Cs-Ce cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is phenyl optionally substituted by 1-5 R4agroups, and wherein each R4ais independently selected from the group consisting of halogen, -OR8, -CN, and -S(O)2R8. In another aspect of the foregoingAttorney Docket No.: 199C-436282-WOembodiment, RC2is Ca-Ce cycloalkyl substituted by 1-5 RC2bgroups, wherein at least one of the RC2ggroups is 5- to 10-membered heteroaryl. In some embodiments, RC2is Ca-Ce cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl of RC2gis optionally substituted by 1-5 R4agroups, wherein each R4ais independently selected from the group consisting of halogen, Ci-Ce alkyl, -OR8, and -CN, wherein the Ci-Ce alkyl of R4ais optionally substituted with 1-5 groups selected from the group consisting of halogen and -O-Ci-Ce alkyl. In another aspect of the foregoing embodiment, RC2is Ca-Ce cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is pyridyl substituted by 0-5 R4agroups, and wherein each R4ais independently selected from the group consisting of halogen, Ci-Ce alkyl, and -OR8. In some embodiments, RC2is Ca-Ce cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is pyridyl optionally substituted by 1-5 R4agroups, and wherein each R4ais independently selected from the group consisting of halogen, Ci-Ce alkyl, and -OR8, wherein the Ci-Ce alkyl of R4ais optionally substituted with 1-5 halogen. In another aspect of the foregoing embodiment, RC2is Ca-Cs cycloalkyl substituted by 1-5 RC2ggroups, and wherein at least one RC2ggroup is 3- to 10-membered partially unsaturated heterocyclyl optionally substituted by 1-5 R4agroups. In some embodiments, RC2is Ca-Cs cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is 3- to 10-membered partially unsaturated heterocyclyl optionally substituted by 1 -5 R4agroups, and wherein each R4ais independently selected from the group consisting of halogen, Ci-Cg alkyl, and oxo. In another aspect of the foregoing embodiment, RC2is Ca-Ce cycloalkyl substituted by 1-5 RC2ggroups, wherein at least one RC2ggroup is 5- to 10-membered partially unsaturated heterocyclyl, and wherein the 5- to 10-membered partially unsaturated heterocyclyl is substituted by oxo. In another aspect of the foregoing embodiment, RC2is Ca-Ce cycloalkyl substituted by 2-5 RC2ggroups, wherein at least one RC2ggroup is halogen and at least one RC2ggroup is phenyl substituted by 0-5 Ci-Ce alkyl. In another aspect of the foregoing embodiment, RC2is Ca-Ce cycloalkyl substituted by 2-5 RC2ggroups, wherein at least one RC2ggroup is -OH and at least one RC2ggroup is phenyl.

[0181] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the group(RC29)n, RC2gis as defined for formula (RA-I), and n is 1, 2, or 3. In one variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.Attorney Docket No.: 199C-436282-WO

[0182] In some embodiments of formula (RA-I), R2is RC2wherein RC2is unsubstitutedC3-C10 cycloalkenyl. In some embodiments, RC2is unsubstituted bicyclic C9-C12 cycloalkenyl. In another aspect of the foregoing embodiment, RC2is C3-C10 cycloalkenyl substituted by 1-5 RC2cgroups, and wherein each RC2cis independently selected from the group consisting of oxo, halogen, Ci-Ce alkyl, -CN, -OR5, -C(O)R5, -C(O)OR5, and -S(O)2R5. In another aspect of the foregoing embodiment, RC2is C3-C10 cycloalkenyl substituted by oxo.

[0183] In some embodiments of formula (RA-I), R2is RC2whereinRC2is, wherein RC2care each defined as formula (RA-I) and can be on any of the annular atoms, and wherein n is 0, 1, 2, or 3.

[0184] In some embodiments of formula (RA-I), R2is RC2wherein RC2is 3- to 12-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, such that the atom of the 3- to 12-membered partially unsaturated heterocyclyl that is bonded to the -C(O) is a carbon. In another aspect of the foregoing embodiment, the 3- to 12-membered partially unsaturated heterocyclyl of RC2is monocyclic. In another aspect of the foregoing embodiment, the 3- to 12-membered partially unsaturated heterocyclyl of RC2is bicyclic. In some embodiments, RC2is 4- to 10-membered partially unsaturated heterocyclyl comprising at least one annular N atom. In another aspect of the foregoing embodiment, RC2is unsubstituted 4- to 10-membered partially unsaturated heterocyclyl. In another aspect of the foregoing embodiment, RC2is 3- to 12-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, wherein each RC2dis independently selected from the group consisting of oxo, halogen, Ci-Ce alkyl, Cs-Ci4 aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -C(O)R5, -C(O)OR5, and -S(O)2R5. In another aspect of the foregoing embodiment, RC2is 3- to 12-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, wherein each RC2dis independently selected from the group consisting of oxo, halogen, Ci-Ce alkyl, -CN, -OR5, -C(O)R5, -C(O)OR5, and -S(O)2R5. In some embodiments, RC2is 3- to 12-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, such that the atom of the 3- to 12-membered partially unsaturated heterocyclyl that is bonded to the -C(O) is a carbon, and wherein each RC2dis independently selected from the group consisting of oxo and Ci-Ce alkyl. In another aspect of the foregoing embodiment, RC2is 4- to 6-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, wherein at least one of the RC2dgroups is halogen. In some embodiments, RC2is 4- to 10-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, and wherein at least one RC2dgroup is oxo. In another aspect of the foregoing embodiment, RC2is 4- to 6-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, wherein at least one of the RC2dgroups is Ci-Ce alkyl, wherein the Ci-Cg alkyl of RC2dis optionally substituted by 1-5 R4agroups. In another aspect of theAttorney Docket No.: 199C-436282-WOforegoing embodiment, RC2dis C1-C2 alkyl substituted by 1-5 R4agroups, wherein each R4agroups is independently selected from halogen, phenyl, 6-membered heteroaryl, and -NR8C(O)OR10, wherein the phenyl and 6-membered heteroaryl of R4aare each independently substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RC2is 4- to 6-membered partially unsaturated heterocyclyl substituted by 1-5 RC2dgroups, wherein at least one of the RC2dgroups is oxo.

[0185] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the group JRC2d)np^(RC2d)nN^(RC2d)n jfjUy Uyconsisting of:', ' and ', wherein RC2dare each defined as formula (RA-I) and can be on any of the annular atoms, and wherein n is 0, 1, 2, or 3.

[0186] In some embodiments of formula (RA-I), R2is RC2wherein RC2is Cg-Cn aryl optionally substituted by 1-5 RC2agroups. In another aspect of the foregoing embodiment, the Cg-Ciz aryl of RC2is monocyclic. In another aspect of the foregoing embodiment, the Cg-Ci2 aryl of RC2is bicyclic. In another aspect of the foregoing embodiment, RC2is unsubstituted Cg-C 12 aryl. In some embodiments, RC2is unsubstituted phenyl. In another aspect of the foregoing embodiment, RC2is Cg-Cn aryl substituted by 1-5 RC2agroups, wherein each RC2agroup is independently selected from the group consisting of halogen, Ci-Cg alkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -C(O)R5, -C(O)OR5, -S(O)2R5, and -S(O)2OH, and wherein the Ci-Cg alkyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl are independently substituted by 0-5 R4a. In some embodiments, RC2is Cg-C12 aryl substituted by 1-5 RC2agroups, wherein each RC2agroup is independently selected from the group consisting of halogen, Ci-Cg alkyl, 5- to 10-membered heteroaryl, -CN, -OR5, -S(O)2R5, and -S(O)2OH, and wherein the Ci-Cg alkyl and 5- to 10-membered heteroaryl are independently and optionally substituted by 1-5 R4a. In another aspect of the foregoing embodiment, RC2is Cg-Ci2 aryl substituted by 1-5 RC2agroups, and wherein at least one RC2agroup is halogen or -CN. In another aspect of the foregoing embodiment, RC2is Cg-Cn aryl substituted by 1-5 RC2agroups, and wherein at least one RC2agroup is Ci-Cg alkyl substituted by 0-5 halogen. In some embodiments, RC2is Cg-Cn aryl substituted by 1-5 RC2agroups, wherein at least one RC2agroup is Ci-Cg alkyl, and wherein the Ci-Cg alkyl of RC2ais optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RC2is phenyl substituted by 1-5 RC2agroups, wherein at least one RC2agroup is Ci-Cg alkyl, and wherein the Ci-Cg alkyl is substituted by 1-5 halogen. In some embodiments, RC2is phenyl substituted by 1-5 RC2agroup, wherein at least one RC2agroup is -CF3. In another aspect of the foregoing embodiment, RC2is phenyl substituted by at least one -CF3. In another aspect of the foregoing embodiment, RC2is phenyl substituted by 1-5 RC2agroups, wherein at least one RC2agroup is -OR5, and wherein R5is Ci-Cg alkyl substituted with 0-5 halogen. In some embodiments, RC2is phenyl substituted by 1-5 RC2agroups, wherein at least one RC2agroup is -OR5, and wherein R5is Ci-Attorney Docket No.: 199C-436282-WOCs alkyl optionally substituted with 1-5 R5agroups, wherein at least one R5agroup is halogen or -O-Ci-Ce alkyl. In some embodiments, R5is unsubstituted C1-C3 alkyl. In another aspect of the foregoing embodiment, RC2is phenyl substituted by 1-5 RC2agroups, wherein at least one RC2agroup is -OR5, and wherein R5is unsubstituted C1-C3 alkyl. In another aspect of the foregoing embodiment, RC2is C6-C12 aryl substituted by 2-5 RC2agroups, wherein at least one RC2agroup is Ci-Ce alkyl optionally substituted by 1-5 halogen, and wherein at least one RC2agroup is selected from the group consisting of halogen, -CN, and -OR5. In another aspect of the foregoing embodiment, RC2is C6-C12 aryl substituted by 1-5 RC2agroups, and wherein at least one RC2agroup is 5- to 10-membered heteroaryl optionally substituted by 1-5 Ci-Ce alkyl.

[0187] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the group (RC2a)nconsisting of:', wherein RC2ais as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.

[0188] In some embodiments of formula (RA-I), R2is RC2wherein RC2is 5- to 12-mcmbcrcd heteroaryl optionally substituted by 1-5 RC2bgroups. In another aspect of the foregoing embodiment, tire 5- to 12-membered heteroaryl of RC2is monocyclic. In another aspect of the foregoing embodiment, the 5- to 12-membered heteroaryl of RC2is bicyclic. In another aspect of tire foregoing embodiment, tire 5- to 12-membered heteroaryl of RC2has one heteroatom selected from N, 0, and S. In another aspect of the foregoing embodiment, the 5- to 12-membered heteroaryl of RC2has two heteroatoms selected from N, O, and S. In another aspect of tire foregoing embodiment, the 5- to 12-membered heteroaryl of RC2has three heteroatoms selected from N, 0, and S. In another aspect of the foregoing embodiment, RC2is unsubstituted 5- to 12-membered heteroaryl. In some embodiments, RC2is unsubstituted pyridyl. In another aspect of the foregoing embodiment, RC2is 5- to 12-membered heteroaryl substituted by 1-5 RC2bgroups, wherein each RC2bgroup is independently selected from the group consisting of halogen, Ci-Ce alkyl, -CN, -OR5, -C(O)R5, -C(O)OR5, and -S(O)2R5, and wherein the Ci-Ce alkyl is independently substituted by 0-5 R4a. In some embodiments, RC2is 5- to 12-membered heteroaryl substituted by 1-5 RC2bgroups, wherein each RC2bgroup is independently selected from the group consisting of halogen, Ci-Ce alkyl, and -OR5, and wherein the Ci-Cg alkyl is independently and optionally substituted by 1 -5 R4a. In another aspect of the foregoing embodiment, RC2is Ce-Cn aryl substituted by 1-5 RC2agroups, and wherein at least one RC2agroup is halogen or -CN. In another aspect of the foregoing embodiment, RC2is 5- to 12-membered heteroaryl substituted by 1-5 RC2bgroups, and wherein at least one RC2bgroup is halogen. In another aspect of the foregoing embodiment, RC2is 5- to 12-membered heteroaryl substituted by 1-5 RC2bgroups, and wherein at least one RC2bgroup is Ci-Ce alkyl optionally substituted by 1-5 halogen. In another aspect of the foregoingAttorney Docket No.: 199C-436282-WOembodiment, RC2is pyridyl substituted by 1-5 RC2bgroups, and wherein at least one RC2bgroup is Ci-(>, alkyl substituted by 0-5 halogen. In some embodiments, RC2is pyridyl substituted by 1-5 RC2bgroups, and wherein at least one RC2bgroup is Ci-Ce alkyl optionally substituted by 1-5 halogen. In another aspect of the foregoing embodiment, RC2is pyridyl substituted by 1-5 RC2bgroups, and wherein at least one RC2bgroup is -CF3. In another aspect of the foregoing embodiment, RC2is 5- to 12-membered heteroaryl substituted by 1-5 RC2bgroups, and wherein at least one RC2bgroup is -OR5, and wherein R5is Ci-Ce alkyl substituted with 0-5 halogen. In another aspect of the foregoing embodiment, RC2is 5- to 12-membered heteroaryl substituted by 2-5 RC2bgroups, wherein at least one RC2bgroup is Ci-Ce alkyl substituted by 0-5 halogen, and wherein at least one RC2bgroup is selected from the group consisting of halogen, -CN, and -OR5. In another aspect of the foregoing embodiment, RC2is 5- to 12-membered heteroaryl substituted by 2-5 RC2bgroups, wherein at least one RC2bgroup is Ci-Cg alkyl substituted by 0-5 halogen, and wherein at least one RC2bgroup is halogen.

[0189] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the groupdefined as formula (RA-I) and can be on any of the annular atoms, and 11 is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3. In the above structures that depict an -N(H)- moiety, it is understood that one of the RC2bgroups can replace the hydrogen atom of the -N(H)- moiety.

[0190] In some embodiments of formula (RA-I), R2is RC2wherein RC2is 3- to 12-membered fully saturated heterocyclyl substituted by 1-5 RC2hgroups, such that the atom of the 3- to 12-membered fully saturated heterocyclyl that is bonded to the -C(O) is a carbon. In another aspect of the foregoing embodiment, the 3- to 12-membered fully saturated heterocyclyl of RC2is monocyclic. In another aspect of the foregoing embodiment, the 3- to 12-membered fully saturated heterocyclyl of RC2is bicyclic. In another aspect of the foregoing embodiment, RC2is 3- to 12-membered fully saturated heterocyclyl substituted by 1-5 RC2hgroups, wherein at least one RC2hgroup is 3- to 12-memberedAttorney Docket No.: 199C-436282-WOpartially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of tire other RC2hgroups, when present, is independently oxo or R4. In another aspect of the foregoing embodiment, RC2is 3- to 12-membered fully saturated heterocyclyl substituted by 1-5 RC2hgroups, wherein al least one RC2hgroup is Ce-Cu aryl optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4. In another aspect of the foregoing embodiment, RC2is 3- to 12-membered fully saturated heterocyclyl substituted by 1-5 RC2hgroups, wherein at least one RC2hgroup is phenyl.

[0191] In some variations of formula (RA-I), R2is RC2wherein RC2is selected from the groupRC2his as defined for formula (RA-I), and n is 1, 2, or 3. In one variation, n is 1. In another variation, n is 2. In yet another variation, n is 3. In the above structures that depict an -N(H)- moiety, it is understood that one of the RC2hgroups can replace the hydrogen atom of the -N(H)- moiety.

[0192] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the groupAttorney Docket No.: 199C-436282-WO NC'O^F NC'^Xo'' CI'^Xo" "o'^^'F - ' ■ -. ' >„. ' / .. ' -:, ', >, 5, > > > F F CN7; „, ° A A cA OH. FAttorney Docket No.: 199C-436282-WO. - ■ ■z;'X) CjXFX^NCIX^,0ONC'JB "ci^c F F I Cl cXX QCI. JX, *Clji. 0 zy ' / zy zy zy / V QCINO, Q Q=o O=0FNOJQ vy. O v / zy y^y Vy My LyAttorney Docket No.: 199C-436282-WO F F■"r 9. ' W -;>0Yr' vy > vyF> w >Fvy > vy > vyFN^N rf^N rf^N N^N <N^ AciT^F CI^CF FV¥ A^CIFvy > vy > vy > vy >Fvy> vy:N;y. F N y. yy, Fcly «yN. N N yy J, O « «yNN3Cl>v yyAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WO F FAttorney Docket No.: 199C-436282-WOFAttorney Docket No.: 199C-436282-WO

[0193] In some embodiments of formula (RA-I), R2is RC2wherein RC2is selected from the groupAttorney Docket No.: 199C-436282-WO

[0194] In some embodiments of formula (RA-I), R2is RD2wherein RD2is -NRD3(CI-CS alkyl) substituted by 0-5 RD2agroups. In one aspect of the foregoing embodiment, RD2is -NRD3(unsubstituted Ci-Ce alkyl). In one aspect of the foregoing embodiment, the Ci-Ce alkyl of -NRD3(Ci-Ce alkyl) of RD2is straight-chain alkyl. In another aspect of the foregoing embodiment, the Ci-Ce alkyl of -NRD3(Ci-Ce alkyl) of RD2is branched alkyl. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C5 alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 1-5 RD2agroups, wherein each RD2ais independently selected from halogen, Ci-Ce alkyl, C3-Cs: cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -NR6R7, -NR5C(O)OR6, and -S(O)2R5, wherein the Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RD2aare independently optionally substituted by R4a. In another aspect of the foregoing embodiment, RD2is - NRD3(CI-C5 alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Cj alkyl) is substituted by 1-5 RD2agroups, wherein at least one of the RD2agroups is halogen. In another aspect of the foregoing embodiment, RD2is -NRD3(Ci-Cs alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 1-5 RD2agroups, wherein at least one of the RD2agroups is Ci-Cs cycloalkyl. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C3 alkyl) wherein the C1-C3 alkyl of -NRD3(CI-C3 alkyl) is substituted by C3-C.6 cycloalkyl, wherein the C3-C.6 cycloalky] is substituted by 0-5 groups selected from the group consisting of halogen, Ci-Ce alkyl, and -OR5. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C3 alkyl) wherein the C1-C3 alkyl of -NRD3(CI-C3 alkyl) is substituted by C3-Cs cycloalkyl, wherein the Cs-Ce cycloalkyl is unsubstituted. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C3alkyl) wherein the C1-C3 alkyl of -NRD3(CI-C3alkyl) is substituted by C3-C6 cycloalkyl, wherein the C3-C.6 cycloalkyl is substituted by 1-2 C1-C3 alkyl groups. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C5 alkyl) wherein the C1-C5 alkyl of -NRD3(CI-C5 alkyl) is substituted by 1-5 RD2agroups, wherein at least one of tire RD2agroups is 3- to 12-membered heterocyclyl. In another aspect of the foregoing embodiment, RD2is -NRD3(Ci-Cs alkyl) wherein die C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 1-5 RD2agroups, wherein at least one of the RD2agroups is Ce-Cu aryl, wherein the C6-C14 aryl is independently substituted by 0-5 R4agroups. In anodrer aspect of the foregoing embodiment, RD2is -NRD3(CI-C4 alkyl) wherein die C1-C4 alkyl of -NRD3(CI-C4 alkyl) is substituted by phenyl, wherein the phenyl is unsubstituted. In another aspect of die foregoing embodiment, RD2is -NRD3(CI-C4 alkyl) wherein the C1-C4 alkyl of -NRD3(CI-C4 alkyl) is substituted by RD2a, wherein RD2ais phenyl substituted by 1-5 R4agroups, wherein at least one R4agroup is selected from halogen and Ci-Ce alkyl substituted by 0-5 halogen. In another aspect of die foregoing embodiment, RD2is -NRD3(CI-C4 alkyl) wherein the C1-C4 alkyl of -NRD3(CI-C4 alkyl) is substituted by RD2a, wherein RD2ais phenyl substituted by 2-5 R4agroups, wherein at least two R4agroups are halogen. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C4 alkyl) wherein the C1-C4 alkyl of -NRD3(CI-C4 alkyl) is substituted by RD2a, wherein RD2ais phenyl substituted by 2-5 R4agroups, wherein at least one R4agroup is halogen and at least one R4aAttorney Docket No.: 199C-436282-WOgroup is Ci-Cg alkyl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C5alkyl) wherein the C1-C5 alkyl of -NRD3(CI-C5alkyl) is substituted by 1-5 RD2agroups, wherein at least one of tire RD2agroups is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is substituted by substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RD2is -NRD3(Ci-Cs alkyl) wherein tire C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 1-5 RD2agroups, wherein at least one of the RD2agroups is -OR5, wherein each R5is independently selected from hydrogen, Ci-Ce alkyl, and Ce-Cu aryl. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C5 alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by -OR5, wherein R5is hydrogen or C1-C3 alkyl. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C2 alkyl) wherein the C1-C2 alkyl of -NRD3(CI-C2 alkyl) is substituted by -OR5, wherein R5is Ce-Cu aryl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C.5 alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Ce alkyl) is substituted by 1-5 RD2agroups, wherein at least one of the RD2agroups is -CN, -NR6R7, -NR5C(O)OR6, or -S O R5. In another aspect of the foregoing embodiment, RD2is -NRD3(CI-C5 alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 2-5 RD2agroups, wherein each RD2ais independently selected from halogen, Ci-Ce alkyl, Ca-Cg cycloalkyl, 5- to 10-membered heteroaryl, C.6-C14 aryl, -CN, -OR5, and -NR5C(O)OR6. In another aspect of the foregoing embodiment, RD2is -NRD3(Ci-Cs alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 2-5 RD2agroups, wherein at least one RD2agroup is phenyl substituted by 0-5 halogen and at least one RD2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl. In another aspect of the foregoing embodiment, RD2is -NRD3(Ci-Cs alkyl) wherein the C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 2-5 RD2agroups, wherein at least one RD2agroup is phenyl substituted by 0-5 halogen and at least one RD2agroup is halogen. In another aspect of the foregoing embodiment, RD2is -NRD3(Ci-Cs alkyl) wherein tire C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 2-5 RD2agroups, wherein at least one RD2agroup is halogen and at least one RD2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl. In another aspect of tire foregoing embodiment, RD2is -NRD3(CI-C5 alkyl) wherein tire C1-C5 alkyl of -NRD3(Ci-Cs alkyl) is substituted by 2-5 RD2agroups, wherein at least one RD2agroup is C3-C6 cycloalkyl and at least one RD2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl.

[0195] In some embodiments of formula (RA-I), R2is RD2wherein RD2is -NRD3(Ci-Ce alkyl) substituted by RD2a, and the Ci-Ce alkyl of -NRD3(Ci-Ce alkyl) is selected from tire group consisting RD2awherein each RD2ais independently as defined for formula (RA-I).Attorney Docket No.: 199C-436282-WO

[0196] In some embodiments of formula (RA-I), R2is RD2wherein RD2is -NRD3(CI-C6 alkyl)pD2asubstituted by RD2a, and the Ci-Ce alkyl of -NRD3(Ci-Ce alkyl) is r, wherein each RD2ais C4- Cs alkyl or Cs-Cs cycloalkyl, wherein the Cs-Ce cycloalkyl of RD2ais optionally substituted by C1-C3 alkyl.

[0197] In some embodiments of formula (RA-I), R2is RD2wherein RD2is -NRD3(Ci-Ce alkyl) optionally substituted by RD2a, and the Ci-Cg alkyl optionally substituted by RD2ais selected from tire: I i xi T I T 1 X. group consisting of: ', ',, ',4,, ',, and

[0198] In some embodiments of formula (RA-I), R2is RD2wherein RD2is -NRD3(C3-Cs cycloalkyl) wherein the Ca-Cs cycloalkyl of -NRD3(Ca-Cs cycloalkyl) is substituted by 0-5 RD2bgroups. In another aspect of the foregoing embodiment, the Cs-Cs cycloalkyl of -NRD3(C.3-Cs cycloalkyl) of RD2is monocyclic. In another aspect, the Cs-Cs cycloalkyl of -NRD3(C3-Cs cycloalkyl) of RD2is bicyclic. In another aspect, RD2is -NRD3(unsubstituted Cs-Cs cycloalkyl). In another aspect of the foregoing embodiment, RD2is -NRD3(C3-Cs cycloalkyl) wherein the Cs-Cs cycloalkyl of - NRD3(C3-CS cycloalkyl) is substituted by 1-5 RD2bgroups, wherein each RD2bis independently selected from halogen, Ci-Cg alkyl, 3- to 12-membered heterocyclyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and -OR5, wherein the Ci-Cg alkyl, 3- to 12-membered heterocyclyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl of RD2bare substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RD2is -NRD3(C3-Ce cycloalkyl) wherein the (':,-( / > cycloalkyl of - NRD3(C3-Ce cycloalkyl) is substituted by 1-5 RD2bgroups, wherein at least one of the RD2bgroups is halogen. In another aspect of the foregoing embodiment, RD2is -NRD3(C3-Cg cycloalkyl) wherein the Cs-Cg cycloalkyl of -NRD3(C3-C6 cycloalkyl) is substituted by 1-5 RD2bgroups, wherein at least one of the RD2bgroups is Ci-Ce alkyl, wherein the Ci-Ce alkyl of RD2bis substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RD2is -NRD3(C3-Cg cycloalkyl) wherein theC3-C6 cycloalkyl of -NRD3(C3-Cg cycloalkyl) is substituted by 1-5 RD2bgroups, wherein at least one of the RD2bgroups is C1-C3 alkyl. In another aspect of the foregoing embodiment, RD2is - NRD3(C3-Cg cycloalkyl) wherein the C3-C6 cycloalkyl of -NRD3(C3-C6 cycloalkyl) is substituted by 1-5 RD2t> gr0UpSwherein at least one of the RD2bgroups is 3- to 12-membered heterocyclyl. In another aspect of the foregoing embodiment, RD2is -NRD3(C3-C4 cycloalkyl) wherein the C3-C4 cycloalkyl of -NRD3(C3-C4cycloalkyl) is substil uted by 1-5 RD2bgroups, wherein at least one of the RD2bgroups is C6-Ci4 aryl substituted by 0-5 R4agroups, wherein each R4ais independently selected from halogen, Ci-Cg alkyl, and -OR8. In another aspect of the foregoing embodiment, RD2is -Attorney Docket No.: 199C-436282-WONRD3(C3-C7cycloalkyl) wherein the C3-C7 cycloalkyl of -NRD3(Cs-C7 cycloalkyl) is substituted by 1-5 RD2bgroups, wherein at least one of tire RD2bgroups is 5- to 10-membered heteroaryl. In another aspect of the foregoing embodiment, RD2is -NRD3(C3-C6 cycloalkyl) wherein the C3-C6 cycloalkyl of -NRD3(C3-Ce cycloalkyl) is substituted by 2-5 RD2bgroups, wherein each RD2bis independently selected from halogen, Ci-Ce alkyl, Ce-Cu aryl, and -OR5. In another aspect of the foregoing embodiment, RD2is -NRD3(C3-Ce cycloalkyl) wherein the C3-Ce cycloalkyl of -NRD3(C3-C6 cycloalkyl) is substituted by 2-5 RD2bgroups, wherein at least one RD2bgroup is halogen and at least one RD2bgroup is phenyl substituted by 0-5 Ci-Ce alkyl. In another aspect of tire foregoing embodiment, RD2is - NRD3(C3-C6cycloalkyl) wherein the C3-C6 cycloalkyl of -NRD3(C3-Ce cycloalkyl) is substituted by 2-5 RD2bgroups, wherein at least one RD2bgroup is -OH and at least one RD2bgroup is phenyl.

[0199] In some variations of formula (RA-I), R2is RD2wherein RD2is -NRD3(C3-C8 cycloalkyl) optionally substituted by RD2band the C3-C8 cycloalkyl optionally substituted by RD2bis selected from (RD2b)n / pD2b\" L>(R )ntire group consisting of:, and, wherein RD2bis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. hi another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.

[0200] In some embodiments of formula (RA-I), R2is RD2wherein RD2is -NRD3(3- to 12-membered heterocyclyl) such that a carbon atom of tire 3- to 12-membered saturated heterocyclyl of -NRD3(3- to 12-membered saturated heterocyclyl) is bonded to the N of -NRD3, wherein the 3- to 12-membered heterocyclyl of -NRD3(3- to 12-membered heterocyclyl) is substituted by 0-5 RD2cgroups. In another aspect of the foregoing embodiment, the 3- to 12-membered heterocyclyl of -NRD3(3- to 12-membered heterocyclyl) of RD2is monocyclic. In another aspect of the foregoing embodiment, die 3-to 12-membered heterocyclyl of -NRD3(3- to 12-membered heterocyclyl) of RD2is bicyclic. In another aspect of the foregoing embodiment, RD2is -NRD3(unsubstituted 4- to 10-membered heterocyclyl). In another aspect of the foregoing embodiment, RD2is -NRD3(3- to 12-membered heterocyclyl) wherein the 3- to 12-membered heterocyclyl of -NRD3(3- to 12-membered heterocyclyl) is substituted by 1-5 RD2cgroups, wherein each RD2cis independently selected from oxo, halogen, Ci-Ce alkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -C(O)R5, -C(O)OR5, and -S(O)? R5. In another aspect of the foregoing embodiment, RD2is -NRD3(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 1-5 RD2cgroups, wherein at least one of the RD2cgroups is halogen. In another aspect of the foregoing embodiment, RD2is -NRD3(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 1-5 RD2cgroups, wherein at least one of the RD2cgroups is Ci-Cg alkyl, wherein the Ci-Ce alkyl of RD2cis substituted by 0-5 R4agroups. In another aspect of die foregoing embodiment, RD2cis C1-C2 alkyl substituted by 1-5 R4agroups, wherein each R4agroups isAttorney Docket No.: 199C-436282-WOindependently selected from halogen, phenyl 6-membered heteroaryl, and -NR8C(O)OR10, wherein tire phenyl and 6-membered heteroaryl of R4aare each independently substituted by 0-5 halogen. In another aspect of the foregoing embodiment, Rrais -NRD3(4- to 6-membered heterocyclyl) wherein tire 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 1-5 RD2cgroups, wherein at least one of (lie RD2cgroups is unsubslituted Ce-Cu aryl. In another aspect of the foregoing embodiment, RD2is -NRD3(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 1-5 RD2cgroups, wherein at least one of the RD2cgroups is 5- to 10-membered heteroaryl substituted by 0-5 Ci-Cs alkyl. In another aspect of the foregoing embodiment, RD2is -NRD3(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 1-5 RD2cgroups, wherein at least one RD2cgroup is -OR5, -C(O)R5, or -C(O)OR5, wherein each R5is independently hydrogen or Ci-Ce alkyl. In another aspect of the foregoing embodiment, RD2is -NRD3(4- to 6-membered heterocyclyl) wherein die 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 1-5 RD2cgroups, wherein at least one RD2cgroup is oxo. In another aspect of the foregoing embodiment, RD2is -NRD3(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 2-5 RD2cgroups, wherein each RD2cis independently selected from halogen, Ci-Ce alkyl, -C(O)R5, and -C(O)OR5, wherein each R5is independently Ci-Ce alkyl. In another aspect of the foregoing embodiment, RD2is -NRD3(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -NRD3(4- to 6-membered heterocyclyl) is substituted by 2-5 RD2cgroups, wherein at least one RD2cgroup is Ci-Ce alkyl substituted by 0-5 halogen and at least one RD2cgroup is -C(O)R5or -C(O)OR5. In another aspect of the foregoing embodiment, the 3- to 12-membered heterocyclyl of -NRD3(3- to 12-membered heterocyclyl) of RD2is azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxabicyclohexanyl, oxabicyclooctanyl, tetrahydro-2H-thiopyranyl, morpholinyl, or benzodioxanyl, each of which is independently substituted by 0-5 RD2cgroups.

[0201] In some variations of formula (RA-I), R2is RD2wherein RD2is -NRD3(3- to 12-membered saturated heterocyclyl) and the 3- to 12-membered saturated heterocyclyl optionally substituted by H(RD2c)n / NA Q-<RD“>"RD2cis selected from the group consisting of:— and, wherein RD2cis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3. In the above structures that depict an -N(H)-moiety and n is 1, 2, or 3, it is understood that one of the RD2cgroups can replace the hydrogen atom of the -N(H)- moiety.Attorney Docket No.: 199C-436282-WO

[0202] In some embodiments of formula (RA-I), R2is RD2wherein RD3is hydrogen, deuterium, Ci-C, alkyl optionally substituted by one or more RD3a, or Cs-Cs cycloalkyl optionally substituted by one or more RD3b. In one embodiment, RD3is hydrogen. In one embodiment, RD3is unsubstituted Ci-Ce alkyl. In one embodiment, RD3is methyl, ethyl, propyl, isopropyl, isobutyl, or tert-butyl. In one embodiment, RD3is unsubstiluted Cr-G cycloalkyl. In one embodiment, RD3is cyclopropyl, cyclobutyl, or cyclopentyl. In one embodiment, RD3is cyclobutyl. In one embodiment, RD3is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, isobutyl, and cyclobutyl.

[0203] In some embodiments of formula (RA-I), R2is RD2wherein RD2is 3- to 12-membered N-containing saturated or partially saturated heterocyclyl substituted by 0-5 RD2dgroups, such that a nitrogen atom of the 3- to 12-membered N-containing saturated or partially saturated heterocyclyl is bonded to the carbon of -C(O)-. In another aspect of the foregoing embodiment, 3- to 12-membered N-containing saturated or partially saturated heterocyclyl of RD2is monocyclic. In another aspect of the foregoing embodiment, 3- to 12-membered N-containing saturated or partially saturated heterocyclyl of RD2is bicyclic. In another aspect of the foregoing embodiment, 3- to 12-membered N-containing saturated or partially saturated heterocyclyl of RD2is unsubstituted. In another aspect of the foregoing embodiment, RD2is 3- to 12-membered N-containing saturated or partially saturated heterocyclyl substituted by 1 -5 RD2dgroups, wherein each RD2dis independently selected from oxo, halogen, Ci-Ce alkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -C(O)R5, -C(O)OR5, and -S(O) R5. In another aspect of the foregoing embodiment, RD2is 4- to 8-membered N-containing saturated or partially saturated heterocyclyl substituted by 1-5 RD2dgroups, wherein at least one of the RD2dgroups is halogen. In another aspect of the foregoing embodiment, RD2is 4- to 6-membered N-containing saturated heterocyclyl substituted by 1-5 RD2dgroups, wherein at least one of the RD2dgroups is Ci-Ce alkyl, wherein the Ci-Cg alkyl of RD2dis substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RD2dis C1-C2 alkyl substituted by 1-5 R4agroups, wherein each R4agroups is independently selected from halogen, phenyl 6-membered heteroaryl,and -NR8C(O)OR10, wherein tire phenyl and 6-membered heteroaryl of R4aare each independently substituted by 0-5 halogen.

[0204] In some variations of formula (RA-I), R2is RD2wherein RD2is 3- to 12-membered N-containing saturated or partially saturated heterocyclyl substituted by 0-5 RD2dgroups, and tire 3- to 12-membered N-containing saturated or partially saturated heterocyclyl is selected from the group, and4, wherein RD2dis as defined for formula (RA-I), and n is 0, 1, 2, or 3. InAttorney Docket No.: 199C-436282-WOone variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.N^NL N;r(RD2e)"

[0205] In some variations of formula (RA-I), R2is RD2wherein RD2is, wherein RD2eis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.

[0206] In some embodiments of formula (RA-I), R2is RD2wherein RD2is selected from the groupAttorney Docket No.: 199C-436282-WO[02071 In some embodiments of formula (RA-I), R2is RE2wherein RE2is -O(Ci-Cs alkyl) wherein the Ci-Ce alkyl of -O(Ci-Ce alkyl) is substituted by 0-5 RE2agroups. In one aspect of the foregoing embodiment, RE2is -Ofunsubstituted Ci-Ce alkyl). In one aspect of the foregoing embodiment, the Ci-Ce alkyl of -O(Ci-Ce alkyl) of RE2is straight-chain alkyl. In another aspect of the foregoing embodiment, the Ci-Ce alkyl of -O(C i-G, alkyl) of RE2is branched alkyl. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein tire C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 1-5 RE2agroups, wherein each RE2ais independently selected from halogen, Ci-Ce alkyl, C3-C.8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -NR6R7, -NR5C(O)OR6, and -S(O): R5, wherein the Ci-Ce alkyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RE2aare independently optionally substituted by R4a. In anotiier aspect of the foregoing embodiment, RE2is -O(Ci-C5 alkyl) wherein die C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 1-5 RE2agroups, wherein at least one of die RE2agroups is halogen. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein die C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 1-5 RE2agroups, wherein at least one of die RE2agroups is C3-C8 cycloalkyl. In anodier aspect of the foregoing embodiment, RE2is - O(Ci-Cs alkyl) wherein the C1-C3 alkyl of -O(Ci-C3 alkyl) is substituted by C3-C6 cycloalkyl, wherein the C3-C6 cycloalkyl is substituted by 0-5 groups selected from the group consisting of halogen, Ci-Ce alkyl, and -OR5. In another aspect of the foregoing embodiment, RE2is -O(Ci-C3 alkyl) wherein the C1-C3 alkyl of -O(Ci-C3 alkyl) is substituted by C3-C6 cycloalkyl, wherein tire C3-C6 cycloalkyl is unsubstituted. In another aspect of tire foregoing embodiment, RE2is -O(Ci-C3 alkyl) wherein the C1-C3 alkyl of -O(Ci-C3 alkyl) is substituted by C3-C6 cycloalkyl, wherein tire C3-C6 cycloalkyl is substituted by 1-2 C1-C3 alkyl groups. In another aspect of the foregoing embodiment, RE2is -O(Ci-C5 alkyl) wherein tire C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 1-5 RE2agroups, wherein at least one of the RE2agroups is 3- to 12-membered heterocyclyl. In another aspect of the foregoing embodiment, RE2is -O(Ci-C? alkyl) wherein die C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 1-5 RE2agroups, wherein at least one of the RE2agroups is C6-C14aryl, wherein the Ce-Cu aryl is independently substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RE2is -CXC1-C4 alkyl) wherein the C1-C4 alkyl of -0(Ci-C4 alkyl) is substituted by phenyl, wherein the phenyl is unsubstituted. In another aspect of the foregoing embodiment, RE2is -O(Ci-C4 alkyl) wherein the C1-C4 alkyl of -O(Ci-C,4 alkyl) is substituted by RE2a, wherein RE2ais phenyl substitutedAttorney Docket No.: 199C-436282-WOby 1-5 R4agroups, wherein at least one R4agroup is selected from halogen and Ci-Ce alkyl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RE2is -O(Ci-C4 alkyl) wherein the C1-C4 alkyl of -O(Ci-C4 alkyl) is substituted by RE2a, wherein RE2ais phenyl substituted by 2-5 R4agroups, wherein at least two R4agroups are halogen. In another aspect of the foregoing embodiment, RE2is -O(Ci-C4 alkyl) wherein the C1-C4 alkyl of -O(Ci-C4 alkyl) is substituted by RE2a, wherein RE2ais phenyl substituted by 2-5 R4agroups, wherein at least one R4agroup is halogen and at least one R4agroup is Ci-Ce alkyl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein the C1-C5 alkyl of -O(Ci-C? alkyl) is substituted by 1-5 RE2agroups, wherein at least one of the RE2agroups is 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is substituted by substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RE2is -O(Ci-C? alkyl) wherein the C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 1-5 RE2agroups, wherein at least one of the RE2agroups is -OR5, wherein each R5is independently selected from hydrogen, Ci-Ce alkyl, and Ce-Cu aryl. In another aspect of the foregoing embodiment, RE2is -OlCi-Cs alkyl) wherein the C1-C5 alkyl of -OlCi-C? alkyl) is substituted by -OR5, wherein R5is hydrogen or C1-C3 alkyl. In another aspect of the foregoing embodiment, RE2is -OlCi-Ci alkyl) wherein the C1-C2 alkyl of -O(Ci-C2 alkyl) is substituted by -OR5, wherein R5is Ce-Cu aryl substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein the C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 1-5 RE2agroups, wherein at least one of the RE2agroups is -CN, -NR6R7, -NR5C(O)OR6, or -SIO^R5. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein the C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 2-5 RE2agroups, wherein each RE2ais independently selected from halogen, Ci-Ce alkyl, C3-C.8 cycloalkyl, 5- to 10-membered heteroaryl, Ce-Cu aryl, -CN, -OR5, and -NR5C(O)OR6. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein the C1-C5 alkyl of -O(Ci-C5 alkyl) is substituted by 2-5 RE2agroups, wherein at least one RE2agroup is phenyl substituted by 0-5 halogen and at least one RE2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Cs alkyl. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein theC1-C5 alkyl of -O(Ci-C5 alkyl) is substituted by 2-5 RE2agroups, wherein at least one RE2agroup is phenyl substituted by 0-5 halogen and at least one RE2agroup is halogen. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein the C1-C5 alkyl of -O(Ci-C5 alkyl) is substituted by 2-5 RE2agroups, wherein at least one RE2agroup is halogen and at least one RE2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl. In another aspect of the foregoing embodiment, RE2is -O(Ci-Cs alkyl) wherein the C1-C5 alkyl of -O(Ci-Cs alkyl) is substituted by 2-5 RE2agroups, wherein at least one RE2agroup is C3-C6 cycloalkyl and at least one RE2agroup is -OR5, wherein each R5is independently selected from hydrogen and Ci-Ce alkyl.

[0208] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -O(Ci-Ce alkyl) substituted by RE2a, and the Ci-Ce alkyl of -O(Ci-Ce alkyl) is selected from the group consisting of:Attorney Docket No.: 199C-436282-WO, wherein each RE2ais independently as defined for formula (RA-I).

[0209] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -O(Ci-Ce alkyl)RE2asubstituted by RE2a, and the Ci-Ce alkyl of -O(Ci-Ce alkyl) is, wherein each RE2ais C4-C5 alkyl or Cj-Ce cycloalkyl, wherein the Ca-Ce cycloalkyl of RE2ais optionally substituted by C1-C3 alkyl.

[0210] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -O(Ci-Cs alkyl) optionally substituted by RE2a, wherein the Ci-Ce alkyl optionally substituted by RE2ais selected from tire groupAttorney Docket No.: 199C-436282-WOF, and '.

[0211] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -O(Ca-Cs cycloalkyl) wherein the Cs-Cs cycloalkyl of -©(Cs-Cg cycloalkyl) is substituted by 0-5 RE2bgroups. In another aspect of the foregoing embodiment, the Ca-Cs cycloalkyl of -O(Ca-Cs cycloalkyl) of RE2is monocyclic. In another aspect, the Cs-Cs cycloalkyl of -O(Ca-C8 cycloalkyl) of RE2is bicyclic. In another aspect, RE2is -O(unsubstituted Ca-Cs cycloalkyl). In another aspect of the foregoing embodiment, RE2is -O(Ca-Cs cycloalkyl) wherein the Ca-Cs cycloalkyl of -O(Ca-Cs cycloalkyl) is substituted by 1-5 RE2bgroups, wherein each RE2bis independently selected from halogen, Ci-Cg alkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and -OR5, wherein the Ci-Ce alkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RE2bare substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RE2is -O(Ca-Ce cycloalkyl) wherein the Ca-Ce cycloalkyl of -O(Ca-Ce cycloalkyl) is substituted by 1-5 RE2bgroups, wherein at least one of the RE2bgroups is halogen. In another aspect of the foregoing embodiment, RE2is -O(Ca-Ce cycloalkyl) wherein the Ca-Ce cycloalkyl of -O(Ca-Ce cycloalkyl) is substituted by 1-5 RE2bgroups, wherein at least one of the RE2bgroups is Ci-Ce alkyl, wherein the Ci-Cg alkyl of RE2bis substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RE2is -OlCa-Cs cycloalkyl) wherein the Ca-Ce cycloalkyl of -O(Ca-Cs cycloalkyl) is substituted by 1-5 RE2bgroups, wherein at least one of the RE2bgroups is Ci-Ca alkyl. In another aspect of the foregoing embodiment, RE2is -O(Ca-Ce cycloalkyl) wherein the Ca-Ce cycloalkyl of -O(Ca-Ce cycloalkyl) is substituted by 1 -5 RE2bgroups, wherein at least one of the RE2bgroups is 3- to 12-membered heterocyclyl. In another aspect of the foregoing embodiment, RE2is -O(Ca-C4 cycloalkyl) wherein the C3-C4 cycloalkyl of -CXC3-C4 cycloalkyl) is substituted by 1-5 RE2bgroups, wherein at least one of the RE2bgroups is Ce-Cu aryl substituted by 0-5 R4agroups, wherein each R4ais independently selected from halogen, Ci-Ce alkyl, and -OR8. In another aspect of the foregoing embodiment, RE2is -O(C3-C? cycloalkyl) wherein the C3-C7 cycloalkyl of -OtCs-C? cycloalkyl) is substituted by 1-5 RE2bgroups, wherein at least one of the RE2bgroups is 5- to 10-membered heteroaryl. In another aspect ofAttorney Docket No.: 199C-436282-WOthe foregoing embodiment, RE2is -O(C3-Ce cycloalkyl) wherein the Cs-Cs cycloalkyl of -CXC3-C6 cycloalkyl) is substituted by 2-5 RE2bgroups, wherein each RE2bis independently selected from halogen, Ci-Ce alkyl, Ce-Cu aryl, and -OR5. In another aspect of the foregoing embodiment, RE2is -O(C3-Ce cycloalkyl) wherein the C3-C6 cycloalkyl of -O(C3-Ce cycloalkyl) is substituted by 2-5 RE2bgroups, wherein at least one RE2bgroup is halogen and at least one RE2bgroup is phenyl substituted by 0-5 Ci-Ce alkyl. In another aspect of the foregoing embodiment, RE2is -O(C3-Ce cycloalkyl) wherein the C3-C6 cycloalkyl of -OlCs-Ce cycloalkyl) is substituted by 2-5 RE2bgroups, wherein at least one RE2bgroup is -OH and at least one RE2bgroup is phenyl.

[0212] In some variations of formula (RA-I), R2is RE2wherein RE2is -OlCs-Cs cycloalkyl) substituted by 0-5 RE2band the Cs-Cs cycloalkyl of -O(C3-Cs cycloalkyl) is selected from the groupis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.

[0213] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -0(3- to 12-membered heterocyclyl) wherein the 3- to 12-membered heterocyclyl of -0(3- to 12-membered heterocyclyl) is substituted by 0-5 RE2cgroups. In another aspect of the foregoing embodiment, the 3- to 12-membered heterocyclyl of -0(3- to 12-membered heterocyclyl) of RE2is monocyclic. In another aspect of the foregoing embodiment, the 3- to 12-membered heterocyclyl of -0(3- to 12-membered heterocyclyl) of RE2is bicyclic. In another aspect of the foregoing embodiment, RE2is -O(unsubstituted 4- to 10-membered heterocyclyl). In another aspect of the foregoing embodiment, RE2is -0(3- to 12-membered heterocyclyl) wherein the 3- to 12-membered heterocyclyl of -0(3- to 12-membered heterocyclyl) is substituted by 1-5 RE2cgroups, wherein each RE2cis independently selected from oxo, halogen, Ci-Ce alkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -C(0)R5, -C(0)0R5, and -S(O)2R5. In another aspect of the foregoing embodiment, RE2is -0(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -0(4- to 6-membered heterocyclyl) is substituted by 1-5 RE2cgroups, wherein at least one of the RE2cgroups is halogen. In another aspect of the foregoing embodiment, RE2is -0(4- to 6-membcrcd heterocyclyl) wherein the 4- to 6-mcmbcrcd heterocyclyl of -0(4- to 6-membered heterocyclyl) is substituted by 1-5 RE2cgroups, wherein at least one of the RE2cgroups is Ci-Ce alkyl, wherein the Ci-C& alkyl of RE2cis substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RE2cis C1-C2 alkyl substituted by 1-5 R4agroups, wherein each R4agroups is independently selected from halogen, phenyl 6-membered heteroaryl, and -NR8C(O)OR10, wherein the phenyl and 6-membered heteroaryl of R4aare each independently substituted by 0-5 halogen. In another aspect of the foregoing embodiment, RE2is -0(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -0(4- to 6-memberedAttorney Docket No.: 199C-436282-WOheterocyclyl) is substituted by 1-5 RE2cgroups, wherein at least one of the RE2cgroups is unsubstituted C6-C14 aryl. In another aspect of the foregoing embodiment, RE2is -0(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -0(4- to 6-membered heterocyclyl) is substituted by 1-5 RE2cgroups, wherein at least one of die RE2cgroups is 5- to 10-membered heleroaryl substituted by 0-5 Ci-Ce alkyl. In another aspect of the foregoing embodiment, RE2is -0(4-to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -0(4- to 6-membered heterocyclyl) is substituted by 1-5 RE2cgroups, wherein at least one RE2cgroup is -OR5, -C(0)R5, or -C(0)0R5, wherein each R5is independendy hydrogen or Ci-Cg alkyl. In another aspect of the foregoing embodiment, RE2is -0(4- to 6-membered heterocyclyl) wherein die 4- to 6-membered heterocyclyl of -0(4- to 6-membered heterocyclyl) is substituted by 1-5 RE2cgroups, wherein at least one RE2cgroup is oxo. In another aspect of the foregoing embodiment, RE2is -0(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -0(4- to 6-membered heterocyclyl) is substituted by 2-5 RE2cgroups, wherein each RE2cis independently selected from halogen, Ci-Cg alkyl, -C(0)R5, and -C(0)0R5, wherein each R5is independently Ci-Ce alkyl. In another aspect of the foregoing embodiment, RE2is -0(4- to 6-membered heterocyclyl) wherein the 4- to 6-membered heterocyclyl of -0(4- to 6-membered heterocyclyl) is substituted by 2-5 RE2cgroups, wherein at least one RE2cgroup is Ci-Cg alkyl substituted by 0-5 halogen and at least one RE2cgroup is -C(0)R5or -C(0)0R5. In another aspect of the foregoing embodiment, the 3- to 12-membered heterocyclyl of -0(3- to 12-membered heterocyclyl) of RE2is azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxabicyclohexanyl, oxabicyclooctanyl, tetrahydro-2H-thiopyranyl, morpholinyl, or benzodioxanyl, each of which is independently substituted by 0-5 RE2cgroups.

[0214] In some variations of formula (RA-I), R2is RE2wherein RE2is -0(3- to 12-membered saturated heterocyclyl) substituted by RE2cand the 3- to 12-membered saturated heterocyclyl of -0(3-to 12-membered saturated heterocyclyl) substituted by RE2cis, wherein RE2cis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.

[0215] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -0(Ce-C aryl) wherein the Ce-Cu aryl of -O(Ce-Ci4 aryl) is substituted by 0-5 RE2dgroups. In another aspect of the foregoing embodiment, RE2is -O(unsubstituted Ce-Cio aryl). In another aspect of the foregoing embodiment, RE2is -0(Ce-Ci4 aryl) wherein the Ce-Cu aryl of -0(Ce-Cu aryl) substituted by 1-5 RE2dgroups, wherein each RE2dis independently selected from halogen, Ci-Ce alkyl, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, -CN, and -OR5, wherein the Ci-Ce alkyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl of RE2dare eachAttorney Docket No.: 199C-436282-WOindependently substituted by 0-5 halogen, Ci-Ce alkyl or OR8. In another aspect of the foregoing embodiment, RE2is -O(Ce-Ci4 aryl) wherein the Ce-C aryl of -O(C6-Ci4 aryl) is substituted by 1-5 RE2dgroups, wherein at least one of the RE2dgroups is halogen. In another aspect of the foregoing embodiment, RE2is -O(Ce-C aryl) wherein die Ce-Cu aryl of -O(Ce-Cu aryl) is substituted by 1-5 RE2dgroups, wherein at least one of die RE2dgroups is Ci-Ce alkyl, wherein die Ci-Ce alkyl of RE2dis substituted by 0-5 R4agroups. In another aspect of the foregoing embodiment, RE2dis C1-C2 alkyl substituted by 1-5 R4agroups, wherein each R4agroups is independendy selected from halogen and OR8. In another aspect of die foregoing embodiment, RE2is -O(Ce-C aryl) wherein the Ce-C aryl of -O(Ce-Ci4 aryl) is substituted by 1-5 RE2dgroups, wherein at least one of the RE2dgroups is C3-Cg cycloalkyl. In another aspect of the foregoing embodiment, RE2is -O(Ce-Cu aryl) substituted by 1-5 RE2dgroups, wherein at least one of the RE2dgroups is 6-membered heterocyclyl. In another aspect of die foregoing embodiment, RE2is -O(Ce-Cu aryl) wherein the Ce-Cu aryl of -O(Ce-Cu aryl) is substituted by 1-5 RE2dgroups, wherein at least one of the RE2dgroups is 5- to 6-membered heteroaryl, wherein the heteroaryl of RE2dis substituted by 0-5 Ci-Ce alkyl groups. In another aspect of the foregoing embodiment, RE2is -O(Cs-Cu aryl) wherein the Ce-C aryl of -O(Ce-Cu aryl) is substituted by 1-5 RE2dgroups, wherein at least one of the RE2dgroups is -OR5, wherein each R5is independently C1-C2 alkyl substituted by 0-5 groups selected from halogen and -OR10. In another aspect of the foregoing embodiment, RE2is -O(Ce-Cu aryl) wherein the Ce-Cu aryl of -O(Ce-Cu aryl) is substituted by 2-5 RE2dgroups, wherein each RE2dis independently selected from halogen, Ci-Cg alkyl, -CN, and -OR5. In another aspect of the foregoing embodiment, RE2is -O(Ce-Cu aryl) wherein the Ce-Cu aryl of -O(Ce-Cu aryl) is substituted by 1-3 RE2dgroups, wherein each RE2dis halogen. In another aspect of the foregoing embodiment, RE2is -O(Ce-Ci4 aryl) wherein the Ce-Cu aryl of -O(Ce-C aryl) is substituted by 2-5 RE2dgroups, wherein at least two of the RE2dgroups are halogen. In another aspect of the foregoing embodiment, RE2is -O(Ce-Cu aryl) wherein die Ce-C aryl of -O(Ce-Cu aryl) is substituted by 2-5 RE2dgroups, wherein at least one of the RE2dgroups is Ci-Ce alkyl substituted by 0-5 halogen and at least one of the RE2dgroups is selected from die group consisting of halogen, -CN, and -OR5. In anodier aspect of the foregoing embodiment, RE2is phenyl, indanyl, or 1,2,3,4-tetrahydronaphdialenyl, each of which is substituted by 0-5 RE2dgroups.

[0216] In some variations of formula (RA-I), R2is RE2wherein RE2is -O(Ce-Cu aryl) substituted by RE2d, and die Ce-Cu aryl of -O(Ce-Cu aryl) substituted by RE2dis selected from die group consisting / => / (RE2d)nof:—J—, —J—, and, wherein RE2dis as defined for formula (RA-I), and 11 is 0, 1, 2, or 3. In one variation, 11 is 0. In another variation, n is 1. In another variation, n is 2. In yet anodier variation, n is 3.Attorney Docket No.: 199C-436282-WO

[0217] In some variations of formula (RA-I), R2is RE2wherein RE2is -O(Ce-Ci4 aryl) substituted by RE2d, and the Ce-Cu aryl of -O(C6-Ci4 aryl) substituted by RE2dis selected from the group consisting

[0218] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 0-5 RE2egroups. In another aspect of the foregoing embodiment, RE2is -O(unsubstituted 5- to 10-membered heteroaryl). In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 1-5 RE2egroups, wherein each RE2eis independently selected from halogen, Ci-Ce alkyl substituted by 0-5 halogen, -OR5, C3-Ce cycloalkyl, -CN, and -NR6R7. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein tire 5-to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 1-5 RE2egroups, wherein at least one of tire RE2egroups is halogen. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 1-5 RE2egroups, wherein at least one of the RE2egroups is Ci-C4 alkyl, wherein the C1-C4 alkyl of RE2eis substituted by 0-5 halogen groups. In another aspect of the foregoing embodiment, RE2is -0(6-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 1-5 RE2egroups, wherein at least one of the RE2egroups is -OR5, wherein each R5is independently selected from hydrogen and C1-C3 alkyl. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 2-5 RE2egroups, wherein each RE2eis independently selected from halogen, Ci-Ce alkyl, and -CN. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 2-5 RE2egroups, wherein at least two of the RE2egroups are halogen. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 2-5 RE2egroups, wherein at least two of the RE2egroups are Ci-Ce alkyl. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by 3-5 RE2egroups, wherein each RE2eis independently selected from halogen, Ci-Ce alkyl, and -CN. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by three -CH3groups. In another aspect of the foregoing embodiment, RE2is -0(5- to 10-membered heteroaryl) wherein the 5- to 10-Attorney Docket No.: 199C-436282-WOmembered heteroaryl of -0(5- to 10-membered heteroaryl) is substituted by two -CH3 groups and one halogen group.

[0219] In some variations of formula (RA-I), R2is RE2wherein RE2is -0(5- to 10-membered heteroaryl) substituted by RE2eand the 5- to 10-membered heteroaryl of -0(5- to 10-memberedheteroaryl) substituted by RE2eis selected from the group consisting of(RE2e)n (RE2e),, and, RE2eis as defined for formula (RA-I), and n is 0, 1, 2, or 3. In one variation, n is 0. In another variation, n is 1. In another variation, n is 2. In yet another variation, n is 3.

[0220] In some embodiments of formula (RA-I), R2is RE2wherein RE2is -0(5- to 10-membered heteroaryl) and the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is selected

[0221] In some embodiments of formula (RA-I), R2is RE2wherein RE2is selected from the groupAttorney Docket No.: 199C-436282-WO

[0222] In some variations of formula (RA-I), one or more hydrogen atoms on the R2group is replaced by deuterium.

[0223] In some variations of formula (RA-I), the fragment RAhas any one or more of the following features:(b) -L1-(N-*)-L2-Y-L3- are taken together to form a moiety selected from the group consisting of:Attorney Docket No.: 199C-436282-WO(c) R2is RB2, wherein RB2is:(i) Ci-Ce alkyl optionally substituted by one or more RB2a;(ii) Cj-Cs cycloalkyl optionally substituted by one or more RB2b; or(iii) 3- to 12-membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from 0 and N optionally substituted by one or more RB2c, such that the atom of the 3- to 12-membered heterocyclyl that is bonded to the -C(O) is a carbon;wherein:each RB2a, RB2b, and RB2cis, where possible, independently halogen, Ci-Ce alkyl, C3-C8cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -NR6R7, -C(O)R5, -C(O)OR5, or -NR5C(O)OR6, wherein the Ci-Ce alkyl, Cs-Cs cycloalkyl, and 3- to 12-membered saturated heterocyclyl of RB2a, RB2b, and RB2care independently optionally substituted by one or more R4a, each R4ais independently halogen, oxo, -OR8, -NR8R9, -CN, Ca-Cs cycloalkyl, 5- to 10-membered heteroaryl, or Ci-Ce alkyl, wherein the Ci-Ce alkyl of R4ais independently optionally substituted by one or more R4b,each R4bis independently halogen,each R5is independently hydrogen, Ci-Cg alkyl, C3-C6 cycloalkyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, C3-C6 cycloalkyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R5are each independently optionally substituted by one or more R5a,each R5ais independently halogen, deuterium, -OR10, or Ci-Ce alkyl,each R6is independently hydrogen or Ci-Cs alkyl,each R7is hydrogen,each R8is independently hydrogen or Ci-Ce alkyl,each R9is hydrogen, andeach R10is independently Ci-Ce alkyl.

[0224] In one aspect of this variation, (a), (b), and (c)(i) apply. In another variation, (a), (b), and (c)(ii) apply. In another variation, (a), (b), and (c)(iii) apply.

[0225] In some variations of formula (RA-I), the fragment RAhas any one or more of the following features:Attorney Docket No.: 199C-436282-WO(b) -L1-(N-*)-L2-Y-L3- are taken together to form a moiety selected from the group consisting of:(c) R2is RC2, wherein RC2is:(i) C6-C12 aryl optionally substituted by one or more RC2a;(ii) 5- to 12-membered heteroaryl optionally substituted by one or more RC2b;(iii) C3-C10 cycloalkenyl optionally substituted by one or more RC2c;(iv) 3- to 12-membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d;(v) Ci-Ce alkyl substituted by one or more RC2e, wherein at least one RC2egroup is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a, and each of the other RC2egroups, when present, is independently R4;(vi) C2-C6 alkenyl substituted by one or more RC2f, wherein at least one RC2fgroup is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cw aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl of RC2fare independently optionally substituted by one or more R4a, and each of the other RC2fgroups, when present, is independently R4;(vii) Cs-Cs cycloalkyl substituted by one or more RC2g, wherein at least one RC2ggroup is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein die 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, and 5- to 10-memberedAttorney Docket No.: 199C-436282-WOheteroaryl of RC2gare independently optionally substituted by one or more R4a, and each of the other RC2ggroups, when present, is independently R4; or(viii) 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h, wherein at least one RC2hgroup is 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a, and each of the other RC2hgroups, when present, is independently oxo or R4;wherein:each RC2a, RC2b, RC2cand RC2dis independently R4,each R4is independently halogen, Ci-Ce alkyl, 5- to 10-membered heteroaryl, -CN, -OR5, -S(O R5, or -SfOhOH, wherein the Ci-Ce alkyl and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a,each R4ais independently halogen, oxo, -OR8, -CN, -SlOhR8, or Ci-Ce alkyl, wherein the Ci-Ce alkyl of R4aare independently optionally substituted by one or more halogen,each R5is independently hydrogen, Ci-Cs alkyl, Ci-Cs cycloalkyl, Cs-Cu aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, Cs-Ce cycloalkyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R5are each independently optionally substituted by one or more R5a,each R5ais independently halogen, -OR10, Ca-Ce cycloalkyl, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo,each R8is independently hydrogen or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, or oxo, andeach R10is independently Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, or oxo.

[0226] In one aspect of this variation, (a), (b), and (c)(i) apply. In another variation, (a), (b), and (c)(ii) apply. In another variation, (a), (b), and (c)(iii) apply. In another variation, (a), (b), and (c)(iv) apply. In another variation, (a), (b), and (c)(v) apply. In another variation, (a), (b), and (c)(vi) apply. In another variation, (a), (b), and (c)(vii) apply. In another variation, (a), (b), and (c)(viii) apply.

[0227] In some variations of formula (RA-I), the fragment RAhas any one or more of the following features:(II) -L1-(N-*)-L2-Y-L3- are taken together to form a moiety selected from tire group consisting of:Attorney Docket No.: 199C-436282-WO(III) R2is RD2wherein RD2is:(i) -NRD3(Ci-Ce alkyl) optionally substituted by one or more RD2a;(ii) -NRD3(C3-CS cycloalkyl optionally substituted by one or more RD2b;(iii) -NRD3(3- to 12-membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N) optionally substituted by one or more RD2c;(iv) 3- to 12-membered heterocyclyl containing 1 N and 0 or 1 additional heteroatom selected from 0 and N, wherein the 3- to 12-membered heterocyclyl is optionally substituted by one or more RD2d; or(v) 5- to 10-membered N-containing heteroaryl optionally substituted by one or more RD2e; wherein each RD2a, RD2b, RD2c, RD2d, and RD2eis independently R4, and each R4is independently halogen, Ci-Ce alkyl, Cs-Cg cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5-to 10-membered heteroaryl, -CN, -OR5, -C(O)R5, -C(O)OR5, -NR6R7, or -NR5C(O)OR6, wherein the Ci-Ce alkyl, Cs-Cg cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by R4a, wherein R4ais halogen, -OR8, -NR8R9, -C(O)OR8, -NR8C(O)OR10, -CN, 5- to 10-membered heteroaryl, C6-Ci4aryl, or Ci-C6alkyl independently optionally substituted by halogen, whereinR5is hydrogen, Ci-Ce alkyl optionally substituted by halogen or -OR10, or Ce-Cu aryl optionally substituted by halogen,R6is hydrogen or Ci-Ce alkyl,R7is hydrogen,R8is hydrogen or Ci-Ce alkyl optionally substituted by halogen,R9is hydrogen, andR10is Ci-Ce alkyl optionally substituted by halogen.

[0228] In one aspect of this variation, (I), (II), and (III)(i) apply. In another variation, (I), (II), and (III)(ii) apply. In another variation, (I), (II), and (III)(iii) apply. In another variation, (I), (II), and (III)(iv) apply. In another variation, (I), (II), and (III)(v) apply. In another variation, (I), (II), and (III)(vi) apply. In another variation, (I), (II), and (III)(vii) apply.Attorney Docket No.: 199C-436282-WO

[0229] In some variations of (RA-I), R2is RD2wherein RD2is -NRD3(Ci-Cs alkyl), - NRD3(C3-CS cycloalkyl), -NRD3(3- to 12-membered heterocyclyl), 3- to 12-membered heterocyclyl containing 1 N and 0 or 1 additional heteroatom selected from O and N, or 5- to 10-membered N-containing heteroaryl, wherein the Ci-Ce alkyl of tire -NRD3(Ci-Ce alkyl) of RD2is optionally substituted by RD2a, the Cs-Cg cycloalkyl of the -NRD3(C3-C8 cycloalkyl) of RD2is optionally substituted by RD2b, the 3- to 12-membered heterocyclyl of the -NRD3(3- to 12-membered heterocyclyl) of RD2is optionally substituted by RD2c, the 3- to 12-membered heterocyclyl containing 1 N and 0 or 1 additional heteroatom selected from 0 and N of RD2is optionally substituted by RD2d, the 5- to 10-membered N-containing heteroaryl is optionally substituted by RD2e, wherein each RD2\ RD2b, RD2c, RD2d, and RD2eis independently R4, wherein each R4is independently selected from the_ 1_ Z-p4a) H 'n■— L-, wherein each R4ais independently halogen, -OR8, -NR8Rq, -C(O)OR8,-NR8C(O)OR10, -CN, 5- to 10-membered heteroaryl, C6-Ci4aryl, or Ci-C6alkyl, wherein R8, Rq, and R10are as defined for formula (I), and n is 0, 1, or 2. In one variation, n is 0. In another variation, n is 1. In yet another variation, n is 2.

[0230] In another variation of (RA-I), R2is RD2wherein RD2is -NRD3(Ci-Ce alkyl) optionally substituted by RD2a, -NRD3(C3-Cs cycloalkyl optionally substituted by RD2b, -NRD3(3- to 12-membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N) optionally substituted by RD2c, or 3- to 12-membered heterocyclyl containing 1 N and 0 or 1 additional heteroatom selected from O and N optionally substituted by RD2d, or 5- to 10-membered N-containing heteroaryl substituted by 0-5 RD2e, wherein each RD2a, RD2b, RD2c, RD2d, and RD2eis independently R4, wherein each R4isAttorney Docket No.: 199C-436282-WO

[0231] In some variations of formula (RA-I), the fragment RAhas any one or more of the following features:(II) -L1-(N-*)-L2-Y-L3- are taken together to form a moiety selected from tire group consisting of:(III) R2is RE2wherein RE2is:(i) -O(Ci-Ce alkyl) wherein the Ci-Ce alkyl of -O(Ci-Ce alkyl) is optionally substituted by one or more RE2a;(ii) -O(C3-Cs cycloalkyl) wherein the Cs-Cs cycloalkyl of -()((>, -Cs cycloalkyl) is optionally substituted by one or more RE2b; or(iii) -0(3- to 12-membered heterocyclyl) optionally substituted by one or more RE2c;(iv) -0(Ce-Cio aryl) optionally substituted by one or more RE2d;Attorney Docket No.: 199C-436282-WO(iv) -0(5- to 10-membered heteroaryl) optionally substituted by one or more RE2e; wherein each RE2a, RE2b, RE2c, RE2d, and RE2eis independently R4, and R4is halogen, Ci- Cg alkyl, C3-C3cycloalkyl, 3- to 12-membered heterocyclyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -C(0)R5, -C(0)0R5, -NR6R7, or -NR5C(O)OR6, wherein the Ci-C6alkyl, C3-Cs: cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heleroaryl of R4are independently optionally substituted by R4a, wherein R4ais halogen, -OR8, -NR8R9, -C(0)0R8, -NR8C(O)OR10, -CN, 5- to 10-membered heteroaryl, Ce-Cu aryl, or Ci-Ce alkyl independently optionally substituted by halogen, whereinR5is hydrogen, Ci-Ce alkyl optionally substituted by halogen or -OR10, or Ce-C aryl optionally substituted by halogen,R6is hydrogen or Ci-Ce alkyl,R7is hydrogen,R8is hydrogen or Ci-Ce alkyl optionally substituted by halogen,R9is hydrogen, andR10is Ci-Ce alkyl optionally substituted by halogen.

[0232] In one aspect of this variation, (I), (II), and (III)(i) apply. In another variation, (I), (II), and (III)(ii) apply. In another variation, (I), (II), and (III)(iii) apply. In another variation, (I), (II), and (III)(iv) apply. In another variation, (I), (II), and (III)(v) apply. In another variation, (I), (II), and (III)(vi) apply. In another variation, (I), (II), and (III)(vii) apply.

[0233] In some variations of (RA-I), R2is RE2wherein RE2is -O(Ci-Ce alkyl) wherein the Ci-Ce alkyl of -O(Ci-Ce alkyl) is optionally substituted by RE2a, -O(C3-C8cycloalkyl) wherein the C3-C8cycloalkyl of -O(C3-C8cycloalkyl) is optionally substituted by RE2b, -0(3- to 12-membered heterocyclyl containing 1 or 2 heteroatoms selected from 0 and N) wherein the 3- to 12-membered heterocyclyl of -0(3- to 12-membered heterocyclyl) is optionally substituted by RE2c, -0(Ce-Cio aryl) wherein die Ce-Cw aryl of -0(Ce-Cio aryl) is optionally substituted by RE2d, or -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is optionally substituted by RE2egroups, wherein each R4is independently selected from die group(R4a)n, wherein each R4ais independently halogen, -OR8, -NR8R9, -C(0)0R8, -NR8C(O)OR10, -CN, 5- to 10-membered heteroaryl, Ce-Cu aryl, or Ci-Ce alkyl, wherein R8, Rq, and R10are as defined for formula (I), and n is 0, 1, or 2. hi one variation, n is 0. In anodier variation, n is 1. In yet another variation, n is 2.Attorney Docket No.: 199C-436282-WO

[0234] In some variations of formula (RA-I) R2is RE2wherein RE2is -O(Ci-Ce alkyl) wherein the Ci-Ce alkyl of -O(Ci-C6 alkyl) is optionally substituted by RE2a, -C Cs-Cs cycloalkyl) wherein the Cs-Cs cycloalkyl ofcycloalkyl) is optionally substituted by RF2h, -0(3- to 12-membered heterocyclyl containing 1 or 2 heteroatoms selected from 0 and N) wherein the 3- to 12-membered helerocyclyl of -0(3- to 12-membered heterocyclyl) is optionally substituted by RE2c, -0(Ce-Cio aryl) wherein the Ce-Cw aryl of -0(Ce-Cio aryl) is optionally substituted by REM, or -0(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) is optionally substituted by RE2cgroups, wherein each RE2a, RE2b, RE2c, RE2d, and RE2cis independently F Cl CH3CF3R4, wherein each R4is independently selected from the group consisting of:—L”,,IV. Fragments of Formula (RA-II)

[0235] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II):IQ (RA-II) wherein * denotes the point of attachment to RB;Attorney Docket No.: 199C-436282-WOR3is Cs-Cu arylene or 5- to 10-membered heteroarylene, wherein the Cs-Cu arylene or 5- to 10-membered heteroarylene are optionally substituted by one or more R4;Rxis unsubstituted Cs-Cs alkyl, Ci-Cs alkyl substituted by one or more Rxa, C3-C6 cycloalkyl optionally substituted by one or more Rxb, 3- to 12-membered heterocyclyl optionally substituted by one or more Rxc, Ce-Cu aryl optionally substituted by one or more Rxd, 5- to 10-membered heleroaryl optionally substituted by one or more Rxe, or -S(O)2Rxf;each Rxais independently halogen, Ci-Cs alkenyl, C2-C6 alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, oxo, -CN, -OR5, -SR5, -NR6R7, -NO2, -N3, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(ORG), wherein the C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of Rxaare independently optionally substituted by one or more R4a;Rxfis Ci-Ce alkyl optionally substituted by one or more Rxgor C3-C5 cycloalkyl optionally substituted by one or more Rxh;each Rxb, Rxc, Rxd, Rxe, Rxg, Rxh, and Yais independently oxo or R4;I? is C2-C4 alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Ce alkylene optionally substituted by one or more R4;L3is C2-C4 alkylene optionally substituted by one or more R4;Y is a bond or C3-C5 cycloalkylene optionally substituted by one or more oxo or R4; each R4is independently deuterium, halogen, Ci-Ce alkyl, Ci-Cs alkenyl, C2-C6 alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Cs-C aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -SR5, -NR6R7, -NO2, -Ns, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -S(O)2OH, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-C6alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently deuterium, halogen, oxo, -OR8, -NR8R9, -C(O)R8, -C(O)OR8, -NR8C(O)OR10, -CN, -S(O)R8, -S(O)2R8, -P(O)(OR8)(OR9), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-Cu aryl, or Ci-Cs alkyl, wherein tire 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-Cu aryl, and Ci-Cs alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently deuterium, oxo, -OH, -O-Ci-Cs alkyl, -O(2H), halogen, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R5is independently hydrogen, deuterium, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, C3-Cs cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, C3-C6 cycloalkyl, Ce-Cu aryl, 5- to 10-memberedAttorney Docket No.: 199C-436282-WOheteroaryl, and 3- to 10-membered heterocyclyl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, oxo, -CN, -OR10, -NR1'R12, -P(O)(ORn)(OR12), C3-C6 cycloalkyl, 3- to 12-membered heterocyclyl, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R6is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3- Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Cg alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R7is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C -Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;or R6and R7are taken together with tire atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, oxo, -OH, or -O(2H);each R8, R9, and R10is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz-Ce alkynyl, wherein the Ci-Cg alkyl, Cz-Ce alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andeach R11and R12is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz- Ce alkynyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo;or R11and R12are taken together with die atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, or Ci-Cg alkyl optionally substituted by one or more deuterium, oxo, or halogen.

[0236] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-1):Rx□3 H I H'Y y YO OH (RA-II-1 ), wherein R3and Rxare as defined for (RA-II).Attorney Docket No.: 199C-436282-WO

[0237] In some embodiments of formula (RA-II), R3is a Ce-Cu aryl optionally substituted by one or more R4. In some embodiments, R3is a 5- to 12-membered heteroaryl optionally substituted by one or more R4. In some embodiments, R3is phenyl substituted by 1-3 R4. In some embodiments, R3is pyridinyl substituted by 1-3 R4.

[0238] In some embodiments of formula (RA-II), each R4is independently halogen, -CN, -OR5, -NR6R7, Ci-Ce alkyl, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-C aryl, or 5- to 10-membered heteroaryl, wherein the Ci-Ce alkyl, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a.

[0239] In some embodiments of formula (RA-II), each R4is independently halogen. In some embodiments, each R4is independently fluorine or chlorine.

[0240] In some embodiments of formula (RA-I1), R3is phenyl substituted by 1-2 halogen. In some embodiments, R3is phenyl substituted by 1-2 fluorine or chlorine.

[0241] In some embodiments of formula (RA-II), Rxis Ci-Cs alkyl substituted by one or more Rxa. In some embodiments, Rxis Ci-Ce alkyl substituted by 1-5 Rxagroups, wherein each Rxais independently selected from the group consisting of halogen, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-C aryl, 5- to 10-membered heteroaryl, -CN, -OR5, and -S aR5, and wherein the Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of Rxaare independently optionally substituted by one or more R4a. In some embodiments, Rxis C1-C4 alkyl substituted by -OR5. In some embodiments, Rxis C1-C4 alkyl substituted by -OCHa. In some embodiments, Rxis methoxyethyl.

[0242] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-2):wherein Rxand R4arc as defined for (RA-II).

[0243] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-2a):wherein R4is as defined for (RA-II).

[0244] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-2b):Attorney Docket No.: 199C-436282-WO(RA-II-2b), wherein R4is as defined for (RA-II).

[0245] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-2c):(RA-II-2c), wherein R4is as defined for (RA-II).

[0246] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-2d):(RA-II-2d), Wherein R4is as defined for (RA-II).

[0247] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-3):wherein Rxand R4are as defined for (RA-II).

[0248] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-3a):(RA-II-3a), wherein R4is as defined for (RA-II).Attorney Docket No.: 199C-436282-WO

[0249] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-3b):wherein R4is as defined for (RA-II).

[0250] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-3c):(RA-II-3c), wherein R4is as defined for (RA-II).

[0251] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-3d):(RA-ll-3d), wherein R4is as defined for (RA-II).

[0252] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-3e):(RA-II-3e), wherein R4is as defined for (RA-II).

[0253] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-4):Attorney Docket No.: 199C-436282-WOwherein Rxand R4are as defined for (RA-II).

[0254] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-4a):wherein R4is as defined for (RA-II).

[0255] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-4b):(RA-II-4b), wherein R4is as defined for (RA-II).

[0256] In some embodiments, the fragment of formula (RA-1I) is a fragment of formula (RA-Il-4c):(RA-II-4c), wherein R4is as defined for (RA-II).

[0257] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-4d):(RA-II-4d), wherein R4is as defined for (RA-II).

[0258] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-4e):wherein R4is as defined for (RA-II).Attorney Docket No.: 199C-436282-WO

[0259] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-5):wherein Rxand R4are as defined for (RA-II).

[0260] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-5a):wherein R4is as defined for (RA-II).

[0261] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-5b):(RA-II-5b), wherein R4is as defined for (RA-II).

[0262] In some embodiments, tlie fragment of formula (RA-II) is a fragment of formula (RA-II-5c):(RA-II-5c), wherein R4is as defined for (RA-II).

[0263] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-5d):(RA-II-5d), wherein R4is as defined for (RA-II).IllAttorney Docket No.: 199C-436282-WO

[0264] In some embodiments, the fragment of formula (RA-II) is a fragment of formula (RA-II-5e):H N I I(RA-II-5e), wherein R4is as defined for (RA-II).TV. Linkers

[0265] In some embodiments, RBis a bond. In some embodiments, RBcomprises an optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted alkenylene, optionally substituted heteroalkenylene, optionally substituted alkynylene, optionally substituted heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, or any combination thereof.

[0266] In some embodiments, RBis C1-C300 alkylene, whereinthe C1-C300 alkylene is optionally substituted by one or more deutero, halo, Ci-Cc alkyl, Ci-Cc haloalkyl, oxo, -O(Ci-Ce alkyl), -CXCi-Cshaloalkyl), -OfCa-Cs cycloalkyl), -N(RL1)(RL3)-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20-membered heteroaryl; and one or more of the C atoms in the C1-C300 alkyl is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -C=C-, -N(RL1)C(O)O-, -N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)Lq-, -S(O)LqO-, -OS(O)Lq-, -OS(O)LqO-, - 0S(0)LqN(R14)-, -N(R, J)S(O)LqO-, -N(R’4)S(O)LqN(RL3)-, -S(O)LqN(RL’)-, -N(RL1)S(O)Lq-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Cg-Cu aryl, or 5- to 20-membered heteroaryl; wherein,each C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20- membered heteroaryl is optionally substituted with one or more deutero, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Ce haloalkyl), -O(Ci-Ce cycloalkyl), - N(RL2)(RU), -C(O)RL5, -C(O)ORL5, -OC(O)RL5, -OC(O)ORL5, -OC(O)N(RL2)(RL4), - N(RL2)C(O)ORL5, -N(RL2)C(O)N(RL2)(RL4), -C(O)N(RL2)(RL4), -N(RL2)C(O)RL5, - N(RL2)(RL4), -S(O)LqRL5, -S(O)LqORL5, -OS(O)LqRL5, -OS(O)LqORL5, -OS(O)LqN(RL2)(RL4), - N(RL2)S(O)LqORL5, -N(RL2)S(O)LqN(RL2)(RL4), -S(O)LqN(RL2)(RL4), or -N(RL2)S(O)LqRL5;each RL1, RL2, RL3, RL4, and RL5is independently H, Ci-C6alkyl, Ci-C6haloalkyl, or Ci-Cs cycloalkyl; each andeach Lq is independently 0, 1, or 2.

[0267] In some embodiments, RBis C1-C200 alkylene, whereinAttorney Docket No.: 199C-436282-WOthe C1-C200 alkylene is optionally substituted by one or more deutero, halo, Ci-Ce alkyl, Ci-Cs haloalkyl, oxo (C=O), -O(Ci-C6alkyl), -O(Ci-C6haloalkyl), -O(C3-C6cycloalkyl), -N(RL1)(RL3)-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Cg-Cu aryl, or 5- to 20-membered heteroaryl; and one or more of the C atoms in the C1-C200 alkylene is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -OC-, -N(RL1)C(O)O-, - N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)Lq-, -S(O)LqO-, -OS(O)Lq-, -OS(O)LqO-, - OS(O)LqN(RL1)-, -N(RL1)S(O)LqO-, -N(RL1)S(O)LqN(RL3)-, -S(O)LqN(RL1)-, -N(RL1)S(O)Lq-, C3-Ci5 cycloalkyl, 3- to 15-membered heterocyclyl, Cg-Cu aryl, or 5- to 20-membered heteroaryl; wherein,each C3-Ci5 cycloalkyl, 3- to 15-membered heterocyclyl, Cg-Cu aryl, or 5- to 20- membered heteroaryl is optionally substituted with one or more deutero, halo, Ci-Cg alkyl, Ci-Cg haloalkyl, oxo (C=O), -O(Ci-Cg alkyl), -O(Ci-Cg haloalkyl), -O(Ci-Cg cycloalkyl), - N(RL2)(RU), -C(O)RL5, -C(O)ORL5, -OC(O)RL5, -OC(O)ORLS, -0C(0)N(RL2)(RL4), - N(RL2)C(O)ORL5, -N(RL2)C(O)N(RL2)(RL4), -C(O)N(RL2)(RL4), -N(RL2)C(O)RL5, - N(RL2)(RU), -S(O)i.qRL5, -S(O)i.qORL5, -OS(OkqRL5, -OS(O)T.qORL5, -OS(O)LqN(RL2)(RL4), - N(RL2)S(O)LqORL5, -N(RL2)S(O)LqN(RL2)(RL4), -S(O)LqN(RL2)(RL4), or -N(RL2)S(O)LqRL5;each RL1, RL2, RL3, RL4, and RL5is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Ce cycloalkyl; andeach Lq is independently 0, 1, or 2.

[0268] In some embodiments, RBis C1-C100 alkylene, whereinthe C1-C100 alkylene is optionally substituted by one or more deutero, halo, Ci-Cg alkyl, Ci-Cg haloalkyl, oxo (C=O), -O(Ci-C6alkyl), -O(Ci-Cghaloalkyl), -O(C3-C6cycloalkyl), -N(RL1)(RL3)-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Cg-Cu aryl, or 5- to 20-membered heteroaryl; and one or more of the C atoms in the C1-C100 alkylene is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -OC-, -N(RL1)C(O)O-, - N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)Lq-, -S(O)LqO-, -OS(O)Lq-, -OS(O)LqO-, - OS(O)LQN(RL1)-, -N(RL1)S(O)LQO-, -N(RL1)S(O)LqN(RL3)-, -S(O)LqN(RL1)-, - N(R'4)S(O)Lq-, C3-Ci5 cycloalkyl, 3- to 15-membered heterocyclyl, Cg-Cu aryl, or 5- to 20-membered heteroaryl; wherein,each C3-Ci5 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20- membered heteroaryl is optionally substituted with one or more deutero, halo, Ci-Cg alkyl, Ci-Ce haloalkyl, oxo (C=O), -O(Ci-Cg alkyl), -O(Ci-Cg haloalkyl), -O(Ci-Cg cycloalkyl), - NCR^KR141), -C(O)RL5, -C(O)ORL5, -OC(O)RL5, -OC(O)ORLS, -OC(O)N(RL2)(RL4), - N(RL2)C(O)ORL5, -N(RL2)C(O)N(RL2)(RL4), -C(O)N(RL2)(RL4), -N(RL2)C(O)RL5, - N(RL2)(RU), -S(O)LqRL5, -S(O)LqORL5, -OS(O)LqRL5, -OS(O)LqORL5, -OS(O)LqN(RL2)(RL4), - N(RL2)S(O)LqORL5, -N(RL2)S(O)LqN(RL2)(RL4), -S(O)LqN(RL2)(RL4), or -N(RL2)S(O)LqRL5;Attorney Docket No.: 199C-436282-WOeach RL1, RL2, RL3, RL4, and RL5is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce cycloalkyl; andeach Lq is independently 0, 1, or 2.

[0269] In some embodiments, RBis C1-C300 alkylene, wherein one or more of the C atoms in the C1-C100 alkylene is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -C=C-, -N(RL1)C(O)O-, - N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)Lq-, -S(O)LqO-, -OS(O)Lq-, -OS(O)LqO-, - OS(O)LqN(RL1)-, -N(RL1)S(O)LqO-, -N(RL1)S(O)LqN(RL3)-, -S(O)LqN(RL1)-, -N(RL1)S(O)Lq-, C3-Ci5cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20-membered heteroaryl; wherein each RL1and RL3is independently H, C1-G5 alkyl, Ci-Ce haloalkyl, or Ci-Cg cycloalkyl; and each Lq is independently 0, 1, or 2.

[0270] In some embodiments, RBis C1-C200 alkylene, wherein one or more of the C atoms in the C1-C50 alkylene is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -C=C-, -N(RL1)C(O)O-, - N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)i.q-, -S(O)i4O-, -OS(O)i4-, -OS(O)i.qO-, - OS(O),4N(RL1)-, -N(RL1)S(O)LqO-, -N(RL1)S(O)LqN(RL3)-, -S(O)LqN(RL1)-, -N(RL1)S(O)Lq-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Cg-Cu aryl, or 5- to 20-membered heteroaryl; wherein each RL1and RL3is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg cycloalkyl; and each Lq is independently 0, 1, or 2.

[0271] In some embodiments, RBis C1-C100 alkylene, wherein one or more of the C atoms in the C1-C20 alkylene is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -C=C-, -N(RL1)C(O)O-, - N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)Lq-, -S(O)LqO-, -OS(O)Lq-, -OS(O)LqO-, - OS(O)LqN(RL1)-, -N(RL1)S(O)LQO-, -N(RL1)S(O)LqN(RL3)-, -S(O)LqN(RL1)-, -N(RL1)S(O)Lq-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, C -Ci4 aryl, or 5- to 20-membered heteroaryl; wherein each RL1and RL3is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Cg cycloalkyl; and each Lq is independently 0, 1, or 2.

[0272] In some embodiments, RBis unsubstituted C1-C40 alkylene, wherein tire alkylene may be linear or branched. In some embodiments, RBis unsubstituted linear C1-C40 alkylene. In some embodiments, RBis unsubstituted branched C1-C40 alkylene. In some embodiments, RBis unsubstituted C4-C24 alkylene, wherein the alkylene may be linear or branched. In some embodiments, RBis unsubstituted linear C4-C24 alkylene. In some embodiments, RBis unsubstituted branched C4-C24 alkylene.

[0273] In some embodiments, RBis unsubstituted linear C4 alkylene. In some embodiments, RDis unsubstituted branched C4 alkylene. In some embodiments, RBis unsubstituted linear G, alkylene. In some embodiments, RBis unsubstituted branched Cg alkylene. In some embodiments, RBis unsubstituted linear G alkylene. In some embodiments, RBis unsubstituted branched Cg alkylene. InAttorney Docket No.: 199C-436282-WOsome embodiments, RBis unsubstituted linear Cio alkylene. In some embodiments, RBis unsubstituted branched Cio alkylene. In some embodiments, RBis unsubstituted linear C12 alkylene. In some embodiments, RBis mis nbsti tilted branched C12 alkylene. In some embodiments, RBis unsubstituted linear C14 alkylene. In some embodiments, RBis unsubstituted branched C14 alkylene. In some embodiments, RBis unsubstiluted linear Cie alkylene. In some embodiments, RBis un substituted branched Cie alkylene. In some embodiments, RBis unsubstituted linear Cis alkylene. In some embodiments, RBis unsubstituted branched Cis alkylene. In some embodiments, RBis unsubstituted linear C20 alkylene. In some embodiments, RBis unsubstituted branched C20 alkylene. In some embodiments, RBis unsubstituted linear C22 alkylene. In some embodiments, RBis unsubstituted branched C22 alkylene. In some embodiments, RBis unsubstituted linear C24 alkylene. In some embodiments, RBis unsubstituted branched C24 alkylene.L0274J In some embodiments, RBcomprises a polymer. In some embodiments, the polymer is polyethylene glycol (PEG). In some embodiments, die polyethylene glycol comprises about 3 to about 100 ethylene glycol units. In some embodiments, the polyethylene glycol comprises about 3 to about 50 ethylene glycol units. In some embodiments, the polyethylene glycol comprises about 3 to about 24 ethylene glycol units. In some embodiments, the polyethylene glycol comprises about 3 to about 20 ethylene glycol units. In some embodiments, the polyethylene glycol comprises about 3 to about 10 ethylene glycol units.

[0275] In some embodiments, RBcomprises a polymer. In some embodiments, the polymer is polyethylene glycol (PEG). In some embodiments, the polyethylene glycol comprises 3 to 100 ethylene glycol units. In some embodiments, the polyethylene glycol comprises 3 to 50 ethylene glycol units. In some embodiments, tire polyethylene glycol comprises 3 to 24 ethylene glycol units. In some embodiments, the polyethylene glycol comprises 3 to 20 ethylene glycol units. In some embodiments, the polyethylene glycol comprises 3 to 10 ethylene glycol units.

[0276] In some embodiments, RBcomprises a polyethylene glycol chain comprising about 3 to about 100 ethylene glycol units, about 3 to about 50 ethylene glycol units, about 3 to about 20 ethylene glycol units, or about 3 to about 10 ethylene glycol units, wherein:each C atom in the polyethylene glycol chain is optionally substituted by one or more deutero, halo, Ci-Ce alkyl, Ci-Cehaloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Cehaloalkyl), -O(C3-Ce cycloalkyl), -N(RL1)(RL3)-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Ci4 aryl, or 5- to 20-membered heteroaryl; andone or more of the C atoms in the polyethylene glycol chain is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -C=C-, -N(RL1)C(O)O-, - N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)Lq-, -S(O)LqO-, -OS(O)Lq-, -OS(O)LqO-, - OS(O)LqN(RL1)-, -N(RL1)S(O)LqO-, -N(RL1)S(O)LqN(RL3)-, -S(O)LqN(RL1)-, -N(RL1)S(O)Lq-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Ci4 aryl, or 5- to 20-membered heteroaryl, whereinAttorney Docket No.: 199C-436282-WOeach C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20- membered heteroaryl is optionally substituted with one or more deutero, halo, Ci-C& alkyl, Ci-Ce haloalkyl, oxo (('=()), -O(Ci-Ce alkyl), -O(Ci-Ce haloalkyl), -O(Ci-Ce cycloalkyl), - N(RL2)(RL4), -C(O)RLS, -C(O)ORLS, -OC(O)RL5, -OC(O)ORL5, -OC(O)N(RL2)(RL4), - N(RL2)C(O)ORL5, -N(RL2)C(O)N(RL2)(RL4), -C(O)N(RL2)(RL4), -N(RL2)C(O)RL5, - N(RL2)(RM), -S(O)LqRLS, -S(O)LqORL5, -OS(O)LqRL5, -OS(O)LqORL5, -OS(O)LqN(RL2)(RL4), - N(RL2)S(O)LqORL5, -N(RL2)S(O)LqN(RL2)(RL4), -S(O)LqN(RL2)(RL4), or -N(RL2)S(O)LqRL5; each RL1, RL2,RL3, RL4, and RL5is independently H, Ci-C6alkyl, Ci-C6haloalkyl, or Ci-Ce cycloalkyl; andeach Lq is independently 0, 1, or 2.

[0277] In some embodiments, RBcomprises a polyethylene glycol chain comprising 3 to 100 ethylene glycol units, 3 to 50 ethylene glycol units, 3 to 20 ethylene glycol units, or 3 to 10 ethylene glycol units, wherein:each C atom in the polyethylene glycol chain is optionally substituted by one or more deutero, halo, Ci-Csalkyl, Cj-Ce haloalkyl, oxo (C=O), -O(Ci-C6alkyl), -OlCj-Ce haloalkyl), -O(C3-C6cycloalkyl), -N(RL1)(RL3)-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20-membered heteroaryl; andone or more of the C atoms in the polyethylene glycol chain is optionally replaced with one or more -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(RL1)-, -C(RL1)=C(RL1)-, -C=C-, -N(RL1)C(O)O-, - N(RL1)C(O)N(RL3)-, -C(O)N(RL1)-, -N(RL1)C(O)-, -N(RL1)-, -S(O)Lq-, -S(O)LqO-, -OS(O)Lq-, -OS(O)LqO-, - OS(O)LqN(RL1)-, -N(RL1)S(O)LqO-, -N(RL1)S(O)LqN(RL3)-, -S(O)LqN(RL1)-, -N(RL1)S(O)Lq-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20-membered heteroaryl, whereineach C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20- membered heteroaryl is optionally substituted with one or more deutero, halo, Ci-Cg alkyl, Ci-Ce haloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Ce haloalkyl), -O(Ci-Ce cycloalkyl), - N(RL2)(RL4), -C(O)RL5, -C(O)ORL5, -OC(O)RL5, -OC(O)ORL5, -OC(O)N(RL2)(RL4), - N(RL2)C(O)ORL5, -N(RL2)C(O)N(RL2)(R1'4), -C(0)N(RL2)(R14), -N(RL2)C(O)RL5, - N(RL2)(RL4), -S(O)LQRLS, -S(O)LqORL5, -OS(O)LqRL5, -OS(O)LqORLS, -OS(O)LqN(RL2)(RL4), - N(RL2)S(O)LqORL5, -N(RL2)S(O)LqN(RL2)(RL4), -S(O)LqN(RL2)(RL4), or -N(RL2)S(O)LqRL5;each RL1, RL2, RL3, RL4, and RL5is independently H, Ci-C6alkyl, Ci-C6haloalkyl, or Ci-Ce cycloalkyl; andeach Lq is independently 0, 1, or 2.

[0278] In some embodiments, RBcomprises a polyethylene glycol chain comprising about 3 to about 100 ethylene glycol units, about 3 to about 50 ethylene glycol units, about 3 to about 20 ethylene glycol units, or about 3 to about 10 ethylene glycol units, whereinAttorney Docket No.: 199C-436282-WOeach C atom in the polyethylene glycol chain is optionally substituted by one or more deutero, halo, Ci-C6alkyl, Ci-C6haloalkyl, oxo (C=O), -O(Ci-C6alkyl), -O(Ci-C6haloalkyl), -O(C3-C6cycloalkyl), -N(R' ’)(R'3)-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20-membered heteroaryl, whereineach C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20- membered heteroaryl is optionally substituted with one or more deutero, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Ce haloalkyl), -O(Ci-Ce cycloalkyl), - NCR^KR1^), -C(O)RL5, -C(O)ORL5, -OC(O)RL5, -OC(O)ORLS, -OC(O)N(RL2)(RL4), - N(RL2)C(O)ORL5, -N(RL2)C(O)N(RL2)(RL4), -C(O)N(RL2)(RL4), -N(RL2)C(O)RL5, - N(RL2)(RU), -S(O)LqRL5, -S(O)LqORL5, -OS(O)LqRL5, -OS(O)LqORL5, -OS(O)LqN(RL2)(RL4), -N(RL2)S(O)LqORL5, -N(RL2)S(O)LqN(RL2)(RL4), -S(O)LqN(RL2)(RL4), or -N(RL2)S(O)LqRL5;each RL1, RL2, RL3, RL4, and RL5is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Cg cycloalkyl; andeach Lq is independently 0, 1, or 2.

[0279] In some embodiments, RBcomprises a polyethylene glycol chain comprising 3 to 100 ethylene glycol units, 3 to 50 ethylene glycol units, 3 to 20 ethylene glycol units, or 3 to 10 ethylene glycol units, whereineach C atom in the polyethylene glycol chain is optionally substituted by one or more deutero, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Ce haloalkyl), -O(C3-Ce cycloalkyl), -N(RL1)(RL3)-, C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-Cu aryl, or 5- to 20-membered heteroaryl, whereineach C3-C15 cycloalkyl, 3- to 15-membered heterocyclyl, Ce-C aryl, or 5- to 20- membered heteroaryl is optionally substituted with one or more deutero, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Ce haloalkyl), -O(Ci-Ce cycloalkyl), - N(RL2)(RL4), -C(O)RL5, -C(O)ORL5, -OC(O)RL5, -OC(O)ORL5, -OC(O)N(RL2)(RL4), - N(RL2)C(O)ORL5, -N(RL2)C(O)N(RL2)(RL4), -CIOW2)^14), -N(RL2)C(O)RL5, - N(RL2)(RL4), -S(O)LQRL5, -S(O)LQORL5, -OS(O)LqRL5, -OS(O)LQORL5, -OS(O)LqN(RL2)(RL4), - N(RL2)S(O)LqORL5, -N(RL2)S(O)LqN(RL2)(RL4), -S(O)LqN(RL2)(RL4), or -N(RL2)S(O)LqRLS;each RL1, RL2, RL3, RL4, and RL5is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce cycloalkyl; andeach Lq is independently 0, 1, or 2.

[0280] In some embodiments, RBcomprises a polyethylene glycol chain comprising about 3 to about 100 ethylene glycol units, about 3 to about 50 ethylene glycol units, about 3 to about 20 ethylene glycol units, or about 3 to about 10 ethylene glycol units, wherein each C atom in the polyethylene glycol chain is optionally substituted by one or more deutero, halo, Ci-Ce alkyl, Ci-Ce haloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Cehaloalkyl), -O(C3-Ce cycloalkyl), -N(RL1)(RL3)-, and wherein each RL1and RL3is independently H, Ci-Cg alkyl, Ci-Cg haloalkyl, or Ci-Ce cycloalkyl.Attorney Docket No.: 199C-436282-WO

[0281] In some embodiments, RBcomprises a polyethylene glycol chain comprising 3 to 100 ethylene glycol units, 3 to 50 ethylene glycol units, 3 to 20 ethylene glycol units, or 3 to 10 ethylene glycol units, wherein each C atom in the polyethylene glycol chain is optionally substituted by one or more deutero, halo, Ci-Ce alkyl, Ci-Cehaloalkyl, oxo (C=O), -O(Ci-Ce alkyl), -O(Ci-Cehaloalkyl), -O(C3-Ce cycloalkyl), -N(RL1)(RL3)-, and wherein each RL1and RL3is independently H, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce cycloalkyl.

[0282] In some embodiments, RBis a linker of formula (RB-I):L Jn (RB-I)wherein * denotes the point of attachment to RA, ** denotes the point of attachment to Rc, and n is an integer from 3 to 100. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 100. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 90. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 80. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 70. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 60. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 50. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 40. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 30. In some embodiments, RBis a linker of formula (RB-I) and n is an integer from 3 to 24. In some embodiments, RBis a linker of formula (RB-I) and n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24. In some embodiments, RBis a linker of formula (RB-I) and n is 3, 4, 6, 8, 10, 12, or 24. In some embodiments, RBis a linker of formula (RB-I) and n is 1, 2, 3, 4, 6, 8, 10, or 12. In some embodiments, RBis a linker of formula (RB-I) and n is 4.V. Conjugatable and Conjugated Groups

[0283] In some embodiments, the conjugatable group of Rccomprises a reactive site suitable for conjugation to a payload. For example, in some embodiments, Rccomprises a reactive site suitable for undergoing click chemistry. Reactive sites suitable for undergoing click chemistry are known in the art, and are described, for example, in Chemical Reviews 2021 Volume 121, Issue 12, Pages 6697-7248 and Click Reactions in Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA. (2016) (DOI: 10.1002 / 9783527694174), each of which is hereby incorporated by reference in its entirety.

[0284] In some embodiments, Rccomprises sulfhydryl groups to form disulfides or thioethers; aldehyde, ketone, and hydrazine groups to form hydrazones; carboxylic and amino groups to form amides; carboxylic and hydroxy groups to form esters; sulfonic acids to form sulfonamides; alcohols to form carbamates; and amines to form amides, sulfonamides or carbamates.Attorney Docket No.: 199C-436282-WO

[0285] In some embodiments, Rcis Ci-Cs alkynyl. In some embodiments, Rcis a terminal Ci-Cs alkynyl. In some embodiments, Rcis selected from the group consisting of, and, wherein ** denotes the point of attachment to RB.

[0286] In some embodiments, Rcis an azide. In some embodiments, Rcis Ci-Ce alkyl substituted by an azide.

[0287] In some embodiments, Rcmay be conjugated to RBthrough a disulfide bond, a thioether bond, a hydrazone bond, a peptide bond, an ester bond, a sulfonamide bond, a carbamate bond, or an amide bond. In some embodiments, Rcis a fragment of formula (Rc-I):HN— LEND(Rc-I)wherein each LRCis independently a bond or Ci-Ce alkyl, LENDis selected from H and a protecting group (e.g., -C(O)OC(CH3)3), and wherein ** denotes the point of attachment to RB.

[0288] In some embodiments, Rcis:N=N, wherein ** denotes the point of attachment to RB.

[0289] In some embodiments, the conjugated group of RDcomprises a group formed through the reaction of Rcwith a moiety on a reporting compound or a payload compound. For example, in some embodiments, RDis a group comprising a cycloalkyl, a heterocycle, an aryl, a heteroaryl, a disulfide, a thioether, a hydrazone, an ester, a sulfonamide, a carbamate, or an amide. In some embodiments, RDis a covalent bond.

[0290] In some embodiments, RDis a triazole. In some embodiments, RDis selected from the groupconsisting of, wherein ** denotes the point of attachment toRB, and *** denotes the point of attachment to RE. In some embodiments, RDiswherein ** denotes the point of attachment to RB, and *** denotes the point of attachment to RE.Attorney Docket No.: 199C-436282-WO

[0291] In some embodiments, Rcmay be conjugated to RBthrough a cycloalkyl, a heterocycle, an aryl, a heteroaryl, a disulfide, a thioether, a hydrazone, an ester, a sulfonamide, a carbamate, or an amide.

[0292] In some embodiments, RDis a fragment of formula (RD-I):(RD-Dwherein each LRCis independently a bond or Ci-Cs alkyl, wherein ** denotes the point of attachment to RBand *** denotes the point of attachment to RE.

[0293] In some embodiments, RDis:N=NL N O, wherein ** denotes the point of attachment to RB, and *** denotes the point of attachment to RE.

[0295] In some embodiments, Rccomprises a nitrone. In some embodiments, Rccomprises a substituted nitrone. In some embodiments, Rcis Ci-Ce alkyl substituted by a nitrone.Rck27®o

[0296] In some embodiments,Rcis. In some embodiments, Rcklis not hydrogen. In some embodiments, Rcklis the point of attachment to RB, and Rck2and Rck3are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, one of Rck2and Rck3is the point of attachment to RB, the other of Rck2and Rck3is hydrogen, Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl, and Rcklis Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck3is the point of attachment to RB, Rck2and Rckltaken together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl.

[0297] In some embodiments, Rccomprises a cyclooctyne. In some embodiments, Rcis Ci-Ce alkyl substituted by cyclooctyne. In some embodiments, Rccomprises a / rans-cyclooctcne. In some embodiments, Rcis Ci-Ce alkyl substituted by / m -cyclooclcne. In some embodiments, Rcis Rcis C2-C.6 alkynyl. In some embodiments, Rcis a terminal C2-C.6 alkynyl. In some embodiments, Rcisselected from the group consisting ofwherein ** denotes the point of attachment to RB.Attorney Docket No.: 199C-436282-WOVck4

[0298] In some embodiments, Rcis ' — ', wherein Rck4is the point of attachment to RB. In \ Rck4some embodiments, Rcis, wherein Rck4is the point of attachment to RB.

[0299] In some embodiments, RDis an optionally substituted octahydrocycloacta[d]isoxazole. In some embodiments, RDis a substituted octahydrocycloacta[d]isoxazole. In some embodiments, RDis an optionally substituted decahydrocycloocta[d]isoxazole. In some embodiments, RDis a substituted decahydrocycloocta [d]isoxazole. In some embodiments, RDis an optionally substituted azetidinone. In some embodiments, RDis a substituted azetidinone.Rck3rs \ _ I Rck2

[0300] In some embodiments,RDis O RcIn some embodiments, Rck5is the point of attachment to RB, one of Rck2and Rck3is the point of attachment to RE, the other of Rck2and Rck3is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rcklis Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl. In some embodiments, Rck5is tire point of attachment to RE, one of Rck2and Rck3is the point of attachment to RB, the other of Rck2and Rck3is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl 1, and Rcklis Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck5is the point of attachment to RB, Rcklis the point of attachment to RE, and Rck2and Rck3are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, or Rck2and Rckltaken together with tire atoms to which they are attached form a 4- to 7-membered heterocyclyl. In some embodiments, Rck5is the point of attachment to RE, Rcklis the point of attachment to RB, and Rck2and Rck3are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, or Rck2and Rckltaken together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl.Rck1

[0301] In some embodiments,RDis. In some embodiments, Rck4is the point of attachment to RB, one of Rck2and Rck3is die point of attachment to RE, the other of Rck2and Rck3is hydrogen, Ci-Cg alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rcklis Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl. In some embodiments, Rck4is the point of attachment to RE, one of Rck2and Rck3is the point of attachment to RB, the other of Rck2and Rck3is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rcklis Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck4is the point of attachment to RB, Rcklis the point of attachment to RE, andAttorney Docket No.: 199C-436282-WORck2and Rck3are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, or Rck2and Rckltaken together with tire atoms to which they are attached form a 4- to 7-membered heterocyclyl. In some embodiments, Rck4is the point of attachment to RE, Rcklis the point of attachment to RB, and Rck2and Rck3are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, or Rck2and Rckltaken together with tire atoms to which they are attached form a 4- to 7-membered heterocyclyl.Rck1N Rck2O pck3

[0302] In some embodiments,RDis R‘. In some embodiments, Rck4is the point of attachment to RB, one of Rck2and Rck3is the point of attachment to RE, the other of Rck2and Rck3is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rcklis Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl. In some embodiments, Rck4is the point of attachment to RE, one of Rck2and Rck3is the point of attachment to RB, the other of Rck2and Rck3is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rcklis Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck4is the point of attachment to RB, Rcklis the point of attachment to RE, and Rck2and Rck3are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, or Rck2and Rckltaken together with tire atoms to which they are attached form a 4- to 7-membered heterocyclyl. In some embodiments, Rck4is the point of attachment to RE, Rcklis the point of attachment to RB, and Rck2and Rck3arc each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, or Rck2and Rckltaken together with the atoms to which they are attached form a 4- to 7-membered heterocyclyl.

[0303] In some embodiments, Rccomprises a mesoionic group. In some embodiments, Rccomprises a syndone. In some embodiments, Rccomprises a 1,3-dithiolium-4-olale. In some embodiments, Rccomprises an azaiminosydnone. In some embodiments, Rccomprises an iminosyndnone.

[0304] In some embodiments,Rcis. In some embodiments, Rck6is the point of connection to RB, and Rck7and Rck8are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RB, and Rck6and Rcksare each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RB, and Rck6and Rck7are each independently hydrogen, Ci-Cg alkyl, phenyl, or 5- to 6-membered heteroaryl.Attorney Docket No.: 199C-436282-WO, _ pck10

[0305] In some embodiments, Rcis R. In some embodiments, one of Rck9and Rckl° is the point of attachment to RB, and the other of Rck9and Rckl° is hydrogen, Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl." T" S Ik I r"^ck9

[0306] In some embodiments, RcisN R, wherein Rck9is the point of attachment to RB.N'°\®N / ° ®N / NRCk7 pck8 Rck7 pck8

[0307] In some embodiments, R isKorK. In some embodiments, Rck7is tire point of connection to RB, and Rcksis hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rcksis the point of connection to RB, and Rck7is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.N'°\=M®N AZ—rLz7 / N QN

[0308] In some embodiments, Rcis Rc, wherein Rck7is the point of connection to RB.pck6 ©00S

[0309] In some embodiments,Rcis Rck8. In some embodiments, Rck6is the point of connection to RB, and Rck8is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RB, and Rck6is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.

[0310] In some embodiments, RDis a pyrazole. In some embodiments, RDis a thiophene. In some embodiments, RDis a 1,2,3-triazole.^ck10^ck6 j| \ _ pck9

[0311] In some embodiments,RDis Rck8. In some embodiments, Rck6is the point of connection to RB, Rck9is the point of connection to RE, and Rck7, Rck8, and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck6is the point of connection to RB, Rckl° is tire point of connection to RE, and Rck7, Rck8, and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RB, Rck9is the point of connection to RE, and Rck6, Rck8, and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RB, Rckl° is the point of connection to RE, and Rck6, Rcks, and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is tire point of connection to RB, Rck9is the point of connection to RE, andAttorney Docket No.: 199C-436282-WORck6, Rck7, and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RB, Rckl° is the point of connection to RE, and Rckfi, Rck7, and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl. In some embodiments, Rck6is the point of connection to RE, Rck9is the point of connection to RB, and Rck7, Rcks, and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck6is the point of connection to RE, Rckl° is the point of connection to RB, and Rck7, Rck8, and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RE, Rck9is the point of connection to RB, and Rck6, Rck8, and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RE, Rckl° is the point of connection to RB, and Rck6, Rck8, and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rcksis the point of connection to RE, Rck9is the point of connection to RB, and Rck6, Rck7, and Rckl° are each independently hydrogen, Ci-Cg alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RE, Rckl° is the point of connection to RB, and Rck6, Rck7, and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.j^ck6pck9r>ck8 i

[0312] In some embodiments,R isRK. In some embodiments, R is the point of attachment to RB, Rck6is the point of attachment to RE, and Rck7and Rck8are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck9is the point of attachment to RB, Rck7is the point of attachment to RE, and Rck6and Rck8are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck9is the point of attachment to RB, Rck8is the point of attachment to RE, and Rck6and Rck7are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck9is the point of attachment to RE, Rck6is the point of attachment to RB, and Rck7and Rck8are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-mcmbcrcd hctcroaryl. In some embodiments, Rck9is the point of attachment to RE, Rck7is the point of attachment to RB, and Rck6and Rck8are each independently hydrogen, Ci-Cs alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck9is the point of attachment to RE, Rck8is tire point of attachment to RB, and Rck6and Rck7are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.pck10

[0313] In some embodiments,RDis Rck8. In some embodiments, Rck7is the point of connection to RB, Rck9is the point of connection to RE, and Rck8and Rckl° are each independentlyAttorney Docket No.: 199C-436282-WOhydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RB, Rckl° is the point of connection to RE, and Rck8and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rcksis the point of connection to RB, Rck9is the point of connection to RE, Rck7and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rcksis the point of connection to RB, Rckl° is the point of connection to RE, and Rck7and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RE, Rck9is the point of connection to RB, and Rck8and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck7is the point of connection to RE, Rckl° is the point of connection to RB, and Rcksand Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RE, Rck9is the point of connection to RB, and Rck7and Rckl° are each independently hydrogen, Ci-Cg alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RE, Rckl° is the point of connection to RB, and Rck7and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.

[0314] In some embodiments, RDis Rck7. In some embodiments, Rck7is the point of connection to RB, and Rck9is the point of connection to RE. In some embodiments, Rck7is the point of connection to RE, and Rck9is the point of connection to RB.pck10ock6 / | pck9

[0315] In some embodiments,RDis Rck8. In some embodiments, Rck6is the point of connection to RB, Rck9is the point of connection to RE, and Rcksand Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck6is the point of connection to RB, Rckl° is the point of connection to RE, and Rck8and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RB, Rck9is the point of connection to RE, and Rck6and Rckl° are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RB, Rckl° is the point of connection to RE, and Rck6and Rck9are each independently hydrogen, Ci-Cg alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck6is die point of connection to RE, Rck9is the point of connection to RB, and Rck8and Rckl° are each independently hydrogen, Ci-Cg alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck6is the point of connection to RE, Rckl° is the point of connection to RB, and Rck8and Rck9are each independently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RE, Rck9is the point of connection to RB, and Rck6and Rckl° are eachAttorney Docket No.: 199C-436282-WOindependently hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck8is the point of connection to RE, Rckl° is die point of connection to RB, and Rck6and Rck9are each independendy hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.

[0316] In some embodiments, Rccomprises a propiolate. In some embodiments, Rccomprises a propiolamide. In some embodiments, Rccomprises a propionitrile. In some embodiments, Rccomprises a ynone. In some embodiments, Rccomprises an ethynylsulfone.

[0317] In some embodiments, Rccomprises a thiol. In some embodiments, Rccomprises an amine. In some embodiments, Rccomprises a hydroxyl. In some embodiments, Rccomprises a sodium thiophenolate.ck12Rck11— =

[0318] In some embodiments, Rcis 0. In some embodiments, Rcknis the point of connection to RB, and Rck12is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck12is the point of connection to RB, and Rcknis hydrogen or Ci-Ce alkyl.k1„ nck13 _ kii i

[0319] In some embodiments, RcisRCSHorn2 wherein Rck13is the point of connection to RB.N-Rck15Rck14— =

[0320] In some embodiments, Rcis 0 in some embodiments, Rck14is die point of connection to RB, and Rck15is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck15is the point of connection to RB, and Rck14is hydrogen or Ci-Ce alkyl.pck16 _ kii i

[0321] In some embodiments, Rcis2, wherein Rck16is die point of connection to RB. In ck16 ck17some embodiments, Rcis H, wherein one of Rck16and Rck17is the point of connection to RB, and the other of Rck16and Rck17is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.

[0322] In some embodiments, RDis a benzodiiazine. In some embodiments, RDis a benzothiazole. In some embodiments, RDis a vinylic diiol.

[0323] In some embodiments,RDis embodiments, Rck11is die point of connection to RB, Rck13is the point of connection to RE, and Rck12is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck12is the point of connection to RB, Rck13is the point of connection to RE, and Rck11is hydrogen or Ci-Ce alkyl. In some embodiments, Rck11is the point of connection to RE, Rck13is the point of connection to RD, and Rck12isAttorney Docket No.: 199C-436282-WOCi-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck12is the point of connection to RE, Rck13is the point of connection to RB, and Rck11is hydrogen or Ci-Ce alkyl.^ck13pckn Q NH Opck13 I II || ^N'^J<A / ^Rck12 / \ / <'RCk12

[0324] In some embodiments, RDis H or Rck11. In some embodiments, Rcknis tine point of connection to RB, Rck13is the point of connection to RE, and Rck12is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck12is the point of connection to RB, Rck13is the point of connection to RE, and Rck11is hydrogen or Ci-Ce alkyl. In some embodiments, Rck11is the point of connection to RE, Rck13is the point of connection to RB, and Rck12is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck12is the point of connection to RE, Rck13is the point of connection to RB, and Rck11is hydrogen or Ci-Ce alkyl.pckieXNH O1 11 Rck15Ck^i

[0325] In some embodiments,RDis RcH. In some embodiments, Rck14is the point of connection to RB, Rck15is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck16is the point of connection to RE. In some embodiments, Rck15is the point of connection to RB, Rck14is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck16is the point of connection to RE. In some embodiments, Rck14is the point of connection to RE, Rck15is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck16is the point of connection to RB. In some embodiments, Rck15is the point of connection to RE, Rck14is Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck16is the point of connection to RB.Rck14Opck16 I II pck15

[0326] In some embodiments, RDisR. In some embodiments, Rck14is the point of connection to RB, Rck15and Rck17are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck16is the point of connection to RE. In some embodiments, Rck15is the point of connection to RB, Rck14and Rck17are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck16is the point of connection to RE. In some embodiments, Rck14is the point of connection to RB, Rck15and Rck16are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck17is the point of connection to RE. In some embodiments, Rck15is the point of connection to RB, Rck14and Rck16are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck17is tine point of connection to RE. In some embodiments, Rck14is the point of connection to RE, Rck15and Rck17are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck16is tine point of connection to RB. In some embodiments, Rck15is the point of connection to RE, Rck14and Rck17are each independently Ci-Cs alkyl, phenyl, or 5- to 6-Attorney Docket No.: 199C-436282-WOmembered heteroaryl, and Rck16is the point of connection to RB. In some embodiments, Rck14is the point of connection to RE, Rck15and Rck16are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck17is the point of connection to RB. In some embodiments, Rck15is the point of connection to RE, Rck14and Rck16are each independently Ci-Ce alkyl, phenyl, or 5- to 6-menibered heteroaryl, and Rck17is the point of connection to RB.Rck18Rck18N'NII, N0 pCk19

[0327] In some embodiments,Rcis or N'O u °. T In some embodiments, Rck18is the point of connection to RB, and Rck19is hydrogen, Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl. In some embodiments, Rck19is the point of connection to RB, and Rck18is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl.pck21

[0328] In some embodiments, Rcis Rck20in some embodiments, Rck18is the point of connection to RB, and Rck19is hydrogen, Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, Rck19is the point of connection to RB, and Rck18is hydrogen, Ci-Ce alkyl, phenyl, or 5-to 6-membered heteroaryl.Rck18pM'N Rck2iJ RCk20

[0329] In some embodiments, RDis Rck19in someembodiments, Rcklsis the point of connection to RB, Rck19and Rck21are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck2CIis the point of connection to RE. In some embodiments, Rck19is the point of connection to RB, Rck18and Rck21are each independently Ci-Cg alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck2° is the point of connection to RE. In some embodiments, Rck18is the point of connection to RB, Rck19and Rck2° are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck21is the point of connection to RE. In some embodiments, Rck19is the point of connection to RB, Rck18and Rck2° are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck21is the point of connection to RE. In some embodiments, Rck18is the point of connection to RE, Rck19and Rck21are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck20is the point of connection to RB. In some embodiments, Rck19is the point of connection to RE, Rck18and Rck21are each independently Ci-Ce alkyl, phenyl, or 5- to 6-memberedAttorney Docket No.: 199C-436282-WOheteroaryl, and Rck20is the point of connection to RB. In some embodiments, Rck18is die point of connection to RE, Rck19and Rck2° are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heteroaryl, and Rck21is the point of connection to RB. In some embodiments, Rck19is the point of connection to RE, Rcklsand Rck2° are each independently Ci-Ce alkyl, phenyl, or 5- to 6-membered heleroaryl, and Rck21is the point of connection to RB.

[0330] In some embodiments, RDis a fragment of formula (RD-II):(RD-II)wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and m is an integer from 1 to 100. In some embodiments, RDis a fragment of formula (RD-II) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and m is an integer from 1 to 50. In some embodiments, RDis a fragment of formula (RD-II) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and m is an integer from 1 to 20. In some embodiments, RDis a fragment of formula (RD-II) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and m is an integer from 1 to 10.

[0331] In some embodiments, RDis a fragment of formula (RD-III):wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and p is an integer from 1 to 100. In some embodiments, RDis a fragment of formula (RD-III) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and p is an integer from 1 to 50. In some embodiments, RDis a fragment of formula (RD-III) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and p is an integer from 1 to 20. In some embodiments, RDis a fragment of formula (RD-III) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and p is an integer from 1 to 10.

[0332] In some embodiments, RDis a fragment of formula (RD-IV):wherein ** denotes the point of attachment to RB; *** denotes tire point of attachment to RE; and qi and q2 are each independently an integer from 1 to 100. In some embodiments, RDis a fragment of formula (RD-IV) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and qi and q2 are each independently an integer from 1 to 50. In some embodiments,Attorney Docket No.: 199C-436282-WORDis a fragment of formula (RD-IV) wherein ** denotes the point of attachment to RB; *** denotes tire point of attachment to RE; and qi and cp are each independently an integer from 1 to 20. In some embodiments, RDis a fragment of formula (RD-IV) wherein ** denotes tire point of attachment to RB; *** denotes tire point of attachment to RE; and qi and2are each independently air integer from 1 to 10.

[0333] In some embodiments, RDis a fragment of formula (RD-V):wherein ** denotes the point of attachment to RB; *** denotes tire point of attachment to RE; and n, r2, and r3are each independently an integer from 1 to 100. In some embodiments, RDis a fragment of formula (RD-V) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and n, r2, and r-, are each independently an integer from 1 to 50. In some embodiments, RDis a fragment of formula (RD-V) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and ri, r2, and r3are each independently an integer from 1 to 20. In some embodiments, RDis a fragment of formula (RD-V) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and ri, r2, and r3are each independently an integer from 1 to 10.

[0334] In some embodiments, RDis a fragment of formula (RD-VI):(RD-VI)wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and s is an integer from 1 to 100. In some embodiments, RDis a fragment of formula (RD-VI) wherein ** denotes tire point of attachment to RB; *** denotes the point of attachment to RE; and s is an integer from 1 to 50. In some embodiments, RDis a fragment of formula (RD-VI) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and s is an integer from 1 to 20. In some embodiments, RDis a fragment of formula (RD-VI) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and s is an integer from 1 to 10.Attorney Docket No.: 199C-436282-WO

[0335] In some embodiments, provided herein is a compound selected from the group consisting of tire compounds in Table 1, or a pharmaceutically acceptable salt thereof.Table 1Compound StructureNo.FuQoSI J1 1 H / \ T Io X I I JHO o' XF \ / °-CI-x ° > < z ' —S2 UCo z — < i1 1 HHy o oNz.^ -Nxz^z / VzN N\_ \ / X X X I I jHO" X)Fr x?S3 T 1 HH NK / \z NX X I J HO X)FXvCIo-^zo\z''x'C).'X.zo\X ULoS4 J1 1 H nNv^NxAXAx zN^NzX X I jHO' X)7S5H N N VO9S6 HN^, N.ixxAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOX.0^0 7S21 / \ \ \ HI I A JH0" X) X / \Z\, O^O )S22 '•" T i l H7 Q JHO X\ X.,0 )S23 '7 T 1 HT HO' X) I \XI\X J0'7S24 7r°7° HN N HO' X) UMFS25 Oto J >HN1N\ Hv^- xX\X'x / N\ / N\I HO" X3 I I J0'5S26 TX° HN N I I J HQ- X)S27 " 7XX°X r^07 r5HTHO' XD 1 X^ 1-X^X JAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOVI. Payloads

[0336] A payload as used herein includes may be, but is not limited to, a pharmaceutically active ingredient or compound, a prodrug, or another substance with known therapeutic or diagnostic benefit. In some embodiments, a payload can be, but is not limited to, a small molecule, an antibody, an antibody fragment, an immunoglobulin, a monoclonal antibody, a label or marker, a lipid, a natural or modified oligonuclcotidc-bascd compound (e.g., an antisense oligonucleotide or an RNAi agent), a natural or modified nucleic acid, a peptide, an aptamer, a polymer, a polyamine, a protein, a toxin, a vitamin, a polyethylene glycol, a hapten, a digoxigenin, a biotin, a radioactive atom or molecule, or a fluorophore. In some embodiments, the payload is a reporting group or label. In some embodiments, the label may be a dye, such as a fluorescent dye.

[0337] In some embodiments, REis a reporting group or label. In some embodiments, REis a fluorescent label or a dye. In some embodiments, REis a radioactive label.

[0338] The reporting group or label of REmay, for example: (i) provide a detectable signal; (ii) interact with a second label to modify the detectable signal provided by the first or second label, e.g. to give FRET (fluorescence resonance energy transfer); (iii) stabilize interactions or increase affinity of ligand binding; (iv) affect mobility, e.g. electrophoretic mobility or cell-permeability, by charge, hydrophobicity, shape, or other physical parameters, or (v) provide a capture moiety, to modulate ligand affinity, or ionic complexation.Attorney Docket No.: 199C-436282-WO

[0339] Compounds of formula (II) wherein REis a reporting group or label may be useful in diagnostic assays, e.g., for detecting expression of integrins of interest in specific cells, tissues, or serum. For diagnostic applications, RRmay be a detectable moiety, such as a reporting group or label. Numerous labels are available which can be generally grouped into the following categories:

[0340] Radioisotopes (radionuclides), such as3H,nC,14C,32P,64Cu,68Ga,S6Y,wTc,niIn,1231,124I,1251,1311,133Xe,177Lu,211At or213Bi. Radioisotope labelled conjugates are useful in targeted imaging experiments. In some embodiments, REmay comprise a ligand group that binds, chelates or otherwise complexes a radioisotope metal. Chelating ligands which may complex a metal ion include DOTA, DOTP, DOTMA, DTPA and TETA (Macrocyclics, Dallas, Tex., see https: / / www.macrocyclics.com / , the contents of which are incorporated herein by reference.).

[0341] Metal-chelate complexes suitable as labels for imaging experiments are disclosed in, e.g., U. S. Pat. No. 5,342,606; U. S. Pat. No. 5,428,155; U. S. Pat. No. 5,316,757; U. S. Pat. No. 5,480,990; U. S. Pat. No. 5,462,725; U. S. Pat. No. 5,428,139; U. S. Pat. No. 5,385,893; U. S. Pat. No. 5,739,294; U. S. Pat. No. 5,750,660; U. S. Pat. No. 5,834,456; Hnatowich et al (1983) J. Immunol. Methods 65:147-157; Meares et al (1984) Anal. Biochem. 142:68-78; Mirzadeh et al (1990) Bioconjugate Chem. 1:59-65; Meares et al (1990).1. Cancer 1990, Suppl. 10:21-26; Izard et al (1992) Bioconjugate Chem. 3:346-350; Nikula et al (1995) Nucl. Med. Biol. 22:387-90; Camera et al (1993) Nucl. Med. Biol. 20:955-62; Kukis et al (1998) J. Nucl. Med. 39:2105-2110; Verel et al (2003) I. Nucl. Med. 44:1663-1670; Camera et al (1994) J. Nucl. Med. 21:640-646; Ruegg et al (1990) Cancer Res.50:4221-4226; Verel et al (2003) J. Nucl. Med. 44:1663-1670; Lee et al (2001) Cancer Res. 61:4474-4482; Mitchell, et al (2003) I. Nucl. Med. 44:1105-1112; Kobayashi et al (1999) Bioconjugate Chem.10:103-111; Miederer et al (2004) J. Nucl. Med. 45:129-137; DeNardo et al (1998) Clinical Cancer Research 4:2483-90; Blend et al (2003) Cancer Biotherapy & Radiopharmaceuticals 18:355-363; Nikula et al (1999) J. Nucl. Med. 40: 166-76; Kobayashi et al (1998) J. Nucl. Med. 39:829-36;Mardirossian et al (1993) Nucl. Med. Biol. 20:65-74; Roselli et al (1999) Cancer Biotherapy & Radiopharmaceuticals, 14:209-20, each of which is hereby incorporated by reference in its entirety.

[0342] Fluorescent labels such as rare earth chelates (europium chelates), fluorescein types including FITC, 5 -carboxy fluorescein, 6-carboxy fluorescein; rhodamine types including TAMRA; dansyl; Lissamine; cyanines; phycoerythrins; Texas Red; and analogs thereof. Fluorescent dyes and fluorescent label reagents include those which are commercially available from ThermoFisher Scientific (see https: / / www.thermofisher.com / us / en / liome / brands / molecular-probes.html, and https: / / www.thermofisher.com / us / en / liome / brands / thermo-scientific / pierce-protein-biology.html, each of which is incorporated by reference herein in its entirety).

[0343] In some embodiments, REcomprises a cyanine dye. In some embodiments, REis a fragment of formula (RE-A):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

[0344] Various enzyme-substrate labels are available or disclosed (U. S. Pat. No. 4,275,149, which is incorporated by reference herein in its entirety). The enzyme generally catalyzes a chemical alteration of a chromogenic substrate that can be measured using various techniques. For example, the enzyme may catalyze a color change in a substrate, which can be measured spcctrophotomctrically. Alternatively, tire enzyme may alter the fluorescence or chemiluminescence of the substrate.Techniques for quantifying a change in fluorescence are described above. The chemiluminescent substrate becomes electronically excited by a chemical reaction and may then emit light which can be measured (using a chemiluminomeler, for example) or donates energy to a fluorescent acceptor. Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U. S. Pat. No. 4,737,456, which is incorporated by reference herein in its entirety), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRP), alkaline phosphatase (AP), p-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like.

[0345] Examples of enzyme-substrate combinations include, for example:(i) horseradish peroxidase (HRP) with hydrogen peroxidase as a substrate, wherein the hydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylene diamine (OPD) or 3, 3', 5,5'-tetramethylbenzidine hydrochloride (TMB));(ii) alkaline phosphatase (AP) with para-nitrophenyl phosphate as chromogenic substrate; and (iii) P-D-galactosidase (P-D-Gal) with a chromogenic substrate (e.g., p-nitrophenyl-(P-D-galactosidase) or Anorogenic substrate 4-methylumbelliferyl-P-D-galactosidase.

[0346] Numerous other enzyme-substrate combinations are available to those skilled in the art. See U. S. Pat. No. 4,275,149 and U. S. Pat. No. 4,318,980, each of which is incorporated by reference herein in its entirety.

[0347] Compounds of formula (II) may be useful as imaging biomarkers and probes by the various methods and techniques of biomedical and molecular imaging such as: (i) MRI (magnetic resonanceAttorney Docket No.: 199C-436282-WOimaging); (ii) MicroCT (computerized tomography); (iii) SPECT (single photon emission computed tomography); (iv) PET (positron emission tomography) (Chen et al (2004) Bioconjugate Chem. 15:41-49 which is incorporated by reference herein in its entirety); (v) bioluminescence; (vi) fluorescence; and (vii) ultrasound.

[0348] In some embodiments, REcomprises an antineoplaslic agent, such as monomelhyl auristatin E (MMAE). In some embodiments, REis a fragment of formula (RE-B):wherein *** denotes the point of attachment to RD.

[0349] In some embodiments, REcomprises a drug payload optionally conjugated to a cleavable group, such as a cathepsin B-cleavable group. In some embodiments, REcomprises a drug payload conjugated to a cleavable group and a self-immolative group, such as p-aminobenzyl (PAB). In some embodiments, RE comprises a drug payload conjugated to Val-Cit-PAB, CBu-Cit-PAB (cyclobutane-1,1-dicarboxamide-Citrulline -p-aminobenzyl), GGFG-PAB (Gly-Gly-Phe-Gly-p-aminobenzyl), Ala-Ala-Asp-PAB, Exo-EVC-PAB (Glu-Val-Cit at the exo position of PAB), or Exo-EEVC-PAB (Glu-Glu-Val-Cit at the exo position of PAB). Additional examples of suitable cleavable groups can be found in Su et al., Acta Pharmaceutica Sinica B (2021); 11(12): 3889-3907.

[0350] In some embodiments, REcomprises an antineoplastic agent optionally conjugated to a cleavable and / or self-immolative group. In some embodiments, REcomprises MMAE conjugated to a cathepsin B-cleavable group and / or p-aminobenzyl (PAB).

[0351] In some embodiments, REis a fragment of formula (RE-C):wherein *** denotes the point of attachment to RDand AA1is a cleavable peptide such as Val-Cit, CBu-Cit, Gly-Gly-Phe-Gly, or Ala-Ala-Asp.

[0352] In some embodiments, REis a fragment of formula (RE-D):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RDand AA2is a cleavable peptide such as Glu-Val-Cit or Glu-Glu-Val-Cit.

[0353] In some embodiments, REis a fragment of formula (RE-E):wherein *** denotes the point of attachment to RD.

[0354] In some embodiments, REis a fragment of formula (RE-F):wherein *** denotes the point of attachment to RD.

[0355] In some embodiments, REis a fragment of formula (RE-G):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

[0356] In some embodiments, REis a fragment of formula (RE-H):wherein *** denotes the point of attachment to RD.

[0357] In some embodiments, REis a fragment of formula (RE-I):O (RE-I) wherein *** denotes the point of attachment to RD.

[0358] In some embodiments, REis a fragment of formula (RE-J):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

[0359] In some embodiments, provided herein is a compound of formula (II) selected from the group consisting of the compounds in Table 2, or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOTable 2 - ContinuedCompoundStructureNo.i0P i0r° ' °"C9 0 / * ONO3JH / °^n N" I\ °x_ p 0 / N / X x\0HN \-= / 0\ / / jj, o 1 90hOhO— HN'^ = N H" Y JN,’< rX^N p^N J S UHX?F pO. N,=N / o L ^N H- -- CIO H1 Cl _ o _ J ' Xx N J J-s, HO rj^l^ 0^^ '^'^0 '-^'0 H2N^OXX\f5>0 XI l HH0" X>Attorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOAttorney Docket No.: 199C-436282-WOPharmaceutical Compositions and Formulations

[0360] Pharmaceutical compositions of any of the compounds detailed herein, including compounds of die formulae (I) and (II) or a pharmaceutically acceptable salt thereof, are embraced herein. Thus, the disclosure includes pharmaceutical compositions comprising a compound herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In one aspect, tire pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid. Pharmaceutical compositions according to the disclosure may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration or a form suitable for administration by inhalation. In one embodiment, the pharmaceutical composition is prepared from mixtures of any of the compounds detailed herein, or salts thereof. In one embodiment, the pharmaceutical composition is a composition for controlled release of any of the compounds detailed herein.

[0361] A compound as detailed herein may in one aspect be in a purified form and compositions comprising a compound in purified forms are detailed herein. In one embodiment, compositions may have no more than about 35% impurity, wherein the impurity denotes a compound other than the compound comprising the majority of the composition or a pharmaceutically acceptable salt thereof, for example, a composition of a compound of formula (II) may contains no more than about 35% impurity, wherein the impurity denotes a compound other than the compound of formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, compositions may contain no more than about 25% impurity. In one embodiment, compositions may contain no more than about 20% impurity. In still further embodiments, compositions comprising a compound as detailed herein or a pharmaceutically acceptable salt thereof are provided as compositions of substantially pure compounds. " Substantially pure" compositions comprise no more than about 10% impurity, such as a composition comprising less than about 9%, about 7%, about 5%, about 3%, about 1%, or about 0.5% impurity. In some embodiments, a composition containing a compound as detailed herein or a pharmaceutically acceptable salt thereof is in substantially pure form. In still anodrer variation, a composition of substantially pure compound or a pharmaceutically acceptable salt drereof is provided wherein die composition contains or no more than about 10% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt diereof is provided wherein the composition contains or no more than about 9% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 7% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 5% impurity. In another variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein the composition contains or no more than about 3% impurity. In still another variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is providedAttorney Docket No.: 199C-436282-WOwherein the composition contains or no more than about 1% impurity. In a further variation, a composition of substantially pure compound or a pharmaceutically acceptable salt thereof is provided wherein die composition contains or no more than about 0.5% impurity. In yet other variations, a composition of substantially pure compound means that die composition contains no more dian about 10% or preferably no more than about 5% or more preferably no more than about 3% or even more preferably no more dian about 1% impurity or most preferably no more than about 0.5% impurity, which impurity may be the compound in a different stereochemical form. For instance, a composition of substantially pure (5) compound means that the composition contains no more than about 10% or no more than about 5% or no more than about 3% or no more than about 1% or no more than about 0.5% of the (R) form of the compound.

[0362] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual such as a human. In another variation, compositions are provided containing a compound in substantially pure form. In another variation, pharmaceutical compositions comprising a compound detailed herein and a pharmaceutically acceptable carrier or excipient are embraced. In another variation, methods of administering a compound are provided. The purified forms, pharmaceutical compositions and methods of administering the compounds are suitable for any compound or form thereof detailed herein.

[0363] The compound detailed herein or pharmaceutically acceptable salts thereof may be formulated for any available delivery route, including an oral, mucosal (e.g., nasal, sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular, subcutaneous or intravenous), topical or transdermal delivery form. A compound or salt thereof may be formulated with suitable carriers to provide delivery forms that include, but are not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0364] One or several compounds described herein or pharmaceutically acceptable salts thereof can be used in the preparation of a formulation, such as a pharmaceutical formulation, by combining die compound or compounds, or a pharmaceutically acceptable salt thereof, as an active ingredient with a pharmaceutically acceptable carrier, such as those mentioned above. Depending on die dierapeutic form of the system (e.g., transdermal patch vs. oral tablet), the carrier may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants. Formulations comprising the compound may also contain other substances which have valuable therapeutic properties. Pharmaceutical formulations may be prepared by known pharmaceutical methods. Suitable formulations can be found, e.g., in Remington:Attorney Docket No.: 199C-436282-WOThe Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 23rded. (2020), herein incorporated by reference in its entirety.

[0365] Compounds as described herein or pharmaceutically acceptable salts thereof may be administered to individuals (e.g., a human) in a form of generally accepted oral compositions, such as tablets, coated tablets, and gel capsules in a hard or in soft shell, emulsions or suspensions. Examples of carriers, which may be used for the preparation of such compositions, are lactose, com starch or its derivatives, talc, stearate or its salts, etc. Acceptable carriers for gel capsules with soft shell are, for instance, plant oils, wax, fats, semisolid and liquid polyols, and so on. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, re-wetting agents, emulgators, sweeteners, dyes, adjusters, and salts for the adjustment of osmotic pressure, buffers, coating agents or antioxidants.

[0366] Any of the compounds described herein or pharmaceutically acceptable salts thereof can be formulated in a tablet in any dosage form described.

[0367] In some embodiments, the dosage for one or more compounds as disclosed herein, or a stereoisomer or mixture of stereoisomers thereof, is determined based on a multiple factors including, but not limited to, type, age, weight, sex, medical condition of the patient, severity of the medical condition of the patient, route of administration, and activity of the compound or pharmaceutically acceptable salt thereof. In some embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, is administered at a dose from about 0.1 mg / kg to about 1000 mg / kg. In some embodiments, a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, is administered to the subject one or more times per day.

[0368] Compositions comprising a compound provided herein or pharmaceutically acceptable salts thereof are also described. In one variation, the composition comprises a compound and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided. In some embodiments, the composition is for use as a human or veterinary medicament. In some embodiments, the composition is for use in a method described herein. In some embodiments, the composition is for use in the treatment of a disease or disorder described herein.Methods of Use

[0369] Compounds and compositions described herein, such as a pharmaceutical composition containing a compound of any formula provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, may be used in methods of administration and treatment as provided herein. In some embodiments, the compounds and compositions may also be used in in vitro methods, such as in vitro methods of administering a compound or composition to cells for screening purposes and / or for conducting quality control assays.Attorney Docket No.: 199C-436282-WO

[0370] Provided herein is a method of treating a disease in a subject in need thereof, comprising administering to tire subject a compound of formula (I) or formula (II), a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. Also provided herein is a method of treating a disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a compound of formula (I) or formula (II), a compound selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excip...

Claims

Attorney Docket No.: 199C-436282-WO CLAIMSWhat is claimed is:

1. A compound of formula (I):RA-RB-RC(I)or a pharmaceutically acceptable salt thereof, wherein:RAis a fragment of formula (RA-I) or (RA-II):IQ (RA-I) orQ (RA-II),* denotes the point of attachment to RB;R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, l,2,3,4-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, 6-aminopyridin-2-yl optionally substituted by one or more R4, or (pyridin-2-yl)amino optionally substituted by one or more R4;Q is H or Ci-Ce alkyl;R3is Ce-Cu arylene or 5- to 10-membered heteroarylene, wherein the Ce-Cu arylene or 5- to 10-membered heteroarylene are optionally substituted by one or more R4;R2is:(i) RB2, wherein:RB2is Ci-Ce alkyl optionally substituted by one or more RB2a, C i-C: cycloalkyl optionally substituted by one or more RB2b, 3- to 12- membered saturated heterocyclyl optionally substituted by one or more RB2cwherein a carbon atom of the 3- to 12-membered saturated heterocyclyl is bonded to the -C(O), or Ci-Ce alkenyl optionally substituted by one or more RB2d;wherein each RB2‘, RB2b, RB2c, and RB2dis independently oxo, deuterium, halogen, Ci-Ce alkyl, Ci-Ce alkenyl, (S-C-, alkynyl, Cs- Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -SR5, -NR6R7, -NO2, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7,Attorney Docket No.: 199C-436282-WO-NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl of RB2a, RB2b, RB2c, and RB2dare independently optionally substituted by one or more R4a;(ii) RC2, wherein:RC2is Cg-Ci2aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, C3-C10 cycloalkenyl optionally substituted by one or more RC2c, 3- to 12- membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Cg alkyl substituted by one or more RC2e, C2-Cg alkenyl substituted by one or more RC2f, C3-C8 cycloalkyl substituted by one or more RC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h; whereinat least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-C.14 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- C14 aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2fgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Cu aryl, and 5- to 10-membered heteroaryl of RC2fare independently optionally substituted by one or more R4a; and each of the other RC2fgroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, C -Ci4 aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Cu aryl, and 5- to 10-membered heteroaryl of RC2gare independently optionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, C -Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Cu aryl, and 5- to 10-membered heteroaryl of RC2hare independentlyAttorney Docket No.: 199C-436282-WOoptionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4; andeach RC2a, RC2b, RC2c, and RC2dis, where possible, independently oxo or R4;(iii) RD2, whereinRD2is -NRD3(CI-C6alkyl), -NRD3(C3-Cs cycloalkyl), -NRD3(3- to 12- membered saturated heterocyclyl) such that a carbon atom of the 3- to 12- membered saturated heterocyclyl of -NRD3(3- to 12-membered saturated heterocyclyl) is bonded to the N of -NRD3, 3- to 12-membered N-containing saturated heterocyclyl such that a nitrogen atom of the 3- to 12-membered N- containing saturated heterocyclyl is bonded to the carbon of -C(O)-, or 5- to 10-membered heteroaryl such that a nitrogen atom of the 5- to 10-membered heteroaryl is bonded to the carbon of -C(O)-,wherein the Ci-C6alkyl of the -NRD3(C!-Cfialkyl) of RD2is optionally substituted by one or more RD2a, the Cs-Cg cycloalkyl of the - NRD3(C,3-CS cycloalkyl) of RD2is optionally substituted by one or more RD2b, the 3- to 12-membered saturated heterocyclyl of the -NRD3(3- to 12- membered saturated heterocyclyl) of RD2is optionally substituted by one or more RD2c, the 3- to 12-membered N-containing saturated heterocyclyl of RD2is optionally substituted by one or more RD2d, and the 5- to 10-membered heteroaryl is optionally substituted by one or more RD2e;RD3is H, deuterium, Ci-Cs alkyl, C3-Cs cycloalkyl, or 3- to 12- membered saturated heterocyclyl,wherein the Ci-Ce alkyl of RD3is optionally substituted by one or more RD3a, the C3-Cs cycloalkyl of RD3is optionally substituted by one or more RD3b, and tire 3- to 12-membered saturated heterocyclyl of RD3is optionally substituted by one or more RD3c'; andeach RD2a, RD2b, RD2c, RD2d, RD2e, RD3a, RD3b, and RD3cis, where possible, independently oxo or R4; or(iv) RE2, whereinRE2is -O(Ci-Ce alkyl), -O(C3-Cs cycloalkyl), -0(3- to 12-membered saturated heterocyclyl) such that a carbon atom of the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) is bonded to the -0C(0)-, -0(5- to 10-membered aryl) such that a carbon atom of the 5- to 10-membered aryl of -0(Ce-Ci4 aryl) is bonded to the -0C(0)-, orAttorney Docket No.: 199C-436282-WO-0(5- to 10-membered heteroaryl) such that a carbon atom of the 5- to 10- membered heteroaryl of -0(5- to 10-membered heteroaryl) is bonded to the - 0C(0)-,wherein the Ci-Ce alkyl of -O(Ci-Ce alkyl) of RE2is optionally substituted by one or more RE2a, (lie C3-Cs cycloalkyl -0(C3-Cs cycloalkyl) of RE2is optionally substituted by one or more RE2b, the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) of RE2is optionally substituted by one or more RE2c, the 5- to 10-membered heteroaryl of -0(Ce-Ci4 aryl) of RE2is optionally substituted by one or more RE2d, the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) of RE2eis optionally substituted by one or more RE2e; andeach RE2a, RE2b, RE2c, RE2d, and RE2eis, where possible, independently oxo or R4;Rxis unsubstituted C3-Cs alkyl, Ci-Cs alkyl substituted by one or more Rxa, C3-Ce cycloalkyl optionally substituted by one or more Rxb, 3- to 12-membered heterocyclyl optionally substituted by one or more Rxc, Ce-Cu aryl optionally substituted by one or more Rxd, 5- to 10-membered heteroaryl optionally substituted by one or more Rxe, or -S(O)2Rxf;each Rxais independently halogen, C2-Ce alkenyl, Cz-Cs alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-C aryl, 5- to 10-membered heteroaryl, oxo, -CN, -OR5, -SR5, -NR6R7, -NOz, -N3, -C=NH(0R5), -C(0)R5, -0C(0)R5, -C(0)0R5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the C2-Ce alkenyl, C2-Ce alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of Rxaare independently optionally substituted by one or more R4a;Rxfis Ci-Ce alkyl optionally substituted by one or more Rxgor C3-Cs cycloalkyl optionally substituted by one or more Rxh;each Rxb, Rxc, Rxd, Rxe, Rxg, and Rxhis independently oxo or R4;L1is C2-C4alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Ce alkylene optionally substituted by one or more R4;L3is C0-C4 alkylene optionally substituted by one or more R4;Y is a bond or C3-Cs cycloalkylene optionally substituted by one or more oxo or R4; each R4is independently deuterium, halogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, C3-Cs: cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -SR5, -NR6R7, -N02, -N3, -C=NH(0R5), -C(0)R5, -0C(0)R5, -C(0)0R5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -S(O)2OH, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-C6alkyl, CoAttorney Docket No.: 199C-436282-WOCe alkenyl, Cz-Ce alkynyl, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently deuterium, halogen, oxo, -OR8, -NR8R9, -C(O)R8, -C(O)OR8, -NR8C(O)OR10, -CN, -S(O)R8, -S(O)2R8, -P(O)(OR8)(OR9), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-Cu aryl, or Ci-Ce alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Ce-C aryl, and Ci-Ce alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently deuterium, oxo, -OH, -O-Ci-Ce alkyl, -O(2H), halogen, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R5is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-Cg cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-C6 cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12, -P(O)(ORn)(OR12), Cs-Ce cycloalkyl, 3- to 12-membered heterocyclyl, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R6is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, C3-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R7is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ca-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl, Cz-Ce alkynyl, Ca-Ce cycloalkyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NR" R12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;or R6and R7are taken together with the atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, -OR10, -NRnR12, or Ci-Ce alkyl optionally substituted by one or more deuterium, halogen, oxo, -OH, or -O(2H);each R8, R9, and R10is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz-Ce alkynyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andAttorney Docket No.: 199C-436282-WOeach R11and R12is independently hydrogen, deuterium, Ci-Ce alkyl, Cz-Ce alkenyl, or Cz- (7, alkynyl, wherein the Ci-Ce alkyl, Cz-Ce alkenyl and Cz-Ce alkynyl are optionally substituted by one or more deuterium, halogen, or oxo;or R11and R12are taken together with die atom to which diey are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, or Ci-Ce alkyl optionally substituted by one or more deuterium, oxo, or halogen;RBis a linker; andRcis a conjugatable group.

2. A compound of formula (II):or a pharmaceutically acceptable salt thereof, wherein:RAis a fragment of formula (RA-I) or (RA-II):IQ (RA-I) orIQ (RA-II),* denotes the point of attachment to RB;R1is 5,6,7,8-tetrahydro-l,8-naphthyridin-2-yl optionally substituted by one or more R4, l,2,3,4-tetrahydro-l,8-naphdiyridin-2-yl optionally substituted by one or more R4, 6-aminopyridin-2-yl optionally substituted by one or more R4, or (pyridin-2-yl)amino optionally substituted by one or more R4;Q is H or Ci-Ce alkyl;R3is Ce-Cu arylene or 5- to 10-membered heteroarylene, wherein die Ce-Cu arylene or 5- to 10-membered heteroarylene are optionally substituted by R4;R2is:(i) RB2, wherein:RB2is Ci-Ce alkyl optionally substituted by one or more RB2a, Cz-Cg cycloalkyl optionally substituted by one or more RB2b, 3- to 12- membered saturated heterocyclyl optionally substituted by one or more RB2cwherein a carbon atom of the 3- to 12-membered saturated heterocyclyl isAttorney Docket No.: 199C-436282-WObonded to the -C(O), or Ci-Cs alkenyl optionally substituted by one or more B2d.wherein each RB2a, RB2b, RB2c, and RBMis, where possible, independently oxo, deuterium, halogen, Ci-Cg alkyl, (b-Cg alkenyl, C2- Cg alkynyl, Cs-Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl, -CN, -OR5, -SR5, -NR6R7, -NO2, -C=NH(OR5), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NRSR7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NRSR7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein the Ci-Cg alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- Cs cycloalkyl, 3- to 12-membered saturated heterocyclyl of RB2a, RB2b, RB2c, and RB2dare independently optionally substituted by one or more R4a;(ii) RC2, wherein:RC2is C6-C12 aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b, C3-C10 cycloalkenyl optionally substituted by one or more RC2c, 3- to 12- membered partially unsaturated heterocyclyl optionally substituted by one or more RC2d, Ci-Cg alkyl substituted by one or more RC2e, Ci-Cg alkenyl substituted by one or more RC2f, Cj-Cs cycloalkyl substituted by one or more RC2g, or 3- to 12-membered fully saturated heterocyclyl substituted by one or more RC2h; whereinat least one RC2egroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-C aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Cu aryl, and 5- to 10-membered heteroaryl of RC2eare independently optionally substituted by one or more R4a; and each of the other RC2egroups, when present, is independently R4;at least one RC2fgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Cu aryl, and 5- to 10-membered heteroaryl of RC2fare independently optionally substituted by one or more R4a; and each of the other RC2fgroups, when present, is independently R4;at least one RC2ggroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Cg-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Cg- Cu aryl, and 5- to 10-membered heteroaryl of RC2gare independentlyAttorney Docket No.: 199C-436282-WOoptionally substituted by one or more R4a; and each of the other RC2ggroups, when present, is independently R4;at least one RC2hgroup, when present, is 3- to 12-membered partially unsaturated heterocyclyl, Ce-Cu aryl, or 5- to 10-membered heteroaryl, wherein the 3- to 12-membered partially unsaturated heterocyclyl, Ce- Cu aryl, and 5- to 10-membered heteroaryl of RC2hare independently optionally substituted by one or more R4a; and each of the other RC2hgroups, when present, is independently oxo or R4; andeach RC2a, RC2b, RC2c, and RC2dis, where possible, independently oxo or R4;(iii) RD2, whereinRD2is -NRD3(CI-C6alkyl), -NRD3(C3-C8cycloalkyl), -NRD3(3- to 12- membered saturated heterocyclyl) such that a carbon atom of the 3- to 12- membered saturated heterocyclyl of -NRD3(3- to 12-membered saturated heterocyclyl) is bonded to the N of -NRD3, - to 12-membered N-containing saturated heterocyclyl such that a nitrogen atom of the 3- to 12-membered N- containing saturated heterocyclyl is bonded to the carbon of -C(O)-, or 5- to 10-membered heteroaryl such that a nitrogen atom of the 5- to 10-membered heteroaryl is bonded to the carbon of -C(O)-,wherein the Ci-C6alkyl of the -NRD3(CI-C6alkyl) of RD2is optionally substituted by one or more RD2a, the C3-C8cycloalkyl of the - NRD3(C3-C8cycloalkyl) of RD2is optionally substituted by one or more RD2b, the 3- to 12-membered saturated heterocyclyl of the -NRD3(3- to 12- membered saturated heterocyclyl) of RD2is optionally substituted by one or more RD2c, the 3- to 12-membered N-containing saturated heterocyclyl of RD2is optionally substituted by one or more RD2d, and the 5- to 10-membered heteroaryl is optionally substituted by one or more RD2e;RD3is H, deuterium, Ci-Ce alkyl, C3-C8cycloalkyl, or 3- to 12- membered saturated heterocyclyl,wherein the Ci-Ce alkyl of RD3is optionally substituted by one or more RD3a, the C3-C8cycloalkyl of RD3is optionally substituted by one or more RD3b, and the 3- to 12-membered saturated heterocyclyl of RD3is optionally substituted by one or more RD3c'; andeach RD2a, RD2b, RD2c, RD2d, RD2e, RD3a, RD3b, and RD3cis, where possible, independently oxo or R4; orAttorney Docket No.: 199C-436282-WO(iv) RE2, whereinRE2is -O(Ci-Ce alkyl), -CXC3-C8 cycloalkyl), -0(3- to 12-membered saturated heterocyclyl) such that a carbon atom of the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) is bonded to the -0C(0)-, -0(5- to 10-membered aryl) such that a carbon atom of the 5- to 10-membered aryl of -0(Ce-Ci4 aryl) is bonded to the -0C(0)-, or -0(5- to 10-membered heteroaryl) such that a carbon atom of the 5- to 10- membered heteroaryl of -0(5- to 10-membered heteroaryl) is bonded to the - 0C(0)-,wherein the Ci-Ce alkyl of -O(Ci-Ce alkyl) of RE2is optionally substituted by one or more RE2a, the Ca-Cs cycloalkyl -0(C3-Cs cycloalkyl) of RE2is optionally substituted by one or more RE2b, the 3- to 12-membered saturated heterocyclyl of -0(3- to 12-membered saturated heterocyclyl) of RE2is optionally substituted by one or more RE2c, the 5- to 10-membered heteroaryl of -0(Cs-Ci4 aryl) of RE2is optionally substituted by one or more RE2d, the 5- to 10-membered heteroaryl of -0(5- to 10-membered heteroaryl) of RE2eis optionally substituted by one or more RE2e; andeach RE2a, RE2b, RE2c, RE2d, and RE2eis, where possible, independently oxo or R4;Rxis unsubstituted Ca-Cs alkyl, Ci-Cs alkyl substituted by one or more Rxa, Ca-Ce cycloalkyl optionally substituted by one or more Rxb, 3- to 12-membered heterocyclyl optionally substituted by one or more Rxc, Ce-Cu aryl optionally substituted by one or more Rxd, 5- to 10-membered heteroaryl optionally substituted by one or more Rxe, or -S(O)2Rxf;each Rxais independently halogen, C2-Cs alkenyl, C2-Ce alkynyl, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, 5- to 10-membered heteroaryl, oxo, -CN, -OR5, -SR5, -NR6R7, -NO2, -N3, -C=NH(0R5), -C(0)R5, -0C(0)R5, -C(0)0R5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -NR5S(O)R6, -NR5S(O)2R6, -S(O)NR6R7, -S(O)2NR6R7, or -P(O)(OR5)(OR6), wherein tire C2-Ce alkenyl, C2-Ce alkynyl, Ca-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Ce-Cu aryl, and 5- to 10-membered heteroaryl of Rxaare independently optionally substituted by one or more R4a;Rxfis Ci-Ce alkyl optionally substituted by one or more Rxgor C3-C5 cycloalkyl optionally substituted by one or more Rxh;each Rxb, Rxc, Rxd, Rxo, Rxg, and Rxhis independently oxo or R4;L1is C2-C4alkylene optionally substituted by one or more by oxo or R4;L2is a bond or Ci-Ce alkylene optionally substituted by one or more R4;L3is C2-C4alkylene optionally substituted by one or more R4;Y is a bond or C3-C5 cycloalkylene optionally substituted by one or more oxo or R4;Attorney Docket No.: 199C-436282-WOeach R4is independently deuterium, halogen, Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cs cycloalkyl, 3- to 12-membered heterocyclyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, -CN, -OR5, -SR5, -NRfiR7, -NOz, -N3, -C=NH(ORS), -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR6R7, -NR5C(O)R6, -NR5C(O)OR6, -NR5C(O)NR6R7, -S(O)R5, -S(O)2R5, -S(O)2OH, -NR5S(O)R6, -NRsS(O)zR6, -S(O)NR6R7, -S(O)ZNR6R7, or -P(O)(OR5)(OR6), wherein die Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, Cg-Cu aryl, and 5- to 10-membered heteroaryl of R4are independently optionally substituted by one or more R4a;each R4ais independently deuterium, halogen, oxo, -OR8, -NR8R9, -C(O)R8, -C(O)OR8, -NR8C(O)OR10, -CN, -S(O)R8, -S(O)2R8, -P(O)(OR8)(OR9), C3-C8cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Cg-C aryl, or Ci-Cg alkyl, wherein the 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, Cg-Cu aryl, and Ci-Cg alkyl of R4aare independently optionally substituted by one or more R4b;each R4bis independently deuterium, oxo, -OH, -O-Ci-Cg alkyl, -O(2H), halogen, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R5is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, Cz-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl, wherein the Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocyclyl of R5are each independently optionally substituted by one or more R5a;each R5ais independently halogen, deuterium, oxo, -CN, -OR10, -NRnR12, -P(O)(ORn)(OR12), C3-Cg cycloalkyl, 3- to 12-membered heterocyclyl, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R6is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein tire Ci-Cg alkyl, Cz-Cg alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R6are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;each R7is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-Cu aryl, 5- to 10-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein the Ci-Cg alkyl, C2-Cg alkenyl, Cz-Cg alkynyl, C3-Cg cycloalkyl, Cg-C aryl, 5- to 10-membered heteroaryl, and 3- to 6-membered heterocyclyl of R7are independently optionally substituted by one or more deuterium, halogen, oxo, -CN, -OR10, -NRnR12, or Ci-Cg alkyl optionally substituted by one or more deuterium, halogen, -OH, -O(2H), or oxo;or R6and R7are taken together with the atom to which they are attached to form a 3- to 10-membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, -OR10,Attorney Docket No.: 199C-436282-WO-NRnR12, or Ci-Cs alkyl optionally substituted by one or more deuterium, halogen, oxo, -OH, or -O(2II);each R8, R9, and R’° is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, or Cz-Cg alkynyl, wherein the Ci-Ce alkyl, Cz-Cg alkenyl and Cz-Cg alkynyl are optionally substituted by one or more deuterium, halogen, or oxo; andeach R11and R12is independently hydrogen, deuterium, Ci-Cg alkyl, Cz-Cg alkenyl, or Cz-Cg alkynyl, wherein the Ci-Cg alkyl, Cz-Cg alkenyl and Cz-Cg alkynyl are optionally substituted by one or more deuterium, halogen, or oxo;or R11and R12are taken together with the atom to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by one or more deuterium, halogen, oxo, or Ci-Cg alkyl optionally substituted by one or more deuterium, oxo, or halogen;RBis a linker;RDis a conjugated group; andREis a payload.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein RAis a fragment of formula (RA-I);IQ (RA-I).

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein RAis a fragment of formula (RA-I- 1):

5. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein RAis a fragment of formula (RA-I-7):(RA-I-7).Attorney Docket No.: 199C-436282-WO6. The compound of claim 4 or claim 5, or a pharmaceutically acceptable salt thereof, wherein R2is RB2.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein RB2is Ci-Ce alkyl optionally substituted by one or more RB2aor C3-C g cycloalkyl optionally substituted by one or more RB2b.

8. The compound of claim 4 or claim 5, or a pharmaceutically acceptable salt thereof, wherein R2is RC2.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein RC2is G,-C12 aryl optionally substituted by one or more RC2a, 5- to 12-membered heteroaryl optionally substituted by one or more RC2b.

10. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein RC2is phenyl substituted by 0-2 halogen.

11. The compound of claim 4 or claim 5, or a pharmaceutically acceptable salt thereof, wherein R2is RD2.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein RD2is 3- to 12-membered N-containing saturated heterocyclyl such that a nitrogen atom of the 3- to 12-membered N-containing saturated heterocyclyl is bonded to the carbon of -C(O)-, wherein the 3- to 12-membered N-containing saturated heterocyclyl of RD2is optionally substituted by one or more RD2d.

13. The compound of claim 4 or claim 5, or a pharmaceutically acceptable salt thereof, wherein R2 is RE2.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein RE2is -O(Ci-Ce alkyl) wherein the Ci-Ce alkyl of -O(Ci-Ce alkyl) of RE2is optionally substituted by one or more RE2a,15. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein RAis a fragment of formula (RA-II):Attorney Docket No.: 199C-436282-WOIQ (RA-II).

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein RAis a fragment of formula (RA-II- 1):

17. The compound of claim 15 or claim 16, or a pharmaceutically acceptable salt thereof, wherein R3is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl, each of which is optionally substituted by R4.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein RAis a fragment of formula (RA-II-2):

19. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein RAis a fragment of formula (RA-II-2a):(RA-II-2a).

20. The compound of any one of claims 17-19, or a pharmaceutically acceptable salt thereof, wherein each R4is independently halogen.Attorney Docket No.: 199C-436282-WO21. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein each R4is independently fluorine or chlorine.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein RBis a linker of formula (RB-I):n (RB-I)wherein * denotes the point of attachment to RA, ** denotes the point of attachment to Rcor RD, and n is an integer from 0 to 100.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 1 to 24.

24. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein n is an integer from 2 to 20.

25. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 1, 2, 3, 4, 6, 8, 10, and 12.

26. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein n is 4.

27. The compound of any one of claims 1 or 3-26, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I) and Rcis -G, alkynyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein Rcis, wherein ** denotes the point of attachment to RB.

29. The compound of any one of claims 1 or 3-26, wherein the compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and Rcis a fragment of formula (Rc-I):Attorney Docket No.: 199C-436282-WOwherein each LRCis independently a bond or Ci-Ce alkyl, LENDis selected from H and a protecting group, and wherein ** denotes the point of attachment to RB.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein the protecting group is -C(O)OC(CH3)3.

31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein Rcis:N^NL N, wherein ** denotes the point of attachment to RB.

32. The compound of any one of claims 1 or 3-26, wherein the compound is a compound of formula (I), or a pharmaceutically acceptable salt thereof, and Rcis Ci-Ce alkyl substituted by an azide.

33. The compound of any one of claims 2-26, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, and RDis a group comprising a cycloalkyl, a heterocycle, an aryl, a heteroaryl, a disulfide, a thioether, a hydrazone, an ester, a sulfonamide, a carbamate, or an amide.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein RDis Nselected from the group consisting of, wherein ** denotes the point of attachment to RB, and *** denotes the point of attachment to RE.

35. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein RDis, wherein ** denotes the point of attachment to RB, and *** denotes the point of attachment to RE.

36. The compound of any one of claims 2-26, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, and RDis a fragment of formula (RD-I):Attorney Docket No.: 199C-436282-WO**(RD-I),wherein each LRCis independently a bond or Ci-Ce alkyl, wherein ** denotes the point of attachment to RBand *** denotes the point of attachment to RE.The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein RDis:* denotes the point of attachment to RB, and *** denotes the point of attachment to RE.

38. The compound of any one of claims 2-26, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein RDis a fragment of formula (RD-II):wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and m is an integer from 1 to 20.

39. The compound of any one of claims 2-26, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein RDis a fragment of formula (RD-III):(RD-III) wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and p is an integer from 1 to 20.

40. The compound of any one of claims 2-26, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein RDis a fragment of formula (RD-IV):Attorney Docket No.: 199C-436282-WOwherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and qi and cp are each independently an integer from 1 to 20.

41. The compound of any one of claims 2-26, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein RDis a fragment of formula (RD-V):wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and, r2, and r3are each independently an integer from 1 to 20.

42. The compound of any one of claims 2-26, wherein the compound is a compound of formula (II), or a pharmaceutically acceptable salt thereof, wherein RDis a fragment of formula (RD-VI):wherein ** denotes the point of attachment to RB; *** denotes the point of attachment to RE; and 2 is an integer from 1 to 20.

43. The compound of any one of claims 2-26 or 33-42, or a pharmaceutically acceptable salt thereof, wherein REis a reporting group or a label.

44. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein REis a fragment of formula (RE-A):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

45. The compound of any one of claims 2-26 or 33-42, or a pharmaceutically acceptable salt thereof, wherein REis an antineoplastic agent optionally conjugated to a cleavable group and / or self-immolativc group..

46. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein RFis a fragment of formula (RE-B):wherein *** denotes the point of attachment to RD.

47. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein REis a fragment of formula (RE-E):Attorney Docket No.: 199C-436282-WOwherein *** denotes the point of attachment to RD.

48. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein REis a fragment of formula (RE-F):wherein *** denotes the point of attachment to RD.

49. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein REis a fragment of formula (RE-G):wherein *** denotes the point of attachment to RD.

50. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein REis a fragment of formula (RE-H):Attorney Docket No.: 199C-436282-WO(RE-H), wherein *** denotes the point of attachment to RD.

51. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein REis a fragment of formula (RE-I):wherein *** denotes the point of attachment to RD.

52. The compound of claim 45, or a pharmaceutically acceptable salt thereof, wherein REis a fragment of formula (RE-J):wherein *** denotes the point of attachment to RD.

53. A compound, or a pharmaceutically acceptable salt thereof, selected from compounds S1-S69 in Table 1.

54. A compound, or a pharmaceutically acceptable salt thereof, selected from compounds C1-C26 in Table 2.Attorney Docket No.: 199C-436282-WO55. A method of delivering a pay load to a cell, comprising (a) contacting the cell with a compound of any one of claims 2-26, 33-52, or 54, and (b) incubating the cell wherein the compound is internalized into the cell.

56. Use of a compound of any one of claims 2-26, 33-52, or 54 in delivering a payload to a cell, comprising (a) contacting the cell with the compound, and (b) incubating the cell wherein the compound is internalized into the cell.

57. Use of a compound of any one of 2-26, 33-52, or 54 in the manufacture of a medicament for delivering a payload to a cell, comprising (a) contacting the cell with the compound, and (b) incubating the cell wherein the compound is internalized into the cell.

58. A method of treating cancer in a subject in need thereof, comprising administering a compound of any one of claims 45-52 to the subject.

59. The method of claim 58, wherein the cancer is melanoma, colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, squamous cell lung cancer, renal cell carcinoma, lymphoma (e.g., Hodgkin's lymphoma), cutaneous squamous cell carcinoma (CSCC), urothelial carcinoma, metastatic Merkel cell carcinoma, gastric cancer, lung cancer, pancreatic cancer, or mesothelioma.

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