Compounds and compositions as cbp / p300 degraders and uses thereof

Abstract

Described herein are compounds of Formula I and their pharmaceutically acceptable salts, solvates, or stereoisomers thereof, as well as their uses (e.g., for degrading certain proteins such as p300 / CBP proteins).

Description

Attorney Docket No. PRSC-094 / 001WO 343170-2295 COMPOUNDS AND COMPOSITIONS AS CBP / P300 DEGRADERS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 579,538, filed August 30, 2023, the contents of which are incorporated herein by reference in their entireties. BACKGROUND

[0002] Bifunctional protein degraders are heterobifunctional compounds that simultaneously bind a target protein and an E3 ligase complex, resulting in the transfer of ubiquitin and initiating a process ultimately causing the proteasomal degradation of the target protein. By catalyzing the formation of a ternary complex involving an E3 ligase receptor, a protein of interest, and a small molecule, Bifunctional protein degraders may yield enhanced substrate specificity. There is an ongoing need for selective Bifunctional protein degraders for treating and / or preventing cancer and other diseases responsive to the inhibition or degradation of CBP / p300 proteins. p300 selective degraders can display strong selectivity for p300 over CBP and demonstrate a time-dependent loss of p300, enhancer acetylation, and transcriptional output in cancer cells both in vitro and in vivo with limited toxicity to untransformed cells. Enhanced dependency on p300 is found across numerous cancer lineages. SUMMARY

[0003] In certain aspects, the present disclosure provides compounds of Formula I: T-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: C is of Formula I-1T is i) of Formula I-3-iAttorney Docket No. PRSC-094 / 001WO 343170-2295ii) of Formula I-3-ii’ii’), iii) of Formula I-3-iii(I-3-iii), iv) of Formula I-3-ivv) of Formula I-3-vor vi) of Formula I-3-viAttorney Docket No. PRSC-094 / 001WO 343170-2295 L is of Formula I-2wherein each of the variables in Formulae I-1, I-2, I-3-i, I-3-ii, I-3-iii, I-3-iv, I-3-v, and I-3- vi is described, embodied, and exemplified herein.

[0004] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient.

[0005] In certain aspects, the present disclosure provides methods of degrading a protein in a subject or biological sample comprising administering a compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein.

[0006] In certain aspects, the present disclosure provides uses of a compound disclosed herein in the manufacture of a medicament for degrading a protein in a subject or biological sample.

[0007] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a protein in a subject or biological sample.

[0008] In certain aspects, the present disclosure provides methods for treating a disease or disorder.

[0009] In certain aspects, the present disclosure provides uses of the compounds disclosed herein in the manufacture of a medicament for treating a disease or disorder.

[0010] In certain aspects, the present disclosure provides compounds disclosed herein for treating a disease or disorder. DETAILED DESCRIPTION

[0011] The present disclosure relates to compounds that show activity in degrading certain proteins (e.g., p300 / CBP), and pharmaceutical compositions comprising such compounds. Compounds of the Present Disclosure

[0012] In certain aspect, the present disclosure provides compounds of Formula I: T-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: C is of Formula I-1Attorney Docket No. PRSC-094 / 001WO 343170-2295wherein: denotes a single bond or a double bond; B1is CRB1or N, NRB1’, O, or S; B2is CRB2or N, NRB2’, O, or S; B3is absent, CRB3, or N; B4is CRB4or N, NRB4’, O, or S; B5is CRB5, N, NRB5’, O, or S, as valency permits; B6is C or N; RB1, RB2, RB3, RB4, and RB5are independently, oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, and one of RB1, RB2, RB3, RB4, and RB5isor RB1and RB2, RB2and RB3, RB3and RB4, or RB4and RB5, together with the carbon atoms to which they are attached, form optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocycle, wherein the heteroaryl or heterocycle is attached to L; RB1’, RB2’, RB4’, and RB5’are independently hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- to 4- membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, CRX1, or C(RX1)2, as valency permits; each RX1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; two RX1together form an oxo; orAttorney Docket No. PRSC-094 / 001WO 343170-2295 two RX1, together with the carbon atom to which they are bonded, form C3-4 carbocyclyl or 3- or 4-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; or RX1and RB5or RX1and RB5’, together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C6 aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted 5- or 6-membered heterocycle, or optionally substituted C5-6carbocycle; each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; or two RD, together with the carbon atom(s) to which they are bonded, form C3-5 carbocyclyl or 3- or 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; d is an integer from 0 to 6, as valency permits; and q is an integer from 0 to 2, T is i) of Formula I-3-idenotes attachment to L; RE1, RE2, RE3, and RE4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -Attorney Docket No. PRSC-094 / 001WO 343170-2295 S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; F1is C or N; F2is NRF2’or CRF2; RF2’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; F3is CRF3, N, or NRF3’; RF3is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF3’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 RF4is -C(=O)NR3aR3bor 5- to 6-membered heteroaryl optionally substituted with one or more Ru; and R3aand R3bare independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or R3aand R3b, together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocycle or 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more Ru, ii) of Formula I-3-ii’denotes attachment to L; RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; H1is C(RH1)2, NRH1’, or O;Attorney Docket No. PRSC-094 / 001WO 343170-2295 H2is C(RH2)2, NRH2’, or O; each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RH1or two RH2, together with the carbon atom to which they are attached, form C3-6carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; and RH1’and RH2’are independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, iii) of Formula I-3-iiiwherein:denotes attachment to L; I1is C(RI1)2, NRI1’, or O; I2is C(RI2)2, NRI2’, or O; each occurrence of RI1and RI2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RI1or two RI2, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 RI1’and RI2’are independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RIis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; i is an integer selected from 0 to 4; J1is N or CRJ1; J2is N or CRJ2; and RJ1, RJ2, and RJ3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, iv) of Formula I-3-ivAttorney Docket No. PRSC-094 / 001WO 343170-2295wherein denotes attachment to L; and at least one of M1, M2, M3, and M4is N or ; RM2, RM3, and RM4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RK’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; K1is -C(=O)- or -C(RK1)2-; each RK1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and k is an integer selected from 0 to 4;Attorney Docket No. PRSC-094 / 001WO 343170-2295 v) of Formula I-3-vdenotes attachment to L; each RNis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; n is an integer selected from 0 to 6; RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1- 6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and R4is -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru, or vi) of Formula I-3-vivi), wherein: Q1is NRQ1’, C(RQ1)2, or O; RQ1’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RQ1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RQ1, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; when is a double bond, then Q2is N or CRQ2; and Q3is N or CRQ3; when is a single bond, then Q2is NRQ2’, C(RQ2)2, or O; Q3is NRQ3’, C(RQ3)2, or O; RQ2’and RQ3’are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each occurrence of RQ2and RQ3is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RQ2or two RQ3, together with the carbon atom to which they are attached, form C3-6carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; S1is CRS1or N;to L; and RS1, RS2, RS3, and RS4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; L is of Formula I-2 (I-2), wherein: ** denotes attachment to T and * denotes attachment to C; L’’ is absent; or L’’ is C1-3alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 RLis hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; wherein: i) when L’’ is C1-3 alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2- , wherein the alkylene is optionally substituted with one or more Ru, then Cy1is optionally substituted C6arylene or 5- or 6-membered heteroarylene; ii) when L’’ is absent, then Cy1is, wherein: ** denotes attachment to T; T1is CRT1or N; V1is CRV1or N; V2is CRV2or N; RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1- 6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; t is an integer selected from 0 to 6, as valency permits; or Cy1is, wherein: when is single bond, Y1is N or CRY1; when is double bond, Y1is C;Attorney Docket No. PRSC-094 / 001WO 343170-2295 ** denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Y2is C(RY2)2, O, or N(RY2’); each RY2is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; RY2’is hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Z1is CRZ1or N; Z2is CRZ2or N; RZ1and RZ2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z; Cy2is 5- or 6-membered heteroarylene optionally substituted with one or more Ru; L1is -C(=O)NH- or 5- or 6-membered heteroaryl optionally substituted with one or more Ru; L2is [C(RL2)2]l, wherein each RL2is independently hydrogen, C1-3 alkyl, or C1-3 haloalkyl; or two geminal RL2, together with the carbon atom to which they are bonded, form C3-5 carbocyclyl or 3- to 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; l is 1 or 2; and L3is E-ethenylene, ethynylene, C6arylene, or 5- or 6-membered heteroarylene, wherein the E- ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl; each Rais independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 6-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; and each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

[0013] In certain embodiments, the present disclosure provides compounds of Formula I: T-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein: C is of Formula I-1wherein: denotes a single bond or a double bond; B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5, N, or NRB5’, as valency permits; B6is C or N; RB1, RB2, RB3, RB4, and RB5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, and oneX is absent, CRX1, or C(RX1)2, as valency permits; each RX1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; two RX1together form an oxo; or two RX1, together with the carbon atom to which they are bonded, form C3-4carbocyclyl or 3- or 4-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; or RX1and RB5or RX1and RB5’, together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C6aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted 5- or 6-membered heterocycle, or optionally substituted C5-6carbocycle; each RDis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; or two RD, together with the carbon atom(s) to which they are bonded, form C3-5carbocyclyl or 3- or 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; d is an integer from 0 to 6, as valency permits; and q is an integer from 0 to 2, T is i) of Formula I-3-iwherein:Attorney Docket No. PRSC-094 / 001WO 343170-2295to L; RE1, RE2, RE3, and RE4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; F1is C or N; F2is NRF2’or CRF2; RF2’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; F3is CRF3, N, or NRF3’; RF3is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- toAttorney Docket No. PRSC-094 / 001WO 343170-2295 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF3’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF4is -C(=O)NR3aR3bor 5- to 6-membered heteroaryl optionally substituted with one or more Ru; and R3aand R3bare independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or R3aand R3b, together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocycle or 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more Ru; ii) of Formula I-3-iiAttorney Docket No. PRSC-094 / 001WO 343170-2295denotes attachment to L; RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; H1is C(RH1)2, NRH1’, or O; H2is C(RH2)2, NRH2’, or O; each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RH1or two RH2, together with the carbon atom to which they are attached, form C3-6carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; and RH1’and RH2’are independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, iii) of Formula I-3-iii(I-3-iii), wherein:denotes attachment to L;Attorney Docket No. PRSC-094 / 001WO 343170-2295 I1is C(RI1)2, NRI1’, or O; I2is C(RI2)2, NRI2’, or O; each occurrence of RI1and RI2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RI1or two RI2, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; RI1’and RI2’are independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RIis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; i is an integer selected from 0 to 4; J1is N or CRJ1; J2is N or CRJ2; and RJ1, RJ2, and RJ3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 iv) of Formula I-3-ivwhereindenotes attachment to L; and at least one of M1, M2, M3, and M4is N or; RM2, RM3, and RM4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RK’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; K1is -C(=O)- or -C(RK1)2-; each RK1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy,Attorney Docket No. PRSC-094 / 001WO 343170-2295 alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and k is an integer selected from 0 to 4; v) of Formula I-3-vdenotes attachment to L; each RNis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 n is an integer selected from 0 to 6; RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1- 6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and R4is -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or vi) of Formula I-3-viwherein: Q1is NRQ1’, C(RQ1)2, or O; RQ1’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RQ1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; orAttorney Docket No. PRSC-094 / 001WO 343170-2295 two RQ1, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; when is a double bond, then Q2is N or CRQ2; and Q3is N or CRQ3; when is a single bond, then Q2is NRQ2’, C(RQ2)2, or O; Q3is NRQ3’, C(RQ3)2, or O; RQ2’and RQ3’are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each occurrence of RQ2and RQ3is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RQ2or two RQ3, together with the carbon atom to which they are attached, form C3-6carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; S1is CRS1or N;to L; and RS1, RS2, RS3, and RS4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -Attorney Docket No. PRSC-094 / 001WO 343170-2295 C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; L is of Formula I-2 (I-2), wherein: ** denotes attachment to T and * denotes attachment to C; L’’ is absent; or L’’ is C1-3 alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru; RLis hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; wherein: i) when L’’ is C1-3 alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2- , wherein the alkylene is optionally substituted with one or more Ru, then Cy1is optionally substituted C6arylene or 5- or 6-membered heteroarylene; ii) when L’’ is absent, then Cy1is, wherein: ** denotes attachment to T; T1is CRT1or N; V1is CRV1or N; V2is CRV2or N; RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1- 6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; t is an integer selected from 0 to 6, as valency permits; or Cy1is, wherein: Y1is N or CRY1; ** denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Y2is C(RY2)2, O, or N(RY2’); each RY2is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; RY2’is hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Z1is CRZ1or N; RZ1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z; Cy2is 5- or 6-membered heteroarylene optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 L1is -C(=O)NH- or 5- or 6-membered heteroaryl optionally substituted with one or more Ru; L2is [C(RL2)2]l, wherein each RL2is independently hydrogen, C1-3alkyl, or C1-3haloalkyl; or two geminal RL2, together with the carbon atom to which they are bonded, form C3-5 carbocyclyl or 3- to 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; l is 1 or 2; and L3is E-ethenylene, ethynylene, C6 arylene, or 5- or 6-membered heteroarylene, wherein the E- ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru, wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, each Rais independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 6-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; and each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

[0014] In certain embodiments, C is of Formula I-1wherein: denotes a single bond or a double bond; B1is CRB1or N, NRB1’, O, or S; B2is CRB2or N, NRB2’, O, or S;Attorney Docket No. PRSC-094 / 001WO 343170-2295 B3is absent, CRB3, or N; B4is CRB4or N, NRB4’, O, or S; B5is CRB5, N, NRB5’, O, or S, as valency permits; B6is C or N; RB1, RB2, RB3, RB4, and RB5are independently, oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, and one of RB1, RB2, RB3, RB4, and RB5isor RB1and RB2, RB2and RB3, RB3and RB4, or RB4and RB5, together with the carbon atoms to which they are attached, form optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocycle, wherein the heteroaryl or heterocycle is attached to L; RB1’, RB2’, RB4’, and RB5’are independently hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- to 4- membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, CRX1, or C(RX1)2, as valency permits; each RX1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; two RX1together form an oxo; or two RX1, together with the carbon atom to which they are bonded, form C3-4 carbocyclyl or 3- or 4-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; or RX1and RB5or RX1and RB5’, together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C6 aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted 5- or 6-membered heterocycle, or optionally substituted C5-6carbocycle;Attorney Docket No. PRSC-094 / 001WO 343170-2295 each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; or two RD, together with the carbon atom(s) to which they are bonded, form C3-5 carbocyclyl or 3- or 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; d is an integer from 0 to 6, as valency permits; and q is an integer from 0 to 2.

[0015] In certain embodiments, C is of Formula I-1wherein: denotes a single bond or a double bond; B1is CRB1or N; B2is CRB2or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5, N, or NRB5’, as valency permits; B6is C or N; RB1, RB2, RB3, RB4, and RB5are independently , hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, and one of RB1, RB2, RB3, RB4, and RB5is ; X is absent, CRX1, or C(RX1)2, as valency permits; each RX1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 two RX1together form an oxo; or two RX1, together with the carbon atom to which they are bonded, form C3-4 carbocyclyl or 3- or 4-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; or RX1and RB5or RX1and RB5’together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C6aryl, optionally substituted 5-membered heteroaryl, optionally substituted 5- or 6-membered heterocycle, or optionally substituted C5-6 carbocycle; each RDis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; or two RD, together with the carbon atom(s) to which they are bonded, form C3-5 carbocyclyl or 3- or 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; d is an integer from 0 to 6, as valency permits; and q is an integer from 0 to 2.

[0016] In certain embodiments, X is absent, CRX1, or C(RX1)2, as valency permits. In certain embodiments, X is absent. In certain embodiments, X is CRX1, as valency permits. In certain embodiments, X is C(RX1)2.

[0017] In certain embodiments, each RX1is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i- butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C3-4 carbocyclyl (e.g., cyclopropyl (C3),Attorney Docket No. PRSC-094 / 001WO 343170-2295 cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0018] In certain embodiments, each RX1is independently hydrogen or C1-6 alkyl, and at least one RX1is hydrogen.

[0019] In certain embodiments, two RX1together form an oxo.

[0020] In certain embodiments, two RX1, together with the carbon atom to which they are bonded, form C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)) or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru.

[0021] In certain embodiments, B1is CRB1, N, NRB1’, O, or S. In certain embodiments, B1is CRB1. In certain embodiments, B1is N. In certain embodiments, B1is NRB1’. In certain embodiments, B1is O.

[0022] In certain embodiments, B2is CRB2, N, NRB2’, O, or S. In certain embodiments, B2is CRB2. In certain embodiments, B2is N. In certain embodiments, B2is NRB2’. In certain embodiments, B2is O.

[0023] In certain embodiments, B3is absent, CRB3, or N. In certain embodiments, B3is absent. In certain embodiments, B3is CRB3. In certain embodiments, B3is N.

[0024] In certain embodiments, B4is CRB4, N, NRB4’, O, or S. In certain embodiments, B4is CRB4. In certain embodiments, B4is N. In certain embodiments, B4is NRB4’. In certain embodiments, B4is O.

[0025] In certain embodiments, B5is CRB5, N, NRB5’, O, or S. In certain embodiments, B5is CRB5. In certain embodiments, B5is N. In certain embodiments, B5is NRB5’. In certain embodiments, B5is O.

[0026] In certain embodiments, B6is C or N. In certain embodiments, B6is C. In certain embodiments, B6is N.

[0027] In certain embodiments, RB1’, RB2’, RB4’, and RB5’are independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N,Attorney Docket No. PRSC-094 / 001WO 343170-2295 O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0028] In certain embodiments, at most two of B1, B2, B3, B4, B5, and B6are independently N, NRB1’, NRB2’, NRB4’, NRB5’, O, or S.

[0029] In certain embodiments, two of B1, B2, B3, B4, B5, and B6are independently N, NRB1’, NRB2’, NRB4’, NRB5’, O, or S.

[0030] In certain embodiments, one of B1, B2, B3, B4, B5, and B6is N, NRB1’, NRB2’, NRB4’, NRB5’, O, or S.

[0031] In certain embodiments, none of B1, B2, B3, B4, B5, and B6is N, NRB1’, NRB2’, NRB4’, NRB5’, O, or S.

[0032] In certain embodiments, at most two of B1, B2, B3, B4, B5, and B6are independently N, NRB1’, NRB2’, NRB4’, or NRB5’.

[0033] In certain embodiments, two of B1, B2, B3, B4, B5, and B6are independently N, NRB1’, NRB2’, NRB4’, or NRB5’.

[0034] In certain embodiments, one of B1, B2, B3, B4, B5, and B6is N, NRB1’, NRB2’, NRB4’, or NRB5’.

[0035] In certain embodiments, none of B1, B2, B3, B4, B5, and B6is N, NRB1’, NRB2’, NRB4’, or NRB5’.

[0036] In certain embodiments, B1is CRB1; B2is CRB2; B3is CRB3; B4is CRB4; B5is CRB5; and B6is C.

[0037] In certain embodiments, B1is N; B2is CRB2; B3is CRB3; B4is CRB4; B5is CRB5; and B6is C.

[0038] In certain embodiments, B1is CRB1; B2is CRB2; B3is CRB3; B4is CRB4; B5is N; and B6is C.

[0039] In certain embodiments, B1is NRB1’; B2is CRB2; B3is CRB3; B4is CRB4; B5is CRB5; and B6is C.

[0040] In certain embodiments, B1is CRB1; B2is CRB2; B3is CRB3; B4is CRB4; B5is NRB5’; and B6is C.

[0041] In certain embodiments, B1is CRB1; B2is CRB2; B3is CRB3; B4is CRB4; B5is CRB5; and B6is N.

[0042] In certain embodiments, B1is N; B2is NRB2’; B3is absent; B4is CRB4; B5is CRB5; and B6is C.

[0043] In certain embodiments, B1is CRB1; B2is CRB2; B3is absent; B4is NRB4’; B5is N; and B6is C.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0044] In certain embodiments, B1is N; B2is CRB2; B3is N; B4is CRB4; B5is CRB5; and B6is C.

[0045] In certain embodiments, B1is CRB1; B2is CRB2; B3is N; B4is CRB4; B5is N; and B6is C.

[0046] In certain embodiments, B1is CRB1; B2is CRB2; B3is CRB3; B4is N; B5is N; and B6is C.

[0047] In certain embodiments, B1is N; B2is N; B3is CRB3; B4is CRB4; B5is CRB5; and B6is C.

[0048] In certain embodiments, C is of Formula I-1-A, I-1-B, I-1-C, I-1-D, I-1-E, I-1-F, I-1-G, I-1-H, I- 1-I, I-1-J, I-1-K, or I-1-L:Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0049] In certain embodiments, C is of Formula I-1-i(I-1-i).

[0050] In certain embodiments, C is of Formula I-1-i-1 or I-1-i-2

[0051] In certain embodiments, C is of Formula I-1-i’

[0052] In certain embodiments,are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6Attorney Docket No. PRSC-094 / 001WO 343170-2295 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s- butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0053] In certain embodiments, RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, RB3, RB4, and RB5are independently hydrogen or C1-6alkyl.

[0054] In certain embodiments, RB1and RB2, RB2and RB3, RB3and RB4, or RB4and RB5, together with the carbon atoms to which they are attached, form optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocycle, wherein the heteroaryl or heterocycle is attached to L.

[0055] In certain embodiments, C is of Formula I-1-i’’wherein: Ring E is optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6- membered heterocycle, and B1aand B2aare independently C or N.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0056] In certain embodiments, Ring E is optionally substituted 5- or 6-membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered rings and 1-3 heteroatoms selected from N, O, and S).

[0057] In certain embodiments, Ring E is optionally substituted 5- or 6-membered heterocycle (e.g., heterocycle comprising one or two 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S).

[0058] In certain embodiments, B1aand B2aare independently C or N.

[0059] In certain embodiments, C is of Formula I-1-i’’-1

[0060] In certain embodiments, RX1and RB5or RX1and RB5’, together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C6 aryl or optionally substituted 5- or 6-membered heteroaryl.

[0061] In certain embodiments, RX1and RB5or RX1and RB5’, together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C5-6 carbocyclyl or optionally substituted 5- or 6-membered heterocyclyl.

[0062] In certain embodiments, Ring C is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, and -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6- membered heterocyclyl.

[0063] In certain embodiments, Ring C is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0064] In certain embodiments, Ring C is optionally substituted with one or more RB7, RB8, RB7’, RB9, RB10, or RB11.

[0065] In certain embodiments, Ruis RB7, RB8, RB7’, RB9, RB10, or RB11.

[0066] In certain embodiments, C is of Formula I-1-ii(I-1-ii), wherein: B5ais C or N; B7is CRB7, N, NRB7’, O, or S; B8is CRB8, N, NRB8’, O, or S; RB7and RB8are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and RB7’and RB8’are independently hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, wherein at least one of B5a, B6, B7, and B8is N, NRB7’, NRB8’, O, or S.

[0067] In certain embodiments, B5ais C or N.

[0068] In certain embodiments, R5is R5a.

[0069] In certain embodiments, B7is CRB7, N, or NRB7’.

[0070] In certain embodiments, B8is CRB8or N.

[0071] In certain embodiments, at least one of B7and B8is N.

[0072] In certain embodiments, each of B7and B8is N.

[0073] In certain embodiments, B7is N and B8is CRB8.

[0074] In certain embodiments, B5is N, B7is N, and B8is CRB8.

[0075] In certain embodiments, C is of Formula I-1-ii-1, I-1-ii-2, I-1-ii-3, I-1-ii-4, or I-1-ii-5Attorney Docket No. PRSC-094 / 001WO 343170-2295, wherein B7is O or S.

[0076] In certain embodiments, C is of Formula I-1-ii-3wherein B7is O or S.

[0077] In certain embodiments, RB7and RB8are independently hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1- 6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino,Attorney Docket No. PRSC-094 / 001WO 343170-2295 methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0078] In certain embodiments, RB8is hydrogen or C1-6 alkyl.

[0079] In certain embodiments, RB7’is hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4- membered rings and 1 heteroatom selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0080] In certain embodiments, RB7’is hydrogen or C1-6alkyl.

[0081] In certain embodiments, RB1, RB3, and RB4are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di- i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-Attorney Docket No. PRSC-094 / 001WO 343170-2295 butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0082] In certain embodiments, B1is CRB1, B3is CRB3, and B4is CRB4, and each of RB1, RB3, and RB4is hydrogen.

[0083] In certain embodiments, C is of Formula I-1-iiiwherein: B9is CRB9or N; B10is CRB10or N; and B11is CRB11or N. RB9, RB10, and RB11are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl.

[0084] In certain embodiments, C is of Formula I-1-iii-1 or I-1-iii-2iii-2).

[0085] In certain embodiments, C is of Formula I-1-iii-1’

[0086] In certain

[0087] In certain embodiments, one of RB9, RB10, and RB11is N.

[0088] In certain embodiments, two of RB9, RB10, and RB11are N.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0089] In certain embodiments, three of RB9, RB10, and RB11are N.

[0090] In certain embodiments, none of B9and B11is N.

[0091] In certain embodiments, one of RB9and RB11is N.

[0092] In certain embodiments, each of RB9and RB11is N.

[0093] In certain embodiments, RB9, RB10, and RB11, when applicable, are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i- propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i- propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0094] In certain embodiments, each of RB9, RB10, and RB11, when applicable, is hydrogen.

[0095] In certain embodiments, none of RB1, RB2, and RB3or none of RB1, RB3, and RB4is N.

[0096] In certain embodiments, one of RB1, RB2, and RB3or one of RB1, RB3, and RB4is N.

[0097] In certain embodiments, two of RB1, RB2, and RB3or two of RB1, RB3, and RB4are N.

[0098] In certain embodiments, three of RB1, RB2, and RB3or three of RB1, RB3, and RB4are N.

[0099] In certain embodiments, RB1, RB2, and RB3or RB1, RB3, and RB4, when applicable, are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-Attorney Docket No. PRSC-094 / 001WO 343170-2295 propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0100] In certain embodiments, each of RB1, RB2, and RB3or each of RB1, RB3, and RB4, when applicable, is hydrogen.

[0101] In certain embodiments, each RDis independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0102] In certain embodiments, two RD, together with the carbon atom(s) to which they are bonded, form C3-5 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), or cyclopentenyl (C5)) or 3- or 5-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 5-membered rings and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru.

[0103] In certain embodiments, d is an integer from 0 to 6, as valency permits. In certain embodiments, d is 1. In certain embodiments, d is 2. In certain embodiments, d is 3, as valency permits. In certain embodiments, d is 4, as valency permits. In certain embodiments, d is 5, as valency permits. In certain embodiments, d is 6, as valency permits.

[0104] In certain embodiments, q is an integer from 0 to 2. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0105] In certain embodiments, T is Formula I-3-idenotes attachment to L; RE1, RE2, RE3, and RE4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -Attorney Docket No. PRSC-094 / 001WO 343170-2295 C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; F1is C or N; F2is NRF2’or CRF2; RF2’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; F3is CRF3, N, or NRF3’; RF3is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF3’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RF4is -C(=O)NR3aR3bor 5- to 6-membered heteroaryl optionally substituted with one or more Ru; andAttorney Docket No. PRSC-094 / 001WO 343170-2295 R3aand R3bare independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or R3aand R3b, together with the nitrogen atom to which they are attached, form 3- to 12- membered heterocycle or 5- to 10-membered heteroaryl, wherein the heterocycle or heteroaryl is optionally substituted with one or more Ru.

[0106] In certain embodiments, T is of Formula I-3-i-a(I-3-i-a).

[0107] In certain embodiments, T is of Formula I-3-i-b

[0108] In certain embodiments,

[0109] In certain embodiments,

[0110] In certain embodiments,

[0111] In certain embodiments, one of E1, E2, and E3is N. In certain embodiments, two of E1, E2, and E3are N.

[0112] In certain embodiments, RE1, RE2, RE3, and RE4are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-Attorney Docket No. PRSC-094 / 001WO 343170-2295 butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0113] In certain embodiments, RE1, RE2, RE3, and RE4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0114] In certain embodiments, RE1, RE2, RE3, and RE4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0115] In certain embodiments, RE1, RE2, RE3, and RE4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0116] In certain embodiments, RE1, RE2, RE3, and RE4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0117] In certain embodiments, RE1and RE3are independently or RE1or RE2is hydrogen, halogen, or C1-6 alkyl optionally substituted with one or more Ru.

[0118] In certain embodiments, RE4is hydrogen, halogen, -CN, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, or -S(=O)2Ra, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0119] In certain embodiments, F1is C or N.

[0120] In certain embodiments, F2is NRF2’or CRF2.

[0121] In certain embodiments, F3is NRF3’, N, or CRF3.

[0122] In certain embodiments, RF2’and RF3’are independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclylAttorney Docket No. PRSC-094 / 001WO 343170-2295 comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0123] In certain embodiments, RF2’and RF3’are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6- membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0124] In certain embodiments, RF2’and RF3’are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0125] In certain embodiments, RF2’and RF3’are independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0126] In certain embodiments, RF2’is hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0127] In certain embodiments, RF2and RF3are independently hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1- 6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-Attorney Docket No. PRSC-094 / 001WO 343170-2295 butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0128] In certain embodiments, RF2and RF3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0129] In certain embodiments, RF2and RF3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0130] In certain embodiments, RF2and RF3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0131] In certain embodiments, RF2and RF3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0132] In certain embodiments, RF3is hydrogen.

[0133] In certain embodiments, RF4is -C(=O)NR3aR3bor 5- to 6-membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more Ru.

[0134] In certain embodiments, R3aand R3bare independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0135] In certain embodiments, R3aand R3bare independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6- membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0136] In certain embodiments, R3aand R3bare independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)2Ra, -Attorney Docket No. PRSC-094 / 001WO 343170-2295 S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0137] In certain embodiments, R3aand R3bare independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0138] In certain embodiments, R3aand R3b, together with the nitrogen atom to which they are attached, form 3- to 12-membered heterocycle (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S) or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the heterocycle or heteroaryl is optionally substituted with one or more Ru.

[0139] In certain embodiments, R3aand R3bare independently hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0140] In certain embodiments, T is of Formula I-3-ii’denotes attachment to L; RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -Attorney Docket No. PRSC-094 / 001WO 343170-2295 OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; H1is C(RH1)2, NRH1’, or O; H2is C(RH2)2, NRH2’, or O; each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RH1or two RH2, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; and RH1’and RH2’are independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0141] In certain embodiments, at most one of G1, G2, G3, and G4is N or NRB5.

[0142] In certain embodiments, one of G1, G2, G3, and G4is N or NRB5.

[0143] In certain embodiments, none of G1, G2, G3, and G4is N or NRB5.

[0144] In certain embodiments,

[0145] In certain embodiments,

[0146] In certain embodiments,

[0147] In certain embodiments,

[0148] In certain embodiments,

[0149] In certain embodiments,

[0150] In certain embodiments, T of Formula I-3-ii’ is of Formula I-3-ii’-A, I-3-ii’-B, I-3-ii’- C, I-3-ii’-D, I-3-ii’-E, or I-3-ii’-F:Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0151] In certain embodiments, T is of Formula I-3-iidenotes attachment to L; RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; H1is C(RH1)2, NRH1’, or O;Attorney Docket No. PRSC-094 / 001WO 343170-2295 H2is C(RH2)2, NRH2’, or O; each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RH1or two RH2, together with the carbon atom to which they are attached, form C3-6carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; and RH1’and RH2’are independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0152] In certain embodiments, T is of Formula I-3-ii-aii-a).

[0153] In certain embodiments, G1is , N, or CRG1.

[0154] In certain embodiments,

[0155] In certain embodiments, G3is , N, or CRG3.

[0156] In certain embodiments, RG1, RG2, RG3, and RG4are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n- butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-Attorney Docket No. PRSC-094 / 001WO 343170-2295 butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0157] In certain embodiments, RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0158] In certain embodiments, RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0159] In certain embodiments, RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0160] In certain embodiments, RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0161] In certain embodiments, RG1and RG3are both hydrogen.

[0162] In certain embodiments, RG4is hydrogen, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, or heterocyclyl is optionally substituted with one or more Ru.

[0163] In certain embodiments, H1is C(RH1)2, NRH1’, or O.

[0164] In certain embodiments, H2is C(RH2)2, NRH2’, or O.

[0165] In certain embodiments, H1is NRH1’and H2is NRH2’.

[0166] In certain embodiments, each occurrence of RH1and RH2are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5),Attorney Docket No. PRSC-094 / 001WO 343170-2295 cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0167] In certain embodiments, each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0168] In certain embodiments, each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0169] In certain embodiments, each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0170] In certain embodiments, RH1’and RH2’are independently C1-6 alkyl

[0171] In certain embodiments, two RH1or two RH2, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru.

[0172] In certain embodiments, RH1’and RH2’are independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenylAttorney Docket No. PRSC-094 / 001WO 343170-2295 (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0173] In certain embodiments, T is of Formula I-3-iii(I-3-iii), wherein:denotes attachment to L; I1is C(RI1)2, NRI1’, or O; I2is C(RI2)2, NRI2’, or O; each occurrence of RI1and RI2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RI1or two RI2, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; RI1’and RI2’are independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RIis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -Attorney Docket No. PRSC-094 / 001WO 343170-2295 C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; i is an integer selected from 0 to 4; J1is N or CRJ1; J2is N or CRJ2; and RJ1, RJ2, and RJ3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0174] In certain embodiments, T is of Formula I-3-iii-a(I-3-iii-a).

[0175] In certain embodiments, I1is C(RI1)2, NRI1’, or O.

[0176] In certain embodiments, I2is C(RI2)2, NRI2’, or O.

[0177] In certain embodiments, I1is NRI1’and I2is NRI2’.

[0178] In certain embodiments, each occurrence of RI1and RI2are independently oxo, hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i- propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i- propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i- propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-Attorney Docket No. PRSC-094 / 001WO 343170-2295 butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0179] In certain embodiments, each occurrence of RI1and RI2are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6- membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0180] In certain embodiments, each occurrence of RI1and RI2are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0181] In certain embodiments, each occurrence of RI1and RI2are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0182] In certain embodiments, two RI1or two RI2, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutylAttorney Docket No. PRSC-094 / 001WO 343170-2295 (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru;

[0183] In certain embodiments, RI1’and RI2’are independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered ring and 1-3 heteroatoms selected from N, O, and S), - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0184] In certain embodiments, RI1’and RI2’are independently hydrogen or C1-6alkyl.

[0185] In certain embodiments, each RIis independently oxo, hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8),Attorney Docket No. PRSC-094 / 001WO 343170-2295 cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0186] In certain embodiments, each RIis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0187] In certain embodiments, each RIis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0188] In certain embodiments, each RIis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0189] In certain embodiments, each RIis C1-6 alkyl. In certain embodiments, at least one RIis C1-6 alkyl.

[0190] In certain embodiments, each RIis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0191] In certain embodiments, i is an integer selected from 0 to 4. In certain embodiments, i is 0. In certain embodiments, i is 1. In certain embodiments, i is 2. In certain embodiments, i is 3. In certain embodiments, i is 4.

[0192] In certain embodiments, J1is N or CRJ1.

[0193] In certain embodiments, J2is N or CRJ2.

[0194] In certain embodiments, RJ1, RJ2, and RJ3are independently hydrogen, halogen (e.g., - F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di- i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -Attorney Docket No. PRSC-094 / 001WO 343170-2295 NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0195] In certain embodiments, RJ1, RJ2, and RJ3are independently hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0196] In certain embodiments, RJ1, RJ2, and RJ3are independently hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0197] In certain embodiments, RJ1, RJ2, and RJ3are independently hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0198] In certain embodiments, RJ1, RJ2, and RJ3are independently hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0199] In certain embodiments, RJ3is hydrogen, halogen, C1-6alkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, or -C(=O)NRcRd, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more Ru.

[0200] In certain embodiments, RJ1and RJ2are independently hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0201] In certain embodiments, T is of Formula I-3-iviv), wherein: M1is N or C;Attorney Docket No. PRSC-094 / 001WO 343170-2295wherein denotes attachment to L; and at least one of M1, M2, M3, and M4is N or ; RM2, RM3, and or RM4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RK’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; K1is -C(=O)- or -C(RK1)2-; each RK1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and k is an integer selected from 0 to 4.

[0202] In certain embodiments, T is of Formula I-3-iv-a

[0203] In certain embodiments, T is of Formula I-3-iv-b

[0204] In certain embodiments, two of M1, M2, M3, and M4are N or.

[0205] In certain embodiments,

[0206] In certain embodiments, T is of Formula I-3-iv-c

[0207] In certain embodiments,

[0208] In certain embodiments, T is of Formula I-3-iv-dAttorney Docket No. PRSC-094 / 001WO 343170-2295

[0209] In certain embodiments, M1is N or C.

[0210] In certain embodiments,

[0211] In certain embodiments,

[0212] In certain embodiments, M3is N.

[0213] In certain embodiments,

[0214] In certain embodiments, at least one of M1, M2, M3, and M4is N or.

[0215] In certain embodiments, at least two of M1, M3, and M4are N. In certain embodiments, at least one of M1, M3, and M4is N.

[0216] In certain embodiments, RM2, RM3, and or RM4are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n- butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5),Attorney Docket No. PRSC-094 / 001WO 343170-2295 pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0217] In certain embodiments, RM2, RM3, and or RM4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0218] In certain embodiments, RM2, RM3, and or RM4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0219] In certain embodiments, RM2, RM3, and or RM4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0220] In certain embodiments, RM2, RM3, and or RM4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-Attorney Docket No. PRSC-094 / 001WO 343170-2295 membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0221] In certain embodiments, RM2is C1-6alkyl, C1-6alkoxy, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, or heterocyclyl is optionally substituted with one or more Ru.

[0222] In certain embodiments, RM3is hydrogen.

[0223] In certain embodiments, RK’is hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0224] In certain embodiments, RK’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, 5- to 6-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0225] In certain embodiments, RK’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0226] In certain embodiments, RK’is hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -Attorney Docket No. PRSC-094 / 001WO 343170-2295 C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0227] In certain embodiments, RK’is hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0228] In certain embodiments, K1is -C(=O)- or -C(RK1)2-.

[0229] In certain embodiments, each RK1is independently hydrogen, halogen (e.g., -F, -Cl, - Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0230] In certain embodiments, each RK1is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0231] In certain embodiments, each RK1is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0232] In certain embodiments, each RK1is independently hydrogen, halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0233] In certain embodiments, each RKis independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8),Attorney Docket No. PRSC-094 / 001WO 343170-2295 cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0234] In certain embodiments, each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0235] In certain embodiments, each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0236] In certain embodiments, each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0237] In certain embodiments, each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0238] In certain embodiments, each RKis independently hydrogen or C1-6 alkyl. In certain embodiments, at least one RKis hydrogen. In certain embodiments, at least one RKis C1-6alkyl.

[0239] In certain embodiments, one RKis hydrogen, the other geminal RKis C1-6alkyl.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0240] In certain embodiments, k is an integer selected from 0 to 4. In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4.

[0241] In certain embodiments, T is of Formula I-3-vdenotes attachment to L; each RNis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; n is an integer selected from 0 to 6; RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; andAttorney Docket No. PRSC-094 / 001WO 343170-2295 R4is -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0242] In certain embodiments, T is of Formula I-3-v-a(I-3-v-a).

[0243] In certain embodiments,

[0244] In certain embodiments,

[0245] In certain embodiments, each RNis independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptylAttorney Docket No. PRSC-094 / 001WO 343170-2295 (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0246] In certain embodiments, each RNis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0247] In certain embodiments, each RNis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0248] In certain embodiments, each RNis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0249] In certain embodiments, each RNis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0250] In certain embodiments, n is an integer selected from 0 to 6. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, nAttorney Docket No. PRSC-094 / 001WO 343170-2295 is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.

[0251] In certain embodiments, n is 0.

[0252] In certain embodiments, RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0253] In certain embodiments, RP1, RP2, and RP3are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di- i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9),Attorney Docket No. PRSC-094 / 001WO 343170-2295 cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0254] In certain embodiments, RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0255] In certain embodiments, RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0256] In certain embodiments, RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0257] In certain embodiments, RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0258] In certain embodiments, RP3is hydrogen, C1-6alkyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0259] In certain embodiments, R4is -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), orAttorney Docket No. PRSC-094 / 001WO 343170-2295 hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n- butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6 alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0260] In certain embodiments, R4is C1-6 alkyl or C1-6 alkylamino, wherein the alkyl or alkylamino is optionally substituted with one or more Ru.

[0261] In certain embodiments, T is of Formula I-3-vi, wherein:Attorney Docket No. PRSC-094 / 001WO 343170-2295 Q1is NRQ1’, C(RQ1)2, or O; RQ1’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RQ1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RQ1, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; when is a double bond, then Q2is N or CRQ2; and Q3is N or CRQ3; when is a single bond, then Q2is NRQ2’, C(RQ2)2, or O; Q3is NRQ3’, C(RQ3)2, or O; RQ2’and RQ3’are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each occurrence of RQ2and RQ3is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RQ2or two RQ3, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; S1is CRS1or N;Attorney Docket No. PRSC-094 / 001WO 343170-2295to L; and RS1, RS2, RS3, and RS4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0262] In certain embodiments, T is of Formula I-3-vi, wherein: is a double bond; Q1is NRQ1’; Q2is CRQ2; Q3is CRQ3; S1is CRS1; S2is CRS2; S3is CRS3; and

[0263] In certain embodiments, none of S1, S2, S3, and S4is N.

[0264] In certain embodiments, T is of Formula I-3-vi-a or I-3-vi-bvi-b).

[0265] In certain embodiments, T is of Formula I-3-vi-a-iAttorney Docket No. PRSC-094 / 001WO 343170-2295

[0266] In certain embodiments, Q1is NRQ1’, C(RQ1)2, or O.

[0267] In certain embodiments, RQ1’is hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10- membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0268] In certain embodiments, RQ1’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, 5- to 6-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0269] In certain embodiments, RQ1’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0270] In certain embodiments, RQ1’is hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0271] In certain embodiments, RQ1’is hydrogen or C1-6 alkyl.

[0272] In certain embodiments, each RQ1is independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0273] In certain embodiments, each RQ1is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0274] In certain embodiments, each RQ1is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0275] In certain embodiments, each RQ1is independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0276] In certain embodiments, two RQ1, together with the carbon atom to which they are attached, form C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru.

[0277] In certain embodiments, when is a double bond, then Q2is N or CRQ2.

[0278] In certain embodiments, when is a single bond, then Q2is NRQ2’, C(RQ2)2, or O.

[0279] In certain embodiments, RQ2’and RQ3’are independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, andAttorney Docket No. PRSC-094 / 001WO 343170-2295 S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0280] In certain embodiments, RQ2’and RQ3’are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, 5- to 6- membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0281] In certain embodiments, RQ2’and RQ3’are independently hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0282] In certain embodiments, RQ2’and RQ3’are independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0283] In certain embodiments, each occurrence of RQ2and RQ3is independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5),Attorney Docket No. PRSC-094 / 001WO 343170-2295 pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10aryl (e.g., phenyl or naphthyl), or 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0284] In certain embodiments, each occurrence of RQ2and RQ3is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0285] In certain embodiments, each occurrence of RQ2and RQ3is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0286] In certain embodiments, each occurrence of RQ2and RQ3is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0287] In certain embodiments, each RQ2is hydrogen.

[0288] In certain embodiments, two RQ2or two RQ3, together with the carbon atom to which they are attached, form C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)) or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 6-membered rings and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0289] In certain embodiments, S1is CRS1or N.

[0290] In certain embodiments,

[0291] In certain embodiments,

[0292] In certain embodiments,

[0293] In certain embodiments, RS1, RS2, RS3, and RS4are independently oxo, hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n- butylamino, di-i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected fromAttorney Docket No. PRSC-094 / 001WO 343170-2295 N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, - NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0294] In certain embodiments, RS1, RS2, RS3, and RS4are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0295] In certain embodiments, RS1, RS2, RS3, and RS4are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0296] In certain embodiments, RS1, RS2, RS3, and RS4are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0297] In certain embodiments, RS1, RS2, RS3, and RS4are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0298] In certain embodiments, RS1and RS3are both hydrogen.

[0299] In certain embodiments, RS2is hydrogen, C1-6 alkyl, C1-6 alkoxy, or 3-12-membered heterocyclyl.

[0300] In certain embodiments, RS4is hydrogen or C1-6alkyl.

[0301] In certain embodiments, L is of Formula I-2 (I-2), wherein:Attorney Docket No. PRSC-094 / 001WO 343170-2295 ** denotes attachment to T and * denotes attachment to C; L’’ is absent; or L’’ is C1-3alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru; RLis hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; wherein: i) when L’’ is C1-3alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2- , wherein the alkylene is optionally substituted with one or more Ru, then Cy1is optionally substituted C6 arylene or 5- or 6-membered heteroarylene; ii) when L’’ is absent, then Cy1is, wherein: ** denotes attachment to T; T1is CRT1or N; V1is CRV1or N; V2is CRV2or N; RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; t is an integer selected from 0 to 6, as valency permits; or Cy1isAttorney Docket No. PRSC-094 / 001WO 343170-2295, wherein: when is single bond, Y1is N or CRY1; when is double bond, Y1is C; ** denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Y2is C(RY2)2, O, or N(RY2’); each RY2is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; RY2’is hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Z1is CRZ1or N; Z2is CRZ2or N; RZ1and RZ2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z; Cy2is 5- or 6-membered heteroarylene optionally substituted with one or more Ru; L1is -C(=O)NH- or 5- or 6-membered heteroaryl optionally substituted with one or more Ru; L2is [C(RL2)2]l, wherein each RL2is independently hydrogen, C1-3 alkyl, or C1-3 haloalkyl; orAttorney Docket No. PRSC-094 / 001WO 343170-2295 two geminal RL2, together with the carbon atom to which they are bonded, form C3-5 carbocyclyl or 3- to 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; l is 1 or 2; and L3is E-ethenylene, ethynylene, C6 arylene, or 5- or 6-membered heteroarylene, wherein the E- ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0302] In certain embodiments, L is of Formula I-2wherein: ** denotes attachment to T and * denotes attachment to C; L’’ is absent; or L’’ is C1-3 alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru; RLis hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; wherein: i) when L’’ is C1-3alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2- , wherein the alkylene is optionally substituted with one or more Ru, then Cy1is optionally substituted C6arylene or 5- or 6-membered heteroarylene; ii) when L’’ is absent, then Cy1is, wherein: ** denotes attachment to T; T1is CRT1or N; V1is CRV1or N; V2is CRV2or N; RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, whereinAttorney Docket No. PRSC-094 / 001WO 343170-2295 the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; t is an integer selected from 0 to 6, as valency permits; or Cy1is, wherein: Y1is N or CRY1; ** denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Y2is C(RY2)2, O, or N(RY2’); each RY2is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; RY2’is hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Z1is CRZ1or N; RZ1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z; Cy2is 5- or 6-membered heteroarylene optionally substituted with one or more Ru; L1is -C(=O)NH- or 5- or 6-membered heteroaryl optionally substituted with one or more Ru; L2is [C(RL2)2]l, wherein each RL2is independently hydrogen, C1-3 alkyl, or C1-3 haloalkyl; or two geminal RL2, together with the carbon atom to which they are bonded, form C3-5carbocyclyl or 3- to 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; l is 1 or 2; and L3is E-ethenylene, ethynylene, C6arylene, or 5- or 6-membered heteroarylene, wherein the E-ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0303] In certain embodiments, L’’ is absent.

[0304] In certain embodiments, L’’ is C1-3alkylene (e.g., methylene, ethylene, n-propylene, or iso-propylene), -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru.

[0305] In certain embodiments, L’’ is -N(RL)- or -O-.

[0306] In certain embodiments, Cy1is optionally substituted C6arylene (i.e., phenylene, e.g., 1,2-phenylene, 1,3-phenylene, or 1,4-phenylene) or 5- or 6-membered heteroarylene (e.g., heteroarylene comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from O, N, and S).

[0307] In certain embodiments, when L’’ is C1-3 alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O- , -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru, then Cy1is optionally substituted C6arylene or 5- or 6-membered heteroarylene.

[0308] In certain embodiments, RLis hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0309] In certain embodiments, Cy1is optionally substituted with one or more substituent selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -Attorney Docket No. PRSC-094 / 001WO 343170-2295 NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, - OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, and -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6- membered heterocyclyl.

[0310] In certain embodiments, Cy1is optionally substituted with one or more Ru. In certain embodiments, Cy1is optionally substituted with one or more RV’1. In certain embodiments, Cy1is optionally substituted with one or more RV’.

[0311] In certain embodiments, Ruis RV’1. In certain embodiments, Ruis RV’.

[0312] In certain embodiments, Cy1is,

[0313] In certain embodiments, when L’’ is absent, then Cy1is.

[0314] In certain embodiments, Cy1is.

[0315] In certain embodiments, when L’’ is absent, then Cy1is.

[0316] In certain embodiments, T1is CRT1or N. In certain embodiments, T1is CRT1. In certain embodiments, T1is N.

[0317] In certain embodiments, V1is CRV1or N. In certain embodiments, V1is CRV1. In certain embodiments, V2is N.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0318] In certain embodiments, V2is CRV2or N. In certain embodiments, V2is CRV2. In certain embodiments, V2is N.

[0319] In certain embodiments, RT1, RV1, and RV2are independently hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di- i-butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0320] In certain embodiments, RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, C6 aryl, or 5- or 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0321] In certain embodiments, RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0322] In certain embodiments, RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0323] In certain embodiments, RT1and RV2are both hydrogen.

[0324] In certain embodiments, each RTis independently halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n- butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0325] In certain embodiments, each RTis independently C1-6 alkyl. In certain embodiments, at least one RTis C1-6alkyl.

[0326] In certain embodiments, t is 0. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3. In certain embodiments, t is 4. In certain embodiments, t is 5. In certain embodiments, t is 6.

[0327] In certain embodiments, Cy1is.

[0328] In certain embodiments, Cy1isAttorney Docket No. PRSC-094 / 001WO 343170-2295

[0329] In certain embodiments, Cy1is.

[0330] In certain embodiments, Cy1is, wherein RZ1is C1-6alkyl substituted with one or more halogen.

[0331] In certain embodiments, Y1is N or CRY1. In certain embodiments, Y1is N. In certain embodiments, Y1is CRY1.

[0332] In certain embodiments, when is single bond, Y1is N or CRY1. In certain embodiments, when is double bond, Y1is C

[0333] In certain embodiments, RY1is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-Attorney Docket No. PRSC-094 / 001WO 343170-2295 butylhexylamino, or pentylhexylamino), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0334] In certain embodiments, Y2is C(RY2)2, O, or N(RY2’).

[0335] In certain embodiments, each RY2is independently hydrogen, halogen (e.g., -F, -Cl, - Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0336] In certain embodiments, each RY2is hydrogen.

[0337] In certain embodiments, RY2’is hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4- membered rings and 1 heteroatom selected from N, O, and S), -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0338] In certain embodiments, Z1is CRZ1or N.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0339] In certain embodiments, Z2is CRZ2or N.

[0340] In certain embodiments, none of Z1and Z2is N.

[0341] In certain embodiments, at least one of Z1and Z2is N.

[0342] In certain embodiments, RZ1is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C3-4 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0343] In certain embodiments, RZ2is hydrogen, halogen (e.g., -F, -Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t- butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s- butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n- propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s- butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n- propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i- butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino,Attorney Docket No. PRSC-094 / 001WO 343170-2295 propylhexylamino, n-butylpentylamino, i-butylpentylamino, s-butylpentylamino, t- butylpentylamino, n-butylhexylamino, i-butylhexylamino, s-butylhexylamino, t- butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0344] In certain embodiments, each RZis independently oxo, hydrogen, halogen (e.g., -F, - Cl, -Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0345] In certain embodiments, each RZis independently halogen or C1-6 alkyl.

[0346] In certain embodiments, at least one RZis oxo.

[0347] In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2, as valency permits. In certain embodiments, z is 3, as valency permits. In certain embodiments, z is 4, as valency permits. In certain embodiments, z is 5, as valency permits. In certain embodiments, z is 6, as valency permits.

[0348] In certain embodiments, Cy1isAttorney Docket No. PRSC-094 / 001WO 343170-2295, wherein: ** denotes attachment to L’’; V’1is CRV’1or N; V’2is CRV’2or N; RV’1and RV’2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RV’is independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and v’ is an integer selected from 0 to 5.

[0349] In certain embodiments, Cy1is, wherein: ** denotes attachment to L’’; V’1is CRV’1or N; RV’1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RV’is independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and v’ is an integer selected from 0 to 5.

[0350] In certain embodiments, when L’’ is C1-3alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O- , -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru, then Cy1isAttorney Docket No. PRSC-094 / 001WO 343170-2295, wherein: ** denotes attachment to L’’; V’1is CRV’1or N; RV’1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3- 4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RV’is independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and v’ is an integer selected from 0 to 5.

[0351] In certain embodiments, V’1is CRV’1or N. In certain embodiments, V’1is CRV’1. In certain embodiments, V’1is N.

[0352] In certain embodiments, V’2is CRV’2or N. In certain embodiments, V’2is CRV’2. In certain embodiments, V’2is N.

[0353] In certain embodiments, at least one of V’1and V’2is N.

[0354] In certain embodiments, each RV’1is independently hydrogen, halogen (e.g., -F, -Cl, - Br, or -I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4 carbocyclyl (e.g., cyclopropylAttorney Docket No. PRSC-094 / 001WO 343170-2295 (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0355] In certain embodiments, each RV’2is independently hydrogen, halogen (e.g., -F, -Cl, - Br, or -I), -CN, -NO2, -OH, -NH2, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i- propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0356] In certain embodiments, RV’1and RV’2, when available, are independently hydrogen, halogen, C1-6 alkyl, or C1-6 haloalkyl.

[0357] In certain embodiments, each RV’is independently halogen (e.g., -F, -Cl, -Br, or -I), - CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n- butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s- butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino, di-i- butylamino, di-s-butylamino, di-t-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl-i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t-butylamino, methylpentylamino,Attorney Docket No. PRSC-094 / 001WO 343170-2295 methylhexylamino, ethyl-n-propylamino, ethyl-i-propylamino, ethyl-n-butylamino, ethyl-s- butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, i-butylpentylamino, s- butylpentylamino, t-butylpentylamino, n-butylhexylamino, i-butylhexylamino, s- butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- or 4-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- or 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0358] In certain embodiments, v’ is an integer selected from 0 to 5. In certain embodiments, v’ is 0. In certain embodiments, v’ is 1. In certain embodiments, v’ is 2. In certain embodiments, v’ is 3. In certain embodiments, v’ is 4. In certain embodiments, v’ is 5.

[0359] In certain embodiments, Cy2is 5- or 6-membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein heteroarylene is optionally substituted with one or more Ru.

[0360] In certain embodiments, Cy2is pyridinylene optionally substituted with one or more halogen, C1-6 alkyl, or C1-6 alkoxy.

[0361] In certain embodiments, Cy2iswherein ## denotes attachment to Cy1.

[0362] In certain embodiments, L1is -C(=O)NH- or 5- or 6-membered heteroaryl optionally substituted with one or more Ru.

[0363] In certain embodiments, L1is -C(=O)NH-.

[0364] In certain embodiments, L1is 5- or 6-membered heteroaryl (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from O, N, or S) optionally substituted with one or more Ru.

[0365] In certain embodiments, L2is [C(RL2)2]l, wherein each RL2is independently hydrogen, C1-3 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or i-propyl (C3)), or C1-3 haloalkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), or i-propyl (C3) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I)).Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0366] In certain embodiments, two geminal RL2, together with the carbon atom to which they are bonded, form C3-5 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), or cyclopentenyl (C5)) or 3- to 5-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 5-membered rings and 1-3 heteroatoms selected from N, O, and S), wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru.

[0367] In certain embodiments, L2is CH2.

[0368] In certain embodiments, -L1-L2- is -C(=O)NH-CH2-.

[0369] In certain embodiments, l is 1 or 2. In certain embodiments, l is 1. In certain embodiments, l is 2.

[0370] In certain embodiments, l is 1.

[0371] In certain embodiments, L3is E-ethenylene, ethynylene, C6 arylene, or 5- or 6- membered heteroarylene (e.g., heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S), wherein the E-ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0372] In certain embodiments, L3is E-ethenylene optionally substituted with one or more Ru.

[0373] In certain embodiments, L3is unsubstituted E-ethenylene.

[0374] In certain embodiments, L3is C6 arylene optionally substituted with one or more Ru.

[0375] In certain embodiments, L3is -(1,4-phenylene)- optionally substituted with one or more Ru.

[0376] In certain embodiments, L3is unsubstituted -(1,4-phenylene)-.

[0377] In certain embodiments, L3is ethynylene.

[0378] In certain embodiments, L3is 5- or 6-membered heteroarylene optionally substituted with one or more Ru.

[0379] In certain embodiments, L3is unsubstituted 5- or 6-membered heteroarylene.

[0380] In certain embodiments, L3is unsubstituted 5-membered heteroarylene.

[0381] In certain embodiments, L3is unsubstituted 1,3-linked 5-membered heteroarylene.

[0382] In certain embodiments, L3is unsubstituted 6-membered heteroarylene.

[0383] In certain embodiments, L3is unsubstituted 1,4-linked 6-membered heteroarylene.

[0384] In certain embodiments, each Rais independently C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprisingAttorney Docket No. PRSC-094 / 001WO 343170-2295 one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0385] In certain embodiments, each Rbis independently hydrogen, C1-6alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C3-6 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0386] In certain embodiments, each Rcand each Rdis independently hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t- butyl (C4), pentyl (C5), or hexyl (C6)), C3-6carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), or cyclohexadienyl (C6)), or 3- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0387] In certain embodiments, Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz.

[0388] In certain embodiments, Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0389] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6 alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)), C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n- propylamino, di-i-propylamino, di-n-butylamino, di-i-butylamino, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-n-propylamino, methyl- i-propylamino, methyl-n-butylamino, methyl-i-butylamino, methyl-s-butylamino, methyl-t- butylamino, methylpentylamino, methylhexylamino, ethyl-n-propylamino, ethyl-i- propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-i-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-i-butylamino, propyl-s- butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, n-Attorney Docket No. PRSC-094 / 001WO 343170-2295 butylpentylamino, i-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n- butylhexylamino, i-butylhexylamino, s-butylhexylamino, t-butylhexylamino, or pentylhexylamino), C2-6alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (C5), or hexenyl (C6)), C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (C6)), C3-12carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)), 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S), C6-10 aryl (e.g., phenyl or naphthyl), 5- to 10-membered heteroaryl (e.g., heteroaryl comprising one or two 5- or 6-membered rings and 1-5 heteroatoms selected from N, O, and S), -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, - NRcS(=O)2ORb, -NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - OS(=O)2Ra, -OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd; wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0390] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl.

[0391] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, 3- to 6- membered heterocyclyl, C6aryl, or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2,Attorney Docket No. PRSC-094 / 001WO 343170-2295 C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, and 3- to 6- membered heterocyclyl.

[0392] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocyclyl, or 3- to 6- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6 carbocyclyl, and 3- to 6-membered heterocyclyl.

[0393] In certain embodiments, each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6carbocyclyl, and 3- to 6-membered heterocyclyl.

[0394] In certain embodiments, the compound is of Formula I-Awherein: Cy2Ais hydrogen or C1-6 alkyl;; denotes attachment to Ring D; XBis O or S; RB’ is hydrogen or halogen; T is of Formula I-3-ii’ or I-3-vi; and Formula I-3-ii’, Formula I-3-vi, L” and Cy1are as defined herein.

[0395] In certain embodiments, Cy2Ais hydrogen.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0396] In certain embodiments, Cy2Ais C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i-butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i- butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (C5), or hexoxy (C6)).

[0397] In certain embodiments, Cy2Ais methyl.

[0398] In certain embodiments, B’ is .

[0399] In certain embodiments, XBis O. In certain embodiments, XBis S.

[0400] In certain embodiments, RB’is hydrogen.

[0401] In certain embodiments, RB’is halogen (e.g., -F, -Cl, -Br, or -I).

[0402] In certain embodiments, RB’is -F.

[0403] In certain embodiments,

[0404] In certain embodiments, B’ is .

[0405] In certain embodiments, B’ is or .

[0406] In certain embodiments, T of Formula (I-A) is of Formula I-3-ii. In certain embodiments, T of Formula (I-A) is of Formula I-3-ii-a.

[0407] In certain embodiments, T of Formula (I-A) is of Formula I-3-ii-a, wherein RG4is hydrogen, C1-6 alkyl (e.g., methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), i- butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (C5), or hexyl (C6)), or 3- to 12-membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S).

[0408] In certain embodiments, T of Formula (I-A) is of Formula I-3-ii-a, wherein G1is CRG1; and G3is CRG3.

[0409] In certain embodiments, T of Formula (I-A) is of Formula I-3-ii-a, wherein G1and G3are each CH.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0410] In certain embodiments, T of Formula (I-A) is of Formula I-3-ii’-A.

[0411] In certain embodiments, T of Formula (I-A) is of Formula I-3-ii’-A, wherein H1is NRH1’; and H2is NRH2’.

[0412] In certain embodiments, T of Formula (I-A) is, , or, denotes attachment to L”.

[0413] In certain embodiments, T of Formula (I-A) is of Formula I-3-vi-a.

[0414] In certain embodiments, T of Formula (I-A) is of Formula I-3-vi-a-i.

[0415] In certain embodiments, T of Formula (I-A) is, whereindenotes attachment to L”.

[0416] In certain embodiments, L” of Formula (I-A) is absent or -N(RL)-.

[0417] In certain embodiments, L” of Formula (I-A) is absent. In certain embodiments, L” of Formula (I-A) is -NCH3-.

[0418] In certain embodiments, Cy1of Formula (I-A)is 5- or 6-membered heteroarylene.

[0419] In certain embodiments, Cy1of Formula (I-A) is, whereindenotes attachment to L”.

[0420] In certain embodiments, Cy1of Formula (I-A) isdenotes attachment to T.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0421] In certain embodiments, Cy1of Formula (I-A) is

[0422] In certain embodiments, the compound of Formula I-A is of Formula I-A-i or I-A-ii:

[0423] Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I, I-1, I-1-i, I-1-i-1, I-1-i-2, I-1-ii, I-1-ii-1, I-1-ii-2, I-1-iii, I-1-iii-1, I-2, I-3-i, I-3-ii, I-3-iii, I- 3-iv, I-3-v, and I-3-vi, as applicable, are described below. Any of the variables can be any moiety as described in the embodiments below. In addition, the combination of any moieties described for any of the variables, as applicable, with any moieties described for any of the remaining variables, is also contemplated.

[0424] Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operableAttorney Docket No. PRSC-094 / 001WO 343170-2295 embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0425] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0426] In certain embodiments, the compound is selected from the compounds in Tables 1-4 and pharmaceutically acceptable salts thereof.

[0427] In certain embodiments, the compound is selected from the compounds in Tables 1-4.

[0428] In certain embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0429] In certain embodiments, the compound is selected from the compounds in Table 1.

[0430] In certain embodiments, the compound is selected from the compounds in Table 2 and pharmaceutically acceptable salts thereof.

[0431] In certain embodiments, the compound is selected from the compounds in Table 2.

[0432] In certain embodiments, the compound is selected from the compounds in Table 3 and pharmaceutically acceptable salts thereof.

[0433] In certain embodiments, the compound is selected from the compounds in Table 3.

[0434] In certain embodiments, the compound is selected from the compounds in Table 4 and pharmaceutically acceptable salts thereof.

[0435] In certain embodiments, the compound is selected from the compounds in Table 4.5922--l-]l0- -- )3-l -o3- - - 3lo71343OW100 / 490-CSRP.oNtekcoDyenrottAutcurtS.oN d n.u 1 2 31oA A lpA ebmaoTC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAtS.oN d nuo4 5 6pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottA511erutcurtS.oN d nuo7 8pA A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottA611erutcurtS.oN d nuo90A1pA moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAS .oN d nu1o12131pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAerutcurtS.oN d nu41516o1pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottA11erutcurtS.oN d nu718 9o1 1pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAS .oN d nu0o21222pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAutcurtS.oN d nu3242526o2pA A A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAurtS.oN d nu72829o2pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAerutcurtS.oN d nu03132o3pA A A moC5922-0-71343OW100 / 490-CSRP.oNtekcoDyenrottAe N H ruO tcurN tSN N N N N O .oN d nu3 4 5o3 3 3pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAtS.oN d nu63738o3pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAerutcurtS.oN d nu93041o4pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAS .oN d nu2o4344454pA A A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAerutcurtS.oN d nu64748o4pA A A moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottA1erutcurtS.oN d nu9405152o5pA A A A moC592-2- 3,-1- -20- --5 --71343OW100 / 490-CSRP.oNtekcoDyenrottAtS.oN d nu12oB2B3BelpbmaoTC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottArtS.oN d nu4 5 6op B B BmoC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAerutcu H N rtO S N O N N N N .oN d nu7 8op B B9B moC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottAerutcurtS.oN d nu 01112oB B1pBmoC5922-071343OW100 / 490-CSRP.oNtekcoDyenrottA431erutcurtS.oN d nu 3 4o1B1pBmoC5922- -- 105- -71343OW100 / 490-CSRP.oNtekcoDyen- )r3(ly7,6 yott -4A (n,-eNh 5,p4)l -yoxo531erutcurtS.oN d nu 13oC elpbmaoTC592-2- 3 -- )3 -0 - - ) e71343OW100 / 490-CSRP.oNtekcoDyenrottA631erutcurtS.oN d nu 1 24oD D elpbmaoTCAttorney Docket No. PRSC-094 / 001WO 343170-2295

[0436] In certain embodiments, the compound is selected from Compound Nos. A10, A21, A32, A36, A40, A41, A43, B8, B12, and B14, and pharmaceutically acceptable salts thereof.

[0437] In certain embodiments, the compound is selected from Compound Nos. A10, A21, A32, A36, A40, A41, A43, B8, B12, and B14.

[0438] In certain embodiments, the compound is selected from Compound Nos. A10, A21, A32, A36, A40, A41, and A43, and pharmaceutically acceptable salts thereof.

[0439] In certain embodiments, the compound is selected from Compound Nos. A10, A21, A32, A36, A40, A41, and A43.

[0440] In certain embodiments, the compound is selected from Compound Nos. B8, B12, and B14, and pharmaceutically acceptable salts thereof.

[0441] In certain embodiments, the compound is selected from Compound Nos. B8, B12, and B14.

[0442] To date, heterobifunctional protein degraders carry both opportunities and challenges. The biggest challenge is that, unlike traditional small-molecule drugs, degraders do not meet the classic ‘‘rule of 5’’ (RO5) which was proposed by Christopher A. Lipinski in 1997: molecular weight (MW) < 500 kDa; solubility (LogP) < 5; H-bond donors (HBDs) < 5; H-bond acceptors (HBAs) < 10; and number of rotatable bonds (nRotB) < 10. Compounds conforming to Lipinski’s rule have a higher probability of possessing good pharmacokinetic (PK) properties and high oral bioavailability compared with compounds that don’t satisfy the RO5. Although heterobifunctional degraders are considered small-molecule compounds, they typically violate the RO5 due to molecular weight >500 kDa and several other RO5 parameters above the cutoffs. As a result, poor oral absorption is a common and major problem for heterobifunctional degraders.

[0443] In order to screen for degraders with acceptable oral bioavailability, parameters such as molecular weight, solubility, topological polar surface area (tPSA), H-bond donor, H-bond acceptor, number of rotatable bonds, as well as metabolic stability / permeability, need to be carefully characterized and optimized. In addition, selectivity off-target proteins needs to be optimized as well. In fact, many current studies only demonstrate the effectiveness and anti- proliferative activity of the designed degraders on target protein degradation at the cellular levels, with acknowledgement of the challenge of achieving orally bioavailable compounds.

[0444] The present disclosure is based, at least in part, on the discovery that the compounds disclosed herein may possess improved oral bioavailability relative to other p300 degraders.

[0445] The compounds of the present disclosure may also possess advantageous characteristics, as compared to other p300 degraders. For example, the compounds of theAttorney Docket No. PRSC-094 / 001WO 343170-2295 present disclosure may potentially show selectivity for p300 over CBP, may display more potent degradation activity against p300, more favorable pharmacokinetic properties (e.g., as measured by Cmax, Tmax, and / or AUC), and / or less interaction with other cellular targets (e.g., hepatic cellular transporter such as OATP1B1) and accordingly improved safety (e.g., drug- drug interaction).

[0446] In certain embodiments, a compound disclosed herein shows selective degradation of p300 over CBP when a compound has a DC50for p300 that is lower than its DC50for CBP when both values are measured at the same time point. In certain embodiments, a compound disclosed herein shows selectivity when a compound has a Dmaxfor p300 that is greater than its Dmaxfor CBP when both values are measured at the same time point. In certain embodiments, a compound disclosed herein shows selectivity through a combination of both lower DC50 and greater Dmax for p300, as compared to those for CBP. In certain embodiments, a compound disclosed herein shows selectivity when a compound has a DC50for p300 at least 10-fold lower than its DC50 for CBP and / or a value of Dmax for p300 minus Dmax for CBP (∆Dmax) of at least 30, at least 35, at least 40, or at least 45 percentage points. In certain preferred embodiments, a compound disclosed herein shows selectivity when a compound has a DC50for p300 at least 30-fold lower than its DC50for CBP and / or a value of Dmaxfor p300 minus Dmax for CBP (∆Dmax) of at least 50, at least 55, at least 60, or at least 65 percentage points. In certain more preferred embodiments, a compound disclosed herein shows selectivity when a compound has a DC50for p300 at least 100-fold lower than its DC50for CBP and / or a value of Dmax for p300 minus Dmax for CBP (∆Dmax) of at least 70, at least 75, at least 80, at least 85, or at least 90 percentage points. In certain embodiments, a compound disclosed herein shows selectivity when it has a Dmaxfor p300 measured at a short time point (for instance, 2 hours) that is equivalent or greater than its Dmax for CBP measured at a significantly longer time point (for instance, 24 hours). In certain preferred embodiments, a compound has a (∆Dmax) of at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, or at least 90 percentage points even when measured stringently (at 2 hours for p300 and 24 hours for CBP). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein.

[0447] Due to the existence of double bonds, the compounds of the present disclosure may be in cis or trans, or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0448] In one embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a pharmaceutically acceptable salt. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a solvate. In another embodiment, a compound of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein) is a hydrate. Pharmaceutically acceptable salts

[0449] In certain embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In certain embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0450] In certain embodiments, the compounds described herein possess acidic or basic groups and therefor react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In certain embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0451] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0452] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4- methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3- hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid.

[0453] In certain embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, or sulfate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.

[0454] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In certain embodiments, water or oil-soluble or dispersible products are obtained by such quaternization. Solvates

[0455] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the disclosure may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. InAttorney Docket No. PRSC-094 / 001WO 343170-2295 certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0456] Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates are within the scope of the disclosure.

[0457] It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms or the pharmaceutically acceptable solvates thereof are contemplated and are within the scope of the present disclosure.

[0458] In certain embodiments, the compounds described herein exist as solvates. The present disclosure provides for methods of treating diseases by administering such solvates. The present disclosure further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0459] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Isomers (stereoisomers, geometric isomer, tautomer, etc.)

[0460] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.”

[0461] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized lightAttorney Docket No. PRSC-094 / 001WO 343170-2295 and designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)- isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is termed a “racemic mixture”.

[0462] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” denotes that the compound comprises more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0463] As used herein and unless otherwise indicated, the term “enantiomerically pure (R)- compound” refers to at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, at least about 99% by weight (R)-compound and at most about 1% by weight (S)-compound, or at least about 99.9 % by weight (R)-compound and at most about 0.1% by weight (S)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0464] As used herein and unless otherwise indicated, the term “enantiomerically pure (S)- compound” refers to at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, at least about 99% by weight (S)-compound and at most about 1% by weight (R)-compound or at least about 99.9% by weight (S)-compound and at most about 0.1% by weight (R)-compound. In certain embodiments, the weights are based upon total weight of compound.

[0465] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure (R)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (R)-compound. In certain embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)- compound can comprise, for example, about 90% excipient and about 10% enantiomericallyAttorney Docket No. PRSC-094 / 001WO 343170-2295 pure (S)-compound. In certain embodiments, the enantiomerically pure (S)-compound in such compositions can, for example, comprise, at least about 95% by weight (S)-compound and at most about 5% by weight (R)-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0466] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0467] In certain embodiments, the compounds described herein exist as geometric isomers. In certain embodiments, the compounds described herein possess one or more double bonds. The compounds disclosed herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. All geometric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure.

[0468] In certain embodiments, the compounds disclosed herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds disclosed herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. All diastereomeric, enantiomeric, and epimeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure.

[0469] In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In certain embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In certain embodiments, dissociable complexes are preferred. In certain embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In certain embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In certain embodiments, the optically pure enantiomer is then recovered, along with the resolving agent. TautomersAttorney Docket No. PRSC-094 / 001WO 343170-2295

[0470] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0471] Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and an adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest. All tautomeric forms of the compounds disclosed herein are contemplated and are within the scope of the disclosure. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Pharmaceutical Compositions

[0472] In certain embodiments, the compound described herein is administered as a pure chemical. In certain embodiments, the compound described herein is combined with one or more pharmaceutically suitable or acceptable carriers (also referred to herein as one or more pharmaceutically suitable (or acceptable) excipients, physiologically suitable (or acceptable) excipients, or physiologically suitable (or acceptable) carriers) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0473] Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0474] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, less than about 1%, or less than about 0.1% of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0475] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method ofAttorney Docket No. PRSC-094 / 001WO 343170-2295 administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0476] In certain embodiments, the pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal and epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In certain embodiments, the pharmaceutical composition is formulated for oral administration. In certain embodiments, the pharmaceutical composition is formulated for intravenous injection. In certain embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In certain embodiments, the pharmaceutical composition is formulated as a tablet. Preparation and Characterization of the Compounds

[0477] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. The compounds of the present disclosure (i.e., a compound of the present application (e.g., a compound of any of the formulae or any individual compounds disclosed herein)) can be synthesized by following the general synthetic scheme below as well as the steps outlined in the examples, schemes, procedures, and / or synthesis described herein (e.g., Examples). General Synthetic Scheme

[0478] A compound of formula I-1 may be prepared according to the procedures shown in SCHEME 1a or SCHEME 1b.Attorney Docket No. PRSC-094 / 001WO 343170-2295SCHEME 1a

[0479] According to SCHEME 1a, commercially available or synthetically accessible substituted aryl halide, heteroaryl halide, or benzyl halide of formula I-1-1a (Y = Cl, Br, I, OTf, and the like) are coupled with commercially available or synthetically accessible substituted urea compounds of formula I-1-2a; with a suitable inorganic base such as K3PO4, Cs2CO3 and the like; with a suitable metal catalyst such as copper(I) iodide, or the like; with a suitable ligand such as (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine, or the like; in a suitable solvent such as 1,4-dioxane, DMF, or the like; at temperatures ranging from 80 °C to 120 °C, preferably 80 °C; to provide a coupled compound of formula I-1-3a. Alternatively, commercially available or synthetically accessible substituted aryl halide, heteroaryl halide, or benzyl halide of formula I-1-1a undergoes nucleophilic displacement with commercially available or synthetically accessible substituted urea compounds of formula I-1-2a; with a suitable inorganic base such as K2CO3, NaH, or the like; in a suitable solvent such as DMF, or the like; at temperatures ranging from 0 ºC to 60 ºC; to provide a coupled compound of formula I-1-3a. Coupled compounds of formula I-1-3a are then deprotected with a suitable acid such as TFA, or the like; in a suitable solvent such as DCM, or the like; at temperatures ranging from 0 ºC to 50 ºC; followed by treatment with a suitable aqueous base such as ammonium hydroxide or the like; at temperatures ranging from 0 ºC to 50 ºC, preferably 0 ºC; to provide a compound of formula I-1.

[0480] Alternatively, a compound of formula I-1 may be prepared according to the procedures shown in SCHEME 1b.Attorney Docket No. PRSC-094 / 001WO 343170-2295SCHEME 1b

[0481] According to SCHEME 1b, a commercially available or synthetically accessible substituted arylamine, heteroarylamine, or benzylamine of formula I-1-1b is reacted with commercially available or synthetically accessible substituted Michael acceptors of formula I- 1-2b (U = O, NH, or the like); with or without a suitable strong base such as KOtBu or the like; in a suitable solvent such as toluene, NMP, AcOH, and the like; at temperatures ranging from 20 °C to 120 °C; to provide a coupled compound of formula I-1-4b. Alternatively, commercially available or synthetically accessible substituted arylamine, heteroarylamine, or benzylamine of formula I-1-1b are reacted with commercially available or synthetically accessible substituted electrophiles of formula I-1-3b (U = O, NH, or the like; Y = Br, I, OMs, or the like); with a suitable base such as TEA, DIPEA, NaH, or the like; in a suitable solvent such as DMF, 1,4-dioxane, or the like; at temperatures ranging 20 °C to 120 °C; to provide a coupled compound of formula I-1-4b. Coupled compounds of formula I-1-4b were cyclized with an appropriate carbonyl source, such as urea or the like when U = O, or CDI or the like when U = NH; with or without a suitable base such as DIPEA or the like; in a suitable solvent such as AcOH, 1,4-dioxane, or the like; at temperatures ranging from 20 °C to 120 °C; to provide a cyclized compound of formula I-1.

[0482] A compound of formula I-3-i may be prepared according to the procedures shown in SCHEME 2.Attorney Docket No. PRSC-094 / 001WO 343170-2295SCHEME 2

[0483] According to SCHEME 2, commercially available or synthetically accessible substituted nitro compound of formula I-3-i-1 is reacted with a vinyl Grignard agent of formula I-3-i-2 (X= Br, Cl or I) and the like; in a suitable solvent such as THF, dioxane, and the like; at temperatures ranging from –60 °C to 25 °C; to provide cyclized compound of formula I-3-i-3. Cyclized compound of formula I-3-i-3 is acylated with commercially available 2,2,2- trichloroacetyl chloride; with a suitable Lewis acid such as AlCl3, BF3 etherate and the like; in a suitable solvent such as DCM, dichloroethane and the like; at temperatures ranging from 0 °C to 60 °C, preferably 25 °C; to provide an acylated compound of formula I-3-i-4. Acylated compound of formula I-3-i-4 is hydrolyzed with a suitable inorganic base such as KOH, NaOH and the like; in a suitable mixed solvent such as THF, MeOH, and the like mixed with water; at temperatures ranging from 25 °C to 80 °C; to provide an acid of formula I-3-i-5. An acid of formula I-3-i-5 is then acylated with a suitable chlorine source such as SOCl2or oxalyl chloride and the like; with a catalyst such as DMF and the like; in a suitable solvent such as DCM, dichloroethane, and the like; at temperatures ranging from 0 °C to 80 °C; to provide acyl chloride compound of formula I-3-i-6. Acyl chloride compound of formula I-3-i-6 is coupled with a commercially available or synthetically accessible amine source with a suitable organic base such as TEA, DIPEA and the like; in a suitable solvent such as DCM, THF and the like; at temperatures ranging from –10 °C to 20 °C; to provide an amide of formula I-3-i (RF4= amide).Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0484] A compound of formula I-3-ii may be prepared according to the procedures shown in SCHEME 3.SCHEME 3

[0485] According to SCHEME 3, commercially available or synthetically accessible bis- aniline of formula I-3-ii-1 is reacted with a carbon monoxide insertion agent such as CDI, tri- phosgene or the like; with an organic base such as TEA or DIPEA or the like; in a suitable solvent such as DCM, DMF, and the like; at temperatures ranging from 0 °C to 60 °C; to provide urea compound of formula I-3-ii-2. A urea compound of formula I-3-ii-2 is alkylated with commercially available or synthetically accessible substituted alkyl halide with a suitable inorganic base such as NaH, t-BuOK and the like; in a suitable solvent such as DMF, THF, and the like; at temperatures ranging from 0 °C to 60 °C, preferably 40 °C; to provide a substituted urea compound of formula I3-ii-3. A urea compound of formula I-3-ii-3 (X= halide) is reacted with commercially available or synthetically accessible substituted alkyl or vinyl borate (Suzuki), zinc (Negishi) or magnesium (Kumada) agent I-3-ii-4; with a suitable catalysis such as Pd(Ph3P)4, PdCl2(Ph3P)2 and the like; in an inorganic base such as Na2CO3, K3PO4 and the like; in a suitable solvent such as THF, dioxane and the like; at temperatures ranging from 0 °C to 100 °C, preferably 40 °C; to provide a substituted compound of formula I3-ii.

[0486] A compound of formula I-3-iii may be prepared according to the procedures shown in SCHEME 4.Attorney Docket No. PRSC-094 / 001WO 343170-2295Reduction and cyclizationI-3-iii SCHEME 4

[0487] According to SCHEME 4, commercially available or synthetically accessible substituted aryl nitro compound of formula I-3-iii-1 is reacted with commercially available or synthetically accessible substituted amino acid of formula I-3-iii-2; with a suitable inorganic base such as K2CO3, Cs2CO3 and the like; in a suitable solvent such as DMF, DMSO and the like; at temperatures ranging from 50 °C to 120 °C; to provide coupled compound of formula I-3-iii-3. A nitro compound of formula I-3-iii-3 is reduced with a suitable reductant such as Fe, SnCl2 and the like; in an acidic solvent such as HOAc, 1N HCl aqueous solution, and the like; at temperatures ranging from 80 °C to 120 °C, preferably 100 °C; to provide a cyclized compound of formula I-3-iii.

[0488] A compound of formula I-3-iv may be prepared according to the procedures shown in SCHEME 5.SCHEME 5Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0489] According to SCHEME 5, commercially available or synthetically accessible substituted keto ester compound of formula I-3-iv-1 is alkylated with commercially available or synthetically accessible substituted bromo-ester of formula I-3-iv-2; with a suitable inorganic base such as K2CO3, Cs2CO3 and the like; in a suitable solvent such as acetone, DMF, DMSO and the like; at temperatures ranging from 50 °C to 120 °C; to provide coupled compound of formula I-3-iv-3. A keto ester compound of formula I-3-iv-3 is de-carboxylated with a suitable acid such as HCl, H2SO4and the like; in an acidic solvent such as HOAc, 1N HCl aqueous solution, and the like; at temperatures ranging from 40 °C to 100 °C, preferably 60 °C; to provide a keto acid compound of formula I-3-iv-4. A keto acid compound of formula I-3-iv-4 is coupled with a commercially available or synthetically accessible substituted amino ester compound of formula I-3-iv-5; with a suitable coupling agent such as T3P, HATU and the like; in a suitable solvent such as DMF, DMSO and the like; at temperatures ranging from 0 °C to 80 °C; to provide coupled compound of formula I-3-iv-6. A coupled compound of formula I-3-iv-6 is cyclized under adol condensation condition; with a suitable base such as LDA, LiHMDS and the like; in a suitable solvent such as THF, dioxane and the like; at temperatures ranging from –78 °C to 0 °C; to provide cyclized keto-enol compound of formula I-3-iv-7. A keto-enol compound of formula I-3-iv-7 is reacted with commercially available or synthetically accessible substituted hydrazine compound of formula I-3-iv-8; in a suitable solvent such as MeOH, EtOH and the like; at temperatures ranging from 25 °C to 80 °C; to provide coupled compound of formula I-3-iv.

[0490] A compound of formula I-3-v may be prepared according to the procedures shown in SCHEME 6.SCHEME 6

[0491] According to SCHEME 6, commercially available or synthetically accessible substituted amine compound of formula I-3-v-1 is coupled with commercially available or synthetically accessible substituted acid of formula I-3-v-2; with a suitable coupling agent suchAttorney Docket No. PRSC-094 / 001WO 343170-2295 as HATU, T3P and the like; with a suitable organic base such as TEA, DIPEA and the like; in a suitable solvent such as DMF, DMSO and the like; at temperatures ranging from 0 °C to 80 °C; to provide coupled amide compound of formula I-3-v-3. An amide compound of formula I-3-v-3 is cyclized with a suitable reactive chloride source such as POCl3, SOCl2 and the like; in aprotic polar solvent such as DMF, and the like; at temperatures ranging from 60 °C to 100 °C, preferably 80 °C; to provide a cyclized pyrazine compound of formula I-3-v-4. A cyclized pyrazine compound of formula I-3-v-4 is reduced with a suitable reducing agent such as up to 50 psi of H2 gas, ammonium formate and the like; with a suitable catalysis such as 10% Pd / C, Pd(OH)2 / C and the like; in a suitable solvent such as EtOAc, MeOH and the like; at temperatures ranging from 25 °C to 80 °C; to provide reduced compound of formula I-3-v-5. A reduced compound of formula I-3-v-5 is acylated with a commercially available or synthetically accessible acylating agent of formula I-3-v-6; in a suitable organic base such as TEA, DIPEA and the like; in a suitable solvent such as DCM, dichloroethane and the like; at temperatures ranging from –10 °C to 25 °C; to provide acylated compound of formula I-3-v.

[0492] A compound of formula I-3-vi-a or I-3-vi-b may be prepared according to the procedures shown in SCHEME 7.SCHEME 7

[0493] According to SCHEME 7, commercially available or synthetically accessible substituted aniline of formula I-3-vi-a-1 or I-3-vi-b-1 is reacted with commercially available or synthetically accessible substituted acyl halide (X= Cl or Br) of formula I-3-vi-2; with a suitable organic base such as TEA, DIPEA and the like; in a suitable solvent such as DCM, dichloroethane and the like; at temperatures ranging from –10 °C to 50 °C; to provide coupled compound of formula I-3-vi-a-3 or I-3-vi-b-3. An acylated compound of formula I-3-vi-a-3 or I-3-vi-b-3 is reduced with a suitable chlorine source agent such as POCl3, SOCl2 and the like; in an aprotic polar solvent such as DMF, and the like; at temperatures ranging from 0 °C to 80 °C; to provide a cyclized compound of formula I-3-vi-a-4 or I-3-vi-b-4. An aryl chloride compound of formula I-3-vi-a-4 or I-3-vi-b-4 is hydrolized with a suitable base such as NaOH,Attorney Docket No. PRSC-094 / 001WO 343170-2295 KOH and the like; in a mixed solvent such as MeOH, and the like; with aqueous solution; at temperatures ranging from 0 °C to 60 °C; to provide a cyclized compound of formula I-3-vi-a or I-3-vi-b.

[0494] When L1is -C(=O)NH- optionally substituted with one or more Ru, a compound of formula I-2 may be prepared according to the procedures shown in SCHEME 8a.SCHEME 8a

[0495] According to SCHEME 8a, commercially available or synthetically accessible substituted aryl halide (X = Cl, Br, OTf, or the like) of formula I-2-1a is reacted with commercially available or synthetically accessible aryl metal agent (Y = B, Zn, Sn, Mg, or the like) of formula I-2-2a; with a suitable catalyst such as Pd(Ph3P)4, PdCl2(dppf) or the like; with or without an inorganic base such as Na2CO3, K3PO4, or the like; in a suitable solvent such as 1,4-dioxane, DMF, or the like; at temperatures ranging from 60 °C to 100 °C; to provide coupled compound of formula I-2-3a. A coupled compound of formula I-2-3a is hydrolyzed with a suitable hydroxide source like lithium hydroxide or the like; in a suitable solvent like THF mixed with water, or the like; at temperatures ranging from 0 °C to 30 °C; to provide a carboxylate of formula I-2-4a. An acid of formula I-2-4a is reacted with commercially available or synthetically accessible substituted amine of formula I-2-5a; with a coupling agent such as HATU, T3P, or the like; in an organic solvent such as DCM, DMF, or the like; at temperatures ranging from 0 °C to 60 °C; to provide a coupled amide compound of formula I- 2.

[0496] Alternatively, when L1is 5- to 6-membered heteroaryl optionally substituted with one or more Ru, a compound of formula I-2 may be prepared according to the procedures shown in SCHEME 8b.Attorney Docket No. PRSC-094 / 001WO 343170-2295SCHEME 8b

[0497] According to SCHEME 8b, commercially available or synthetically accessible substituted aryl halide (X = Cl, Br, OTf, or the like) of formula I-2-1b is reacted with commercially available or synthetically accessible aryl metal reagent (Y = B, Zn, Mg, Sn, or the like) of formula I-2-2b; with a suitable catalyst such as Pd(Ph3P)4, PdCl2(dppf) or the like; with or without an inorganic base such as Na2CO3, K3PO4, or the like; in a suitable solvent such as 1,4-dioxane, DMF, or the like; at temperatures ranging from 60 °C to 100 °C; to provide coupled compound of formula I-2-5b. Alternatively, for certain instances of L1, commercially available or synthetically accessible substituted aryl halide (X = Cl, Br, OTf, or the like) of formula I-2-3b (where U is an appropriate functional group to allow heterocycle synthesis) is reacted with commercially available or synthetically accessible alkyl reagent of formula I-2- 4b (where V is a functional group that is complementary to U to allow for heterocycle synthesis); with reagents and under conditions known to those that are skilled in the art of organic synthesis; to provide a coupled compound of formula I-2-5b. An aryl halide of formula I-2-5b is converted to an aryl metal species of formula I-2-6b (Y = B, Zn, Mg, Sn, or the like); with an appropriate metal source such as B2Pin2, Bu6Sn2, ZnCl2or the like; with or without a suitable catalyst such as Pd(Ph3P)4, PdCl2(dppf) or the like; with or without a lithiation reagent such astBuLi or the like; in a suitable solvent such as 1,4-dioxane, THF, or the like; at temperatures ranging from 0 °C to 100 °C; to provide an aryl metal compound of formula I-2- 6b. A nucleophile of formula I-2-6b is coupled with a synthetically accessible substituted aryl halide of formula I-2-7b (X = Cl, Br, OTf, or the like); with a suitable catalyst such as Pd(Ph3P)4, PdCl2(dppf) or the like; with or without an inorganic base such as Na2CO3, K3PO4,Attorney Docket No. PRSC-094 / 001WO 343170-2295 or the like; in a suitable solvent such as 1,4-dioxane, DMF, or the like; at temperatures ranging from 60 °C to 100 °C; to provide a coupled compound of formula I-2.

[0498] A compound of formula I may be prepared according to the procedures shown in SCHEME 9. SCHEME 9

[0499] According to SCHEME 9, synthetically accessible substituted aryl halide as target ligand (Cl, Br or OTf) of formula T is reacted with synthetically accessible L (linker) (boronic ester, Zn or Mg halide) of formula L; with a suitable catalyst such as Pd(Ph3P)4, PdCl2dppf, or the like (Suzuki); or with a suitable catalysis such as Pd2(dba)3, Pd(OAc)2 and the like (Buchwald); with or without an inorganic base such as Na2CO3, K3PO4, t-BuONa and the like; in a suitable solvent such as dioxane, DMF and the like; at temperatures ranging from 60 °C to 120 °C; to provide coupled compound of formula T-L. A coupled compound of formula T-L (target ligand and linker) is reacted with commercially available or synthetically accessible E3 ligand of formula C; with Suzuki coupling by catalysis of Pd(Ph3P)4, Pd2(dba)3and the like; in an organic solvent such as dioxane, DMF, water, and the like; with an inorganic base such as Na2CO3, K3PO4 and the like; at temperatures ranging from 0 °C to 100 °C; to provide a coupled degrader compound of formula T-L-C (I).

[0500] Alternatively, a coupled compound of formula T-L (target ligand and linker) is reacted with commercially available or synthetically accessible E3 ligand of formula C; with Sonogashira coupling by catalysis of Pd(Ph3P)4, PdCl2dppf and the like; or with a co-catalyst such as CuBr, CuI, and the like; in an organic solvent such as dioxane, DMF, and the like; with an organic base such as TEA, DIPEA and the like; at temperatures ranging from 0 °C to 100 °C; to provide a coupled degrader compound of formula T-L-C (I).

[0501] Those skilled in the art will recognize that the steps described above may be inverted, depending on the specific compound. Those skilled in the art will also recognize that the steps may be interspersed with those described in SCHEMES 1–8b above, as the reactivity of the specific compounds allow.

[0502] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure (e.g., a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individualAttorney Docket No. PRSC-094 / 001WO 343170-2295 enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0503] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and / or from compounds described in the chemical literature. “Commercially available chemicals” are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka) (Pittsburgh, PA).

[0504] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., New York; S. R. Sandler et al., “Organic Functional Group Preparations,” 2nd Ed., Academic Press, New York, 1983; H. O. House,“Advanced Organic Chemistry: Reactions, Mechanisms and Structure”, 4th Ed., Wiley-Interscience, New York, 1992;and “Chemistry of Functional Groups” John Wiley & Sons, in 73 volumes.

[0505] Specific and analogous reactants are optionally identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag Helvetica Chimica Acta, Zurich, 2002. Analytical Methods, Materials, and Instrumentation

[0506] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (δ) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) were collected using a SHIMADZU LCMS-Attorney Docket No. PRSC-094 / 001WO 343170-2295 2020EV or Agilent 1260-6125B LCMS. Purity and low resolution mass spectral data were measured using Agilent 1260-6125B LCMS system (with Diode Array Detector, and Agilent G6125BA Mass spectrometer) or using Waters Acquity UPLC system (with Diode Array Detector, and Waters 3100 Mass Detector). The purity was characterized by UV wavelength 214 nm, 220 nm, 254 nm and ESI. Column: poroshell 120 EC-C182.7 μm 4.6 X 100 mm; Flow rate 0.8 mL / min; Solvent A (100 / 0.1 water / formic acid), Solvent B (100 acetonitrile); gradient: hold 5% B to 0.3 min, 5-95% B from 0.3 to 2 min, hold 95% B to 4.8 min, 95-5% B from 4.8 to 5.4 min, then hold 5% B to 6.5 min. Or, column: Acquity UPLC BEH C181.7 µm 2.1 X 50 mm; Flow rate 0.5 mL / min; Solvent A (0.1%formic acid water), Solvent B (acetonitrile); gradient: hold 5%B for 0.2 min, 5-95% B from 0.2 to 2.0 min, hold 95% B to 3.1 min, then 5% B at 3.5 min. Biological Assays

[0507] The biological activities of the compounds of the present disclosure can be assessed with methods and assays known in the art.

[0508] The binding potencies of the compounds to p300 may be determined using HTRF assay technology. HTRF signals may be measured by displacing the fluorescent probe, 5-(8-(7- acetyl-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1- yl)isoquinolin-3-yl)-N-(2-(2-(2-(3-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'- xanthen]-5-yl)thioureido)ethoxy)ethoxy)ethyl)picolinamide, from FLAG-tagged p300 with the tested compounds. Data analysis may be performed using appropriate software (e.g., TIBCO Spotfire) using a four-parameter dose response curve to determine the IC50of the tested compounds.

[0509] The binding potencies of the compounds to CBP may be determined using HTRF assay technology. HTRF signals may be measured by displacing the fluorescent probe, 5-(8-(7- acetyl-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1- yl)isoquinolin-3-yl)-N-(2-(2-(2-(3-(3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'- xanthen]-5-yl)thioureido)ethoxy)ethoxy)ethyl)picolinamide, from a FLAG-tagged (C- terminal) and His-tagged (N-terminal) CBP construct with the tested compounds. Data analysis may be performed using appropriate software (e.g., TIBCO Spotfire) using a four-parameter dose response curve to determine the IC50 of the tested compounds.

[0510] The cellular degradation activities of the compounds against p300 may be measured by HiBit technology in certain cells (e.g., A549 P300 HiBit cells) with the tested compounds at certain initial concentrations (e.g., 0.000064, 0.00019, 0.00057, 0.0017, 0.0051, 0.015, 0.046,Attorney Docket No. PRSC-094 / 001WO 343170-2295 0.14, 0.42, and 1.25 µM) for a certain period of time (e.g., 2 hours). The resulting protein concentration may be assessed using a detection buffer (e.g., HiBit Lytic detection buffer). The resultant luminescence may be measured with an appropriate instrument (e.g., a PerkinElmer EnVision plate reader). Dose-response curves may be generated and analyzed using appropriate software (e.g., TIBCO Spotfire) to determine the DC50 and Dmax of the tested compounds.

[0511] The cellular degradation activities of the compounds against CBP may be measured by HiBit technology in certain cells (e.g., A549 CBP HiBit cells) with the tested compounds at certain initial concentrations (e.g., 0.000064, 0.00019, 0.00057, 0.0017, 0.0051, 0.015, 0.046, 0.14, 0.42, and 1.25 µM) for a certain period of time (e.g., 24 hours). The resulting protein concentration may be assessed using a detection buffer (e.g., HiBit Lytic detection buffer). The resultant luminescence may be measured with an appropriate instrument (e.g., a PerkinElmer EnVision plate reader). Dose-response curves may be generated and analyzed using appropriate software (e.g., TIBCO Spotfire) to determine the DC50 and Dmax of the tested compounds.

[0512] The cellular degradation activities of the compounds against p300 may be measured by in-cell Western blot technology in certain cells (e.g., H1299 cells) with the tested compounds at certain initial concentrations (e.g., 0.0005, 0.0015, 0.0046, 0.014, 0.041, 0.12, 0.37, 1.1, 3.3, and 10 µM) for a certain period of time (e.g., 16 hours). The resulting protein concentration may be assessed using an anti-p300 primary antibody (e.g., anti-human p300 clone D8Z4E) and an IRDye 800CW secondary antibody (e.g., IRDye 800CW goat anti-rabbit IgG). The resultant fluorescence may be measured with appropriate instrument (e.g., the LI-COR Odyssey CLx instrument). Dose-response curves may be generated and analyzed using appropriate software (e.g., TIBCO Spotfire) to determine the DC50 and Dmax of the tested compounds.

[0513] The cellular degradation activities of the compounds against CBP may be measured by, e.g., in-cell Western blot technology in certain cells (e.g., H1299 cells with the tested compounds at certain initial concentrations (e.g., 0.0005, 0.0015, 0.0046, 0.014, 0.041, 0.12, 0.37, 1.1, 3.3, and 10 µM) for a certain period of time (e.g., 16 hours). The resulting protein concentration may be assessed using an anti-CBP primary antibody (e.g., anti-human CBP clone D6C5) and an IRDye 800CW secondary antibody (e.g., IRDye 800CW goat anti-rabbit IgG). The resultant fluorescence may be measured with appropriate instrument (e.g., the LI- COR Odyssey CLx instrument). Dose-response curves may be generated and analyzed usingAttorney Docket No. PRSC-094 / 001WO 343170-2295 appropriate software (e.g., TIBCO Spotfire) to determine the DC50 and Dmax of the tested compounds.

[0514] The ability of the compounds to inhibit cellular proliferation may be assessed by, e.g., Cell Titer-Glo technology in wild-type, knock-out, and knock-out cell lines (e.g., H1299 wild- type, H1299 p300 knock-out, and H1299 CBP knock-out cell lines). The tested compounds may be assessed at certain initial concentrations (e.g., 0.0005, 0.0015, 0.0046, 0.014, 0.041, 0.12, 0.37, 1.1, 3.3, and 10 µM) for a certain period of time (e.g., 6 days). Cell growth may be assessed using the appropriate reagent and instrument (e.g., Cell Titer-Glo Luminescent Cell Viability reagent and a Perkin Elmer Envision instrument). Dose-response curves may be generated and analyzed using appropriate software (e.g., (TIBCO Spotfire) to determine the gIC50 and the growth-death index (i.e. the percentage of remaining cell growth or cell death observed relative to untreated cells). Methods of Use

[0515] In certain aspects, the present disclosure provides methods of degrading a protein in a subject or biological sample comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein.

[0516] In certain aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for degrading a protein in a subject or biological sample.

[0517] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a protein in a subject or biological sample.

[0518] In certain aspects, the present disclosure provides methods of reducing a protein in a subject or biological sample comprising administering the compound disclosed herein to the subject or contacting the biological sample with the compound disclosed herein.

[0519] In certain aspects, the present disclosure provides uses of the compound disclosed herein in the manufacture of a medicament for reducing a protein in a subject or biological sample.

[0520] In certain aspects, the present disclosure provides compounds disclosed herein for use in reducing a protein in a subject or biological sample.

[0521] In certain embodiments, the protein is p300. In certain embodiments, the protein is CBP.

[0522] In certain aspects, the present disclosure provides methods for treating a disease or disorder.Attorney Docket No. PRSC-094 / 001WO 343170-2295

[0523] In certain aspects, the present disclosure provides uses of the compounds disclosed herein in the manufacture of a medicament for treating a disease or disorder.

[0524] In certain aspects, the present disclosure provides compounds disclosed herein for treating a disease or disorder.

[0525] In certain embodiments, the disease or disorder is driven by gene activation such as cancer, inflammatory disorders, or autoimmune diseases.

[0526] In certain embodiments, the disease or disorder is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute T-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes, embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen alfa receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, head and neck cancer, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, lymphoid malignancies of T- cell or B-cell origin, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, 282 WO 2020 / 173440 PCT / CN2020 / 076648 stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0527] In certain embodiments, the disease or disorder is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, KawasakiAttorney Docket No. PRSC-094 / 001WO 343170-2295 disease, lupus nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, Polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.

[0528] In certain embodiments, the disease or disorder is selected from the group consisting of prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and melanoma.

[0529] In certain embodiments, the subject is a mammal.

[0530] In certain embodiments, the subject is a human. Definitions

[0531] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions

[0532] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0533] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill,Attorney Docket No. PRSC-094 / 001WO 343170-2295 NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (E.F. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0534] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0535] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0536] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (i.e., at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0537] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In certain embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alkyl”). In certain embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanylAttorney Docket No. PRSC-094 / 001WO 343170-2295 (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10alkyl (e.g., -CH3). In certain embodiments, the alkyl ...

Claims

Attorney Docket No. PRSC-094 / 001WO 343170-2295 CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula I: T-L-C (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: C is of Formula I-1wherein: denotes a single bond or a double bond; B1is CRB1or N, NRB1’, O, or S; B2is CRB2or N, NRB2’, O, or S; B3is absent, CRB3, or N; B4is CRB4or N, NRB4’, O, or S; B5is CRB5, N, NRB5’, O, or S, as valency permits; B6is C or N; RB1, RB2, RB3, RB4, and RB5are independently, oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, and one of RB1, RB2, RB3, RB4, and RB5is ; or RB1and RB2, RB2and RB3, RB3and RB4, or RB4and RB5, together with the carbon atoms to which they are attached, form optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocycle, wherein the heteroaryl or heterocycle is attached to L; RB1’, RB2’, RB4’, and RB5’are independently hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- to 4- membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 X is absent, CRX1, or C(RX1)2, as valency permits; each RX1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; two RX1together form an oxo; or two RX1, together with the carbon atom to which they are bonded, form C3-4carbocyclyl or 3- or 4-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; or RX1and RB5or RX1and RB5’, together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C6 aryl, optionally substituted 5- or 6-membered heteroaryl, optionally substituted 5- or 6-membered heterocycle, or optionally substituted C5-6carbocycle; each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; or two RD, together with the carbon atom(s) to which they are bonded, form C3-5carbocyclyl or 3- or 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; d is an integer from 0 to 6, as valency permits; and q is an integer from 0 to 2, T is ii) of Formula I-3-ii’Attorney Docket No. PRSC-094 / 001WO 343170-2295 G4is , N, or CRG4;denotes attachment to L; RG1, RG2, RG3, and RG4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; H1is C(RH1)2, NRH1’, or O; H2is C(RH2)2, NRH2’, or O; each occurrence of RH1and RH2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RH1or two RH2, together with the carbon atom to which they are attached, form C3-6carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; and RH1’and RH2’are independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 3- to 6-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, iv) of Formula I-3-iviv), wherein: M1is N or C;Attorney Docket No. PRSC-094 / 001WO 343170-2295wherein denotes attachment to L; and at least one of M1, M2, M3, and M4is N or ; RM2, RM3, and RM4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; RK’is hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; K1is -C(=O)- or -C(RK1)2-; each RK1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and k is an integer selected from 0 to 4; v) of Formula I-3-vdenotes attachment to L; each RNis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, -NRcS(=O)2NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, -OS(=O)2ORb, - OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; n is an integer selected from 0 to 6; RP1, RP2, and RP3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and R4is -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru,vi), wherein: Q1is NRQ1’, C(RQ1)2, or O; RQ1’is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; each RQ1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RQ1, together with the carbon atom to which they are attached, form C3-6 carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; when is a double bond, then Q2is N or CRQ2; and Q3is N or CRQ3; when is a single bond, then Q2is NRQ2’, C(RQ2)2, or O; Q3is NRQ3’, C(RQ3)2, or O; RQ2’and RQ3’are independently hydrogen, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 each occurrence of RQ2and RQ3is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; or two RQ2or two RQ3, together with the carbon atom to which they are attached, form C3-6carbocycle or 3- to 6-membered heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more Ru; S1is CRS1or N;to L; and RS1, RS2, RS3, and RS4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, - S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -NRcS(=O)2Ra, -NRcS(=O)Ra, -NRcS(=O)2ORb, - NRcS(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -OS(=O)2Ra, - OS(=O)2ORb, -OS(=O)2NRcRd, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; L is of Formula I-2wherein: ** denotes attachment to T and * denotes attachment to C; L’’ is absent; or L’’ is C1-3alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 RLis hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; wherein: i) when L’’ is C1-3 alkylene, -C(=O)-, -C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2- , wherein the alkylene is optionally substituted with one or more Ru, then Cy1is optionally substituted C6arylene or 5- or 6-membered heteroarylene; ii) when L’’ is absent, then Cy1is, wherein: ** denotes attachment to T; T1is CRT1or N; V1is CRV1or N; V2is CRV2or N; RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1- 6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; t is an integer selected from 0 to 6, as valency permits; or Cy1is, wherein: when is single bond, Y1is N or CRY1; when is double bond, Y1is C;Attorney Docket No. PRSC-094 / 001WO 343170-2295 ** denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Y2is C(RY2)2, O, or N(RY2’); each RY2is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; RY2’is hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- or 4-membered heterocyclyl, -S(=O)2Ra, - S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; Z1is CRZ1or N; Z2is CRZ2or N; RZ1and RZ2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z; Cy2is 5- or 6-membered heteroarylene optionally substituted with one or more Ru; L1is -C(=O)NH- or 5- or 6-membered heteroaryl optionally substituted with one or more Ru; L2is [C(RL2)2]l, wherein each RL2is independently hydrogen, C1-3 alkyl, or C1-3 haloalkyl; or two geminal RL2, together with the carbon atom to which they are bonded, form C3-5 carbocyclyl or 3- to 5-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with one or more Ru; l is 1 or 2; and L3is E-ethenylene, ethynylene, C6arylene, or 5- or 6-membered heteroarylene, wherein the E- ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 wherein: each Ruis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl; each Rais independently C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl; and each Rcand Rdis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; or Rcand Rd, together with the nitrogen atom to which they are attached, form 3- to 6-membered heterocyclyl, wherein each occurrence of Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz; and each Rzis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-6 carbocyclyl, or 3- to 6-membered heterocyclyl.

2. The compound of claim 1, wherein X is absent or C(RX1)2.

3. The compound of claim 1, wherein C is of Formula I-1-i or I-1-i’4. The compound of claim 3, wherein each RX1is independently hydrogen or C1-6alkyl, and at least one RX1is hydrogen.

5. The compound of claim 3 or 4, wherein none of B1, B3, B4, and B5is N, or one of B1and B5is N, wherein RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are independently hydrogen, halogen, -CN, -OH, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino.

6. The compound of claim 1, wherein RB1and RB2, RB2and RB3, RB3and RB4, or RB4and RB5, together with the carbon atoms to which they are attached, form optionally substituted 5-Attorney Docket No. PRSC-094 / 001WO 343170-2295 or 6-membered heteroaryl or optionally substituted 5- or 6-membered heterocycle, wherein the heteroaryl or heterocycle is attached to L.

7. The compound of claim 1, wherein C is of Formula I-1-i’’wherein: Ring E is optionally substituted 5- or 6-membered heteroaryl or optionally substituted 5- or 6- membered heterocycle, and B1aand B2aare independently C or N.

8. The compound of claim 1, wherein C is of Formula I-1-i’’-19. The compound of claim 1, wherein RX1and RB5or RX1and RB5’, together with the atoms to which they are bonded, form Ring C, wherein Ring C is optionally substituted C6 aryl or optionally substituted 5- or 6-membered heteroaryl.

10. The compound of claim 1, wherein C is of Formula I-1-ii(I-1-ii),Attorney Docket No. PRSC-094 / 001WO 343170-2295 wherein: B5ais C or N; B7is CRB7, N, NRB7’, O, or S; B8is CRB8, N, NRB8’, O, or S; RB7and RB8are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and RB7’and RB8’are independently hydrogen, C1-6alkyl, C1-6alkoxy, C3-4carbocyclyl, 3- or 4- membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORb, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru, wherein at least one of B5a, B6, B7, and B8is N, NRB7’, NRB8’, O, or S.

11. The compound of claim 10, wherein C is of Formula I-1-ii-1, I-1-ii-2, I-1-ii-3, I-1-ii- 4, or I-1-ii-5wherein B7is O or S.Attorney Docket No. PRSC-094 / 001WO 343170-2295 12. The compound of claim 11, wherein C is of Formula I-1-ii-1, and RB8is hydrogen or C1-6alkyl, or C is of Formula I-1-ii-2, and RB7’is hydrogen or C1-6alkyl.

13. The compound of claim 11, wherein C is of Formula I-1-ii-3wherein B7is O or S.

14. The compound of any one of claims 10-13, wherein B1is CRB1, B3is CRB3, and B4is CRB4, and each of RB1, RB3, and RB4is hydrogen.

15. The compound of claim 14, wherein C is of Formula I-1-iiiiii), wherein: B9is CRB9or N; B10is CRB10or N; and B11is CRB11or N. RB9, RB10, and RB11are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

16. The compound of claim 15, wherein C is of Formula I-1-iii-1’Attorney Docket No. PRSC-094 / 001WO 343170-229517. The compound of claim 16, wherein B9is CRB9and B11is CRB11, and each of RB9and RB11is hydrogen.

18. The compound of claim 16, wherein at least one of B9and B11is N.

19. The compound of any one of claims 1-18, wherein d is 0.

20. The compound of any one of claims 1-19, wherein q is 1.

21. The compound of any one of claims 1-20, wherein T is of Formula I-3-ii’22. The compound of claim 21, wherein T is of Formula I-3-ii-aii-a).

23. The compound of claim 20 or 21, wherein G1is CRG1, and G3is CRG3, wherein RG1and RG3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-12 carbocyclyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.Attorney Docket No. PRSC-094 / 001WO 343170-2295 24. The compound of claim 23, wherein each of RG1and RG3is hydrogen.

25. The compound of any one of claims 20-24, wherein RG4is hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-12 carbocyclyl, or 3- to 12- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

26. The compound of claim 25, wherein RG4is hydrogen, C1-6alkyl, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, or heterocyclyl is optionally substituted with one or more Ru.

27. The compound of any one of claims 20-26, wherein H1is NRH1’, and H2is NRH2’, wherein RH1’and RH2’are independently C1-6 alkyl.

28. The compound of any one of claims 1-20, wherein T is of Formula I-3-iviv).

29. The compound of claim 28, wherein T is of Formula I-3-iv-a(I-3-iv-a).

30. The compound of claim 28 or 29, wherein K1is -C(=O)-.

31. The compound of claim 28 or 29, wherein K1is -CH2-.

32. The compound of any one of claims 28-31, wherein at least two of M1, M3, and M4are N.Attorney Docket No. PRSC-094 / 001WO 343170-2295 33. The compound of any one of claims 28-31, wherein at least one of M1, M3, and M4is N.

34. The compound of any one of claims 28-33, wherein M3is N.

35. The compound of any one of claims 28-33, wherein M3is CRM3, wherein RM3is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

36. The compound of claim 35, wherein RM3is hydrogen.

37. The compound of any one of claims 28-36, wherein each RKis independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10- membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

38. The compound of any one of claims 28-37, wherein k is an integer selected from 0 to 2.

39. The compound of claim 28, wherein T is of Formula I-3-iv-b(I-3-iv-b).

40. The compound of any one of claims 28-39, wherein each RKis independently hydrogen, or C1-6 alkyl.Attorney Docket No. PRSC-094 / 001WO 343170-2295 41. The compound of any one of claims 28-40, wherein RK’is hydrogen or C1-6 alkyl.

42. The compound of any one of claims 28-41, wherein RM2is hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

43. The compound of claim 42, wherein RM2is C1-6alkyl, C1-6alkoxy, or 3- to 12-membered heterocyclyl.

44. The compound of any one of claims 1-20, wherein T is of Formula I-3-v45. The compound of claim 44, wherein T is of Formula I-3-v-a46. The compound of claim 44 or 45, wherein each RNis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

47. The compound of any one of claims 44-46, wherein n is 0.

48. The compound of any one of claims 44-47, wherein R4is C1-6 alkyl or C1-6 alkylamino.Attorney Docket No. PRSC-094 / 001WO 343170-2295 49. The compound of any one of claims 44-48, wherein RP3is hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, or or - C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

50. The compound of claim 49, wherein RP3is hydrogen, C1-6alkyl, C3-12carbocyclyl, 3- to 12-membered heterocyclyl, or -C(=O)NRcRd.

51. The compound of any one of claims 1-20, wherein T is of Formula I-3-vi.

52. The compound of claim 51, wherein T is of Formula I-3-vi-a or I-3-vi-b53. The compound of claim 51 or 52, wherein RS2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

54. The compound of claim 53, wherein RS2is hydrogen, C1-6alkyl, C1-6alkoxy, or 3- to 12-membered heterocyclyl.

55. The compound of any one of claims 51-54, wherein RS4is hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl,Attorney Docket No. PRSC-094 / 001WO 343170-2295 wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

56. The compound of claim 55, wherein RS4is hydrogen or C1-6 alkyl.

57. The compound of any one of claims 51-56, wherein Q1is NRQ1’, wherein RQ1’is hydrogen or C1-6alkyl.

58. The compound of any one of claims 51-57, wherein is a double bond, and Q2is N or CRQ2and Q3is CRQ3, wherein RQ2and RQ3are independently hydrogen, halogen, -CN, - NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl.

59. The compound of claim 58, wherein RQ2and RQ3are independently hydrogen or C1-6 alkyl.

60. The compound of any one of claims 51-57, wherein is a single bond, then Q2is C(RQ2)2 and Q3is NRQ3’or C(RQ3)2, wherein each RQ2and RQ3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl; and RQ3’ ishydrogen, C1-6alkyl, C3-4carbocyclyl, or 3- or 4- membered heterocyclyl.

61. The compound of claim 60, wherein each RQ2is hydrogen or C1-6alkyl, and RQ3’is C1-6 alkyl, and each RQ2and RQ3are independently hydrogen or C1-6 alkyl.

62. The compound of any one of claims 51-61, wherein S1is CRS1, and S3is CRS3, wherein RS1and RS3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

63. The compound of claim 62, wherein each of RS1and RS3is hydrogen.Attorney Docket No. PRSC-094 / 001WO 343170-2295 64. The compound of any one of claims 1-63, wherein L’’ is absent.

65. The compound of claim 64, wherein Cy1is.

66. The compound of claim 65, wherein V1is N.

67. The compound of claim 65 or 66, wherein T1is CRT1and V2is CRV2, wherein RT1and RV2are hydrogen.

68. The compound of claim 65, wherein Cy1is.

69. The compound of claim 68, wherein at least one RTis C1-6alkyl.

70. The compound of claim 68 or 69, wherein t is 0 or 1.

71. The compound of claim 64, wherein Cy1is.

72. The compound of claim 71, wherein Y1is CH or N, or Y1is C.

73. The compound of claim 71 or 72, wherein Y2is CH2 or O.

74. The compound of claim 71, wherein Cy1isAttorney Docket No. PRSC-094 / 001WO 343170-229575. The compound of any one of claims 71-74, wherein Z1is CRZ1and Z2is CRZ2.

76. The compound of any one of claims 71-74, wherein at least one of Z1and Z2is N.

77. The compound of any one of claims 71-76, wherein each RZis independently halogen or C1-6alkyl.

78. The compound of any one of claims 71-77, wherein z is an integer selected from 0 to 3.

79. The compound of any one of claims 1-63, wherein L’’ is C1-3 alkylene, -C(=O)-, - C(=O)N(RL)-, -C(=O)O-, -N(RL)-, -O-, -S-, or -S(=O)2-, wherein the alkylene is optionally substituted with one or more Ru.

80. The compound of claim 79, wherein L’’ is -N(RL)- or -O-.

81. The compound of claim 80, wherein Cy1is, wherein: ** denotes attachment to L’’; V’1is CRV’1or N; V’2is CRV’2or N; RV’1and RV’2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-094 / 001WO 343170-2295 each RV’is independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- or 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; and v’ is an integer selected from 0 to 5.

82. The compound of claim 81, wherein at least one of V’1and V’2is N, and RV’1and RV’2, when available, is hydrogen, halogen, C1-6alkyl, or C1-6haloalkyl.

83. The compound of claim 81 or 82, wherein each RV’is independently halogen, C1-6alkyl, or C1-6haloalkyl, and v’ is 0 or 1.

84. The compound of any one of claims 1-83, wherein Cy2is pyridinylene optionally substituted with one or more halogen, C1-6alkyl, or C1-6alkoxy.

85. The compound of claim 84, wherein Cy2iswherein ## denotes attachment to Cy1.

86. The compound of any one of claims 1-85, wherein L2is CH2.

87. The compound of any one of claims 1-86, wherein L3is ethynylene or 1,4-phenylene.

88. The compound of claim 87, wherein L3is ethynylene.

89. A compound selected from the compounds in Tables 1-4 and pharmaceutically acceptable salts thereof.

90. A pharmaceutical composition comprising the compound of any one of claims 1-89, and a pharmaceutically acceptable excipient.Attorney Docket No. PRSC-094 / 001WO 343170-2295 91. A method of degrading a protein in a subject or biological sample comprising administering the compound of any one of claims 1-89 to the subject or contacting the biological sample with the compound of any one of claims 1-89.

92. Use of the compound of any one of claims 1-89 in the manufacture of a medicament for degrading a protein in a subject or biological sample.

93. A compound of any one of claims 1-89 for use in degrading a protein in a subject or biological sample.

94. The method, use, or compound for use of any one of claims 91-93, wherein the protein is p300 or CBP.

95. A method of treating a p300-mediated disorder comprising administering to a patient in need thereof a compound of any one of claims 1-89.

96. Use of a compound of any one of claims 1-89 in the manufacture of a medicament for treating a p300-mediated disorder.

97. A compound of any one of claims 1-89 for use in treating a p300-mediated disorder.

98. The method, use, or compound for use of any one of claims 95-97, wherein the p300- mediated disorder is cancer, an inflammatory disorder, or an autoimmune disease.

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