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 CBP / p300 proteins).

Description

Attorney Docket No. PRSC-091 / 001WO 343170-2288 COMPOUNDS AND COMPOSITIONS AS CBP / P300 DEGRADERS AND USES THEREOF RELATED APPLICATIONS [1] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 505,201, filed May 31, 2023; and U.S. Provisional Application No. 63 / 519,002, filed August 11, 2023, the contents of each of which are incorporated herein by reference in their entireties. BACKGROUND [2] Proteolysis Targeting Chimera (PROTAC) molecules 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, PROTACs may yield enhanced substrate specificity. There is an ongoing need for selective PROTAC molecules 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 [3] 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-1’Attorney Docket No. PRSC-091 / 001WO 343170-2288(I-1’), T is i) of Formula I-3-iii) of Formula I-3-iiii), iii) of Formula I-3-iii(I-3-iii), iv) of Formula I-3-ivv) of Formula I-3-vAttorney Docket No. PRSC-091 / 001WO 343170-2288or vi) of Formula I-3-vivi), and L is of Formula I-2’’wherein 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. [4] In certain aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and a pharmaceutically acceptable excipient. [5] 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. [6] 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. [7] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a protein in a subject or biological sample. DETAILED DESCRIPTION [8] 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 [9] 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-1’Attorney Docket No. PRSC-091 / 001WO 343170-2288(I-1’), wherein: denotes attachment to L; B1is CRB1or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; B6is C or N; RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1- 6 alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 5-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, O, S, or NRX; RXis hydrogen, C1-3alkyl, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; RD1is hydrogen, deuterium, or C1-6alkyl; each RDis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, 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-iAttorney Docket No. PRSC-091 / 001WO 343170-2288denotes attachment to L; RE1, RE2, RE3, and RE4are 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, 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, C1-6alkyl, 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; RF2is 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, -Attorney Docket No. PRSC-091 / 001WO 343170-2288wherein 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, C6-10aryl, 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; 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, C6-10aryl, 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; 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-091 / 001WO 343170-2288to L;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, -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;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; andAttorney Docket No. PRSC-091 / 001WO 343170-2288 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, C6-10aryl, 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 C3-6carbocycle 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, C1-6alkyl, 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; 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, C6-10aryl, 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 -Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C6-10aryl, 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; iv) of Formula I-3-ivwherein: M1is N or C; M2is , , N, or CRM2; M3is , , N, or CRM3;wherein 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, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C1-6alkyl, 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; 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, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -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-vAttorney Docket No. PRSC-091 / 001WO 343170-2288denotes 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, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -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, C1-6alkyl, 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;Attorney Docket No. PRSC-091 / 001WO 343170-2288 or vi) of Formula I-3-viwherein: Q1is NRQ1’, C(RQ1)2, or O; RQ1’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,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, C6-10aryl, 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 C3-6carbocycle 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, C1-6alkyl, 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; orAttorney Docket No. PRSC-091 / 001WO 343170-2288 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;denotes attachment 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’’wherein: * denotes attachment to C; Cy1is, wherein: denotes attachment to T;Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 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- to 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 a double bond, then Y1is C; when is a single bond, then Y1is N or CRY1; denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 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- to 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- 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; Z1is CRZ1or N;Attorney Docket No. PRSC-091 / 001WO 343170-2288 Z2is CRZ2or N; RZ1and RZ2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- to 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- to 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 C6 arylene or 5- to 6-membered heteroarylene, wherein the arylene or heteroarylene is optionally substituted with one or more Ru; L2is CH2or CH(C1-3alkyl); and L3is E-ethenylene, ethynylene, C6arylene, or 5- to 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, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 6-membered heterocyclyl, each Rais independently C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; and each Rcand Rdis independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 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, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0010] In certain aspects, the present disclosure provides compounds of Formula I: T-L-C (I), and pharmaceutically acceptable salts, solvates, or stereoisomers thereof, wherein:Attorney Docket No. PRSC-091 / 001WO 343170-2288 C is of Formula I-1’wherein: denotes attachment to L; B1is CRB1or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; B6is C or N; RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, O, or NRX; RXis hydrogen, C1-3alkyl, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; RD1is hydrogen, deuterium, or C1-6alkyl; each RDis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, 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-iAttorney Docket No. PRSC-091 / 001WO 343170-2288denotes attachment to L; RE1, RE2, RE3, and RE4are 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, 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, C1-6alkyl, 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; RF2is 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, -Attorney Docket No. PRSC-091 / 001WO 343170-2288wherein 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, C6-10aryl, 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; 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, C6-10aryl, 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; 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-091 / 001WO 343170-2288to L; 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, -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;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; andAttorney Docket No. PRSC-091 / 001WO 343170-2288 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, C6-10aryl, 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 C3-6carbocycle 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, C1-6alkyl, 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; 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, C6-10aryl, 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 -Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C6-10aryl, 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; iv) of Formula I-3-ivwherein: M1is N or C; M2is , , N, or CRM2; M3is , , N, or CRM3;wherein 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, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C1-6alkyl, 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; 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, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -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-vAttorney Docket No. PRSC-091 / 001WO 343170-2288denotes 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, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -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, C1-6alkyl, 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;Attorney Docket No. PRSC-091 / 001WO 343170-2288 or vi) of Formula I-3-viwherein: Q1is NRQ1’, C(RQ1)2, or O; RQ1’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,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, C6-10aryl, 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 C3-6carbocycle 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, C1-6alkyl, 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; orAttorney Docket No. PRSC-091 / 001WO 343170-2288 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;denotes attachment 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’wherein: * denotes attachment to C; Cy1is, wherein: denotes attachment to T;Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 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- to 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, C3-4carbocyclyl, or 3- to 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- to 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- 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; Z1is CRZ1or N;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RZ1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- to 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- to 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- to 6-membered heteroarylene optionally substituted with one or more Ru; L2is CH2or CH(C1-3alkyl); and L3is E-ethenylene, ethynylene, C6 arylene, or 5- to 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, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, each Rais independently C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 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, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0011] 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-1Attorney Docket No. PRSC-091 / 001WO 343170-2288wherein: B1is CRB1or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; RB1, RB3, RB4, and RB5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, O, or NRX; RXis hydrogen, C1-3alkyl, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; or when X is NRXand B5is CRB5, then RXand RB5, together with the atoms to which they are bonded, form 5-membered heteroaryl; RD1is hydrogen, deuterium, or C1-6alkyl; each RDis independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, 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-091 / 001WO 343170-2288 E1is , CRE1, or N; E2is , CRE2, or N;to L; RE1, RE2, RE3, and RE4are 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, 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, C1-6alkyl, 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; RF2is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, 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; F3is CRF3, N, or NRF3’;Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C6-10aryl, 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; 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, C6-10aryl, 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; 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-091 / 001WO 343170-2288to 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, -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;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, C6-10aryl, 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-iiiAttorney Docket No. PRSC-091 / 001WO 343170-2288wherein: 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, C6-10aryl, 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, C1-6alkyl, 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; 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, C6-10aryl, 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; andAttorney Docket No. PRSC-091 / 001WO 343170-2288 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, 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-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, C1-6alkyl, 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, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl,Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C1-6alkyl, 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; 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, 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-091 / 001WO 343170-2288each 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, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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,are 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; and R4is -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; or vi) of Formula I-3-viwherein: Q1is NRQ1’, C(RQ1)2, or O;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RQ1’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; 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, C6-10aryl, 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 C3-6carbocycle 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, C1-6alkyl, 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; 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;Attorney Docket No. PRSC-091 / 001WO 343170-2288to L; and RS1, RS2, RS3, and RS4are 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, 5- to 10-membered heteroaryl, -SRb, -S(=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 C;, 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- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-091 / 001WO 343170-2288 each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 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, C3-4carbocyclyl, or 3- to 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- to 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- 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; Z1is CRZ1or N; RZ1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- to 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- to 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;Attorney Docket No. PRSC-091 / 001WO 343170-2288 Cy2is 5- to 6-membered heteroarylene optionally substituted with one or more Ru; and L3is E-ethenylene, ethynylene, C6arylene, or 5- to 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, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, each Rais independently C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 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, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl.

[0012] In certain embodiments, the present disclosure provides compounds of Formula IA:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: G3is N or CH; RG4is C1-6 alkyl or 3- to 12-membered heterocyclyl; Cy1isAttorney Docket No. PRSC-091 / 001WO 343170-2288wherein: denotes attachment to Ring G; Z1is CRZ1or N; RZ1is halogen; andattachment to Cy1.

[0013] In certain embodiments, the present disclosure provides compounds of Formula IB:or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein: S1is CH or N; S3is CH or N; and RS2is C1-6alkyl or 3- to 12-membered heterocyclyl.

[0014] In certain embodiments, the compound of Formula I is notAttorney Docket No. PRSC-091 / 001WO 343170-2288

[0016] In certain embodiments, C is of Formula I-1’wherein:denotes attachment to L; B1is CRB1or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; B6is C or N;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 5-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, O, S, or NRX; RXis hydrogen, C1-3alkyl, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; RD1is hydrogen, deuterium, or C1-6alkyl; each RDis indepdnently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, 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.

[0017] In certain embodiments, C is of Formula I-1’(I-1’), wherein: denotes attachment to L; B1is CRB1or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; B6is C or N; RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, O, or NRX; RXis hydrogen, C1-3alkyl, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RD1is hydrogen, deuterium, or C1-6alkyl; each RDis indepdnently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, 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.

[0018] In certain embodiments C is of Formula I-1’, wherein: B1is CRB1or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; B6is C or N; RB1is hydrogen or halogen; RB3is hydrogen, halogen, -CN, or C1-6alkyl; RB4is hydrogen, halogen, -CN, C1-6alkyl, C1-6alkylamino, or 3- to 4-membered heterocyclyl; RB5is oxo, hydrogen, halogen, C1-6alkyl optionally substituted with one or more halogen, C1-6alkoxy optionally substituted with one or more halogen, or C1-6alkylamino. X is absent, O, or NRX; RXis hydrogen or C1-3alkyl; RD1is hydrogen; d is 0; and q is 1.

[0019] In certain embodiments, C is of Formula I-1wherein: B1is CRB1or N; B3is CRB3or N; B4is CRB4or N;Attorney Docket No. PRSC-091 / 001WO 343170-2288 B5is CRB5or N; RB1, RB3, RB4, and RB5are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, O, or NRX; RXis hydrogen, C1-3alkyl, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; or when X is NRXand B5is CRB5, then RXand RB5, together with the atoms to which they are bonded, form 5-membered heteroaryl; RD1is hydrogen, deuterium, or C1-6alkyl; each RDis indepdnently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, 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.

[0020] In certain embodiments, C is of Formula I-1’(I-1’), wherein: denotes attachment to L; B1is CRB1; B3is CRB3; B4is CRB4; B5is CRB5; B6is C; RB1, RB3, RB4, and RB5are independently hydrogen; X is NRX;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RXis hydrogen; RD1is hydrogen; d is 0; and q is 1,

[0021] In certain embodiments, X is absent, O, S, or NRX. In certain embodiments, X is O. In certain embodiments, X is S. In certain embodiments, X is NRX.

[0022] In certain embodiments, X is absent, O, or NRX. In certain embodiments, X is absent or NH. In certain embodiments, X is absent.

[0023] In certain embodiments, RXis hydrogen, C1-3alkyl (e.g., methyl (C1), ethyl (C2), n- propyl (C3), or i-propyl (C3)), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- to 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-membered rings and 1 heteroatom selected from N, O, and S).

[0024] In certain embodiments, C is of Formula I-1’-X or I-1’-Y

[0025] In certain embodiments, C is of Formula I-1-i, I-1-ii, or I-1-iii

[0026] In certain embodiments, C is of Formula I-1-i

[0027] In certain embodiments, C is of Formula I-1-i-2’, I-1-i-3, I-1-ii-1, I-1-ii-2, I- 1-ii-3, I-1-iii-1, I-1-iii-2, or I-1-iii-3Attorney Docket No. PRSC-091 / 001WO 343170-2288.

[0028] In certain embodiments, C is of Formula I-1-i-1 or I-1-i-2Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0029] InB1is CRB1. In certain embodiments, B1is N.

[0030] In certain embodiments, B3is CRB3or N. In certain embodiments, B3is CRB3. In certain embodiments, B3is N.

[0031] In certain embodiments, B4is CRB4or N. In certain embodiments, B4is CRB4. In certain embodiments, B4is N.

[0032] In certain embodiments, B5is CRB5or N. In certain embodiments, B5is CRB5. In certain embodiments, B5is N.

[0033] In certain embodiments, B6is C or N. In certain embodiments, B6is C. In certain embodiments, B6is N.

[0034] In certain embodiments, none of B1, B3, B4, and B5is N.

[0035] In certain embodiments, one of B1and B5is N, and the other one of B1and B5is CRB1or CRB5.

[0036] In certain embodiments, RB1, RB3, RB4, and RB5are 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)), C1-6alkylamino (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, orAttorney Docket No. PRSC-091 / 001WO 343170-2288 pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- to 5-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 5-membered ring and at least 1 heteroatom independently selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0037] In certain embodiments, RB1, RB3, and RB4are 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- to 5- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 5-membered ring and at least 1 heteroatom independently selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0038] In certain embodiments, RB3, RB4, and RB5are 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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 5- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 5-membered ring and at least 1 heteroatom independently selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0039] In certain embodiments, RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are 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)), C1-6alkylamino (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- to 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 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.

[0040] In certain embodiments, RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 5-membered heterocyclyl.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0041] In certain embodiments, RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl.

[0042] In certain embodiments, RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, C1-6alkyl, or C1-6alkoxy.

[0043] In certain embodiments, RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 5-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more halogen.

[0044] In certain embodiments, RB1, 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- to 5-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more halogen.

[0045] In certain embodiments, RB1, RB3, and RB4are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 5- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more halogen.

[0046] In certain embodiments, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 5- membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more halogen.

[0047] In certain embodiments, RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more halogen.

[0048] In certain embodiments, RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6alkylamino.

[0049] In certain embodiments, RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are independently hydrogen, halogen, or C1-6alkyl.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0050] In certain embodiments, RD1is hydrogen, deuterium, or 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)).

[0051] In certain embodiments, RD1is hydrogen.

[0052] 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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-membered rings and 1 heteroatom selected from N, O, and S), wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl

[0053] In certain embodiments, d is an integer from 0 to 6, as valency permits. In certain embodiments, d is 0. 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.

[0054] In certain embodiments, d is 0.

[0055] 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.

[0056] In certain embodiments, q is 1.Attorney Docket No. PRSC-091 / 001WO 343170-2288 ,Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0059] In certain embodiments, T is Formula I-3-iRE1, RE2, RE3, and RE4are 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, 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;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RF2’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; RF2is 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; 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; 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, C6-10aryl, 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; orAttorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0060] In certain embodiments, T is of Formula I-3-i-a(I-3-i-a).

[0061] In certain embodiments, T is of Formula I-3-i-b(I-3-i-b).

[0062] In certain embodiments, E1is , CRE1, or N.

[0063] In certain embodiments, E2is , CRE2, or N.

[0064] In certain embodiments,

[0065] In certain embodiments, one of E1, E2, and E3is N. In certain embodiments, two of E1, E2, and E3are N.

[0066] In certain embodiments, RE1, RE2, RE3, and RE4are 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,Attorney Docket No. PRSC-091 / 001WO 343170-2288 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), C6-10aryl (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.

[0067] 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, C3-12carbocyclyl, 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.

[0068] 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, 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0069] 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.

[0070] In certain embodiments, RE1, RE2, RE3, and RE4are 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.

[0071] In certain embodiments, RE1and RE3are independently or RE1or RE2is hydrogen, halogen, or C1-6alkyl optionally substituted with one or more Ru.

[0072] In certain embodiments, RE4is hydrogen, halogen, -CN, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-12 carbocyclyl, 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.

[0073] In certain embodiments, F1is C or N.

[0074] In certain embodiments, F2is NRF2’or CRF2.

[0075] In certain embodiments, F3is NRF3’, N, or CRF3.

[0076] 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)), C2-6alkenyl (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), C6-10aryl (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, -Attorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0077] In certain embodiments, RF2’and RF3’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.

[0078] In certain embodiments, RF2’and RF3’are independently 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.

[0079] In certain embodiments, RF2’and RF3’are independently hydrogen, C1-6 alkyl, C3-6 carbocyclyl, 3- to 6-membered heterocyclyl,c d-S(=O)2NR R , - 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, RF2’is hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0081] 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)), C1-6alkoxy (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,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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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), C6-10aryl (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.

[0082] 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.

[0083] In certain embodiments, RF2and RF3are 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.

[0084] 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.

[0085] In certain embodiments, RF2and RF3are 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-091 / 001WO 343170-2288

[0086] In certain embodiments, RF3is hydrogen.

[0087] 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.

[0088] 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)), C2-6alkenyl (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), C6-10aryl (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.

[0089] In certain embodiments, R3aand R3bare 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.

[0090] In certain embodiments, R3aand R3bare independently 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.

[0091] 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, -Attorney Docket No. PRSC-091 / 001WO 343170-2288 C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0092] 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.

[0093] In certain embodiments, R3aand R3bare independently hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0094] 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, C1-6 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-091 / 001WO 343170-2288each 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, C6-10aryl, 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.

[0095] In certain embodiments, T is of Formula I-3-iiG3is N or CRG3; denotes attachment to L; RG1, RG3, and RG4are independently hydrogen, C1-6alkyl, or 3- to 12-membered heterocyclyl; H1is NRH1’; H2is NRH2’; and RH1’and RH2’are independently C1-6alkyl.

[0096] In certain embodiments, T is of Formula I-3-ii-aAttorney Docket No. PRSC-091 / 001WO 343170-2288ii-a).

[0097] In certain embodiments,

[0098] In certain embodiments,

[0099] In certain embodiments,

[0100] 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)), C1-6alkoxy (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)), C3-12 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),Attorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0101] 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.

[0102] 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, 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.

[0103] 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, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0104] 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.

[0105] In certain embodiments, RG1and RG3are both hydrogen.

[0106] 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0107] In certain embodiments, RG4is C1-6alkyl, C1-6alkylamino, and 3- to 12-membered heterocyclyl, wherein the alkyl, alkylamino, or heterocyclyl is optionally substituted with one or more Ru.

[0108] In certain embodiments, RG4is C1-6alkyl, C1-6alkylamino, and 3- to 12-membered heterocyclyl, wherein the alkyl, alkylamino, or heterocyclyl is optionally substituted with one or more -OH, halogen, and C1-6alkyl.

[0109] In certain embodiments, H1is C(RH1)2, NRH1’, or O.

[0110] In certain embodiments, H2is C(RH2)2, NRH2’, or O.

[0111] In certain embodiments, H1is NRH1’and H2is NRH2’.

[0112] 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)), C1-6 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)), C2-6alkynyl (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., heterocyclylAttorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0113] 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, C3-6carbocyclyl, 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.

[0114] 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, C3-6 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.

[0115] 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.

[0116] In certain embodiments, RH1’and RH2’are independently C1-6alkyl.

[0117] In certain embodiments, RH1’and RH2’are independently hydrogen or C1-6alkyl.

[0118] In certain embodiments, two RH1or two RH2, 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 ring and 1-3 heteroatoms selected from N, O, and S), wherein the carbocycle or heterocycle is optionally substituted with one or more Ru.

[0119] 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)), C3-6carbocyclyl (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,Attorney Docket No. PRSC-091 / 001WO 343170-2288wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0120] In certain embodiments, T is of Formula I-3-ii-a-1, I-3-ii-a-2, I-3-ii-a-3, I-3-ii-a-4, or I-3-ii-a-5

[0121] In certain embodiments, T is selected from the group consisting

[0122] In certain embodiments, T is of Formula I-3-iiiAttorney Docket No. PRSC-091 / 001WO 343170-2288wherein: 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, C6-10aryl, 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, C1-6alkyl, 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; 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, C6-10aryl, 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; andAttorney Docket No. PRSC-091 / 001WO 343170-2288 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, 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.

[0123] In certain embodiments, T is of Formula I-3-iii-a(I-3-iii-a).

[0124] In certain embodiments, I1is C(RI1)2, NRI1’, or O.

[0125] In certain embodiments, I2is C(RI2)2, NRI2’, or O.

[0126] In certain embodiments, I1is NRI1’and I2is NRI2’.

[0127] 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)), C1-6alkylamino (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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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), C6-10aryl (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.

[0128] In certain embodiments, each occurrence of RI1and RI2are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, 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.

[0129] In certain embodiments, each occurrence of RI1and RI2are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, 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.

[0130] 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.

[0131] In certain embodiments, two RI1or two RI2, 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 ring 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-091 / 001WO 343170-2288

[0132] In certain embodiments, RI1’and RI2’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)), C3-6carbocyclyl (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.

[0133] In certain embodiments, RI1’and RI2’are independently hydrogen or C1-6alkyl.

[0134] In certain embodiments, each RIis 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), C2-6 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), 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 1-5Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0135] In certain embodiments, each RIis 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.

[0136] 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.

[0137] 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, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0138] In certain embodiments, each RIis C1-6alkyl. In certain embodiments, at least one RIis C1-6 alkyl.

[0139] 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.

[0140] 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.

[0141] In certain embodiments, J1is N or CRJ1.

[0142] In certain embodiments, J2is N or CRJ2.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0143] 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), C6-10aryl (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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0144] 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.

[0145] 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, 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.

[0146] 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, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0147] 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.

[0148] 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.

[0149] In certain embodiments, RJ1and RJ2are independently hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0150] In certain embodiments, T is of Formula I-3-ivAttorney Docket No. PRSC-091 / 001WO 343170-2288wherein 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, C1-6alkoxy, 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, C6-10aryl, 5- to 10-membered heteroaryl, -S(=O)2Ra, -S(=O)2ORb, - S(=O)2NRcRd,-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, C6-10aryl, 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, C1-6 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-091 / 001WO 343170-2288 carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru; and k is an integer selected from 0 to 4.

[0151] In certain embodiments, T is of Formula I-3-iv-a(I-3-iv-a).

[0152] In certain embodiments, T is of Formula I-3-iv-b(I-3-iv-b).

[0153] In certain embodiments, M1is N or C.

[0154] In certain embodiments,

[0155] In certain embodiments,

[0156] In certain embodiments, M3is N.

[0157] In certain embodiments,, N, or CRM4.

[0158] In certain embodiments, at least one of M1, M2, M3, and M4is N or.

[0159] In certain embodiments, at least two of M1, M3, and M4are N. In certain embodiments, at least one of M1, M3, and M4is N.

[0160] In certain embodiments, RM2, RM3, and RM4are 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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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)), C3-12 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.

[0161] In certain embodiments, RM2, RM3, and 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.

[0162] In certain embodiments, RM2, RM3, and RM4are independently hydrogen, halogen, - CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-6Attorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0163] In certain embodiments, RM2, RM3, and 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.

[0164] In certain embodiments, RM2, RM3, and RM4are 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.

[0165] In certain embodiments, RM2is C1-6 alkyl, C1-6 alkoxy, or 3- to 12-membered heterocyclyl, wherein the alkyl, alkoxy, or heterocyclyl is optionally substituted with one or more Ru.

[0166] In certain embodiments, RM3is hydrogen.

[0167] 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)), C3-12carbocyclyl (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), C6-10aryl (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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0168] In certain embodiments, RK’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.

[0169] 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, -wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0170] 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 - C(=O)NRcRd, wherein the alkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0171] In certain embodiments, RK’is hydrogen or C1-6alkyl optionally substituted with one or more Ru.

[0172] In certain embodiments, K1is -C(=O)- or -C(RK1)2-.

[0173] 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)), C3-12Attorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0174] In certain embodiments, each RK1is independently 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.

[0175] 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.

[0176] In certain embodiments, each RK1is 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.

[0177] In certain embodiments, each RKis 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,Attorney Docket No. PRSC-091 / 001WO 343170-2288 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), C6-10aryl (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.

[0178] In certain embodiments, 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.

[0179] 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0180] 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, 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 RKis 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, each RKis independently hydrogen or C1-6alkyl. In certain embodiments, at least one RKis hydrogen. In certain embodiments, at least one RKis C1-6alkyl.

[0183] In certain embodiments, one RKis hydrogen, the other geminal RKis C1-6 alkyl.

[0184] 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.

[0185] In certain embodiments, T is of Formula I-3-iv-a-1

[0186] In certain

[0187] In certain embodiments, T is of Formula I-3-vAttorney Docket No. PRSC-091 / 001WO 343170-2288each 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, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2ORb, -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,are 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; and R4is -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.

[0188] In certain embodiments, T is of Formula I-3-v-a(I-3-v-a).

[0189] In certain embodiments,Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0190] In certain embodiments, P2is, , N, or CRP2.

[0191] In certain embodiments, each RNis 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)), C2-6 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 -Attorney Docket No. PRSC-091 / 001WO 343170-2288 C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0192] In certain embodiments, each RNis 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.

[0193] 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, 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.

[0194] 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, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0195] 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.

[0196] 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, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5. In certain embodiments, n is 6.

[0197] In certain embodiments, n is 0.

[0198] 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, C6-10aryl, 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-091 / 001WO 343170-2288

[0199] In certain embodiments, RP1, RP2, and RP3are 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), C6-10aryl (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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0200] 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, C6-10aryl, 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.

[0201] 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, 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.

[0202] 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, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0203] In certain embodiments, RP1, RP2, and RP3are 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.

[0204] 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.

[0205] 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), 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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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)), C2-6alkynylethynyl (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), wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0206] In certain embodiments, R4is C1-6alkyl or C1-6alkylamino, wherein the alkyl or alkylamino is optionally substituted with one or more Ru.

[0207] In certain embodiments, T is of Formula I-3-vi ,RQ1’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; 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, C6-10aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, alkoxy,Attorney Docket No. PRSC-091 / 001WO 343170-2288 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 C3-6carbocycle 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, C1-6alkyl, 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; 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, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -Attorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0208] In certain embodiments, T is of Formula I-3-vivi), wherein: Q1is NRQ1’; RQ1’is C1-6 alkyl; is a double bond;each occurrence of RQ2and RQ3is independently hydrogen or C1-6alkyl; S1is CRS1or N; S2is CRS2; S3is CRS3or N;denotes attachment to L; andindependently hydrogen, C1-6 alkyl, or 3- to 12-membered heterocyclyl.

[0209] In certain embodiments, T is of Formula I-3-vi-a or I-3-vi-b

[0210] In certain embodiments, Q1

[0211] In certain embodiments, RQ1’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)), C2-6alkynylAttorney Docket No. PRSC-091 / 001WO 343170-2288 (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), C6-10aryl (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.

[0212] 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.

[0213] In certain embodiments,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, -wherein the alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0214] 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.

[0215] In certain embodiments, RQ1’is hydrogen or C1-6alkyl.

[0216] 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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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)), C3-12 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.

[0217] 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, 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.

[0218] 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0219] In certain embodiments, each RQ1is 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.

[0220] In certain embodiments, two RQ1, 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.

[0221] In certain embodiments, when is a double bond, then Q2is N or CRQ2.

[0222] In certain embodiments, when is a single bond, then Q2is NRQ2’, C(RQ2)2, or O.

[0223] In certain embodiments, RQ2’and RQ3’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)), 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), C6-10aryl (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, 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 -Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, RQ2’andare independently 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, RQ2’and RQ3’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.

[0227] In certain embodiments, each occurrence of RQ2and RQ3is 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), C2-6alkenyl (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), decahydronaphthalenylAttorney Docket No. PRSC-091 / 001WO 343170-2288 (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.

[0228] 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, C3-6carbocyclyl, 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.

[0229] 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, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0230] In certain embodiments, each occurrence of RQ2and RQ3is 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.

[0231] In certain embodiments, each RQ2is hydrogen.

[0232] 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.

[0233] In certain embodiments, S1is CRS1or N.

[0234] In certain embodiments,

[0235] In certain embodiments,, CRS3, or N.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0236] In certain embodiments,

[0237] 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)), C1-6alkoxy (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)), C2-6 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), C6-10aryl (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, andC(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd, wherein the alkyl, alkoxy, alkylamino, alkenyl,Attorney Docket No. PRSC-091 / 001WO 343170-2288 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more Ru.

[0238] 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, C3-12carbocyclyl, 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.

[0239] 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, C3-6carbocyclyl, 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.

[0240] 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, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0241] 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.

[0242] In certain embodiments, RS1and RS3are both hydrogen.

[0243] In certain embodiments, RS2is hydrogen, C1-6alkyl, or C1-6alkoxy.

[0244] In certain embodiments, RS2is C1-6 alkyl, C1-6 alkoxy, or C3-12 carbocyclyl, wherein the alkyl, alkoxy, or carbocyclyl is optionally substituted with one or more Ru.

[0245] In certain embodiments, RS2is C1-6alkyl, C1-6alkoxy, or C3-12carbocyclyl, wherein the alkyl, alkoxy, or carbocyclyl is optionally substituted with one or more oxo, halogen, and C1-6alkyl.

[0246] In certain embodiments, RS4is hydrogen or C1-6alkyl.

[0247] In certain embodiments, T is of Formula I-3-vi-a-1 or I-3-vi-a-2vi-a-2).Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0248] In certain embodiments, T is of Formula I-3-vi-a-1-a, I-3-vi-a-1-b, I-3-vi-a-2-a, or I- 3-vi-a-2-b

[0249] In certain embodiments, T is selected from the group consisting of,

[0250] In certain embodiments, T is of Formula I-3-ii, I-3-iv, or I-3-vi.

[0251] In certain embodiments, L is of Formula I-2’’wherein: denotes attachment to C;Attorney Docket No. PRSC-091 / 001WO 343170-2288 Cy1is, wherein: 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- to 4-membered heterocyclyl; each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; t is an integer selected from 0 to 6, as valency permits; or Cy1is, wherein: when is a double bond, then Y1is C; when is a single bond, then Y1is N or CRY1; denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; 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- to 4-membered heterocyclyl; RY2’is hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- to 4-membered heterocyclyl, -S(=O)2Ra, -Attorney Docket No. PRSC-091 / 001WO 343170-2288 Z2is CRZ2or N; RZ1and RZ2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z; Cy2is C6arylene or 5- to 6-membered heteroarylene, wherein the arylene or heteroarylene is optionally substituted with one or more Ru; L2is CH2or CH(C1-3alkyl); and L3is E-ethenylene, ethynylene, C6 arylene, or 5- to 6-membered heteroarylene, wherein the E-ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0252] In certain embodiments, L is of Formula I-2’’wherein: denotes attachment to C; Cy1is, wherein: denotes attachment to T; T1is CRT1; V1is N; V2is CRV2; RT1and RV2are independently hydrogen; t is 0; or Cy1isAttorney Docket No. PRSC-091 / 001WO 343170-2288, wherein: is a single bond; Y1is N; denotes attachment to T; Y2is O; Z1is CRZ1or N; Z2is CRZ2; RZ1and RZ2are independently hydrogen or halogen; z is 0, Cy2is 5- to 6-membered heteroarylene; L2is CH2; and L3is ethynylene.

[0253] In certain embodiments, L is of Formula I-2’wherein: denotes attachment to C; Cy1is, wherein: denotes attachment to T; T1is CRT1or N; V1is CRV1or N; V2is CRV2or N;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RT1, RV1, and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 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- to 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, C3-4carbocyclyl, or 3- to 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- to 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- 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; Z1is CRZ1or N; RZ1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- to 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- to 4-membered heterocyclyl, wherein the alkyl,Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 6-membered heteroarylene, wherein heteroarylene is optionally substituted with one or more Ru; L2is CH2or CH(C1-3alkyl); and L3is E-ethenylene, ethynylene, C6arylene, or 5- to 6-membered heteroarylene, wherein the E-ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0254] In certain embodiments, L is of Formula I-2wherein: denotes attachment to C; 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- to 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- to 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; orAttorney Docket No. PRSC-091 / 001WO 343170-2288 Cy1is, wherein: Y1is N or CRY1; denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 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- to 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- 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; Z1is CRZ1or N; RZ1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- to 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- to 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- to 6-membered heteroarylene; and L3is E-ethenylene, ethynylene, C6arylene, or 5- to 6-membered heteroarylene.

[0255] In certain embodiments, L is of Formula I-2-a’’Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0256] In certain embodiments, Cy1is, wherein: denotes attachment to T; T1is CRT1; V1is N; V2is CRV2; RT1and RV2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; t is an integer selected from 0 to 6, as valency permits.

[0257] In certain embodiments, Cy1is.

[0258] In certain embodiments, T1is CRT1or N. In certain embodiments, T1is CRT1. In certain embodiments, T1is N.

[0259] In certain embodiments, V1is CRV1or N. In certain embodiments, V1is CRV1. In certain embodiments, V2is N.

[0260] In certain embodiments, V2is CRV2or N. In certain embodiments, V2is CRV2. In certain embodiments, V2is N.

[0261] In certain embodiments, RT1, RV1, and RV2are 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)), C1-6Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 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.

[0262] 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, 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.

[0263] 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, or 3- to 6-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, alkenyl, alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru.

[0264] 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.

[0265] In certain embodiments, RT1and RV2are both hydrogen.

[0266] 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)), C1-6alkoxy (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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 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.

[0267] In certain embodiments, each RTis independently C1-6alkyl. In certain embodiments, at least one RTis C1-6alkyl.

[0268] 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.

[0269] In certain embodiments, Cy1is, wherein: Y1is N or CRY1; denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 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- to 4-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RY2’is 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; Z1is CRZ1or N; RZ1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, 3- to 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- to 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.

[0270] In certain embodiments, Cy1is, wherein: when is a double bond, then Y1is C; when is a single bond, then Y1is N or CRY1; denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; 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- to 4-membered heterocyclyl; RY2’is hydrogen, C1-6alkyl, C3-4carbocyclyl, 3- to 4-membered heterocyclyl, -S(=O)2Ra, -Z2is CRZ2or N;Attorney Docket No. PRSC-091 / 001WO 343170-2288 RZ1and RZ2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z.

[0271] In certain embodiments, Cy1is, wherein RZ1is C1-6alkyl substituted with one or more halogen. ,Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0274] In certain embodiments, Y1is N or CRY1. In certain embodiments, Y1is N. In certain embodiments, Y1is CRY1.

[0275] In certain embodiments, Y1is C.

[0276] In certain embodiments, is a single bond. In certain embodiments, is a double bond.

[0277] 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,Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 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.

[0278] In certain embodiments, Y2is C(RY2)2, O, or N(RY2’).

[0279] In certain embodiments, Y2is CH2, O, or NMe.

[0280] 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)), C1-6alkylamino (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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 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.

[0281] In certain embodiments, each RY2is hydrogen.

[0282] In certain embodiments, RY2’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)), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), 3- to 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0283] In certain embodiments, Z1is CRZ1or N.

[0284] In certain embodiments, RZ1is 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)), C1-6haloalkyl (C1-6alkyl independently substituted with one or more halogen, e.g., 1, 2, or 3 halogen), 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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-membered ring 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.

[0285] In certain embodiments, RZ1is 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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-membered ring 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.

[0286] In certain embodiments, Z2is CRZ2or N.

[0287] 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 haloalkyl (C1-6 alkyl independently substituted with one or more halogen, e.g., 1, 2, or 3 halogen), 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- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-membered ring 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.

[0288] 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)), C1-6alkoxy (e.g., methoxy (C1), ethoxy (C2), propoxy (C3), i-propoxy (C3), n-butoxy (C4), i-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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,butylhexylamino, t-butylhexylamino, or pentylhexylamino), C3-4carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), or cyclobutenyl (C4)), or 3- to 4- membered heterocyclyl (e.g., heterocyclyl comprising one or two 3- to 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.

[0289] In certain embodiments, at least one RZis oxo.

[0290] 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0293] In certain embodiments, Cy2is C6arylene or 5- to 6-membered heteroarylene (e.g., heteroaryl comprising one 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S), wherein the arylene or heteroarylene is optionally substituted with one or more Ru.

[0294] In certain embodiments, Cy2is C6arylene optionally substituted with one or more Ru.In certain embodiments, Cy2is C6arylene.

[0295] In certain embodiments, Cy2is 5- to 6-membered heteroarylene (e.g., heteroarylene comprising one 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S) optionally substituted with one or more Ru.

[0296] In certain embodiments, Cy2is 5- to 6-membered heteroarylene (e.g., heteroarylene comprising one 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S).

[0297] In certain embodiments, Cy2is 5- to 6-membered heteroarylene (e.g., heteroarylene comprising one 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S) optionally substituted with one or more Ru.

[0298] In certain embodiments, Cy2is pyridinylene.

[0299] In certain embodiments, Cy2is pyridinylene optionally substituted with one or more Ru.

[0300] In certain embodiments, Cy2is pyridinylene optionally substituted with one or more halogen, C1-6alkyl or C1-6alkoxy, wherein the C1-6alkoxy is optionally substituted with one or more C1-6alkoxy.

[0301] In certain embodiments, Cy2is, whereindenotes attachment to Cy1.

[0302] In certain embodiments, Cy2isdenotes attachment to Cy1.Attorney Docket No. PRSC-091 / 001WO 343170-2288,denotes attachment to Cy1.

[0304] In certain embodiments, Cy2iswherein ## denotes attachment to Cy1.

[0305] In certain embodiments, L2is CH2. In certain embodiments, L2is CH(C1-3alkyl). In certain embodiments, L2is CH(CH3).

[0306] In certain embodiments, L3is E-ethenylene, ethynylene, C6arylene, or 5- to 6- membered heteroarylene, wherein the E-ethenylene, arylene, or heteroarylene is optionally substituted with one or more Ru.

[0307] In certain embodiments, L3is E-ethenylene, ethynylene, C6arylene, or 5- to 6- membered heteroarylene.

[0308] In certain embodiments, L3is E-ethenylene optionally substituted with one or more Ru.

[0309] In certain embodiments, L3is unsubstituted E-ethenylene.

[0310] In certain embodiments, L3is C6arylene optionally substituted with one or more Ru.

[0311] In certain embodiments, L3is 1,4-phenylene optionally substituted with one or more Ru.

[0312] In certain embodiments, L3is unsubstituted 1,4-phenylene.

[0313] In certain embodiments, L3is ethynylene.

[0314] In certain embodiments, L3is 5- to 6-membered heteroarylene optionally substituted with one or more Ru.

[0315] In certain embodiments, L3is unsubstituted 5- to 6-membered heteroarylene.

[0316] 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), pentylAttorney Docket No. PRSC-091 / 001WO 343170-2288 (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

[0318] In certain embodiments,

[0319] In certain embodiments, L is selected from the group consisting ofAttorney Docket No. PRSC-091 / 001WO 343170-2288

[0321] 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)), C3-6carbocyclyl (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.

[0322] In certain embodiments, each Rcand each Rdis 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)), C3-6carbocyclyl (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.

[0323] In certain embodiments, Ra, Rb, Rc, and Rdis independently and optionally substituted with one or more Rz.

[0324] 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0325] In certain embodiments, each Ruis independently oxo, halogen, -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- 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, alkoxy, alkylamino, 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, C3-4carbocyclyl, and 3- to 4-membered heterocyclyl.

[0326] In certain embodiments, each Ruis independently oxo, halogen, -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-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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- to 4-membered heterocyclyl (e.g., heterocyclyl comprising one 3- to 4-membered ring and 1 heteroatom selected from N, O, and S); wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more substituents selected from oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, and 3- to 4-membered heterocyclyl.

[0327] 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-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.

[0328] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. 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.

[0329] In certain embodiments, the compound is selected from the compounds in Tables 1-3 and pharmaceutically acceptable salts thereof.

[0330] In certain embodiments, the compound is selected from the compounds in Tables 1-3.

[0331] In certain embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0332] In certain embodiments, the compound is selected from the compounds in Table 1.

[0333] In certain embodiments, the compound is selected from the compounds in Table 2 and pharmaceutically acceptable salts thereof.

[0334] In certain embodiments, the compound is selected from the compounds in Table 2.

[0335] In certain embodiments, the compound is selected from the compounds in Table 3 and pharmaceutically acceptable salts thereof.

[0336] In certain embodiments, the compound is selected from the compounds in Table 3.$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^ -4- -ededmehC .oN dnuo1 2 3 4pA A A A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^tSlacimehC .oN dnuo5 6 7 8pA A A A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^lacimehC .oN dnu 901112oA A A1pA moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^lacimehC .oN dnu3141516oA A A1pA moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu7 8 9o1A1 1pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu0 1 2o2A2 2pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu3 4 5o2A2 2pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^cimehC .oN dnu6272829oA A A2pA moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^acimehC .oN dnu0313233oA A A3pA moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^cimehC .oN dnu4353637oA A A3pA moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^lacimehC .oN dnu8393041oA A A4pA moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu2 3 4o4A4 4pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^O N H erutcurtSlaH N ciO meN h C N N ON.oN dnu546o4pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu748o4pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^O N H O N H N N N erN utcurtSlaH N H N ciO O meN N h C N N ONONN N .oN dnu9o405pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu152o5pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu354o5pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu556o5pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu758o5pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^O N H O N H N N F erutcurtSlaH N H N ciO O meN N h C N N ONONN N .oN dnu9o506pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu162o6pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu364o6pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu566o6pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^O N H erutcurtSlaH N ciO meN h C N O N NO.oN dnu768o6pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu960o7pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu172o7pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu374o7pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^O N H erutcurtH N SlaO ciN mehC N ONN N O H .oN dnu576o7pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu778o7pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu970o8pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu182o8pA A moCAttorney Docket No. PRSC-091 / 001WO 343170-2288erutcurtSlacimehC .oN dnu3 4o8 8pA A moC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^ - -)- -acimehC .oN dnuo 1 2 3 4pB B B BmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^tSlacimehC .oN dnuo 5 6 7 8pB B B BmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^aciO meN h O C N N N N .oN dnu9011 2oB B1 1pB BmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^lacimehC .oN dnu 3141516oB B B1pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^cimehC .oN dnu 7181910oB B B2pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^erutcurtSlacimehC .oN dnu 1 2 3o2B2 2pB BmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^rtSlacimehC .oN dnu 425 6oB2B2pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^SlacimehC .oN dnu 728 9oB2B2pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^acimehC .oN dnu 031 2oB3B3pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^mehC .oN dnu 33435oB B3pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^cimehC .oN dnu 637 8oB3B3pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^lacimehC .oN dnu 930 1oB4B4pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^aciN mehO F C N N O N S O O .oN dnu 2 3 4o4B4 4pB BmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^SlacimehC .oN dnu 546 7oB4B4pBmoC$WWRUQH\^'RFNHW^1R^^356&^^^^^^^^:2^^^^^^^^^^^^^ -l-y4,-4- - -1-erutcurtSlacimehC .oN dnuo1pC2C moCAttorney Docket No. PRSC-091 / 001WO 343170-2288

[0337] In certain embodiments, the compound is selected from Compound Nos. A6, A15, A16, A41, A45, A46, A66, A70, A71, A79, B1, B5, B30, and B45, and pharmaceutically acceptable salts thereof.

[0338] In certain embodiments, the compound is selected from Compound Nos. A6, A15, A16, A41, A45, A46, A66, A70, A71, A79, B1, B5, B30, and B45.

[0339] In certain embodiments, the compound is selected from Compound Nos. A6, A15, A16, A41, A45, A46, A66, A70, A71, and A79, and pharmaceutically acceptable salts thereof.

[0340] In certain embodiments, the compound is selected from Compound Nos. A6, A15, A16, A41, A45, A46, A66, A70, A71, and A79.

[0341] In certain embodiments, the compound is selected from Compound Nos. B1, B5, B30, and B45, and pharmaceutically acceptable salts thereof.

[0342] In certain embodiments, the compound is selected from Compound Nos. B1, B5, B30, and B45.

[0343] 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.

[0344] 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.

[0345] 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0346] The compounds of the present disclosure may also possess advantageous characteristics, as compared to other p300 degraders. For example, the compounds of the 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).

[0347] 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 Dmax for 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 DC50and greater Dmaxfor 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 DC50for CBP and / or a value of Dmaxfor p300 minus Dmaxfor 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 Dmaxfor 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 Dmaxfor p300 minus Dmaxfor 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 Dmaxfor 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 48 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.

[0348] 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 mayAttorney Docket No. PRSC-091 / 001WO 343170-2288 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.

[0349] 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

[0350] 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.

[0351] 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.

[0352] 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,Attorney Docket No. PRSC-091 / 001WO 343170-2288 phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0353] 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.

[0354] 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+(C1-4alkyl)4, and the like.

[0355] 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

[0356] “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 beAttorney Docket No. PRSC-091 / 001WO 343170-2288 solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In 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.

[0357] 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.

[0358] 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.

[0359] 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.

[0360] 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.)

[0361] 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.”

[0362] 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 absoluteAttorney Docket No. PRSC-091 / 001WO 343170-2288 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 light 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”.

[0363] 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.

[0364] 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.

[0365] 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.

[0366] 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, byAttorney Docket No. PRSC-091 / 001WO 343170-2288 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% enantiomerically 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.

[0367] 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.

[0368] 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.

[0369] 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.

[0370] 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288 Tautomers

[0371] In certain embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0372] 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

[0373] 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)).

[0374] 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.

[0375] 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.

[0376] 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 andAttorney Docket No. PRSC-091 / 001WO 343170-2288 severity of the patient's disease, the particular form of the active ingredient, and the method of 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.

[0377] 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

[0378] 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

[0379] A compound of formula I-1’ may be prepared according to the procedures shown in SCHEME 1A.Attorney Docket No. PRSC-091 / 001WO 343170-2288SCHEME 1A

[0380] According to SCHEME 1A, commercially available or synthetically accessible substituted arene of formula I-1’-1a is reacted with commercially available or synthetically accessible substituted bromide of formula I-1’-2a; with a suitable organic base such as TEA, DIPEA, DBU, and the like; at temperatures ranging from 60 ºC to 100 ºC, preferably 60 ºC; to provide a compound of formula I-1’.

[0381] A compound of formula I-1’ with RD1= H may alternately be prepared according to the procedures shown in SCHEME 1B.SCHEME 1BAttorney Docket No. PRSC-091 / 001WO 343170-2288

[0382] According to SCHEME 1B, commercially available or synthetically accessible substituted arene I-1’-1b (Y = Cl, Br, I, OTf, or the like) is coupled with commercially available or synthetically accessible substituted pyridine I-1’-2b (U = H, B(OR)2, ZnCl, SnR3, or the like) according to standard Buchwald–Hartwig conditions, standard Suzuki– Miyuara conditions, standard Negishi conditions, standard Stille conditions, or the like; with a suitable palladium catalyst such as Pd(dppf)Cl2, Pd(PPh3)4, Pd X-Phos G2, or the like; with or without a suitable base such as Na2CO3, Cs2CO3, K3PO4, KOtBu or the like; in a suitable solvent such as dioxane, THF, DMF, toluene, mixed with water or anhydrous, or the like; at temperatures ranging from 40 ºC to 120 ºC; to provide a coupled compound of formula I-1’- 3b. A bis(benzyloxy)pyridine of formula I-1’-3b is then reduced with a suitable inorganic catalyst such as Pd / C, Pd(OH)2or the like; in a suitable solvent such as EtOH, MeOH, or the like; with a suitable hydride source such as H2 atmosphere or the like; at temperatures ranging from 40 ºC to 120 ºC; to provide a compound of formula I-1’.

[0383] A compound of formula I-3-i may be prepared according to the procedures shown in SCHEME 2.Acylation HydrolysisI-3-i-5 ChlorinationSCHEME 2

[0384] 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 ofAttorney Docket No. PRSC-091 / 001WO 343170-2288 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, BF3etherate 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).

[0385] A compound of formula I-3-ii may be prepared according to the procedures shown in SCHEME 3.SCHEME 3

[0386] 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 alkylatedAttorney Docket No. PRSC-091 / 001WO 343170-2288 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)2and the like; in an inorganic base such as Na2CO3, K3PO4and 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.

[0387] A compound of formula I-3-iii may be prepared according to the procedures shown in SCHEME 4., SCHEME 4

[0388] 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, Cs2CO3and 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, SnCl2and 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.

[0389] A compound of formula I-3-iv may be prepared according to the procedures shown in SCHEME 5.Attorney Docket No. PRSC-091 / 001WO 343170-2288SCHEME 5

[0390] 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, Cs2CO3and 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0391] A compound of formula I-3-v may be prepared according to the procedures shown in SCHEME 6.SCHEME 6

[0392] 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 such 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, SOCl2and 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.

[0393] A compound of formula I-3-vi-a or I-3-vi-b may be prepared according to the procedures shown in SCHEME 7.Attorney Docket No. PRSC-091 / 001WO 343170-2288SCHEME 7

[0394] 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, SOCl2and 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, 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.

[0395] A compound of formula I-2 may be prepared according to the procedures shown in SCHEME 8.SCHEME 8

[0396] According to SCHEME 8, commercially available or synthetically accessible substituted aryl halide (X = Cl, Br or OTf) of formulais reacted with commercially available or synthetically accessible aryl metal agent (Y= B, Zn or Mg) of formula I-2’-2; with a suitable catalysis such as Pd(Ph3P)4, PdCl2dppf and the like; with or without anAttorney Docket No. PRSC-091 / 001WO 343170-2288 inorganic base such as Na2CO3, K3PO4and the like; in a suitable solvent such as dioxane, DMF and the like; at temperatures ranging from 60 °C to 100 °C; to provide coupled compound of formula I-2’-3. An ester of formula I-2’-3 is reacted with a suitable reagent for saponification, such as LiOH or the like; in a suitable solvent such as THF mixed with water, or the like; at temperatures ranging from 0 ºC to 60 ºC, preferably room temperature; to provide a carboxylic acid of formula I-2’-4. An acid of formula I-2’-4 is reacted with commercially available or synthetically accessible substituted amine of formula I-2’-5; with a coupling agent such as HATU, T3P and the like; in an organic solvent such as DCM, DMF, and the like; at temperatures ranging from 0 °C to 60 °C; to provide a coupled amide compound of formula I-2’.

[0397] A compound of formula I may be prepared according to the procedures shown in SCHEME 9.SCHEME 9

[0398] 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 catalysis such as Pd(Ph3P)4, PdCl2dppf and the like (Suzuki); or with a suitable catalysis such as Pd2(dba)3, Pd(OAc)2and 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, PdCl2dppf and the like; or with coupling by catalysis of PdCl2(Ph3P)2and CuI, and the like; in an organic solvent such as dioxane, DMF, and the like; with or without 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). Those skilled in the art will recognize that these steps may be inverted, depending on the specific compound. Those skilled in the art will also recognize that these steps may be interspersed with those described in SCHEMES 1–8 above, as the reactivity of the specific compounds allow.

[0399] 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 compoundsAttorney Docket No. PRSC-091 / 001WO 343170-2288 disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual 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).

[0400] 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).

[0401] 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.

[0402] 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

[0403] 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,Attorney Docket No. PRSC-091 / 001WO 343170-2288 are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. Liquid chromatography-mass spectrometry (LC / MS) were collected using a SHIMADZU LCMS- 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

[0404] The biological activities of the compounds of the present disclosure can be assessed with methods and assays known in the art.

[0405] 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 IC50 of the tested compounds.

[0406] 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 IC50of the tested compounds.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0407] 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, 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 DC50and Dmaxof the tested compounds.

[0408] 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 DC50and Dmaxof the tested compounds.

[0409] 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 DC50and Dmaxof the tested compounds.

[0410] 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-rabbitAttorney Docket No. PRSC-091 / 001WO 343170-2288 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 DC50and Dmaxof the tested compounds.

[0411] 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

[0412] 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.

[0413] 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.

[0414] In certain aspects, the present disclosure provides compounds disclosed herein for use in degrading a protein in a subject or biological sample.

[0415] 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.

[0416] 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.

[0417] In certain aspects, the present disclosure provides compounds disclosed herein for use in reducing a protein in a subject or biological sample.

[0418] In certain embodiments, the protein is p300. In certain embodiments, the protein is CBP.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0419] In certain aspects, the present disclosure provides methods for treating a disease or disorder.

[0420] 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.

[0421] In certain aspects, the present disclosure provides compounds disclosed herein for treating a disease or disorder.

[0422] In certain embodiments, the disease or disorder is driven by gene activation such as cancer, inflammatory disorders, or autoimmune diseases.

[0423] 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, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0424] 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,Attorney Docket No. PRSC-091 / 001WO 343170-2288 dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, Kawasaki 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.

[0425] 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.

[0426] In certain embodiments, the subject is a mammal.

[0427] In certain embodiments, the subject is a human. Definitions

[0428] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below. Chemical Definitions

[0429] 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.

[0430] 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 liquidAttorney Docket No. PRSC-091 / 001WO 343170-2288 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, 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).

[0431] The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0432] 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.

[0433] 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.

[0434] “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 (“C1-10alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). 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 (“C1-6alkyl”, 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”).Attorney Docket No. PRSC-091 / 001WO 343170-2288 In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). 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-butanyl (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 group is substituted C1-10alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), i-Pr (-CH(CH3)2), n-Pr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0435] “Alkylene” as used herein, refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkylene” group may be unsubstituted or substituted or with one or more substituents as described herein. Exemplary unsubstituted divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (- CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted divalent alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene(-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,-CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), and the like.

[0436] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon- carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbonAttorney Docket No. PRSC-091 / 001WO 343170-2288 atoms (“C2-7alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) 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 alkenyl group is unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is substituted C2-10alkenyl.

[0437] “Alkenylene” as used herein, refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkenylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkenylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (- CH=CH-) and propenylene (e.g., - CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted divalent alkenylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ethylene (-C(CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, - CH=CHC(CH3)2-, -CH(CH3)-CH=CH-,-C(CH3)2-CH=CH-, -CH2-C(CH3)=CH-, -CH2- CH=C(CH3)-), and the like.

[0438] “Alkynyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon- carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In certain embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10alkynyl”). In certain embodiments, an alkynylAttorney Docket No. PRSC-091 / 001WO 343170-2288 group has 2 to 9 carbon atoms (“C2-9alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1- propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) 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 alkynyl group is unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is substituted C2-10alkynyl.

[0439] “Alkynylene” as used herein, refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. An “alkynylene” group may be substituted or unsubstituted with one or more substituents as described herein. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0440] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-10alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9alkyl”). In certain embodiments, aAttorney Docket No. PRSC-091 / 001WO 343170-2288 heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7alkyl”). In certain embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“heteroC1-4alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10alkyl.

[0441] The term “heteroalkenyl,” as used herein, refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC2-6alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4Attorney Docket No. PRSC-091 / 001WO 343170-2288 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC2-4alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10alkenyl.

[0442] The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-10alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-9alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-8alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-7alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms (“heteroC2-4alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.Attorney Docket No. PRSC-091 / 001WO 343170-2288

[0443] Analogous to “alkylene,” “alkenylene,” and “alkynylene” as defined above, “heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” as used herein, refer to a divalent radical of heteroalkyl, heteroalkenyl, and heteroalkynyl group respectively. When a range or number of carbons is provided for a particular “heteroalkylene,” “heteroalkenylene,” or “heteroalkynylene,” group, it is understood that the range or number refers to the range or number of carbons in the linear divalent chain. “Heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene” groups may be substituted or unsubstituted with one or more substituents as described herein.

[0444] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl).

[0445] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, az...

Claims

Attorney Docket No. PRSC-091 / 001WO 343170-2288 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-1’wherein: denotes attachment to L; B1is CRB1or N; B3is CRB3or N; B4is CRB4or N; B5is CRB5or N; B6is C or N; RB1, RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 5-membered heterocyclyl, wherein the alkyl, alkoxy, alkylamino, carbocyclyl, or heterocyclyl is optionally substituted with one or more Ru; X is absent, O, S, or NRX; RXis hydrogen, C1-3alkyl, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; RD1is hydrogen, deuterium, or C1-6alkyl; each RDis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; d is an integer from 0 to 6, as valency permits; and q is an integer from 0 to 2,Attorney Docket No. PRSC-091 / 001WO 343170-2288 i) of Formula I-3-ito L; RE1, RE2, RE3, and RE4are 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, 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, C1-6alkyl, 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; RF2is 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, -Attorney Docket No. PRSC-091 / 001WO 343170-2288wherein 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, C6-10aryl, 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; 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, C6-10aryl, 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; 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-091 / 001WO 343170-2288to L; 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, -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;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; andAttorney Docket No. PRSC-091 / 001WO 343170-2288 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, C6-10aryl, 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 C3-6carbocycle 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, C1-6alkyl, 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; 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, C6-10aryl, 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 -Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C6-10aryl, 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 iv) of Formula I-3-ivwherein: M1is N or C; M2is , , N, or CRM2; M3is , , N, or CRM3;wherein 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, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12-Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C1-6alkyl, 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; 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, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -S(=O)2Ra, -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-vAttorney Docket No. PRSC-091 / 001WO 343170-2288denotes 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, C1-6alkoxy, C1-6alkylamino, C2-6alkenyl, C2-6alkynyl, C3-12carbocyclyl, 3- to 12- membered heterocyclyl, C6-10aryl, 5- to 10-membered heteroaryl, -SRb, -S(=O)Ra, -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, C1-6alkyl, 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,Attorney Docket No. PRSC-091 / 001WO 343170-2288 or vi) of Formula I-3-viwherein: Q1is NRQ1’, C(RQ1)2, or O; RQ1’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,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, C6-10aryl, 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 C3-6carbocycle 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, C1-6alkyl, 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; orAttorney Docket No. PRSC-091 / 001WO 343170-2288 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; S2is , CRS2, or N; S3is , CRS3, or 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’’wherein: denotes attachment to C; Cy1is, wherein:Attorney Docket No. PRSC-091 / 001WO 343170-2288 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, C1-6 alkoxy, C1-6 alkylamino, C3-4 carbocyclyl, or 3- to 4-membered heterocyclyl; each RTis independently halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; t is an integer selected from 0 to 6, as valency permits; or Cy1is, wherein: when is a double bond, then Y1is C; when is a single bond, then Y1is N or CRY1; denotes attachment to T; RY1is hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; 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- to 4-membered heterocyclyl; RY2’is hydrogen, C1-6 alkyl, C3-4 carbocyclyl, 3- to 4-membered heterocyclyl, -S(=O)2Ra, -Z2is CRZ2or N; RZ1and RZ2are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl;Attorney Docket No. PRSC-091 / 001WO 343170-2288 each RZis independently oxo, halogen, -CN, -NO2, -OH, -NH2, C1-6alkyl, C1-6alkoxy, C1-6alkylamino, C3-4carbocyclyl, or 3- to 4-membered heterocyclyl; z is an integer selected from 0 to 6, as valency permits, wherein RZmay be present on either Ring Y or Ring Z; Cy2is C6arylene or 5- to 6-membered heteroarylene, wherein the arylene or heteroarylene is optionally substituted with one or more Ru; L2is CH2or CH(C1-3alkyl); and L3is E-ethenylene, ethynylene, C6arylene, or 5- to 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, C3-4 carbocyclyl, or 3- to 6-membered heterocyclyl; each Rais independently C1-6alkyl, C3-6carbocyclyl, or 3- to 6-membered heterocyclyl; each Rbis independently hydrogen, C1-6alkyl, C3-6carbocyclyl, 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, provided that the compound of Formula I is notThe compound of claim 1, wherein C is of Formula I-1-i, I-1-ii, or I-1-iiiAttorney Docket No. PRSC-091 / 001WO 343170-22883. The compound of claim 2, wherein none of B1, B3, B4, and B5is N; or one of B1and B5is N.

4. The compound of claim 3, wherein C is of FormulaI-1-i-2’, I-1-i-3, I-1-ii-1, I-1-ii-2, I-1-ii-3, I-1-iii-1, I-1-iii-2, or I-1-iii-3, ,Attorney Docket No. PRSC-091 / 001WO 343170-2288.

5. The compound of any one of claims 2-4, wherein RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are independently oxo, hydrogen, halogen, -CN, -OH, C1-6alkyl, C1-6 haloalkyl, C1-6 alkoxy, or C1-6 alkylamino.

6. The compound of claim 5, wherein RB1, RB3, RB4, and RB5, RB1, RB3, and RB4, or RB3, RB4, and RB5are independently hydrogen, halogen, or C1-6alkyl.

7. The compound of any one of claims 1-6, wherein T is of Formula I-3-ii8. The compound of claim 7, wherein T is of Formula I-3-ii-a(I-3-ii-a).Attorney Docket No. PRSC-091 / 001WO 343170-2288 9. The compound of claim 6 or 7, wherein G1is CRG1, and G3is N or CRG3, wherein RG1and RG3are 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.

10. The compound of claim 9, wherein each of RG1andis hydrogen.

11. The compound of any one of claims 7-10, wherein RG4is 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.

12. The compound of claim 11, wherein 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.

13. The compound of any one of claims 7-12, wherein H1is NRH1’, and H2is NRH2’, wherein RH1’and RH2’are independently hydrogen or C1-6alkyl.

14. The compound of any one of claims 1-6, wherein T is of Formula I-3-iv15. The compound of claim 14, wherein T is of Formula I-3-iv-aAttorney Docket No. PRSC-091 / 001WO 343170-2288(I-3-iv-a).

16. The compound of claim 14 or 15, wherein K1is -C(=O)-.

17. The compound of any one of claims 14-16, wherein at least two of M1, M3, and M4are N.

18. The compound of any one of claims 14-17, wherein at least one of M1, M3, and M4is N.

19. The compound of any one of claims 14-18, wherein M3is N.

20. The compound of any one of claims 14-18, wherein M3is CRM3, wherein RM3is 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.

21. The compound of claim 14, wherein T is of Formula I-3-iv-b(I-3-iv-b).Attorney Docket No. PRSC-091 / 001WO 343170-2288 22. The compound of any one of claims 14-21, wherein each RKis independently hydrogen, or C1-6alkyl.

23. The compound of any one of claims 14-22, wherein RK’is hydrogen or C1-6alkyl.

24. The compound of any one of claims 14-23, wherein RM2is 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.

25. The compound of any one of claims 1-6, wherein T is of Formula I-3-vi.

26. The compound of claim 25, wherein T is of Formula I-3-vi-a or I-3-vi-b27. The compound of claim 25 or 26, wherein RS2is 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288 28. The compound of any one of claims 25-27, wherein RS4is 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.

29. The compound of any one of claims 25-28, wherein Q1is NRQ1’, wherein RQ1’is hydrogen or C1-6alkyl.

30. The compound of any one of claims 25-29, 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- to 4- membered heterocyclyl.

31. The compound of claim 30, wherein RQ2and RQ3are independently hydrogen or C1-6alkyl.

32. The compound of any one of claims 25-31, wherein is a single bond, then Q2is C(RQ2)2and 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- to 4-membered heterocyclyl; and RQ3’ ishydrogen, C1-6alkyl, C3-4carbocyclyl, or 3- to 4- membered heterocyclyl.

33. The compound of claim 32, wherein each RQ2is hydrogen or C1-6 alkyl, and RQ3’is C1-6alkyl, and each RQ2and RQ3are independently hydrogen or C1-6alkyl.

34. The compound of any one of claims 25-33, wherein S1is CRS1, and S3is CRS3, wherein RS1and RS3are 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.Attorney Docket No. PRSC-091 / 001WO 343170-2288 35. The compound of any one of claims 1-34, wherein Cy1is.

36. The compound of claim 35, wherein V1is N.

37. The compound of claim 35 or 36, wherein T1is CRT1and V2is CRV2, wherein RT1and RV2are hydrogen.

38. The compound of claim 37, wherein Cy1is.

39. The compound of any one of claims 1-38, wherein Cy1is.

40. The compound of claim 39, wherein Cy1is.

41. The compound of any one of claims 1-40, wherein Cy2is pyridinylene optionally substituted with one or more halogen, C1-6alkyl or C1-6alkoxy, wherein the C1-6alkoxy is optionally substituted with one or more C1-6alkoxy.Attorney Docket No. PRSC-091 / 001WO 343170-2288 42. The compound of claim 41, wherein Cy2iswherein ## denotes attachment to Cy1.

43. The compound of any one of claims 1-42, wherein L2is CH2.

44. The compound of any one of claims 1-43, wherein L3is E-ethenylene, ethynylene, or 1,4-phenylene.

45. A compound selected from the compounds in Tables 1-3 or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising the compound of any one of claims 1-45, and a pharmaceutically acceptable excipient.

47. A method of degrading a protein in a subject or biological sample comprising administering the compound of any one of claims 1-45 to the subject or contacting the biological sample with the compound of any one of claims 1-45.

48. Use of the compound of any one of claims 1-45 in the manufacture of a medicament for degrading a protein in a subject or biological sample.

49. A compound of any one of claims 1-45 for use in degrading a protein in a subject or biological sample.Attorney Docket No. PRSC-091 / 001WO 343170-2288 50. The method, use, or compound for use of any one of claims 47-49, wherein the protein is p300 or CBP.

51. A method of treating a p300-mediated disorder comprising administering to a patient in need thereof a compound of any one of claims 1-45.

52. Use of a compound of any one of claims 1-45 in the manufacture of a medicament for treating a p300-mediated disorder.

53. A compound of any one of claims 1-45 for use in treating a p300-mediated disorder.

54. The method, use, or compound for use of any one of claims 51-53, wherein the p300- mediated disorder is cancer, an inflammatory disorder, or an autoimmune disease.

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