Spirocyclic compounds as CBP / p300 degraders and uses thereof

Abstract

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

Description

Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)SPIROCYCLIC COMPOUNDS AS CBP / P300 DEGRADERS AND USES THEREOFRELATED APPLICATION

[0001] This application claims the benefit of and priority to U. S. Provisional Application No.63 / 775,444, filed March 21, 2025, the contents of which are incorporated herein by reference in their entireties.BACKGROUND

[0002] Bifunctional protein degraders are heterobifunctional compounds that simultaneously bind a target protein and an E3 ligase complex, resulting in the transfer of ubiquitin and initiating a process ultimately causing the proteasomal degradation of the target protein. By catalyzing the formation of a ternary complex involving an E3 ligase receptor, a protein of interest, and a small molecule, Bifunctional protein degraders may yield enhanced substrate specificity. There is an ongoing need for selective bifunctional protein degraders for treating and / or preventing cancer and other diseases responsive to the inhibition or degradation of CBP / p300 proteins. P300 selective degraders can display strong selectivity for p300 over CBP and demonstrate a time-dependent loss of p300, enhancer acetylation, and transcriptional output in cancer cells both in vitro and in vivo with limited toxicity to untransformed cells. Enhanced dependency on p300 is found across numerous cancer lineages.SUMMARY

[0003] In some aspects, the present disclosure provides compounds of Formula I:T-L-C (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:C is of Formula 1-1RD"RD'Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)wherein:** denotes atachment to L;=^= denotes a single bond or a double bond, as valency permits;B1is absent, N, or C(RB);B2is N, O, S, or C(RB);B3is N or C;B4is N or C(RB);each RBis independently hydrogen, halogen, -CN, -NO2, -OH, -NHz, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;C1is absent or C(Rcl)2;C2is O, C(=O), C(RC1), or C(Rcl)2;C3is absent, N(RC2), C(RCi), or C(Rcl)2;each RCiis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;each RC2is independently hydrogen or C1-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;D1is absent or C(RD)z;each RDis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;L is of Formula 1-2*,S c* **1* (1-2),wherein:* denotes attachment to T, and ** denotes attachment to C;each L’ is independently -C(=O)-, -C(=O)N(RL)-, -N(RL)C(=O)-, -C(=O)O-, - OC(=O)-, -N(RL’)-, -O-, -O-(Ci-6 alkylene)-, -(C1-6 alkylene)-O-, -S-, -S(=O)2-, C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, Ce-io arylene, or 5- to 10-membered heteroarylene, wherein the -O-(Ci-6 alkylene)-, -(Ci-6 alkylene)-O-, Ci-e alkylene, C1-6 heteroalkylene, C2-6 alkenylene, C2-6Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)alkynylene, Cs-n carbocyclylene, 3- to 12-membered heterocyclylene, C6-10 arylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C 1-6 alkyl, or C 1-6 alkoxy;each occurrence of RLis independently hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C’3-8 carbocyclyl, 3- to 8-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, - C(=O)Ra, -C(=O)ORa, or -C(=O)N(Ra)2, wherein the Ct-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, or 3- to 8-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; andeach Raindependently is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;1 is an integer selected from 0 to 10;i) of Formula I-3-i(I-3-i),wherein:* denotes attachment to L;G1is N or C(RGi);G2is N or C(RG2);each RHis independently hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;RG1, RG2, and RG3are independently hydrogen, halogen, -CN, -NO2, -OH, -NHz, 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 C1-6 alkyl, Ci-6 alkoxy, C1-6 alkyl mino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-memberedAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2;J1is N; and RJ1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RJ1and RK4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or J1is C; and RJ1and RK4, together with the intervening atoms to which they are attached, form Ce aryl or 6-membered heteroaryl, wherein the Co aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;K2is N or C(RK2);K3is N or C(RK3); andRK1, RK2, RK3, and Rk4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C 1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C’3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;ii) of Formula I-3-iiwherein:*denotes attachment to L;RQ1is hydrogen or C1-6 alkyl, wherein the Ci-e alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RQ2and RQ3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-memberedAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 1 O-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;S1is CRS1or N;S3is CRS3orN;andRS1, RS2, and RS3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-e 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 C1-6 alkyl, Ci-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 is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;M1is N; and RM1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RM1and RT4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or M1is C; and RM1and RT4, together with the intervening atoms to which they are attached, form Ce aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;T2is N or C(RT2);T3is N or C(R13); andRT1, RT2, RT3, and RT4are 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, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;oriii) of Formula I-3-iiiAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)wherein:* denotes attachment to L;each RNis independently hydrogen, halogen, -CN, -NOz, -OH, -NHz, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;RP3is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C’6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-w aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz; andR4is C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino, wherein the C1-6 alkyl, C1-6 alkoxy, or Ci-6 alkylamino is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;U1is N; and RU1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or Ruland RV4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or U1is C; and RIJ1and RV4, together with the intervening atoms to which they are attached, form C aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;V2is N or C(RV2);V3is N or C(RV3); andRV1, R3''2, R3 J, and R3''4are independently hydrogen, halogen, -CN, -NO2, -OH, -NHz, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0004] In some aspects, the present disclosure provides conjugates comprising a compound disclosed herein, wherein the compound is attached to a conjugate partner.

[0005] In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein, and one or more pharmaceutically acceptable excipient.

[0006] In some 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.

[0007] In some 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.

[0008] In some aspects, the present disclosure provides compounds disclosed herein for use in degrading a protein in a subject or biological sample.

[0009] In some aspects, the present disclosure provides methods for treating a disease or disorder.

[0010] In some aspects, the present disclosure provides uses of the compounds disclosed herein in the manufacture of a medicament for treating a disease or disorder.

[0011] In some aspects, the present disclosure provides compounds disclosed herein for treating a disease or disorder.DETAILED DESCRIPTION

[0012] The present disclosure relates to compounds that may show activity in degrading certain proteins (e.g., p300 / CBP), and pharmaceutical compositions comprising such compounds.Compounds of the Present Disclosure

[0013] In some aspects, the present disclosure provides compounds of Formula I:T-L-C (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:C is of Formula 1-1Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)0(1-1),wherein:** denotes attachment to L;denotes a single bond or a double bond, as valency permits;B’ is absent, N, or C(RB);B2is N, O, S, or C(RB);B3is N or C;B4is N or C(RB);each RBis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;C1is absent or C(Rcl)2;C2is O, C(==O), C(Rcl), or C(RCi)2;C3is absent, N(RC2), C(RC!), or C(RC!)2;each RCiis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;each RC2is independently hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;D1is absent or C(RD)2;each RDis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;L is of Formula 1-20-2),wherein:Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)* denotes attachment to T, and ** denotes attachment to C;each L’ is independently -C(::::O)-, -C(::::O)N(RL)-, -N(RL)C(=O)-, -C(=O)O-, -OC(=O)-, -N(RL)-, -O-, -O-(Ci-6 alkylene)-, -(Ci-6 alkylene)-O-, -S-, -S(=O)2-, Ci-6 alkylene, Ci -6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, Cs-io arylene, or 5- to 10-membered heteroarylene, wherein the -O-(Ci-6 alkylene)-, -(C1-6 alkylene)-O-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, Ce-io arylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, or C1-6 alkoxy;each occurrence of R1is independently hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3- to 8-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -C(=O)Ra, -C(=O)ORa, or -C(=O)N(Ra)2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, or 3- to 8-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; andeach Raindependently is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;1 is an integer selected from 0 to 10;T isi) of Formula I-3-iwherein:* denotes attachment to L;G1is N or C(RG1);G2is N or C(RG2);Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)each RHis independently hydrogen or Ci-6 alkyl, wherein the Ci-e alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RG1, R2, and RG3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2;J1is N; and RJ1is hydrogen or C1-6 lkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RJIand RK4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or J1is C; and RJ1and RK4, together with the intervening atoms to which they are attached, form Co aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;K2is N or C(RK2);K3is N or C(RK3); andRK1, RK2, RK3,anj RK4ARQintjepentjently hydrogen, halogen, -CN, -NO2, -OH, -NHz, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Co-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;ii) of Formula I-3-iiAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)wherein:*denotes attachment to L;RQ1is hydrogen or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -Nth, -OH, or -NH;RQ2and RQ3are 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, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, Ci -6 alkylamino, C 2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Co-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;S1is CRS1or N;S3is CRS3orN;andRS1, RS2, and RS3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C’6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;M1is N; and RM1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz; or RMland RT4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NHz, or Ci-6 alkyl; or Mlis C; and RM1and Rr4, together with the intervening atoms to which they are attached, form C& aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz, T2is N or C(RT2);T3is N or C(RT3); andRT1, RT2, RT3, and RT4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-memberedAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;oriii) of Formula 1-3-iiiwherein:* denotes attachment to L;each RNis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RP3is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; andR4is C1-6 alkyl, Ci-6 alkoxy, or C1-6 alkylamino, wherein the Ci-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;U1is N; and RU1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RU1and RV4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or U1is C; and RU1and RV4, together with the intervening atoms to which they are attached, form Ce aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)V2is N or C(RV2);V3is N or C(RV3); andRVi, RV2, RV3, and RV4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci -6 alkyl, Ci-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0014] In some embodiments, the present disclosure provides compounds of Formula I-a or I-bor a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Ri is hydrogen or C1-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or - NH2.

[0015] In some embodiments, Ri is hydrogen.

[0016] In some embodiments, Ri is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), i-propyl (C3), w-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0017] In some embodiments, Ri is methyl.Variable C

[0018] In some embodiments, C is of Formula I-l-i, I-l-ii, I-l-iii, I-l-iv, I-l-v, I-l-vi, I-l-vii, or I-l-viiiAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0019] In some embodiments, - denotes a single bond, as valency permits.

[0020] In some embodiments, - denotes a double bond, as valency permits.

[0021] In some embodiments, B1is absent.

[0022] In some embodiments, B1is N.

[0023] In some embodiments, B1is C(RB).

[0024] In some embodiments, B2is N.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0025] In some embodiments, B2is O.

[0026] In some embodiments, B2is S.

[0027] In some embodiments, B2is C(RB).

[0028] In some embodiments, B3is N.

[0029] In some embodiments, B3is C.

[0030] In some embodiments, B4is N.

[0031] In some embodiments, B4is C(RB).

[0032] In some embodiments, B1is C(RB), B2is C(RB), B3is C, and B4is C(RB).

[0033] In some embodiments, B1is C(RB), B2is C(RB), B3is C, and B4is N.

[0034] In some embodiments, B1is C(RB), B2is N, B3is C, and B4is C(RB).

[0035] In some embodiments, B1is N, B2is C(RB), B3is C, and B4is C(RB).

[0036] In some embodiments, B1is absent, B2is S or O, B3is C, and B4is C(RB).

[0037] In some embodiments, B1is absent, B2is N, B3is N, and B4is C(RB).

[0038] In some embodiments,(i) B1is C(RB), B2is C(RB), B3is C, and B4is C(RB);(ii) B1is C(RB), B2is C(RB), B3is C, and B4is N;(iii) B1is C(RB), B2is N, B3is C, and B4is C(RB);(iv) B1is N, B2is C(RB), B3is C, and B4is C(RB);(v) Blis absent, B is S or O, B3is C, and B4is C(RB); or(vi) B1is absent, B2is N, B3is N, and B4is C(RB).

[0039] In some embodiments, at least one RBis hydrogen.

[0040] In some embodiments, each RBis hydrogen.

[0041] In some embodiments, at least one RBis halogen (e.g, F, Cl, Br, or I).

[0042] In some embodiments, each RBis independently hydrogen or halogen.

[0043] In some embodiments, at least one RBis -CN.

[0044] In some embodiments, at least one RBis -Nth.

[0045] In some embodiments, at least one RBis -OH.

[0046] In some embodiments, at least one RBis -NH2.

[0047] In some embodiments, at least one RBis C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), / -propyl (C3), w-butyl (C4), / -butyl (C4), -butyl (C4), r-butyl (C4), pentyl (C5), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0048] In some embodiments, C1is absent.

[0049] In some embodiments, C1is C(Rcl)2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0050] In some embodiments, C2is O.

[0051] In some embodiments, C2is C(=O)

[0052] In some embodiments, C2is C(Rcl).

[0053] In some embodiments, C2is C(Rcl)2.

[0054] In some embodiments, C3is absent.

[0055] In some embodiments, CJis N(RC2).

[0056] In some embodiments, C3is C(Rcl).

[0057] In some embodiments, C3is C(Rcl)2.

[0058] In some embodiments, C1is absent, C2is C(Rcl)2, and C3is C(Rcl)2.

[0059] In some embodiments, C!is C(Rcl)2, C2is C(Rcl)2, and C3is C(Rcl).

[0060] In some embodiments, C1is C(Rcl)2, C2is O, and C3is C(Rcl)2.

[0061] In some embodiments, C1is C(Rcl)2, C2is C(Rcl), and C3is C(RC!).

[0062] In some embodiments, C1is absent, C2is C(Rcl)2, and C3is absent.

[0063] In some embodiments, C1is absent, C2is C(=O), and C3is N(RC2).

[0064] In some embodiments,(i) C1is absent, C2is C(RC!)2, and C3is C(Rcl)2;(ii) C1is C(RC1)2, C2is C(Rcl)2, and C3is C(RC1)2;(iii) C1is C(RC1)2, C2is O, and C is C(Rcl)2;(iv) C1is C(RC1)2, C2is C(RC!), and C3is C(Rcl);(v) C1is absent, C2is C(Rcl)2, and C3is absent; or(vi) C1is absent, C2is C(=O), and C3is N(RC2).

[0065] In some embodiments, at least one RC1is hydrogen.

[0066] In some embodiments, each Rt!is hydrogen.

[0067] In some embodiments, at least one RC1is halogen (e.g, F, Cl, Br, or I).

[0068] In some embodiments, at least one RC1is -CN.

[0069] In some embodiments, at least one RC1is -NO2.

[0070] In some embodiments, at least one RC1is -OH.

[0071] In some embodiments, at least one RC1is -NH2.

[0072] In some embodiments, at least one RC1is C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), / -propyl (C3), w-butyl (C4), / -butyl (C4), -butyl (C4), r-butyl (C4), pentyl (C5), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0073] In some embodiments, each RC1is independently hydrogen, halogen, or C1-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0074] In some embodiments, at least one RC2is hydrogen.

[0075] In some embodiments, each RC2is hydrogen.

[0076] In some embodiments, at least one RC2is Ci-6 alkyl e.g., methyl (Ci), ethyl (C2), n-propyl (C3), / -propyl (C3), w-butyl (C4), z-butyl (C4), -butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0077] In some embodiments, D1is absent.

[0078] In some embodiments, D1is C(RD)2.

[0079] In some embodiments, at least one RDis hydrogen.

[0080] In some embodiments, each RDis hydrogen.

[0081] In some embodiments, at least one RDis halogen e.g., F, Cl, Br, or I).

[0082] In some embodiments, at least one RDis -CN.

[0083] In some embodiments, at least one RDis -NO2

[0084] In some embodiments, at least one RDis -OH.

[0085] In some embodiments, at least one RDis -NH2.

[0086] In some embodiments, at least one Ruis C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), / -propyl (C3), / z-butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0087] In some embodiments,C isVariable L

[0001] In some embodiments, at least one L’ is -C(=O)-.

[0002] In some embodiments, at least one L’ is -C(=O)N(RL)-.

[0003] In some embodiments, at least one L’ is -N(RL)C(=O)-.

[0004] In some embodiments, at least one L’ is -C(=O)O-.

[0005] In some embodiments, at least one L’ is -OC(=O)-.

[0006] In some embodiments, at least one L’ is -N(RL)-.

[0007] In some embodiments, at least one L’ is -O-.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0008] In some embodiments, at least one L’ is -O-(Ci-6 alkylene)- (e.g, -O-methylene- (Ci), -O-ethylene- (C2), -O-z -propylene- (C3), -O-z'-propylene- (C3), -O-zz-butylene- (C4), -O-i-butylene- (C4), -O-s-butylene- (C4), -O-t-butylene- (C4), -O-pentylene- (Cs), or -O-hexylene-(Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, - NH2, C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), 5-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)), or Cue alkoxy (e.g.. methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), t-butoxy (C4), pent oxy (Cs), or hexoxy (Ce)).

[0009] In some embodiments, at least one L’ is -(C1-6 alkylene)-O- (e.g, -methylene-O- (Ci), -ethylene-O- (C2), -zz-propylene-O- (C3), -z-propylene-O- (C3), -zz-butylene-O- (C4), -z-butylene-O- (C4), -s-butylene-O- (C4), -Z-butylene-O- (C4), -pentylene-O- (Cs), or -hexylene-O- (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, - OH, -NH2, C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), 5-butyl (C4), / -butyl (C4), pentyl (C5), or hexyl (Ce)), or C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), t- butoxy (C4), pentoxy (Cs), or hexoxy (Co)).

[0010] In some embodiments, at least one L’ is -S-.

[0011] In some embodiments, at least one L’ is -S(=O)2-.

[0012] In some embodiments, at least one L’ is Ci-6 alkylene (e.g, methylene (Ci), ethylene (C2), zz-propylene (C3), z-propylene (C3), zz-butylene (C-t), z-butylene (C4), -butylene (C ), t-butylene (C4), pentylene (Cs), or hexylene (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, C 1-6 alkyl (e.g, methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), -butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)), or C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), n-butoxy (C4), z-butoxy (C4), -butoxy (C4), -butoxy (C ), pentoxy (Cs), or hexoxy (Ce)).

[0013] In some embodiments, at least one L’ is C1-6 heteroalkylene optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), -butyl (C4), -butyl (C4), pentyl (Cs), or hexyl (Ce)), or C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z- propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), Z-butoxy (C4), pentoxy (Cs), or hexoxy (Co)).

[0014] In some embodiments, at least one L’ is C2-6 alkenylene (e.g, ethenylene (C2), 1- propenylene (C3), 2-propenylene (C3), 1-butenylene (C4), 2-butenylene (C4), butadienylene (C4), pentenylene (Cs), pentadienylene (Cs), or hexenylene (Co)) optionally substituted withAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), / / -propyl (C3), z-propyl (C3), w-butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)), or C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z- propoxy (C3), / / -butoxy (C4), / '-butoxy (C4), -butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (Ce)).

[0015] In some embodiments, at least one L’ is C2-6 alkynylene (e.g., ethynylene (C2), 1-propynylene (C3), 2-propynylene (C3), 1-butynylene (C4), 2-butynylene (C4), pentynylene (C5), or hexynylene (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), / / -propyl (C3), / -propyl (C3), / / -butyl (C4), / -butyl (C4), 5-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)), or C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), / '-propoxy (C3), / -butoxy (C4), / '-butoxy (C4), s-butoxy (C4), / -butoxy (C4), pentoxy (C.s), or hexoxy (Ce)).

[0016] In some embodiments, at least one L’ is C3-12 carbocyclylene (e.g, cyclopropylene (C3), cyclopropenylene (C3), cyclobutylene (C4), cyclobutenylene (CU), cyclopentylene (Cs), cyclopentenylene (Cs), cyclohexylene (Ce), cyclohexenylene (Ce), cyclohexadienylene (Ce), cycloheptylene (C7), cycloheptenylene (C7), cycloheptadienylene (C7), cycloheptatrienylene (C7), cyclooctylene (Cs), cyclooctenylene (Cs), bicyclo[2.2.1]heptanylene (C7), bicyclo[2.2.2]octanylene (Cs), cyclononylene (C9), cyclononenylene (C9), cyclodecylene (Cio), cyclodecenylene (Cio), octahydro- 1 / 7-indenylene (C9), decahydronaphthalenylene (Cio), or spiro[4.5]decanylene (Cio)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2. C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), / / -propyl (C3), z'-propyl (C3), / / -butyl (C4), z-butyl (C4), s-butyl (C4), -butyl (C4), pentyl (Cs), or hexyl (Ce)), or C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z'-propoxy (C3), / / -butoxy (C4), z'-butoxy (C4),.s-butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (Ce)).

[0017] In some embodiments, at least one L’ is 3- to 12-membered heterocyclylene (e.g, heterocyclylene comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), / / -propyl (C3), / -propyl (C3), / / -butyl (C4), / '-butyl (C4), 5-butyl (CU), / -butyl (C4), pentyl (C.s), or hexyl (Ce)), or C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), / '-propoxy (C3), / / -butoxy (C4), / -butoxy (C4), -butoxy (C4), / -butoxy (C4), pentoxy (C ), or hexoxy (Ce)).

[0018] In some embodiments, at least one L’ is Ce-io arylene (e.g, phenylene or naphthylene) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, Ci -6 alkyl (e.g, methyl (Ci), ethyl (C2), / / -propyl (C3), / -propyl (C3), / / -butyl (C4), / '-butyl (C4),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)5-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Co)), or C1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), w-butoxy (C4), / -butoxy (C4), -butoxy (C4), / -butoxy (C4), pentoxy (Cs ), or hexoxy (Ce)).

[0019] In some embodiments, at least one L’ is 5- to 10-membered heteroarylene (e.g, heteroarylene comprising one or two 5- to 6-membered rings and 1-5 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), / -propyl (C3), w-butyl (C4), / -butyl (C4), 5-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Co)), or Ci -6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), w-butoxy (C4), / -butoxy (C4), butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (C6)).

[0020] In some embodiments, at least one RLis hydrogen.

[0021] In some embodiments, each R1is hydrogen.

[0022] In some embodiments, at least one RLis C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), z-propyl (C3), w-butyl (C4), / -butyl (C4), -butyl (C4), -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0023] In some embodiments, at least one R1is C2-6 alkenyl (e.g, ethenyl (C2), 1 -propenyl (C3), 2 -propenyl (C3), 1-butenyl (C-t), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0024] In some embodiments, at least one R1is C2-6 alkynyl (e.g, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0025] In some embodiments, at least one R1is C’3-8 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C$>), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / Z-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0026] In some embodiments, at least one RLis 3- to 8-membered heterocyclyl (e.g, heterocyclyl comprising one or two 3- to 8-membered rings and 1-5 heteroatoms selected fromAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)N, O, and S) optionally substituted with one or more halogen F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0027] In some embodiments, at least one RLis -S(=O)2Raoptionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0028] In some embodiments, at least one R1is -S(=O)2ORaoptionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0029] In some embodiments, at least one RLis -S(= )2N(Ra)2 optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0030] In some embodiments, at least one RLis -C(::O)Raoptionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0031] In some embodiments, at least one RLis -C(=O)ORaoptionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0032] In some embodiments, at least one RLis -C(=O)N(Ra)2 optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0033] In some embodiments, at least one Rais hydrogen.

[0034] In some embodiments, each Rais hydrogen.

[0035] In some embodiments, at least one Rais C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), / '-propyl (C3), w-butyl (Ci), / -butyl (C4), s-butyl (C4), Cbutyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0036] In some embodiments, at least one Rais C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2 -propenyl (C3), 1-butenyl (C-i), 2-butenyl (Ci), butadienyl (Ci), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), - CN, -NO2, -OH, or -NH2.

[0037] In some embodiments, at least one Rais C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NHz.

[0038] In some embodiments, I is an integer selected from 1 to 10, an integer selected from 2 to 10, an integer selected from 3 to 10, an integer selected from 4 to 10, an integer selected from 5 to 10, an integer selected from 6 to 10, an integer selected from 7 to 10, or an integer selected from 8 to 10.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0039] In some embodiments, 1 is an integer selected from 1 to 9, an integer selected from 1 to 8, an integer selected from 1 to 7, an integer selected from 1 to 6, an integer selected from 1 to 5, an integer selected from 1 to 4, or an integer selected from 1 to 3.

[0040] In some embodiments, 1 is an integer selected from 2 to 9, an integer selected from 3 to 8, or an integer selected from 4 to 7.

[0041] In some embodiments, 1 is 0. In some embodiments, 1 is 1. In some embodiments, 1 is 2. In some embodiments, 1 is 3. In some embodiments, 1 is 4. In some embodiments, 1 is 5. In some embodiments, 1 is 6. In some embodiments, 1 is 7. In some embodiments, 1 is 8. In some embodiments, 1 is 9. In some embodiments, 1 is 10.

[0042] In some embodiments, each L’ is independently -C(=O)-, -C(=O)N(RL)-, - N(RL)C(=O)-, -N(RL’)-, CI-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5- to 10-membered heteroarylene, wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5- to 10- membered heteroarylene is optionally substituted with one or more halogen, -CN, -Nth, -OH, -NH2, Ci -6 alkyl, or C 1-6 alkoxy.

[0043] In some embodiments, L is *-(5- to 6-membered heteroarylene)-C(=O)N(RL)-(Ci-6 alkylene)-(C2-6 alkenylene)-** or *-(5- to 6-membered heteroarylene)-C(=O)N(RL)-(Ci-6 alkylene)-(C2-6 alkynylene)-**, wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, or C1-6 alkoxy.

[0044] In some embodiments, L is *-(pyridinylene)-C(::::O)N(H)-(Ci-6 alkylene)-(C2-6 alkenylene)-** or *-(pyridinylene)-C(=O)N(H)-(Ci-6 alkylene)-(C2-6 alkynylene)-**, wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or pyridinylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, or Ci-6 alkoxy.I S ' * h ** ll \ Z]_3 11 » '1-3

[0045] In some embodiments, L isuoru, wherein the pyridinylene is optionally substituted with one or more halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, or Ci-6 alkoxy.

[0046] In some embodiments, L is, wherein the pyridinylene is optionally substituted with one or more halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, or C1-6 alkoxy.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)** HN

[0047] In some embodiments, L isVariable T

[0048] In some embodiments, T is of Formula I-3-i

[0049] In some embodiments, T is of Formula I-3-i-a, I-3-i-b, I-3-i-c, I-3-i-d, I-3-i-e, I-3-i-f, or I-3-i-gAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0050] In some embodiments, G1is N.

[0051] In some embodiments, G1is C(RG1).

[0052] In some embodiments, G2is N.

[0053] In some embodiments, G2is C(RG2).

[0054] In some embodiments, G1is N and G2is C(RG2), or G1is C(RG!) and G2is N.

[0055] In some embodiments, G1is C(RG1) and G2is C(RG2).

[0056] In some embodiments,(i) G1is N and G2is C(RG2);(ii) G1is C(RG!) and G2is N; or(iii) G1is C(RG1) and G2is C(RG2).

[0057] In some embodiments, at least one RHis hydrogen.

[0058] In some embodiments, each RHis hydrogen.

[0059] In some embodiments, at least one RHis Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), z'-propyl (C3), zz-butyl (C4), / -butyl (C4), -butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0060] In some embodiments, each RHis C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), z-propyl (C3), w-butyl (C4), z-butyl ((':). -butyl (C4), / -butyl (C4), pentyl (C5), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0061] In some embodiments, each RHis methyl.

[0062] In some embodiments, each RHis independently hydrogen or methyl.

[0063] In some embodiments, RG1is hydrogen.

[0064] In some embodiments, RG1is halogen (e.g., F, Cl, Br, or I).

[0065] In some embodiments, RG1is -CN.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0066] In some embodiments, RG1is -NO2.

[0067] In some embodiments, RG1is -OH

[0068] In some embodiments, RG1is -NH2

[0069] In some embodiments, RG1is Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), w-butyl (C4), z'-butyl (C4), -butyl (C4), Z-butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0070] In some embodiments, RGlis Ci-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), Z-butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), - CN, -NO2, -OH, or -NH2.

[0071] In some embodiments, RG1is Ci-6 alkylamino (e.g, dimethylamino, diethylamino, di-w-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di-Z- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-wbutylamino, ethyl-z-butylamino, ethyl-Z-butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z'-butyl amino, propyl-s-butylamino, propyl-Z-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z'-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n-butylhexylamino, z'-butylhexylamino, s-butylhexylamino, z-butylhexylamino, or pentyl hexyl amino) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0072] In some embodiments, RG1is C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), - CN, -NO2, -OH, or -NH2.

[0073] In some embodiments, RG1is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0074] In some embodiments, RG1is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10) ) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0075] In some embodiments, RG1is 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) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0076] In some embodiments, RG1is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0077] In some embodiments, RG1is 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) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0078] In some embodiments, RG2is hydrogen.

[0079] In some embodiments, RG2is halogen (e.g., F, Cl, Br, or I).

[0080] In some embodiments, RG2is -CN.

[0081] In some embodiments, RG2is -NO2.

[0082] In some embodiments, RG2is -OH.

[0083] In some embodiments, RG2is -NH2.

[0084] In some embodiments, RG2is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), i-propyl (C3), w-butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Cs)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0085] In some embodiments, RG2is C1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), w-butoxy (C4), z-butoxy (C4), s-butoxy (C4), / -butoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), - CN, -NO2, -OH, or -NH2.

[0086] In some embodiments, RG2is C1-6 alkylamino (e.g., dimethylamino, diethylamino, di- zz-propylamino, di - / -propyl amino, di-w-butylamino, di - / -butyl ami no, di-s-butylamino, di- - butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl- / -propyl ami no, methyl-zz-butylamino, methyl - / -butylamino, methyl-x-butylamino, methyl- / -butylamino, methylpentylamino, methylhexylamino, ethyl-w-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl -x-butyl amino, ethyl-z-butylamino, ethyl - / -butylamino, ethylpentylamino, ethylhexylamino, propyl-n-butylamino, propyl-z-butylamino, propyl-x-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)butylamino, propyl- / -butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z'-butylpentylamino, s-butylpentylamino, / -butyl pentylamino, n-butyl hexyl ami no, z-butylhexylamino, -buty I hexyl amino, / -butyl hexyl amino, or pentylhexylamino) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0087] In some embodiments, RG2is C2-6 alkenyl (e.g, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (Cs), or hexenyl (C6)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), - CN, -NO2, -OH, or -NH2.

[0088] In some embodiments, RG2is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO, -OH, or -NH2.

[0089] In some embodiments, RG2is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (Cio)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -\H2

[0090] In some embodiments, RG2is 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) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NFI2

[0091] In some embodiments, RG2is Ce-ioaryl (e.g, phenyl or naphthyl) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0092] In some embodiments, R2is 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) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0093] In some embodiments, RG3is hydrogen.

[0094] In some embodiments, RG3is halogen (e.g, F, Cl, Br, or I).

[0095] In some embodiments, RGjis -CN.

[0096] In some embodiments, RG3is -NO2.

[0097] In some embodiments, RG3is -OH.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0098] In some embodiments, RGjis -NH2.

[0099] In some embodiments, RG3is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), i-propyl (C3), w-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0100] In some embodiments, RG3is C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z'-propoxy (C3), w-butoxy (C4), z-butoxy (C4), -butoxy (C4), -butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), - CN, -NO2, -OH, or -NH2.

[0101] In some embodiments, RG3is C1-6 alkylamino e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propyl amino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di- / - butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl- / -butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propyl amino, ethyl-z-propylamino, ethyl-w-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl- / -butylamino, ethylpentyl amino, ethyl hexyl amino, propyl-zz-butylamino, propyl -z-butyl ami no, propyl-s-butylamino, propyl- / -butylamino, propylpentylylamino, propylhexylamino, n-butylpentyl amino, z-butylpentyl amino, s-butylpentyl amino, / -butylpentyl amino, n-butylhexylamino, z-butylhexylamino, s-butylhexylamino, / -butylhexylamino, or pentylhexylamino) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0102] In some embodiments, RG3is C2-6 alkenyl (e.g, ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0103] In some embodiments, RG3is C2-6 alkynyl e.g, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0104] In some embodiments, RG3is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 f-indenyl (C9), decahydronaphthalenylAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)(Cio), or spiro[4.5]decanyl (Cio)) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -\H2

[0105] In some embodiments, R3is 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) optionally substituted with one or more oxo, halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0106] In some embodiments, RG3is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0107] In some embodiments, RG3is 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) optionally substituted with one or more oxo, halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0108] In some embodiments, RGl, RG2, and RG3are independently hydrogen, C1-6 alkyl, or 3-to 12-membered heterocyclyl, wherein the C1-6 alkyl or 3- to 12-membered heterocyclyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2.

[0109] In some embodiments, J1is N.

[0110] In some embodiments, R" is hydrogen.

[0111] In some embodiments, RJ1is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), / - propyl (C3), w-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0112] In some embodiments, RJ1and RK4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl (e.g, heterocyclyl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, or C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), z-propyl (C3), z'-propyl (C3), / z-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Co)).

[0113] In some embodiments, J1is N, and(i) RJ1is Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or(ii) RJ1and RK4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl.

[0114] In some embodiments, J1is C.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0115] In some embodiments, RJ1and RK4, together with the intervening atoms to which they are attached, form Co aryl optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0116] In some embodiments, RJ1and Rk4, together with the intervening atoms to which they are attached, form Ce aryl.

[0117] In some embodiments, J1is C, and RJ1and RK4, together with the intervening atoms to which they are attached, form Ce aryl.

[0118] In some embodiments, K2is N.

[0119] In some embodiments, K2is C(RK2).

[0120] In some embodiments, K3is N.

[0121] In some embodiments, K3is C(RK3).

[0122] In some embodiments, K2is N and K3is N.

[0123] In some embodiments, K2is N and K3is C(RK3), or K2is C(RK2) and K3is N.

[0124] In some embodiments, K2is C(RK2) and K3is C(RK3), wherein RK2is C1-6 alkyl optionally substituted with one or more halogen.

[0125] In some embodiments,(i) K2is N and K3is N;(ii) K2is N and K3is C(RK3);(iii) K2is C(RK2) and K3is N; or(iv) K2is C(RK2) and K3is C(RK3), wherein RK2is C1-6 alkyl optionally substituted with one or more halogen.

[0126] In some embodiments, RJ1and RK4, together with the intervening atoms to which they are attached, form 5-membered heteroaryl (e.g, heteroaryl comprising one 5-membered ring and I -3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, or C 1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), / -propyl (C3), / z-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)).

[0127] In some embodiments, RJ1and RK4, together with the intervening atoms to which they are attached, form 6-membered heteroaryl (e.g, heteroaryl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NFI2, or C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), z'-propyl (C3), / z-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Co)).

[0128] In some embodiments, RK1is hydrogen.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0129] In some embodiments, RK1is halogen (e.g., F, Cl, Br, or I).

[0130] In some embodiments, Rklis -CN.

[0131] In some embodiments, RK1is -NO2

[0132] In some embodiments, RK1is -OH.

[0133] In some embodiments, RK1is -NH2.

[0134] In some embodiments, RK1is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), i- propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0135] In some embodiments, RKIis Cue alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), Cbutoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0136] In some embodiments, RK1is C1-6 alkylamino (e.g., dimethyl amino, diethylamino, di-zz-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di-Z-butylamino, dipentylamino, dihexylamino, methyl ethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl- / - butylamino, methylpentylamino, methylhexylamino, ethyl -zz-propyl amino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl- / -butylamino, ethylpentyl amino, ethyl hexyl amino, propyl -zz-butyl amino, propyl-z'-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, zz-butylpentyl amino, z-butylpentylamino, s-butylpentyl amino, t-butylpentylamino, n-butylhexylamino, z'-butylhexylamino, -butylhexylamino, t-butylhexylamino, or pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0137] In some embodiments, RK1is C2-6 alkenyl (e.g, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0138] In some embodiments, RKIis C2-6 alkynyl (e.g, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0139] In some embodiments, RK1is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C$>), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2

[0140] In some embodiments, RK1is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0141] In some embodiments, RK1is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0142] In some embodiments, RK1is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0143] In some embodiments, RK2is hydrogen.

[0144] In some embodiments, RK2is halogen (e.g., F, Cl, Br, or I).

[0145] In some embodiments, RK2is -C.

[0146] In some embodiments, RK2is -NO2

[0147] In some embodiments, RK2is -OH.

[0148] In some embodiments, RK2is -NH2.

[0149] In some embodiments, RK2is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), / / -propyl (C3), i-propyl (C3), zz-butyl (C4), z-butyl (C4), -butyl (C4), r-butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0150] In some embodiments, RK2is Ci-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), / / -butoxy (C4), z-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0151] In some embodiments, RK2is Ci-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propyl amino, di-z-propylamino, di -w-butyl amino, di-z-butylamino, di -s-butyl amino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propyl amino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl- / - butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl-z-butylamino, ethylpentyl amino, ethyl hexyl amino, propyl -zz-butyl amino, propyl-z'-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylyl amino, propyl hexyl amino, n-butylpentylamino, z-butylpentylamino, wbutylpentylamino, r-butylpentylamino, n-butylhexylamino, / -butylhexylamino, s-butylhexylamino, 6-butylhexylamino, or pentylhexylamino) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0152] In some embodiments, RK2is C2-6 alkenyl (<?.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0153] In some embodiments, RK2is C2-6 alkynyl (e.g, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0154] In some embodiments, RK2is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4). cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0155] In some embodiments, RK2is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0156] In some embodiments, RK2is Ce-ioaryl (e.g, phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0157] In some embodiments, RK2is 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) optionally substituted with one or more halogen (e’.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0158] In some embodiments, RK3is hydrogen.

[0159] In some embodiments, RK3is halogen (e.g, F, Cl, Br, or I).

[0160] In some embodiments, RK3is -CN.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0161] In some embodiments, RK3is -NO2.

[0162] In some embodiments, Rk3is -OH

[0163] In some embodiments, Rk3is -NH2

[0164] In some embodiments, Rk3is Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), i- propyl (C3), w-butyl (C4), z'-butyl (C4), -butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0165] In some embodiments, RK3is Ci-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), Z-butoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0166] In some embodiments, Rk3is Ci-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl-Z-butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z'-butyl amino, propyl-s-butylamino, propyl-Z-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z'-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n-butylhexylamino, z'-butylhexylamino, s-butylhexylamino, z-butylhexylamino, or pentyl hexyl amino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0167] In some embodiments, Rk3is 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 (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0168] In some embodiments, Rk3is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0169] In some embodiments, RK3is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0170] In some embodiments, RKis 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0171] In some embodiments, RK3is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0172] In some embodiments, RK3is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0173] In some embodiments, RK4is hydrogen.

[0174] In some embodiments, RK4is halogen (e.g, F, Cl, Br, or I).

[0175] In some embodiments, RK4is -CN.

[0176] In some embodiments, RK4is -NO2.

[0177] In some embodiments, RK4is -OH.

[0178] In some embodiments, RK4is -NH2

[0179] In some embodiments, RK4is C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), w-propyl (C3), i-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Cs)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0180] In some embodiments, RK4is C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z'-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), Cbutoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0181] In some embodiments, Rk4is C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propylamino, di -z'-propyl amino, di-zz-butylamino, di -z-butyl ami no, di-s-butylamino, di-t- butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl- z -propyl ami no, methyl-zz-butylamino, methyl -z-butylami no, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-w-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl -s-butyl amino, ethyl-z-butylamino, ethyl - / -butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl- -Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)butylamino, propyl- / -butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z'-butylpentylamino, s-butylpentylamino, / -butyl pentylamino, n-butyl hexyl ami no, z-butylhexylamino, -buty I hexyl amino, / -butyl hexyl amino, or pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0182] In some embodiments, Rk4is C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (Cs), or hexenyl (C )) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0183] In some embodiments, RK4is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0184] In some embodiments, RK4is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0185] In some embodiments, Rk4is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0186] In some embodiments, RK4is Ce-io aryl (e.g, phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0187] In some embodiments, RK4is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0189] In some embodiments, T is or

[0190] In some embodiments, T is of Formula I-3-ii:

[0191] In some embodiments, T is of Formula I-3-ii-a or I-3-ii-bAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0192] In some embodiments, RQ1is hydrogen.

[0193] In some embodiments, RQ1is Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), n- propyl (C3), i-propyl (C3), / z-butyl (C4), z-butyl (C4), s-butyl (C4), Z-butyl (C4), pentyl (Cs), or hexyl (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0194] In some embodiments, RQ1is methyl.

[0195] In some embodiments, RQ2is hydrogen.

[0196] In some embodiments, RQ2is halogen (e.g., F, Cl, Br, or I).

[0197] In some embodiments, RQ2is -CN.

[0198] In some embodiments, RQ2is -NO2

[0199] In some embodiments, RQ2is -OH.

[0200] In some embodiments, RQ2is -NH2.

[0201] In some embodiments, RQ2is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), / / -propyl (C3), i-propyl (C3), / z-butyl (C4), z-butyl (C4), -butyl (C4), Z-butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0202] In some embodiments, RQ2is methyl.

[0203] In some embodiments, RQ2is C1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), / z-butoxy (C4), z-butoxy (C4), s-butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0204] In some embodiments, RQ2is C1-6 alkylamino (e.g., dimethyl amino, diethylamino, di- / z-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di-Z-butylamino, dipentyl amino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-t-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)butylamino, methylpentylamino, methylhexylamino, ethyl-w-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl -s-butyl amino, ethyl-z-butylamino, ethyl - / -butylamino, ethylpentyl amino, ethyl hexyl amino, propyl-zz-butylamino, propyl -z-butyl ami no, propyl-s-butylamino, propyl-A-butylamino, propylpentylylamino, propylhexylamino, n-butylpentyl amino, z-butylpentylamino, s-butylpentyl amino, 1-butylpentylamino, n-butylhexylamino, z-butylhexylamino, s-butylhexylamino, / -butylhexylamino, or pentylhexylamino) optionally substituted with one or more halogen e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0205] In some embodiments, RQ2is C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (C6)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0206] In some embodiments, RQ2is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0207] In some embodiments, RQ2is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0208] In some embodiments, RQ2is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0209] In some embodiments, RQ2is Ce-io aryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0210] In some embodiments, RQ2is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0211] In some embodiments, RQ3is hydrogen.

[0212] In some embodiments, RQ3is halogen (e.g., F, Cl, Br, or I).Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0213] In some embodiments, RQ3is -CN.

[0214] In some embodiments, RQ3is -NO2.

[0215] In some embodiments, RQ3is -OH.

[0216] In some embodiments, RQ3is -NH2.

[0217] In some embodiments, RQ3is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), i- propyl (C3), zz-butyl (C4), z-butyl (C4),.s-butyl (C4), Z-butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NHz.

[0218] In some embodiments, RQ3is C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), n-butoxy (C4), z-butoxy (C4), -butoxy (C4), Z-butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0219] In some embodiments, RQ3is Ci -6 alkylamino (e.g, dimethylamino, diethylamino, di-zz-propyl amino, di-z'-propylamino, di -zz-butyl amino, di-z'-butylamino, di - -butyl amino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z'-propyl amino, methyl-zz-butylamino, methyl-z'-butylamino, methyl -s-butylamino, methyl-t-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-propylamino, ethyl -zz-butyl amino, ethyl - -butyl ami no, ethyl-z-butylamino, ethyl-Z-butyl amino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl- -butylamino, propyl-Cbutylamino, propylpentylyl amino, propyl hexyl amino, n-butylpentylamino, z-butylpentylamino, s-butylpentylamino, z-butylpentylamino, n-butylhexyl amino, z-butylhexylamino, -butylhexylamino, Z-butylhexylamino, or pentylhexylamino) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0220] In some embodiments, RQ3is C2-6 alkenyl (e.g, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0221] In some embodiments, RQ3is C2-6 alkynyl (e.g, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (C6)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0222] In some embodiments, RQ3is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 177-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g., F, Ci, Br, or I), -CN, -NO2, -OH, or -NH2.

[0223] In some embodiments, RQ3is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0224] In some embodiments, RQ3is Cs-io aryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0225] In some embodiments, RQ3is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0226] In some embodiments, RQ2and RQ3are independently hydrogen and Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0227] In some embodiments, RQ2is methyl and RQ3is hydrogen.

[0228] In some embodiments, RQ1is methyl, RQ2is methyl, and RQ3is hydrogen,

[0229] In some embodiments, S1is CRS1.

[0230] In some embodiments, S1isN.

[0231] In some embodiments, S3is CRS3.

[0232] In some embodiments, S3is N,

[0233] In some embodiments, RS1is hydrogen.

[0234] In some embodiments, RS1is halogen (e.g., F, Cl, Br, or I),

[0235] In some embodiments, RS1is -CN.

[0236] In some embodiments, RS1is -Nth.

[0237] In some embodiments, RS1is -OH.

[0238] In some embodiments, RS1is -NH2.

[0239] In some embodiments, RS1is C 1-6 alkyl (e.g, methyl (Ci), ethyl (C2), w-propyl (C3), i-propyl (C3), w-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0240] In some embodiments, RS1is C1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), / -butoxy (C4), pentoxy (Cs),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0241] In some embodiments, RS1is C 1-6 alkyl amino (e.g., di methyl ami no, diethylamino, di-w-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di- / - butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl- / -butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl - / '-butyl amino, propyl-s-butylamino, propyl-z-butylamino, propylpentylylamino, propylhexylamino, zz-butylpentylamino, z'-butylpentylamino, s-butylpentylamino, t-butylpentylamino, n-butylhexylamino, z'-butylhexylamino, s-butylhexylamino, r-butylhexylamino, or pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0242] In some embodiments, RS1is C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0243] In some embodiments, RS1is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0244] In some embodiments, RS1is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (Cs), cyclohexyl (Co), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0245] In some embodiments, RS1is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0246] In some embodiments, RS1is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0247] In some embodiments, RS1is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0248] In some embodiments, RS2is hydrogen.

[0249] In some embodiments, RS2is halogen (e.g., F, Cl, Br, or I).

[0250] In some embodiments, RS2is -CN.

[0251] In some embodiments, RS2is -NO2.

[0252] In some embodiments, RS2is -OH.

[0253] In some embodiments, RS2is -NH2.

[0254] In some embodiments, RS2is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), i-propyl (C3), zz-butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0255] In some embodiments, RS2is C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), z?-butoxy (C4), / -butoxy (C4), s-butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0256] In some embodiments, RS2is C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-n-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di- / - butylamino, dipentylamino, dihexylamino, methylethyl amino, methyl-w-propylamino, methyl- / -propylamino, methyl-w-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl- / -butylamino, methylpentylamino, methylhexylamino, ethyl -zz-propyl ami no, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl- s-butyl amino, ethyl-z'-butylamino, ethyl- / -butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-x-butylamino, propyl- -butyl amino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z-butylpentylamino, s-butylpentylamino, / -butylpentylamino, zz- butyl hexyl ami no, z-butylhexylamino, -buty I hexyl amino, / -butyl hexyl amino, or pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0257] In some embodiments, RS2is C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (Cs),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)or hexenyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0258] In some embodiments, RS2is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0259] In some embodiments, RS2is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4). cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0260] In some embodiments, RS2is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0261] In some embodiments,RS2is

[0262] In some embodiments, RS2is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0263] In some embodiments, RS2is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0264] In some embodiments, RS3is hydrogen.

[0265] In some embodiments, RS3is halogen (e.g., F, Cl, Br, or I).

[0266] In some embodiments, RS3is -CN.

[0267] In some embodiments, RS3is -NO2.

[0268] In some embodiments, RS3is -OH.

[0269] In some embodiments, RS3is -NH2.

[0270] In some embodiments, RS3is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), / / -propyl (C3), i-propyl (C3), w-butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (Q), pentyl (Cs), or hexyl (Ce))Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0271] In some embodiments, RS3is C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), z?-butoxy (C4), z'-butoxy (C4), x-butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (Cs)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0272] In some embodiments, RS3is C 1-6 al yl amino (e.g, di methyl ami no, diethylamino, di-zz-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di- / -butylamino, dipentylamino, dihexylamino, methylethyl amino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl -w-propyl ami no, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl- / -butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-x-butylamino, propyl-Z-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, / -butylpentylamino, n- butyl hexyl ami no, z-butylhexylamino, -buty I hexyl amino, Z-butyl hexyl amino, or pentylhexylamino) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0273] In some embodiments, RS3is C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Cs)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0274] In some embodiments, RS3is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0275] In some embodiments, RS3is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0276] In some embodiments, RS3is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0277] In some embodiments, RS3is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0278] In some embodiments, RS3is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NFh. In some embodiments, RS1and RS3are independently hydrogen, and RS2is 3- to 12-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2

[0279] In some embodiments, M1is N.

[0280] In some embodiments, RM1is hydrogen.

[0281] In some embodiments, RM1is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), i- propyl (C3), n-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0282] In some embodiments, RM1and RT4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl (e.g, heterocyclyl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, or C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), w-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (C ).

[0283] In some embodiments, M1isN, and(i) RM1is C1-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or(ii) RM1and RT4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, - NH>, or C 1-6 alkyl.

[0284] In some embodiments, M1is C.

[0285] In some embodiments, RM1and RT4, together with the intervening atoms to which they are attached, form C6 aryl optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0286] In some embodiments, T2is N.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0287] In some embodiments, T2is C(RT2).

[0288] In some embodiments, T3is N.

[0289] In some embodiments, T3is C(RT3).

[0290] In some embodiments, T2is N and T3is N.

[0291] In some embodiments, T2is N and T3is C(RT3), or T2is C(RT2) and T3is N.

[0292] In some embodiments, T2is C(RT2) and T3is C(RT3), wherein RT2is halogen or Ci-6 alkyl optionally substituted with one or more halogen.

[0293] In some embodiments,(i) T2is N and T3is N;(ii) T2is N and T3is C(RT3);(iii) T2is C(RT2) and T3is N; or(iv) T2is C(RT2) and T3is C(RT3), wherein RT2is halogen or C1-6 alkyl optionally substituted with one or more halogen.

[0294] In some embodiments, RM1and RT4, together with the intervening atoms to which they are attached, form 5-membered heteroaryl (e.g, heteroaryl comprising one 5-membered ring and 1 -3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, or Ci-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), / '-propyl (C3), n-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Cs)).

[0295] In some embodiments, RM1and RT4, together with the intervening atoms to which they are attached, form 6-membered heteroaryl (e.g, heteroaryl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, or C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), / -propyl (C3), / / -butyl (C4), / -butyl (C4), s-butyl (C4), t-butyl (C4), pentyl (Cs), or hexyl (Cs)).

[0296] In some embodiments, RT1is hydrogen.

[0297] In some embodiments, RT1is halogen (e.g, F, Cl, Br, or I).

[0298] In some embodiments, RT1is -CN.

[0299] In some embodiments, RT1is -NO2.

[0300] In some embodiments, RT1is -OH.

[0301] In some embodiments, RT1is -NH2.

[0302] In some embodiments, RT1is C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), w-propyl (C3), / -propyl (C3), / -butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Cs))Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0303] In some embodiments, RT1is C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), z?-butoxy (C4), z'-butoxy (C4), s-butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0304] In some embodiments, RT1is C1-6 alkylamino (e.g., di methyl ami no, diethylamino, di-n-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di- / -butylamino, dipentylamino, dihexylamino, methylethyl amino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl -w-propyl ami no, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl- / -butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-s-butylamino, propyl-r-butyl amino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z-butylpentylamino, s-butylpentylamino, / -butylpentylamino, zz- butylhexylamino, z-butylhexylamino, -buty I hexyl amino, / -butyl hexyl amino, or pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0305] In some embodiments, RT1is Cz-e alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0306] In some embodiments, RT1is C2-6 alkynyl (e.g, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0307] In some embodiments, RT1is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C ), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0308] In some embodiments, RT1is 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) optionally substituted with one or more halogen (e.g, F, Ci, Br, or I), -CN, -NO2, -OH, or - NH2.

[0309] In some embodiments, RT1is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0310] In some embodiments, RT1is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0311] In some embodiments, RT2is hydrogen.

[0312] In some embodiments, RT2is halogen (e.g., F, Cl, Br, or I).

[0313] In some embodiments, RT2is -CN.

[0314] In some embodiments, RT2is -NO2

[0315] In some embodiments, RT2is -OH.

[0316] In some embodiments, RT2is -NH2.

[0317] In some embodiments, RT2is C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), / / -propyl (C3), / '-propyl (C3), / / -butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0318] In some embodiments, RT2is C 1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), / / -butoxy (C4), / -butoxy (C4), -butoxy (C4), -butoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0319] In some embodiments, RT2is C1-6 alkylamino e.g., dimethylamino, diethylamino, di- / z-propylamino, di - / '-propyl amino, di - / / -butyl ami no, di - / '-butyl ami no, di-s-butylamino, di- / - butylamino, dipentylamino, dihexylamino, methylethylamino, methyl- / z-propylamino, methyl-z'-propylamino, methyl-w-butylamino, methyl-z'-butylamino, methyl-s-butylamino, methyl- -butylamino, methylpentylamino, methylhexylamino, ethyl- / / -propylamino, ethyl-z-propylamino, ethyl-w-butylamino, ethyl- s-butyl amino, ethyl-z'-butylamino, ethyl- / -butylamino, ethylpentylamino, ethylhexylamino, propyl- / / -butylamino, propyl-z-butylamino, propyl-x-butylamino, propyl- / -butyl amino, propylpentylylamino, propylhexylamino, n-butylpentylamino, / '-butylpentylamino, s-butylpentylamino, / -butylpentylamino, / / -butyl hexyl ami no, / -butylhexylamino, s-butyl hexyl amino, / -butyl hexyl amino, orAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0320] In some embodiments, RT2is C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0321] In some embodiments, RT2is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (C6)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0322] In some embodiments, RT2is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0323] In some embodiments, RT2is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0324] In some embodiments, RT2is C6-10 aryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0325] In some embodiments, RT2is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0326] In some embodiments, RT3is hydrogen.

[0327] In some embodiments, RT3is halogen (e.g., F, Cl, Br, or I).

[0328] In some embodiments, RT3is -CN.

[0329] In some embodiments, RT3is -NO2.

[0330] In some embodiments, RT3is -OH

[0331] In some embodiments, RT3is -NH2.

[0332] In some embodiments, RT3is 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))Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0333] In some embodiments, Rr3is C 1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), z?-butoxy (C4), z'-butoxy (C4), x-butoxy (C4), / -butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0334] In some embodiments, RT3is C1-6 alkylamino (e.g., di methyl ami no, diethylamino, di-zz-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di- / -butylamino, dipentylamino, dihexylamino, methylethyl amino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl -w-propyl ami no, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl- / -butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-x-butylamino, propyl-Z-butylamino, propylpentylylamino, propylhexylamino, n- butylpentylamino, z-butylpentylamino, s-butylpentylamino, / -butylpentylamino, n- butyl hexyl ami no, z-butylhexylamino, -buty I hexyl amino, Z-butyl hexyl amino, or pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0335] In some embodiments, RT3is C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (C )) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0336] In some embodiments, R’3is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0337] In some embodiments, R13is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0338] In some embodiments, RTJis 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) optionally substituted with one or more halogen (e.g, F, Ci, Br, or I), -CN, -NO2, -OH, or - NH2.

[0339] In some embodiments, R° is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0340] In some embodiments, RT3is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0341] In some embodiments, RT4is hydrogen.

[0342] In some embodiments, RT4is halogen (e.g., F, Cl, Br, or I).

[0343] In some embodiments, R14is -CN.

[0344] In some embodiments, RT4is -NO2

[0345] In some embodiments, R14is -OH.

[0346] In some embodiments, RT4is -NH2.

[0347] In some embodiments, R14is C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), / / -propyl (C3), / '-propyl (C3), / / -butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0348] In some embodiments, RT4is C 1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), / / -butoxy (C4), / -butoxy (C4), -butoxy (C4), -butoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0349] In some embodiments, RT4is C1-6 alkylamino e.g., dimethylamino, diethylamino, di- / z-propylamino, di - / '-propyl amino, di - / / -butyl ami no, di - / '-butyl ami no, di-s-butylamino, di- / - butylamino, dipentylamino, dihexylamino, methylethylamino, methyl- / z-propylamino, methyl-z'-propylamino, methyl-w-butylamino, methyl-z'-butylamino, methyl-s-butylamino, methyl- -butylamino, methylpentylamino, methylhexylamino, ethyl- / / -propylamino, ethyl-z-propylamino, ethyl-w-butylamino, ethyl- s-butyl amino, ethyl-z'-butylamino, ethyl- / -butylamino, ethylpentylamino, ethylhexylamino, propyl- / / -butylamino, propyl-z-butylamino, propyl-x-butylamino, propyl- / -butyl amino, propylpentylylamino, propylhexylamino, n-butylpentylamino, / '-butylpentylamino, s-butylpentylamino, / -butylpentylamino, / / -butyl hexyl ami no, / -butylhexylamino, s-butyl hexyl amino, / -butyl hexyl amino, orAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0350] In some embodiments, R14is C2-6 alkenyl (e.g., ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0351] In some embodiments, R14is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (C6)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0352] In some embodiments, RT4is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0353] In some embodiments, RT4is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0354] In some embodiments, RI4is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0355] In some embodiments, RT4is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0356] In some embodiments, TisAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0357] In some embodiments, T is!

[0358] In some embodiments, T is of Formula I-3-iii:

[0359] In some embodiments, T is of Formula I-3-iii-a:

[0360] In some embodiments, at least one RNis hydrogen.

[0361] In some embodiments, each RNis hydrogen.

[0362] In some embodiments, at least one RNis halogen (e.g., F, Cl, Br, or I).Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0363] In some embodiments, at least one RNis -CN.

[0364] In some embodiments, at least one RNis -NO2.

[0365] In some embodiments, at least one RNis -OH.

[0366] In some embodiments, at least one RNis -NH2.

[0367] In some embodiments, at least one RNis C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), n-propyl (C3), / '-propyl (C3), rz-butyl (C4), z-butyl (C4), -butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0368] In some embodiments, RP3is hydrogen.

[0369] In some embodiments, RP3is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), i-propyl (C3), w-butyl (C4), / -butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Co)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0370] In some embodiments, RP3is ethyl.

[0371] In some embodiments, RP3is C2-6 alkenyl e.g, ethenyl (C2), 1-propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (C5), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0372] In some embodiments, RP3is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0373] In some embodiments, RP3is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0374] In some embodiments, RP3is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)fxo

[0375] In some embodiments, RP3is.

[0376] In some embodiments, RP3is C6-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0377] In some embodiments, RP3is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0378] In some embodiments, RP3is C1-6 alkyl or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl or 3- to 12-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0379] In some embodiments, RP3is ethyl or.

[0380] In some embodiments, R4is C1-6 alkyl (e.g, methyl (Ci), ethyl (C2), zz-propyl (C3), i-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Co)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0381] In some embodiments, R4is methyl.

[0382] In some embodiments, R4is C1-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), / -propoxy (C3), n-butoxy (C4), / -butoxy (C4), s-butoxy (C4), / -butoxy (C4), pentoxy (C5), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0383] In some embodiments, R4is C1-6 alkylamino (e.g, dimethylamino, diethylamino, di-zz-propylamino, di- / -propylamino, di -zz-butyl ami no, di - / -butyl ami no, di-s-butylamino, di- / - butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl- / -propylamino, methyl-zz-butylamino, methyl - / -butylamino, methyl-s-butylamino, methyl- / -butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl -s-butyl amino, ethyl-z-butylamino, ethyl - / -butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z'-butylamino, propyl- -butylamino, propyl- / -butylamino, propylpentylylamino, propylhexylamino, n-butylpentyl amino, / -butylpentylamino, s-butylpentyl amino, / -butylpentylamino, n-butylhexylamino, z-butylhexylamino, s-butylhexylamino, / -butylhexylamino, orAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0384] In some embodiments, R4is methyl; each RNis independently hydrogen; and RP3is Ci-6 alkyl or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl or 3- to 12-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0385] In some embodiments, U1is N.

[0386] In some embodiments, RU1is hydrogen.

[0387] In some embodiments, RL!is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), i-propyl (C3), w-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NIH. In some embodiments, U1is N, and RU1and Rv4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, -NHz, or Ci-6 alkyl.

[0388] In some embodiments, Rbland RV4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl (e.g., heterocyclyl comprising one 5- or 6- membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, -NHz, or Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), w-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)).

[0389] In some embodiments, U1is C.

[0390] In some embodiments, RL 1and RV4, together with the intervening atoms to which they are attached, form Ce aryl optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0391] In some embodiments, U1is C, and RL 1and RV4, together with the intervening atoms to which they are attached, form Ce aryl.

[0392] In some embodiments, V2is N.

[0393] In some embodiments, V2is C(RV2).

[0394] In some embodiments, V3is N.

[0395] In some embodiments, V3is C(Rv3).

[0396] In some embodiments, V2is N and V3is N.

[0397] In some embodiments, V2is N and V3is C(RV3), or V2is C(R2) and V3is N.

[0398] In some embodiments, V2is C(RV2) and V3is C(RV3), wherein R2is Ci-e alkyl optionally substituted with one or more halogen.

[0399] In some embodiments,Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)(i) V2is N and V3is N;(ii) V2is N and V3is C(RV3);(iii) V2is C(RV2) and V3is N;(ivj V2is C(R3'2) and VJis C(R3), wherein R'2is Ci-6 alkyl optionally substituted with one or more halogen.

[0400] In some embodiments, RU1and R3'4, together with the intervening atoms to which they are attached, form 5-membered heteroaryl (e.g., heteroaryl comprising one 5-membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, or C 1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), z-propyl (C3), zz-butyl (C4), z-butyl (C4), -butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Co)).

[0401] In some embodiments, RU1and RV4, together with the intervening atoms to which they are attached, form 6-membered heteroaryl (e.g., heteroaryl comprising one 6-membered ring and 1-3 heteroatoms selected from N, O, and S) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, -NH2, or C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), z-propyl (C3), zz-butyl (Ch), z-butyl (C4), s-butyl (C4), Z-butyl (C4), pentyl (C5), or hexyl (Cs)).

[0402] In some embodiments, R3 1is hydrogen.

[0403] In some embodiments, R3'1is halogen (e.g., F, Cl, Br, or I).

[0404] In some embodiments, RV1is -CN.

[0405] In some embodiments, R1is -NO2.

[0406] In some embodiments, R3 1is -OH.

[0407] In some embodiments, R3'1is -NH2.

[0408] In some embodiments, R3'1is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), i-propyl (C3), zz-butyl (C4), z-butyl (C4), -butyl (C4), Z-butyl (C4), pentyl (Cs), or hexyl (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0409] In some embodiments, R31is C1-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), -butoxy (C4), / -butoxy (C4), pentoxy (C5), or hexoxy (C6)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0410] In some embodiments, RV1is C1-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propyl amino, di -zz-butyl ami no, di -z-butyl ami no, di-s-butylamino, di- / -butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)z-propylamino, methyl- z-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-z-butylamino, methylpentylamino, methylhexylamino, ethyl -zz-propyl ami no, ethyl-z-propylamino, ethyl -zz-butyl ami no, ethyl- y-butyl amino, ethyl-z'-butylamino, ethyl-t-butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z-butylamino, propyl-x-butylamino, propyl-Z-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z-butylpentylamino, s-butylpentylamino, / -butylpentylamino, zz-butyl hexyl ami no, z-butylhexylamino, -buty I hexyl amino, Z-butyl hexyl amino, or pentylhexylamino) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0411] In some embodiments, RV1is C2-6 alkenyl (e.g, ethenyl (C2), 1 -propenyl (C3), 2- propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Cs)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0412] In some embodiments, Rvlis C2-6 alkynyl e., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0413] In some embodiments, RV1is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0414] In some embodiments, RV1is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NHz.

[0415] In some embodiments, R1is Ce-ioaryl (e.g, phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0416] In some embodiments, RV1is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0417] In some embodiments, RV2is hydrogen.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0418] In some embodiments, R^2is halogen (e.g, F, Cl, Br, or I).

[0419] In some embodiments, RV2is -CN.

[0420] In some embodiments, RV2is -NO2

[0421] In some embodiments, R2is -OH.

[0422] In some embodiments, R2is -NH2.

[0423] In some embodiments, R2is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), n-propyl (C3), i- propyl (C3), zz-butyl (C4), z-butyl (C4), s-butyl (C4), / -butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0424] In some embodiments, RV2is Cue alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), Cbutoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0425] In some embodiments, RV2is C1-6 alkylamino (e.g., dimethyl amino, diethylamino, di-zz-propylamino, di-z-propylamino, di-zz-butylamino, di-z-butylamino, di-s-butylamino, di-Z-butylamino, dipentylamino, dihexylamino, methyl ethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl- / - butylamino, methylpentylamino, methylhexylamino, ethyl -zz-propyl amino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl- / -butylamino, ethylpentyl amino, ethyl hexyl amino, propyl -zz-butyl amino, propyl-z'-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylylamino, propylhexylamino, zz-butylpentyl amino, z-butylpentylamino, s-butylpentyl amino, t-butylpentylamino, n-butylhexylamino, z'-butylhexylamino, -butylhexylamino, t-butylhexylamino, or pentylhexylamino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0426] In some embodiments, R'2is C2-6 alkenyl (e.g, ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0427] In some embodiments, RV2is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0428] In some embodiments, RV2is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C$>), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2

[0429] In some embodiments, RV2is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0430] In some embodiments, R2is Ce-ioaryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0431] In some embodiments, RV2is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0432] In some embodiments, RV3is hydrogen.

[0433] In some embodiments, R3is halogen (e.g., F, Cl, Br, or I).

[0434] In some embodiments, R3is -C.

[0435] In some embodiments, R^Jis -NO2

[0436] In some embodiments, RV3is -OH.

[0437] In some embodiments, R3is -NH2.

[0438] In some embodiments, RV3is C1-6 alkyl (e.g., methyl (Ci), ethyl (C2), rz-propyl (C3), i-propyl (C3), zz-butyl (C4), z-butyl (C4), -butyl (C4), r-butyl (C4), pentyl (Cs), or hexyl (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0439] In some embodiments, RV3is Ci-6 alkoxy (e.g., methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), t-butoxy (C4), pentoxy (Cs), or hexoxy (Ce)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0440] In some embodiments, RV3is Ci-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propyl amino, di-z-propylamino, di -zz-butyl amino, di-z-butylamino, di -s-butyl amino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propyl amino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl- / - butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)propylamino, ethyl-n-butylamino, ethyl-s-butylamino, ethyl-z-butylamino, ethyl-z-butylamino, ethylpentyl amino, ethyl hexyl amino, propyl -zz-butyl amino, propyl-z'-butylamino, propyl-s-butylamino, propyl-t-butylamino, propylpentylyl amino, propyl hexyl amino, n-butylpentylamino, z-butylpentylamino, s-butylpentylamino, r-butylpentylamino, n-butylhexylamino, / -butylhexylamino, s-butylhexylamino, 6-butylhexylamino, or pentylhexylamino) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0441] In some embodiments, RV3is C2-6 alkenyl (<?.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0442] In some embodiments, R3is C2-6 alkynyl (e.g, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (Cs), or hexynyl (Ce)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0443] In some embodiments, RV3is C3-12 carbocyclyl (e.g, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4). cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0444] In some embodiments, RV3is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0445] In some embodiments, RV3is Ce-ioaryl (e.g, phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0446] In some embodiments, RV3is 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) optionally substituted with one or more halogen (e’.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0447] In some embodiments, R3'4is hydrogen.

[0448] In some embodiments, RV4is halogen (e.g, F, Cl, Br, or I).

[0449] In some embodiments, RV4is -CN.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0450] In some embodiments, R^4is -NO2.

[0451] In some embodiments, RV4is -OH

[0452] In some embodiments, RV4is -NH2

[0453] In some embodiments, RV4is Ci-6 alkyl (e.g., methyl (Ci), ethyl (C2), zz-propyl (C3), z-propyl (C3), w-butyl (C4), z'-butyl (C4), -butyl (C4), Z-butyl (C4), pentyl (Cs), or hexyl (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0454] In some embodiments, RV4is Ci-6 alkoxy (e.g, methoxy (Ci), ethoxy (C2), propoxy (C3), z-propoxy (C3), zz-butoxy (C4), z-butoxy (C4), s-butoxy (C4), Z-butoxy (C4), pentoxy (Cs), or hexoxy (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, - NO2, -OH, or -NH2.

[0455] In some embodiments, RV4is Ci-6 alkylamino (e.g., dimethylamino, diethylamino, di-zz-propylamino, di-z-propylamino, di-w-butylamino, di-z-butylamino, di-s-butylamino, di-Z-butylamino, dipentylamino, dihexylamino, methylethylamino, methyl-zz-propylamino, methyl-z-propylamino, methyl-zz-butylamino, methyl-z-butylamino, methyl-s-butylamino, methyl-Z-butylamino, methylpentylamino, methylhexylamino, ethyl-zz-propylamino, ethyl-z-propylamino, ethyl-zz-butylamino, ethyl-wbutylamino, ethyl-z-butylamino, ethyl-Z-butylamino, ethylpentylamino, ethylhexylamino, propyl-zz-butylamino, propyl-z'-butyl amino, propyl-s-butylamino, propyl-Z-butylamino, propylpentylylamino, propylhexylamino, n-butylpentylamino, z'-butylpentylamino, s-butylpentylamino, Z-butylpentylamino, n-butylhexylamino, z'-butylhexylamino, s-butylhexylamino, z-butylhexylamino, or pentyl hexyl amino) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0456] In some embodiments, RV4is C2-6 alkenyl (e.g., ethenyl (C2), 1 -propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), pentenyl (Cs), pentadienyl (Cs), or hexenyl (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0457] In some embodiments, RV4is C2-6 alkynyl (e.g., ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), pentynyl (C5), or hexynyl (Cs)) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0458] In some embodiments, R4is C3-12 carbocyclyl (e.g., cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs),Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1 / 7-indenyl (C9), decahydronaphthalenyl (C10), or spiro[4.5]decanyl (C10)) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0459] In some embodiments, RV4is 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) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or - NH2.

[0460] In some embodiments, R?4is Ce-io aryl (e.g., phenyl or naphthyl) optionally substituted with one or more halogen (e.g, F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.

[0461] In some embodiments, RV4is 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) optionally substituted with one or more halogen (e.g., F, Cl, Br, or I), -CN, -NO2, -OH, or -NH2.RP3RP3

[0462] In some embodiments, T is or

[0463] In some embodiments, T is or

[0464] In some embodiments, T isAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0088] Embodiments of the variables in any of the Formulae described herein, e.g., Formulae I, 1-1, 1-2, 1-3-i, I-3-ii, and I-3-iii, 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 moi eties described for any of the variables, as applicable, with any moi eties described for any of the remaining variables, is also contemplated.

[0089] Without wishing to be limited by this statement, while various options for variables are described herein, it is understood that the present disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options.

[0090] When a range of values is listed, each discrete value and sub-range within the range are also contemplated. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, Cs, Ce, Ci -6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0091] In some embodiments, the compound is selected from the compounds in Tables 1-3 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0092] In some embodiments, the compound is selected from the compounds in Tables 1-3 and pharmaceutically acceptable salts thereof.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0093] In some embodiments, the compound is selected from the compounds in Tables 1-3.

[0094] In some embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0095] In some embodiments, the compound is selected from the compounds in Table 1 and pharmaceutically acceptable salts thereof.

[0096] In some embodiments, the compound is selected from the compounds in Table 1.

[0097] In some embodiments, the compound is selected from the compounds in Table 2 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0098] In some embodiments, the compound is selected from the compounds in Table 2 and pharmaceutically acceptable salts thereof.

[0099] In some embodiments, the compound is selected from the compounds in Table 2.

[0100] In some embodiments, the compound is selected from the compounds in Table 3 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0101] In some embodiments, the compound is selected from the compounds in Table 3 and pharmaceutically acceptable salts thereof.

[0102] In some embodiments, the compound is selected from the compounds in Table 3.Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)Table 1CompoundChemical Structure Chemical NameNo.A-(3-(2',6'-Dioxo-2,3-dihydrospiro[indene-I,3'- piperidin] -6-yl)prop-2-yn- 1 -yl) -5 -(8 -(7-i sopropyl - Al 1,3-dimethyI-2-oxo-2,3-dihydro-lH- 1 \ benzo[<7]imidazol-5-yl)isoquinolin-3- O / yl)picolinamide1 < t / •,.< ' ' i i< ■ / J- A'-(3-(5-Fluoro-2',6'-dioxo-2,3-dihydrospiro[inder!e- zz l,3'-piperidin]-6-yl)prop-2-yn-l-yl)-5-(8-(7- A2 isopropyl-l,3-dimethyl-2-oxo-2,3-dihydro-lH- benzo[( / Jimidazol-5-yl)isoquinolin-3- \V Tl 5 yl)picolinamide. V0\ A-'1M J^4 0- —." O T_ \ IZ > / i / Qz / •—p wz\Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.0NACJ A-(3-(2',6'-Dioxo-6,7- dihydrospiro[cyclopenta[ / ?]pyridine-5,3'-piperidinj- A3 3 -yl)prop-2-yn- 1 -yl)-5 -(8-(7-isopropyl- 1,3 - dimethyl-2-oxo-2;3-dihydro-I7Z-benzo[< / |imidazoI- 5-yl)isoquinolin-3-yl)picolinamide■, NH0, VX(1S’*)-A-(3-(2',6'-Dioxo-2,3-dihydrospiro[indene- l,3'-piperidin]-6-yl)prop-2-yn-l-yl)-5-(8-(7- A4 isopropyl-l,3-dimethyl-2-oxo-2,3-dihydro-177- benzo[<7]imidazol-5-yl)isoquinoIin-3- ra ro yl)picolinamideNH.NA / NA y NHo J0o° / / A-(3-(2',6'-Dioxo-2,3-dihydrospiro[indene-l,3’- piperidin]-6-yl)prop-2-yn-l-yl)-5-(5-((7-isopropyl- A5 Y A / Y CTXYHTT A 1,3 -dimethyl-2 -oxo-2, 3 -dihydro- IH- benzo[<7]imidazol-5-yl)(methyl)amino)pyrimidin-2- °AXJ.NU yl)pi col inamide / 1Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.. A i..A'r-(3-(2,6-Dioxo-6',7'-dihydro-5' / f-spiro[piperidine- 3,4'-pyrazolo [ 1,5 -«]py ridin] -2'-yl)prop-2-yn- 1 -yl)- A6 5-(8-(7-isopropyl-l,3-dimethyl-2-oxo-2,3-dihydro- 1 H-benzo [d\ imidazol -5 -yl )isoquinolin-3 - UA ^.Nn / -A yl)pi col inamideJ b01 L N._A T (7?*)-A-(3-(2',6'-Dioxo-2,3-dihydrospiro[indene- l,3'-piperidin]-6-yl)prop-2-yn-l-yl)-5-(8-(7- A7 \ / ANisopropyl- 1,3 -dimethyl-2-oxo-2, 3 -dihydro- IH- benzo[J]imidazol-5-yl)isoquinolin-3- yl)picolinamide" s. A %^ 6 '~^NH00 / / JV-(3-(2',6'-Dioxo-2,3-dihydrospiro[indene-l,3'- \ / ZNXAM / \ / SIH piperidin]-6-yl)prop-2-yn-l-yl)-5-(5-((7-isopropyl- AS 1,3 -dimethyl -2 -oxo-2, 3 -dihydro- 1 H- A rNvTAHbenzo[< / |imidazol-5-yl)(niethyl)amino)pyrimidin-2- °U W bJL / yl)-3-methylpicolinamide1Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.0yv— -N \ In. A’-(3-(2',6'-Dioxo-3,4-dihydro-22 / - spiro [naphthalene- 1,3 '-piperidin] - 7-yl)prop-2-yn- 1 - A9 yl)-5-(8-(7-isopropyl-l,3-dimethyl-2-oxo-2,3- ox i., i „ H oc dihydro-177-benzo[cf|imidazol-5-yI)isoquinolin-3-,0 yl)pi col inamide UHIoXN-Z5-(8-(l, 3-Dimethyl-2 -oxo-2, 3 -dihydro- 177- benzo[dJimidazol-5-yl)isoquinolin-3-yl)-jV-(3-(2',6'- AW z Z Zr, dioxo-2, 3 -dihydrospiro [indene- 1,3 '-piperidin] -6- UkA / ^N L L? z° yI)prop-2-yn- 1 -yl)picolinamide■* t ".oAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.A-(3-(2',6'-Dioxo-22 / -spiro[benzofuran-3,3'- piperidin]-5-yl)prop-2-yn-l-yl)-5-(8-(7-isopropyl- All 1,3 -dimethyl-2 -oxo-2, 3 -dihydro- IH- benzo[r / ]imidazol-5-yl)isoquinolin-3- yl)pi col inamideA° / =0X Xbk- V J '- w A-(3-(2',6'-Dioxospiro[indene-l,3'-piperidin]-6- yl)prop-2-yn- 1 -yl)-5 -(8-(7-isopropyl- 1,3 -dimethyl - A13 kJZI 2-oxo-2,3-dihydro-l / / -benzo[afjimidazoi-5-nh( xxx° yl)isoquinolin-3-yl)picolinamider X 04 '. O K i xA io IAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo.Ow,A-(3 -(2',6’-Dioxo-6,7-dihydro-5H- spiro [benzofuran-4,3 '-piperidin ] -2-yl)prop-2-yn- 1 - A14 yl)-5-(8-(7-isopropyl-l,3-dimethyl-2-oxo-2,3- f Y? Y dihydro- IH-benzo [d\ imidazol-5 -yl)isoquinolm -3 - yl)picolinamideo_ M Y-Y" Iv / \V / V 1[! JoV-NH Ar-(3-(2',6'-Dioxo-6,7-dihydro-5H- spiro [benzo [d]thiophene-4, 3 '-piperidin] -2 -yl)prop- A15 I Q ° 2-yn- 1 -yl)-5-(8-(7-isopropyl- l,3-dimethyl-2-oxo- 2,3-dihydro-lH-benzo[ri]imidazol-5-yl)isoquinolin- CC ' Y li. YlH YJ 3 -yl)pi col inamideAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.0NA5-(8-(7-Isopropyi-l,3-dimethyl-2-oxo-2,3-dihydro- 17 / -benzo[« / ]imidazol-5-yl)isoquinoiin-3-yl)-jV-(3- A16(3-methyl-2',6'-dioxo-2,3-dihydrospiro[inder!e-l,3'- piperidin]-6-yl)prop-2-yn-l-yl)picoiinamide \ \ _ / bX XlM r '° > Z ■—A’-(3-(6-Fluoro-2',6'-dioxo-2Br-spiro[benzofuran- 3,3'-piperidin]-5"yl)prop-2-yn-l-yl)-5-(8-(7- Al 7 ^ o= ZI isopropyl-l,3-dimethyl-2-oxo-2,3-dihydro-17 / - / benzo[<7]imidazol-5-yl)isoquinoIin-3- yl)picolinamide\ X ~nr0>0w.;0JJ 5 -(5 -(( 1,3 -Dimethyl -2 -oxo-7-(tetrahy dro-2 / f-pyran- \ - X X° / X. c i XH 4-yl)-2,3-dihydro-l / / -benzo|t / ]imidazol-5- A18 ^-X, / NXXkHxxx o I > yl)(metliyl)amino)pyrimidin-2-yl)-A-(3-(2',6!- o=KXN- T'X^ / 1XN / X If^ 1.NLv dioxospiro[indene-l,3'-piperidin]-6-yl)prop-2-yn-l- yl)-3-methylpicolinamide / 1Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.0A’-(3 -( 2',6'-Di oxo-2 H-spi ro [fiiro [2,3-c]pyridine- 3,3'-piperidin]-5-yl)prop-2-yn-l-yl)-5-(8-(7- A19 isopropy 1-1,3 -dimethyl-2-oxo-2.3 -dihydro- 1 / 7- f lTZ N^V°- benzo[t / ]imidazol-5-yl)isoquinolin-3- yl)pi col inamideb5-(5-(l,3-Dimethyl-2-oxo-2,3-dihydro-l / 7- benzo[J]imidazol-5-yl)-6,7-dihydro-5 / f- A20 pyrimido[4,5-d][l,4]oxazin-2-yI)-7V-(3-(2',6'- dioxospiro[indene-l,3'-piperidin]-6-yl)prop-2-yn-l- yl)picolinamideo^ / \OQ.:z>Q2TZ!\ / / 1 AVK 2r Cz. _= V \ / \\ V_ / _ / z zAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.0i / Vv1'o A-(3-(2',6'-Dioxo-277-spiro[furo[2,3- / ?]pyridine- 3,3'-piperidin]-5-yl)prop-2-yn-l-yi)-5-(8-(7- All N o isopropy 1-1,3 -dimethyl-2-oxo-2.3 -dihydro- 1 / 7- benzo[t / ]imidazol-5-yl)isoquinolin-3- U-A-N yl)pi col inamideLiHN / \ NHo0A-(3-(2',6'-Dioxo-2 / / -spiro[furo[3,2-Z> Jpyridine- 3,3'-piperidin]-5-yl)prop-2-yn-l-yl)-5-(8-(7- A22 isopropyl-l,3-dimethyl-2-oxo-2,3-dihydro-l / 7- benzo[< / ]imidazol-5-yl)isoquinoIin-3- x x? / ° yl)picolinamideujB. ":>0Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo.0NA5-(8-(7-Isopropyi-l,3-dimethyl-2-oxo-2,3-dihydro- 17 / -benzo[«7]imidazol-5-yl)isoquinoiin-3-yl)-jV-(3- A23(3 -methyl-2',6'-dioxospiro[inder!e- 1,3 '-piperidin] -6- yi)prop-2-yn- 1 -yl)picolinamide( kA-(3-(2',6'-Dioxo-2,3-dihydrospiro[indene-l,3'- piperidin]-6-yl)prop"2-yn-l"yl)-5-(5-(7-isopropyl" A24 1,3 -dim ethyl -2 -oxo-2, 3 -dihydro- 177- benzo[r / ]imidazoI-5-yl)-6,7-dihydro-5Z7- pyrimido [4,5 -b] [ 1,4] oxazin -2 -yl )picolinamide Otfvf / Z ~p / . I\^_ \ _ / / \\ / z\\ o / _\Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo.On 5-(8-(l,3-Dimethyl-2-oxo-2,3-dihydro-lH- imidazo[4,5-d]pyndin-6-yI)isoquinolin-3-yl)-7V-(3- A25(2',6'-dioxo-2,3-dihydrospiro[indene-l,3'- ■>-,. C2 / piperidin] -6-yl)prop-2-yn- 1 -yl)picolinamide '■" S". ' r < o”0XN--7'Kl^jj5-(8-(l,3-Dimethyl-4-morpholino-2-oxo-2,3- dihydro-lH-imidazo[4,5-c]pyridin-6-yl)isoquinolin- A263-yl)-jV-(3-(2',6'-dioxo-2,3-dihydrospiro[indene- 1,3 '-piperidin] -6-yl)prop-2-yn- 1 -y l)picolinamide H ’N\ N H~bAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.Or T\ V-C5-(8-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-l,3- dimethyl-2 -oxo-2, 3 -dihydro- IH-imidazo [4,5- A27 c]pyridin-6-yl)isoquinolin-3-yl)-2V-(3-(2',6'-dioxo- 2,3 -dihydrospiro [indene- 1,3 '-piperidin] -6-yl )prop- A; M C jL / > O 2-yn- 1 -yDpicolinamideIl J HCNHn cv. 0A-(4-(2',6’-Dioxospiro[indene-l,3’-piperidin]-6- yl)but-3 -yn- 1 -yl)-5 -(8-(7-isopropyl- 1,3 -dimethyl-2- A29oxo-2, 3 -dihydro- 177-benzo [r / jimidazol-S - y I)isoquinol in-3 -yl)pi col inami de / o "i oAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.O1Li A"(3-(2'.5'-DioxO"2,3-dihydrospiro[indene-l,3'- pyrroiidin]-6-yl)prop-2-yn-l-yl)-5-(8-(7-isopropyl- A30 1,3 -dim ethyl -2 -oxo-2.3 -dihydro- 177- & C benzo [tfjimidazol -5 -yl )isoquinolin-3 - < U. rn yl)picolinamideN 7 \>NH0zLXNA\v fl - O A-(3-(2',6'-Dioxo-2,3-dihydrospiro[indene-l,3'- piperidin] -5 -yl)prop-2-yn- 1 -yl)-5-(8-(7-isopropyl- A31 / NH 1,3 -dimethyl -2 -oxo-2, 3 -dihydro- 177- 6o^ nV* benzo[<7]imidazol-5-yl)isoquinolin-3- yl)picolinamideAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.(S*)-Ar-(3-(2',6'-Dioxospiro[indene-l,3'-piperidin]- 6-yl)prop-2-yn- 1 -yl)-5 -(8-(7-isopropyl- 1,3 - A32dimethyl-2-oxo-2,3-dihydro-lH-benzo[cZ]imidazol- 5 -yl)isoquinolin-3 -yl)picolinamide \ \ _ / _ / 0z o,1 / 'XJ ’ o J — (7?*)- / V-(3-(2',6'-Dioxospiro[indene-l,3'-piperidin]- 6-yi)prop-2-yn-l-yl)-5-(8-(7-isopropyl-l,3- A33rA / ^ dimethyl-2 -oxo-2, 3-dihydro-lH-benzo[J] imidazol- 5 -yl)isoquinolin-3 -y l)picolinamidefiH, N\ IXI n0 v0g.,' Oi oAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.o oX IT 5 -( 8 -(4 - ( 1, 1 -Dioxidothiomorpholino)- 1, 3 -dimethyl- 2 -oxo-2, 3 -dihydro- IH-imidazo [4,5 -c]pyridin-6- A34 Jr« yl)isoquinolin-3-yl)-A-(3-(2',6'-dioxo-2,3- dihydrospiro [indene- 1,3'-piperidin] -6-yl)prop-2-yn- l-yl)picolin amideN'S''' y N H0A-(3-(3,3-Difluoro-2',6’-dioxo-2,3- dihydrospiro [indene- 1,3'-piperidin] -6-yl)prop-2-yn- A35 F l-yl)-5-(8-(7-isopropyl-l,3-dimethyl-2-oxo-2,3- dihydro-lH-benzo[£Z]imidazol-5-yI)isoquinolin-3- CG. „. O: X» yl)picolinamide M J. «• M.00Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.O|A-(3-(2',6'-Dioxo-5,6- dihydrospiro[cyclopenta[6]thiophene-4,3'- piperidin]-2-yl)pi’op-2-yn-l-yD"5’(8"(^"isopropyl- A361,3 -dimethyl -2 -oxo-2, 3 -dihydro- IH- L I m benzo [rf|imidazol-5 -yl)isoquinolin-3 - IuH JUv / Unhyl)pi col inamide< / IL A. NXQ0E o...''I 0 f NH (E)-5 -(5 -(( 1,3 -Dimethyl-2-oxo-7 -(tetrahydro-2H- pyran-4-yl)-2,3-dihydro-lH-benzo[d]imidazo]-5- A37 Z Li N iC 'C ''O yl)(methyl)amino)pyrimidin-2-yi)-A-(3-(2',6’- Y JULHUQ dioxo-2#-spiro[benzofuran-3,3'-piperidin]-5- OU | H H l yl)allyl)-3-metliylpicolinamide / 1o / °5-(5-((l,3-Dimethyl-2-oxo-7-(tetrahydro-27 / -pyran- Q ( / NH4-yl) -2, 3-d ihydro- 1 H-benzo [d\ imidazol-5 - A38 yl)(methyl)amino)pyrimidin-2-yl)-A-(3-(2',6'- dioxo-227-spiro [benzofuran-3,3 '-piperidin] -5 - "^:u.,iJ '-A yl)prop-2-yn-l-yl)-3-methylpicolinamide1Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.O1A-(3-(2',6'-Dioxospiro[bicyclo[4.2.0]octane-7,3!- piperidine ] - 1 (6),2,4-trien-4-yl)prop-2-yn- 1 -yl)-5 - A39 (8-(7-isopropyI-l,3-dimethyl-2-oxo-23-dihydro- lH-benzo[cZ]imidazol-5-yl)isoquinolin-3- yl)picolinamideT i H L u _ / _--4 NHN ( / JO^-NZxi (J?*)-5-(5 -( 1,3 -Dimethyl-2 -oxo-2, 3 -dihydro- 177 - benzo[<7]imidazol-5-yl)-6,7-dihydro-577- A40 pyrimido[4,5- / >][l,4]oxazin-2-yl)-A’-(3-(2',6'- dioxospiro [indene- 1,3 '-piperidin] -6-yl)prop-2-yn- 1 - c xx.. m oi iHn / / X^AX y 1 ) -3 -methy Ipicolinamide. ’X•w / zPX N A \'N" OHoAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo.(E)-A-(3-(2',6'-Dioxospiro[mdene-l,3'-piperidin]-6- yl )al lyl)-5 -(8-(7-isopropyl- 1,3 -dimethyl -2-oxo-2.3 - A41dihydro- lH-benzo[ri'Jimidazol-5-yl)isoquinolin-3- yl)picolinamide°?\ / \0 / (i?*)-5-(5-(l,3-Dimethyl-2-oxo-2.3-dihydro-12 / - benzo[< / ]imidazol-5-yl)-8-methyl-5, 6,7,8- A42 ZIztetrahydropteridin-2-yl)- / V-(3-(2',6'- < dioxospiro[indene-l,3'-piperidin]-6-yl)prop-2-yn-l- yl)picolinamide e; o i0? 2.. F A o I\\ / ®z / - 84pPPCP ^Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.5-(8-(7-Isopropyi-l,3-dimethyl-2-oxo-2,3-dihydro- 17 / -benzo[«7]imidazol-5-yl)isoquinoiin-3-yl)-jV-(3- A43(2-methyl-2',3,6'-trioxospiro[isoindoline- 1,3'- piperidin]-6-yl)prop-2-yn-l-yl)picolinamide(7?* )- / V-(3 -(2',6'-Dioxospiro[indene- 1,3 '-piperidin] - 6-yl)prop-2-yn- 1 -y 1) -3 -methyl-5 -(4-methyl-7 - A44 (trifluoromethyi)-l-(l,3,7-trimethyl-2-oxo-2,3- dihydro-lH-benzo[cf|imidazol-5-yI)-l,2,3\4- tetrahydroquinoxal in-6-yl)pi col inami de 5 Oe\ rC vs... JrQ o\ / z ~\\ LL LL / O / z / - / ? <\ / / \ '< i \ < 2: z _\ — \ / —\\Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.qV-N7...... M X J(R* )-5 -(5 -( 1,3 -Dimethyl -2 -oxo-7 -(tetrahydro-2 / / - pyran-4-yi)-2,3-dihydro-12 / -benzo[<7jimidazol-5- A45 yl)-6,7-dihydro-5H-pyrimido[4,5-d]| l,4]oxazin-2- r iNyl)-V-(3-(2;6'-dioxospiro[indene-l,3'-piperidin]-6- L A A f yl)prop-2-yn-l-yl)-3-methylpicolinamide YB- ■*. 0”0oAt - (7?* )- / V-(3 -(2',6’" Oioxospiro[indene- 1,3 '-piperidin] - 6-yl)prop-2-yn-l-yl)-3-methyl-5-(8-methyl-5- A46 ( 1.3,7-trimethyl-2-oxo-2,3 -dihydro- 1 H - benzo [cf| imidazol-5 -y I)-5,6,7?8-tetrahydropteridin- eV " m 2 -y l)pi col inami d e3^N7''|'N'-ZZ7y klHbAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.O'"'AA-(3-(2',6'-Dioxo-227-spiro[benzofuran-3,3'- piperidin] -5 -yl)prop-2-yn- 1 -yi)-5-(8-methyl-5 - A47 r A "r| ( 1.3,7-trimethyl-2-oxo-2,3 -dihydro- 1H~ Nbenzo[<7]imidazol-5-yI)-5?6,7,8-tetrahydropteridin- 2-yl)picolin amidei Il J, N / ~f" s -r ojV-(3-(2',6'-Dioxo-2J7-spiro[benzofi.jran-3,3'- piperidin] -5 -yl)prop-2-yn- 1 -yl)-5 -(5 -(7-isopropy 1- A48 1,3 -dim ethyl -2 -oxo-2.3 -dihydro- 177- benzo[< / ]imidazol-5-yl)-8-methyl-5, 6,7,8- tetrahydropteridin-2-yl)picolinamide o / V,0 / X c / OZ-,r >0J!0(R* )-5 -(5 -(( 1,3 -Dimethyl-2-oxo-7 -(tetrahydro-277- L > ZNXAM / \ O / XNHpyrati-4-yl)-2,3-dihydro-177-benzo[d]imidazol-5- A49 yl)(metliyl)amino)pyrimidin-2-yl)-A-(3-(2',6!- * dioxo-2H-spiro [benzofuran-3,3 '-piperidin] -5 - °.... / zz A v yl)prop-2-yn- 1 -y 1) -3 -methylpicolinamide! 187A"( < / / / v / 2 \. J — £-~—' ■ A 4 \ )A_ _ \ / / X / X ' / A “Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.I O.0M AOk J AK!Z\ / XNH (5* )-5 -(5 -(( 1,3 -Dim ethyl-2-oxo-7 -(tetrahydro-2H- pyran-4-yl)-2,3-dihydro-lH-benzo[d]imidazo]-5- A50 vl, VAHyl)(methyl)amino)pyrimidin-2-yl)-7V-(3-(2',6'- dioxo-27f-spiro[benzofuran-3.3'-piperidin]-5- yl)prop-2-yn-l-yl)-3-methylpicolinamide! 1Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)Table 2CompoundChemical Structure Chemical NameNo.5-(4-(l,3-Dimethyl-2-oxo-7-(tetrahydro-2H-pyran- 4-yl)-l,2-dihydroquinolin-5-yl)-6-fluoro-3,4- Bl dihydro-2 / / -benzo[d | [ 1.4 |oxazin-7-yl)-A-(3-(2',6'- dioxo-2, 3 -dihydrospiro [indene- l,3'-piperidin]-6- yl)prop-2-yn-l-yl)picolinamide5 -(5 -( 1,3 -Dimethyl-2 -oxo-7 -(tetrahy dro-277-pyran- 4-yl)-l, 2-dihydroquinolin-5-y1)-5, 6,7,8- B2 tetrahydropyrido [3,2-d]pyrimidin-2-yl)-lV-(3 -(2',6'- dioxospiro [indene- 1,3 ’-piperidin] -6-y l)prop-2-yn- 1 - yl)picolinamide ft O ™ o.o< >. / > \IZ>o 89u-oft- 'ft.?-?ft. / ■■■■O o ' / zAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.|L N N,.oTXZ 5 -(5 -( 1,3 -Dimethy l-7-morpholino-2-oxo- 1,2- dihydro-l,6-naphthyridin-5-yl)-5, 6,7,8- 83 tetrahydropyrido[3,2-i7]pyrimidin-2-yl)-JV-(3-(2',6'- d i oxo- 2 / / -sp i ro [benzofuran -3,3 '-piperidin] -5 - yl)prop-2-yn- 1 -yl)picolinamide u v n „<■ iI Us. u, / 7Ay*- hl.05 -(5-( 1,3 -Dimethy l-2-oxo-7 -(tetrahydro-2 / 7-pyran- 4-yl)-l,2-dihydroquinolin-5-yl)-5, 6,7,8- 84 tetrahydropyrido[3,2-a']pyrimidin-2-yl)-Ar-(3-(2',6'- f ZN-u^V'0k F / d i oxo-2Z / -sp i ro [benzofuran-3, 3 ’-piperidin] -5 - oyl)prop-2-yn- 1 -yl)picolinamide( NHo 'Z0Attorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.(7?*)-5-(5-(l,3-Dimethyl-7-morpholino-2-oxo-l,2- dihydroquinolin-5 -yl)-5,6, 7, 8-tetrahydropyrido [3,2- B5J]pyrimidin-2-yl)-Ar-(3-(2',6'-dioxospiro[indene- 1,3 '-piperidin] -6-yl)prop-2-yn- 1 -yl)picolinamide(R*)-5 -(5 -(1,3 -Dimethyl -2 -oxo-7-(tetrahydro-27f- pyran-4-yl)-l,2-dihydroquinolin-5-yl)-6,7-dihydro- B6 52 / -pyrimido|4,5-d][l,4]oxazin-2-yl)-A7-(3-(2',6'- dioxospiro[indene-l,3'-piperidin]-6-yl)prop-2-yn-l- H -JOQ Z° yl)-3 -methylpicolinam ideL. IL N AYNY N o. ™H1)y •X)n / °ZZ ( Z w ' —' < >_ \ \ / —\ / / Yv-y\ / ) Z)oAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo.(R* )-5-(l-( 1,3 -Dimethyl -2 -oxo-7-(tetrahy dro-2H- pyran-4-yI)-l,2-dihydroquinolin-5-yl)-4-methyl-7- B7 (trifluoromethyl)- 1,2,3, 4-tetrahydroquinoxalin-6- yl)-2 / -(3-(2',6'-dioxospiro[indene-l,3'-piperidin]-6- o \ yl)prop-2-yn- 1 -yl)-3 -methylpicolinamide X--.0 N t \J i Jt J Q (J^*)-5-(4-( 1,3 -Dimethyl -2 -oxo-7-(tetrahydro-2H- pyran-4-yl)- 1,2-dihydroquinolin-5 -yl)- 1 -methy 1- B8 ° "" A z V -n -n l,2,3,4-tetrahydropyrido[3,4-d]pyrazin-7-yl)-7V-(3- (2',6'-dioxospiro[indene-l,3'-piperidin]-6-yl)prop-2-k? 1^V k 0r H ^ Nh / \ yn- 1 -yl)-3-methylpicolinamideN" J 1) N*"1O IAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.C\ N 1 JJJX (7?*)-5-(5-(l,3-Dimethyl-2-oxo-7-(tetrahydro-2H- pyran-4-yl)-l,2-dihydroquinolin-5-yl)-8-methyl- B9 5,6?7,8-tetrahydropteridin-2-yl)-A7-(3-(2;6'- dioxospiro [indene- 1,3 '-piperidin] -6-yl)prop-2-yn - 1 - yl)-3 -methylpicolinamide° \ -!f1KH...,.HM-x\2A / (J^*)-5-(4-( 1,3 -Dimethyl -2 -oxo-7-(tetrahydro-2H- / pyran-4-yl)- 1,2-dihydroquinolin-5 -yl)-3,4-dihydro- BIO { r \ ^2H-pyrido[4,3-d][l,4]oxazin-7-yi)-J¥-(3-(2',6'- dioxospiro [indene- 1,3 '-piperidin] -6-yl)prop-2-yn- 1 -xx / yl)-3 -methylpicolinamide\0O TAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.■ A0(J?*)-5-(7"(Difluoromethyl)-r,3'-dimethyl-2'-oxo-7'- (tetrahydro-2J7-pyran-4-yl)-l\2',3,4-tetrahydro-2 / Z- Bll [l,5'-biquinolin]-6-yl)-jV-(3-(2',6'- dioxospiro [indene- 1,3 '-piperidin] -6-yl)prop-2-yn - 1 - A Tp \ k L IfN I H re- yl)-3 -methylpicolinamideN <• \" ^V \ NHA •- > M"" z - V / - O KL2A 5 -(5-( 1,3 -Dimethyl-2-oxo-7 -(tetrahydro-2 / / -pyran- 4-yl)- 1,2-dihy droq uinolin-5 -yl)-8-methyl-5,6,7, 8- B12 / =\ tetrahydropteridin-2-yl)-JV-(3-(2',6'-dioxo-2 / / - w spiro[benzofuran-3,3'-piperidin]-5-yl)prop-2-yn-l- yl)picolinamideZI' <A0..oAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.CL N ■ A X" J°Xu 5 -(4-( 1,3 -Dimethyl-2-oxo-7 -(tetrahydro-2 / f-pyran- 4-yI)- 1,2-dihy droquinolin-5 -yl)- 1 -methyl- 1,2,3,4- B13 tetrahydropyrido[3,4-h]pyrazin-7-yI)-Ar-(3-(2',6'- d i oxo- 2 / / -sp i ro [benzofuran -3,3 '-piperidin] -5 - ■■ N >< H ux yl)prop-2-yn- 1 -yl)-3 -methylpicolinamide \ N°H!-io° ° X\K, X N / NH 5 - ( 5 -(( 1,3 -Dimethyl-2-oxo-7-(tetrahydro-2 / / -pyran- N |UN\ 1 4-yl)- 1,2-dihydroquinolin-5- B14 xAX ^XU-LixX Y) yl)(methyI)amino)pyrimidin-2-yl)-N-(3-(2',6'-dioxo- 2 / / -spi ro [benzofuran-3,3 '-piperidin] -5 -yl)prop-2-yn- U U U ^"o1 -yl)-3 -methylpicolinamideAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)Table 3CompoundChemical Structure Chemical NameNo.5 -(5 -(5 -Acetyl- 1 -ethyl -4, 5,6,7-tetrahydro- \H- pyrazolo[4,3-c]pyridin-3-yl)-5, 6,7,8- Cl tetrahydropyrido[3,2-J|pyrimidin-2-yl)-A-(3-(2',6'- dioxospiro [indene- 1,3'-piperidin] -6-yl)prop-2-yn- 1 - yl)picolinamideJ / \ -z.O-A / )\_ / / J / Ayr s z~5 -(5 -(5 -Acetyl- 1 -(tetrahydro-2H-pyran-4-yl)-NyV / 1 O 4,5,6,7-tetrahydro- 1 H-py razolo [ 4,3 -c]py ridin-3 -yl)- C2 / 5,6,7,8-tetrahydropyrido[3,2-i / jpyrimidin-2-yl)-A7- rV " ZI (3-(2',6'-dioxospiro[indene-l,3'-piperidin]-6- H I H' < yl)prop-2-yn- 1 -yl)picolinamideN\H6o0' 7o TAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo. / -- O( Jy€n 5-(8-(5-Acetyl-l-(tetrahydro-2H-pyran-4-yl)- 4,5,6,7-tetrahy dro- IH-pyrazolo [4,3 -c]pyridin-3 - C3yi)isoquinolm-3-yl)’;iV"(3"(2',6'-dioxospiro[ir!dene- 1,3'-piperidin] -6-yl)prop-2-yn- 1 -yl)picolinamideO 6( } _ / >\ O hO / r v / , N N F (S* )-5 -( 1 -(5 - Acetyl- 1 -(tetrahydro-2H-pyran-4-yl)- 4,5,6,7-tetrahydro- IfiT-pyrazoio [4,3 -c]pyridin-3 -yl)- C4 N A 7-(difluoromethyl)-l,2,3,4-tetrahydroquinoiin-6-yl)- c O I no o A’-(3-(2',6'-dioxospiro|indene-l,3'-piperidin]-6- yl)prop-2-yn- 1 -yl)picolinamide1 7. N >0715 oAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo.nvArl'7(J?* )-5 -( 1 -(5 -Acetyl- 1 -(tetrahydro-2H-pyran-4-yl)- 0 / T vA Y F 4,5,6,7-tetrahydro- 1 H-pyrazol o [4,3 -cJpyridin-3 -yi)- C5. N 1 7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl)- r I f An A7-(3-(2',6'-dioxospiro[indene-l,3'-piperidin|-6- 'AY N Y A yl)prop-2-yn-l-yl)picolinamideIf A N Y / \Y V"6'8r~QY X KC ANZ(5*)-5-(8-(5-Acetyl-l-(tetrahydro-277r-pyran-4-yl)- 4,5,6,7-tetrahydro- 177-pyrazolo [4,3 -c]py ri din-3 - C6 A I / yl)isoquinoiin-3-yl)-A-(3-(2',6'-dioxospiro[indene- I!i O 1,3'-piperidin] -6-yl)prop-2-yn- 1 -yl)picolinanndeoAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO)CompoundChemical Structure Chemical NameNo.n / T V-A7XNo Y (i?*)-5-(8-(5-Acetyl-l-(tetraliydro-2H-pyran-4-yl)- 4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridin-3- C7 YY'^Nyl)isoquinolin-3-yi)-jV-(3-(2';,6'-dioxospiro[indene- 1,3 '-piperidin] -6-yl)prop-2-y n- 1 -yl)picolinamide < A N A' ZUQ / , \°Y V"r~Q'YJA \_-<XN (7?*)-5-(l-(5-Acetyl-l-(tetrahydro-2H-pyran-4-yl)- O Y F 4,5,6,7-tetrahydro- 1 H-pyrazoio [4,3 -c]pyridm-3 -yl)- C8 N A 7-(difluorometliyl)-l,2,3,4-tetrahydroquinoiin-6-yl)- A’-(3 -(2',6'-dioxospiro [indene- 1,3 '-piperidin] -6- CCC m o yl)prop-2-yn- 1 -yl)-3-methylpicolinamide L l( N 'A5 Y<oAttorney Docket No.: 43807-02407 VO (PRSC-104 / 001WO) CompoundChemical Structure Chemical NameNo. / -- °(J?* )-5 -( 1 -(5 -Acetyl- 1 -(tetrahydro-2H-pyran-4-yl)- 0 X F 4,5,6,7-tetrahydro- 1 H-pyrazol o [4,3 -cJpyridin-3 -yi)- C9 X 1,F7-(difluoromethyl)-l,2,3,4-tetrahydroquinolin-6-yl)- A / -(3 -(2!,6'-dioxospiro [indene- 1,3 '-piperidin] -6- yl)prop-2-yn- 1 -yl)-3 -methoxypicolinamide1XAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0103] In some embodiments, the compound is selected from Compound Nos. Al 1, A13, A33, A48, B8, B9, C7, and C8 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0104] In some embodiments, the compound is selected from Compound Nos. All, A13, A33, A48, B8, B9, C7, and C8 and pharmaceutically acceptable salts thereof.

[0105] In some embodiments, the compound is selected from Compound Nos. Al 1, A13, A33, A48, B8, B9, C7, and C8.

[0106] In some embodiments, the compound is selected from Compound Nos. All, A13, A33, A48 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0107] In some embodiments, the compound is selected from Compound Nos. Al 1, A13, A33, A48 and pharmaceutically acceptable salts thereof.

[0108] In some embodiments, the compound is selected from Compound Nos. All, A13, A33, A48.

[0109] In some embodiments, the compound is selected from Compound Nos. B8 and B9 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0110] In some embodiments, the compound is selected from Compound Nos. B8 and B9 and pharmaceutically acceptable salts thereof.

[0111] In some embodiments, the compound is selected from Compound Nos. B8 and B9.

[0112] In some embodiments, the compound is selected from Compound Nos. C7 and C8 and pharmaceutically acceptable salts, solvates, and stereoisomer thereof.

[0113] In some embodiments, the compound is selected from Compound Nos. C7 and C8 and pharmaceutically acceptable salts thereof.

[0114] In some embodiments, the compound is selected from Compound Nos. C7 and C8.

[0115] 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.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0116] 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.

[0117] 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.

[0118] 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, I max, 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, drugdrug interaction).

[0119] In some embodiments, a compound disclosed herein shows selective degradation of p300 over CBP when a compound has a DCso for p300 that is lower than its DCso for CBP when both values are measured at the same time point. In some embodiments, a compound disclosed herein shows selectivity when a compound has a Dmax for p300 that is greater than its Dmax for CBP when both values are measured at the same time point. In some embodiments, a compound disclosed herein shows selectivity through a combination of both lower DCso and greater Dmax for p300, as compared to those for CBP. In some embodiments, a compound disclosed herein shows selectivity when a compound has a DCso for p300 at least 10-fold lower than its DCso for CBP and / or a value of Dmax for p300 minus Dmax for CBP (ADmax) 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 DCso for p300 at least 30-fold lower than its DCso for CBP and / or a value of Dmax for p300 minus Dmax for CBP (ADmax) 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 DCso for p300 at least 100-fold lower than its DCso for CBP and / or a value of Dmax for p300 minus Dmax for CBP (ADmax) of at least 70, at least 75, at least 80, at least 85, or at least 90 percentage points. In some embodiments, a compound disclosed herein shows selectivity when it has a Dma for p300 measured at a short time point (for instance, 2 hours) that is equivalentAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)or greater than its Dmax for CBP measured at a significantly longer time point (for instance, 24 hours). In certain preferred embodiments, a compound has a (ADmax) of at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, or at least 90 percentage points even when measured stringently (at 2 hours for p300 and 24 hours for CBP). These beneficial properties of the compounds of the present disclosure can be measured according to methods commonly available in the art, such as methods exemplified herein.

[0120] Due to the existence of double bonds, the compounds of the present disclosure may be in cis or trans or Z or E, configuration. It is understood that although one configuration may be depicted in the structure of the compounds or formulae of the present disclosure, the present disclosure also encompasses the other configuration. For example, the compounds or formulae of the present disclosure may be depicted in cis or trans, or Z or E, configuration.

[0121] 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

[0122] In some embodiments, the compounds disclosed herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0123] In some 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 some 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.

[0124] 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-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate,Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycol ate, hemi sulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, y-hydroxy butyrate, 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, phenyl acetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate, and xylenesulfonate.

[0125] 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-l -carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l -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.

[0126] In some 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+(CI-4 alkyl)4, and the like.

[0127] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and theAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0128] “Solvate” refers to forms of the compound that are associated with a solvent or water (also referred to as “hydrate”), usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the disclosure may be prepared e.g., in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. 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.

[0129] 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.

[0130] 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.

[0131] In some 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.

[0132] Solvates contain either stoichio etric 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.)Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0133] 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.”

[0134] Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R - and S - sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized 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”.

[0135] 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 some embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0136] 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 some embodiments, the weights are based upon total weight of compound.

[0137] 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%Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)by weight (R)-compound. In some embodiments, the weights are based upon total weight of compound.

[0138] 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 some embodiments, the enantiomerically pure (R)-compound in such compositions can, for example, comprise, at least about 95% by weight (R)-compound and at most about 5% by weight (S)-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure (S)-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure (S)-compound. In some 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 some embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0139] 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.

[0140] In some embodiments, the compounds described herein exist as geometric isomers. In some 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,

[0141] In some 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.

[0142] 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 some 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 ofAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some 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 some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent.Tautomers

[0143] In some embodiments, compounds described herein exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein.

[0144] 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.Conjugates

[0145] In some aspects, the present disclosure provides conjugates comprising the compound described herein, wherein the compound is directly or indirectly attached to a conjugate partner.

[0146] In some aspects, the present disclosure provides a compound described herein, wherein the compound is conjugated to a conjugate partner.

[0147] In some embodiments, the conjugate comprises a compound described herein directly attached (e.g., via a bond) to a conjugate partner.

[0148] In some embodiments, the conjugate comprises a compound described herein indirectly attached (e.g., via a linker moiety) to a conjugate partner.

[0149] In some embodiments, the conjugate comprises one or more compound described herein.

[0150] In some embodiments, the conjugate partner is an antibody or fragment thereof.

[0151] In some embodiments, the conjugate partner is an antibody.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0152] In some embodiments, the conjugate partner is an antibody fragment.

[0153] In some embodiments, the conjugate partner is a half-life extending moiety (i.e., a moiety that increases the circulatory half-life of the conjugate in vivo, compared to the unconjugated compound).

[0154] In some embodiments, the compound described herein is conjugated to a conjugate partner.

[0155] In some embodiments, the compound described herein is conjugated to an antibody or fragment thereof.

[0156] In some embodiments, the compound described herein is conjugated to a half-life extending moiety.

[0157] In some embodiments, the present disclosure provides a compound for conjugating with a conjugate partner.

[0158] In some embodiments, the present disclosure provides a compound for conjugating with an antibody or fragment thereof.

[0159] In some embodiments, the present disclosure provides a compound for conjugating with a half-life extending moiety.

[0160] In some embodiments, the antibody and / or linker moiety of the conjugate is described in PCT Application No. PCT / US2023 / 085698; Hong, B. K. etal. J. Med. Chem. 2023, 66 (1), 140-148; Dragovich, P. S. Chem. Soc. Rev. 2022, 51(10), 3886-3897; orPoudel, Y. B. etal. J. Med. Chem. 2024, 67 (18), 15996-16001 (each incorporated herein by reference).

[0161] In some embodiments, the half-life extending moiety comprises one or more moiety each independently selected from albumin, albumin binding domain, XTEN polypeptide, and polyalkylene glycol (PAO).

[0162] In some embodiments, the half-life extending moiety is selected from albumin, albumin binding domain, XTEN polypeptide, and polyalkylene glycol (PAO).

[0163] In some embodiments, the half-life extending moiety is albumin

[0164] In some embodiments, the half-life extending moiety is albumin binding domain.

[0165] In some embodiments, the half-life extending moiety is XTEN polypeptide.

[0166] In some embodiments, the half-life extending moiety is polyalkylene glycol (PAO).

[0167] In some embodiments, the PAO comprises a polymer of alkylene oxide.

[0168] In some embodiments, the PAO comprises a polymer of ethylene oxide.

[0169] In some embodiments, the PAO comprises a polymer of propylene oxide.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0170] In some embodiments, the PAO is polypropylene glycol, polyethylene glycol (PEG), polyethylene glycol methyl ether (mPEG), or polyoxy ethylenated polyol, or a copolymer (e.g., block copolymer) thereof.

[0171] In some embodiments, the PAO is polyethylene glycol (PEG) or polyethylene glycol methyl ether (mPEG).

[0172] In some embodiments, the PAO is polyethylene glycol (PEG).

[0173] In some embodiments, the PAO is polyethylene glycol methyl ether (mPEG).

[0174] In some embodiments, the PEG is polydisperse PEG, monodisperse PEG, or discrete PEG. In some embodiments, polydisperse PEGs are heterogeneous mixtures of sizes and molecular weights, whereas monodisperse PEGs are purified from heterogeneous mixtures and provide a single chain length and molecular weight. In some embodiments, the PEG units are discrete PEGs. In some embodiments, the discrete PEGs provide a single molecule with defined and specified chain length.

[0175] In some embodiments, the half-life extending moiety is described in Binder, U. et al. Expert Opinion on Biological Therapy, 2024, 25, 93-118, or Zaman, R. et al. Journal of Controlled Release, 2019, 301(10), 176-189 (each incorporated herein by reference).Pharmaceutical Compositions

[0176] In some embodiments, the compound described herein is administered as a pure chemical. In some 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)).

[0177] 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.

[0178] In some 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.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0179] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the coniposition(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.

[0180] In some 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 some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some 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 some embodiments, the pharmaceutical composition is formulated as a tablet.Preparation and Characterization of the Compounds

[0181] 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 ( / .<?., 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).Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)General Synthetic Scheme

[0182] A compound of formula I may be prepared according to the procedures shown in SCHEMES 1 6Coupling Coupling j(L’)i+X-C T-(L')1 +(L')2'CSCHEME 1

[0183] According to SCHEME 1, synthetically accessible aryl halide (X:::Cl, Br, I, or OTf) of formula X-C is reacted with synthetically accessible linker of formula (L’)i; under standard conditions as the specific linker allows. In some embodiments, the linker of formula (L’)i contains a terminal alkyne, and the portions are coupled under standard Sonagashira coupling conditions, i.e. with a suitable catalyst such as Pd(Ph3P)4, PdC12(dppf), or the like; with a cocatalyst such as CuBr, Cui, and the like; with an organic base such as triethylamine, DIPE / X, or the like; in a suitable solvent such as dioxane, DMF, or the like; at temperatures ranging from 60 °C to 120 °C; to provide coupled compound of formula (L’)2-C. A coupled compound of formula (L’)2-C (target ligand and linker) is further reacted with synthetically accessible CBP / p300 ligand of formula T-(L’)1; under standard conditions as the specific linker allows to provide a complete degrader compound of formula T-L-C (I). In some embodiments, the CBP / p300 ligand of formula T-(L’)1contains a carboxylic acid, and the E3 ligand and linker of formula (L’)2-C is an amine, and the two are coupled under standard amide coupling conditions, i.e. with a suitable coupling agent such as HATU, T3P, or the like; with a suitable organic base such as TEA, DIPEA, or the like; in a suitable solvent such as DMF, DMSO, or the like; at temperatures ranging from 0 °C to 80 °C; to provide an amide degrader compound of formula T-L-C (I).

[0184] A compound of Formula X-C may be prepared according to the procedures shown in SCHEMES 2-3.Homologation Alkyiation Cyclization2-12-6 RDO2-4SCHEME 2Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0185] According to SCHEME 2, a commercially available or synthetically accessible and halide 2-1 is homologated; with a suitable reagent such as TosMIC or the like; with a suitable base such as potassium fert-butoxide or the like; in a suitable solvent such as DME, ethanol, or the like; at temperatures ranging from 0 °C to 60 °C; to provide the corresponding cyanide compound 2-2. The cyanide compound 2-2 is alkylated; with a suitable electrophile 2-3 or 2-4; with a suitable strong base such as KHMDS, KOtBu, or the like; in a suitable organic solvent such as THF, DMF, or the like; at temperatures ranging from -78 °C to 22 °C; to provide the alkylated product 2-5. The ester compound 2-5 is cyclized; using a suitable inorganic acid such as sulfuric acid or the like; in a suitable solvent such as acetic acid or the like; at temperatures ranging from 60 °C to 120 °C; to provide the cyclized compound 2-6 (X-C).Alkylation. OHCyclization R ' _SCHEME 3

[0186] According to SCHEME 3, a commercially available or synthetically accessible aryl halide 3-1 is alkylated; with a suitable electrophile 3-2 or 3-3; with a suitable strong base such as Triton B, KHMDS, or the like; in a suitable organic solvent such as THF, DMF, or the like; at temperatures ranging from -78 °C to 22 °C; to provide the alkylated product 3-4. The cyanide compound 3-4 is hydrolyzed; using a suitable reagents like indium(lll) chloride and acetaldehyde oxime; in a suitable solvent such as toluene or the like; at temperatures ranging from 80 °C to 120 °C; to provide the amide compound 3-5. The amide compound 3-5 is cyclized; using a suitable base such as Triton B or the like; in a suitable solvent such as acetonitrile or the like; at temperatures ranging from 0 °C to 50 °C; to provide the cyclized compound 3-6 (X-C).Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO) CouplingSCHEME 4 CouplingSCHEME 5CouplingSCHEME 6Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0187] According to SCHEMES 4-6, commercially available or synthetically accessible warheads of type 4-1, type 5-1, or type 6-1 (X:::I, Br, Cl, OTf, OTs, OMs, B(OH)2, BPin, or the like) are coupled with commercially available or synthetically accessible partners of type 4-2, type 5-2, or type 6-2 (Y = H, I, Br, Cl, OTf, OTs, OMs, B(OH)2, BPin, or the like), under standard coupling conditions corresponding to the specific functional groups associated with each specific compound, such as Buchwald-Hartwig conditions, Suzuki-Miyaura conditions, or the like. The coupling partners are reacted with a suitable catalyst such as Pd(Ph₃P)₄, PdCl₂(dppf), or the like, with or without an inorganic base such as Na₂CO₃, K₃PO₄, t-BuONa and the like; in a suitable solvent such as 1,4-dioxane, DMF, or the like; at temperatures ranging from 60 °C to 120 °C; to provide a coupled compound 4-3, 5-3, or 6-3 (T-(L’)1).

[0188] Those skilled in the art will recognize that the steps described above may be inverted, as the reactivity of the specific compounds allow. Those skilled in the art will also recognize that the steps in one scheme may be interspersed with those described in another scheme above, as the reactivity of the specific compounds allow.

[0189] Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure (e.g, a compound of any of the formulae or any individual compounds disclosed herein). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the 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),

[0190] 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).

[0191] 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,Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)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.

[0192] 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.

[0193] In some embodiments, each of the intermediates prepared in the Schemes herein are considered embodiments of the present disclosure.

[0194] In some embodiments, each of the intermediates prepared in the Examples herein are considered embodiments of the present disclosure.

[0195] In some embodiments, each synthetic step as disclosed in the Schemes herein is separately considered as part of the present disclosure.

[0196] In some embodiments, each synthetic step as disclosed in the Examples herein is separately considered as part of the present disclosure.Biological Assays

[0197] The biological activities of the compounds of the present disclosure can be assessed with methods and assays known in the art.

[0198] 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[l,5-a]pyrazin-l-yl)isoquinolin-3-yl)-Ar-(2-(2-(2-(3-(3',6'-dihydroxy-3-oxo-3 / / -spiro[isobenzofuran-l,9'-xanthen]-5-yl)thioureido)ethoxy)ethoxy)ethyl)picolinamide, from FL / \G-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 ICso of the tested compounds.

[0199] 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[l,5-a]pyrazin-l-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)yl)isoquinolin-3-yl)-jV-(2-(2-(2-(3-(3',6'-dihydroxy-3-oxo-37 -spiro[isobenzofuran-l,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 ICso of the tested compounds.

[0200] 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 pM) 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 DCso and Dmax of the tested compounds.

[0201] 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 pM) 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 DCso and Dmax of the tested compounds.

[0202] The cellular degradation activities of the compounds against p300 may be measured by in-cell Western blot technology in certain cells (e.g., Hl 299 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 pM) 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 DCso and Dmax of the tested compounds.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0203] 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 pM) for a certain period of time (e.g., 16 hours). The resulting protein concentration may be assessed using an anti-CBP primary antibody (e.g., anti-human CBP clone D6C5) and an IRDye 800CW secondary antibody (e.g., IRDye 800CW goat anti-rabbit IgG). The resultant fluorescence may be measured with appropriate instrument (e.g., the LI-COR Odyssey CLx instrument). Dose-response curves may be generated and analyzed using appropriate software (e.g., TIBCO Spotfire) to determine the DCso and Dmax of the tested compounds.

[0204] The ability of the compounds to inhibit cellular proliferation may be assessed by, e.g., Cell Titer-Gio 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 pM) 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-Gio 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 glCso and the growth-death index (i.e. the percentage of remaining cell growth or cell death observed relative to untreated cells).Methods of Use

[0205] In some 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.

[0206] In some 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.

[0207] In some aspects, the present disclosure provides compounds disclosed herein for use in degrading a protein in a subject or biological sample.

[0208] In some 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.

[0209] In some aspects, the present discl osure provides uses of the compound disclosed herein in the manufacture of a medicament for reducing a protein in a subject or biological sample.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0210] In some aspects, the present disclosure provides compounds disclosed herein for use in reducing a protein in a subject or biological sample.

[0211] In some embodiments, the protein is p300. In some embodiments, the protein is CBP.

[0212] In some aspects, the present disclosure provides methods for treating a disease or disorder.

[0213] In some aspects, the present disclosure provides uses of the compounds disclosed herein in the manufacture of a medicament for treating a disease or disorder.

[0214] In some aspects, the present disclosure provides compounds disclosed herein for treating a disease or disorder.

[0215] In some embodiments, the disease or disorder is driven by gene activation such as cancer, inflammatory disorders, or autoimmune diseases.

[0216] In some embodiments, the disease or disorder is a p300-mediated disease or disorder.

[0217] In some embodiments, the disease or disorder is a CBP-mediated disease or disorder.

[0218] In some embodiments, the disease or disorder is cancer.

[0219] In some 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, genu 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 lungAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0220] In some embodiments, the disease or disorder is selected from the group consisting of Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, fibrosis, glomerulonephritis, hepatic vascular occlusion, hepatitis, hypophysitis, immunodeficiency syndrome, inflammatory bowel disease, 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.

[0221] In some embodiments, the disease or disorder is selected from the group consisting of prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and melanoma.

[0222] In some embodiments, the disease or disorder is selected from the group consisting of prostate cancer, breast cancer, bladder cancer, colorectal cancer, small cell lung cancer, non¬ small cell lung cancer, urothelial cancer, diffuse large B cell lymphoma (DLBCL), ovarian cancer, and endometrial cancer.

[0223] In some embodiments, the disease or disorder is ovarian cancer.

[0224] In some embodiments, the disease or disorder is leukemia.

[0225] In some embodiments, the disease or disorder is acute myeloid leukemia.

[0226] In some embodiments, the disease or disorder is prostate cancer.

[0227] In some embodiments, the disease or disorder is androgen receptor-positive prostate cancer.

[0228] In some embodiments, the subject is a mammal.

[0229] In some embodiments, the subject is a human.Definitions

[0230] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.Chemical Definitions

[0231] 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 theAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)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.

[0232] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPFC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, 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).

[0233] The present disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0234] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-6 alkyl” is intended to encompass, Ci, C2, C3, C4, C5, Ce, Ci -6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0235] 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 disclosure. When describing the present disclosure, 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. UnlessAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)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.

[0236] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has I to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C 1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), w-butyl (C4), / crt-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (Cs), 3-pentanyl (Cs), amyl (Cs), neopentyl (Cs), 3-methyl-2-butanyl (Cs), tertiary amyl (Cs), and n-hexyl (Cs). Additional examples of alkyl groups include w-heptyl (C7), w-octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “un substituted 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 some embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In some embodiments, the alkyl group is substituted C1-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), z-Pr (-CH(CH3)2), rz-Pr (-CH2CH2CH3), w-Bti (- CH2CH2CH2CH3), or z-Bu (-CH2CH(CH3)2).

[0237] “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 (-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)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 (-CHfCHs)-, (-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.

[0238] “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) (“C2-20 alkenyl”). In some embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2- 9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon ato s (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon ato s (“C2 alkenyl”). 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 C2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2 -propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (Cs), pentadienyl (Cs), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs), 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 some embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In some embodiments, the alkenyl group is substituted C2-10 alkenyl.

[0239] “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. ExemplaryAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)unsub sti tilted 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.

[0240] “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) (“C2-20 alkynyl”). In some embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2- 9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). 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 C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2- propynyl (C3), 1-butynyl (C4), 2-butynyl (Q), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cs), and the like. Unless otheiwise 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 some embodiments, the alkynyl group is unsubstituted C2-10 alkynyl. In some embodiments, the alkynyl group is substituted C2-10 alkynyl.

[0241] “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. ExemplaryAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0242] 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 some embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-io alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCn 8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroCi-7 alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroCi-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroCi-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and / or 2 heteroatoms (“heteroCi-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroCi-3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroCi-2 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having I carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroal kyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In some embodiments, the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In some embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.

[0243] 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 some embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbonAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-io alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and I, 2, 3, or 4 heteroatoms (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-s alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“het eroC?-? alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and I, 2, or 3 heteroatoms (“heteroC2-e alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms (“heteroC2-4 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-6 alkenyl”). 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 some embodiments, the heteroalkenyl group is an unsub stituted heteroC2-io alkenyl. In some embodiments, the heteroalkenyl group is a substituted heteroC2-io alkenyl.

[0244] 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 some 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 (“heteroCk-io alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC'2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC2-s alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“het eroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatomsAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)(“heteroC2-4 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom (“heteroC2-3 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms (“heteroC2-6 alkynyl”). 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 some embodiments, the heteroalkynyl group is an unsubstituted heteroC2-io alkynyl. In some embodiments, the heteroalkynyl group is a substituted heteroC2-io alkynyl.

[0245] 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.

[0246] “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 147t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatonis provided in the aromatic ring system (“C6-i4aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio and”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“Ci4 aryl”; e.g., anthracyl).

[0247] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octal ene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In some embodiments, the aryl group is unsubstituted Ce-i aryl. In some embodiments, the and group is substituted Ce-waryl.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0248] “Arylene” as used herein, refers to an and group wherein two hydrogens are removed to provide a divalent radical. When a range or number of carbons is provided for a particular “arylene” group, it is understood that the range or number refers to the range or number of carbons in the aryl group. An “arylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0249] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 n electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0250] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl / heteroaryl ) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0251] In some embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In some embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In some embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In some embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In some embodiments, the 5- to 6-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)membered heteroaryl has 1-3 ring heteroatonis independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In some embodiments, the heteroaryl group is unsubstituted 5-to 14-membered heteroaryl. In some embodiments, the heteroaryl group is substituted 5- to 14- membered heteroaryl.

[0252] Exemplary 5-membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatonis include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatonis include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatonis include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6- membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary' 5,6-bicyclic heteroaryl include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazol yl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0253] “Heteroarylene” as used herein, refers to a heteroaryl group wherein two hydrogens are removed to provide a divalent radical. When a range or number of ring members is provided for a particular “heteroarylene” group, it is understood that the range or number refers to the number of ring members in the heteroaryl group. A “heteroarylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0254] “Carbocyclyl” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”) and zero heteroatoms in the nonaromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 12 ring carbon atoms (“Cs- 12 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5- 10 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“Cs- 8 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 or 6 ring carbon atoms f ‘Cs-6 carbocyclyl”). Exemplary C3-6 carbocyclyl include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (Cs), cyclopentenyl (Cs), cyclohexyl (Ce), cyclohexenyl (Ce), cyclohexadienyl (Ce), and the like. Exemplary C3-8 carbocyclyl include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (Cs), cyclooctenyl (Cs), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cs), and the like. Exemplary C3-10 carbocyclyl include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- U / -indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C10), and the like.

[0255] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 5 to 12 ring carbon atoms (“C5-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms (“C’5-8 carbocyclyl”). In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having 5 or 6 ring carbon atoms (“C’5-6 carbocyclyl”). Examples of C5-6 carbocyclyl include cyclopentyl (Cs) and cyclohexyl (Cs). Examples of C3-6 carbocyclyl include the aforementioned Cs-6 carbocyclyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 carbocyclyl include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7) and cyclooctyl (Cs). Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group isAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)unsubstituted C3-12 carbocyclyl. In some embodiments, the carbocyclyl group is substituted C3-12 carbocyclyl.

[0256] As the foregoing examples illustrate, in some embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (“polycyclic carbocyclyl”) that contains a fused, bridged or spiro ring system and can be saturated or can be partially unsaturated. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In some embodiments, the carbocyclyl group is unsubstituted C3-12 carbocyclyl. In some embodiments, the carbocyclyl group is a substituted C3-12 carbocyclyl.

[0257] “Fused carbocyclyl” or “fused carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond), one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of carbons designates the total number of carbons in the fused ring system. When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

[0258] “Spiro carbocyclyl” or “spiro carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on the carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on the carbocyclyl rings in which the spiro structure is embedded.

[0259] “Bridged carbocyclyl” or “bridged carbocycle” refers to ring systems wherein the carbocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more carbocyclyl groups, as defined above, wherein the point of attachment is on any of the carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of carbons designates the total number of carbons of the carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the carbocyclyl rings in which the bridged structure is embedded.

[0260] “Carbocyclylene” as used herein, refers to a carbocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the carbocyclylene group. When a range or number of carbons isAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)provided for a particular “carbocyclyl” group, it is understood that the range or number refers to the range or number of carbons in the carbocyclyl group. A “carbocyclyl” group may be substituted or unsubstituted with one or more substituents as described herein.

[0261] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0262] In some embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 10-Atorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatonis, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In some embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0263] As the foregoing examples illustrate, in some embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings, “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., un substituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In some embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In some embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl.

[0264] “Fused heterocyclyl” or “fused heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, is fused with, i.e., share two common atoms (as such, share one common bond) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on any of the fused rings. In such instances, the number of ring members designates the total number of ring members in the fused ring system.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)When substitution is indicated, unless otherwise specified, substitution can occur on any of the fused rings.

[0265] “Spiro heterocyclyl” or “spiro heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form spiro structure with, i.e., share one common atom with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the spiro structure is embedded.

[0266] “Bridged heterocyclyl” or “bridged heterocycle” refers to ring systems wherein the heterocyclyl group, as defined above, form bridged structure with, i.e., share more than two atoms (as such, share more than one bonds) with, one or more heterocyclyl or carbocyclyl groups, as defined above, wherein the point of attachment is on the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. In such instances, the number of ring members designates the total number of ring members of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded. When substitution is indicated, unless otherwise specified, substitution can occur on any of the heterocyclyl or carbocyclyl rings in which the bridged structure is embedded.

[0267] “Heterocyclylene” as used herein, refers to a heterocyclyl group wherein two hydrogens are removed to provide a divalent radical. The divalent radical may be present on different atoms or the same atom of the heterocyclylene group. When a range or number of ring members is provided for a particular “heterocyclylene” group, it is understood that the range or number refers to the number of ring members in the heterocyclylene group. A “heterocyclylene” group may be substituted or unsubstituted with one or more substituents as described herein.

[0268] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl as defined herein. Ci-6 alkoxy refers to the group -OR, wherein each R is Ci-6 alkyl, as defined herein. Exemplary Ci-6 alkyl is set forth above.

[0269] “Alkylamino” as used herein, refers to the group -NHR or -NR2, wherein each R is independently alkyl, as defined herein. C1-6 alkylamino refers to the group -NHR or -NR2, wherein each R is independently C1-6 alkyl, as defined herein. Exemplary C1-6 alkyl is set forth above.

[0270] “Oxo” refers to =O, When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atomAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure / tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.

[0271] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In some embodiments, the halo group is either fluoro or chloro.

[0272] “Protecting group” as used herein is art “rec gnized and refers to a chemical moiety introduced into a molecule by chemical modification of a functional group (e.g., hydroxyl, amino, thio, and carboxylic acid) to obtain chemoselectivity in a subsequent chemical reaction, during which the unmodified functional group may not survive or may interfere with the chemical reaction. Common functional groups that need to be protected include but not limited to hydroxyl, amino, thiol, and carboxylic acid. Accordingly, the protecting groups are termed hydroxyl-protecting groups, amino-protecting groups, thiol-protecting groups, and carboxylic acid-protecting groups, respectively.

[0273] Common types of hydroxyl -protecting groups include but not limited to ethers (e.g., methoxymethyl (MOM), P-Methoxyethoxymethyl (MEM), tetrahydropyranyl (THP), p-methoxyphenyl (PMP), / -butyl, triphenylmethyl (Trityl), allyl, and benzyl ether (Bn)), silyl ethers (e.g., / -butyldiphenylsilyl (TBDPS), trimethylsilyl (TMS), tri isopropyl silyl (TIPS), tri- / .w-propylsilyloxymethyl (TOM), and t-butyldimethylsilyl (TBDMS)), and esters (e.g., pivalic acid ester (Piv) and benzoic acid ester (benzoate; Bz))

[0274] Common types of amino-protecting groups include but not limited to carbamates e.g., / -butyl oxy carbonyl (Boe), 9-fluorenylmethyloxycarbonyl (Fmoc), -methoxybenzyl carbonyl (Moz or MeOZ), 2,2,2-trichloroethoxycarbonyl (Troc), and benzyl carbamate (Cbz)), esters (e.g., acetyl (Ac); benzoyl (Bz), tri fluoroacetyl, and phthalimide), amines (e.g., benzyl (Bn), -methoxybenzyl (PMB), p-methoxyphenyl (PMP), and tri phenyl methyl (trityl)), and sulfonamides (e.g., tosyl (Ts), N-alkyl nitrobenzenesulfonamides (Nosyl), and 2-nitrophenylsulfenyl (Nps)).

[0275] Common types of thiol-protecting groups include but not limited to sulfide (e.g., p-methylbenzyl (Mob), / -butyl, acetamidomethyl (Acm), and triphenylmethyl (Trityl)).

[0276] Common types of carboxylic acid-protecting groups include but not limited to esters (e.g., methyl ester, tri phenyl methyl (Trityl), / -butyl ester, benzyl ester (Bn), S-t-butyl ester, silyl esters, and orthoesters) and oxazoline.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0277] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and claims. The disclosure is not intended to be limited in any manner by the above exemplary listing of substituents.Other Definitions

[0278] “Antibody” is used in the broadest sense and specifically encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity. “Antibody fragment” and all grammatical variants thereof as used herein are defined as a portion of an intact antibody comprising the antigen binding site or variable region of the intact antibody, wherein the portion is free of the constant heavy chain domains (i.e., CH2, CH3, and CH4, depending on antibody isotype) of the Fc region of the intact antibody. Examples of antibody fragments include Fab, Fab', Fab'-SH, F(ab')2, and Fv fragments; diabodies; any antibody fragment that is a polypeptide having a primary structure consisting of one uninterrupted sequence of contiguous amino acid residues (referred to herein as a “single-chain antibody fragment” or “single chain polypeptide”), including without limitation (1) single-chain Fv (scFv) molecules; (2) single chain polypeptides containing only one light chain variable domain, or a fragment thereof that contains the three CDRs of the light chain variable domain, without an associated heavy chain moiety; (3) single chain polypeptides containing only one heavy chain variable region, or a fragment thereof containing the three CDRs of the heavy chain variable region, without an associated light chain moiety; (4) nanobodies comprising single Ig domains from non-human species or other specific singledomain binding modules; and (5) multispecific or multivalent structures formed from antibody fragments. In an antibody fragment comprising one or more heavy chains, the heavy chain(s) can contain any constant domain sequence (e.g., CHI in the IgG isotype) found in a non-Fc region of an intact antibody, and / or can contain any hinge region sequence found in an intact antibody, and / or can contain a leucine zipper sequence fused to or situated in the hinge region sequence or the constant domain sequence of the heavy chain(s). “Antibody” refers to a polypeptide comprising an antigen binding region (including the complementarity determining region (CDRs)) from an immunoglobulin gene or fragments thereof. The term “antibody” specifically encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that exhibit the desired biological activity. An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identicalAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa) connected by disulfide bonds. Each chain is composed of structural domains, which are referred to as immunoglobulin domains. These domains are classified into different categories by size and function, e.g., variable domains or regions on the light and heavy chains (VL and VH, respectively) and constant domains or regions on the light and heavy chains (CL and CH, respectively). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids, referred to as the paratope, primarily responsible for antigen recognition, i.e., the antigen binding domain. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. IgG antibodies are large molecules of about 150 kDa composed of four peptide chains. IgG antibodies contain two identical class y heavy chains of about 50 kDa and two identical light chains of about 25 kDa, thus a tetrameric quaternary structure. The two heavy chains are linked to each other and to a light chain each by disulfide bonds. The resulting tetramer has two identical halves, which together form the Y-like shape. Each end of the fork contains an identical antigen binding domain. There are four IgG subclasses (IgGl, IgG2, IgG3, and IgG4) in humans, named in order of their abundance in serum (i.e., IgGl is the most abundant). Typically, the antigen binding domain of an antibody will be most critical in specificity and affinity of binding to cancer cells. An antibody that targets a particular antigen includes a bispecific or multispecific antibody with at least one antigen binding region that targets the particular antigen. In some embodiments, the targeted monoclonal antibody is a bispecific antibody with at least one antigen binding region that targets tumor cells. “ Antibody construct” refers to an antibody or a fusion protein comprising (i) an antigen binding domain and (ii) an Fc domain. In some embodiments, the binding agent is an antigen-binding antibody “fragment,” which is a construct that comprises at least an antigen-binding region of an antibody, alone or with other components that together constitute the antigen-binding construct. Many different types of antibody “fragments” are known in the art, including, for instance, (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CHi domains, (ii) a F(ab’)2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, (iii) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (iv) a Fab’ fragment, which results from breaking the disulfide bridge of an F(ab’)2 fragment using mild reducing conditions, (v) a disulfide-stabilized Fv fragment (dsFv), and (vi) a single chain Fv (scFv), which is a monovalent molecule consisting of the two domains of the Fv fragment (i.e., VL and VH) joined by a synthetic linker whichAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)enables the two domains to be synthesized as a single polypeptide chain. The antibody or antibody fragments can be part of a larger construct, for example, a conjugate or fusion construct of the antibody fragment to additional regions. For instance, in some embodiments, the antibody fragment can be fused to an Fc region as described herein. In other embodiments, the antibody fragment (e.g., a Fab or scFv) can be part of a chimeric antigen receptor or chimeric T-cell receptor, for instance, by fusing to a transmembrane domain (optionally with an intervening linker or “stalk” (e.g., hinge region)) and optional intercellular signaling domain. For instance, the antibody fragment can be fused to the gamma and / or delta chains of a T-cell receptor, so as to provide a T-cell receptor like construct that binds TROP2. In yet another embodiment, the antibody fragment is part of a bispecific T-cell engager (BiTEs) comprising a CD19 or CD3 binding domain and linker. “Epitope” means any antigenic determinant or epitopic determinant of an antigen to which an antigen binding domain binds (i.e., at the paratope of the antigen binding domain). Antigenic determinants usually consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. The terms “Fc receptor” or “FcR” refer to a receptor that binds to the Fc region of an antibody. There are three main classes of Fc receptors: (1) FcyR which bind to IgG, (2) FcaR which binds to IgA, and (3) Fce. R which binds to IgE. The FcyR family includes several members, such as Fcyl (CD64), FcyRIIA (CD32A), FcyRIIB (CD32B), FcyRIIIA (CD16A), and FcyRIIIB (CD16B). The Fey receptors differ in their affinity for IgG and also have different affinities for the IgG subclasses (e.g., IgGl, IgG2, IgG3, and IgG4).

[0279] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0280] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, tri methyl acetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxy naphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanol amine, diethanolami ne, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkyl ammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

[0281] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle aged adult or senior adult) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0282] An “effective amount” means the amount of a compound that, when administered to a subject for treating or preventing a disease, is sufficient to affect such treatment or prevention. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A “therapeutically effective amount” refers to the effective amount for therapeutic treatment. A “prophylatically effective amount” refers to the effective amount for prophylactic treatment.

[0283] “Preventing”, “prevention” or “prophylactic treatment” refers to a reduction in risk of acquiring or developing a disease or disorder i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject not yet exposed to a disease-causing agent, or in a subject who is predisposed to the disease in advance of disease onset).

[0284] The term “prophylaxis” is related to “prevention,” and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization, and the administration of an anti-malarial agent such as chloroquine, inAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0285] “Treating” or “treatment” or “therapeutic treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0286] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability or within statistical experimental error, and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. In some embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% of the stated number or numerical range. In some embodiments, the number or numerical range vary by 1%, 2%, 3%, 4%, or 5% of the stated number or numerical range. In some embodiments, the number or numerical range vary by 1%, 2%, or 3% of the stated number or numerical range.

[0287] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other some embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of' or “consist essentially of' the described features.

[0288] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” may refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B onlyAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)(optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0289] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by ter s of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary' meaning as used in the field of patent law.

[0290] As used herein, when a moiety is “optionally substituted with one or more A, B, C, D, or E,” it is understood that the moiety is optionally substituted with one more substituent, wherein each substituent is independently selected from A, B, C, D, and E.

[0291] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B” ) may refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0292] While the present teachings have been described in conjunction with various embodiments and examples, it is not intended that the present teachings be limited to such embodiments or examples. On the contrary, the present teachings encompass variousAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.

[0293] While various inventive embodiments have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the function and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the inventive embodiments described herein. More generally, those skilled in the art will readily appreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the inventive teachings is / are used. Those skilled in the art will recognize many equivalents to the specific inventive embodiments described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, inventive embodiments may be practiced otherwise than as specifically described and claimed. Inventive embodiments of the present disclosure are directed to each individual feature, system, article, material, kit, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, kits, and / or methods, if such features, systems, articles, materials, kits, and / or methods are not mutually inconsistent, is included within the inventive scope of the present disclosure.

[0294] The claims should not be read as limited to the described order or elements unless stated to that effect. It should be understood that various changes in form and detail may be made by one of ordinary skill in the art without departing from the spirit and scope of the appended claims. All embodiments that come within the spirit and scope of the following claims and equivalents thereto are claimed.EXEMPLARY EMBODIMENTS

[0295] Exemplary Embodiment No. 1. A compound of Formula I:T-L-C (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:C is of Formula 1-1Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)wherein:** denotes attachment to L;denotes a single bond or a double bond, as valency permits;B1is absent, N, or C(RB);B2is N, O, S, or C(RB);B3is N or C;B4is N or C(RB);each RBis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;C1is absent or C(Rcl)2;C2is O, C(=O), C(Rcl), or C(Rc,)2;C3is absent, N(RC2), C(Rcl), or C(Rcl)2;each RC1is independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;each RC2is independently hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;Dlis absent or C(RD)z;each RDis independently hydrogen, halogen, -CN, -NO2, -OH, -NHz, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;L is of Formula 1-2wherein:Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)* denotes attachment to T, and ** denotes attachment to C;each L’ is independently -C(::::O)-, -C(::::O)N(RL)-, -N(RL)C(=O)-, -C(=O)O-, -OC(=O)-, -N(RL)-, -O-, -O-(Ci-6 alkylene)-, -(Ci-6 alkylene)-O-, -S-, -S(=O)2-, Ci-6 alkylene, Ci -6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, Cs-io arylene, or 5- to 10-membered heteroarylene, wherein the -O-(Ci-6 alkylene)-, -(C1-6 alkylene)-O-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, Ce-io arylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, - OH, -NH2, C1-6 alkyl, or C1-6 alkoxy;each occurrence of R1is independently hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3- to 8-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -C(=O)Ra, -C(=O)ORa, or -C(=O)N(Ra)2, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, or 3- to 8-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; andeach Raindependently is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;1 is an integer selected from 0 to 10;T isi) of Formula I-3-i(I-3-i),wherein:** denotes attachment to L;G1is N or C(RG1);G2is N or C(RG2);Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)each RHis independently hydrogen or Ci-6 alkyl, wherein the Ci-e alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RG1, R2, and RG3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2;J1is N; and RJ1is hydrogen or C1-6 lkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RJIand RK4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or J1is C; and RJ1and RK4, together with the intervening atoms to which they are attached, form Co aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;K2is N or C(RK2);K3is N or C(RK3); andRK1, RK2, RK3, and RK4are independently hydrogen, halogen, -CN, -NO2, -OH, -NHz, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Co-10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;ii) of Formula I-3-iiAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)wherein:** denotes attachment to L;RQ1is hydrogen or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -Nth, -OH, or -NH;RQ2and RQ3are 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, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, Ci -6 alkylamino, C 2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Co-io ryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz;S1is CRS1or N;S3is CRS3orN;andRS1, RS2, and RS3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, C’6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-i2 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;M1is N; and RM1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz; or RMland RT4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NHz, or Ci-6 alkyl; or Mlis C; and RM1and Rr4, together with the intervening atoms to which they are attached, form C& aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NHz, T2is N or C(RT2);T3is N or C(RT3); andRT1, RT2, RT3, and RT4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-memberedAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;oriii) of Formula 1-3-iiiwherein:** denotes attachment to L;each RNis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RP3is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; andR4is C1-6 alkyl, Ci-6 alkoxy, or Cue alkylamino, wherein the Ci-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;U1is N; and RU1is hydrogen or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RU1and RV4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl or 6- membered heteroaryl, wherein the 6-membered heterocyclyl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or Ci-6 alkyl; or U1is C; and RUiand RV4, together with the intervening atoms to which they are attached, form C6 aryl or 6-membered heteroaryl, wherein the C6 aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)V2is N or C(RV2);V3is N or C(RV3); andRVi, RV2, RV3, and RV4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci -6 alkyl, Ci-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0296] Exemplary Embodiment No. 2. The compound of Exemplary Embodiment No, 1, wherein T is of Formula I-3-i.

[0297] Exemplary Embodiment No. 3. The compound of Exemplary Embodiment No. 1 or 2, wherein each RHis independently hydrogen.

[0298] Exemplary Embodiment No. 4. The compound of Exemplary Embodiment No. 1 or 2, wherein each RHis independently C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0299] Exemplary Embodiment No. 5. The compound of Exemplary Embodiment No. 4, wherein each RHis independently methyl.

[0300] Exemplary Embodiment No. 6. The compound of any one of Exemplary Embodiment Nos. 1-5, wherein G1is N and G2is C(RG2), or G1is C(RG1) and G2is N.

[0301] Exemplary Embodiment No. 7. The compound of any one of Exemplary Embodiment Nos. 1-5, wherein G1is C(RG1) and G2is C(RG2).

[0302] Exemplary Embodiment No. 8. The compound of any one of Exemplary Embodiment Nos. 1-7, wherein RG1, RG2, and RG3are independently hydrogen, C1-6 alkyl, or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl or 3- to 12-membered heterocyclyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2.

[0303] Exemplary Embodiment No. 9. The compound of any one of Exemplary Embodiment Nos. 1-8, wherein J1is N.

[0304] Exemplary Embodiment No. 10. The compound of Exemplary Embodiment No. 9, wherein RJ1is C1-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0305] Exemplary Embodiment No. 11. The compound of Exemplary Embodiment No, 10, wherein RJ1and RK4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C i-6 alkyl.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0306] Exemplary Embodiment No. 12. The compound of any one of Exemplary Embodiment Nos, 1-8, wherein J1is C.

[0307] Exemplary Embodiment No. 13. The compound of Exemplary Embodiment No.12, wherein RJiand RK4, together with the intervening atoms to which they are attached, form C’6 aryl.

[0308] Exemplary Embodiment No. 14. The compound of any one of Exemplary Embodiment Nos. 1-13, wherein K2is N and K3is N.

[0309] Exemplary Embodiment No. 15. The compound of any one of Exemplary Embodiment Nos. 1-13, wherein K2is N and K3is C(RK3), or K2is C(RK2) and K3is N.

[0310] Exemplary Embodiment No. 16. The compound of any one of Exemplary Embodiment Nos. 1-13, wherein K2is C(RK2) and K3is C(RK3), wherein RK2is Ci-6 alkyl optionally substituted with one or more halogen.

[0311] Exemplary Embodiment No. 17. The compound of Exemplary Embodiment No. 1, wherein T is of Formula I-3-ii.

[0312] Exemplary Embodiment No. 18. The compound of Exemplary Embodiment No. 1 or 17, wherein RQiis Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, - OH, or -NH2.

[0313] Exemplary Embodiment No. 19. The compound of Exemplary Embodiment No, 18, wherein RQris methyl.

[0314] Exemplary Embodiment No. 20. The compound of any one of Exemplary Embodiment Nos. 1 and 17-19, wherein RQ2and RQ3are independently hydrogen and Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2

[0315] Exemplary Embodiment No. 21. The compound of Exemplary Embodiment No.20, wherein RQ2is methyl and RQ3is hydrogen.

[0316] Exemplary Embodiment No. 22. The compound of any one of Exemplary Embodiment Nos. 1 and 17-21, wherein RS1and RS3are independently hydrogen.

[0317] Exemplary Embodiment No. 23. The compound of any one of Exemplary Embodiment Nos. 1 and 17-22, wherein RS2is 3- to 12-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0318] Exemplary Embodiment No. 24. The compound of Exemplary Embodiment No.23, wherein RS2isAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0319] Exemplary Embodiment No. 25. The compound of any one of Exemplary Embodiment Nos, 1 and 17-24, wherein M1is N.

[0320] Exemplary Embodiment No. 26. The compound of Exemplary Embodiment No.25, wherein RM1is C1-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, - OH, or -NH2.

[0321] Exemplary Embodiment No. 27. The compound of Exemplary Embodiment No.25, wherein RM1and RT4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, - NH2, orCi-6 alkyl.

[0322] Exemplary Embodiment No. 28. The compound of any one of Exemplary Embodiment Nos, 1 and 17-27, wherein T2is N and T3is N.

[0323] Exemplary Embodiment No. 29. The compound of any one of Exemplary Embodiment Nos. 1 and 17-27, wherein T2is N and T3is C(RTJ), or T2is C(RT2) and T3is N.

[0324] Exemplary Embodiment No. 30. The compound of any one of Exemplary Embodiment Nos. 1 and 17-27, wherein T2is C(RT2) and T3is C(RTJ), wherein RT2is halogen or C1-6 alkyl optionally substituted with one or more halogen.

[0325] Exemplary Embodiment No. 31. The compound of Exemplary Embodiment No. 1, wherein T is of Formula I-3-iii.

[0326] Exemplary Embodiment No. 32. The compound of Exemplary Embodiment No. 1 or 31, wherein R4is methyl.

[0327] Exemplary Embodiment No. 33. The compound of Exemplary Embodiment No. 1, 31, or 32, wherein each RNis independently hydrogen.

[0328] Exemplary Embodiment No. 34. The compound of any one of Exemplary Embodiment Nos. 1 and 31-33, wherein RP3is Ci-6 alkyl or 3- to 12-membered heterocyclyl, wherein the Ci-6 alkyl or 3- to 12-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

[0329] Exemplary Embodiment No. 35. The compound of Exemplary Embodiment No.34, wherein RP3is ethylor

[0330] Exemplary Embodiment No. 36. The compound of any one of Exemplary Embodiment Nos. 1 and 31-35, wherein U1is N.

[0331] Exemplary Embodiment No. 37. The compound of Exemplary Embodiment No.36, wherein RU1and RV4, together with the intervening atoms to which they are attached, formAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, - NH2, or C1-6 alkyl.

[0332] Exemplary Embodiment No. 38. The compound of any one of Exemplary Embodiment Nos. 1 and 31-35, wherein U1is C.

[0333] Exemplary Embodiment No. 39. The compound of Exemplary Embodiment No.38, wherein RU1and RV4, together with the intervening atoms to which they are attached, form Ce and.

[0334] Exemplary Embodiment No. 40. The compound of any one of Exemplary Embodiment Nos. 1 and 31-39, wherein V2is N and V3is N.

[0335] Exemplary Embodiment No. 41. The compound of any one of Exemplary Embodiment Nos. 1 and 31-39, wherein V2is N and V3is C(RV3), or V2is C(RV2) and V3is N.

[0336] Exemplary Embodiment No. 42. The compound of any one of Exemplary Embodiment Nos. 1 and 31-39, wherein V2is C(RV2) and V3is C(R3'3), wherein R3'2is Ci-6 alkyl optionally substituted with one or more halogen.

[0337] Exemplary Embodiment No. 43. The compound of any one of Exemplary Embodiment Nos. 1-42, wherein B!is C(RB), B2is C(RB), B3is C, and B4is C(RB).

[0338] Exemplary Embodiment No. 44. The compound of any one of Exemplary Embodiment Nos. 1-42, wherein B1is C(RB), B2is C(RB), B3is C, and B4is N.

[0339] Exemplary Embodiment No. 45. The compound of any one of Exemplary Embodiment Nos, 1-42, wherein B1is C(RB), B2is N, B3is C, and B4is C(RB).

[0340] Exemplary Embodiment No. 46. The compound of any one of Exemplary Embodiment Nos. 1-42, wherein B1is N, B2is C(RB), B3is C, and B4is C(RB).

[0341] Exemplary Embodiment No. 47. The compound of any one of Exemplary Embodiment Nos. 1-42, wherein B1is absent, B2is S or O, B3is C, and B4is C(RB).

[0342] Exemplary Embodiment No. 48. The compound of any one of Exemplary Embodiment Nos. 1-42, wherein B1is absent, B2is N, B3is N, and B4is C(RB).

[0343] Exemplary Embodiment No. 49. The compound of any one of Exemplary Embodiment Nos. 1-48, wherein each RBis independently hydrogen or halogen.

[0344] Exemplary Embodiment No. 50. The compound of any one of Exemplary Embodiment Nos. 1-49, wherein C1is absent, C2is C(Rc,)2, and C3is C(Rcl)2.

[0345] Exemplary Embodiment No. 51. The compound of any one of Exemplary Embodiment Nos. 1-49, wherein C1is C(Rcl)2, C2is C(Rc,)2, and CJis C(Rcl)2.

[0346] Exemplary Embodiment No. 52. The compound of any one of Exemplary Embodiment Nos. 1-49, wherein C!is C(Rcl)2, C2is O, and C3is C(RCi)2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0347] Exemplary Embodiment No. 53. The compound of any one of Exemplary Embodiment Nos. 1-49, wherein C1is C(Rcl)2, C2is C(Rcl), and C3is C(Rcl).

[0348] Exemplary Embodiment No. 54. The compound of any one of Exemplary Embodiment Nos. 1-49, wherein C1is absent, C2is C(Rcl)2, and C3is absent.

[0349] Exemplary Embodiment No. 55. The compound of any one of Exemplary Embodiment Nos. 1-49, wherein C1is absent, C2is C(=O), and C3is N(RC2).

[0350] Exemplary Embodiment No. 56. The compound of any one of Exemplary Embodiment Nos. 1-54, wherein each RC1is independently hydrogen, halogen, or Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2

[0351] Exemplary Embodiment No. 57. The compound of any one of Exemplary Embodiment Nos, 1-56, wherein D1is C(RD)2.

[0352] Exemplary Embodiment No. 58. The compound of any one of Exemplary Embodiment Nos. 1-57, wherein each RDis independently hydrogen.

[0353] Exemplary Embodiment No. 59. The compound of any one of Exemplary Embodiment Nos. 1-58, wherein each L’ is independently -C(=O)-, -C(=O)N(RL)-, - N(RL)C(=O)-, -N(RL’)-, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5- to 10-membered heteroarylene, wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5- to 10- membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, or Ci-6 alkoxy.

[0354] Exemplary Embodiment No. 60. The compound of any one of Exemplary Embodiment Nos. 1-59, wherein L is *-(5- to 6-membered heteroarylene)-C(=O)N(RL)-(Ci-e alkylene)-(C2-6 alkenyl ene)-** or *-(5- to 6-membered heteroarylene)-C(=O)N(RL)-(Ci-6 alkylene)-(C2-6 alkynylene)-**, wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, or C1-6 alkoxy.

[0355] Exemplary Embodiment No. 61. The compound of Exemplary Embodiment No.60, wherein L is *-(pyridinylene)-C(=O)N(H)-(Ci-6 alkylene)-(C2-6 alkenylene)-** or *- (pyridinylene)-C(=O)N(H)-(C]-6 alkylene)-(C2-6 alkynylene)-**, wherein the C1-6 alkylene, C2- 6 alkenylene, C2-6 alkynylene, or pyridinylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, or C1-6 alkoxy.

[0356] Exemplary Embodiment No. 62. A compound selected from the compounds in Tables 1-3 and pharmaceutically acceptable salts thereof.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0357] Exemplary Embodiment No. 63. A pharmaceutical composition comprising the compound of any one of Exemplary / Embodiment Nos. 1-62, and a pharmaceutically acceptable excipient.

[0358] Exemplary Embodiment No. 64. A method of degrading a protein in a subject or biological sample comprising administering the compound of any one of Exemplary Embodiment Nos. 1-62 to the subject or contacting the biological sample with the compound of any one of Exemplary Embodiment Nos. 1-62.

[0359] Exemplary Embodiment No. 65. Use of the compound of any one of Exemplary Embodiment Nos. 1-62 in the manufacture of a medicament for degrading a protein in a subject or biological sample.

[0360] Exemplary Embodiment No. 66. A compound of any one of Exemplary Embodiment Nos. 1-62 for use in degrading a protein in a subject or biological sample.

[0361] Exemplary Embodiment No. 67. The method, use, or compound for use of any one of Exemplary Embodiment Nos. 64-66, wherein the protein is p300 or CBP.

[0362] Exemplary Embodiment No. 68. A method of treating a p300-mediated disorder comprising administering to a patient in need thereof a compound of any one of Exemplary Embodiment Nos. 1-62.

[0363] Exemplary Embodiment No. 69. Use of a compound of any one of Exemplary Embodiment Nos. 1-62 in the manufacture of a medicament for treating a p300-mediated disorder.

[0364] Exemplary Embodiment No. 70. A compound of any one of Exemplary Embodiment Nos. 1-62 for use in treating a p300-mediated disorder.

[0365] Exemplary Embodiment No. 71. The method, use, or compound for use of any one of Exemplary Embodiment Nos. 68-70, wherein the p300-mediated disorder is cancer, an inflammatory disorder, or an autoimmune disease.EXAMPLES

[0366] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.I. SYNTHESIS AND CHARACTERIZATION OF INTERMEDIATES AND COMPOUNDS A1-C9Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)

[0367] In the following examples, the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification.

[0368] In obtaining the compounds described in the examples below and the corresponding analytical data, the following experimental and analytical protocols were followed unless otherwise indicated.

[0369] Unless otherwise stated, reaction mixtures were magnetically stirred at room tem...

Claims

Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)CLAIMS WHAT IS CL AIMED IS:

1. A compound of F ormul a I:T-L-C (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:C is of Formula 1-1wherein:** denotes attachment to L;denotes a single bond or a double bond, as valency permits;B’ is absent, N, or C(RB);B2is N, O, S, or C(RB);B3is N or C;B4is N or C(RB);each RBis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;C1is absent or C(Rcl)2;C2is O, C(==O), C(Rcl), or C(Rcl)2;C3is absent, N(RC2), C(RC!), or C(RC!)2;each RCiis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;each RC2is independently hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;D1is absent or C(RD)2;Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)each RDis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or Ci-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;L is of Formula 1-2wherein:* denotes attachment to T, and ** denotes attachment to C;each L’ is independently -C(=O)-, -C(=O)N(RL)-, -N(RL)C(=O)-, -C(=O)O-, - OC(=O)-, -N(RL)-, -O-, -O-(Ci-6 alkylene)-, -(C1-6 alkylene)-O-, -S-, -S(=O)2-, C1-6 alkylene, Ci -6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, Cs-io arylene, or 5- to 10-membered heteroarylene, wherein the -O-(Ci-6 alkylene)-, -(C1-6 alkylene)-O-, C1-6 alkylene, Ci-6 heteroalkylene, C2-6 alkenylene, C2-6 alkynylene, C3-12 carbocyclylene, 3- to 12-membered heterocyclylene, Cs-io arylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, - OH, -NH2, C 1-6 alkyl, or C1-6 alkoxy;each occurrence of R1is independently hydrogen, Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, 3- to 8-membered heterocyclyl, -S(=O)2Ra, -S(=O)2ORa, -S(=O)2N(Ra)2, -C(=O)Ra, -C(=O)ORa, or -C(=O)N(Ra)2, wherein the C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 carbocyclyl, or 3- to 8-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; andeach Raindependently is hydrogen, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;1 is an integer selected from 0 to 10;T isi) of Formula I-3-iAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)wherein:** denotes attachment to L;Glis N or C(RGi);G2isN or C(RG2);each RHis independently hydrogen or Ci-6 alkyl, wherein the Ci-e alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RGi, R2, and RG3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-e alkyl, C1-6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2;J1is N; and RJ1is hydrogen or C1-6 lkyl, wherein the C1-6 lkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RJIand RK4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or J1is C; and R1and RK4, together with the intervening atoms to which they are attached, form Ce aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;K2is N or C(RK2);K3is N or C(RK3); andRK1, RK2, RK3, and RK4are independently hydrogen, halogen, -CN, -NO2, -OH, -NHz, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci- 6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-memberedAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)heterocyclyl, Ce-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;ii) of Formula I-3-iiwherein:**denotes attachment to L;RQiis hydrogen or Ci-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RQ2and RQ3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C 1-6 alkyl amino, C2-6 alkenyl, C 2-6 alkynyl, C’3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Cs-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C1-6 alkoxy, C 1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-ioaryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NI-I2;S1is CRslorN;S3is CRS3orN;andRS1, RS2, and RS3are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, Ci-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;Mlis N; and RM1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RM1and RT4, together with the intervening atoms to which they are attached, form 5- to 6-membered heterocyclyl or 5-Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)membered heteroaryl, wherein the 5- to 6-membered heterocyclyl or 5-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or Mlis C; and RM1and Rr4, together with the intervening atoms to which they are attached, form C& and or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;T2is N or C(RT2);T3is N or C(RT3); andRT1, RT2, RT3, and RT4are independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, Ci-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 is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;oriii) of Formula I-3-iii(I-3-iii),wherein:** denotes attachment to L;each RNis independently hydrogen, halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl, wherein the Ci-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;RPjis hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, C6-10 aryl, or 5- toAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; andR4is C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylamino, wherein the C1-6 alkyl, C1-6 alkoxy, or Ci-6 alkylamino is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;U1is N; and RU1is hydrogen or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or RU1and RV4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl or 6- membered heteroaryl, wherein the 6-membered heterocyclyl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl; or U1is C; and RU1and RV4, together with the intervening atoms to which they are attached, form Ce aryl or 6-membered heteroaryl, wherein the Ce aryl or 6-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2;V2is N or C(RV2);V3is N or C(RV3); andRVi, RV2, RV3, and RV4are independently hydrogen, halogen, -CN, -NO2, -OH, -NHz, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12- membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkylamino, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocyclyl, 3- to 12-membered heterocyclyl, Ce-io aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH22, The compound of claim 1, wherein T is of Formula I-3-i.

3. The compound of claim 1 or 2, wherein each RHis independently hydrogen or methyl.

4. The compound of any one of claims 1-3, wherein:(i) Glis N and G2is C(R2);(ii) G1is C(RG1) and G2is N; or(iii) G1is C(RGi) and G2is C(RG2).5, The compound of any one of claims 1-4, wherein RG1, RG2, and RG3are independently hydrogen, C1-6 alkyl, or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl or 3- to 12- membered heterocyclyl is optionally substituted with one or more oxo, halogen, -CN, -NO2, -OH, or -NH2.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)6. The compound of any one of claims 1-5, wherein J1is N, and(i) RJlis Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or(ii) RJ1and RK4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, - NH2, or C1-6 alkyl.

7. The compound of any one of cl aims 1 -6, wherein J1is C, and RJ1and RK4, together with the intervening atoms to which they are attached, form Ce aryl.

8. The compound of any one of claims 1-7, wherein:(i) K2is N and K3is N;(ii) K2is N and K3is C(RK3);(iii) K2is C(RK2) and K3is N; or(iv) K2is C(RK2) and K3is C(RK3), wherein RK2is C1-6 alkyl optionally substituted with one or more halogen.

9. The compound of claim 1, wherein T is of Formula I-3-ii.

10. The compound of claim 1 or claim 9, wherein RQ1is methyl, RQ2is methyl, and RQ3is hydrogen.

11. The compound of any one of cl aims 1, 9, and 10, wherein RS1and RS3are independently hydrogen, and RS2is 3- to 12-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH212. The compound of any one of claims 1 and 9-11, wherein RS2isAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)13. The compound of any one of claims 1 and 9-12, wherein M1is N, and(i) RM1is Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2; or(ii) RM1and RT4, together with the intervening atoms to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, - NH2, or C j-6 alkyl.

14. The compound of any one of claims 1 and 9-13, wherein:(i) T2is N and T3is N;(ii) T2is N and T3is C(RT3);(iii) T2is C(RT2) and T3is N; or(iv) T2is C(R12) and T3is C(R13), wherein R is halogen or Ci-e alkyl optionally substituted with one or more halogen.

15. The compound of claim 1, wherein T is of Formula I-3-iii.

16. The compound of claim 1 or claim 15, whereinR4is methyl;each RNis independently hydrogen; andRP3is C1-6 alkyl or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl or 3- to 12-membered heterocyclyl is optionally substituted with one or more halogen, -CN, -NO2, -OH, or -NH2.

17. The compound of any one of claims 1, 15, and 16, wherein RP3is ethyl or18. The compound of any one of claims 1 and 15-17, wherein U1is N, and RU1and R3'4, together with the intervening ato s to which they are attached, form 6-membered heterocyclyl optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, or C1-6 alkyl.

19. The compound of any one of claims 1 and 15-18, wherein U1is C, and RU1and R3'4, together with the intervening atoms to which they are attached, form Ce aryl.

20. The compound of any one of claims 1 and 15-19, wherein:Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)(i) V2is N and V3is N;(ii) V2is N and V3is C(R3);(iii) V2is C(RV2) and V3is N;(iv) V2is C(RV2) and VJis C(RV3), wherein R'2is Ci-6 alkyl optionally substituted with one or more halogen.

21. The compound of any one of claims 1-20, wherein:(i) B1is C(RB), B2is C(RB), B3is C, and B4is C(RB);(ii) B1is C(RB), B2is C(RB), B3is C, and B4is N;(iii) B1is C(RB), B2is N, B3is C, and B4is C(RB);(iv) B1is N, B2is C(RB), B3is C, and B4is C(RB);(v) B1is absent, B2is S or O, B3is C, and B4is C(RB); or(vi) B1is absent, B2is N, B3is N, and B4is C(RB).

22. The compound of any one of claims 1-21, wherein each RBis independently hydrogen or halogen.

23. The compound of any one of clai s 1-22, wherein:(i) C1is absent, C2is C(RC1)2, and C3is C(Rcl)2;(ii) C1is C(RC1)2, C2is C(Rcl)2, and C3is C(Rcl)2;(iii) Clis C(RC1)2, C2is O, and C3is C(Rcl)2;(iv) C1is C(RC1)2, C2is C(Rcl), and C3is C(Rcl);(v) Clis absent, C2is C(RC!)2, and C3is absent; or(vi) C1is absent, C2is C(=O), and C3is N(RC2).

24. The compound of any one of claims 1-23, wherein each RC1is independently hydrogen, halogen, or Ci-6 alkyl optionally substituted with one or more halogen, -CN, -NO2, -OH, or - NH2.

25. The compound of any one of claims 1-24, wherein Dlis C(RD)2.

26. The compound of any one of claims 1-25, wherein each RDis independently hydrogen.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)27. The compound of any one of claims 1-26, wherein each L’ is independently -C(=O)-, -C(::::O)N(RL’)-, -N(RL)C(=O)~, -N(RL’)-, CI-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5-to 10-membered heteroarylene, wherein the C 1-6 alkylene, C2-6 alkenyl ene, C2-6 alkynylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, or C1-6 alkoxy.

28. The compound of any one of claims 1-27, wherein L is *-(5- to 6-membered heteroarylene)-C(=O)N(RL)-(Ci-6 alkylene)-(C2-6 alkenylene)-** or *-(5- to 6-membered heteroarylene)-C(=O)N(RL)-(Ci-6 alkylene)-(C2-6 alkynylene)-**, wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or 5- to 10-membered heteroarylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, or C1-6 alkoxy.

29. The compound of claim 28, wherein L is *-(pyridinylene)-C(=O)N(H)-(Ci-6 alkylene)-(C2-6 alkenylene)-** or *-(pyridinylene)-C(=O)N(H)-(Ci-6 alkyl ene )-(C2-6 alkynylene)-**, wherein the C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, or pyridinylene is optionally substituted with one or more halogen, -CN, -NO2, -OH, -NH2, C1-6 alkyl, or C1-6 alkoxy.

30. The compound of claim 1, wherein the compound is of Formula I-a or I-b.or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein:Ri is hydrogen or Ci-6 alkyl optionally substituted with one or more halogen, -CN, - NO2, -OH, or -NH2.

31. The compound of claim 1 or claim 30, wherein T isAttorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)32. A compound selected from the compounds in Tables 1-3 and pharmaceutically acceptable salts thereof.

33. A pharmaceutical composition comprising the compound of any one of claims 1-32, and one or more pharmaceutically acceptable excipient.

34. A method of treating a p300-mediated disease or disorder comprising administering to a patient in need thereof a compound of any one of claims 1-32.

35. Use of a compound of any one of claims 1-32 in the manufacture of a medicament for treating a p300-mediated disease or disorder.

36. A compound of any one of claims 1-32 for use in treating a p300-mediated disease or disorder.Attorney Docket No.: 43807-02407 / WO (PRSC-104 / 001WO)37. The method, use, or compound for use of any one of claims 34-36, wherein the p300-mediated disease or disorder is cancer, an inflammatory disorder, or an autoimmune disease.

38. The compound of any one of claims 1-32, wherein the compound is conjugated with a conjugate partner.

39. A conjugate comprising the compound of any one of claims 1-32 and a conjugate partner.

40. The compound of claim 38 or the conjugate of claim 39, wherein the conjugate partner is an antibody.

41. The compound of claim 38 or the conjugate of claim 39, wherein the conjugate partner is a half-life extending moiety.

42. A method of preparing a compound according to any one of claims 1-32, or any intermediate in the Examples, according to a scheme of the present disclosure or a synthetic description in the Examples.

43. An intermediate described in one or more Examples,

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