Bicyclic and heterocyclic amide compounds

Abstract

Provided herein are compounds that stabilize immunoglobulin light chains, and pharmaceutically acceptable derivatives thereof. Also provided are pharmaceutical compositions containing the compounds and methods of using the compounds for treating a subject with light chain amyloidosis.

Description

Attorney Docket No. PRTE-018 / 01WO 345214-2084 BICYCLIC AND HETEROCYCLIC AMIDE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 641,313, filed on May 1, 2024, the contents of which are incorporated by reference herein in their entireties for all purposes. BACKGROUND

[0002] Light chain (LC) amyloidosis (AL amyloidosis) is a progressive and often fatal degenerative disease caused by monoclonal plasma cell proliferation, resulting in an abnormal free light chain (FLC) ratio and conformational changes within involved immunoglobulin light chains (iFLC) after secretion by clonal plasma cells that result in organ toxicity, e.g., cardiomyopathy, nephrotic syndrome and end-stage renal failure. Organ damage remains the major source of mortality and morbidity. Lambda light chains are more often amyloidogenic than the kappa light chains (~80%). The light chain conformational changes also often lead to light chain aggregation, which may also drive proteotoxicity in some post-mitotic tissues. The pathologic mechanisms of disease leading to organ toxicity include both toxicity of amyloidogenic LC and mass effects of deposits, both modulated by misfolded LC concentration.

[0003] Light chain amyloidosis patients are treated today by targeting the cancer component of this disease (proliferating clonal plasma cells) employing chemotherapy cocktails typically involving proteasome inhibitors (and, when possible, stem cell transplants), which ideally eliminate the clonal plasma cells secreting full-length light chains. However, complete clonal plasma cell eradication is achieved in only 30-40% of the patients and most eventually relapse. Restoration of organ function in treated patients is highly variable and often incomplete, resulting in poor outcomes. The current hematologic response criteria for AL amyloidosis define complete response (CR) as no evidence of monoclonal protein based on serum and urine immunofixation, as well as achieving a normal FLC ratio. The response criteria do not take the levels of iFLC into consideration. It has been shown that increased levels of iFLCs at the time of normal FLC ratio and complete or very good partial hematological response are associated with inferior incomes, i.e., lower organ response and lower overall survival. However, even low levels of amyloidogenic monoclonal FLC can result in organ dysfunction. Moreover, light chain amyloidosis patients exhibiting cardiac involvement are often too sick to tolerate chemotherapy and die within a year of diagnosis. 1 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0004] Thus, there is a need for additional treatments of light chain amyloidosis. The present disclosure addresses such need. SUMMARY

[0005] In some aspects, the present disclosure provides a compound of Formula (0):or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, R0a, R0band R0care as disclosed herein.

[0006] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein m, n, X, R1, R2a, R2b, R2c, R2d, Y, and T are as disclosed herein.

[0007] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein m, n, X, R1, R2a, R2b, R2c, R2d, Y, E, U1, U2, and RVare as disclosed herein.

[0008] In some aspects, the present disclosure provides a compound of Formula (I’’-i) or (I’’- ii):2 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein R1, Y, T, W, E, U1, U2, and RVare as disclosed herein.

[0009] In some aspects, the present disclosure provides a compound of Formula (I’’’-i) or (I’’’- ii):or a pharmaceutically acceptable salt thereof, wherein R1, Y, T, E, U1, U2, and RVare as disclosed herein.

[0010] In some aspects, the present disclosure provides a compound of Formula (VIII):or a pharmaceutically acceptable salt thereof, wherein m, n, X, R1, R2a, R2b, R2c, R2d, Y, RTa, RTb, RTb1, Z, ringdisclosed herein.

[0011] In some aspects, the present disclosure provides a compound selected from Tables 1-5, or a pharmaceutically acceptable salt thereof.

[0012] In some aspects, the present disclosure features pharmaceutical compositions comprising a compound described herein, and one or more pharmaceutically acceptable carriers or excipients.

[0013] In some aspects, the present disclosure provides a method of treating or preventing a disease (e.g., light chain amyloidosis) in a subject, comprising administering to the subject a 3 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 compound or composition provided herein (e.g., in a therapeutically effective amount).

[0014] In some aspects, the present disclosure provides a compound or composition provided herein, for treating or preventing a disease (e.g., light chain amyloidosis) in a subject.

[0015] In some aspects, the present disclosure provides use of a compound provided herein in the manufacture of a medicament for treating or preventing a disease (e.g., light chain amyloidosis) in a subject.

[0016] In some embodiments, the disease is light chain amyloidosis.

[0017] In some aspects, the present disclosure provides a method of treating or preventing light chain amyloidosis in a subject, comprising administering to the subject a compound or composition provided herein (e.g., in a therapeutically effective amount).

[0018] In some aspects, the present disclosure provides a compound or composition provided herein, for treating or preventing light chain amyloidosis in a subject.

[0019] In some aspects, the present disclosure provides use of a compound provided herein in the manufacture of a medicament for treating or preventing light chain amyloidosis in a subject.

[0020] In some aspects, the present disclosure provides a method of stabilizing immunoglobulin light chains in a subject, comprising administering to the subject a compound or composition provided herein (e.g., in a therapeutically effective amount).

[0021] In some aspects, the present disclosure provides a compound or composition provided herein, for stabilizing immunoglobulin light chains in a subject.

[0022] In some aspects, the present disclosure provides use of a compound provided herein in the manufacture of a medicament for stabilizing immunoglobulin light chains in a subject.

[0023] In some aspects, the present disclosure provides a method of preventing or lessening immunoglobulin light chain misfolding and / or endoproteolysis in a subject, comprising administering to the subject a compound or composition provided herein (e.g., in a therapeutically effective amount).

[0024] In some aspects, the present disclosure provides a compound or composition provided herein, for preventing or lessening immunoglobulin light chain misfolding and / or endoproteolysis in a subject.

[0025] In some aspects, the present disclosure provides use of a compound provided herein in the manufacture of a medicament for preventing or lessening immunoglobulin light chain misfolding and / or endoproteolysis in a subject.

[0026] In some embodiments, the immunoglobulin light chains are stabilized in a native conformation thereof. In some embodiments, the immunoglobulin light chains are dimers.

[0027] In some aspects, the present disclosure provides a method of maintenance therapy upon 4 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 recurrence of light chain amyloidosis following primary treatment by administering to a subject a compound or composition provided herein.

[0028] In some aspects, the present disclosure provides a compound or composition provided herein, for maintenance therapy upon recurrence of light chain amyloidosis following primary treatment.

[0029] In some aspects, the present disclosure provides use of a compound provided herein in the manufacture of a medicament for maintenance therapy upon recurrence of light chain amyloidosis following primary treatment.

[0030] In some aspects, the present disclosure provides a method of combination therapy using a compound or composition provided herein in combination with one or more additional active agents that treat light chain amyloidosis, deplete clonal plasma cells, stabilize immunoglobulin light chains, prevent or lessen immunoglobulin light chain misfolding and / or endoproteolysis, promote clearance of fibrils, or that are effective in maintenance therapy upon recurrence of light chain amyloidosis following primary treatment.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0032] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION Compounds of the Present Disclosure Compounds of Formula (0)

[0033] In some aspects, the present disclosure provides a compound of Formula (0): 5 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein: X1is N or C; X2is N, O, or CH; X3is N, O, or CR0d; R0dis H or optionally substituted C1-C6alkyl; R0ais halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6alkyl, wherein the -O(C1-C6alkyl), -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6alkyl is optionally substituted; R0bis -Lb1-Lb2; Lb1is absent or -O(C1-C6 alkylene)-; Lb2is 4- to 7-membered heterocyclyl, C3-C6cycloalkyl, or C1-C6alkyl, wherein the 4- to 7-membered heterocyclyl, C3-C6cycloalkyl, or C1-C6alkyl is optionally substituted; R0cis -Lc1-Lc2; Lc1is absent, -C(=O)-, -C(=O)-NH-, -C(=O)-NH-(C1-C6alkylene)-, -C(=O)-N(C1-C6alkyl)-, -C(=O)-O-, -C(=S)-, -S(=O)2-, -S(=O)2-NH-, -S(=O)2-NH-(C1-C6alkylene)-, or - S(=O)2-O-; and Lc2is H, C1-C6 alkyl, 4- to 12-membered heterocyclyl, or C3-C8 cycloalkyl, wherein the C1-C6alkyl, 4- to 12-membered heterocyclyl, or C3-C8cycloalkyl is optionally substituted. Compounds of Formula (I)

[0034] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 0 or 1; X is -CH2- or -O-; 6 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 R1is halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6 alkyl), -NHS(=O)2(C1-C6 alkyl), or -C(=O)NH2; R2ais C1-C6alkyl optionally substituted with one or more halogen, cyano, -OH, or - NH2; R2bis H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen; R2cis H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen; R2dis H; or R2aand R2dtogether form C1-C6alkylene optionally substituted with one or more halogen; Y is C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), or -C(=O)-N(C1-C6 alkyl)2; T is -ORT1, -N(RT1)2, or -N(RT2)2; each RT1independently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1- C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6 alkyl)- (C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6alkyl, C2- C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa; two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more RTa; each RTaindependently is oxo, halogen, cyano, -OH, -ORb, -NH2, -NHRb, -N(Rb)2, - 7 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)-NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; each Rbindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each RTbindependently is oxo, halogen, cyano, -OH, -ORc, -NH2, -NHRc, -N(Rc)2, - C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each Rcindependently is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each RTcindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0035] It is understood that, for a compound of the present disclosure, variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, Rb, and Rccan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, Rb, and Rccan be combined, where applicable, with any group described herein for one or more of the remainder of variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, Rb, and Rc. Compounds of Formula (I’)

[0036] In some aspects, the present disclosure provides a compound of Formula (I’): 8 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 0 or 1; X is -CH2- or -O-; R1is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen, cyano, -OH, or -NH2; R2ais C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, or - NH2; R2bis H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen; R2cis H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen; R2dis H; or R2aand R2dtogether form C1-C6 alkylene optionally substituted with one or more halogen; Y is C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), or -C(=O)-N(C1-C6alkyl)2; E is -(C1-C6 alkylene)- optionally substituted with one or more oxo, halogen, cyano, - OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; 9 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 one of U1and U2is -O-, and the other one of U1and U2is -C(RU)2-; each RUindependently is H, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; each RVindependently is H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-RA, -C(=O)-H, -C(=O)-RA, -C(=O)-OH, - C(=O)-ORA, -C(=O)-NH2, -C(=O)-NHRA, -C(=O)-N(RA)2, -S(=O)2-RA, -NH-S(=O)2-RA, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVa; each RAindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RVaindependently is oxo, halogen, cyano, -OH, -ORB, -NH2, -NHRB, -N(RB)2, - NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)-ORB, -C(=O)- NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RBindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RVbindependently is oxo, halogen, cyano, -OH, -ORC, -NH2, -NHRC, -N(RC)2, - NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)-ORC, -C(=O)- NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RCindependently is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each RVcindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- 10 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0037] It is understood that, for a compound of the present disclosure, variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RCcan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RCcan be combined, where applicable, with any group described herein for one or more of the remainder of variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RC.

[0038] In some aspects, the present disclosure provides a compound of Formula (I’’-i) or (I’’- ii):or a pharmaceutically acceptable salt thereof, wherein: R1is halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, cyano, -OH, or -NH2; W is -(C1-C6alkylene)- or -(C3-C6cycloalkylene)-, wherein the -(C1-C6alkylene)- or - (C3-C6 cycloalkylene)- is optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; Y is C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - 11 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), or -C(=O)-N(C1-C6 alkyl)2; T is -ORT1, -N(RT1)2, or -N(RT2)2; each RT1independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1- C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6alkyl)- (C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa; two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more RTa; each RTaindependently is oxo, halogen, cyano, -OH, -ORb, -NH2, -NHRb, -N(Rb)2, - C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)-NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; each Rbindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each RTbindependently is oxo, halogen, cyano, -OH, -ORc, -NH2, -NHRc, -N(Rc)2, - C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each Rcindependently is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; 12 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 each RTcindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; E is -(C1-C6 alkylene)- optionally substituted with one or more oxo, halogen, cyano, - OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; one of U1and U2is -O-, and the other one of U1and U2is -C(RU)2-; each RUindependently is H, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; each RVindependently is H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-RA, -C(=O)-H, -C(=O)-RA, -C(=O)-OH, - C(=O)-ORA, -C(=O)-NH2, -C(=O)-NHRA, -C(=O)-N(RA)2, -S(=O)2-RA, -NH-S(=O)2-RA, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVa; each RAindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RVaindependently is oxo, halogen, cyano, -OH, -ORB, -NH2, -NHRB, -N(RB)2, - NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)-ORB, -C(=O)- NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RBindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RVbindependently is oxo, halogen, cyano, -OH, -ORC, -NH2, -NHRC, -N(RC)2, - NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)-ORC, -C(=O)- NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6alkyl, C2-C613 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RCindependently is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each RVcindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0039] It is understood that, for a compound of the present disclosure, variables W, Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, Rb, Rc, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RCcan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables W, Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RCcan be combined, where applicable, with any group described herein for one or more of the remainder of variables W, Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RC. Compounds of Formula (I’’’-i) or Formula (I’’’-ii)

[0040] In some aspects, the present disclosure provides a compound of Formula (I’’’-i) or (’- ii):or a pharmaceutically acceptable salt thereof, wherein: R1is halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, cyano, -OH, or -NH2; Y is C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C814 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), or -C(=O)-N(C1-C6alkyl)2; T is -ORT1, -N(RT1)2, or -N(RT2)2; each RT1independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1- C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6alkyl)- (C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa; two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more RTa; each RTaindependently is oxo, halogen, cyano, -OH, -ORb, -NH2, -NHRb, -N(Rb)2, - C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)-NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; each Rbindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each RTbindependently is oxo, halogen, cyano, -OH, -ORc, -NH2, -NHRc, -N(Rc)2, - C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- 15 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each Rcindependently is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; each RTcindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; E is -(C1-C6 alkylene)- optionally substituted with one or more oxo, halogen, cyano, - OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2; one of U1and U2is -O-, and the other one of U1and U2is -C(RU)2-; each RUindependently is H, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; each RVindependently is H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-RA, -C(=O)-H, -C(=O)-RA, -C(=O)-OH, - C(=O)-ORA, -C(=O)-NH2, -C(=O)-NHRA, -C(=O)-N(RA)2, -S(=O)2-RA, -NH-S(=O)2-RA, C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVa; each RAindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RVaindependently is oxo, halogen, cyano, -OH, -ORB, -NH2, -NHRB, -N(RB)2, - NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)-ORB, -C(=O)- NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RBindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, 16 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RVbindependently is oxo, halogen, cyano, -OH, -ORC, -NH2, -NHRC, -N(RC)2, - NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)-ORC, -C(=O)- NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6alkyl, C2-C6alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RCindependently is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; each RVcindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0041] It is understood that, for a compound of the present disclosure, variables Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, Rb, Rc, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RCcan each be, where applicable, selected from the groups described herein, and any group described herein for any of variables Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, Rb, Rc, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RCcan be combined, where applicable, with any group described herein for one or more of the remainder of variables Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTc, Rb, Rc, E, U1, U2, RU, RV, RVa, RVb, RVc, RA, RB, and RC. Compounds of Formula (II), (II-a), (II-b), (III), (III-a), (III-b), (IV), (IV-a), (IV-b), (V), (V-a), (V-b), (VI), (VI-a), (VI-b), (VII), (VII-a), (VII-b), (VIII), (VIII-a), and (VIII-b)

[0042] In some aspects, the present disclosure provides a compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein n, R1, R2a, R2b, R2c, R2d, Y, and T are each as defined in Formula (I), or as described herein in any combination.

[0043] In some aspects, the present disclosure provides a compound of Formula (II-a) or (II- b): 17 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein n, R1, R2a, R2b, R2c, R2d, Y, and T are each as defined in Formula (I), or as described herein in any combination.

[0044] In some aspects, the present disclosure provides a compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R2c, R2d, Y, and T are each as defined in Formula (I), or as described herein in any combination.

[0045] In some aspects, the present disclosure provides a compound of Formula (III-a) or (III-or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R2c, R2d, Y, and T are 18 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 each as defined in Formula (I), or as described herein in any combination.

[0046] In some aspects, the present disclosure provides a compound of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R2c, R2d, RYa, and T are each as defined in Formula (I), or as described herein in any combination.

[0047] In some aspects, the present disclosure provides a compound of Formula (IV-a) or Formula (IV-b):or a pharmaceutically acceptable salt thereof, wherein R1, R2a, R2b, R2c, R2d, RYa, and T are each as defined in Formula (I), or as described herein in any combination.

[0048] In some aspects, the present disclosure provides a compound of Formula (V):(V), or a pharmaceutically acceptable salt thereof, wherein RYaand T are each as defined in Formula (I), or as described herein in any combination.

[0049] In some aspects, the present disclosure provides a compound of Formula (V-a) or Formula (V-b): 19 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein RYaand T are each as defined in Formula (I), or as described herein in any combination.

[0050] In some aspects, the present disclosure provides a compound of Formula (VI):(VI), or a pharmaceutically acceptable salt thereof, wherein RYaand RT1are each as defined in Formula (I), or as described herein in any combination.

[0051] In some aspects, the present disclosure provides a compound of Formula (VI-a) or Formula (VI-b):or a pharmaceutically acceptable salt thereof, wherein RYaand RT1are each as defined in Formula (I), or as described herein in any combination. 20 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0052] In some aspects, the present disclosure provides a compound of Formula (VII):or a pharmaceutically acceptable salt thereof, wherein RYaand RT2are each as defined in Formula (I), or as described herein in any combination.

[0053] In some aspects, the present disclosure provides a compound of Formula (VII-a) or Formula (VII-b):or a pharmaceutically acceptable salt thereof, wherein RYaand RT2are each as defined in Formula (I), or as described herein in any combination.

[0054] In some aspects, the present disclosure provides a compound of Formula (VIII):, or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; R1is halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6 alkyl), -NHS(=O)2(C1-C6 alkyl), or -C(=O)NH2; R2ais C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, or - 21 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 NH2; R2bis H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen; R2cis H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen; R2dis H; or R2aand R2dtogether form C1-C6 alkylene optionally substituted with one or more halogen; Y is C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), or -C(=O)-N(C1-C6alkyl)2;, 22 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084connectivity to the carbonyl group at triazolopyridine (i.e., not the connectivity to Z); B is absent (B is H) or ring B is C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl; Z is absent, -CH2-, -O-, or -C(=O)-; each RTaindependently is oxo, halogen, cyano, -OH, -ORTb, -NH2, -NHRTb, -N(RTb)2, -C(=O)-H, -C(=O)-RTb, -C(=O)-OH, -C(=O)-ORTb, -C(=O)-NH2, -C(=O)-NHRTb, -C(=O)- N(RTb)2, -S(=O)2-RTb, -S(=O)(=NH)-RTb, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, or C2-C6 alkynyl; each RTbis C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, or C2-C6 alkynyl; and each RTb1independently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; wherein when B is absent (B is H), Z is absent.

[0055] As used herein, when a bicyclic ring is presented with a bond that is not fixed at a ringatom, such as in , the bond can be formed at any available ring atom not limitedto the particular ring which the line is drawn unless expressly stated. For example, 23 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084other structures formed by placing the floating bond on the pyrrolidine ring or the oxetane ring.

[0056] In some aspects, the present disclosure provides a compound of Formula (VIII-a) or (VIII-b):- , or a pharmaceutically acceptable salt thereof, wherein n, R1, R2a, R2b, R2c, R2d, RTa, RTb1, Y, Z, ring A and ring B are each as defined in Formula (VIII), or as described herein in any combination.

[0057] It is understood that, for a compound of the present disclosure, variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, T, RT1, RT2, RTa, RTb, RTb1, RTc, Z, ring A, and ring B can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, T, RT1, RT2, RTa, RTb1, RTc, Z, ring A, and ring B can be combined, where applicable, with any group described herein for one or more of the remainder of variables m, n, X, R1, R2a, R2b, R2c, R2d, Y, RYa, RYb, T, RT1, RT2, RTa, RTb1, RTc, Z, ring A, and ring B. Compounds of Formula (II’), (II’-a), (II’-b), (II’-c), (II’-d), (II’-e), (II’-f), (III’), (III’-a), (III’- b), (III’-c), (III’-d), (III’-e), (III’-f), (IV’), (IV’-a), (IV’-b), (IV’-c), (IV’-d), (IV’-e), (IV’-f), (V’), ((V’-a), (V’-b), (V’-c), (V’-d), (V’-e), and (V’-f)

[0058] In some aspects, the present disclosure provides a compound of Formula (II’): 24 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein R1, R2a, Y, E, U1, U2, and RVare each as defined in Formula (I’), or as described herein in any combination.

[0059] In some aspects, the present disclosure provides a compound of Formula (II’-a), (II’- b), (II’-c), (II’-d), (II’-e), or (II’-f):or a pharmaceutically acceptable salt thereof, wherein R1, R2a, Y, E, U1, U2, and RVare each as defined in Formula (I’), or as described herein in any combination. 25 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0060] In some aspects, the present disclosure provides a compound of Formula (III’):or a pharmaceutically acceptable salt thereof, wherein R1, R2a, E, U1, U2, and RVare each as defined in Formula (I’), or as described herein in any combination.

[0061] In some aspects, the present disclosure provides a compound of Formula (III’-a), (III’- b), (III’-c), (III’-d), (III’-e), or (III’-f):26 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein R1, R2a, E, U1, U2, and RVare each as defined in Formula (I’), or as described herein in any combination.

[0062] In some aspects, the present disclosure provides a compound of Formula (IV’):or a pharmaceutically acceptable salt thereof, wherein R2a, E, U1, U2, and RVare each as defined in Formula (I’), or as described herein in any combination.

[0063] In some aspects, the present disclosure provides a compound of Formula (IV’-a), (IV’- b), (IV’-c), (IV’-d), (IV’-e), or (IV’-f):27 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein R2a, E, U1, U2, and RVare each as defined in Formula (I’), or as described herein in any combination.

[0064] In some aspects, the present disclosure provides a compound of Formula (V’):or a pharmaceutically acceptable salt thereof, wherein RUand RVare each as defined in Formula (I’), or as described herein in any combination.

[0065] In some aspects, the present disclosure provides a compound of Formula (V’-a), (V’- b), (V’-c), (V’-d), (V’-e), or (V’-f):28 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0066] or a pharmaceutically acceptable salt thereof, wherein RUand RVare each as defined in Formula (I’), or as described herein in any combination. Variables m, n, and X

[0067] In some embodiments, m is 0. In some embodiments, m is 1.

[0068] In some embodiments, n is 0. In some embodiments, n is 1.

[0069] In some embodiments, X is -CH2-. In some embodiments, X is -O-. Variable R1

[0070] In some embodiments, R1is halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6 alkyl), -NHS(=O)2(C1-C6 alkyl), or -C(=O)NH2.

[0071] In some embodiments, R1is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is substituted with one or more halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6alkyl), -NHS(=O)2(C1-C6alkyl), or -C(=O)NH2.

[0072] In some embodiments, R1is halogen (e.g., -F, -Cl, -Br, or -I).

[0073] In some embodiments, R1is cyano.

[0074] In some embodiments, R1is -OH.

[0075] In some embodiments, R1is -O(C1-C6alkyl) (e.g., -O(methyl), -O(ethyl), -O(n-propyl), 29 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 -O(isopropyl), -O(n-butyl), -O(t-butyl), -O(isobutyl), or -O(sec-butyl)).

[0076] In some embodiments, R1is -NH2.

[0077] In some embodiments, R1is -NH(C1-C6 alkyl) (e.g., -NH(methyl), -NH(ethyl), -NH(n- propyl), -NH(isopropyl), -NH(n-butyl), -NH(t-butyl), -NH(isobutyl), or -NH(sec-butyl)).

[0078] In some embodiments, R1is -N(C1-C6 alkyl)2 (e.g., -N(methyl)2, -N(ethyl)2, -N(n- propyl)2, -N(isopropyl)2, -N(n-butyl)2, -N(t-butyl)2, -N(isobutyl)2, or -N(sec-butyl)2).

[0079] In some embodiments, R1is C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl).

[0080] In some embodiments, R1is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6alkyl), -NHS(=O)2(C1-C6alkyl), or -C(=O)NH2.

[0081] In some embodiments, R1is C1-C3 alkyl optionally substituted with one or more of halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6 alkyl), -NHS(=O)2(C1-C6 alkyl), or -C(=O)NH2.

[0082] In some embodiments, R1is C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more -OH.

[0083] In some embodiments, R1is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more -NH2.

[0084] In some embodiments, R1is C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I).

[0085] In some embodiments, R1is C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more -NHC(=O)(C1-C6 alkyl).

[0086] In some embodiments, R1is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more -NHS(=O)2(C1-C6alkyl).

[0087] In some embodiments, R1is C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more -C(=O)NH2.

[0088] In some embodiments, R1is methyl. Variables R2a, R2b, R2c, and R2d

[0089] In some embodiments, R2ais C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) optionally substituted with one or more halogen, cyano, - OH, or -NH2.

[0090] In some embodiments, R2ais C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more halogen, cyano, -OH, or - 30 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 NH2.

[0091] In some embodiments, R2ais C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl).

[0092] In some embodiments, R2ais C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I).

[0093] In some embodiments, R2ais C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more cyano.

[0094] In some embodiments, R2ais C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more -OH.

[0095] In some embodiments, R2ais C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more -NH2.

[0096] In some embodiments, R2ais C1-C3 alkyl optionally substituted with one or more halogen, cyano, -OH, or -NH2. In some embodiments, R2ais C1alkyl optionally substituted with one or more halogen, cyano, -OH, or -NH2. In some embodiments, R2ais C1-C3 alkyl. In some embodiments, R2ais methyl.

[0097] In some embodiments, R2bis H or C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl), wherein the C1-C6alkyl is optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I).

[0098] In some embodiments, R2bis H.

[0099] In some embodiments, R2bis C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl).

[0100] In some embodiments, R2bis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I).

[0101] In some embodiments, R2cis H or C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl), wherein the C1-C6alkyl is optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I).

[0102] In some embodiments, R2cis H.

[0103] In some embodiments, R2cis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl).

[0104] In some embodiments, R2cis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I). 31 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0105] In some embodiments, R2dis H.

[0106] In some embodiments, R2aand R2dtogether form C1-C6 alkylene (e.g., methylene, ethylene, n-propylene, isopropylene, n-butylene, t-butylene, isobutylene, or sec-butylene) optionally substituted with one or more halogen (e.g., -F, -Cl, -Br, or -I).

[0107] In some embodiments, R2aand R2dtogether form methylene.

[0108] In some embodiments, R2b, R2c, and R2dare each H or C1-C3 alkyl.

[0109] In some embodiments, R2b, R2c, and R2dare each H. Variables Y, RYa, and RYb

[0110] In some embodiments, Y is C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa.

[0111] In some embodiments, Y is C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl.

[0112] In some embodiments, Y is C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more RYa.

[0113] In some embodiments, Y is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa.

[0114] In some embodiments, Y is C3-C8cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, spiropentyl, spirohexyl, spiroheptyl, or spirooctyl).

[0115] In some embodiments, Y is C3-C8 monocyclic cycloalkyl.

[0116] In some embodiments, Y is C3-C8monocyclic cycloalkyl substituted with one or more RYa.

[0117] In some embodiments, Y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0118] In some embodiments, Y is C5-C8spiro bicyclic cycloalkyl.

[0119] In some embodiments, Y is C5-C8 spiro bicyclic cycloalkyl substituted with one or more RYa.

[0120] In some embodiments, Y is spiropentyl, spirohexyl, spiroheptyl, or spirooctyl.

[0121] In some embodiments, Y is spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, or spiro[3.4]octyl. 32 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0122] In some embodiments,.

[0123] In some embodiments,.

[0124] In some embodiments, Y is C6-C10aryl (e.g., phenyl).

[0125] In some embodiments, Y is phenyl.

[0126] In some embodiments, Y is 5- to 10-membered heteroaryl.

[0127] In some embodiments, Y is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0128] In some embodiments, Y is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0129] In some embodiments, Y is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[0130] In some embodiments, Y is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[0131] In some embodiments, Y is oxazolyl.

[0132] In some embodiments,.

[0133] In some embodiments, Y is thiazolyl.

[0134] In some embodiments,.

[0135] In some embodiments, Y is pyrazolyl.

[0136] In some embodiments,.

[0137] In some embodiments,.

[0138] In some embodiments, Y is isoxazolyl.

[0139] In some embodiments, Y is isothiazolyl.

[0140] In some embodiments, Y is imidazolyl.

[0141] In some embodiments, Y is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl).

[0142] In some embodiments, Y is triazolyl. 33 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0143] In some embodiments,.

[0144] In some embodiments, Y is oxadiazolyl.

[0145] In some embodiments,.

[0146] In some embodiments, Y is thiadiazolyl.

[0147] In some embodiments,.

[0148] In some embodiments,.

[0149] In some embodiments, Y is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl)

[0150] In some embodiments, Y is tetrazolyl.

[0151] In some embodiments,.

[0152] In some embodiments, Y is oxatriazolyl.

[0153] In some embodiments, Y is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0154] In some embodiments, Y is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[0155] In some embodiments, Y is pyridinyl.

[0156] In some embodiments,.

[0157] In some embodiments, Y is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[0158] In some embodiments, Y is pyrimidinyl.

[0159] In some embodiments,.

[0160] In some embodiments, Y is pyridazinyl.

[0161] In some embodiments, Y is pyrazinyl.

[0162] In some embodiments, at least one RYais oxo, halogen, cyano, -OH, -O(C1-C6alkyl), - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), - 34 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 C(=O)-NH2, -C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more RYb.

[0163] In some embodiments, at least one RYais oxo, halogen, cyano, -OH, -O(C1-C6alkyl), - NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), - C(=O)-NH2, -C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6alkynyl.

[0164] In some embodiments, at least one RYais oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), - NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), - C(=O)-NH2, -C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is substituted with one or more RYb.

[0165] In some embodiments, at least one RYais oxo.

[0166] In some embodiments, at least one RYais halogen (e.g., e.g., -F, -Cl, -Br, or -I).

[0167] In some embodiments, at least one RYais -F.

[0168] In some embodiments, at least one RYais -Cl.

[0169] In some embodiments, at least one RYais -Br.

[0170] In some embodiments, at least one RYais -I.

[0171] In some embodiments, at least one RYais cyano.

[0172] In some embodiments, at least one RYais -OH.

[0173] In some embodiments, at least one RYais -O(C1-C6alkyl) (e.g., -OCH3, -OCH2CH3, - O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, or -O(CH2)5CH3).

[0174] In some embodiments, at least one RYais -OCH3.

[0175] In some embodiments, at least one RYais -OCH2CH3.

[0176] In some embodiments, at least one RYais -NH2.

[0177] In some embodiments, at least one RYais -NH(C1-C6 alkyl) (e.g., -NHCH3, - NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, or -NH(CH2)5CH3).

[0178] In some embodiments, at least one RYais -N(C1-C6alkyl)2.

[0179] In some embodiments, at least one RYais -C(=O)-H.

[0180] In some embodiments, at least one RYais -C(=O)-OH.

[0181] In some embodiments, at least one RYais -C(=O)-O(C1-C6alkyl) (e.g., is -C(=O)- OCH3, -C(=O)-OCH2CH3, -C(=O)-O(CH2)2CH3, -C(=O)-O(CH2)3CH3, -C(=O)-O(CH2)4CH3, or -C(=O)-O(CH2)5CH3).

[0182] In some embodiments, at least one RYais -C(=O)-NH2. 35 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0183] In some embodiments, at least one RYais -C(=O)-NH(C1-C6alkyl) (e.g., -C(=O)- NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-NH(CH2)3CH3, -C(=O)- NH(CH2)4CH3, or -C(=O)-NH(CH2)5CH3).

[0184] In some embodiments, at least one RYais -C(=O)-N(C1-C6alkyl)2.(e.g., -C(=O)- N(methyl)2, -C(=O)-N(ethyl)2, -C(=O)-N(n-propyl)2, -C(=O)-N(isopropyl)2, -C(=O)-N(n- butyl)2, -C(=O)-N(t-butyl)2, -C(=O)-N(isobutyl)2, or -C(=O)-N(sec-butyl)2).

[0185] In some embodiments, at least one RYais C2-C6alkenyl.

[0186] In some embodiments, at least one RYais C2-C6 alkynyl.

[0187] In some embodiments, at least one RYais -C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[0188] In some embodiments, at least one RYais methyl.

[0189] In some embodiments, at least one RYais ethyl.

[0190] In some embodiments, at least one RYbis oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), - C(=O)-NH2, -C(=O)-NH(C1-C6 alkyl), or -C(=O)-N(C1-C6 alkyl)2.

[0191] In some embodiments, at least one RYbis oxo.

[0192] In some embodiments, at least one RYbis halogen (e.g., e.g., -F, -Cl, -Br, or -I).

[0193] In some embodiments, at least one RYbis -F.

[0194] In some embodiments, at least one RYbis -Cl.

[0195] In some embodiments, at least one RYbis -Br.

[0196] In some embodiments, at least one RYbis -I.

[0197] In some embodiments, at least one RYbis cyano.

[0198] In some embodiments, at least one RYbis -OH.

[0199] In some embodiments, at least one RYbis -O(C1-C6alkyl) (e.g., -OCH3, -OCH2CH3, - O(CH2)2CH3, -O(CH2)3CH3, -O(CH2)4CH3, or -O(CH2)5CH3).

[0200] In some embodiments, at least one RYbis -OCH3.

[0201] In some embodiments, at least one RYbis -OCH2CH3.

[0202] In some embodiments, at least one RYbis -NH2.

[0203] In some embodiments, at least one RYbis -NH(C1-C6 alkyl) (e.g., -NHCH3, - NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, or -NH(CH2)5CH3).

[0204] In some embodiments, at least one RYbis -N(C1-C6alkyl)2(e.g., e.g., -N(methyl)2, - N(ethyl)2, -N(n-propyl)2, -N(isopropyl)2, -N(n-butyl)2, -N(t-butyl)2, -N(isobutyl)2, or -N(sec- butyl)2).

[0205] In some embodiments, at least one RYbis -C(=O)-H. 36 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0206] In some embodiments, at least one RYbis -C(=O)-OH.

[0207] In some embodiments, at least one RYbis -C(=O)-O(C1-C6 alkyl) (e.g., is -C(=O)- OCH3, -C(=O)-OCH2CH3, -C(=O)-O(CH2)2CH3, -C(=O)-O(CH2)3CH3, -C(=O)-O(CH2)4CH3, or -C(=O)-O(CH2)5CH3).

[0208] In some embodiments, at least one RYbis -C(=O)-NH2.

[0209] In some embodiments, at least one RYbis -C(=O)-NH(C1-C6 alkyl) ((e.g., -C(=O)- NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-NH(CH2)3CH3, -C(=O)- NH(CH2)4CH3, or -C(=O)-NH(CH2)5CH3)).

[0210] In some embodiments, at least one RYbis -C(=O)-N(C1-C6 alkyl)2 (e.g., -C(=O)- N(methyl)2, -C(=O)-N(ethyl)2, -C(=O)-N(n-propyl)2, -C(=O)-N(isopropyl)2, -C(=O)-N(n- butyl)2, -C(=O)-N(t-butyl)2, -C(=O)-N(isobutyl)2, or -C(=O)-N(sec-butyl)2). Variables T, RT1, RT2, RTa, RTb, RTb1, RTc, Rb, Rc, ring A, and ring B Variable T

[0211] In some embodiments, T is -ORT1, -N(RT1)2, or -N(RT2)2.

[0212] In some embodiments, T is -ORT1.

[0213] In some embodiments, T is -N(RT1)2.

[0214] In some embodiments, T is -NHRT1or -N(C1-C6alkyl)RT1. In some embodiments, T is -NHRT1or -N(C1-C3 alkyl)RT1. In some embodiments, T is -NHRT1or -N(CH3)RT1.

[0215] In some embodiments, T is -N(RT2)2. Variable RT1

[0216] In some embodiments, at least one RT1is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa.

[0217] In some embodiments, at least one RT1is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl).

[0218] In some embodiments, at least one RT1is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 37 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is substituted with one or more RTa.

[0219] In some embodiments, one RT1is H or C1-C6 alkyl; and the other RT1is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa.

[0220] In some embodiments, one RT1is H or C1-C6 alkyl; and the other RT1is C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, monocyclic C3-C8cycloalkyl, fused bicyclic C4-C8cycloalkyl, bridged bicyclic C5-C8cycloalkyl, spiro bicyclic C5-C8cycloalkyl, monocyclic 4- to 8- membered heterocyclyl, fused bicyclic 4- to 10-membered heterocyclyl, bridged bicyclic 5- to 10-membered heterocyclyl, spiro bicyclic 5- to 10-membered heterocyclyl, phenyl, monocyclic 5- to 6-membered heteroaryl, fused bicyclic 5- to 10-membered heteroaryl, -(C1-C4alkyl)- (monocyclic C3-C8 cycloalkyl), -(C1-C4 alkyl)-(fused bicyclic C4-C8 cycloalkyl), -(C1-C4 alkyl)-(bridged bicyclic C5-C8 cycloalkyl), -(C1-C4 alkyl)-(spiro bicyclic C5-C8 cycloalkyl), - (C1-C4alkyl)-(monocyclic 4- to 7-membered heterocyclyl), -(C1-C4alkyl)-(fused bicyclic 4- to 10-membered heterocyclyl), -(C1-C4alkyl)-(bridged bicyclic 5- to 10-membered heterocyclyl), -(C1-C4 alkyl)-(spiro bicyclic 5- to 10-membered heterocyclyl), -(C1-C4 alkyl)-(phenyl), -(C1- C4alkyl)-(monocyclic 5- to 6-membered heteroaryl), or -(C1-C4alkyl)-(fused bicyclic 5- to 10- membered heteroaryl), wherein the other RT1is optionally substituted with one or more RTa.

[0221] In some embodiments, at least one RT1is H.

[0222] In some embodiments, at least one RT1is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[0223] In some embodiments, at least one RT1is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RTa.

[0224] In some embodiments, at least one RT1is methyl. 38 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0225] In some embodiments, at least one RT1is ethyl.

[0226] In some embodiments, at least one RT1is n-propyl.

[0227] In some embodiments, at least one RT1is isopropyl.

[0228] In some embodiments, at least one RT1is n-butyl.

[0229] In some embodiments, at least one RT1is C2-C6 alkenyl.

[0230] In some embodiments, at least one RT1is C2-C6 alkenyl substituted with one or more RTa.

[0231] In some embodiments, at least one RT1is C2-C6 alkynyl.

[0232] In some embodiments, at least one RT1is C2-C6 alkynyl substituted with one or more RTa.

[0233] In some embodiments, at least one RT1is C3-C8cycloalkyl.

[0234] In some embodiments, at least one RT1is C3-C8 cycloalkyl substituted with one or more RTa.

[0235] In some embodiments, at least one RT1is C3-C8monocyclic cycloalkyl.

[0236] In some embodiments, at least one RT1is C3-C8 monocyclic cycloalkyl substituted with one or more RTa.

[0237] In some embodiments, at least one RT1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0238] In some embodiments, at least one RT1is C4-C8 bicyclic cycloalkyl.

[0239] In some embodiments, at least one RT1is C4-C8bicyclic cycloalkyl substituted with one or more RTa.

[0240] In some embodiments, at least one RT1is bicyclocyclobutyl, bicyclocyclopentyl, bicyclocyclohexyl, bicyclocycloheptyl, or bicyclocyclooctyl.

[0241] In some embodiments, at least one RT1is C4-C8fused bicyclic cycloalkyl.

[0242] In some embodiments, at least one RT1is C4-C8fused bicyclic cycloalkyl substituted with one or more RTa.

[0243] In some embodiments, at least one RT1is, , .

[0244] In some embodiments, at least one RT1is, , , substituted with one or more RTa. 39 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0245] In some embodiments, at least one RT1is.

[0246] In some embodiments, at least one RT1is.

[0247] In some embodiments, at least one RT1is C3-C8 bridged bicyclic cycloalkyl.

[0248] In some embodiments, at least one RT1is C3-C8 bridged bicyclic cycloalkyl substituted with one or more RTa.

[0249] In some embodiments, at least one RT1is, , .

[0250] In some embodiments, at least one RT1is, , , substituted with one or more RTa.

[0251] In some embodiments, at least one RT1is.

[0252] In some embodiments, at least one RT1is.

[0253] In some embodiments, at least one RT1is.

[0254] In some embodiments, at least one RT1is.

[0255] In some embodiments, at least one RT1is.

[0256] In some embodiments, at least one RT1is.

[0257] In some embodiments, at least one RT1is C5-C8 spiro bicyclic cycloalkyl.

[0258] In some embodiments, at least one RT1is C5-C8spiro bicyclic cycloalkyl substituted with one or more RTa.

[0259] In some embodiments, at least one RT1is spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, or spiro[3.4]octyl.

[0260] In some embodiments, at least one RT1is spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[3.3]heptyl, spiro[2.5]octyl, or spiro[3.4]octyl, substituted with one or more RTa.

[0261] In some embodiments, at least one RT1is. 40 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0262] In some embodiments, at least one.

[0263] In some embodiments, at least one RT1is.

[0264] In some embodiments, at least one RT1is 4- to 10-membered heterocyclyl.

[0265] In some embodiments, at least one RT1is 4- to 10-membered heterocyclyl substituted with one or more RTa.

[0266] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl.

[0267] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl substituted with one or more RTa.

[0268] In some embodiments, at least one RT1is 4- to 10-membered bicyclic heterocyclyl.

[0269] In some embodiments, at least one RT1is 4- to 10-membered bicyclic heterocyclyl substituted with one or more RTa.

[0270] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl.

[0271] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RTa.

[0272] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl.

[0273] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RTa.

[0274] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl.

[0275] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RTa.

[0276] In some embodiments, at least one RT1is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[0277] In some embodiments, at least one RT1is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTa.

[0278] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[0279] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl 41 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTa.

[0280] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[0281] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTa.

[0282] In some embodiments, at least one RT1is azetidinyl.

[0283] In some embodiments, at least one RT1is azetidinyl substituted with one or more RTa.

[0284] In some embodiments, at least one RT1i.

[0285] In some embodiments, at least one RT1i.

[0286] In some embodiments, at least one RT1i.

[0287] In some embodiments, at least one RT1is pyrrolidinyl.

[0288] In some embodiments, at least one RT1i.

[0289] In some embodiments, at least one RT1i.

[0290] In some embodiments, at least one RT1i.

[0291] In some embodiments, at least one RT1i

[0292] In some embodiments, at least one RT1i.

[0293] In some embodiments, at least one RT1i.

[0294] In some embodiments, at least one RT1is.

[0295] In some embodiments, at least one RT1is .

[0296] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[0297] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl 42 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTa.

[0298] In some embodiments, at least one

[0299] In some embodiments, at least one, substituted with one or more RTa.

[0300] In some embodiments, at least one RT1is.

[0301] In some embodiments, at least one RT1is

[0302] In some embodiments, at least one.

[0304] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[0305] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more RTa.

[0306] In some embodiments, at least one RT1is, , , ,.

[0307] In some embodiments, at least one RT1is, , , ,, substituted with one or more RTa. 43 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0308] In some embodiments, at least one RT1is.

[0309] In some embodiments, at least one RT1i.

[0310] In some embodiments, at least one RT1i.

[0311] In some embodiments, at least one RT1i.

[0312] In some embodiments, at least one RT1i.

[0313] In some embodiments, at least one RT1is.

[0314] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[0315] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTa.

[0316] In some embodiments, at least one RT1is, , ,

[0317] In some embodiments, at least one RT1is, , ,, substituted with one or more RTa.

[0318] In some embodiments, at least one RT1i

[0319] In some embodiments, at least one RT1i.

[0320] In some embodiments, at least one RT1i. 44 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0321] In some embodiments, at least one RT1is.

[0322] In some embodiments, at least one RT1is.

[0323] In some embodiments, at least one.

[0324] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[0325] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTa.

[0326] In some embodiments, at least one RT1is oxetanyl.

[0327] In some embodiments, at least one RT1i.

[0328] In some embodiments, at least one RT1i.

[0329] In some embodiments, at least one RT1is tetrahydrofuranyl.

[0330] In some embodiments, at least one RT1i.

[0331] In some embodiments, at least one RT1i.

[0332] In some embodiments, at least one RT1is tetrahydropyranyl.

[0333] In some embodiments, at least one RT1i.

[0334] In some embodiments, at least one RT1i.

[0335] In some embodiments, at least one RT1is.

[0336] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[0337] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis 45 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 substituted with one or more RTa.

[0338] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[0339] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RTa.

[0340] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[0341] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl containing one O, wherein the is 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTa.

[0343] In some embodiments, at least one RT1, , , ,, substituted with one or more RTa.

[0344] In some embodiments, at least one RT1i

[0345] In some embodiments, at least one RT1i.

[0346] In some embodiments, at least one RT1i.

[0347] In some embodiments, at least one RT1i.

[0348] In some embodiments, at least one RT1i.

[0349] In some embodiments, at least one RT1i.

[0350] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[0351] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl 46 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTa.

[0352] In some embodiments, at least one RT1is tetrahydrothiophenyl.

[0353] In some embodiments, at least one RT1is.

[0354] In some embodiments, at least one RT1is.

[0355] In some embodiments, at least one RT1is 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[0356] In some embodiments, at least one RT1is 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTa.

[0357] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0358] In some embodiments, at least one RT1is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTa.

[0359] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0360] In some embodiments, at least one RT1is 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTa.

[0361] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0362] In some embodiments, at least one RT1is 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RTa.

[0363] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0364] In some embodiments, at least one RT1is 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTa. 47 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0365] In some embodiments, at least one RT1is, , , ,

[0366] In some embodiments, at least one RT1, ,

[0367] In some embodiments, at least one RT1is.

[0368] In some embodiments, at least one RT1is.

[0369] In some embodiments, at least one RT1is.

[0370] In some embodiments, at least one.

[0371] In some embodiments, at least one RT1is.

[0372] In some embodiments, at least one RT1is.

[0373] In some embodiments, at least one RT1is. 48 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0374] In some embodiments, at least one RT1is.

[0375] In some embodiments, at least one RT1is.

[0376] In some embodiments, at least one RT1is.

[0377] In some embodiments, at least one.

[0378] In some embodiments, at least one RT1is.

[0379] In some embodiments, at least one.

[0380] In some embodiments, at least one.

[0381] In some embodiments, at least one.

[0382] In some embodiments, at least one RT1is C6-C10 aryl (e.g., phenyl).

[0383] In some embodiments, at least one RT1is C6-C10aryl (e.g., phenyl) substituted with one or more RTa.

[0384] In some embodiments, at least one RT1is phenyl.

[0385] In some embodiments, at least one RT1is 5- to 10-membered heteroaryl.

[0386] In some embodiments, at least one RT1is 5- to 10-membered heteroaryl substituted with one or more RTa.

[0387] In some embodiments, at least one RT1is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0388] In some embodiments, at least one RT1is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one 49 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 or more RTa.

[0389] In some embodiments, at least one RT1is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0390] In some embodiments, at least one RT1is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTa.

[0391] In some embodiments, at least one RT1is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[0392] In some embodiments, at least one RT1is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RTa.

[0393] In some embodiments, at least one RT1is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[0394] In some embodiments, at least one RT1is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RTa.

[0395] In some embodiments, at least one RT1is oxazolyl.

[0396] In some embodiments, at least one RT1is .

[0397] In some embodiments, at least one RT1is thiazolyl.

[0398] In some embodiments, at least one RT1is.

[0399] In some embodiments, at least one RT1is pyrazolyl.

[0400] In some embodiments, at least one RT1is .

[0401] In some embodiments, at least one RT1is.

[0402] In some embodiments, at least one RT1is isoxazolyl.

[0403] In some embodiments, at least one RT1is isothiazolyl.

[0404] In some embodiments, at least one RT1is imidazolyl.

[0405] In some embodiments, at least one RT1is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or 50 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 oxathiadiazolyl).

[0406] In some embodiments, at least one RT1is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RTa.

[0407] In some embodiments, at least one RT1is triazolyl.

[0408] In some embodiments, at least one RT1is.

[0409] In some embodiments, at least one RT1is.

[0410] In some embodiments, at least one RT1is

[0411] In some embodiments, at least one RT1is oxadiazolyl.

[0412] In some embodiments, at least one RT1is.

[0413] In some embodiments, at least one RT1is thiadiazolyl.

[0414] In some embodiments, at least one RT1is.

[0415] In some embodiments, at least one RT1is.

[0416] In some embodiments, at least one RT1is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[0417] In some embodiments, at least one RT1is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RTa.

[0418] In some embodiments, at least one RT1is tetrazolyl.

[0419] In some embodiments, at least one RT1is.

[0420] In some embodiments, at least one RT1is oxatriazolyl.

[0421] In some embodiments, at least one RT1is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0422] In some embodiments, at least one RT1is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or 51 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 more RTa.

[0423] In some embodiments, at least one RT1is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[0424] In some embodiments, at least one RT1is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RTa.

[0425] In some embodiments, at least one RT1is pyridinyl.

[0426] In some embodiments, at least one RT1is.

[0427] In some embodiments, at least one RT1is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[0428] In some embodiments, at least one RT1is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RTa.

[0429] In some embodiments, at least one RT1is pyrimidinyl.

[0430] In some embodiments, at least one RT1is.

[0431] In some embodiments, at least one RT1is.

[0432] In some embodiments, at least one RT1is pyridazinyl.

[0433] In some embodiments, at least one RT1is.

[0434] In some embodiments, at least one RT1is pyrazinyl.

[0435] In some embodiments, at least one RT1is 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0436] In some embodiments, at least one RT1is 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTa.

[0437] In some embodiments, at least one. 52 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0438] In some embodiments, at least one.

[0439] In some embodiments, at least one RT1is -(C1-C6alkyl)-(C3-C6cycloalkyl).

[0440] In some embodiments, at least one RT1is -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl).

[0441] In some embodiments, at least one RT1is -(C1-C6alkyl)-(C6-C10aryl).

[0442] In some embodiments, at least one RT1is -(C1-C6alkyl)-(5- to 10-membered heteroaryl).

[0443] In some embodiments, RT1is H or C1-C6alkyl; and the other RT1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ,, , , , , , , 53 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, wherein the other RT1is optionally substituted with one or more RTa.

[0444] In some embodiments, RT1is H or C1-C6 alkyl; and the other RT1is pyrrolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, tetrazolyl, oxatriazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl,, wherein the other RT1is optionally substituted with one or more RTa. Variable RT2

[0445] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more RTa.

[0446] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl.

[0447] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl substituted with one or more RTa.

[0448] In some embodiments, two RT2, together with the atom to which they are attached, form a monocyclic 4- to 8-membered heterocyclyl, a fused bicyclic 4- to 10-membered heterocyclyl, a bridged bicyclic 5- to 10-membered heterocyclyl, or a spiro bicyclic 5- to 10-membered heterocyclyl, each optionally substituted with one or more RTa.

[0449] In some embodiments, two RT2, together with the atom to which they are attached, form a monocyclic 4- to 8-membered heterocyclyl, a fused bicyclic 4- to 10-membered heterocyclyl, a bridged bicyclic 6- to 10-membered heterocyclyl, or a spiro bicyclic 6- to 10-membered heterocyclyl, each optionally substituted with one or more RTa.

[0450] In some embodiments, two RT2, together with the atom to which they are attached, a fused bicyclic 6- to 10-membered heterocyclyl or a spiro bicyclic 6- to 10-membered heterocyclyl, each optionally substituted with one or more RTa.

[0451] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl.

[0452] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl substituted with one or more RTa. 54 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0453] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl containing one nitrogen.

[0454] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and is substituted with one or more RTa.

[0455] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl containing two nitrogens.

[0456] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and is substituted with one or more RTa.

[0457] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl containing three nitrogens.

[0458] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl, wherein the heterocyclyl contains three nitrogens and is substituted with one or more RTa.

[0459] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl containing one nitrogen and one oxygen.

[0460] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and one oxygen, and is substituted with one or more RTa.

[0461] In some embodiments, two RT2, together with the atom to which they are attached, form

[0462] In some embodiments, two RT2, together with the atom to which they are attached, formwith one or more RTa.

[0463] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered bicyclic heterocyclyl.

[0464] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered bicyclic heterocyclyl substituted with one or more RTa. 55 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0465] In some embodiments, the 4- to 10-membered bicyclic heterocyclyl formed by two RT2together with the atom to which they are attached, is a 6- to 10-membered bicyclic heterocycle.

[0466] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl.

[0467] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RTa.

[0468] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl containing one nitrogen.

[0469] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and is substituted with one or more RTa.

[0470] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl containing two nitrogens.

[0471] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and is substituted with one or more RTa.

[0472] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl containing three nitrogens.

[0473] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl, wherein the heterocyclyl contains three nitrogens and is substituted with one or more RTa.

[0474] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl containing four nitrogens.

[0475] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl, wherein the heterocyclyl contains four nitrogens and is substituted with one or more RTa.

[0476] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl containing one nitrogen and one oxygen.

[0477] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and one oxygen, and is substituted with one or more RTa.

[0478] In some embodiments, two RT2, together with the atom to which they are attached, form 4- to 10-membered fused bicyclic heterocyclyl containing two nitrogens and one oxygen.

[0479] In some embodiments, two RT2, together with the atom to which they are attached, form 56 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 4- to 10-membered fused bicyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and one oxygen, and is substituted with one or more RTa.

[0480] In some embodiments, two RT2, together with the atom to which they are attached, form , ,

[0481] In some embodiments, two RT2, together with the atom to which they are attached, formwith one or more RTa.

[0482] In some embodiments, two RT2, together with the atom to which they are attached, form.

[0483] In some embodiments, two RT2, together with the atom to which they are attached, form, substituted with one or more RTa.

[0484] In some embodiments, the 4- to 10-membered fused bicyclic heterocyclyl formed by two RT2together with the atom to which they are attached, is a 6- to 10-membered fused 57 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 bicyclic heterocycle.

[0485] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl.

[0486] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RTa.

[0487] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl containing one nitrogen.

[0488] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and is substituted with one or more RTa.

[0489] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl containing two nitrogens.

[0490] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and is substituted with one or more RTa.

[0491] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl containing one nitrogen and one oxygen.

[0492] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and one oxygen, and is substituted with one or more RTa.

[0493] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl containing two nitrogens and one oxygen.

[0494] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered bridged bicyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and one oxygen, and is substituted with one or more RTa.

[0495] In some embodiments, two RT2, together with the atom to which they are attached, form.

[0496] In some embodiments, two RT2, together with the atom to which they are attached, form 58 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0497] In some embodiments, the 5- to 10-membered bridged bicyclic heterocyclyl formed by two RT2together with the atom to which they are attached, is a 6- to 10-membered bridged bicyclic heterocycle.

[0498] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl.

[0499] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RTa.

[0500] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl containing one nitrogen.

[0501] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and is substituted with one or more RTa.

[0502] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl containing two nitrogens.

[0503] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and is substituted with one or more RTa.

[0504] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl containing three nitrogens.

[0505] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl, wherein the heterocyclyl contains three nitrogens and is substituted with one or more RTa.

[0506] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl containing one nitrogen and one oxygen.

[0507] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and one oxygen, and is substituted with one or more RTa.

[0508] In some embodiments, two RT2, together with the atom to which they are attached, form 59 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 5- to 10-membered spiro bicyclic heterocyclyl containing two nitrogens and one oxygen.

[0509] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and one oxygen, and is substituted with one or more RTa.

[0510] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl containing one nitrogen and two oxygens.

[0511] In some embodiments, two RT2, together with the atom to which they are attached, form 5- to 10-membered spiro bicyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and two oxygens, and is substituted with one or more RTa.

[0512] In some embodiments, two RT2, together with the atom to which they are attached, form

[0513] In some embodiments, two RT2, together with the atom to which they are attached, form, , , , , , 60 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, substituted with one or more RTa.

[0514] In some embodiments, the 5- to 10-membered spiro bicyclic heterocyclyl formed by two RT2together with the atom to which they are attached, is a 6- to 10-membered spiro bicyclic heterocycle. Variable RTa

[0515] In some embodiments, at least one RTais oxo, halogen, cyano, -OH, -ORb, -NH2, - NHRb, -N(Rb)2, -C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)- NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb.

[0516] In some embodiments, at least one RTais oxo, halogen, cyano, -OH, -ORb, -NH2, - NHRb, -N(Rb)2, -C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)- NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl.

[0517] In some embodiments, at least one RTais oxo, halogen, cyano, -OH, -ORb, -NH2, - NHRb, -N(Rb)2, -C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)- NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more RTb.

[0518] In some embodiments, at least one RTais oxo.

[0519] In some embodiments, at least one RTais halogen (e.g., -F, -Cl, -Br, -I). 61 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0520] In some embodiments, at least one RTais cyano.

[0521] In some embodiments, at least one RTais -OH.

[0522] In some embodiments, at least one RTais -ORb.

[0523] In some embodiments, at least one RTais -NH2.

[0524] In some embodiments, at least one RTais -NHRb.

[0525] In some embodiments, at least one RTais -N(Rb)2.

[0526] In some embodiments, at least one RTais -C(=O)-H.

[0527] In some embodiments, at least one RTais -C(=O)-Rb.

[0528] In some embodiments, at least one RTais -C(=O)-OH.

[0529] In some embodiments, at least one RTais -C(=O)-ORb.

[0530] In some embodiments, at least one RTais -C(=O)-NH2.

[0531] In some embodiments, at least one RTais -C(=O)-NHRb.

[0532] In some embodiments, at least one RTais -C(=O)-N(Rb)2.

[0533] In some embodiments, at least one RTais -S(=O)2-Rb.

[0534] In some embodiments, at least one RTais -S(=O)(=NH)-Rb.

[0535] In some embodiments, at least one RTais C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[0536] In some embodiments, at least one RTais C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RTb.

[0537] In some embodiments, at least one RTais methyl.

[0538] In some embodiments, at least one RTais ethyl.

[0539] In some embodiments, at least one RTais n-propyl.

[0540] In some embodiments, at least one RTais isopropyl.

[0541] In some embodiments, at least one RTais n-butyl.

[0542] In some embodiments, at least one RTais C2-C6alkenyl.

[0543] In some embodiments, at least one RTais C2-C6 alkenyl substituted with one or more RTb.

[0544] In some embodiments, at least one RTais C2-C6alkynyl.

[0545] In some embodiments, at least one RTais C2-C6 alkynyl substituted with one or more RTb.

[0546] In some embodiments, at least one RTais C3-C6cycloalkyl.

[0547] In some embodiments, at least one RTais C3-C6 cycloalkyl substituted with one or more RTb.

[0548] In some embodiments, at least one RTais C3-C6monocyclic cycloalkyl. 62 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0549] In some embodiments, at least one RTais C3-C6monocyclic cycloalkyl substituted with one or more RTb.

[0550] In some embodiments, at least one RTais cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0551] In some embodiments, at least one RTais C3-C6 bicyclic cycloalkyl.

[0552] In some embodiments, at least one RTais C3-C6 bicyclic cycloalkyl substituted with one or more RTb.

[0553] In some embodiments, at least one RTais bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[0554] In some embodiments, at least one RTais C4-C6fused bicyclic cycloalkyl.

[0555] In some embodiments, at least one RTais C4-C6fused bicyclic cycloalkyl substituted with one or more RTb.

[0556] In some embodiments, at least one RTais.

[0557] In some embodiments, at least one RTais, substituted with one or more RTb.

[0558] In some embodiments, at least one RTais.

[0559] In some embodiments, at least one RTais.

[0560] In some embodiments, at least one RTais C5-C6bridged bicyclic cycloalkyl.

[0561] In some embodiments, at least one RTais C5-C6 bridged bicyclic cycloalkyl substituted with one or more RTb.

[0562] In some embodiments, at least one RTais.

[0563] In some embodiments, at least one RTaiso , substituted with one or more RTb.

[0564] In some embodiments, at least one RTais.

[0565] In some embodiments, at least one RTais. 63 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0566] In some embodiments, at least one RTais.

[0567] In some embodiments, at least one RTais.

[0568] In some embodiments, at least one RTais C5-C6 spiro bicyclic cycloalkyl.

[0569] In some embodiments, at least one RTais C5-C6spiro bicyclic cycloalkyl substituted with one or more RTb.

[0570] In some embodiments, at least one RTais spiro[2.2]pentyl or spiro[2.3]hexyl.

[0571] In some embodiments, at least one RTais spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RTb.

[0572] In some embodiments, at least one RTais.

[0573] In some embodiments, at least one.

[0574] In some embodiments, at least one RTais 4- to 10-membered heterocyclyl.

[0575] In some embodiments, at least one RTais 4- to 10-membered heterocyclyl substituted with one or more RTb.

[0576] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl.

[0577] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl substituted with one or more RTb.

[0578] In some embodiments, at least one RTais 4- to 10-membered bicyclic heterocyclyl.

[0579] In some embodiments, at least one RTais 4- to 10-membered bicyclic heterocyclyl substituted with one or more RTb.

[0580] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl.

[0581] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RTb.

[0582] In some embodiments, at least one RTais 5- to 10-membered bridged bicyclic heterocyclyl.

[0583] In some embodiments, at least one RTais 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RTb.

[0584] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl.

[0585] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl 64 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 substituted with one or more RTb.

[0586] In some embodiments, at least one RTais 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[0587] In some embodiments, at least one RTais 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTb.

[0588] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[0589] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTb.

[0590] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[0591] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTb.

[0592] In some embodiments, at least one RTais azetidinyl.

[0593] In some embodiments, at least one RTais azetidinyl substituted with one or more RTb.

[0594] In some embodiments, at least one RTais.

[0595] In some embodiments, at least one RTais.

[0596] In some embodiments, at least one RTais.

[0597] In some embodiments, at least one RTais pyrrolidinyl.

[0598] In some embodiments, at least one RTais.

[0599] In some embodiments, at least one RTais.

[0600] In some embodiments, at least one RTais.

[0601] In some embodiments, at least one RTais piperidinyl.

[0602] In some embodiments, at least one RTais. 65 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0603] In some embodiments, at least one RTais.

[0604] In some embodiments, at least one RTais.

[0605] In some embodiments, at least one RTais.

[0606] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[0607] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTb.

[0608] In some embodiments, at least one

[0609] In some embodiments, at least onewith one or more RTb.

[0610] In some embodiments, at least one RTais.

[0611] In some embodiments, at least one RTais

[0612] In some embodiments, at least one.

[0613] In some embodiments, at least one RTais.

[0614] In some embodiments, at least oneis 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[0615] In some embodiments, at least one RTais 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl 66 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 is substituted with one or more RTb.

[0616] In some embodiments, at least one RTai, , , ,.

[0617] In some embodiments, at least one RTais, , , ,, substituted with one or more RTb.

[0618] In some embodiments, at least one RTais.

[0619] In some embodiments, at least one RTais.

[0620] In some embodiments, at least one RTais.

[0621] In some embodiments, at least one RTais.

[0622] In some embodiments, at least one RTais.

[0623] In some embodiments, at least one RTais.

[0624] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[0625] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTb.

[0626] In some embodiments, at least one RTais, , ,

[0627] In some embodiments, at least one RTais, , , 67 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, substituted with one or more RTb.

[0628] In some embodiments, at least one RTais

[0629] In some embodiments, at least one RTais.

[0630] In some

[0631] In some

[0632] In some

[0633] In some embodiments, at least one.

[0634] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[0635] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTb.

[0636] In some embodiments, at least one RTais oxetanyl.

[0637] In some embodiments, at least one RTais.

[0638] In some embodiments, at least one RTais.

[0639] In some embodiments, at least one RTais tetrahydrofuranyl.

[0640] In some embodiments, at least one RTais.

[0641] In some embodiments, at least one RTais.

[0642] In some embodiments, at least one RTais tetrahydropyranyl.

[0643] In some embodiments, at least one RTais. 68 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0644] In some embodiments, at least one RTais.

[0645] In some embodiments, at least one RTais.

[0646] In some embodiments, at least one RTais 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[0647] In some embodiments, at least one RTais 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis substituted with one or more RTb.

[0648] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[0649] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RTb.

[0650] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[0651] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered spiro heterocyclyl is substituted with one or more RTb.

[0652] In some embodiments, at least one RTais, , , ,, , , ,ore RTb.

[0654] In some embodiments, at least one RTais

[0655] In some embodiments, at least one RTais.

[0656] In some embodiments, at least one RTais. 69 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0657] In some embodiments, at least one RTais .

[0658] In some embodiments, at least one RTais .

[0659] In some embodiments, at least one RTais .

[0660] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[0661] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTb.

[0662] In some embodiments, at least one RTais tetrahydrothiophenyl.

[0663] In some embodiments, at least one RTais.

[0664] In some embodiments, at least one RTais.

[0665] In some embodiments, at least one RTais 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[0666] In some embodiments, at least one RTais 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTb.

[0667] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0668] In some embodiments, at least one RTais 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTb.

[0669] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0670] In some embodiments, at least one RTais 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTb.

[0671] In some embodiments, at least one RTais 5- to 10-membered bridged bicyclic 70 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heterocyclyl containing two heteroatoms selected from N, O, and S.

[0672] In some embodiments, at least one RTais 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RTb.

[0673] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0674] In some embodiments, at least one RTais 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTb.

[0677] In some embodiments, at least one RTais.

[0678] In some embodiments, at least one RTais.

[0679] In some embodiments, at least one RTais. 71 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0680] In some embodiments, at least one.

[0681] In some embodiments, at least one RTais.

[0682] In some embodiments, at least one RTais.

[0683] In some embodiments, at least one RTais.

[0684] In some embodiments, at least one RTais.

[0685] In some embodiments, at least one RTais.

[0686] In some embodiments, at least one RTais.

[0687] In some embodiments, at least one.

[0688] In some embodiments, at least one RTais.

[0689] In some

[0690] In some

[0691] In some

[0692] In some embodiments, at least one RTais C6-C10aryl (e.g., phenyl). 72 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0693] In some embodiments, at least one RTais C6-C10aryl (e.g., phenyl) substituted with one or more RTb.

[0694] In some embodiments, at least one RTais phenyl.

[0695] In some embodiments, at least one RTais 5- to 10-membered heteroaryl. In some embodiments, at least one RTais 5- or 6-membered heteroaryl.

[0696] In some embodiments, at least one RTais 5- to 10-membered heteroaryl substituted with one or more RTb. In some embodiments, at least one RTais 5- or 6-membered heteroaryl substituted with one or more RTb.

[0697] In some embodiments, at least one RTais 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. In some embodiments, at least one RTais 5- or 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0698] In some embodiments, at least one RTais 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTb. In some embodiments, at least one RTais 5- or 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTb.

[0699] In some embodiments, at least one RTais 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0700] In some embodiments, at least one RTais 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTb.

[0701] In some embodiments, at least one RTais 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[0702] In some embodiments, at least one RTais 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RTb.

[0703] In some embodiments, at least one RTais 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[0704] In some embodiments, at least one RTais 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RTb.

[0705] In some embodiments, at least one RTais oxazolyl. 73 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0706] In some embodiments, at least one RTais.

[0707] In some embodiments, at least one RTais thiazolyl.

[0708] In some embodiments, at least one RTais.

[0709] In some embodiments, at least one RTais pyrazolyl.

[0710] In some embodiments, at least one RTais.

[0711] In some embodiments, at least one RTais.

[0712] In some embodiments, at least one RTais isoxazolyl.

[0713] In some embodiments, at least one RTais isothiazolyl.

[0714] In some embodiments, at least one RTais imidazolyl.

[0715] In some embodiments, at least one RTais 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl).

[0716] In some embodiments, at least one RTais 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RTb.

[0717] In some embodiments, at least one RTais triazolyl.

[0718] In some embodiments, at least one RTais.

[0719] In some embodiments, at least one RTais.

[0720] In some embodiments, at least one RTais

[0721] In some embodiments, at least one RTais oxadiazolyl.

[0722] In some embodiments, at least one RTais.

[0723] In some embodiments, at least one RTais thiadiazolyl. 74 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0724] In some embodiments, at least one RTais.

[0725] In some embodiments, at least one RTais.

[0726] In some embodiments, at least one RTais 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[0727] In some embodiments, at least one RTais 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RTb.

[0728] In some embodiments, at least one RTais tetrazolyl.

[0729] In some embodiments, at least one RTais.

[0730] In some embodiments, at least one RTais oxatriazolyl.

[0731] In some embodiments, at least one RTais 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0732] In some embodiments, at least one RTais 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTb.

[0733] In some embodiments, at least one RTais 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[0734] In some embodiments, at least one RTais 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RTb.

[0735] In some embodiments, at least one RTais pyridinyl, wherein the pyridinyl is substituted with one or more RTb. In some embodiments, at least one RTais pyridinyl. In some embodiments, pyridinyl is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl.

[0736] In some embodiments, at least one RTais.

[0737] In some embodiments, at least one RTais 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[0738] In some embodiments, at least one RTais 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RTb. 75 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0739] In some embodiments, at least one RTais pyrimidinyl.

[0740] In some embodiments, at least one RTais.

[0741] In some embodiments, at least one RTais.

[0742] In some embodiments, at least one RTais pyridazinyl.

[0743] In some embodiments, at least one RTais.

[0744] In some embodiments, at least one RTais pyrazinyl.

[0745] In some embodiments, at least one RTais 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0746] In some embodiments, at least one RTais 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTb.

[0747] In some embodiments, at least one.

[0748] In some embodiments, at least one. Variable RTb

[0749] In some embodiments, at least one RTbis oxo, halogen, cyano, -OH, -ORc, -NH2, - NHRc, -N(Rc)2, -C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc.

[0750] In some embodiments, at least one RTbis oxo, halogen, cyano, -OH, -ORc, -NH2, - NHRc, -N(Rc)2, -C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- 76 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more RTc.

[0751] In some embodiments, at least one RTbis oxo, halogen, cyano, -OH, -ORc, -NH2, - NHRc, -N(Rc)2, -C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl.

[0752] In some embodiments, at least one RTbis oxo, halogen, cyano, -OH, -ORc, -NH2, - NHRc, -N(Rc)2, -C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0753] In some embodiments, at least one RTbis oxo, halogen, cyano, -OH, -O(C1-C6alkyl), - NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)- (C1-C6 alkyl), -C(=O)-OH, - C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, -C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, - S(=O)2-(C1-C6alkyl), -S(=O)(=NH)- (C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0754] In some embodiments, at least one RTbis oxo.

[0755] In some embodiments, at least one RTbis halogen (e.g., -F, -Cl, -Br, -I).

[0756] In some embodiments, at least one RTbis cyano.

[0757] In some embodiments, at least one RTbis -OH.

[0758] In some embodiments, at least one RTbis -ORc.

[0759] In some embodiments, at least one RTbis -NH2.

[0760] In some embodiments, at least one RTbis -NHRc.

[0761] In some embodiments, at least one RTbis -N(Rc)2.

[0762] In some embodiments, at least one RTbis -C(=O)-H.

[0763] In some embodiments, at least one RTbis -C(=O)-Rc.

[0764] In some embodiments, at least one RTbis -C(=O)-OH.

[0765] In some embodiments, at least one RTbis -C(=O)-ORc.

[0766] In some embodiments, at least one RTbis -C(=O)-NH2.

[0767] In some embodiments, at least one RTbis -C(=O)-NHRc.

[0768] In some embodiments, at least one RTbis -C(=O)-N(Rc)2.

[0769] In some embodiments, at least one RTbis -S(=O)2-Rc.

[0770] In some embodiments, at least one RTbis -S(=O)(=NH)-Rc.

[0771] In some embodiments, at least one RTbis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl). 77 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0772] In some embodiments, at least one RTbis C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RTc.

[0773] In some embodiments, at least one RTbis methyl.

[0774] In some embodiments, at least one RTbis ethyl.

[0775] In some embodiments, at least one RTbis n-propyl.

[0776] In some embodiments, at least one RTbis isopropyl.

[0777] In some embodiments, at least one RTbis n-butyl.

[0778] In some embodiments, at least one RTbis C2-C6 alkenyl.

[0779] In some embodiments, at least one RTbis C2-C6 alkenyl substituted with one or more RTc.

[0780] In some embodiments, at least one RTbis C2-C6alkynyl.

[0781] In some embodiments, at least one RTbis C2-C6 alkynyl substituted with one or more RTc.

[0782] In some embodiments, at least one RTbis C3-C6cycloalkyl.

[0783] In some embodiments, at least one RTbis 4- to 10-membered heterocyclyl.

[0784] In some embodiments, at least one RTbis C6-C10 aryl.

[0785] In some embodiments, at least one RTbis 5- to 10- membered heteroaryl.

[0786] In some embodiments, at least one RTbis C3-C6cycloalkyl substituted with one or more RTc.

[0787] In some embodiments, at least one RTbis C3-C6monocyclic cycloalkyl.

[0788] In some embodiments, at least one RTbis C3-C6monocyclic cycloalkyl substituted with one or more RTc.

[0789] In some embodiments, at least one RTbis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[0790] In some embodiments, at least one RTbis C3-C6bicyclic cycloalkyl.

[0791] In some embodiments, at least one RTbis C3-C6 bicyclic cycloalkyl substituted with one or more RTc.

[0792] In some embodiments, at least one RTbis bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[0793] In some embodiments, at least one RTbis C4-C6 fused bicyclic cycloalkyl.

[0794] In some embodiments, at least one RTbis C4-C6fused bicyclic cycloalkyl substituted with one or more RTc. 78 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0795] In some embodiments, at least one RTbis.

[0796] In some embodiments, at least one RTbis, substituted with one or more RTc.

[0797] In some embodiments, at least one RTbis.

[0798] In some embodiments, at least one RTbis.

[0799] In some embodiments, at least one RTbis C5-C6 bridged bicyclic cycloalkyl.

[0800] In some embodiments, at least one RTbis C5-C6 bridged bicyclic cycloalkyl substituted with one or more RTc.

[0801] In some embodiments, at least one RTbis.

[0802] In some embodiments, at least one RTbis, substituted with one or more RTc.

[0803] In some embodiments, at least one RTbis.

[0804] In some embodiments, at least one RTbis.

[0805] In some embodiments, at least one RTbis.

[0806] In some embodiments, at least one RTbis.

[0807] In some embodiments, at least one RTbis C5-C6 spiro bicyclic cycloalkyl.

[0808] In some embodiments, at least one RTbis C5-C6spiro bicyclic cycloalkyl substituted with one or more RTc.

[0809] In some embodiments, at least one RTbis spiro[2.2]pentyl or spiro[2.3]hexyl.

[0810] In some embodiments, at least one RTbis spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RTc.

[0811] In some embodiments, at least one RTbis. 79 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0812] In some embodiments, at least one.

[0813] In some embodiments, at least one RTbis 4- to 10-membered heterocyclyl.

[0814] In some embodiments, at least one RTbis 4- to 10-membered heterocyclyl substituted with one or more RTc.

[0815] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl.

[0816] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl substituted with one or more RTc.

[0817] In some embodiments, at least one RTbis 4- to 10-membered bicyclic heterocyclyl.

[0818] In some embodiments, at least one RTbis 4- to 10-membered bicyclic heterocyclyl substituted with one or more RTc.

[0819] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl.

[0820] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RTc.

[0821] In some embodiments, at least one RTbis 5- to 10-membered bridged bicyclic heterocyclyl.

[0822] In some embodiments, at least one RTbis 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RTc.

[0823] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl.

[0824] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RTc.

[0825] In some embodiments, at least one RTbis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[0826] In some embodiments, at least one RTbis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTc.

[0827] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[0828] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTc. 80 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0829] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[0830] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[0831] In some embodiments, at least one RTbis azetidinyl.

[0832] In some embodiments, at least one RTbis azetidinyl substituted with one or more RTc.

[0833] In some embodiments, at least one RTbi.

[0834] In some embodiments, at least one RTbi.

[0835] In some embodiments, at least one RTbi.

[0836] In some embodiments, at least one RTbi

[0837] In some embodiments, at least one RTbi.

[0838] In some embodiments, at least one RTbi.

[0839] In some embodiments, at least one RTbi.

[0840] In some embodiments, at least one RTbi

[0841] In some embodiments, at least one RTbi.

[0842] In some embodiments, at least one RTbi.

[0843] In some embodiments, at least one RTbis.

[0844] In some embodiments, at least one RTbis.

[0845] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[0846] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTc. 81 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0847] In some embodiments, at least one

[0848] In some embodiments, at least onewith one or more RTc.

[0849] In some embodiments, at least one RTbis.

[0850] In some embodiments, at least one RTbis

[0851] In some embodiments, at least one.

[0852] In some embodiments, at least one RTbis.

[0853] In some embodiments, at least oneis 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[0854] In some embodiments, at least one RTbis 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more RTc..

[0856] In some embodiments, at least one RTbis, , , ,, substituted with one or more RTc. 82 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0857] In some embodiments, at least one RTbis.

[0858] In some embodiments, at least one RTbi.

[0859] In some embodiments, at least one RTbi.

[0860] In some embodiments, at least one RTbi.

[0861] In some embodiments, at least one RTbi.

[0862] In some embodiments, at least one RTbis.

[0863] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[0864] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTc.

[0865] In some embodiments, at least one RTbis, , ,

[0866] In some embodiments, at least one RTbis, , ,, substituted with one or more RTc.

[0867] In some embodiments, at least one RTbi

[0868] In some embodiments, at least one RTbi.

[0869] In some embodiments, at least one RTbi. 83 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0870] In some embodiments, at least one RTbis.

[0871] In some embodiments, at least one RTbis.

[0872] In some embodiments, at least one.

[0873] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[0874] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[0875] In some embodiments, at least one RTbis oxetanyl.

[0876] In some embodiments, at least one RTbi.

[0877] In some embodiments, at least one RTbi.

[0878] In some embodiments, at least one RTbis tetrahydrofuranyl.

[0879] In some embodiments, at least one RTbi.

[0880] In some embodiments, at least one RTbi.

[0881] In some embodiments, at least one RTbis tetrahydropyranyl.

[0882] In some embodiments, at least one RTbi.

[0883] In some embodiments, at least one RTbi.

[0884] In some embodiments, at least one RTbis.

[0885] In some embodiments, at least one RTbis 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[0886] In some embodiments, at least one RTbis 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis 84 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 substituted with one or more RTc.

[0887] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[0888] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RTc.

[0889] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[0890] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTc.

[0891] In some embodiments, at least one, , , ,, , , ,r more RTc.

[0893] In some embodiments, at least one RTbi

[0894] In some embodiments, at least one RTbi.

[0895] In some embodiments, at least one RTbi.

[0896] In some embodiments, at least one RTbi.

[0897] In some embodiments, at least one RTbi.

[0898] In some embodiments, at least one RTbi.

[0899] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[0900] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl 85 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[0901] In some embodiments, at least one RTbis tetrahydrothiophenyl.

[0902] In some embodiments, at least one RTbis.

[0903] In some embodiments, at least one RTbis.

[0904] In some embodiments, at least one RTbis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[0905] In some embodiments, at least one RTbis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTc.

[0906] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0907] In some embodiments, at least one RTbis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[0908] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0909] In some embodiments, at least one RTbis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTc.

[0910] In some embodiments, at least one RTbis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0911] In some embodiments, at least one RTbis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RTc.

[0912] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[0913] In some embodiments, at least one RTbis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTc. 86 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0914] In some embodiments, at least one RTbis, , , ,

[0915] In some embodiments, at least one RTbis, , , ,

[0916] In some embodiments, at least one RTbis.

[0917] In some embodiments, at least one RTbis.

[0918] In some embodiments, at least one RTbis.

[0919] In some embodiments, at least one.

[0920] In some embodiments, at least one RTbis.

[0921] In some embodiments, at least one RTbis.

[0922] In some embodiments, at least one RTbis. 87 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0923] In some embodiments, at least one RTbis.

[0924] In some embodiments, at least one RTbis.

[0925] In some embodiments, at least one RTbis.

[0926] In some embodiments, at least one.

[0927] In some embodiments, at least one RTbis.

[0928] In some embodiments, at least one.

[0929] In some embodiments, at least one.

[0930] In some embodiments, at least one.

[0931] In some embodiments, at least one RTbis C6-C10 aryl (e.g., phenyl).

[0932] In some embodiments, at least one RTbis C6-C10aryl (e.g., phenyl) substituted with one or more RTc.

[0933] In some embodiments, at least one RTbis phenyl.

[0934] In some embodiments, at least one RTbis 5- to 10-membered heteroaryl.

[0935] In some embodiments, at least one RTbis 5- to 10-membered heteroaryl substituted with one or more RTc.

[0936] In some embodiments, at least one RTbis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0937] In some embodiments, at least one RTbis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one 88 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 or more RTc.

[0938] In some embodiments, at least one RTbis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0939] In some embodiments, at least one RTbis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTc.

[0940] In some embodiments, at least one RTbis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[0941] In some embodiments, at least one RTbis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RTc.

[0942] In some embodiments, at least one RTbis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[0943] In some embodiments, at least one RTbis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RTc.

[0944] In some embodiments, at least one RTbis oxazolyl.

[0945] In some embodiments, at least one RTbis .

[0946] In some embodiments, at least one RTbis thiazolyl.

[0947] In some embodiments, at least one RTbis.

[0948] In some embodiments, at least one RTbis pyrazolyl.

[0949] In some embodiments, at least one RTbis .

[0950] In some embodiments, at least one RTbis.

[0951] In some embodiments, at least one RTbis isoxazolyl.

[0952] In some embodiments, at least one RTbis isothiazolyl.

[0953] In some embodiments, at least one RTbis imidazolyl.

[0954] In some embodiments, at least one RTbis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or 89 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 oxathiadiazolyl).

[0955] In some embodiments, at least one RTbis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RTc.

[0956] In some embodiments, at least one RTbis triazolyl.

[0957] In some embodiments, at least one RTbis.

[0958] In some embodiments, at least one Ris .

[0959] In some embodiments, at least one RTbis

[0960] In some embodiments, at least one RTbis oxadiazolyl.

[0961] In some embodiments, at least one RTbis.

[0962] In some embodiments, at least one RTbis thiadiazolyl.

[0963] In some embodiments, at least one RTbis.

[0964] In some embodiments, at least one RTbis.

[0965] In some embodiments, at least one RTbis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[0966] In some embodiments, at least one RTbis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RTc.

[0967] In some embodiments, at least one RTbis tetrazolyl.

[0968] In some embodiments, at least one RTbis.

[0969] In some embodiments, at least one RTbis oxatriazolyl.

[0970] In some embodiments, at least one RTbis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0971] In some embodiments, at least one RTbis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or 90 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 more RTc.

[0972] In some embodiments, at least one RTbis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[0973] In some embodiments, at least one RTbis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RTc.

[0974] In some embodiments, at least one RTbis pyridinyl.

[0975] In some embodiments, at least one RTbis.

[0976] In some embodiments, at least one RTbis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[0977] In some embodiments, at least one RTbis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RTc.

[0978] In some embodiments, at least one RTbis pyrimidinyl.

[0979] In some embodiments, at least one RTbis.

[0980] In some embodiments, at least one RTbis.

[0981] In some embodiments, at least one RTbis pyridazinyl.

[0982] In some embodiments, at least one RTbis.

[0983] In some embodiments, at least one RTbis pyrazinyl.

[0984] In some embodiments, at least one RTbis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[0985] In some embodiments, at least one RTbis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTc.

[0986] In some embodiments, at least one. 91 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[0987] In some embodiments, at least one. Variable RTb1

[0988] In some embodiments, at least one RTb1is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), - C(=O)-NH2, -C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[0989] In some embodiments, at least one RTb1is present and the at least one RTb1is -C(=O)- H, -C(=O)-OH, or -C(=O)-O(C1-C6alkyl). In some embodiments, at least one RTb1is -C(=O)- OH.

[0990] In some embodiments, at least one RTb1is oxo.

[0991] In some embodiments, at least one RTb1is halogen (e.g., -F, -Cl, -Br, -I).

[0992] In some embodiments, at least one RTb1is cyano.

[0993] In some embodiments, at least one RTb1is -OH.

[0994] In some embodiments, at least one RTb1is -O(C1-C6 alkyl) (e.g., -O(methyl), -O(ethyl), -O(n-propyl), -O(isopropyl), -O(n-butyl), -O(t-butyl), -O(isobutyl), or -O(sec-butyl)).

[0995] In some embodiments, at least one RTb1is -NH2.

[0996] In some embodiments, at least one RTb1is - NH(C1-C6 alkyl) (e.g., -NHCH3, - NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, or -NH(CH2)5CH3).

[0997] In some embodiments, at least one RTb1is -N(C1-C6alkyl)2(e.g., e.g., -N(methyl)2, - N(ethyl)2, -N(n-propyl)2, -N(isopropyl)2, -N(n-butyl)2, -N(t-butyl)2, -N(isobutyl)2, or -N(sec- butyl)2).

[0998] In some embodiments, at least one RTb1is -C(=O)-H.

[0999] In some embodiments, at least one RTb1is -C(=O)-OH.

[1000] In some embodiments, at least one RTb1is -C(=O)-O(C1-C6 alkyl) (e.g., is -C(=O)- OCH3, -C(=O)-OCH2CH3, -C(=O)-O(CH2)2CH3, -C(=O)-O(CH2)3CH3, -C(=O)-O(CH2)4CH3, or -C(=O)-O(CH2)5CH3).

[1001] In some embodiments, at least one RTb1is -C(=O)-NH2.

[1002] In some embodiments, at least one RTb1is -C(=O)-NH(C1-C6 alkyl) ((e.g., -C(=O)- NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-NH(CH2)3CH3, -C(=O)- NH(CH2)4CH3, or -C(=O)-NH(CH2)5CH3)).

[1003] In some embodiments, at least one RTb1is -C(=O)-N(C1-C6 alkyl)2 (e.g., -C(=O)- 92 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 N(methyl)2, -C(=O)-N(ethyl)2, -C(=O)-N(n-propyl)2, -C(=O)-N(isopropyl)2, -C(=O)-N(n- butyl)2, -C(=O)-N(t-butyl)2, -C(=O)-N(isobutyl)2, or -C(=O)-N(sec-butyl)2).

[1004] In some embodiments, at least one RTb1is C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[1005] In some embodiments, at least one RTb1is methyl.

[1006] In some embodiments, at least one RTb1is ethyl.

[1007] In some embodiments, at least one RTb1is n-propyl.

[1008] In some embodiments, at least one RTb1is isopropyl.

[1009] In some embodiments, at least one RTb1is n-butyl.

[1010] In some embodiments, at least one RTb1is C2-C6alkenyl.

[1011] In some embodiments, at least one RTb1is C2-C6alkynyl. Variable RTc

[1012] In some embodiments, at least one RTcis oxo, halogen, cyano, -OH, -O(C1-C6alkyl), - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), - C(=O)-NH2, -C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6alkynyl.

[1013] In some embodiments, at least one RTcis oxo.

[1014] In some embodiments, at least one RTcis halogen (e.g., -F, -Cl, -Br, -I).

[1015] In some embodiments, at least one RTcis cyano.

[1016] In some embodiments, at least one RTcis -OH.

[1017] In some embodiments, at least one RTcis -O(C1-C6 alkyl) (e.g., -O(methyl), -O(ethyl), -O(n-propyl), -O(isopropyl), -O(n-butyl), -O(t-butyl), -O(isobutyl), or -O(sec-butyl)).

[1018] In some embodiments, at least one RTcis -NH2.

[1019] In some embodiments, at least one RTcis - NH(C1-C6alkyl) (e.g., -NHCH3, - NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, or -NH(CH2)5CH3).

[1020] In some embodiments, at least one RTcis -N(C1-C6 alkyl)2 (e.g., e.g., -N(methyl)2, - N(ethyl)2, -N(n-propyl)2, -N(isopropyl)2, -N(n-butyl)2, -N(t-butyl)2, -N(isobutyl)2, or -N(sec- butyl)2).

[1021] In some embodiments, at least one RTcis -C(=O)-H.

[1022] In some embodiments, at least one RTcis -C(=O)-OH.

[1023] In some embodiments, at least one RTcis -C(=O)-O(C1-C6alkyl) (e.g., is -C(=O)-OCH3, -C(=O)-OCH2CH3, -C(=O)-O(CH2)2CH3, -C(=O)-O(CH2)3CH3, -C(=O)-O(CH2)4CH3, or - C(=O)-O(CH2)5CH3). 93 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1024] In some embodiments, at least one RTcis -C(=O)-NH2.

[1025] In some embodiments, at least one RTcis -C(=O)-NH(C1-C6 alkyl) ((e.g., -C(=O)- NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-NH(CH2)3CH3, -C(=O)- NH(CH2)4CH3, or -C(=O)-NH(CH2)5CH3)).

[1026] In some embodiments, at least one RTcis -C(=O)-N(C1-C6 alkyl)2 (e.g., -C(=O)- N(methyl)2, -C(=O)-N(ethyl)2, -C(=O)-N(n-propyl)2, -C(=O)-N(isopropyl)2, -C(=O)-N(n- butyl)2, -C(=O)-N(t-butyl)2, -C(=O)-N(isobutyl)2, or -C(=O)-N(sec-butyl)2).

[1027] In some embodiments, at least one RTcis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[1028] In some embodiments, at least one RTcis methyl.

[1029] In some embodiments, at least one RTcis ethyl.

[1030] In some embodiments, at least one RTcis n-propyl.

[1031] In some embodiments, at least one RTcis isopropyl.

[1032] In some embodiments, at least one RTcis n-butyl.

[1033] In some embodiments, at least one RTcis C2-C6 alkenyl.

[1034] In some embodiments, at least one RTcis C2-C6 alkynyl. Variable Rb

[1035] In some embodiments, at least one Rbis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc.

[1036] In some embodiments, at least one Rbis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl.

[1037] In some embodiments, at least one Rbis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more RTc.

[1038] In some embodiments, at least one Rbis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[1039] In some embodiments, at least one Rbis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RTc.

[1040] In some embodiments, at least one Rbis methyl. 94 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1041] In some embodiments, at least one Rbis ethyl.

[1042] In some embodiments, at least one Rbis n-propyl.

[1043] In some embodiments, at least one Rbis isopropyl.

[1044] In some embodiments, at least one Rbis n-butyl.

[1045] In some embodiments, at least one Rbis C2-C6 alkenyl.

[1046] In some embodiments, at least one Rbis C2-C6 alkenyl substituted with one or more RTc.

[1047] In some embodiments, at least one Rbis C2-C6 alkynyl.

[1048] In some embodiments, at least one Rbis C2-C6 alkynyl substituted with one or more RTc.

[1049] In some embodiments, at least one Rbis C3-C6cycloalkyl.

[1050] In some embodiments, at least one Rbis C3-C6 cycloalkyl substituted with one or more RTc.

[1051] In some embodiments, at least one Rbis C3-C6monocyclic cycloalkyl.

[1052] In some embodiments, at least one Rbis C3-C6 monocyclic cycloalkyl substituted with one or more RTc.

[1053] In some embodiments, at least one Rbis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[1054] In some embodiments, at least one Rbis C3-C6 bicyclic cycloalkyl.

[1055] In some embodiments, at least one Rbis C3-C6bicyclic cycloalkyl substituted with one or more RTc.

[1056] In some embodiments, at least one Rbis bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[1057] In some embodiments, at least one Rbis C4-C6fused bicyclic cycloalkyl.

[1058] In some embodiments, at least one Rbis C4-C6fused bicyclic cycloalkyl substituted with one or more RTc.

[1059] In some embodiments, at least one Rbis.

[1060] In some embodiments, at least one Rbis, substituted with one or more RTc.

[1061] In some embodiments, at least one Rbis. 95 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1062] In some embodiments, at least one Rbis.

[1063] In some embodiments, at least one Rbis C5-C6bridged bicyclic cycloalkyl.

[1064] In some embodiments, at least one Rbis C5-C6 bridged bicyclic cycloalkyl substituted with one or more RTc.

[1065] In some embodiments, at least one Rbis.

[1066] In some embodiments, at least one Rbis, substituted with one or more RTc.

[1067] In some embodiments, at least one Rbis.

[1068] In some embodiments, at least one Rbis.

[1069] In some embodiments, at least one Rbis.

[1070] In some embodiments, at least one Rbis.

[1071] In some embodiments, at least one Rbis C5-C6spiro bicyclic cycloalkyl.

[1072] In some embodiments, at least one Rbis C5-C6 spiro bicyclic cycloalkyl substituted with one or more RTc.

[1073] In some embodiments, at least one Rbis spiro[2.2]pentyl or spiro[2.3]hexyl.

[1074] In some embodiments, at least one Rbis spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RTc.

[1075] In some embodiments, at least one Rbis.

[1076] In some embodiments, at least one.

[1077] In some embodiments, at least one Rbis 4- to 10-membered heterocyclyl.

[1078] In some embodiments, at least one Rbis 4- to 10-membered heterocyclyl substituted with one or more RTc.

[1079] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl.

[1080] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl 96 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 substituted with one or more RTc.

[1081] In some embodiments, at least one Rbis 4- to 10-membered bicyclic heterocyclyl.

[1082] In some embodiments, at least one Rbis 4- to 10-membered bicyclic heterocyclyl substituted with one or more RTc.

[1083] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl.

[1084] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RTc.

[1085] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl.

[1086] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RTc.

[1087] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl.

[1088] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RTc.

[1089] In some embodiments, at least one Rbis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1090] In some embodiments, at least one Rbis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTc.

[1091] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1092] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTc.

[1093] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[1094] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[1095] In some embodiments, at least one Rbis azetidinyl.

[1096] In some embodiments, at least one Rbis azetidinyl substituted with one or more RTc.

[1097] In some embodiments, at least one Rbis. 97 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1098] In some embodiments, at least one Rbis .

[1099] In some embodiments, at least one Rbis .

[1100] In some embodiments, at least one Rbis pyrrolidinyl.

[1101] In some embodiments, at least one Rbis .

[1102] In some embodiments, at least one Rbis.

[1103] In some embodiments, at least one Rbis.

[1104] In some embodiments, at least one Rbis piperidinyl.

[1105] In some embodiments, at least one Rbis.

[1106] In some embodiments, at least one Rbis.

[1107] In some embodiments, at least one Rbis.

[1108] In some embodiments, at least one Rbis.

[1109] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[1110] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTc.

[1111] In some embodiments, at least one

[1112] In some embodiments, at least one, substituted with one or more RTc. 98 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1113] In some embodiments, at least one Rbis.

[1114] In some embodiments, at least one Rbis

[1115] In some embodiments, at least one.

[1116] In some embodiments, at least one Rbis.

[1117] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[1118] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more RTc.

[1119] In some embodiments, at least one Rbis, , , ,.

[1120] In some embodiments, at least one Rbis, , , ,, substituted with one or more RTc.

[1121] In some embodiments, at least one Rbis.

[1122] In some embodiments, at least one Rbis.

[1123] In some embodiments, at least one Rbis.

[1124] In some embodiments, at least one Rbis. 99 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1125] In some embodiments, at least one Rb.

[1126] In some embodiments, at least one Rbis.

[1127] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[1128] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTc.

[1129] In some embodiments, at least one Rbis, , ,

[1130] In some embodiments, at least one Rbis, , ,

[1131] In some embodiments, at least one Rbis

[1132] In some embodiments, at least one Rbis.

[1133] In some embodiments, at least one Rbis.

[1134] In some embodiments, at least one Rbis.

[1135] In some embodiments, at least one Rbis.

[1136] In some embodiments, at least one.

[1137] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl 100 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[1138] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[1139] In some embodiments, at least one Rbis oxetanyl.

[1140] In some embodiments, at least one Rb.

[1141] In some embodiments, at least one Rb.

[1142] In some embodiments, at least one Rbis tetrahydrofuranyl.

[1143] In some embodiments, at least one Rb.

[1144] In some embodiments, at least one Rb.

[1145] In some embodiments, at least one Rbis tetrahydropyranyl.

[1146] In some embodiments, at least one Rb.

[1147] In some embodiments, at least one Rb.

[1148] In some embodiments, at least one Rb.

[1149] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[1150] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis substituted with one or more RTc.

[1151] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[1152] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RTc.

[1153] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[1154] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl 101 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing one O, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTc.

[1155] In some embodiments, at least one Rbis, , , ,, , , ,ore RTc.

[1157] In some embodiments, at least one Rbis

[1158] In some embodiments, at least one Rbis.

[1159] In some embodiments, at least one Rbis.

[1160] In some embodiments, at least one Rbis.

[1161] In some embodiments, at least one Rbis.

[1162] In some embodiments, at least one Rbis.

[1163] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[1164] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[1165] In some embodiments, at least one Rbis tetrahydrothiophenyl.

[1166] In some embodiments, at least one Rbis.

[1167] In some embodiments, at least one Rbis.

[1168] In some embodiments, at least one Rbis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S. 102 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1169] In some embodiments, at least one Rbis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RTc.

[1170] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1171] In some embodiments, at least one Rbis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RTc.

[1172] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1173] In some embodiments, at least one Rbis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RTc.

[1174] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1175] In some embodiments, at least one Rbis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RTc.

[1176] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1177] In some embodiments, at least one Rbis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RTc.

[1178] In some embodiments, at least one Rbis, , , ,103 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1179] In some embodiments, at least one Rbis, , , ,

[1180] In some embodiments, at least one Rbis.

[1181] In some embodiments, at least one Rbis.

[1182] In some embodiments, at least one Rbis.

[1183] In some embodiments, at least one.

[1184] In some embodiments, at least one Rbis.

[1185] In some embodiments, at least one Rbis.

[1186] In some embodiments, at least one Rbis.

[1187] In some embodiments, at least one Rbis.

[1188] In some embodiments, at least one Rbis.

[1189] In some embodiments, at least one Rbis. 104 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1190] In some embodiments, at least one.

[1191] In some embodiments, at least one Rbis.

[1192] In some embodiments, at least one.

[1193] In some embodiments, at least one.

[1194] In some embodiments, at least one.

[1195] In some embodiments, at least one Rbis C6-C10 aryl (e.g., phenyl).

[1196] In some embodiments, at least one Rbis C6-C10 aryl (e.g., phenyl) substituted with one or more RTc.

[1197] In some embodiments, at least one Rbis phenyl.

[1198] In some embodiments, at least one Rbis 5- to 10-membered heteroaryl.

[1199] In some embodiments, at least one Rbis 5- to 10-membered heteroaryl substituted with one or more RTc.

[1200] In some embodiments, at least one Rbis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1201] In some embodiments, at least one Rbis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTc.

[1202] In some embodiments, at least one Rbis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1203] In some embodiments, at least one Rbis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTc.

[1204] In some embodiments, at least one Rbis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). 105 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1205] In some embodiments, at least one Rbis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RTc.

[1206] In some embodiments, at least one Rbis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[1207] In some embodiments, at least one Rbis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RTc.

[1208] In some embodiments, at least one Rbis oxazolyl.

[1209] In some embodiments, at least one Rbis.

[1210] In some embodiments, at least one Rbis thiazolyl.

[1211] In some embodiments, at least one Rbis.

[1212] In some embodiments, at least one Rbis pyrazolyl.

[1213] In some embodiments, at least one Rbis .

[1214] In some embodiments, at least one Rbis.

[1215] In some embodiments, at least one Rbis isoxazolyl.

[1216] In some embodiments, at least one Rbis isothiazolyl.

[1217] In some embodiments, at least one Rbis imidazolyl.

[1218] In some embodiments, at least one Rbis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl).

[1219] In some embodiments, at least one Rbis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RTc.

[1220] In some embodiments, at least one Rbis triazolyl.

[1221] In some embodiments, at least one Rbis. 106 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1222] In some embodiments, at least one Rbis.

[1223] In some embodiments, at least one Rbis

[1224] In some embodiments, at least one Rbis oxadiazolyl.

[1225] In some embodiments, at least one Rbis.

[1226] In some embodiments, at least one Rbis thiadiazolyl.

[1227] In some embodiments, at least one Rbis.

[1228] In some embodiments, at least one Rbis.

[1229] In some embodiments, at least one Rbis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[1230] In some embodiments, at least one Rbis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RTc.

[1231] In some embodiments, at least one Rbis tetrazolyl.

[1232] In some embodiments, at least one Rbis.

[1233] In some embodiments, at least one Rbis oxatriazolyl.

[1234] In some embodiments, at least one Rbis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1235] In some embodiments, at least one Rbis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RTc.

[1236] In some embodiments, at least one Rbis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[1237] In some embodiments, at least one Rbis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RTc.

[1238] In some embodiments, at least one Rbis pyridinyl. 107 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1239] In some embodiments, at least one Rbis.

[1240] In some embodiments, at least one Rbis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[1241] In some embodiments, at least one Rbis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RTc.

[1242] In some embodiments, at least one Rbis pyrimidinyl.

[1243] In some embodiments, at least one Rbis.

[1244] In some embodiments, at least one Rbis.

[1245] In some embodiments, at least one Rbis pyridazinyl.

[1246] In some embodiments, at least one Rbis.

[1247] In some embodiments, at least one Rbis pyrazinyl.

[1248] In some embodiments, at least one Rbis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1249] In some embodiments, at least one Rbis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more .

[1250] In some embodiments, at least one.

[1251] In some embodiments, at least one. Variable Rc

[1252] In some embodiments, at least one Rcis C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[1253] In some embodiments, at least one Rcis C1-C6alkyl (e.g., methyl, ethyl, n-propyl, 108 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[1254] In some embodiments, at least one Rcis methyl.

[1255] In some embodiments, at least one Rcis ethyl.

[1256] In some embodiments, at least one Rcis C2-C6alkenyl.

[1257] In some embodiments, at least one RcC2-C6 alkynyl. Variable ring A109 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, where * indicates connectivity to the carbonyl group at triazolopyridine (i.e., not the connectivity to Z)connectivity to the carbonyl group at triazolopyridine., , , , ,, where * indicates connectivity to the carbonyl group at triazolopyridine.

[1261] In some embodiments, ring A is, 110 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084111 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, where * indicates connectivity to the carbonyl group at triazolopyridine.

[1263] In some embodiments, ring A is .

[1264] In some embodiments, ring A is .

[1265] In some embodiments, ring A is .

[1266] In some embodiments, ring A is.

[1267] In some embodiments, ring A is.

[1268] In some embodiments, ring

[1269] In some embodiments, ring112 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1270] In some embodiments, ring.

[1271] In some embodiments, ring.

[1272] In some embodiments, ring.

[1273] In some embodiments, ring.

[1274] In some embodiments, ring.

[1275] In some embodiments, ring A is .

[1276] In some embodiments, ring A is .

[1277] In some embodiments, ring A is .

[1278] In some embodiments, ring A is .

[1279] In some embodiments, ring A is . 113 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1280] In some embodiments, ring A is .

[1281] In some embodiments, ring A is .

[1282] In some embodiments, ring A is.

[1283] In some embodiments, ring A is.

[1284] In some embodiments, ring A is.

[1285] In some embodiments, ring A is.

[1286] In some embodiments, ring A is.

[1287] In some embodiments, ring A is.

[1288] In some embodiments, ring

[1289] In some embodiments, ring A is.

[1290] In some embodiments, ring114 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1291] In some embodiments, ring

[1292] In some embodiments, ring A is .

[1293] In some embodiments, ring A is .

[1294] In some embodiments, ring A is .

[1295] In some embodiments, ring A is .

[1296] In some embodiments, ring

[1297] In some embodiments, ring A is .

[1298] In some embodiments, ring A is.

[1299] In some embodiments, ring A is . 115 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1300] In some embodiments, ring.

[1301] In some embodiments, ring A is . Variable ring B

[1302] In some embodiments, B is absent (B is H) or ring B is H, C3-C6 cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl.

[1303] In some embodiments, B is absent (B is H).

[1304] In some embodiments, ring B is C3-C6 cycloalkyl.

[1305] In some embodiments, ring B is C3-C6monocyclic cycloalkyl.

[1306] In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[1307] In some embodiments, ring B is C3-C6bicyclic cycloalkyl.

[1308] In some embodiments, ring B is bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[1309] In some embodiments, ring B is C4-C6 fused bicyclic cycloalkyl.

[1311] In some embodiments, ring B is.

[1312] In some embodiments, ring B is.

[1313] In some embodiments, ring B is C5-C6 bridged bicyclic cycloalkyl.

[1314] In some embodiments, ring B is.

[1315] In some embodiments, ring B is .

[1316] In some embodiments, ring B is. 116 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1317] In some embodiments, ring B is.

[1318] In some embodiments, ring B is.

[1319] In some embodiments, ring B is C5-C6spiro bicyclic cycloalkyl.

[1320] In some embodiments, ring B is spiro[2.2]pentyl or spiro[2.3]hexyl.

[1321] In some embodiments, ring B is.

[1322] In some embodiments, ring.

[1323] In some embodiments, ring B is 4- to 10-membered heterocyclyl.

[1324] In some embodiments, ring B is 4- to 10-membered monocyclic heterocyclyl.

[1325] In some embodiments, ring B is 4- to 10-membered bicyclic heterocyclyl.

[1326] In some embodiments, ring B is 4- to 10-membered fused bicyclic heterocyclyl.

[1327] In some embodiments, ring B is 5- to 10-membered bridged bicyclic heterocyclyl.

[1328] In some embodiments, ring B is 5- to 10-membered spiro bicyclic heterocyclyl.

[1329] In some embodiments, ring B is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1330] In some embodiments, ring B is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1331] In some embodiments, ring B is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[1332] In some embodiments, ring B is azetidinyl.

[1333] In some embodiments, ring B is.

[1334] In some embodiments, ring B is.

[1335] In some embodiments, ring B is .

[1336] In some embodiments, ring B is pyrrolidinyl.

[1337] In some embodiments, ring B is. 117 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1338] In some embodiments, ring B is.

[1339] In some embodiments, ring B is.

[1340] In some embodiments, ring B is piperidinyl.

[1341] In some embodiments, ring B is.

[1342] In some embodiments, ring B is.

[1343] In some embodiments, ring B is.

[1344] In some embodiments, ring B is.

[1345] In some embodiments, ring B is 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[1346] In some embodiments, ring

[1347] In some embodiments, ring B is.

[1348] In some embodiments, ring B is

[1349] In some embodiments, ring

[1350] In some embodiments, ring B is.

[1351] In some embodiments, ring B is 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[1352] In some embodiments, ring B is, , , , 118 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084.

[1353] In some embodiments, ring B is.

[1354] In some embodiments, ring B is.

[1355] In some embodiments, ring B is.

[1356] In some embodiments, ring B is.

[1357] In some embodiments, ring B is.

[1358] In some embodiments, ring B is.

[1359] In some embodiments, ring B is 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[1360] In some embodiments, ring B is, , ,

[1361] In some embodiments, ring B is

[1362] In some embodiments, ring B is.

[1363] In some embodiments, ring B is.

[1364] In some embodiments, ring B is.

[1365] In some embodiments, ring B is. 119 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1366] In some embodiments, ring.

[1367] In some embodiments, ring B is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[1368] In some embodiments, ring B is oxetanyl.

[1369] In some embodiments, ring B is.

[1370] In some embodiments, ring B is.

[1371] In some embodiments, ring B is tetrahydrofuranyl.

[1372] In some embodiments, ring B is.

[1373] In some embodiments, ring B is.

[1374] In some embodiments, ring B is tetrahydropyranyl.

[1375] In some embodiments, ring B is.

[1376] In some embodiments, ring B is.

[1377] In some embodiments, ring B is.

[1378] In some embodiments, ring B is 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[1379] In some embodiments, ring B is 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[1380] In some embodiments, ring B is 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[1381] In some embodiments, ring B is, , , , ,.

[1382] In some embodiments, ring B is120 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1383] In some embodiments, ring B is.

[1384] In some embodiments, ring B is.

[1385] In some embodiments, ring B is.

[1386] In some embodiments, ring B is.

[1387] In some embodiments, ring B is.

[1388] In some embodiments, ring B is 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[1389] In some embodiments, ring B is tetrahydrothiophenyl.

[1390] In some embodiments, ring B is.

[1391] In some embodiments, ring B is.

[1392] In some embodiments, ring B is 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[1393] In some embodiments, ring B is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1394] In some embodiments, ring B is 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1395] In some embodiments, ring B is 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1396] In some embodiments, ring B is 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S., 121 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1398] In some embodiments, ring B is.

[1399] In some embodiments, ring B is.

[1400] In some embodiments, ring B is.

[1401] In some embodiments, ring

[1402] In some embodiments, ring B is.

[1403] In some embodiments, ring B is.

[1404] In some embodiments, ring B is.

[1405] In some embodiments, ring B is.

[1406] some embodiments, ring B is.

[1407] In some embodiments, ring B is.

[1408] In some embodiments, ring

[1409] In some embodiments, ring B is. 122 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1410] In some embodiments, ring.

[1411] In some embodiments, ring.

[1412] In some embodiments, ring.

[1413] In some embodiments, ring B is C6-C10 aryl (e.g., phenyl).

[1414] In some embodiments, ring B is phenyl.

[1415] In some embodiments, ring B is 5- to 10-membered heteroaryl.

[1416] In some embodiments, ring B is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1417] In some embodiments, ring B is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1418] In some embodiments, ring B is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[1419] In some embodiments, ring B is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[1420] In some embodiments, ring B is oxazolyl.

[1421] In some embodiments, ring B is.

[1422] In some embodiments, ring B is thiazolyl.

[1423] In some embodiments, ring B is.

[1424] In some embodiments, ring B is pyrazolyl.

[1425] In some embodiments, ring B is.

[1426] In some embodiments, ring B is. 123 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1427] In some embodiments, ring B is isoxazolyl.

[1428] In some embodiments, ring B is isothiazolyl.

[1429] In some embodiments, ring B is imidazolyl.

[1430] In some embodiments, ring B is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl).

[1431] In some embodiments, ring B is triazolyl.

[1432] In some embodiments, ring B is.

[1433] In some embodiments, ring B is.

[1434] In some embodiments, ring B is

[1435] In some embodiments, ring B is oxadiazolyl.

[1436] In some embodiments, ring B is.

[1437] In some embodiments, ring B is thiadiazolyl.

[1438] In some embodiments, ring B is.

[1439] In some embodiments, ring B is.

[1440] In some embodiments, ring B is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[1441] In some embodiments, ring B is tetrazolyl.

[1442] In some embodiments, ring B is.

[1443] In some embodiments, ring B is oxatriazolyl.

[1444] In some embodiments, ring B is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1445] In some embodiments, ring B is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[1446] In some embodiments, ring B is pyridinyl. 124 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1447] In some embodiments, ring B is.

[1448] In some embodiments, ring B is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[1449] In some embodiments, ring B is pyrimidinyl.

[1450] In some embodiments, ring B is.

[1451] In some embodiments, ring B is.

[1452] In some embodiments, ring B is pyridazinyl.

[1453] In some embodiments, ring B is.

[1454] In some embodiments, ring B is pyrazinyl.

[1455] In some embodiments, ring B is 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1456] In some embodiments, ring.

[1457] In some embodiments, ring.

[1458] In some embodiments, ring B is C3-C6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl.

[1459] In some embodiments, ring B is is pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, pyridazinyl, or pyrazinyl. Variable Z

[1460] In some embodiments, Z is absent, -CH2-, -O-, or -C(=O)-.

[1461] In some embodiments, Z is absent.

[1462] In some embodiments, Z is -CH2-.

[1463] In some embodiments, Z is -O-. 125 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1464] In some embodiments, Z is -C(=O)-. Variable E

[1465] In some embodiments, E is -(C1-C6alkylene)- optionally substituted with one or more oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[1466] In some embodiments, E is -(C1-C6 alkylene)- (e.g., -methylene-, -ethylene-, -n- propylene-, -isopropylene-, -n-butylene-, -t-butylene-, -isobutylene-, or -sec-butylene-).

[1467] In some embodiments, E is -(C1-C6 alkylene)- (e.g., -methylene-, -ethylene-, -n- propylene-, -isopropylene-, -n-butylene-, -t-butylene-, -isobutylene-, or -sec-butylene-) substituted with one or more oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[1468] In some embodiments, E is -methylene- substituted with one or more -NH2. Variables U1, U2, and RU

[1469] In some embodiments, one of U1and U2is -O-, and the other one of U1and U2is - C(RU)2-.

[1470] In some embodiments, U1is -O-, and U2is -C(RU)2-.

[1471] In some embodiments, U2is -O-, and U1-C(RU)2-.

[1472] In some embodiments, at least one RUis H, halogen, cyano, -OH, -O(C1-C6 alkyl), - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6alkyl.

[1473] In some embodiments, at least one RUis H.

[1474] In some embodiments, at least one RUis halogen (e.g., -F, -Cl, -Br, or -I).

[1475] In some embodiments, at least one RUis cyano.

[1476] In some embodiments, at least one RUis -OH

[1477] In some embodiments, at least one RUis -O(C1-C6alkyl) (e.g., -O(methyl), -O(ethyl), - O(n-propyl), -O(isopropyl), -O(n-butyl), -O(t-butyl), -O(isobutyl), or -O(sec-butyl)).

[1478] In some embodiments, at least one RUis -NH2.

[1479] In some embodiments, at least one RUis -NH(C1-C6alkyl) (e.g., -NHCH3, - NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, or -NH(CH2)5CH3).

[1480] In some embodiments, at least one RUis -N(C1-C6 alkyl)2 (e.g., e.g., -N(methyl)2, - N(ethyl)2, -N(n-propyl)2, -N(isopropyl)2, -N(n-butyl)2, -N(t-butyl)2, -N(isobutyl)2, or -N(sec- butyl)2).

[1481] In some embodiments, at least one RUis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl). 126 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1482] In some embodiments, at least one RUis methyl.

[1483] In some embodiments, at least one RUis ethyl.

[1484] In some embodiments, at least one RUis n-propyl.

[1485] In some embodiments, at least one RUis isopropyl.

[1486] In some embodiments, at least one RUis n-butyl. Variables RV, RVa, RVb, RVc, RA, RB, and RCVariable RV

[1487] In some embodiments, at least one RVis H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6 alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-(RA), -C(=O)-H, -C(=O)- (RA), -C(=O)-OH, -C(=O)-O(RA), -C(=O)-NH2, -C(=O)-NH(RA), -C(=O)-N(RA)2, -S(=O)2- RA, -NH-S(=O)2-RA, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVa.

[1488] In some embodiments, at least one RVis H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6 alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-(RA), -C(=O)-H, -C(=O)- (RA), -C(=O)-OH, -C(=O)-O(RA), -C(=O)-NH2, -C(=O)-NH(RA), -C(=O)-N(RA)2, -S(=O)2- RA, -NH-S(=O)2-RA, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl.

[1489] In some embodiments, at least one RVis H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-(RA), -C(=O)-H, -C(=O)- (RA), -C(=O)-OH, -C(=O)-O(RA), -C(=O)-NH2, -C(=O)-NH(RA), -C(=O)-N(RA)2, -S(=O)2- RA, -NH-S(=O)2-RA, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more RVa.

[1490] In some embodiments, at least one RVis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, - (C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered 127 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heteroaryl) is optionally substituted with one or more RVa.

[1491] In some embodiments, at least one RVis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, monocyclic C3-C8 cycloalkyl, fused bicyclic C4-C8 cycloalkyl, bridged bicyclic C5-C8 cycloalkyl, spiro bicyclic C5-C8cycloalkyl, monocyclic 4- to 8-membered heterocyclyl, fused bicyclic 4- to 10-membered heterocyclyl, bridged bicyclic 5- to 10-membered heterocyclyl, spiro bicyclic 5- to 10-membered heterocyclyl, phenyl, monocyclic 5- to 6-membered heteroaryl, fused bicyclic 5- to 10-membered heteroaryl, -(C1-C4alkyl)-(monocyclic C3-C8cycloalkyl), -(C1-C4 alkyl)-(fused bicyclic C4-C8 cycloalkyl), -(C1-C4 alkyl)-(bridged bicyclic C5-C8 cycloalkyl), -(C1-C4 alkyl)-(spiro bicyclic C5-C8 cycloalkyl), -(C1-C4 alkyl)-(monocyclic 4- to 7-membered heterocyclyl), -(C1-C4alkyl)-(fused bicyclic 4- to 10-membered heterocyclyl), -(C1-C4alkyl)-(bridged bicyclic 5- to 10-membered heterocyclyl), -(C1-C4alkyl)-(spiro bicyclic 5- to 10-membered heterocyclyl), -(C1-C4 alkyl)-(phenyl), -(C1-C4 alkyl)- (monocyclic 5- to 6-membered heteroaryl), or -(C1-C4 alkyl)-(fused bicyclic 5- to 10- membered heteroaryl), each optionally substituted with one or more RVa.

[1492] In some embodiments, at least one RVis H.

[1493] In some embodiments, at least one RVis oxo.

[1494] In some embodiments, at least one RVis halogen (e.g., -F, -Cl, -Br, -I).

[1495] In some embodiments, at least one RVis cyano.

[1496] In some embodiments, at least one RVis -OH.

[1497] In some embodiments, at least one RVis -ORA.

[1498] In some embodiments, at least one RVis -(C1-C6alkylene)-ORA.

[1499] In some embodiments, at least one RVis -NH2.

[1500] In some embodiments, at least one RVis -NHRA.

[1501] In some embodiments, at least one RVis -N(RA)2.

[1502] In some embodiments, at least one RVis -NH-C(=O)-H.

[1503] In some embodiments, at least one RVis -NH-C(=O)-RA.

[1504] In some embodiments, at least one RVis -C(=O)-H.

[1505] In some embodiments, at least one RVis -C(=O)-RA.

[1506] In some embodiments, at least one RVis -C(=O)-OH.

[1507] In some embodiments, at least one RVis -C(=O)-ORA.

[1508] In some embodiments, at least one RVis -C(=O)-NH2.

[1509] In some embodiments, at least one RVis -C(=O)-NHRA.

[1510] In some embodiments, at least one RVis -C(=O)-N(RA)2.

[1511] In some embodiments, at least one RVis -S(=O)2-RA. 128 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1512] In some embodiments, at least one RVis -NH-S(=O)2-RA.

[1513] In some embodiments, at least one RVis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[1514] In some embodiments, at least one RVis C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RVa.

[1515] In some embodiments, at least one RVis methyl.

[1516] In some embodiments, at least one RVis ethyl.

[1517] In some embodiments, at least one RVis n-propyl.

[1518] In some embodiments, at least one RVis isopropyl.

[1519] In some embodiments, at least one RVis n-butyl.

[1520] In some embodiments, at least one RVis C2-C6alkenyl.

[1521] In some embodiments, at least one RVis C2-C6 alkenyl substituted with one or more RVa.

[1522] In some embodiments, at least one RVis C2-C6alkynyl.

[1523] In some embodiments, at least one RVis C2-C6 alkynyl substituted with one or more RVa.

[1524] In some embodiments, at least one RVis C3-C6cycloalkyl.

[1525] In some embodiments, at least one RVis C3-C6cycloalkyl substituted with one or more RVa.

[1526] In some embodiments, at least one RVis C3-C6monocyclic cycloalkyl.

[1527] In some embodiments, at least one RVis C3-C6monocyclic cycloalkyl substituted with one or more RVa.

[1528] In some embodiments, at least one RVis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[1529] In some embodiments, at least one RVis C3-C6bicyclic cycloalkyl.

[1530] In some embodiments, at least one RVis C3-C6 bicyclic cycloalkyl substituted with one or more RVa.

[1531] In some embodiments, at least one RVis bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[1532] In some embodiments, at least one RVis C4-C6 fused bicyclic cycloalkyl.

[1533] In some embodiments, at least one RVis C4-C6fused bicyclic cycloalkyl substituted with one or more RVa. 129 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1534] In some embodiments, at least one RVis.

[1535] In some embodiments, at least one RVis, substituted with one or more RVa.

[1536] In some embodiments, at least one RVis.

[1537] In some embodiments, at least one RVis.

[1538] In some embodiments, at least one RVis C5-C6 bridged bicyclic cycloalkyl.

[1539] In some embodiments, at least one RVis C5-C6 bridged bicyclic cycloalkyl substituted with one or more RVa.

[1540] In some embodiments, at least one RVis.

[1541] In some embodiments, at least one RVis, substituted with one or more RVa.

[1542] In some embodiments, at least one RVis.

[1543] In some embodiments, at least one RVis.

[1544] In some embodiments, at least one RVis.

[1545] In some embodiments, at least one RVis.

[1546] In some embodiments, at least one RVis C5-C6 spiro bicyclic cycloalkyl.

[1547] In some embodiments, at least one RVis C5-C6 spiro bicyclic cycloalkyl substituted with one or more RVa.

[1548] In some embodiments, at least one RVis spiro[2.2]pentyl or spiro[2.3]hexyl.

[1549] In some embodiments, at least one RVis spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RVa.

[1550] In some embodiments, at least one RVis. 130 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1551] In some embodiments, at least one.

[1552] In some embodiments, at least one RVis 4- to 10-membered heterocyclyl.

[1553] In some embodiments, at least one RVis 4- to 10-membered heterocyclyl substituted with one or more RVa.

[1554] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl.

[1555] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl substituted with one or more RVa.

[1556] In some embodiments, at least one RVis 4- to 10-membered bicyclic heterocyclyl.

[1557] In some embodiments, at least one RVis 4- to 10-membered bicyclic heterocyclyl substituted with one or more RVa.

[1558] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl.

[1559] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RVa.

[1560] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl.

[1561] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RVa.

[1562] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl.

[1563] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RVa.

[1564] In some embodiments, at least one RVis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1565] In some embodiments, at least one RVis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVa.

[1566] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1567] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVa.

[1568] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). 131 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1569] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVa.

[1570] In some embodiments, at least one RVis azetidinyl.

[1571] In some embodiments, at least one RVis azetidinyl substituted with one or more RVa.

[1572] In some embodiments, at least one RV.

[1573] In some embodiments, at least one RV.

[1574] In some embodiments, at least one RV.

[1575] In some embodiments, at least one RVis pyrrolidinyl.

[1576] In some embodiments, at least one RV.

[1577] In some embodiments, at least one RV.

[1578] In some embodiments, at least one RV.

[1579] In some embodiments, at least one RV

[1580] In some embodiments, at least one RV.

[1581] In some embodiments, at least one RV.

[1582] In some embodiments, at least one RV.

[1583] In some embodiments, at least one RV.

[1584] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[1585] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVa. 132 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1586] In some embodiments, at least one

[1587] In some embodiments, at least one, substituted with one or more RVa.

[1588] In some embodiments, at least one RVis.

[1589] In some embodiments, at least one RV

[1590] In some embodiments, at least one.

[1591] In some embodiments, at least one RVis.

[1592] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[1593] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more RVa..

[1595] In some embodiments, at least one RVis, , , ,, substituted with one or more RVa. 133 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1596] In some embodiments, at least one RVis.

[1597] In some

[1598] In some

[1599] In some

[1600] In some

[1601] In some embodiments, at least one RVis.

[1602] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[1603] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVa.

[1604] In some embodiments, at least one RVis, , ,

[1605] In some embodiments, at least one RVis ,, ,, substituted with one or more RVa.

[1606] In some embodiments, at least one RVis

[1607] In some embodiments, at least one RVis.

[1608] In some embodiments, at least one RVis . 134 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1609] In some embodiments, at least one RVis.

[1610] In some embodiments, at least one RVis.

[1611] In some embodiments, at least one.

[1612] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[1613] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVa.

[1614] In some embodiments, at least one RVis oxetanyl.

[1615] In some embodiments, at least one RV.

[1616] In some embodiments, at least one RV.

[1617] In some embodiments, at least one RVis tetrahydrofuranyl.

[1618] In some embodiments, at least one RV.

[1619] In some embodiments, at least one RV.

[1620] In some embodiments, at least one RVis tetrahydropyranyl.

[1621] In some embodiments, at least one RV.

[1622] In some embodiments, at least one RV.

[1623] In some embodiments, at least one RV.

[1624] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[1625] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis 135 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 substituted with one or more RVa.

[1626] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[1627] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RVa.

[1628] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[1629] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl containing one O, wherein the is 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVa.

[1630] In some embodiments, at least one RVis, , , ,, , , ,ore RVa.

[1632] In some embodiments, at least one RV

[1633] In some embodiments, at least one RV.

[1634] In some embodiments, at least one RV.

[1635] In some embodiments, at least one RV.

[1636] In some embodiments, at least one RV.

[1637] In some embodiments, at least one RV.

[1638] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[1639] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl 136 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVa.

[1640] In some embodiments, at least one RVis tetrahydrothiophenyl.

[1641] In some embodiments, at least one RVis.

[1642] In some embodiments, at least one RVis.

[1643] In some embodiments, at least one RVis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[1644] In some embodiments, at least one RVis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVa.

[1645] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1646] In some embodiments, at least one RVis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVa.

[1647] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1648] In some embodiments, at least one RVis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVa.

[1649] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1650] In some embodiments, at least one RVis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RVa.

[1651] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1652] In some embodiments, at least one RVis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVa. 137 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1653] In some embodiments, at least one RVis, , ,

[1655] In some embodiments, at least one RVis.

[1656] In some embodiments, at least one RVis.

[1657] In some embodiments, at least one RVis .

[1658] In some embodiments, at least one.

[1659] In some embodiments, at least one RVis.

[1660] In some embodiments, at least one RVis.

[1661] In some embodiments, at least one RVis. 138 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1662] In some embodiments, at least one RVis.

[1663] In some embodiments, at least one RVis.

[1664] In some embodiments, at least one RVis.

[1665] In some embodiments, at least one.

[1666] In some embodiments, at least one RVis.

[1667] In some embodiments, at least one.

[1668] In some embodiments, at least one.

[1669] In some embodiments, at least one.

[1670] In some embodiments, at least one RVis C6-C10 aryl (e.g., phenyl).

[1671] In some embodiments, at least one RVis C6-C10aryl (e.g., phenyl) substituted with one or more RVa.

[1672] In some embodiments, at least one RVis phenyl.

[1673] In some embodiments, at least one RVis 5- to 10-membered heteroaryl.

[1674] In some embodiments, at least one RVis 5- to 10-membered heteroaryl substituted with one or more RVa.

[1675] In some embodiments, at least one RVis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1676] In some embodiments, at least one RVis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one 139 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 or more RVa.

[1677] In some embodiments, at least one RVis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1678] In some embodiments, at least one RVis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVa.

[1679] In some embodiments, at least one RVis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[1680] In some embodiments, at least one RVis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RVa.

[1681] In some embodiments, at least one RVis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[1682] In some embodiments, at least one RVis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RVa.

[1683] In some embodiments, at least one RVis oxazolyl.

[1684] In some embodiments, at least one RVis.

[1685] In some embodiments, at least one RVis thiazolyl.

[1686] In some embodiments, at least one RVis.

[1687] In some embodiments, at least one RVis pyrazolyl.

[1688] In some embodiments, at least one RVis.

[1689] In some embodiments, at least one RVis.

[1690] In some embodiments, at least one RVis isoxazolyl.

[1691] In some embodiments, at least one RVis isothiazolyl.

[1692] In some embodiments, at least one RVis imidazolyl.

[1693] In some embodiments, at least one RVis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or 140 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 oxathiadiazolyl).

[1694] In some embodiments, at least one RVis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RVa.

[1695] In some embodiments, at least one RVis triazolyl.

[1696] In some embodiments, at least one RVis.

[1697] In some embodiments, at least one RVis.

[1698] In some embodiments, at least one RVis

[1699] In some embodiments, at least one RVis oxadiazolyl.

[1700] In some embodiments, at least one RVis.

[1701] In some embodiments, at least one RVis thiadiazolyl.

[1702] In some embodiments, at least one RVis.

[1703] In some embodiments, at least one RVis.

[1704] In some embodiments, at least one RVis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[1705] In some embodiments, at least one RVis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RVa.

[1706] In some embodiments, at least one RVis tetrazolyl.

[1707] In some embodiments, at least one RVis.

[1708] In some embodiments, at least one RVis oxatriazolyl.

[1709] In some embodiments, at least one RVis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1710] In some embodiments, at least one RVis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more 141 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 RVa.

[1711] In some embodiments, at least one RVis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[1712] In some embodiments, at least one RVis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RVa.

[1713] In some embodiments, at least one RVis pyridinyl.

[1714] In some embodiments, at least one RVis.

[1715] In some embodiments, at least one RVis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[1716] In some embodiments, at least one RVis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RVa.

[1717] In some embodiments, at least one RVis pyrimidinyl.

[1718] In some embodiments, at least one RVis.

[1719] In some embodiments, at least one RVis.

[1720] In some embodiments, at least one RVis pyridazinyl.

[1721] In some embodiments, at least one RVis.

[1722] In some embodiments, at least one RVis pyrazinyl.

[1723] In some embodiments, at least one RVis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1724] In some embodiments, at least one RVis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVa.

[1725] In some embodiments, at least one. 142 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1726] In some embodiments, at least one.

[1727] In some embodiments, at least one RVis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,, ,substituted with one or more RVa.

[1728] In some embodiments, at least one RVis pyrrolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, 143 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 oxathiadiazolyl, tetrazolyl, oxatriazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl,, each optionally substituted with one or more RVa. Variable RVa

[1729] In some embodiments, at least one RVais oxo, halogen, cyano, -OH, -ORB, -NH2, - NHRB, -N(RB)2, -NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)- ORB, -C(=O)-NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb.

[1730] In some embodiments, at least one RVais oxo, halogen, cyano, -OH, -ORB, -NH2, - NHRB, -N(RB)2, -NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)- ORB, -C(=O)-NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl.

[1731] In some embodiments, at least one RVais oxo, halogen, cyano, -OH, -ORB, -NH2, - NHRB, -N(RB)2, -NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)- ORB, -C(=O)-NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is substituted with one or more RVb.

[1732] In some embodiments, each RVaindependently is oxo, halogen, cyano, -OH, -ORB, - NH2, -NHRB, -N(RB)2, -C(=O)-H, -C(=O)-OH, -C(=O)-ORB, -C(=O)-NH2, -C(=O)-NHRB, - C(=O)-N(RB)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

[1733] In some embodiments, at least one RVais oxo.

[1734] In some embodiments, at least one RVais halogen (e.g., -F, -Cl, -Br, -I).

[1735] In some embodiments, at least one RVais cyano.

[1736] In some embodiments, at least one RVais -OH.

[1737] In some embodiments, at least one RVais -ORB. 144 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1738] In some embodiments, at least one RVais -NH2.

[1739] In some embodiments, at least one RVais -NHRB.

[1740] In some embodiments, at least one RVais -N(RB)2.

[1741] In some embodiments, at least one RVais -NH-C(=O)-H.

[1742] In some embodiments, at least one RVais -NH-C(=O)-RB.

[1743] In some embodiments, at least one RVais -C(=O)-H.

[1744] In some embodiments, at least one RVais -C(=O)-RB.

[1745] In some embodiments, at least one RVais -C(=O)-OH.

[1746] In some embodiments, at least one RVais -C(=O)-ORB.

[1747] In some embodiments, at least one RVais -C(=O)-NH2.

[1748] In some embodiments, at least one RVais -C(=O)-NHRB.

[1749] In some embodiments, at least one RVais -C(=O)-N(RB)2.

[1750] In some embodiments, at least one RVais -S(=O)2-RB.

[1751] In some embodiments, at least one RVais -NH-S(=O)2-RB.

[1752] In some embodiments, at least one RVais C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[1753] In some embodiments, at least one RVais C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RVb.

[1754] In some embodiments, at least one RVais methyl.

[1755] In some embodiments, at least one RVais ethyl.

[1756] In some embodiments, at least one RVais n-propyl.

[1757] In some embodiments, at least one RVais isopropyl.

[1758] In some embodiments, at least one RVais n-butyl.

[1759] In some embodiments, at least one RVais C2-C6alkenyl.

[1760] In some embodiments, at least one RVais C2-C6alkenyl substituted with one or more RVb.

[1761] In some embodiments, at least one RVais C2-C6alkynyl.

[1762] In some embodiments, at least one RVais C2-C6alkynyl substituted with one or more RVb.

[1763] In some embodiments, at least one RVais C3-C6 cycloalkyl.

[1764] In some embodiments, at least one RVais C3-C6cycloalkyl substituted with one or more RVb.

[1765] In some embodiments, at least one RVais C3-C6 monocyclic cycloalkyl.

[1766] In some embodiments, at least one RVais C3-C6monocyclic cycloalkyl substituted with 145 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 one or more RVb.

[1767] In some embodiments, at least one RVais cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[1768] In some embodiments, at least one RVais C3-C6bicyclic cycloalkyl.

[1769] In some embodiments, at least one RVais C3-C6 bicyclic cycloalkyl substituted with one or more RVb.

[1770] In some embodiments, at least one RVais bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[1771] In some embodiments, at least one RVais C4-C6 fused bicyclic cycloalkyl.

[1772] In some embodiments, at least one RVais C4-C6fused bicyclic cycloalkyl substituted with one or more RVb.

[1773] In some embodiments, at least one RVais.

[1774] In some embodiments, at least one RVais, substituted with one or more RVb.

[1775] In some embodiments, at least one RVais.

[1776] In some embodiments, at least one RVais.

[1777] In some embodiments, at least one RVais C5-C6 bridged bicyclic cycloalkyl.

[1778] In some embodiments, at least one RVais C5-C6bridged bicyclic cycloalkyl substituted with one or more RVb.

[1779] In some embodiments, at least one RVais.

[1780] In some embodiments, at least one RVais, substituted with one or more RVb.

[1781] In some embodiments, at least one RVais.

[1782] In some embodiments, at least one RVais.

[1783] In some embodiments, at least one RVais. 146 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1784] In some embodiments, at least one RVais.

[1785] In some embodiments, at least one RVais C5-C6 spiro bicyclic cycloalkyl.

[1786] In some embodiments, at least one RVais C5-C6spiro bicyclic cycloalkyl substituted with one or more RVb.

[1787] In some embodiments, at least one RVais spiro[2.2]pentyl or spiro[2.3]hexyl.

[1788] In some embodiments, at least one RVais spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RVb.

[1789] In some embodiments, at least one RVais.

[1790] In some embodiments, at least one.

[1791] In some embodiments, at least one RVais 4- to 10-membered heterocyclyl.

[1792] In some embodiments, at least one RVais 4- to 10-membered heterocyclyl substituted with one or more RVb.

[1793] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl.

[1794] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl substituted with one or more RVb.

[1795] In some embodiments, at least one RVais 4- to 10-membered bicyclic heterocyclyl.

[1796] In some embodiments, at least one RVais 4- to 10-membered bicyclic heterocyclyl substituted with one or more RVb.

[1797] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl.

[1798] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RVb.

[1799] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic heterocyclyl.

[1800] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RVb.

[1801] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl.

[1802] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RVb. 147 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1803] In some embodiments, at least one RVais 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1804] In some embodiments, at least one RVais 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVb.

[1805] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[1806] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVb.

[1807] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[1808] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[1809] In some embodiments, at least one RVais azetidinyl.

[1810] In some embodiments, at least one RVais azetidinyl substituted with one or more RVb.

[1811] In some embodiments, at least one RVai.

[1812] In some embodiments, at least one RVai.

[1813] In some embodiments, at least one RVai.

[1814] In some embodiments, at least one RVais pyrrolidinyl.

[1815] In some embodiments, at least one RVai.

[1816] In some embodiments, at least one RVai.

[1817] In some embodiments, at least one RVai.

[1818] In some embodiments, at least one RVais piperidinyl.

[1819] In some embodiments, at least one RVai. 148 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1820] In some embodiments, at least one RVais.

[1821] In some embodiments, at least one RVais.

[1822] In some embodiments, at least one RVais.

[1823] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[1824] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVb.

[1825] In some embodiments, at least one

[1826] In some embodiments, at least onewith one or more RVb.

[1827] In some embodiments, at least one RVais.

[1828] In some embodiments, at least one RVais

[1829] In some embodiments, at least one.

[1830] In some embodiments, at least one RVais.

[1831] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[1832] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl 149 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 is substituted with one or more RVb.

[1833] In some embodiments, at least one RVai, , , ,.

[1834] In some embodiments, at least one RVais, , , ,, substituted with one or more RVb.

[1835] In some embodiments, at least one RVai.

[1836] In some embodiments, at least one RVais.

[1837] In some embodiments, at least one RVais.

[1838] In some embodiments, at least one RVais.

[1839] In some embodiments, at least one RVais.

[1840] In some embodiments, at least one RVais.

[1841] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[1842] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVb.

[1843] In some embodiments, at least one RVais, , ,

[1844] In some embodiments, at least one RVais, , , 150 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, substituted with one or more RVb.

[1845] In some embodiments, at least one RVais

[1846] In some embodiments, at least one RVais.

[1847] In some embodiments, at least one RVai.

[1848] In some embodiments, at least one RVai.

[1849] In some embodiments, at least one RVai.

[1850] In some embodiments, at least one.

[1851] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[1852] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[1853] In some embodiments, at least one RVais oxetanyl.

[1854] In some embodiments, at least one RVais.

[1855] In some embodiments, at least one RVais.

[1856] In some embodiments, at least one RVais tetrahydrofuranyl.

[1857] In some embodiments, at least one RVais.

[1858] In some embodiments, at least one RVais.

[1859] In some embodiments, at least one RVais tetrahydropyranyl.

[1860] In some embodiments, at least one RVais. 151 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1861] In some embodiments, at least one RVais.

[1862] In some embodiments, at least one RVais.

[1863] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[1864] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis substituted with one or more RVb.

[1865] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[1866] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RVb.

[1867] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[1868] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl containing one O, wherein the is 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVb.

[1869] In some embodiments, at least one RVais, , , ,, , , ,ore RVb.

[1871] In some embodiments, at least one RVais

[1872] In some embodiments, at least one RVais.

[1873] In some embodiments, at least one RVais. 152 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1874] In some embodiments, at least one RVais.

[1875] In some embodiments, at least one RVais.

[1876] In some embodiments, at least one RVais.

[1877] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[1878] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[1879] In some embodiments, at least one RVais tetrahydrothiophenyl.

[1880] In some embodiments, at least one RVais.

[1881] In some embodiments, at least one RVais.

[1882] In some embodiments, at least one RVais 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[1883] In some embodiments, at least one RVais 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVb.

[1884] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1885] In some embodiments, at least one RVais 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[1886] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1887] In some embodiments, at least one RVais 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVb.

[1888] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic 153 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heterocyclyl containing two heteroatoms selected from N, O, and S.

[1889] In some embodiments, at least one RVais 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RVb.

[1890] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[1891] In some embodiments, at least one RVais 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVb.

[1894] In some embodiments, at least one RVais.

[1895] In some embodiments, at least one RVais.

[1896] In some embodiments, at least one RVais. 154 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1897] In some embodiments, at least one.

[1898] In some embodiments, at least one RVais.

[1899] In some embodiments, at least one RVais.

[1900] In some embodiments, at least one RVais.

[1901] In some embodiments, at least one RVais.

[1902] In some embodiments, at least one RVais.

[1903] In some embodiments, at least one RVais.

[1904] In some embodiments, at least one.

[1905] In some embodiments, at least one RVais.

[1906] In some embodiments, at least one.

[1907] In some embodiments, at least one.

[1908] In some embodiments, at least one.

[1909] In some embodiments, at least one RVais C6-C10aryl (e.g., phenyl). 155 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1910] In some embodiments, at least one RVais C6-C10aryl (e.g., phenyl) substituted with one or more RVb.

[1911] In some embodiments, at least one RVais phenyl.

[1912] In some embodiments, at least one RVais 5- to 10-membered heteroaryl.

[1913] In some embodiments, at least one RVais 5- to 10-membered heteroaryl substituted with one or more RVb.

[1914] In some embodiments, at least one RVais 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1915] In some embodiments, at least one RVais 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb.

[1916] In some embodiments, at least one RVais 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1917] In some embodiments, at least one RVais 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb.

[1918] In some embodiments, at least one RVais 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[1919] In some embodiments, at least one RVais 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RVb.

[1920] In some embodiments, at least one RVais 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[1921] In some embodiments, at least one RVais 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RVb.

[1922] In some embodiments, at least one RVais oxazolyl.

[1923] In some embodiments, at least one RVais.

[1924] In some embodiments, at least one RVais thiazolyl.

[1925] In some embodiments, at least one RVais. 156 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1926] In some embodiments, at least one RVais pyrazolyl.

[1927] In some embodiments, at least one RVais.

[1928] In some embodiments, at least one RVais.

[1929] In some embodiments, at least one RVais isoxazolyl.

[1930] In some embodiments, at least one RVais isothiazolyl.

[1931] In some embodiments, at least one RVais imidazolyl.

[1932] In some embodiments, at least one RVais 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl).

[1933] In some embodiments, at least one RVais 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RVb.

[1934] In some embodiments, at least one RVais triazolyl.

[1935] In some embodiments, at least one RVais.

[1936] In some embodiments, at least one RVais .

[1937] In some embodiments, at least one RVais

[1938] In some embodiments, at least one RVais oxadiazolyl.

[1939] In some embodiments, at least one RVais.

[1940] In some embodiments, at least one RVais thiadiazolyl.

[1941] In some embodiments, at least one RVais.

[1942] In some embodiments, at least one RVais.

[1943] In some embodiments, at least one RVais 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[1944] In some embodiments, at least one RVais 5-membered heteroaryl containing four 157 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RVb.

[1945] In some embodiments, at least one RVais tetrazolyl.

[1946] In some embodiments, at least one RVais.

[1947] In some embodiments, at least one RVais oxatriazolyl.

[1948] In some embodiments, at least one RVais 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1949] In some embodiments, at least one RVais 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb.

[1950] In some embodiments, at least one RVais 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[1951] In some embodiments, at least one RVais 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RVb.

[1952] In some embodiments, at least one RVais pyridinyl.

[1953] In some embodiments, at least one RVais.

[1954] In some embodiments, at least one RVais 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[1955] In some embodiments, at least one RVais 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RVb.

[1956] In some embodiments, at least one RVais pyrimidinyl.

[1957] In some embodiments, at least one RVais.

[1958] In some embodiments, at least one RVais.

[1959] In some embodiments, at least one RVais pyridazinyl.

[1960] In some embodiments, at least one RVais. 158 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1961] In some embodiments, at least one RVais pyrazinyl.

[1962] In some embodiments, at least one RVais 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[1963] In some embodiments, at least one RVais 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb.

[1964] In some embodiments, at least one.

[1965] In some embodiments, at least one. Variable RVb

[1966] In some embodiments, at least one RVbis oxo, halogen, cyano, -OH, -ORC, -NH2, - NHRC, -N(RC)2, -NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)- ORC, -C(=O)-NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc.

[1967] In some embodiments, at least one RVbis oxo, halogen, cyano, -OH, -ORC, -NH2, - NHRC, -N(RC)2, -NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)- ORC, -C(=O)-NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl.

[1968] In some embodiments, at least one RVbis oxo, halogen, cyano, -OH, -ORC, -NH2, - NHRC, -N(RC)2, -NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)- ORC, -C(=O)-NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is substituted with one or more RVc. 159 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1969] In some embodiments, at least one RVbis oxo, halogen, cyano, -OH, -ORC, -NH2, - NHRC, -N(RC)2, -C(=O)-H, -C(=O)-OH, -C(=O)-ORC, -C(=O)-NH2, -C(=O)-NHRC, -C(=O)- N(RC)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[1970] In some embodiments, at least one RVbis oxo.

[1971] In some embodiments, at least one RVbis halogen (e.g., -F, -Cl, -Br, -I).

[1972] In some embodiments, at least one RVbis cyano.

[1973] In some embodiments, at least one RVbis -OH.

[1974] In some embodiments, at least one RVbis -ORC.

[1975] In some embodiments, at least one RVbis -NH2.

[1976] In some embodiments, at least one RVbis -NHRC.

[1977] In some embodiments, at least one RVbis -N(RC)2.

[1978] In some embodiments, at least one RVbis -NH-C(=O)-H.

[1979] In some embodiments, at least one RVbis -NH-C(=O)-RC.

[1980] In some embodiments, at least one RVbis -C(=O)-H.

[1981] In some embodiments, at least one RVbis -C(=O)-RC.

[1982] In some embodiments, at least one RVbis -C(=O)-OH.

[1983] In some embodiments, at least one RVbis -C(=O)-ORC.

[1984] In some embodiments, at least one RVbis -C(=O)-NH2.

[1985] In some embodiments, at least one RVbis -C(=O)-NHRC.

[1986] In some embodiments, at least one RVbis -C(=O)-N(RC)2.

[1987] In some embodiments, at least one RVbis -S(=O)2-RC.

[1988] In some embodiments, at least one RVbis -NH-S(=O)2-RC.

[1989] In some embodiments, at least one RVbis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[1990] In some embodiments, at least one RVbis C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RVc.

[1991] In some embodiments, at least one RVbis methyl.

[1992] In some embodiments, at least one RVbis ethyl.

[1993] In some embodiments, at least one RVbis n-propyl.

[1994] In some embodiments, at least one RVbis isopropyl.

[1995] In some embodiments, at least one RVbis n-butyl.

[1996] In some embodiments, at least one RVbis C2-C6 alkenyl.

[1997] In some embodiments, at least one RVbis C2-C6 alkenyl substituted with one or more RVc. 160 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[1998] In some embodiments, at least one RVbis C2-C6alkynyl.

[1999] In some embodiments, at least one RVbis C2-C6 alkynyl substituted with one or more RVc.

[2000] In some embodiments, at least one RVbis C3-C6cycloalkyl.

[2001] In some embodiments, at least one RVbis C3-C6 cycloalkyl substituted with one or more RVc.

[2002] In some embodiments, at least one RVbis C3-C6monocyclic cycloalkyl.

[2003] In some embodiments, at least one RVbis C3-C6 monocyclic cycloalkyl substituted with one or more RVc.

[2004] In some embodiments, at least one RVbis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[2005] In some embodiments, at least one RVbis C3-C6 bicyclic cycloalkyl.

[2006] In some embodiments, at least one RVbis C3-C6 bicyclic cycloalkyl substituted with one or more RVc.

[2007] In some embodiments, at least one RVbis bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[2008] In some embodiments, at least one RVbis C4-C6fused bicyclic cycloalkyl.

[2009] In some embodiments, at least one RVbis C4-C6fused bicyclic cycloalkyl substituted with one or more RVc.

[2010] In some embodiments, at least one RVbis.

[2011] In some embodiments, at least one RVbis, substituted with one or more RVc.

[2012] In some embodiments, at least one RVb.

[2013] In some embodiments, at least one RVb.

[2014] In some embodiments, at least one RVbis C5-C6bridged bicyclic cycloalkyl.

[2015] In some embodiments, at least one RVbis C5-C6 bridged bicyclic cycloalkyl substituted with one or more RVc.

[2016] In some embodiments, at least one RVb. 161 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2017] In some embodiments, at least one RVbis, substituted with one or more RVc.

[2018] In some embodiments, at least one RVb.

[2019] In some embodiments, at least one RVbis.

[2020] In some embodiments, at least one RVbis.

[2021] In some embodiments, at least one RVbis.

[2022] In some embodiments, at least one RVbis C5-C6 spiro bicyclic cycloalkyl.

[2023] In some embodiments, at least one RVbis C5-C6 spiro bicyclic cycloalkyl substituted with one or more RVc.

[2024] In some embodiments, at least one RVbis spiro[2.2]pentyl or spiro[2.3]hexyl.

[2025] In some embodiments, at least one RVbis spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RVc.

[2026] In some embodiments, at least one RVb.

[2027] In some embodiments, at least one.

[2028] In some embodiments, at least one RVbis 4- to 10-membered heterocyclyl.

[2029] In some embodiments, at least one RVbis 4- to 10-membered heterocyclyl substituted with one or more RVc.

[2030] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl.

[2031] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl substituted with one or more RVc.

[2032] In some embodiments, at least one RVbis 4- to 10-membered bicyclic heterocyclyl.

[2033] In some embodiments, at least one RVbis 4- to 10-membered bicyclic heterocyclyl substituted with one or more RVc.

[2034] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl.

[2035] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl 162 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 substituted with one or more RVc.

[2036] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl.

[2037] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RVc.

[2038] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl.

[2039] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RVc.

[2040] In some embodiments, at least one RVbis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[2041] In some embodiments, at least one RVbis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVc.

[2042] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[2043] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVc.

[2044] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[2045] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVc.

[2046] In some embodiments, at least one RVbis azetidinyl.

[2047] In some embodiments, at least one RVbis azetidinyl substituted with one or more RVc.

[2048] In some embodiments, at least one RVbis .

[2049] In some embodiments, at least one RVbis.

[2050] In some embodiments, at least one RVbis .

[2051] In some embodiments, at least one RVbis pyrrolidinyl. 163 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2052] In some embodiments, at least one RVb.

[2053] In some embodiments, at least one RVb.

[2054] In some embodiments, at least one RVb.

[2055] In some embodiments, at least one RVb

[2056] In some embodiments, at least one RVb.

[2057] In some embodiments, at least one RVb.

[2058] In some embodiments, at least one RVb.

[2059] In some embodiments, at least one RVb.

[2060] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[2061] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVc.

[2062] In some embodiments, at least one

[2063] In some embodiments, at least one, substituted with one or more RVc.

[2064] In some embodiments, at least one RVbis.

[2065] In some embodiments, at least one RVb164 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2066] In some embodiments, at least one.

[2068] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[2069] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more RVc.

[2070] In some embodiments, at least one RVbis, , , ,.

[2071] In some embodiments, at least one RVbis, , , ,substituted with one or more RVc.

[2072] In some embodiments, at least one RVbis.

[2073] In some embodiments, at least one RVbis.

[2074] In some embodiments, at least one RVbis.

[2075] In some embodiments, at least one RVbis.

[2076] In some embodiments, at least one RVbis.

[2077] In some embodiments, at least one RVbis.

[2078] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl containing one N. 165 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2079] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVc.

[2080] In some embodiments, at least one RVbis, ,

[2081] In some embodiments, at least one RVbis, ,, substituted with one or more RVc.

[2082] In some embodiments, at least one RVbis

[2083] In some embodiments, at least one RVbis.

[2084] In some embodiments, at least one RVb.

[2085] In some embodiments, at least one RVb.

[2086] In some embodiments, at least one RVb.

[2087] In some embodiments, at least one.

[2088] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[2089] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVc.

[2090] In some embodiments, at least one RVbis oxetanyl.

[2091] In some embodiments, at least one RVbis . 166 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2092] In some embodiments, at least one RVbis.

[2093] In some embodiments, at least one RVbis tetrahydrofuranyl.

[2094] In some embodiments, at least one RVbis.

[2095] In some embodiments, at least one RVbis.

[2096] In some embodiments, at least one RVbis tetrahydropyranyl.

[2097] In some embodiments, at least one RVbis.

[2098] In some embodiments, at least one RVbis.

[2099] In some embodiments, at least one RVbis.

[2100] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[2101] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis substituted with one or more RVc.

[2102] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[2103] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RVc.

[2104] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[2105] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl containing one O, wherein the is 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVc.

[2106] In some embodiments, at least one RVbis, , , ,167 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2107] In some embodiments, at least one RVbis, , , ,, o , substituted with one or more RVc.

[2108] In some embodiments, at least one RVbis

[2109] In some embodiments, at least one RVbis.

[2110] In some embodiments, at least one RVbis.

[2111] In some embodiments, at least one RVbis.

[2112] In some embodiments, at least one RVbis.

[2113] In some embodiments, at least one RVbis.

[2114] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl).

[2115] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVc.

[2116] In some embodiments, at least one RVbis tetrahydrothiophenyl.

[2117] In some embodiments, at least one RVbis.

[2118] In some embodiments, at least one RVbis.

[2119] In some embodiments, at least one RVbis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[2120] In some embodiments, at least one RVbis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVc.

[2121] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S. 168 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2122] In some embodiments, at least one RVbis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVc.

[2123] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[2124] In some embodiments, at least one RVbis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVc.

[2125] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[2126] In some embodiments, at least one RVbis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RVc.

[2127] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[2128] In some embodiments, at least one RVbis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVc.

[2129] In some embodiments, at least one RVbis, , , ,

[2130] In some embodiments, at least one RVbis, , ,, , , , , , , 169 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084substituted with one or more RVc.

[2131] In some embodiments, at least one RVbis.

[2132] In some embodiments, at least one RVbis.

[2133] In some embodiments, at least one RVbis.

[2134] In some embodiments, at least one

[2135] In some embodiments, at least one RVbis.

[2136] In some embodiments, at least one RVbis.

[2137] In some embodiments, at least one RVbis.

[2138] In some embodiments, at least one RVbis.

[2139] In some embodiments, at least one RVbis.

[2140] In some embodiments, at least one RVbis.

[2141] In some embodiments, at least one

[2142] In some embodiments, at least one RVbis. 170 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2143] In some embodiments, at least one.

[2144] In some embodiments, at least one.

[2145] In some embodiments, at least one.

[2146] In some embodiments, at least one RVbis C6-C10 aryl (e.g., phenyl).

[2147] In some embodiments, at least one RVbis C6-C10aryl (e.g., phenyl) substituted with one or more RVc.

[2148] In some embodiments, at least one RVbis phenyl.

[2149] In some embodiments, at least one RVbis 5- to 10-membered heteroaryl.

[2150] In some embodiments, at least one RVbis 5- to 10-membered heteroaryl substituted with one or more RVc.

[2151] In some embodiments, at least one RVbis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[2152] In some embodiments, at least one RVbis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVc.

[2153] In some embodiments, at least one RVbis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[2154] In some embodiments, at least one RVbis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVc.

[2155] In some embodiments, at least one RVbis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[2156] In some embodiments, at least one RVbis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RVc.

[2157] In some embodiments, at least one RVbis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, 171 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 isothiazolyl, or imidazolyl).

[2158] In some embodiments, at least one RVbis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RVc.

[2159] In some embodiments, at least one RVbis oxazolyl.

[2160] In some embodiments, at least one RVbis.

[2161] In some embodiments, at least one RVbis thiazolyl.

[2162] In some embodiments, at least one RVbis.

[2163] In some embodiments, at least one RVbis pyrazolyl.

[2164] In some embodiments, at least one RVbis.

[2165] In some embodiments, at least one RVbis.

[2166] In some embodiments, at least one RVbis isoxazolyl.

[2167] In some embodiments, at least one RVbis isothiazolyl.

[2168] In some embodiments, at least one RVbis imidazolyl.

[2169] In some embodiments, at least one RVbis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl).

[2170] In some embodiments, at least one RVbis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RVc.

[2171] In some embodiments, at least one RVbis triazolyl.

[2172] In some embodiments, at least one RVbis.

[2173] In some embodiments, at least one RVbis.

[2174] In some embodiments, at least one RVbis

[2175] In some embodiments, at least one RVbis oxadiazolyl. 172 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2176] In some embodiments, at least one RVbis.

[2177] In some embodiments, at least one RVbis thiadiazolyl.

[2178] In some embodiments, at least one RVbis.

[2179] In some embodiments, at least one RVbis.

[2180] In some embodiments, at least one RVbis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[2181] In some embodiments, at least one RVbis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RVc.

[2182] In some embodiments, at least one RVbis tetrazolyl.

[2183] In some embodiments, at least one RVbis.

[2184] In some embodiments, at least one RVbis oxatriazolyl.

[2185] In some embodiments, at least one RVbis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[2186] In some embodiments, at least one RVbis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVc.

[2187] In some embodiments, at least one RVbis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[2188] In some embodiments, at least one RVbis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RVc.

[2189] In some embodiments, at least one RVbis pyridinyl.

[2190] In some embodiments, at least one RVbis.

[2191] In some embodiments, at least one RVbis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[2192] In some embodiments, at least one RVbis 6-membered heteroaryl containing two 173 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RVc.

[2193] In some embodiments, at least one RVbis pyrimidinyl.

[2194] In some embodiments, at least one RVbis.

[2195] In some embodiments, at least one RVbis.

[2196] In some embodiments, at least one RVbis pyridazinyl.

[2197] In some embodiments, at least one RVbis.

[2198] In some embodiments, at least one RVbis pyrazinyl.

[2199] In some embodiments, at least one RVbis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[2200] In some embodiments, at least one RVbis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVc.

[2201] In some embodiments, at least one.

[2202] In some embodiments, at least one. Variable RVc

[2203] In some embodiments, at least one RVcis oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), - NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), - C(=O)-NH2, -C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[2204] In some embodiments, at least one RVcis oxo.

[2205] In some embodiments, at least one RVcis halogen (e.g., -F, -Cl, -Br, -I).

[2206] In some embodiments, at least one RVcis cyano. 174 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2207] In some embodiments, at least one RVcis -OH.

[2208] In some embodiments, at least one RVcis -O(C1-C6 alkyl) (e.g., -O(methyl), -O(ethyl), -O(n-propyl), -O(isopropyl), -O(n-butyl), -O(t-butyl), -O(isobutyl), or -O(sec-butyl)).

[2209] In some embodiments, at least one RVcis -NH2.

[2210] In some embodiments, at least one RVcis - NH(C1-C6 alkyl) (e.g., -NHCH3, - NHCH2CH3, -NH(CH2)2CH3, -NH(CH2)3CH3, -NH(CH2)4CH3, or -NH(CH2)5CH3).

[2211] In some embodiments, at least one RVcis -N(C1-C6alkyl)2(e.g., e.g., -N(methyl)2, - N(ethyl)2, -N(n-propyl)2, -N(isopropyl)2, -N(n-butyl)2, -N(t-butyl)2, -N(isobutyl)2, or -N(sec- butyl)2).

[2212] In some embodiments, at least one RVcis -C(=O)-H.

[2213] In some embodiments, at least one RVcis -C(=O)-OH.

[2214] In some embodiments, at least one RVcis -C(=O)-O(C1-C6 alkyl) (e.g., is -C(=O)- OCH3, -C(=O)-OCH2CH3, -C(=O)-O(CH2)2CH3, -C(=O)-O(CH2)3CH3, -C(=O)-O(CH2)4CH3, or -C(=O)-O(CH2)5CH3).

[2215] In some embodiments, at least one RVcis -C(=O)-NH2.

[2216] In some embodiments, at least one RVcis -C(=O)-NH(C1-C6 alkyl) ((e.g., -C(=O)- NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-NH(CH2)3CH3, -C(=O)- NH(CH2)4CH3, or -C(=O)-NH(CH2)5CH3)).

[2217] In some embodiments, at least one RVcis -C(=O)-N(C1-C6 alkyl)2 (e.g., -C(=O)- N(methyl)2, -C(=O)-N(ethyl)2, -C(=O)-N(n-propyl)2, -C(=O)-N(isopropyl)2, -C(=O)-N(n- butyl)2, -C(=O)-N(t-butyl)2, -C(=O)-N(isobutyl)2, or -C(=O)-N(sec-butyl)2).

[2218] In some embodiments, at least one RVcis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[2219] In some embodiments, at least one RVcis methyl.

[2220] In some embodiments, at least one RVcis ethyl.

[2221] In some embodiments, at least one RVcis n-propyl.

[2222] In some embodiments, at least one RVcis isopropyl.

[2223] In some embodiments, at least one RVcis n-butyl.

[2224] In some embodiments, at least one RVcis C2-C6 alkenyl.

[2225] In some embodiments, at least one RVcis C2-C6 alkynyl. Variable RA

[2226] In some embodiments, at least one RAis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, 175 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb.

[2227] In some embodiments, at least one RAis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl.

[2228] In some embodiments, at least one RAis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more RVb.

[2229] In some embodiments, at least one RAis C1-C6alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[2230] In some embodiments, at least one RAis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RVb.

[2231] In some embodiments, at least one RAis methyl.

[2232] In some embodiments, at least one RAis ethyl.

[2233] In some embodiments, at least one RAis n-propyl.

[2234] In some embodiments, at least one RAis isopropyl.

[2235] In some embodiments, at least one RAis n-butyl.

[2236] In some embodiments, at least one RAis C2-C6alkenyl.

[2237] In some embodiments, at least one RAis C2-C6alkenyl substituted with one or more RVb.

[2238] In some embodiments, at least one RAis C2-C6 alkynyl.

[2239] In some embodiments, at least one RAis C2-C6alkynyl substituted with one or more RVb.

[2240] In some embodiments, at least one RAis C3-C6 cycloalkyl.

[2241] In some embodiments, at least one RAis C3-C6cycloalkyl substituted with one or more RVb.

[2242] In some embodiments, at least one RAis C3-C6 monocyclic cycloalkyl.

[2243] In some embodiments, at least one RAis C3-C6 monocyclic cycloalkyl substituted with one or more RVb.

[2244] In some embodiments, at least one RAis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[2245] In some embodiments, at least one RAis C3-C6bicyclic cycloalkyl. 176 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2246] In some embodiments, at least one RAis C3-C6bicyclic cycloalkyl substituted with one or more RVb.

[2247] In some embodiments, at least one RAis bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[2248] In some embodiments, at least one RAis C4-C6 fused bicyclic cycloalkyl.

[2249] In some embodiments, at least one RAis C4-C6 fused bicyclic cycloalkyl substituted with one or more RVb.

[2250] In some embodiments, at least one RAis.

[2251] In some embodiments, at least one RAis, substituted with one or more RVb.

[2252] In some embodiments, at least one RAis.

[2253] In some embodiments, at least one RAis.

[2254] In some embodiments, at least one RAis C5-C6 bridged bicyclic cycloalkyl.

[2255] In some embodiments, at least one RAis C5-C6bridged bicyclic cycloalkyl substituted with one or more RVb.

[2256] In some embodiments, at least one RAis.

[2257] In some embodiments, at least one RAis, substituted with one or more RVb.

[2258] In some embodiments, at least one RAis.

[2259] In some embodiments, at least one RAis.

[2260] In some embodiments, at least one RAis.

[2261] In some embodiments, at least one RAis.

[2262] In some embodiments, at least one RAis C5-C6 spiro bicyclic cycloalkyl.

[2263] In some embodiments, at least one RAis C5-C6 spiro bicyclic cycloalkyl substituted 177 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 with one or more RVb.

[2264] In some embodiments, at least one RAis spiro[2.2]pentyl or spiro[2.3]hexyl.

[2265] In some embodiments, at least one RAis spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RVb.

[2266] In some embodiments, at least one RAis.

[2267] In some embodiments, at least one.

[2268] In some embodiments, at least one RAis 4- to 10-membered heterocyclyl.

[2269] In some embodiments, at least one RAis 4- to 10-membered heterocyclyl substituted with one or more RVb.

[2270] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl.

[2271] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl substituted with one or more RVb.

[2272] In some embodiments, at least one RAis 4- to 10-membered bicyclic heterocyclyl.

[2273] In some embodiments, at least one RAis 4- to 10-membered bicyclic heterocyclyl substituted with one or more RVb.

[2274] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl.

[2275] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RVb.

[2276] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic heterocyclyl.

[2277] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more RVb.

[2278] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl.

[2279] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RVb.

[2280] In some embodiments, at least one RAis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[2281] In some embodiments, at least one RAis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVb.

[2282] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl 178 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing at least one heteroatom selected from N, O, and S.

[2283] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVb.

[2284] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[2285] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[2286] In some embodiments, at least one RAis

[2287] In some embodiments, at least one RAis azetidinyl substituted with one or more RVb.

[2288] In some embodiments, at least one RAis.

[2289] In some embodiments, at least one RAis.

[2290] In some embodiments, at least one RAis .

[2291] In some embodiments, at least one RAis pyrrolidinyl.

[2292] In some embodiments, at least one RAis .

[2293] In some embodiments, at least one RAis.

[2294] In some embodiments, at least one RAis.

[2295] In some embodiments, at least one RAis piperidinyl.

[2296] In some embodiments, at least one RAis.

[2297] In some embodiments, at least one RAis.

[2298] In some embodiments, at least one RAis.

[2299] In some embodiments, at least one RAis.

[2300] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl 179 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 containing one N.

[2301] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVb.

[2302] In some embodiments, at least one

[2303] In some embodiments, at least one, substituted with one or more RVb.

[2304] In some embodiments, at least one RAis.

[2305] In some embodiments, at least one RAi

[2306] In some embodiments, at least one.

[2307] In some embodiments, at least one RAis.

[2308] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic heterocyclyl containing one N.

[2309] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more RVb..

[2311] In some embodiments, at least one RAis, , , , 180 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, substituted with one or more RVb.

[2312] In some embodiments, at least one RAis.

[2313] In some embodiments, at least one RAis.

[2314] In some embodiments, at least one RAis.

[2315] In some embodiments, at least one RAis.

[2316] In some embodiments, at least one RAis.

[2317] In some embodiments, at least one RAis.

[2318] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[2319] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVb.

[2320] In some embodiments, at least one RAis, , ,

[2321] In some embodiments, at least one RAis, , ,, substituted with one or more RVb.

[2322] In some embodiments, at least one RAis

[2323] In some embodiments, at least one RAis. 181 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2324] In some embodiments, at least one RAis.

[2325] In some embodiments, at least one RAis.

[2326] In some embodiments, at least one RAis.

[2327] In some embodiments, at least one.

[2328] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[2329] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[2330] In some embodiments, at least one RAis oxetanyl.

[2331] In some embodiments, at least one RAi.

[2332] In some embodiments, at least one RAi.

[2333] In some embodiments, at least one RAis tetrahydrofuranyl.

[2334] In some embodiments, at least one RAi.

[2335] In some embodiments, at least one RAi.

[2336] In some embodiments, at least one RAis tetrahydropyranyl.

[2337] In some embodiments, at least one RAi.

[2338] In some embodiments, at least one RAi.

[2339] In some embodiments, at least one RAi.

[2340] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[2341] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic 182 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic heterocyclylis substituted with one or more RVb.

[2342] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl containing one O.

[2343] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl containing one O, wherein the 4- to 10-membered fused heterocyclyl is substituted with one or more RVb.

[2344] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl containing one O.

[2345] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVb.

[2346] In some embodiments, at least one, , , ,, , , ,ore RVb.

[2348] In some embodiments, at least one RAi

[2349] In some embodiments, at least one RAi.

[2350] In some embodiments, at least one RAi.

[2351] In some embodiments, at least one RAi.

[2352] In some embodiments, at least one RAi.

[2353] In some embodiments, at least one RAi.

[2354] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl). 183 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2355] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing one S (e.g., tetrahydrothiophenyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[2356] In some embodiments, at least one RAis tetrahydrothiophenyl.

[2357] In some embodiments, at least one RAis.

[2358] In some embodiments, at least one RAis.

[2359] In some embodiments, at least one RAis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S.

[2360] In some embodiments, at least one RAis 4- to 10-membered heterocyclyl (e.g., monocyclic, fused bicyclic, bridged bicyclic, or spiro bicyclic) containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVb.

[2361] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[2362] In some embodiments, at least one RAis 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVb.

[2363] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[2364] In some embodiments, at least one RAis 4- to 10-membered fused bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVb.

[2365] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[2366] In some embodiments, at least one RAis 5- to 10-membered bridged bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10- membered bridged bicyclic heterocyclyl is substituted with one or more RVb.

[2367] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S.

[2368] In some embodiments, at least one RAis 5- to 10-membered spiro bicyclic heterocyclyl containing two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered spiro 184 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 bicyclic heterocyclyl is substituted with one or more RVb.

[2370] In some embodiments, at least one RAis, , ,, , , , , , ,, substituted with one or more RVb.

[2371] In some embodiments, at least one RAis.

[2372] In some embodiments, at least one RAis.

[2373] In some embodiments, at least one RAis.

[2374] In some embodiments, at least one.

[2375] In some embodiments, at least one RAis.

[2376] In some embodiments, at least one RAis. 185 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2377] In some embodiments, at least one RAis.

[2378] In some embodiments, at least one RAis.

[2379] In some embodiments, at least one RAis.

[2380] In some embodiments, at least one RAis.

[2381] In some embodiments, at least one.

[2382] In some embodiments, at least one RAis.

[2383] In some embodiments, at least one.

[2384] In some embodiments, at least one.

[2385] In some embodiments, at least one.

[2386] In some embodiments, at least one RAis C6-C10 aryl (e.g., phenyl).

[2387] In some embodiments, at least one RAis C6-C10aryl (e.g., phenyl) substituted with one or more RVb.

[2388] In some embodiments, at least one RAis phenyl.

[2389] In some embodiments, at least one RAis 5- to 10-membered heteroaryl.

[2390] In some embodiments, at least one RAis 5- to 10-membered heteroaryl substituted with one or more RVb.

[2391] In some embodiments, at least one RAis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. 186 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2392] In some embodiments, at least one RAis 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb.

[2393] In some embodiments, at least one RAis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[2394] In some embodiments, at least one RAis 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb.

[2395] In some embodiments, at least one RAis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl).

[2396] In some embodiments, at least one RAis 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl), wherein the heteroaryl is substituted with one or more RVb.

[2397] In some embodiments, at least one RAis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl).

[2398] In some embodiments, at least one RAis 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more RVb.

[2399] In some embodiments, at least one RAis oxazolyl.

[2400] In some embodiments, at least one RAis.

[2401] In some embodiments, at least one RAis thiazolyl.

[2402] In some embodiments, at least one RAis.

[2403] In some embodiments, at least one RAis pyrazolyl.

[2404] In some embodiments, at least one RAis .

[2405] In some embodiments, at least one RAis.

[2406] In some embodiments, at least one RAis isoxazolyl.

[2407] In some embodiments, at least one RAis isothiazolyl.

[2408] In some embodiments, at least one RAis imidazolyl. 187 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2409] In some embodiments, at least one RAis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl).

[2410] In some embodiments, at least one RAis 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl), wherein the heteroaryl is substituted with one or more RVb.

[2411] In some embodiments, at least one RAis triazolyl.

[2412] In some embodiments, at least one RAis.

[2413] In some embodiments, at least one RAis.

[2414] In some embodiments, at least one RAis

[2415] In some embodiments, at least one RAis oxadiazolyl.

[2416] In some embodiments, at least one RAis.

[2417] In some embodiments, at least one RAis thiadiazolyl.

[2418] In some embodiments, at least one RAis.

[2419] In some embodiments, at least one RAis.

[2420] In some embodiments, at least one RAis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl).

[2421] In some embodiments, at least one RAis 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl), wherein the heteroaryl is substituted with one or more RVb.

[2422] In some embodiments, at least one RAis tetrazolyl.

[2423] In some embodiments, at least one RAis.

[2424] In some embodiments, at least one RAis oxatriazolyl.

[2425] In some embodiments, at least one RAis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. 188 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2426] In some embodiments, at least one RAis 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb.

[2427] In some embodiments, at least one RAis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl).

[2428] In some embodiments, at least one RAis 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl), wherein the heteroaryl is substituted with one or more RVb.

[2429] In some embodiments, at least one RAis pyridinyl.

[2430] In some embodiments, at least one RAis.

[2431] In some embodiments, at least one RAis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl).

[2432] In some embodiments, at least one RAis 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl), wherein the heteroaryl is substituted with one or more RVb.

[2433] In some embodiments, at least one RAis pyrimidinyl.

[2434] In some embodiments, at least one RAi.

[2435] In some embodiments, at least one RAi.

[2436] In some embodiments, at least one RAi

[2437] In some embodiments, at least one RAi.

[2438] In some embodiments, at least one RAi

[2439] In some embodiments, at least one RAis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S.

[2440] In some embodiments, at least one RAis 9-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more RVb. 189 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2441] In some embodiments, at least one.

[2442] In some embodiments, at least one. Variable RB

[2443] In some embodiments, at least one RBis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc.

[2444] In some embodiments, at least one RBis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3- C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl.

[2445] In some embodiments, at least one RBis C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3- C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more RVc.

[2446] In some embodiments, at least one RBis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl).

[2447] In some embodiments, at least one RBis C1-C6 alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, or sec-butyl) substituted with one or more RVc.

[2448] In some embodiments, at least one RBis methyl.

[2449] In some embodiments, at least one RBis ethyl.

[2450] In some embodiments, at least one RBis n-propyl.

[2451] In some embodiments, at least one RBis isopropyl.

[2452] In some embodiments, at least one RBis n-butyl.

[2453] In some embodiments, at least one RBis C2-C6 alkenyl.

[2454] In some embodiments, at least one RBis C2-C6 alkenyl substituted with one or more RVc.

[2455] In some embodiments, at least one RBis C2-C6alkynyl.

[2456] In some embodiments, at least one RBis C2-C6 alkynyl substituted with one or more 190 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 RVc.

[2457] In some embodiments, at least one RBis C3-C6 cycloalkyl.

[2458] In some embodiments, at least one RBis C3-C6 cycloalkyl substituted with one or more RVc.

[2459] In some embodiments, at least one RBis C3-C6 monocyclic cycloalkyl.

[2460] In some embodiments, at least one RBis C3-C6 monocyclic cycloalkyl substituted with one or more RVc.

[2461] In some embodiments, at least one RBis cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.

[2462] In some embodiments, at least one RBis C3-C6bicyclic cycloalkyl.

[2463] In some embodiments, at least one RBis C3-C6bicyclic cycloalkyl substituted with one or more RVc.

[2464] In some embodiments, at least one RBis bicyclocyclobutyl, bicyclocyclopentyl, or bicyclocyclohexyl.

[2465] In some embodiments, at least one RBis C4-C6 fused bicyclic cycloalkyl.

[2466] In some embodiments, at least one RBis C4-C6 fused bicyclic cycloalkyl substituted with one or more RVc.

[2467] In some embodiments, at least one RBis.

[2468] In some embodiments, at least one RBis, substituted with one or more RVc.

[2469] In some embodiments, at least one RBis.

[2470] In some embodiments, at least one RBis.

[2471] In some embodiments, at least one RBis C5-C6 bridged bicyclic cycloalkyl.

[2472] In some embodiments, at least one RBis C5-C6bridged bicyclic cycloalkyl substituted with one or more RVc.

[2473] In some embodiments, at least one RBis.

[2474] In some embodiments, at least one RBis, substituted with one or more RVc. 191 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2475] In some embodiments, at least one RBis .

[2476] In some embodiments, at least one RBis.

[2477] In some embodiments, at least one RBis.

[2478] In some embodiments, at least one RBis.

[2479] In some embodiments, at least one RBis C5-C6 spiro bicyclic cycloalkyl.

[2480] In some embodiments, at least one RBis C5-C6spiro bicyclic cycloalkyl substituted with one or more RVc.

[2481] In some embodiments, at least one RBis spiro[2.2]pentyl or spiro[2.3]hexyl.

[2482] In some embodiments, at least one RBis spiro[2.2]pentyl or spiro[2.3]hexyl, substituted with one or more RVc.

[2483] In some embodiments, at least one RBis .

[2484] In some embodiments, at least one.

[2485] In some embodiments, at least one RBis 4- to 10-membered heterocyclyl.

[2486] In some embodiments, at least one RBis 4- to 10-membered heterocyclyl substituted with one or more RVc.

[2487] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl.

[2488] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl substituted with one or more RVc.

[2489] In some embodiments, at least one RBis 4- to 10-membered bicyclic heterocyclyl.

[2490] In some embodiments, at least one RBis 4- to 10-membered bicyclic heterocyclyl substituted with one or more RVc.

[2491] In some embodiments, at least one RBis 4- to 10-membered fused bicyclic heterocyclyl.

[2492] In some embodiments, at least one RBis 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more RVc.

[2493] In some embodiments, at least one RBis 5- to 10-membered bridged bicyclic heterocyclyl.

[2494] In some embodiments, at least one RBis 5- to 10-membered bridged bicyclic 192 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heterocyclyl substituted with one or more RVc.

[2495] In some embodiments, at least one RBis 5- to 10-membered spiro bicyclic heterocyclyl.

[2496] In some embodiments, at least one RBis 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more RVc.

[2497] In some embodiments, at least one RBis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S.

[2498] In some embodiments, at least one RBis 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVc.

[2499] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S.

[2500] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S, wherein the 4- to 10-membered heterocyclyl is substituted with one or more RVc.

[2501] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl).

[2502] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVc.

[2503] In some embodiments, at least one RBis azetidinyl.

[2504] In some embodiments, at least one RBis azetidinyl substituted with one or more RVc.

[2505] In some embodiments, at least one RBi.

[2506] In some embodiments, at least one RBi.

[2507] In some embodiments, at least one RBi.

[2508] In some embodiments, at least one RBis pyrrolidinyl.

[2509] In some embodiments, at least one RBi.

[2510] In some embodiments, at least one RBi.

[2511] In some embodiments, at least one RBi. 193 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2512] In some embodiments, at least one RBis piperidinyl.

[2513] In some embodiments, at least one RBis.

[2514] In some embodiments, at least one RBis.

[2515] In some embodiments, at least one RBis.

[2516] In some embodiments, at least one RBis.

[2517] In some embodiments, at least one RBis 4- to 10-membered fused bicyclic heterocyclyl containing one N.

[2518] In some embodiments, at least one RBis 4- to 10-membered fused bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered fused bicyclic heterocyclyl is substituted with one or more RVc.

[2519] In some embodiments, at least one

[2520] In some embodiments, at least one, substituted with one or more RVc.

[2521] In some embodiments, at least one RBis.

[2522] In some embodiments, at least one RBi

[2523] In some embodiments, at least one.

[2524] In some embodiments, at least one RBis.

[2525] In some embodiments, at least one RBis 5- to 10-membered bridged bicyclic 194 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heterocyclyl containing one N.

[2526] In some embodiments, at least one RBis 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more RVc.

[2527] In some embodiments, at least one RBis, , , ,.

[2528] In some embodiments, at least one RBis, , , ,, substituted with one or more RVc.

[2529] In some embodiments, at least one RBis.

[2530] In some embodiments, at least one RBis.

[2531] In some embodiments, at least one RBis.

[2532] In some embodiments, at least one RBis.

[2533] In some embodiments, at least one RBis.

[2534] In some embodiments, at least one RBis.

[2535] In some embodiments, at least one RBis 5- to 10-membered spiro bicyclic heterocyclyl containing one N.

[2536] In some embodiments, at least one RBis 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 5- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more RVc.

[2537] In some embodiments, at least one RBis, , , 195 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2538] In some embodiments, at least one RBis, , ,, substituted with one or more RVc.

[2539] In some embodiments, at least one RBis

[2540] In some embodiments, at least one RBis.

[2541] In some embodiments, at least one RBis.

[2542] In some embodiments, at least one RBis.

[2543] In some embodiments, at least one RBis.

[2544] In some embodiments, at least one.

[2545] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl).

[2546] In some embodiments, at least one RBis 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl), wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more RVc.

[2547] In some embodiments, at least one RBis oxetanyl.

[2548] In some embodiments, at least one RBis.

[2549] In some embodiments, at least one RBis .

[2550] In some embodiments, at least one RBis tetrahydrofuranyl.

[2551] In some embodiments, at least one RBis. 196 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084

[2552] In some embodiments, at least one RBis.

[2553] In some embodiments, at least one RBis tetrahydropyranyl.

[2554] In some embodiments, at least one RBis .

[2555] In some embodiments, at least one RBis.

[2556] In some embodiments, at least one RBis.

[2557] In some embodiments, at least one RBis 5- to 10-membered bridged bicyclic heterocyclyl containing one O.

[2558] In some embodiments, at least one RBis 5- to 10-membered bridged bicyclic heterocyclyl containing one O, wherein the 5- to 10-membered bridged bicyclic hete...

Claims

Attorney Docket No. PRTE-018 / 01WO 345214-2084 WHAT IS CLAIMED IS:

1. A compound of Formula (0):or a pharmaceutically acceptable salt thereof, wherein: X1is N or C; X2is N, O, or CH; X3is N, O, or CR0d; R0dis H or optionally substituted C1-C6 alkyl; R0ais halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6alkyl, wherein the -O(C1-C6alkyl), -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6alkyl is optionally substituted; R0bis -Lb1-Lb2; Lb1is absent or -O(C1-C6alkylene)-; Lb2is 4- to 7-membered heterocyclyl, C3-C6cycloalkyl, or C1-C6alkyl, wherein the 4- to 7-membered heterocyclyl, C3-C6 cycloalkyl, or C1-C6 alkyl is optionally substituted; R0cis -Lc1-Lc2; Lc1is absent, -C(=O)-, -C(=O)-NH-, -C(=O)-NH-(C1-C6alkylene)-, -C(=O)-N(C1-C6alkyl)-, -C(=O)-O-, -C(=S)-, -S(=O)2-, -S(=O)2-NH-, -S(=O)2-NH-(C1-C6 alkylene)-, or - S(=O)2-O-; and Lc2is H, C1-C6alkyl, 4- to 12-membered heterocyclyl, or C3-C8cycloalkyl, wherein the C1-C6alkyl, 4- to 12-membered heterocyclyl, or C3-C8cycloalkyl is optionally substituted.

2. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; 861 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 n is 0 or 1; X is -CH2- or -O-; R1is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6 alkyl), -NHS(=O)2(C1-C6 alkyl), or -C(=O)NH2; R2ais C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, or - NH2; R2bis H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen; R2cis H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen; R2dis H; or R2aand R2dtogether form C1-C6 alkylene optionally substituted with one or more halogen; Y is C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), or -C(=O)-N(C1-C6alkyl)2; T is -ORT1, -N(RT1)2, or -N(RT2)2; each RT1independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1- C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6alkyl)- (C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa; 862 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more RTa; each RTaindependently is oxo, halogen, cyano, -OH, -ORb, -NH2, -NHRb, -N(Rb)2, - C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)-NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; each Rbindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each RTbindependently is oxo, halogen, cyano, -OH, -ORc, -NH2, -NHRc, -N(Rc)2, - C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each Rcindependently is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; and each RTcindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

3. The compound of claim 2, wherein the compound has the structure of Formula (I’):or a pharmaceutically acceptable salt thereof, wherein: m is 0 or 1; n is 0 or 1; 863 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 X is -CH2- or -O-; R1is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, cyano, -OH, or -NH2; R2ais C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, or - NH2; R2bis H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen; R2cis H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen; R2dis H; or R2aand R2dtogether form C1-C6alkylene optionally substituted with one or more halogen; Y is C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), or -C(=O)-N(C1-C6 alkyl)2; E is -(C1-C6alkylene)- optionally substituted with one or more oxo, halogen, cyano, - OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2; one of U1and U2is -O-, and the other one of U1and U2is -C(RU)2-; each RUindependently is H, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6alkyl; each RVindependently is H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6 alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-RA, -C(=O)-H, -C(=O)-RA, -C(=O)-OH, - C(=O)-ORA, -C(=O)-NH2, -C(=O)-NHRA, -C(=O)-N(RA)2, -S(=O)2-RA, -NH-S(=O)2-RA, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 864 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVa; each RAindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RVaindependently is oxo, halogen, cyano, -OH, -ORB, -NH2, -NHRB, -N(RB)2, - NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)-ORB, -C(=O)- NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RBindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RVbindependently is oxo, halogen, cyano, -OH, -ORC, -NH2, -NHRC, -N(RC)2, - NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)-ORC, -C(=O)- NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RCindependently is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; and each RVcindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

4. A compound of Formula (I’’-i) or (I’’-ii): 865 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein: R1is halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, cyano, -OH, or -NH2; W is -(C1-C6alkylene)- or -(C3-C6cycloalkylene)-, wherein the -(C1-C6alkylene)- or - (C3-C6cycloalkylene)- is optionally substituted with one or more halogen, cyano, -OH, -O(C1- C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; Y is C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), or -C(=O)-N(C1-C6 alkyl)2; T is -ORT1, -N(RT1)2, or -N(RT2)2; each RT1independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1- C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6alkyl)- (C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10- 866 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa; two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more RTa; each RTaindependently is oxo, halogen, cyano, -OH, -ORb, -NH2, -NHRb, -N(Rb)2, - C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)-NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; each Rbindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each RTbindependently is oxo, halogen, cyano, -OH, -ORc, -NH2, -NHRc, -N(Rc)2, - C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each Rcindependently is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl;each RTcindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1- C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, -C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; E is -(C1-C6alkylene)- optionally substituted with one or more oxo, halogen, cyano, - OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), or -N(C1-C6 alkyl)2; one of U1and U2is -O-, and the other one of U1and U2is -C(RU)2-; each RUindependently is H, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl; each RVindependently is H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6 alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-RA, -C(=O)-H, -C(=O)-RA, -C(=O)-OH, - C(=O)-ORA, -C(=O)-NH2, -C(=O)-NHRA, -C(=O)-N(RA)2, -S(=O)2-RA, -NH-S(=O)2-RA, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6867 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVa; each RAindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RVaindependently is oxo, halogen, cyano, -OH, -ORB, -NH2, -NHRB, -N(RB)2, - NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)-ORB, -C(=O)- NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RBindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RVbindependently is oxo, halogen, cyano, -OH, -ORC, -NH2, -NHRC, -N(RC)2, - NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)-ORC, -C(=O)- NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RCindependently is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; and each RVcindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

5. A compound of Formula (I’’’-i) or (I’’’-ii): 868 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof, wherein: R1is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen, cyano, -OH, or -NH2; Y is C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), or -C(=O)-N(C1-C6alkyl)2; T is -ORT1, -N(RT1)2, or -N(RT2)2; each RT1independently is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1- C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6 alkyl)- (C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein the C1-C6 alkyl, C2- C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, -(C1-C6alkyl)-(C3-C6cycloalkyl), -(C1-C6alkyl)-(4- to 10- membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa; 869 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 two RT2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more RTa; each RTaindependently is oxo, halogen, cyano, -OH, -ORb, -NH2, -NHRb, -N(Rb)2, - C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)-NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; each Rbindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each RTbindependently is oxo, halogen, cyano, -OH, -ORc, -NH2, -NHRc, -N(Rc)2, - C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each Rcindependently is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; each RTcindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; E is -(C1-C6alkylene)- optionally substituted with one or more oxo, halogen, cyano, - OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2; one of U1and U2is -O-, and the other one of U1and U2is -C(RU)2-; each RUindependently is H, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, or C1-C6alkyl; each RVindependently is H, oxo, halogen, cyano, -OH, -ORA, -(C1-C6 alkylene)-ORA, -NH2, -NHRA, -N(RA)2, -NH-C(=O)-H, -NH-C(=O)-RA, -C(=O)-H, -C(=O)-RA, -C(=O)-OH, - C(=O)-ORA, -C(=O)-NH2, -C(=O)-NHRA, -C(=O)-N(RA)2, -S(=O)2-RA, -NH-S(=O)2-RA, C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 870 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVa; each RAindependently is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RVaindependently is oxo, halogen, cyano, -OH, -ORB, -NH2, -NHRB, -N(RB)2, - NH-C(=O)-H, -NH-C(=O)-RB, -C(=O)-H, -C(=O)-RB, -C(=O)-OH, -C(=O)-ORB, -C(=O)- NH2, -C(=O)-NHRB, -C(=O)-N(RB)2, -S(=O)2-RB, -NH-S(=O)2-RB, C1-C6 alkyl, C2-C6 alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVb; each RBindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RVbindependently is oxo, halogen, cyano, -OH, -ORC, -NH2, -NHRC, -N(RC)2, - NH-C(=O)-H, -NH-C(=O)-RC, -C(=O)-H, -C(=O)-RC, -C(=O)-OH, -C(=O)-ORC, -C(=O)- NH2, -C(=O)-NHRC, -C(=O)-N(RC)2, -S(=O)2-RC, -NH-S(=O)2-RC, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RVc; each RCindependently is C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; and each RVcindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

6. The compound of claim 2, wherein the compound has the structure of Formula (II), (II- a), or (II-b): 871 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2 or 6, wherein the compound has the structure of Formula (III), (III-a), or (III-b):872 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2, wherein the compound has the structure of Formula (VIII):or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; R1is halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6alkyl), -NHS(=O)2(C1-C6alkyl), or -C(=O)NH2; R2ais C1-C6 alkyl optionally substituted with one or more halogen, cyano, -OH, or - NH2; R2bis H or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halogen; R2cis H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more halogen; R2dis H; or R2aand R2dtogether form C1-C6 alkylene optionally substituted with one or more halogen; Y is C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl, wherein the C3-C8cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa; each RYaindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6alkyl), -N(C1-C6alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more RYb; each RYbindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), or -C(=O)-N(C1-C6alkyl)2; 873 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084connectivity to the carbonyl group at triazolopyridine; ring B is H, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl; Z is absent, -CH2-, -O-, or -C(=O)-; each RTaindependently is oxo, halogen, cyano, -OH, -ORTb, -NH2, -NHRTb, -N(RTb)2, -C(=O)-H, -C(=O)-RTb, -C(=O)-OH, -C(=O)-ORTb, -C(=O)-NH2, -C(=O)-NHRTb, -C(=O)- 874 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 N(RTb)2, -S(=O)2-RTb, -S(=O)(=NH)-RTb, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6 alkynyl, or C2-C6 alkynyl; each RTbis C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, or C2-C6alkynyl; and each RTb1independently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1-C6alkyl)2, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; wherein when B is H, Z is absent.

9. The compound of claim 8, wherein the compound has the structure of Formula (VIII- a), or (VIII-b):- , or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 2, 6, 7, and 9, wherein the compound has the structure of Formula (IV), (IV-a), or (IV-b):, 875 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084- , or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 2, 6, 7, and 10, wherein the compound has the structure of Formula (V), (V-a) or (V-b):or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 2, 6, 7, 10, and 11, wherein the compound has the structure of Formula (VI), (VI-a), or (VI-b): 876 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 2, 6, 7, and 10-12, wherein the compound has the structure of Formula (VII), (VII-a), or (VII-b):- ), 877 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof.

14. The compound of claim 2 or 6, wherein the compound has the structure of Formula (II’), (II’-a), (II’-b), (II’-c), (II’-d), (II’-e), or (II’-f):878 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof.

15. The compound of any one of claims 2, 6, and 14, wherein the compound has the structure of Formula (III’), (III’-a), (III’-b), (III’-c), (III’-d), (III’-e), or (III’-f):879 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 2, 6, 14, and 15, wherein the compound has the structure of Formula (IV’), (IV’-a), (IV’-b), (IV’-c), (IV’-d), (IV’-e), or (IV’-f):880 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof.

17. The compound of any one of claims 2, 6, and 14-16, wherein the compound has the structure of Formula (V’), (V’-a), (V’-b), (V’-c), (V’-d), (V’-e), or (V’-f):881 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084or a pharmaceutically acceptable salt thereof.

18. The compound of any one of claims 2-9 and 14, wherein Y is phenyl or 5- to 6- membered heteroaryl, wherein the phenyl, or 5- to 10-membered heteroaryl is optionally substituted with one or more RYa.

19. The compound of any one of claims 2-10, 14, 15, and 18, wherein R1is C1-C3 alkyl optionally substituted with one or more of halogen, cyano, -OH, -NH2, -NHC(=O)(C1-C6alkyl), -NHS(=O)2(C1-C6 alkyl), or -C(=O)NH2.

20. The compound of claim 19, wherein R1is methyl.

21. The compound of any one of claims 2, 3, 6-10, 14-16, and 18-20, wherein R2ais C1- C3alkyl. 882 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 22. The compound of any one of claims 2, 3, 6-10, and 18-21, wherein R2b, R2c, and R2dare each H.

23. The compound of any one of claims 2, 4, 6, 7, 10, 11, and 18-22, wherein T is -N(RT1)2or -N(RT2)2.

24. The compound of claim 23, wherein one RT1is H or C1-C6alkyl; and the other RT1is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)- (4- to 10-membered heterocyclyl), -(C1-C6alkyl)-(C6-C10aryl), or -(C1-C6alkyl)-(5- to 10- membered heteroaryl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1- C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6 alkyl)- (C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RTa.

25. The compound of claim 23 or 24, wherein one RT1is H or C1-C6alkyl; and the other RT1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, monocyclic C3-C8cycloalkyl, fused bicyclic C4-C8 cycloalkyl, bridged bicyclic C5-C8 cycloalkyl, spiro bicyclic C5-C8 cycloalkyl, monocyclic 4- to 8-membered heterocyclyl, fused bicyclic 4- to 10-membered heterocyclyl, bridged bicyclic 5- to 10-membered heterocyclyl, spiro bicyclic 5- to 10-membered heterocyclyl, phenyl, monocyclic 5- to 6-membered heteroaryl, fused bicyclic 5- to 10- membered heteroaryl, -(C1-C4 alkyl)-(monocyclic C3-C8 cycloalkyl), -(C1-C4 alkyl)-(fused bicyclic C4-C8cycloalkyl), -(C1-C4alkyl)-(bridged bicyclic C5-C8cycloalkyl), -(C1-C4alkyl)- (spiro bicyclic C5-C8cycloalkyl), -(C1-C4alkyl)-(monocyclic 4- to 7-membered heterocyclyl), -(C1-C4 alkyl)-(fused bicyclic 4- to 10-membered heterocyclyl), -(C1-C4 alkyl)-(bridged bicyclic 5- to 10-membered heterocyclyl), -(C1-C4alkyl)-(spiro bicyclic 5- to 10-membered heterocyclyl), -(C1-C4alkyl)-(phenyl), -(C1-C4alkyl)-(monocyclic 5- to 6-membered heteroaryl), or -(C1-C4 alkyl)-(fused bicyclic 5- to 10-membered heteroaryl), wherein the other RT1is optionally substituted with one or more RTa.

26. The compound of claim 23 or 24, wherein one RT1is H or C1-C6 alkyl; and the other RT1is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, 883 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084one or more RTa.

27. The compound of claim 23 or 24, wherein one RT1is H or C1-C6 alkyl; and the other RT1is pyrrolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, tetrazolyl, oxatriazolyl, 884 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl,, wherein the other RT1is optionally substituted with one or more RTa.

28. The compound of claim 23, wherein two RT2, together with the atom to which they are attached, form a monocyclic 4- to 8-membered heterocyclyl, a fused bicyclic 4- to 10- membered heterocyclyl, a bridged bicyclic 5- to 10-membered heterocyclyl, or a spiro bicyclic 5- to 10-membered heterocyclyl, each optionally substituted with one or more RTa.

29. The compound of claim 28, wherein two RT2, together with the atom to which they are attached, form, , , , , ,, each optionally substituted with one or more RTa.

30. The compound of claim 28, wherein two RT2, together with the atom to which they are885 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 31. The compound of claim 28, wherein two RT2, together with the atom to which they are attached, form, , , , , ,, , each optionally substituted with one or more RTa.

32. The compound of claim 28, wherein two RT2, together with the atom to which they, , , , , ,, each optionally substituted with one or more RTa.

33. The compound of any one of claims 2-7, 10-13 and 18-32, wherein: each RTaindependently is oxo, halogen, cyano, -OH, -ORb, -NH2, -NHRb, -N(Rb)2, - C(=O)-H, -C(=O)-Rb, -C(=O)-OH, -C(=O)-ORb, -C(=O)-NH2, -C(=O)-NHRb, -C(=O)- N(Rb)2, -S(=O)2-Rb, -S(=O)(=NH)-Rb, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered 886 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; each Rbindependently is C1-C6 alkyl optionally substituted with one or more RTc; each RTbindependently is oxo, halogen, cyano, -OH, -ORc, -NH2, -NHRc, -N(Rc)2, - C(=O)-H, -C(=O)-Rc, -C(=O)-OH, -C(=O)-ORc, -C(=O)-NH2, -C(=O)-NHRc, -C(=O)-N(Rc)2, -S(=O)2-Rc, -S(=O)(=NH)-Rc, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; each Rcindependently is C1-C6alkyl; and each RTcindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)-H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, - C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

34. The compound of any one of claims 2-7, 10-13 and 18-32, wherein: at least one RTais C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, wherein the C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTb; or at least one RTais -ORb, -NHRb, -N(C1-C6alkyl)Rb, -N(Rb)2, -C(=O)-Rb, -C(=O)-ORb, -C(=O)-NHRb, -C(=O)-N(Rb)2, -S(=O)2-Rb, or -S(=O)(=NH)-Rb, wherein Rbis C3-C6 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more RTc; or at least one RTais C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6alkenyl, or C2-C6alkynyl is substituted with one group selected from C3-C6cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl, and further optionally substituted with one or more RTb.

35. The compound of any one of claims 2-7, 10-13 and 18-34, wherein at least one RTbor at least one RTcis -C(=O)-OH.

36. The compound of claim 8 or 9, wherein ring A is 887 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, where * indicates connectivity to the carbonyl group at triazolopyridine. ,, , , , ,, o , where * indicates connectivity to the carbonyl group at triazolopyridine. , ,, , , , , 888 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084889 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084, where * indicates connectivity to the carbonyl group at triazolopyridine.

40. The compound of any one of claims 8, 9, and 35-39, wherein ring B is C3-C6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, or 5- to 6- membered heteroaryl.

41. The compound of claim 40, wherein ring B is pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

42. The compound of claim 40, wherein ring B is pyridinyl.

43. The compound of any one of claims 8, 9, and 35-42, wherein at least one RTb1is present and the at least one RTb1is -C(=O)-H, -C(=O)-OH, or -C(=O)-O(C1-C6 alkyl).

44. The compound of any one of claims 8, 9, and 35-42, wherein at least one RTb1is present and the at least one RTb1is -C(=O)-OH.

45. The compound of any one of claims 3-5 and 14-21, wherein E is methylene optionally substituted with one or more -NH2.

46. The compound of any one of claims 3-5, 14-21, and 45, wherein U1is -O- and U2is - C(RU)2-, or U2is -O- and U1-C(RU)2-; wherein RUis H or C1-C6alkyl.

47. The compound of any one of claims 3-5, 14-21, 45, and 46, wherein at least one RVis C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1-C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)- (4- to 10-membered heterocyclyl), -(C1-C6 alkyl)-(C6-C10 aryl), or -(C1-C6 alkyl)-(5- to 10- 890 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 membered heteroaryl), wherein the C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, -(C1- C6 alkyl)-(C3-C6 cycloalkyl), -(C1-C6 alkyl)-(4- to 10-membered heterocyclyl), -(C1-C6 alkyl)- (C6-C10aryl), or -(C1-C6alkyl)-(5- to 10-membered heteroaryl) is optionally substituted with one or more RVa.

48. The compound of claim 47, wherein at least one RVis C1-C6alkyl, C2-C6alkenyl, C2- C6 alkynyl, monocyclic C3-C8 cycloalkyl, fused bicyclic C4-C8 cycloalkyl, bridged bicyclic C5- C8 cycloalkyl, spiro bicyclic C5-C8 cycloalkyl, monocyclic 4- to 8-membered heterocyclyl, fused bicyclic 4- to 10-membered heterocyclyl, bridged bicyclic 5- to 10-membered heterocyclyl, spiro bicyclic 5- to 10-membered heterocyclyl, phenyl, monocyclic 5- to 6- membered heteroaryl, fused bicyclic 5- to 10-membered heteroaryl, -(C1-C4 alkyl)- (monocyclic C3-C8 cycloalkyl), -(C1-C4 alkyl)-(fused bicyclic C4-C8 cycloalkyl), -(C1-C4 alkyl)-(bridged bicyclic C5-C8cycloalkyl), -(C1-C4alkyl)-(spiro bicyclic C5-C8cycloalkyl), - (C1-C4 alkyl)-(monocyclic 4- to 7-membered heterocyclyl), -(C1-C4 alkyl)-(fused bicyclic 4- to 10-membered heterocyclyl), -(C1-C4 alkyl)-(bridged bicyclic 5- to 10-membered heterocyclyl), -(C1-C4alkyl)-(spiro bicyclic 5- to 10-membered heterocyclyl), -(C1-C4alkyl)-(phenyl), -(C1- C4alkyl)-(monocyclic 5- to 6-membered heteroaryl), or -(C1-C4alkyl)-(fused bicyclic 5- to 10- membered heteroaryl), each optionally substituted with one or more RVa.

49. The compound of claim 47, wherein at least one RVis C1-C6alkyl, C2-C6alkenyl, C2- C6alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,, , ,, , , , , , , , 891 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084substituted with one or more RVa.

50. The compound of claim 23 or 24, wherein at least one RVis pyrrolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, oxathiadiazolyl, tetrazolyl, oxatriazolyl, pyridinyl, pyranyl, thiopyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, phenyl,, each optionally substituted with one or more RVa.

51. The compound of any one of claims 3-5, 14-21, and 45-50, each RVaindependently is oxo, halogen, cyano, -OH, -O(C1-C6alkyl), -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -C(=O)- H, -C(=O)-OH, -C(=O)-O(C1-C6 alkyl), -C(=O)-NH2, -C(=O)-NH(C1-C6 alkyl), -C(=O)-N(C1- C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

52. The compound of any one of claims 3-5, 14-21, and 45-51, each RVbindependently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -C(=O)- 892 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 H, -C(=O)-OH, -C(=O)-O(C1-C6alkyl), -C(=O)-NH2, -C(=O)-NH(C1-C6alkyl), -C(=O)-N(C1- C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

53. A compound selected from Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salts thereof.

54. A compound selected from Table 1, or pharmaceutically acceptable salts thereof.

55. A compound selected from Table 2, or pharmaceutically acceptable salts thereof.

56. A compound selected from Table 3, or pharmaceutically acceptable salts thereof.

57. A compound selected from Table 4, or pharmaceutically acceptable salts thereof.

58. A compound selected from Table 5, or pharmaceutically acceptable salts thereof.

59. A pharmaceutical composition comprising a compound of any one of claims 1-58, and one or more pharmaceutically acceptable carriers or excipients.

60. A method of treating or preventing a disease in a subject, comprising administering to the subject a compound of any one of claims 1-58 or a pharmaceutical composition of claim 59.

61. The compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for treating or preventing a disease in a subject.

62. Use of a compound of any one of claims 1-58 in the manufacture of a medicament for treating or preventing a disease in a subject.

63. The method of claim 60, wherein the disease is light chain amyloidosis.

64. The compound of claim 61, wherein the disease is light chain amyloidosis.

65. The use of claim 62, wherein the disease is light chain amyloidosis. 893 318472877Attorney Docket No. PRTE-018 / 01WO 345214-2084 66. A method of stabilizing immunoglobulin light chains in a subject, comprising administering to the subject a compound of any one of claims 1-58 or a pharmaceutical composition of claim 59.

67. The compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for stabilizing immunoglobulin light chains in a subject.

68. Use of a compound of any one of claims 1-58 in the manufacture of a medicament for stabilizing immunoglobulin light chains in a subject.

69. A method of preventing or lessening immunoglobulin light chain misfolding and / or endoproteolysis in a subject, comprising administering to the subject a compound of any one of claims 1-58 or a pharmaceutical composition of claim 59.

70. The compound of any one of claims 1-58 or a pharmaceutical composition of claim 59 for preventing or lessening immunoglobulin light chain misfolding and / or endoproteolysis in a subject.

71. Use of a compound of any one of claims 1-58 in the manufacture of a medicament for preventing or lessening immunoglobulin light chain misfolding and / or endoproteolysis. 894 318472877

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