WO2025255341A1

WO2025255341A1 - Tetrahydrofuranyl ire1/xbp1s activators

Info

Publication number: WO2025255341A1
Application number: PCT/US2025/032437
Authority: WO
Inventors: Huang QIU; Bo QIN; Richard F. Labaudiniere; Steven J. WILKENS; Xiao Hu
Original assignee: Protego Biopharma Inc
Current assignee: Protego Biopharma Inc
Priority date: 2024-06-05
Filing date: 2025-06-05
Publication date: 2025-12-11
Anticipated expiration: 2026-12-05

Abstract

Provided herein are compounds that activate IRE1/XBP1s, and pharmaceutically acceptable derivatives thereof. Also provided are pharmaceutical compositions containing the compounds and methods of using the compounds for treating a subject having a disease or disorder that may be ameliorated by increasing IRE1/XBP1s activity.

Description

Attorney Docket No. PRTE-020/01WO 345214-2086 TETRAHYDROFURANYL IRE1/XBP1s ACTIVATORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to and the benefit of U.S. Provisional Application No.63/656,363, filed on June 5, 2024, the contents of which are incorporated by reference herein in their entireties for all purposes. FIELD [0002] Provided herein are tetrahydrofuranyl compounds for use in compositions and methods of treating IRE1/XBP1s mediated diseases. In one embodiment, the compounds are IRE1/XBP1s activators. BACKGROUND [0003] The unfolded protein response (UPR) is the primary signaling pathway activated in response to endoplasmic reticulum (ER) stress. The UPR is comprised of three signaling cascades activated downstream of the ER stress-sensing proteins IRE1 (inositol requiring enzyme 1), PERK (protein kinase RNA-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6). In response to acute ER stress, activation of these pathways results in transcriptional and translational remodeling to alleviate the misfolded protein load in the ER lumen and promote adaptive remodeling of ER function and global cellular physiology. However, in response to chronic or severe ER insults, prolonged UPR signaling can induce a pro-apoptotic response that results in cellular death. Thus, through this combination of adaptive and pro-apoptotic signaling, the UPR functions at a critical intersection in dictating cellular function and survival in response to diverse pathologic insults that induce ER stress. [0004] The capacity for UPR signaling to promote adaptive remodeling of ER function makes the three UPR signaling pathways attractive targets to ameliorate pathologic imbalances in ER proteostasis implicated in etiologically diverse diseases. The IRE1 pathway is the most evolutionarily conserved arm of the UPR. It is found in organisms ranging from yeast to mammals. IRE1 is an ER transmembrane protein that is activated in response to ER stress through a mechanism involving autophosphorylation and oligomerization. This response leads to the activation of the cytosolic endoribonuclease (RNAse) domain of IRE1 that is involved in the non-canonical splicing of the X-box binding protein 1 (XBP1) mRNA. IRE1- dependent XBP1 splicing produces an mRNA frameshift that leads to the translation of the active spliced XBP1 (or XBP1s) bZIP transcription factor. Upon activation, XBP1s transcriptionally regulates the expression of multiple stress-responsive genes involved in diverse biological functions including ER proteostasis maintenance and lipid homeostasis. 1 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0005] Apart from XBP1 splicing, the activated IRE1 endoribonuclease domain can also promote the degradation of ER-localized mRNAs through a process referred to as regulated IRE1-dependent decay (or RIDD). While the functional implications of this IRE1 activity remain to be fully established, recent results show that RIDD serves a protective role through the selective degradation of mRNA encoding the pro-apoptotic factors (e.g., DR5) and promotion of microautophagy through the degradation of BLOS1 mRNA. [0006] The role of IRE1/XBP1s in these biological processes implicates the importance of same as therapeutic targets. Thus, there is a need for compounds and compositions that activate IRE1/XBP1s. SUMMARY [0007] Provided herein are compounds and pharmaceutical compositions containing the compounds that activate IRE1/XBP1s. [0008] In some aspects, the present disclosure provides a compound of Formula A: Formula A, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R¹, R², R⁵, R⁶, R⁷, X¹, X², Ar¹, and T are as disclosed herein. [0009] In some embodiments, the present disclosure provides a compound of Formula A-I: , or a pharmaceutically acceptable salt thereof, wherein R¹, R², R⁵, R⁶, R⁷, X¹, X², Ar¹, and T are as disclosed herein. [0010] In some embodiments, the present disclosure provides a compound of Formula B: , or a pharmaceutically acceptable salt thereof, wherein T, X¹, X², and Ar¹ are as disclosed herein. 2 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0011] In some embodiments, the present disclosure provides a compound of Formula C: , or a pharmaceutically acceptable salt thereof, wherein T and Ar¹ are as disclosed herein. [0012] In some embodiments, the present disclosure provides a compound of Formula D: Formula D, or a pharmaceutically acceptable salt thereof, wherein R^T1 and Ar¹ are as disclosed herein. [0013] In some embodiments, the present disclosure provides a compound of Formula E: Formula E, or a pharmaceutically acceptable salt thereof, wherein ring A, R^Tc, R^T1, and Ar¹ are as disclosed herein. [0014] In some embodiments, the present disclosure provides a compound of Formula F: Formula F, or a pharmaceutically acceptable salt thereof, wherein R^T2 and Ar¹ are as disclosed herein. [0015] In some embodiments, the present disclosure provides a compound of Formula G: Formula G, or a pharmaceutically acceptable salt thereof, wherein n, m, R^Ta and Ar¹ are as disclosed herein. [0016] In some embodiments, the present disclosure provides a compound of Formula H: 3 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Formula H, or a pharmaceutically acceptable salt thereof, wherein n, ring A, R^Tc, and Ar¹ are as disclosed herein. [0017] In some embodiments, the present disclosure provides a compound selected from Tables 1-2, or a pharmaceutically acceptable salt thereof. [0018] In some embodiments, the present disclosure features pharmaceutical compositions comprising a compound described herein, and one or more pharmaceutically acceptable carriers or excipients. [0019] In some aspects, the present disclosure features methods of activating IRE1 and/or XBP1s with a compound or composition provided herein. In some embodiments, provided herein are methods of enhancing IRE1 signaling in an IRE1 expressing cell with a compound or composition provided herein. In some embodiments, provided herein are methods of treating diseases that may be treated by enhancing IRE1 signaling or by activating IRE1 and/or XBP1s. [0020] In some aspects, the present disclosure features a compound or composition provided herein, for activating IRE1 and/or XBP1s. In some embodiments, provided herein are a compound or composition provided herein for enhancing IRE1 signaling in an IRE1 expressing cell. In some embodiments, provided herein are a compound or composition provided herein for treating diseases that may be treated by enhancing IRE1 signaling or by activating IRE1 and/or XBP1s. [0021] In some aspects, the present disclosure features use of a compound provided herein in the manufacture of a medicament for activating IRE1 and/or XBP1s. In some embodiments, provided herein are use of a compound provided herein in the manufacture of a medicament for enhancing IRE1 signaling in an IRE1 expressing cell. In some embodiments, provided herein are use of a compound provided herein in the manufacture of a medicament for treating diseases that may be treated by enhancing IRE1 signaling or by activating IRE1 and/or XBP1s. [0022] In some embodiments, such diseases include cardiovascular diseases, neurodegenerative diseases, metabolic disorders, hepatic disorders, protein misfolding disorders and gastrointestinal disorders. [0023] 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 4 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 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. [0024] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION Definitions [0025] To facilitate understanding of the disclosure set forth herein, a number of terms are defined below. [0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. [0027] The singular forms "a," "an," and "the" include plural references, unless the context clearly dictates otherwise. [0028] As used herein, the term “subject” refers to a subject having a disease or having an increased risk of developing the disease. A “subject” includes a mammal. The mammal can be e.g., a human or appropriate non-human mammal, such as primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or a pig. The subject can also be a bird or fowl. In one embodiment, the mammal is a human. [0029] In some embodiments, the term “subject in need thereof” can be one who has been previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be one who is suffering from a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be one who has an increased risk of developing such disease or disorder relative to the population at large (i.e., a subject who is predisposed 5 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 to developing such disorder relative to the population at large). A subject in need thereof can have a refractory or resistant a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject in need thereof may be resistant at start of treatment or may become resistant during treatment. In some embodiments, the subject in need thereof received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, the subject in need thereof received at least one prior therapy. [0030] As used herein, the term “treating” or “treat” describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. The term “treat” can also include treatment of a cell in vitro or an animal model. [0031] It is to be understood that a compound provided herein can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes. [0032] As used herein, the term “preventing,” “prevent,” or “protecting against” describes reducing or eliminating the onset of the symptoms or complications of such disease, condition or disorder. [0033] As used herein, biological activity refers to the in vivo activities of a compound or physiological responses that result upon in vivo administration of a compound, composition or other mixture. Biological activity, thus, encompasses therapeutic effects and pharmacokinetic behavior of such compounds, compositions and mixtures. Biological activities can be observed in in vitro systems designed to test for such activities. [0034] As used herein, pharmaceutically acceptable derivatives of a compound include, but are not limited to, salts, esters, enol ethers, enol esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, clathrates, solvates or hydrates thereof. Such derivatives may be readily prepared by those of skill in this art using known methods for such derivatization. The compounds produced may be administered to animals or humans without substantial toxic effects and either are pharmaceutically active or are prodrugs. Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N- benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole, 6 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and inorganic salts, such as but not limited to, sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to formates, acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, mesylates, and fumarates. Pharmaceutically acceptable esters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, aralkyl, and cycloalkyl esters of acidic groups, including, but not limited to, carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids, sulfinic acids and boronic acids. Pharmaceutically acceptable enol ethers include, but are not limited to, derivatives of formula C=C(OR) wherein R is alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable enol esters include, but are not limited to, derivatives of formula C=C(OC(O)R) wherein R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl. Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules. [0035] As used herein, treatment means any manner in which one or more of the symptoms of a disease or disorder are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein, such as use for treating AL amyloidosis. [0036] As used herein, amelioration of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or pharmaceutical composition. [0037] As used herein, and unless otherwise indicated, the terms "manage," "managing" and "management" encompass preventing the recurrence of the specified disease or disorder in a subject who has already suffered from the disease or disorder, and/or lengthening the time that a subject who has suffered from the disease or disorder remains in remission. The terms encompass modulating the threshold, development and/or duration of the disease or disorder, or changing the way that a subject responds to the disease or disorder. [0038] Wherein moieties are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical moieties that would result from writing the structure from right to left, e.g., -CH₂O- is equivalent to -OCH₂-. 7 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0039] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain saturated hydrocarbon radical, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbons). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. [0040] The term "alkenyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain hydrocarbon radical having one or more carbon-carbon double bonds, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbons). Examples of alkenyl groups include, but are not limited to, vinyl (i.e., ethenyl), 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), and the higher homologs and isomers. [0041] The term "alkynyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds, which can include di- and multivalent radicals, having the number of carbon atoms designated (i.e., C₁-C₁₀ means one to ten carbons). Examples of alkynyl groups include, but are not limited to, ethynyl, 1- and 3-propynyl, 3- butynyl, and the higher homologs and isomers. [0042] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH₂CH₂CH₂CH₂-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, including those groups having 10 or fewer carbon atoms. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having six or fewer carbon atoms. [0043] The terms "alkoxy," "alkylamino," and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. [0044] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, consisting of a heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atom may have an alkyl substituent to fulfill valency and/or may optionally be quaternized. The heteroatom(s) O, N, P, Si and S may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH₂-CH₂-O-CH₃, -CH₂-CH₂-NH-CH₃, -CH₂-CH₂-N(CH₃)-CH₃, -CH₂-S-CH₂- 8 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 CH₃, -CH₂-CH₂-S(O)-CH₃, -CH₂-CH₂-S(O)₂-CH₃, -CH=CH-O-CH₃, -CH₂-CH=N-OCH₃, and -CH=CH-N(CH3)-CH3. Up to two heteroatoms may be consecutive, such as, for example, - CH2-NH-OCH3 and –CH2-O-Si(CH3)3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and –CH2-S-CH2-CH2-NH-CH2-. For alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula – C(O)2R'- represents both –C(O)2R'- and –R'C(O)2-. [0045] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro rings) system having 3 to 30 carbon atoms (e.g., C₃-C₁₂, C₃-C₁₀, or C₃-C₈). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl needs to be non- aromatic. [0046] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated 3-8 membered monocyclic, 6-12 membered bicyclic (fused, bridged, or spiro rings), or 11-14 membered tricyclic ring system (fused, bridged, or spiro rings) having one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, _{or e.g. ̧1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of} nitrogen, oxygen and sulphur, unless specified otherwise. Examples of heterocyclyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6- tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane- 1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3- azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4- c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H- pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2- azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl- 9 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa- azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of multicyclic heterocyclyl, only one of the rings in the heterocyclyl needs to be non-aromatic. [0047] The terms "halo," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C1- C₄)alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like. [0048] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (in some embodiments from 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups that contain from one to four heteroatoms selected from N, O, and S in the ring(s), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituent moieties for aryl and heteroaryl ring systems may be selected from the group of acceptable substituent moieties described herein. The term "heteroarylium" refers to a heteroaryl group that is positively charged on one or more of the heteroatoms. [0049] The term "oxo" as used herein means an oxygen atom that is double bonded to a carbon atom. [0050] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") are meant to include both substituted and unsubstituted forms of the indicated radical. Non- limiting examples of substituent moieties for each type of radical are provided below. [0051] Substituent moieties for alkyl, heteroalkyl, alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups are, in some embodiments, selected from, deuterium, -OR', =O, =NR', =N-OR', - NR'R", -SR', halo, -SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)₂R', -NR- 10 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)₂R', -S(O)₂NR'R", -NRSO₂R', - NRSO2NR'R'', -CN and –NO2 in a number ranging from zero to the number of hydrogen atoms in such radical. In some embodiments, substituent moieties for cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups also include substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl. R', R", R"' and R"" each in some embodiments independently are hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1- 3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" is meant to include, but not be limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituent moieties, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF₃ and –CH₂CF₃) and acyl (e.g., -C(O)CH₃, -C(O)CF₃, -C(O)CH₂OCH₃, and the like). [0052] Substituent moieties for aryl and heteroaryl groups are, in some embodiments, selected from deuterium, halo, substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, and substituted and unsubstituted alkynyl, -OR', -NR'R", -SR', - SiR'R"R"', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O)2R', -NR- C(NR'R"R'")=NR"", -NR-C(NR'R")=NR'", -S(O)R', -S(O)₂R', -S(O)₂NR'R", -NRSO₂R', -CN and –NO₂, -R', -N₃, -CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the total number of hydrogens on the aromatic ring system; and wherein R', R", R"' and R"" are, in some embodiments, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl. When a compound provided herein includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present. 11 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0053] Two of the substituent moieties on adjacent atoms of an aryl or heteroaryl ring may optionally form a ring of the formula -Q'-C(O)-(CRR')q-Q''-, wherein Q' and Q'' are independently –NR-, -O-, -CRR'- or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently –CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituent moieties on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula –(CRR')_s-X'-(CR''R''')_d-, wherein s and d are independently integers of from 0 to 3, and X' is –O-, -NR'-, -S-, -S(O)-, -S(O)₂-, or –S(O)₂NR'-. The substituent moieties R, R', R" and R'" are, in some embodiments, independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. [0054] As used herein, the term "heteroatom" or "ring heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0055] As used herein, a prodrug is a compound that upon in vivo administration is metabolized, or otherwise undergoes chemical changes under physiological conditions, by one or more steps or processes or otherwise converted to a biologically, pharmaceutically or therapeutically active form of the compound. Additionally, prodrugs can be converted to a biologically, pharmaceutically or therapeutically active form of the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. [0056] Certain compounds provided herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds provided herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present disclosure. [0057] Certain compounds provided herein possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers and individual isomers are encompassed within the scope of the present disclosure. The 12 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 compounds provided herein do not include those which are known in the art to be too unstable to synthesize and/or isolate. [0058] The compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of the compounds provided herein, whether radioactive or not, are encompassed within the scope of the present disclosure. [0059] As used herein, the term “pharmaceutically acceptable” refers to those compounds, anions, cations, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. [0060] As used herein, the term “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non- toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient. [0061] As used herein, the term “therapeutically effective amount”, refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician. [0062] It is understood that, for the compounds of the present disclosure being capable of further forming salts, all of these forms are also contemplated within the scope of the claimed disclosure. [0063] As used herein, the term “pharmaceutically acceptable salts” refer to derivatives of the compounds of the present disclosure wherein the parent compound is modified by making acid or base salts thereof. In some embodiments, the pharmaceutically acceptable salt of a compound is also a prodrug of the compound. Examples of pharmaceutically acceptable salts 13 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2- hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, subacetic, succinic, sulfamic, sulfanilic, sulfuric, tannic, tartaric, toluene sulfonic, and the commonly occurring amine acids, e.g., glycine, alanine, phenylalanine, arginine, etc. [0064] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentane propionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3- phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. In the salt form, it is understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ration other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3. [0065] It is understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same salt. [0066] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will recognize the advantages of certain routes of administration. 14 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0067] The dosage regimen utilizing the compounds is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition. [0068] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19^th edition, Mack Publishing Co., Easton, PA (1995). In an embodiment, the compounds described herein, and the pharmaceutically acceptable salts thereof, are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. [0069] All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. [0070] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute any admission as to the contents or date of the same. The invention having now been described by way of written description, those of skill in the art will recognize that the invention can be practiced in a variety of embodiments and that the foregoing description and examples below are for purposes of illustration and not limitation of the claims that follow. Compounds of the Present Disclosure Compounds of Formula A [0071] In some aspects, the present disclosure provides a compound of Formula A: 15 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Formula A, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R¹ is H or alkyl and R² is H; or R¹ and R² together form (CH2)x wherein x is 1, 2, or 3; R⁵ is H and R⁶ is haloalkyl; or R⁵ and R⁶ together form oxo; R⁷ is H or alkyl, wherein the alkyl is optionally substituted with one or more -OH or - O(C1-C6 alkyl); X² is CR^s or N; R^s is H or halogen; X¹ is O or NR⁸, wherein R⁸ is H or alkyl; Ar¹ is optionally substituted aryl or optionally substituted heteroaryl; T is -NHR^T1, -N(R^T1)₂, or -N(R^T2)₂; each R^T1 independently is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R^Ta; two R^T2, together with the atom to which they are attached, form heterocyclyl optionally substituted with one or more R^Ta; each R^Ta independently is oxo, halogen, cyano, -OH, -OR^a, -SR^a, -NH₂, -NHR^a, - N(R^a)₂, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, -NH-S(=O)₂-R^a, -N(C₁-C₆ alkyl)-C(=O)-R^a, - N(C1-C6 alkyl)-C(=O)-O-R^a, -N(C1-C6 alkyl)-S(=O)2-R^a, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; each R^a independently is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; each R^Tb independently is oxo, halogen, cyano, -OH, -OR^b, -SR^b, -NH2, -NHR^b, - N(R^b)2, -NH-C(=O)-R^b, -NH-C(=O)-O-R^b, -NH-S(=O)2-R^b, -N(C1-C6 alkyl)-C(=O)-R^a, - 16 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 N(C₁-C₆ alkyl)-C(=O)-O-R^a, -N(C₁-C₆ alkyl)-S(=O)₂-R^a, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, or , wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10- membered heteroaryl, or is optionally substituted with one or more R^Tc; each R^b independently is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and each R^Tc independently is oxo, halogen, cyano, -OH, -O(C₁-C₆ alkyl), -O(C₁-C₆ haloalkyl), -S(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-C(=O)-(C1-C6 alkyl), -NH-C(=O)-O-(C1-C6 alkyl), -NH-S(=O)2-(C1-C6 alkyl), -N(C1-C6 alkyl)-C(=O)-(C1- C₆ alkyl), -N(C₁-C₆ alkyl)-C(=O)-O-(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)-S(=O)₂-(C₁-C₆ alkyl), C₁- C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl. Compounds of Formula A-I [0072] In some embodiments, the present disclosure provides a compound of Formula A-I: , or a pharmaceutically acceptable salt thereof, wherein R¹ is H or C1-C6 alkyl and R² is H; or R¹ and R² together form (CH2)x wherein x is 1, 2, or 3; R⁵ is H and R⁶ is C₁-C₆ haloalkyl; or R⁵ and R⁶ together form oxo; 17 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 R⁷ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more -OH or -O(C1-C6 alkyl); X² is CR^s or N; R^s is H or halogen; X¹ is O or NR⁸, wherein R⁸ is H or C1-C6 alkyl; Ar¹ is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R^t; each R^t independently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 haloalkoxy; T is -NHR^T1, -N(R^T1)₂, or -N(R^T2)₂; each R^T1 independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ 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-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Ta; two R^T2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more R^Ta; each R^Ta independently is oxo, halogen, cyano, -OH, -OR^a, -SR^a, -NH₂, -NHR^a, - N(R^a)2, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, -NH-S(=O)2-R^a, -N(C1-C6 alkyl)-C(=O)-R^a, - N(C₁-C₆ alkyl)-C(=O)-O-R^a, -N(C₁-C₆ alkyl)-S(=O)₂-R^a, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; each R^a independently is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; each R^Tb independently is oxo, halogen, cyano, -OH, -OR^b, -SR^b, -NH2, -NHR^b, - N(R^b)₂, -NH-C(=O)-R^b, -NH-C(=O)-O-R^b, -NH-S(=O)₂-R^b, -N(C₁-C₆ alkyl)-C(=O)-R^b, - N(C1-C6 alkyl)-C(=O)-O-R^b, -N(C1-C6 alkyl)-S(=O)2-R^b, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ 18 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; each R^b independently is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and each R^Tc independently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -O(C1-C6 haloalkyl), -S(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -NH-C(=O)-(C1-C6 alkyl), -NH-C(=O)-O-(C₁-C₆ alkyl), -NH-S(=O)₂-(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)-C(=O)-(C₁- C₆ alkyl), -N(C₁-C₆ alkyl)-C(=O)-O-(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)-S(=O)₂-(C₁-C₆ alkyl), C₁- C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl. [0073] It is understood that, for a compound of the present disclosure, variables R¹, R², x, R⁵, R⁶, R⁷, R⁸, X¹, X², R^s, Ar¹, R^t, T, R^T1, R^T2, R^Ta, R^Tb, R^Tc, R^a, R^b, and R^c can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables R¹, R², x, R⁵, R⁶, R⁷, R⁸, X¹, X², R^s, Ar¹, R^t, T, R^T1, R^T2, R^Ta, R^Tb, R^Tc, R^a, R^b, and R^c can be combined, where applicable, with any group described herein for one or more of the remainder of variables R¹, R², x, R⁵, R⁶, R⁷, R⁸, X¹, X², R^s, Ar¹, R^t, T, R^T1, R^T2, R^Ta, R^Tb, R^Tc, R^a, R^b, and R^c. Compounds of Formula B, Formula B-a, Formula B-b, Formula B-c, or Formula B-d [0074] In some embodiments, the present disclosure provides a compound of Formula B, Formula B-a, Formula B-b, Formula B-c, or Formula B-d: 19 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 o u a - , or a pharmaceutically acceptable salt thereof, wherein T, X¹, X², and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. Compounds of Formula C, Formula C-a, Formula C-b, Formula C-c, or Formula C-d [0075] In some embodiments, the present disclosure provides a compound of Formula C, Formula C-a, Formula C-b, Formula C-c, or Formula C-d: or a pharmaceutically acceptable salt thereof, wherein T and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. 20 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Compounds of Formula D, Formula D-a, Formula D-b, Formula D-c, or Formula D-d [0076] In some embodiments, the present disclosure provides a compound of Formula D, Formula D-a, Formula D-b, Formula D-c, or Formula D-d: ormu a - , or a pharmaceutically acceptable salt thereof, wherein R^T1 and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. Compounds of Formula E, Formula E-a, Formula E-b, Formula E-c, or Formula E-d [0077] In some embodiments, the present disclosure provides a compound of Formula E, Formula E-a, Formula E-b, Formula E-c, or Formula E-d: , 21 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 or a pharmaceutically acceptable salt thereof, wherein ring A is C3-C10 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; and R^Tc, R^T1, and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. [0078] In some embodiments, the compound has the structure of Formula E: Formula E, or a pharmaceutically acceptable salt thereof, wherein ring A is C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; and R^Tc, R^T1, and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. [0079] In some embodiments, the compound has the structure of Formula E-a, Formula E- b, Formula E-c, or Formula E-d: - , 22 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 - , or a pharmaceutically acceptable salt thereof, wherein ring A is C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; and R^Tc, R^T1, and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. Compounds of Formula F, Formula F-a, Formula F-b, Formula F-c, or Formula F-d [0080] In some embodiments, the present disclosure provides a compound of Formula F, Formula F-a, Formula F-b, Formula F-c, or Formula F-d: 23 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Formula F-d, or a pharmaceutically acceptable salt thereof, wherein R^T2 and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. Compounds of Formula G, Formula G-a, Formula G-b, Formula G-c, or Formula G-d [0081] In some embodiments, the present disclosure provides a compound of Formula G, Formula G-a, Formula G-b, Formula G-c, or Formula G-d: o u a -d, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3; m is 1, 2, or 3; and R^Ta and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. 24 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Compounds of Formula H, Formula H-a, Formula H-b, Formula H-c, or Formula H-d [0082] In some embodiments, the present disclosure provides a compound of Formula H, Formula H-a, Formula H-b, Formula H-c, or Formula H-d: , or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3; ring A is C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; and R^Tc and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. [0083] In some embodiments, the compound has the structure of Formula H: Formula H, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3; ring A is C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; and R^Tc and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. 25 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0084] In some embodiments, the compound has the structure of Formula H-a, Formula H- b, Formula H-c, or Formula H-d: - , or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3; ring A is C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl; and R^Tc and Ar¹ are each as defined in Formula A-I, or as described herein in any combination. Variables R¹, R², x, R⁵, R⁶, and R⁷ [0085] In some embodiments, R¹ is H or C1-C6 alkyl. [0086] In some embodiments, R¹ is H. [0087] In some embodiments, R¹ is C₁-C₆ alkyl. [0088] In some embodiments, R¹ is C1 alkyl. [0089] In some embodiments, R¹ is C2 alkyl. [0090] In some embodiments, R¹ is C₃ alkyl. [0091] In some embodiments, R¹ is C4 alkyl. [0092] In some embodiments, R¹ is C5 alkyl. [0093] In some embodiments, R¹ is C₆ alkyl. [0094] In some embodiments, R² is H. [0095] In some embodiments, R¹ and R² together form (CH2)x wherein x is 1, 2, or 3. [0096] In some embodiments, R¹ and R² together form (CH₂). 26 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0097] In some embodiments, R¹ and R² together form (CH₂)₂. [0098] In some embodiments, R¹ and R² together form (CH2)3. [0099] In some embodiments, R⁵ is H. [0100] In some embodiments, R⁶ is C₁-C₆ haloalkyl. [0101] In some embodiments, R⁶ is C1 haloalkyl. [0102] In some embodiments, R⁶ is C2 haloalkyl. [0103] In some embodiments, R⁶ is C₃ haloalkyl. [0104] In some embodiments, R⁶ is C4 haloalkyl. [0105] In some embodiments, R⁶ is C5 haloalkyl. [0106] In some embodiments, R⁶ is C₆ haloalkyl. [0107] In some embodiments, R⁵ and R⁶ together form oxo. [0108] In some embodiments, R⁷ is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more -OH or -O(C1-C6 alkyl). [0109] In some embodiments, R⁷ is H. [0110] In some embodiments, R⁷ is C1-C6 alkyl optionally substituted with one or more - OH or -O(C1-C6 alkyl). [0111] In some embodiments, R⁷ is C₁-C₆ alkyl (e.g., C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl). [0112] In some embodiments, R⁷ is C1-C6 alkyl (e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C₅ alkyl, and C₆ alkyl) substituted with one or more -OH. [0113] In some embodiments, R⁷ is C₁-C₆ alkyl (e.g., C₁ alkyl, C₂ alkyl, C₃ alkyl, C₄ alkyl, C5 alkyl, and C6 alkyl) substituted with one or more -O(C1-C6 alkyl) (e.g., -O(C1 alkyl), - O(C2 alkyl), -O(C3 alkyl), -O(C4 alkyl), -O(C5 alkyl), and -O(C6 alkyl)). [0114] In some embodiments, R⁷ is methyl. [0115] In some embodiments, R⁷ is -CH₂-OH. [0116] In some embodiments, R⁷ is -CH2-O-CH3. Variables X¹, X², R^s, and R⁸ [0117] In some embodiments, X² is CR^s or N. [0118] In some embodiments, X² is CR^s. [0119] In some embodiments, X² is N. [0120] In some embodiments, R^s is H or halogen. [0121] In some embodiments, R^s is H. [0122] In some embodiments, R^s is halogen. 27 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0123] In some embodiments, R^s is -F. [0124] In some embodiments, R^s is -Cl. [0125] In some embodiments, R^s is -Br. [0126] In some embodiments, R^s is -I. [0127] In some embodiments, X² is CF. [0128] In some embodiments, X¹ is O or NR⁸. [0129] In some embodiments, X¹ is O. [0130] In some embodiments, X¹ is NR⁸. [0131] In some embodiments, R⁸ is H or C1-C6 alkyl. [0132] In some embodiments, R⁸ is H. [0133] In some embodiments, R⁸ is C₁-C₆ alkyl. [0134] In some embodiments, R⁸ is C1 alkyl. [0135] In some embodiments, R⁸ is C2 alkyl. [0136] In some embodiments, R⁸ is C₃ alkyl. [0137] In some embodiments, R⁸ is C4 alkyl. [0138] In some embodiments, R⁸ is C5 alkyl. [0139] In some embodiments, R⁸ is C₆ alkyl. [0140] In some embodiments, X¹ is N(CH₃). Variables Ar¹, R^t, and T [0141] In some embodiments, Ar¹ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R^t. [0142] In some embodiments, Ar¹ is C6-C10 aryl or 5- to 10-membered heteroaryl. [0143] In some embodiments, Ar¹ is C₆-C₁₀ aryl or 5- to 10-membered heteroaryl, wherein the C₆-C₁₀ aryl or 5- to 10-membered heteroaryl is substituted with one or more R^t. [0144] In some embodiments, Ar¹ is substituted with 1 or 2 R^t. [0145] In some embodiments, Ar¹ is C₆-C₁₀ aryl, wherein the C₆-C₁₀ aryl is optionally substituted with one or more R^t. [0146] In some embodiments, Ar¹ is C6-C10 aryl. [0147] In some embodiments, Ar¹ is C6-C10 aryl, wherein the C6-C10 aryl is substituted with one or more R^t. [0148] In some embodiments, Ar¹ is phenyl. [0149] In some embodiments, Ar¹ is 5- to 10-membered heteroaryl, wherein the 5- to 10- membered heteroaryl is optionally substituted with one or more R^t. 28 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0150] In some embodiments, Ar¹ is 5- to 10-membered heteroaryl. [0151] In some embodiments, Ar¹ is 5- to 10-membered heteroaryl, wherein the 5- to 10- membered heteroaryl is substituted with one or more R^t. [0152] In some embodiments, Ar¹ is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0153] In some embodiments, Ar¹ is 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 R^t. [0154] In some embodiments, Ar¹ is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0155] In some embodiments, Ar¹ is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^t. [0156] In some embodiments, Ar¹ is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). [0157] In some embodiments, Ar¹ is 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 R^t. [0158] In some embodiments, Ar¹ is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl). [0159] In some embodiments, Ar¹ is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl), wherein the heteroaryl is substituted with one or more R^t. [0160] In some embodiments, Ar¹ is isoxazolyl. [0161] In some embodiments, . [0162] In some embodiments, . [0163] In some embodiments, . 29 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0164] In some embodiments, Ar¹ is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl). [0165] In some embodiments, Ar¹ is 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 R^t. [0166] In some embodiments, Ar¹ is triazolyl. [0167] In some embodiments, . [0168] In some embodiments, . [0169] In some embodiments, . [0170] In some embodiments, . [0171] In some embodiments, . [0172] In some embodiments, Ar¹ is thiadiazolyl. [0173] In some embodiments, . [0174] In some embodiments, . [0175] In some embodiments, . [0176] In some embodiments, Ar¹ is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0177] In some embodiments, Ar¹ is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^t. [0178] In some embodiments, Ar¹ is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl). 30 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0179] In some embodiments, Ar¹ is 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 R^t. [0180] In some embodiments, Ar¹ is pyridinyl. [0181] In some embodiments, . [0182] In some embodiments, . [0183] In some embodiments, . [0184] In some embodiments, Ar¹ is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl). [0185] In some embodiments, Ar¹ is 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 R^t. [0186] In some embodiments, Ar¹ is pyrimidinyl. [0187] In some embodiments, . [0188] In some embodiments, . [0189] In some embodiments, . [0190] In some embodiments, Ar¹ is pyridazinyl. [0191] In some embodiments, . [0192] In some embodiments, . [0193] 31 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0194] In some embodiments, . [0195] In some embodiments, at least one R^t is oxo, halogen, cyano, -OH, -O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -NO₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or C₁-C₆ haloalkoxy. [0196] In some embodiments, at least one R^t is independently halogen, -O(C1-C6 alkyl), - NH₂, -NH(C₁-C₆ alkyl), -NO₂, or C₁-C₆ alkyl. [0197] In some embodiments, at least one R^t is halogen, -NH2, methyl or -OCH3. [0198] In some embodiments, at least one R^t is oxo. [0199] In some embodiments, at least one R^t is halogen. [0200] In some embodiments, at least one R^t is -F. [0201] In some embodiments, at least one R^t is -Cl. [0202] In some embodiments, at least one R^t is -Br. [0203] In some embodiments, at least one R^t is -I. [0204] In some embodiments, at least one R^t is cyano. [0205] In some embodiments, at least one R^t is -OH. [0206] In some embodiments, at least one R^t is -O(C₁-C₆ alkyl). [0207] In some embodiments, at least one R^t is -O(C1 alkyl). [0208] In some embodiments, at least one R^t is -O(C2 alkyl). [0209] In some embodiments, at least one R^t is -O(C₃ alkyl). [0210] In some embodiments, at least one R^t is -O(C4 alkyl). [0211] In some embodiments, at least one R^t is -O(C5 alkyl). [0212] In some embodiments, at least one R^t is -O(C₆ alkyl). [0213] In some embodiments, at least one R^t is -NH₂. [0214] In some embodiments, at least one R^t is -NH(C1-C6 alkyl). [0215] In some embodiments, at least one R^t is -NH(C1 alkyl). [0216] In some embodiments, at least one R^t is -NH(C₂ alkyl). [0217] In some embodiments, at least one R^t is -NH(C3 alkyl). [0218] In some embodiments, at least one R^t is -NH(C4 alkyl). [0219] In some embodiments, at least one R^t is -NH(C₅ alkyl). [0220] In some embodiments, at least one R^t is -NH(C₆ alkyl). [0221] In some embodiments, at least one R^t is -N(C1-C6 alkyl)2. [0222] In some embodiments, at least one R^t is -N(C₁ alkyl)₂. 32 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0223] In some embodiments, at least one R^t is -N(C₂ alkyl)₂. [0224] In some embodiments, at least one R^t is -N(C3 alkyl)2. [0225] In some embodiments, at least one R^t is -N(C4 alkyl)2. [0226] In some embodiments, at least one R^t is -N(C₅ alkyl)₂. [0227] In some embodiments, at least one R^t is -N(C6 alkyl)2. [0228] In some embodiments, at least one R^t is -NO2. [0229] In some embodiments, at least one R^t is C₁-C₆ alkyl. [0230] In some embodiments, at least one R^t is C1 alkyl. [0231] In some embodiments, at least one R^t is C2 alkyl. [0232] In some embodiments, at least one R^t is C₃ alkyl. [0233] In some embodiments, at least one R^t is C₄ alkyl. [0234] In some embodiments, at least one R^t is C5 alkyl. [0235] In some embodiments, at least one R^t is C6 alkyl. [0236] In some embodiments, at least one R^t is C₁-C₆ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0237] In some embodiments, at least one R^t is C1 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0238] In some embodiments, at least one R^t is C₂ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0239] In some embodiments, at least one R^t is C₃ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0240] In some embodiments, at least one R^t is C4 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0241] In some embodiments, at least one R^t is C₅ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0242] In some embodiments, at least one R^t is C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0243] In some embodiments, at least one R^t is C₁-C₆ haloalkoxy (e.g., fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy). [0244] In some embodiments, at least one R^t is C1 haloalkoxy (e.g., fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy). [0245] In some embodiments, at least one R^t is C2 haloalkoxy (e.g., fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy). 33 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0246] In some embodiments, at least one R^t is C₃ haloalkoxy (e.g., fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy). [0247] In some embodiments, at least one R^t is C4 haloalkoxy (e.g., fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy). [0248] In some embodiments, at least one R^t is C5 haloalkoxy (e.g., fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy). [0249] In some embodiments, at least one R^t is C₆ haloalkoxy (e.g., fluoroalkoxy, chloroalkoxy, bromoalkoxy, and iodoalkoxy). [0250] In some embodiments, T is -NHR^T1, -N(R^T1)2, or -N(R^T2)2. [0251] In some embodiments, T is -NHR^T1. [0252] In some embodiments, T is -N(R^T1)₂. [0253] In some embodiments, T is -N(R^T2)2. Variables R^T1 and R^T2 [0254] In some embodiments, at least one R^T1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 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-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Ta. [0255] In some embodiments, at least one R^T1 is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl. [0256] In some embodiments, at least one R^T1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C₃-C₁₀ 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-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10-membered heteroaryl is substituted with one or more R^Ta. [0257] In some embodiments, at least one R^T1 is C₁-C₆ alkyl or C₃-C₁₀ cycloalkyl, wherein the C1-C6 alkyl or C3-C10 cycloalkyl is optionally substituted with one or more R^Ta, and the other R^T1 is C1-C6 alkyl substituted with one or more R^Ta. [0258] In some embodiments, at least one R^T1 is C₁-C₆ alkyl. [0259] In some embodiments, at least one R^T1 is C1-C6 alkyl substituted with one or more R^Ta. [0260] In some embodiments, at least one R^T1 is C₁ alkyl. 34 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0261] In some embodiments, at least one R^T1 is C₂ alkyl. [0262] In some embodiments, at least one R^T1 is C3 alkyl. [0263] In some embodiments, at least one R^T1 is C4 alkyl. [0264] In some embodiments, at least one R^T1 is C₅ alkyl. [0265] In some embodiments, at least one R^T1 is C6 alkyl. [0266] In some embodiments, at least one R^T1 is C2-C6 alkenyl. [0267] In some embodiments, at least one R^T1 is C₂-C₆ alkenyl substituted with one or more R^Ta. [0268] In some embodiments, at least one R^T1 is C2 alkenyl. [0269] In some embodiments, at least one R^T1 is C₃ alkenyl. [0270] In some embodiments, at least one R^T1 is C₄ alkenyl. [0271] In some embodiments, at least one R^T1 is C5 alkenyl. [0272] In some embodiments, at least one R^T1 is C6 alkenyl. [0273] In some embodiments, at least one R^T1 is C₂-C₆ alkynyl. [0274] In some embodiments, at least one R^T1 is C2-C6 alkynyl substituted with one or more R^Ta. [0275] In some embodiments, at least one R^T1 is C₂ alkynyl. [0276] In some embodiments, at least one R^T1 is C₃ alkynyl. [0277] In some embodiments, at least one R^T1 is C4 alkynyl. [0278] In some embodiments, at least one R^T1 is C₅ alkynyl. [0279] In some embodiments, at least one R^T1 is C₆ alkynyl. [0280] In some embodiments, at least one R^T1 is C3-C10 cycloalkyl. [0281] In some embodiments, at least one R^T1 is C3-C10 cycloalkyl substituted with one or more R^Ta. [0282] In some embodiments, at least one R^T1 is C₃-C₁₀ monocyclic cycloalkyl. [0283] In some embodiments, at least one R^T1 is C3-C10 monocyclic cycloalkyl substituted with one or more R^Ta. [0284] In some embodiments, at least one R^T1 is C₃ monocyclic cycloalkyl. [0285] In some embodiments, at least one R^T1 is C3 monocyclic cycloalkyl substituted with one or more R^Ta. [0286] In some embodiments, at least one R^T1 is C₄ monocyclic cycloalkyl. [0287] In some embodiments, at least one R^T1 is C4 monocyclic cycloalkyl substituted with one or more R^Ta. [0288] In some embodiments, at least one R^T1 is C₅ monocyclic cycloalkyl. 35 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0289] In some embodiments, at least one R^T1 is C₅ monocyclic cycloalkyl substituted with one or more R^Ta. [0290] In some embodiments, at least one R^T1 is C6 monocyclic cycloalkyl. [0291] In some embodiments, at least one R^T1 is C₆ monocyclic cycloalkyl substituted with one or more R^Ta. [0292] In some embodiments, at least one R^T1 is C7 monocyclic cycloalkyl. [0293] In some embodiments, at least one R^T1 is C₇ monocyclic cycloalkyl substituted with one or more R^Ta. [0294] In some embodiments, at least one R^T1 is C8 monocyclic cycloalkyl. [0295] In some embodiments, at least one R^T1 is C₈ monocyclic cycloalkyl substituted with one or more R^Ta. [0296] In some embodiments, at least one R^T1 is C9 monocyclic cycloalkyl. [0297] In some embodiments, at least one R^T1 is C9 monocyclic cycloalkyl substituted with one or more R^Ta. [0298] In some embodiments, at least one R^T1 is C10 monocyclic cycloalkyl. [0299] In some embodiments, at least one R^T1 is C10 monocyclic cycloalkyl substituted with one or more R^Ta. [0300] In some embodiments, at least one R^T1 is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0301] In some embodiments, at least one R^T1 is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0302] In some embodiments, at least one R^T1 is C4 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0303] In some embodiments, at least one R^T1 is C₄ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0304] In some embodiments, at least one R^T1 is C5 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0305] In some embodiments, at least one R^T1 is C₅ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0306] In some embodiments, at least one R^T1 is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0307] In some embodiments, at least one R^T1 is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. 36 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0308] In some embodiments, at least one R^T1 is C₇ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0309] In some embodiments, at least one R^T1 is C7 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0310] In some embodiments, at least one R^T1 is C8 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0311] In some embodiments, at least one R^T1 is C₈ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0312] In some embodiments, at least one R^T1 is C9 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0313] In some embodiments, at least one R^T1 is C₉ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0314] In some embodiments, at least one R^T1 is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0315] In some embodiments, at least one R^T1 is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0316] In some embodiments, at least one R^T1 is C₄-C₁₀ fused bicyclic cycloalkyl. [0317] In some embodiments, at least one R^T1 is C₄-C₁₀ fused bicyclic cycloalkyl substituted with one or more R^Ta. [0318] In some embodiments, at least one R^T1 . [0319] In some embodiments, at least one R^T1 substituted with one or more R^Ta. [0320] As used herein, when a ring is presented with a bond that is not fixed at a ring atom, _{such as in} _{, the bond can be formed at any available ring atom not limited to the} particular ring which the line is drawn unless expressly stated. For example, can be , or other structures formed by placing the floating bond on the cyclopentane ring or the benzene ring. [0321] In some embodiments, at least one R^T1 is C5-C10 bridged bicyclic cycloalkyl. 37 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0322] In some embodiments, at least one R^T1 is C₅-C₁₀ bridged bicyclic cycloalkyl substituted with one or more R^Ta. [0323] In some embodiments, at least one R^T1 . [0324] In some embodiments, at least one R^T1 substituted with one or more R^Ta. [0325] In some embodiments, at least one R^T1 is C5-C10 spiro bicyclic cycloalkyl. [0326] In some embodiments, at least one R^T1 is C₅-C₁₀ spiro bicyclic cycloalkyl substituted with one or more R^Ta. [0327] In some embodiments, at least one R^T1 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. [0328] In some embodiments, at least one R^T1 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, substituted with one or more R^Ta. [0329] In some embodiments, at least one R^T1 is . [0330] In some embodiments, at least one R^T1 is substituted with one or more R^Ta. [0331] In some embodiments, at least one R^T1 is . [0332] In some embodiments, at least one R^T1 is substituted with one or more R^Ta. [0333] In some embodiments, at least one R^T1 is 4- to 10-membered heterocyclyl. [0334] In some embodiments, at least one R^T1 is 4- to 10-membered heterocyclyl substituted with one or more R^Ta. [0335] In some embodiments, at least one R^T1 is 4-membered monocyclic heterocyclyl. [0336] In some embodiments, at least one R^T1 is 4-membered monocyclic heterocyclyl substituted with one or more R^Ta. 38 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0337] In some embodiments, at least one R^T1 is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0338] In some embodiments, at least one R^T1 is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0339] In some embodiments, at least one R^T1 is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0340] In some embodiments, at least one R^T1 is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0341] In some embodiments, at least one R^T1 is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0342] In some embodiments, at least one R^T1 is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0343] In some embodiments, at least one R^T1 is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0344] In some embodiments, at least one R^T1 is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0345] In some embodiments, at least one R^T1 is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0346] In some embodiments, at least one R^T1 is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0347] In some embodiments, at least one R^T1 is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0348] In some embodiments, at least one R^T1 is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Ta. [0349] In some embodiments, at least one R^T1 is 4- to 10-membered fused bicyclic heterocyclyl. [0350] In some embodiments, at least one R^T1 is 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more R^Ta. [0351] In some embodiments, at least one R^T1 is 5- to 10-membered bridged bicyclic heterocyclyl. [0352] In some embodiments, at least one R^T1 is 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more R^Ta. [0353] In some embodiments, at least one R^T1 is 5- to 10-membered spiro bicyclic heterocyclyl. 39 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0354] In some embodiments, at least one R^T1 is 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more R^Ta. [0355] In some embodiments, at least one R^T1 is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S. [0356] In some embodiments, at least one R^T1 is 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 R^Ta. [0357] In some embodiments, at least one R^T1 is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S. [0358] In some embodiments, at least one R^T1 is 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 R^Ta. [0359] In some embodiments, at least one R^T1 is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). [0360] In some embodiments, at least one R^T1 is 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 R^Ta. [0361] In some embodiments, at least one R^T1 is 4- to 10-membered fused bicyclic heterocyclyl containing one N. [0362] In some embodiments, at least one R^T1 is 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 R^Ta. [0363] In some embodiments, at least one R^T1 is 5- to 10-membered bridged bicyclic heterocyclyl containing one N. [0364] In some embodiments, at least one R^T1 is 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more R^Ta. [0365] In some embodiments, at least one R^T1 is 5- to 10-membered spiro bicyclic heterocyclyl containing one N. [0366] In some embodiments, at least one R^T1 is 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more R^Ta. [0367] In some embodiments, at least one R^T1 is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl). 40 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0368] In some embodiments, at least one R^T1 is 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 R^Ta. [0369] In some embodiments, at least one R^T1 is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O. [0370] In some embodiments, at least one R^T1 is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O, wherein the 5- to 10-membered bridged heterocyclyl is substituted with one or more R^Ta. [0371] In some embodiments, at least one R^T1 is 4- to 10-membered monocyclic heterocyclyl containing one S. [0372] In some embodiments, at least one R^T1 is 4- to 10-membered monocyclic heterocyclyl containing one S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more R^Ta. [0373] In some embodiments, at least one R^T1 is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S. [0374] In some embodiments, at least one R^T1 is 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 R^Ta. [0375] In some embodiments, at least one R^T1 is . [0376] In some embodiments, at least one R^T1 is substituted with one or more R^Ta. [0377] In some embodiments, at least one R^T1 is . [0378] In some embodiments, at least one R^T1 is substituted with one or more R^Ta. [0379] In some embodiments, at least one R^T1 is . [0380] In some embodiments, at least one R^T1 is substituted with one or more R^Ta. 41 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0381] In some embodiments, at least one R^T1 is . [0382] In some embodiments, at least one R^T1 is substituted with one or more R^Ta. [0383] In some embodiments, at least one R^T1 is C6-C10 aryl (e.g., phenyl or naphthalenyl). [0384] In some embodiments, at least one R^T1 is C₆-C₁₀ aryl (e.g., phenyl or naphthalenyl) substituted with one or more R^Ta. [0385] In some embodiments, at least one R^T1 is phenyl. [0386] In some embodiments, at least one R^T1 is phenyl substituted with one or more R^Ta. [0387] In some embodiments, at least one R^T1 is naphthalenyl. [0388] In some embodiments, at least one R^T1 is naphthalenyl substituted with one or more R^Ta. [0389] In some embodiments, at least one R^T1 is 5- to 10-membered heteroaryl. [0390] In some embodiments, at least one R^T1 is 5- to 10-membered heteroaryl substituted with one or more R^Ta. [0391] In some embodiments, at least one R^T1 is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0392] In some embodiments, at least one R^T1 is 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 R^Ta. [0393] In some embodiments, at least one R^T1 is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0394] In some embodiments, at least one R^T1 is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Ta. [0395] In some embodiments, at least one R^T1 is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). [0396] In some embodiments, at least one R^T1 is 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 R^Ta. [0397] In some embodiments, at least one R^T1 is pyrrolyl. [0398] In some embodiments, at least one R^T1 is pyrrolyl substituted with one or more R^Ta. 42 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0399] In some embodiments, at least one R^T1 is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl). [0400] In some embodiments, at least one R^T1 is 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 R^Ta. [0401] In some embodiments, at least one R^T1 is oxazolyl. [0402] In some embodiments, at least one R^T1 . [0403] In some embodiments, at least one R^T1 [0404] In some embodiments, at least one R^T1 . [0405] In some embodiments, at least one R^T1 . [0406] In some embodiments, at least one R^T1 . [0407] In some embodiments, at least one R^T1 is pyrazolyl. [0408] In some embodiments, at least one R^T1 . [0409] In some embodiments, at least one R^T1 is . [0410] In some embodiments, at least one R^T1 is isoxazolyl. [0411] In some embodiments, at least one R^T1 is isothiazolyl. [0412] In some embodiments, at least one R^T1 is imidazolyl. [0413] In some embodiments, at least one R^T1 is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl). [0414] In some embodiments, at least one R^T1 is 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 R^Ta. [0415] In some embodiments, at least one R^T1 is triazolyl. 43 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0416] In some embodiments, at least one R^T1 is . [0417] In some embodiments, at least one R is . [0418] In some embodiments, at least one R^T1 is . [0419] In some embodiments, at least one R^T1 is oxadiazolyl. [0420] In some embodiments, at least one R^T1 is . [0421] In some embodiments, at least one R^T1 is thiadiazolyl. [0422] In some embodiments, at least one R^T1 . [0423] In some embodiments, at least one R^T1 is . [0424] In some embodiments, at least one R^T1 is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl). [0425] In some embodiments, at least one R^T1 is 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 R^Ta. [0426] In some embodiments, at least one R^T1 is tetrazolyl. [0427] In some embodiments, at least one R^T1 . [0428] In some embodiments, at least one R^T1 is oxatriazolyl. [0429] In some embodiments, at least one R^T1 is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0430] In some embodiments, at least one R^T1 is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Ta. [0431] In some embodiments, at least one R^T1 is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl). 44 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0432] In some embodiments, at least one R^T1 is 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 R^Ta. [0433] In some embodiments, at least one R^T1 is pyridinyl. [0434] In some embodiments, at least one R^T1 . [0435] In some embodiments, at least one R^T1 is . [0436] In some embodiments, at least one . [0437] In some embodiments, at least one R^T1 is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl). [0438] In some embodiments, at least one R^T1 is 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 R^Ta. [0439] In some embodiments, at least one R^T1 is pyrimidinyl. [0440] In some embodiments, at least one R^T1 is . [0441] In some embodiments, at least one . [0442] In some embodiments, at least one R^T1 is . [0443] In some embodiments, at least one R^T1 is pyridazinyl. [0444] In some embodiments, at least one R^T1 . [0445] In some embodiments, at least one . [0446] In some embodiments, at least one R^T1 is pyrazinyl. 45 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0447] In some embodiments, at least one R^T1 is . [0448] In some embodiments, at least one R^T1 is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S. [0449] In some embodiments, at least one R^T1 is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Ta. [0450] In some embodiments, at least one R^T1 . [0451] In some embodiments, at least one R^T1 substituted with one or more R^Ta. [0452] In some embodiments, at least one R^T1 . [0453] In some embodiments, at least one R^T1 substituted with one or more R^Ta. [0454] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more R^Ta. In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 8- membered heterocyclyl optionally substituted with one or more R^Ta. In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 6-membered heterocyclyl optionally substituted with one or more R^Ta. [0455] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl. [0456] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl substituted with one or more R^Ta. In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 6- membered heterocyclyl substituted with one or more R^Ta. [0457] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl. 46 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0458] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl substituted with one or more R^Ta. In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 6- membered monocyclic heterocyclyl substituted with one or more R^Ta. [0459] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl containing one nitrogen. [0460] In some embodiments, two R^T2, 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 R^Ta. In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 6-membered monocyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and is substituted with one or more R^Ta. [0461] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl containing two nitrogens. [0462] In some embodiments, two R^T2, 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 R^Ta. In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 6-membered monocyclic heterocyclyl, wherein the heterocyclyl contains two nitrogens and is substituted with one or more R^Ta. [0463] In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 10-membered monocyclic heterocyclyl containing one nitrogen and one oxygen. [0464] In some embodiments, two R^T2, 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 R^Ta. In some embodiments, two R^T2, together with the atom to which they are attached, form 4- to 6-membered monocyclic heterocyclyl, wherein the heterocyclyl contains one nitrogen and one oxygen, and is substituted with one or more R^Ta. [0465] In some embodiments, two R^T2, together with the atom to which they are attached, form [0466] In some embodiments, two R^T2, together with the atom to which they are attached, form , substituted with one or more R^Ta. 47 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Variables R^Ta [0467] In some embodiments, at least one R^Ta is oxo, halogen, cyano, -OH, -OR^a, -SR^a, - NH2, -NHR^a, -N(R^a)2, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, -NH-S(=O)2-R^a, -N(C1-C6 alkyl)- C(=O)-R^a, -N(C₁-C₆ alkyl)-C(=O)-O-R^a, -N(C₁-C₆ alkyl)-S(=O)₂-R^a, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2- C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb. [0468] In some embodiments, at least one R^Ta is oxo, halogen, cyano, -OH, -OR^a, -SR^a, - NH₂, -NHR^a, -N(R^a)₂, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, -NH-S(=O)₂-R^a, -N(C₁-C₆ alkyl)- C(=O)-R^a, -N(C₁-C₆ alkyl)-C(=O)-O-R^a, -N(C₁-C₆ alkyl)-S(=O)₂-R^a, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl. [0469] In some embodiments, at least one R^Ta is oxo, halogen, cyano, -OH, -OR^a, -SR^a, - NH2, -NHR^a, -N(R^a)2, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, -NH-S(=O)2-R^a, -N(C1-C6 alkyl)- C(=O)-R^a, -N(C1-C6 alkyl)-C(=O)-O-R^a, -N(C1-C6 alkyl)-S(=O)2-R^a, C1-C6 alkyl, C1-C6 haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more R^Tb. [0470] In some embodiments, at least one R^Ta is oxo, halogen, cyano, -OH, -NH₂, C₁-C₆ alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb. [0471] In some embodiments, at least one R^Ta is oxo, halogen, cyano, -OH, -NH₂, or C₁-C₆ alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more R^Tb. [0472] In some embodiments, at least one R^Ta is -OR^a, -SR^a, -NHR^a, -N(R^a)₂, -NH-C(=O)- R^a, -NH-C(=O)-O-R^a, -NH-S(=O)₂-R^a, -N(C₁-C₆ alkyl)-C(=O)-R^a, -N(C₁-C₆ alkyl)-C(=O)-O- R^a, or -N(C1-C6 alkyl)-S(=O)2-R^a.In some embodiments, at least one R^Ta is oxo. [0473] In some embodiments, at least one R^Ta is halogen. [0474] In some embodiments, at least one R^Ta is -F. [0475] In some embodiments, at least one R^Ta is -Cl. [0476] In some embodiments, at least one R^Ta is -Br. [0477] In some embodiments, at least one R^Ta is -I. 48 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0478] In some embodiments, at least one R^Ta is cyano. [0479] In some embodiments, at least one R^Ta is -OH. [0480] In some embodiments, at least one R^Ta is -OR^a. [0481] In some embodiments, at least one R^Ta is -SR^a. [0482] In some embodiments, at least one R^Ta is -NH2. [0483] In some embodiments, at least one R^Ta is -NHR^a. [0484] In some embodiments, at least one R^Ta is -N(R^a)₂. [0485] In some embodiments, at least one R^Ta is -NH-C(=O)-R^a. [0486] In some embodiments, at least one R^Ta is -NH-C(=O)-O-R^a. [0487] In some embodiments, at least one R^Ta is -NH-S(=O)₂-R^a. [0488] In some embodiments, at least one R^Ta is -N(C₁-C₆ alkyl)-C(=O)-R^a. [0489] In some embodiments, at least one R^Ta is -N(C1 alkyl)-C(=O)-R^a. [0490] In some embodiments, at least one R^Ta is -N(C2 alkyl)-C(=O)-R^a. [0491] In some embodiments, at least one R^Ta is -N(C₃ alkyl)-C(=O)-R^a. [0492] In some embodiments, at least one R^Ta is -N(C4 alkyl)-C(=O)-R^a. [0493] In some embodiments, at least one R^Ta is -N(C5 alkyl)-C(=O)-R^a. [0494] In some embodiments, at least one R^Ta is -N(C₆ alkyl)-C(=O)-R^a. [0495] In some embodiments, at least one R^Ta is -N(C₁-C₆ alkyl)-C(=O)-O-R^a. [0496] In some embodiments, at least one R^Ta is -N(C1 alkyl)-C(=O)-O-R^a. [0497] In some embodiments, at least one R^Ta is -N(C₂ alkyl)-C(=O)-O-R^a. [0498] In some embodiments, at least one R^Ta is -N(C₃ alkyl)-C(=O)-O-R^a. [0499] In some embodiments, at least one R^Ta is -N(C4 alkyl)-C(=O)-O-R^a. [0500] In some embodiments, at least one R^Ta is -N(C5 alkyl)-C(=O)-O-R^a. [0501] In some embodiments, at least one R^Ta is -N(C₆ alkyl)-C(=O)-O-R^a. [0502] In some embodiments, at least one R^Ta is -N(C₁-C₆ alkyl)-S(=O)₂-R^a. [0503] In some embodiments, at least one R^Ta is -N(C1 alkyl)-S(=O)2-R^a. [0504] In some embodiments, at least one R^Ta is -N(C₂ alkyl)-S(=O)₂-R^a. [0505] In some embodiments, at least one R^Ta is -N(C₃ alkyl)-S(=O)₂-R^a. [0506] In some embodiments, at least one R^Ta is -N(C4 alkyl)-S(=O)2-R^a. [0507] In some embodiments, at least one R^Ta is -N(C5 alkyl)-S(=O)2-R^a. [0508] In some embodiments, at least one R^Ta is -N(C₆ alkyl)-S(=O)₂-R^a. [0509] In some embodiments, at least one R^Ta is C1-C6 alkyl. [0510] In some embodiments, at least one R^Ta is C1-C6 alkyl substituted with one or more R^Tb. 49 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0511] In some embodiments, at least one R^Ta is C₁ alkyl. [0512] In some embodiments, at least one R^Ta is C2 alkyl. [0513] In some embodiments, at least one R^Ta is C3 alkyl. [0514] In some embodiments, at least one R^Ta is C₄ alkyl. [0515] In some embodiments, at least one R^Ta is C5 alkyl. [0516] In some embodiments, at least one R^Ta is C6 alkyl. [0517] In some embodiments, at least one R^Ta is C₁-C₆ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0518] In some embodiments, at least one R^Ta is C1-C6 haloalkyl substituted with one or more R^Tb. [0519] In some embodiments, at least one R^Ta is C₁ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0520] In some embodiments, at least one R^Ta is C2 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0521] In some embodiments, at least one R^Ta is C3 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0522] In some embodiments, at least one R^Ta is C₄ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0523] In some embodiments, at least one R^Ta is C5 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0524] In some embodiments, at least one R^Ta is C₆ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0525] In some embodiments, at least one R^Ta is C2-C6 alkenyl. [0526] In some embodiments, at least one R^Ta is C₂-C₆ alkenyl substituted with one or more R^Tb. [0527] In some embodiments, at least one R^Ta is C2 alkenyl. [0528] In some embodiments, at least one R^Ta is C₃ alkenyl. [0529] In some embodiments, at least one R^Ta is C₄ alkenyl. [0530] In some embodiments, at least one R^Ta is C5 alkenyl. [0531] In some embodiments, at least one R^Ta is C6 alkenyl. [0532] In some embodiments, at least one R^Ta is C₂-C₆ alkynyl. [0533] In some embodiments, at least one R^Ta is C2-C6 alkynyl substituted with one or more R^Tb. [0534] In some embodiments, at least one R^Ta is C₂ alkynyl. 50 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0535] In some embodiments, at least one R^Ta is C₃ alkynyl. [0536] In some embodiments, at least one R^Ta is C4 alkynyl. [0537] In some embodiments, at least one R^Ta is C5 alkynyl. [0538] In some embodiments, at least one R^Ta is C₆ alkynyl. [0539] In some embodiments, at least one R^Ta is C3-C10 cycloalkyl. [0540] In some embodiments, at least one R^Ta is C3-C10 cycloalkyl substituted with one or more R^Tb. [0541] In some embodiments, at least one R^Ta is C3-C10 monocyclic cycloalkyl. [0542] In some embodiments, at least one R^Ta is C3-C10 monocyclic cycloalkyl substituted with one or more R^Tb. [0543] In some embodiments, at least one R^Ta is C₃ monocyclic cycloalkyl. [0544] In some embodiments, at least one R^Ta is C3 monocyclic cycloalkyl substituted with one or more R^Tb. [0545] In some embodiments, at least one R^Ta is C₄ monocyclic cycloalkyl. [0546] In some embodiments, at least one R^Ta is C4 monocyclic cycloalkyl substituted with one or more R^Tb. [0547] In some embodiments, at least one R^Ta is C₅ monocyclic cycloalkyl. [0548] In some embodiments, at least one R^Ta is C₅ monocyclic cycloalkyl substituted with one or more R^Tb. [0549] In some embodiments, at least one R^Ta is C₆ monocyclic cycloalkyl. [0550] In some embodiments, at least one R^Ta is C₆ monocyclic cycloalkyl substituted with one or more R^Tb. [0551] In some embodiments, at least one R^Ta is C7 monocyclic cycloalkyl. [0552] In some embodiments, at least one R^Ta is C₇ monocyclic cycloalkyl substituted with one or more R^Tb. [0553] In some embodiments, at least one R^Ta is C8 monocyclic cycloalkyl. [0554] In some embodiments, at least one R^Ta is C₈ monocyclic cycloalkyl substituted with one or more R^Tb. [0555] In some embodiments, at least one R^Ta is C9 monocyclic cycloalkyl. [0556] In some embodiments, at least one R^Ta is C9 monocyclic cycloalkyl substituted with one or more R^Tb. [0557] In some embodiments, at least one R^Ta is C10 monocyclic cycloalkyl. [0558] In some embodiments, at least one R^Ta is C10 monocyclic cycloalkyl substituted with one or more R^Tb. 51 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0559] In some embodiments, at least one R^Ta is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0560] In some embodiments, at least one R^Ta is C4-C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0561] In some embodiments, at least one R^Ta is C4 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0562] In some embodiments, at least one R^Ta is C₄ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0563] In some embodiments, at least one R^Ta is C5 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0564] In some embodiments, at least one R^Ta is C₅ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0565] In some embodiments, at least one R^Ta is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0566] In some embodiments, at least one R^Ta is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0567] In some embodiments, at least one R^Ta is C₇ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0568] In some embodiments, at least one R^Ta is C7 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0569] In some embodiments, at least one R^Ta is C₈ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0570] In some embodiments, at least one R^Ta is C8 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0571] In some embodiments, at least one R^Ta is C₉ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0572] In some embodiments, at least one R^Ta is C₉ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0573] In some embodiments, at least one R^Ta is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0574] In some embodiments, at least one R^Ta is C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0575] In some embodiments, at least one R^Ta is C4-C10 fused bicyclic cycloalkyl. 52 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0576] In some embodiments, at least one R^Ta is C₄-C₁₀ fused bicyclic cycloalkyl substituted with one or more R^Tb. [0577] In some embodiments, at least one R^Ta is . [0578] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. [0579] In some embodiments, at least one R^Ta is C5-C10 bridged bicyclic cycloalkyl. [0580] In some embodiments, at least one R^Ta is C5-C10 bridged bicyclic cycloalkyl substituted with one or more R^Tb. [0581] In some embodiments, at least one R^Ta is , , . [0582] In some embodiments, at least one R^Ta is , , substituted with one or more R^Tb. [0583] In some embodiments, at least one R^Ta is C₅-C₁₀ spiro bicyclic cycloalkyl. [0584] In some embodiments, at least one R^Ta is C5-C10 spiro bicyclic cycloalkyl substituted with one or more R^Tb. [0585] In some embodiments, at least one R^Ta 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. [0586] In some embodiments, at least one R^Ta 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, substituted with one or more R^Tb. [0587] In some embodiments, at least one R^Ta is . [0588] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. [0589] In some embodiments, at least one R^Ta is . 53 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0590] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. [0591] In some embodiments, at least one R^Ta is 4- to 10-membered heterocyclyl. [0592] In some embodiments, at least one R^Ta is 4- to 10-membered heterocyclyl substituted with one or more R^Tb. [0593] In some embodiments, at least one R^Ta is 4-membered monocyclic heterocyclyl. [0594] In some embodiments, at least one R^Ta is 4-membered monocyclic heterocyclyl substituted with one or more R^Tb. [0595] In some embodiments, at least one R^Ta is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0596] In some embodiments, at least one R^Ta is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0597] In some embodiments, at least one R^Ta is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0598] In some embodiments, at least one R^Ta is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0599] In some embodiments, at least one R^Ta is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0600] In some embodiments, at least one R^Ta is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0601] In some embodiments, at least one R^Ta is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0602] In some embodiments, at least one R^Ta is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0603] In some embodiments, at least one R^Ta is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0604] In some embodiments, at least one R^Ta is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0605] In some embodiments, at least one R^Ta is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0606] In some embodiments, at least one R^Ta is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. 54 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0607] In some embodiments, at least one R^Ta is 4- to 10-membered fused bicyclic heterocyclyl. [0608] In some embodiments, at least one R^Ta is 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more R^Tb. [0609] In some embodiments, at least one R^Ta is 5- to 10-membered bridged bicyclic heterocyclyl. [0610] In some embodiments, at least one R^Ta is 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more R^Tb. [0611] In some embodiments, at least one R^Ta is 5- to 10-membered spiro bicyclic heterocyclyl. [0612] In some embodiments, at least one R^Ta is 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more R^Tb. [0613] In some embodiments, at least one R^Ta is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S. [0614] In some embodiments, at least one R^Ta is 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 R^Tb. [0615] In some embodiments, at least one R^Ta is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S. [0616] In some embodiments, at least one R^Ta is 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 R^Tb. [0617] In some embodiments, at least one R^Ta is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). [0618] In some embodiments, at least one R^Ta is 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 R^Tb. [0619] In some embodiments, at least one R^Ta is 4- to 10-membered fused bicyclic heterocyclyl containing one N. [0620] In some embodiments, at least one R^Ta is 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 R^Tb. [0621] In some embodiments, at least one R^Ta is 5- to 10-membered bridged bicyclic heterocyclyl containing one N. 55 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0622] In some embodiments, at least one R^Ta is 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more R^Tb. [0623] In some embodiments, at least one R^Ta is 5- to 10-membered spiro bicyclic heterocyclyl containing one N. [0624] In some embodiments, at least one R^Ta is 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more R^Tb. [0625] In some embodiments, at least one R^Ta is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl). [0626] In some embodiments, at least one R^Ta is 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 R^Tb. [0627] In some embodiments, at least one R^Ta is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O. [0628] In some embodiments, at least one R^Ta is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O, wherein the 5- to 10-membered bridged heterocyclyl is substituted with one or more R^Tb. [0629] In some embodiments, at least one R^Ta is 4- to 10-membered monocyclic heterocyclyl containing one S. [0630] In some embodiments, at least one R^Ta is 4- to 10-membered monocyclic heterocyclyl containing one S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more R^Tb. [0631] In some embodiments, at least one R^Ta is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S. [0632] In some embodiments, at least one R^Ta is 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 R^Tb. [0633] In some embodiments, at least one R^Ta is . [0634] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. 56 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0635] In some embodiments, at least one R^Ta is . [0636] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. [0637] In some embodiments, at least one R^Ta is . [0638] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. [0639] In some embodiments, at least one R^Ta is . [0640] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. [0641] In some embodiments, at least one R^Ta is C₆-C₁₀ aryl (e.g., phenyl or naphthalenyl). [0642] In some embodiments, at least one R^Ta is C6-C10 aryl (e.g., phenyl or naphthalenyl) substituted with one or more R^Tb. [0643] In some embodiments, at least one R^Ta is phenyl. [0644] In some embodiments, at least one R^Ta is phenyl substituted with one or more R^Tb. [0645] In some embodiments, at least one R^Ta is naphthalenyl. [0646] In some embodiments, at least one R^Ta is naphthalenyl substituted with one or more R^Tb. [0647] In some embodiments, at least one R^Ta is 5- to 10-membered heteroaryl. [0648] In some embodiments, at least one R^Ta is 5- to 10-membered heteroaryl substituted with one or more R^Tb. [0649] In some embodiments, at least one R^Ta is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0650] In some embodiments, at least one R^Ta is 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 R^Tb. [0651] In some embodiments, at least one R^Ta is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S. 57 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0652] In some embodiments, at least one R^Ta is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tb. [0653] In some embodiments, at least one R^Ta is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). [0654] In some embodiments, at least one R^Ta is 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 R^Tb. [0655] In some embodiments, at least one R^Ta is pyrrolyl. [0656] In some embodiments, at least one R^Ta is pyrrolyl substituted with one or more R^Tb. [0657] In some embodiments, at least one R^Ta is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl). [0658] In some embodiments, at least one R^Ta is 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 R^Tb. [0659] In some embodiments, at least one R^Ta is oxazolyl. [0660] In some embodiments, at least one R^Ta is . [0661] In some embodiments, at least one R^Ta i [0662] In some embodiments, at least one R^Ta is . [0663] In some embodiments, at least one R^Ta is . [0664] In some embodiments, at least one R^Ta is . [0665] In some embodiments, at least one R^Ta i [0666] In some embodiments, at least one R^Ta is . [0667] In some embodiments, at least one R^Ta is . [0668] In some embodiments, at least one R^Ta is isoxazolyl. 58 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0669] In some embodiments, at least one R^Ta is isothiazolyl. [0670] In some embodiments, at least one R^Ta is imidazolyl. [0671] In some embodiments, at least one R^Ta is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl). [0672] In some embodiments, at least one R^Ta is 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 R^Tb. [0673] In some embodiments, at least one R^Ta is triazolyl. [0674] In some embodiments, at least one R^Ta is . [0675] In some embodiments, at least one R^Ta is . [0676] In some embodiments, at least one R^Ta is . [0677] In some embodiments, at least one R^Ta is oxadiazolyl. [0678] In some embodiments, at least one R^Ta is . [0679] In some embodiments, at least one R^Ta is thiadiazolyl. [0680] In some embodiments, at least one R^Ta is . [0681] In some embodiments, at least one R^Ta is . [0682] In some embodiments, at least one R^Ta is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl). [0683] In some embodiments, at least one R^Ta is 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 R^Tb. [0684] In some embodiments, at least one R^Ta is tetrazolyl. [0685] In some embodiments, at least one R^Ta is . 59 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0686] In some embodiments, at least one R^Ta is oxatriazolyl. [0687] In some embodiments, at least one R^Ta is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0688] In some embodiments, at least one R^Ta is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tb. [0689] In some embodiments, at least one R^Ta is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl). [0690] In some embodiments, at least one R^Ta is 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 R^Tb. [0691] In some embodiments, at least one R^Ta is pyridinyl. [0692] In some embodiments, at least one R^Ta is . [0693] In some embodiments, at least one R^Ta is . [0694] In some embodiments, at least one . [0695] In some embodiments, at least one R^Ta is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl). [0696] In some embodiments, at least one R^Ta is 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 R^Tb. [0697] In some embodiments, at least one R^Ta is pyrimidinyl. [0698] In some embodiments, at least one R^Ta is . [0699] [0700] In some embodiments, at least one R^Ta is . 60 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0701] In some embodiments, at least one R^Ta is pyridazinyl. [0702] In some embodiments, at least one R^Ta is . [0703] In some embodiments, at least one . [0704] [0705] In some embodiments, at least one R^Ta is . [0706] In some embodiments, at least one R^Ta is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S. [0707] In some embodiments, at least one R^Ta is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tb. [0708] In some embodiments, at least one R^Ta is . [0709] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. [0710] In some embodiments, at least one R^Ta is . [0711] In some embodiments, at least one R^Ta is substituted with one or more R^Tb. Variables R^a [0712] In some embodiments, at least one R^a is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb. 61 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0713] In some embodiments, at least one R^a is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, or C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl. [0714] In some embodiments, at least one R^a is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, or C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is substituted with one or more R^Tb. [0715] In some embodiments, at least one R^a is C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10- membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb. [0716] In some embodiments, at least one R^a is C1-C6 alkyl. [0717] In some embodiments, at least one R^a is C₁-C₆ alkyl substituted with one or more R^Tb. [0718] In some embodiments, at least one R^a is C1 alkyl. [0719] In some embodiments, at least one R^a is C₂ alkyl. [0720] In some embodiments, at least one R^a is C₃ alkyl. [0721] In some embodiments, at least one R^a is C4 alkyl. [0722] In some embodiments, at least one R^a is C₅ alkyl. [0723] In some embodiments, at least one R^a is C₆ alkyl. [0724] In some embodiments, at least one R^a is C1-C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0725] In some embodiments, at least one R^a is C₁-C₆ haloalkyl substituted with one or more R^Tb. [0726] In some embodiments, at least one R^a is C1 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0727] In some embodiments, at least one R^a is C₂ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0728] In some embodiments, at least one R^a is C3 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0729] In some embodiments, at least one R^a is C4 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). 62 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0730] In some embodiments, at least one R^a is C₅ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0731] In some embodiments, at least one R^a is C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0732] In some embodiments, at least one R^a is C2-C6 alkenyl. [0733] In some embodiments, at least one R^a is C2-C6 alkenyl substituted with one or more R^Tb. [0734] In some embodiments, at least one R^a is C2 alkenyl. [0735] In some embodiments, at least one R^a is C3 alkenyl. [0736] In some embodiments, at least one R^a is C₄ alkenyl. [0737] In some embodiments, at least one R^a is C₅ alkenyl. [0738] In some embodiments, at least one R^a is C6 alkenyl. [0739] In some embodiments, at least one R^a is C2-C6 alkynyl. [0740] In some embodiments, at least one R^a is C₂-C₆ alkynyl substituted with one or more R^Tb. [0741] In some embodiments, at least one R^a is C2 alkynyl. [0742] In some embodiments, at least one R^a is C₃ alkynyl. [0743] In some embodiments, at least one R^a is C₄ alkynyl. [0744] In some embodiments, at least one R^a is C5 alkynyl. [0745] In some embodiments, at least one R^a is C₆ alkynyl. [0746] In some embodiments, at least one R^a is C₃-C₁₀ cycloalkyl. [0747] In some embodiments, at least one R^a is C3-C10 cycloalkyl substituted with one or more R^Tb. [0748] In some embodiments, at least one R^a is C₃-C₁₀ monocyclic cycloalkyl. [0749] In some embodiments, at least one R^a is C₃-C₁₀ monocyclic cycloalkyl substituted with one or more R^Tb. [0750] In some embodiments, at least one R^a is C₃ monocyclic cycloalkyl. [0751] In some embodiments, at least one R^a is C₃ monocyclic cycloalkyl substituted with one or more R^Tb. [0752] In some embodiments, at least one R^a is C4 monocyclic cycloalkyl. [0753] In some embodiments, at least one R^a is C₄ monocyclic cycloalkyl substituted with one or more R^Tb. [0754] In some embodiments, at least one R^a is C5 monocyclic cycloalkyl. 63 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0755] In some embodiments, at least one R^a is C₅ monocyclic cycloalkyl substituted with one or more R^Tb. [0756] In some embodiments, at least one R^a is C6 monocyclic cycloalkyl. [0757] In some embodiments, at least one R^a is C₆ monocyclic cycloalkyl substituted with one or more R^Tb. [0758] In some embodiments, at least one R^a is C7 monocyclic cycloalkyl. [0759] In some embodiments, at least one R^a is C₇ monocyclic cycloalkyl substituted with one or more R^Tb. [0760] In some embodiments, at least one R^a is C8 monocyclic cycloalkyl. [0761] In some embodiments, at least one R^a is C₈ monocyclic cycloalkyl substituted with one or more R^Tb. [0762] In some embodiments, at least one R^a is C9 monocyclic cycloalkyl. [0763] In some embodiments, at least one R^a is C9 monocyclic cycloalkyl substituted with one or more R^Tb. [0764] In some embodiments, at least one R^a is C10 monocyclic cycloalkyl. [0765] In some embodiments, at least one R^a is C10 monocyclic cycloalkyl substituted with one or more R^Tb. [0766] In some embodiments, at least one R^a is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0767] In some embodiments, at least one R^a is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0768] In some embodiments, at least one R^a is C4 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0769] In some embodiments, at least one R^a is C₄ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0770] In some embodiments, at least one R^a is C5 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0771] In some embodiments, at least one R^a is C₅ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0772] In some embodiments, at least one R^a is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0773] In some embodiments, at least one R^a is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. 64 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0774] In some embodiments, at least one R^a is C₇ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0775] In some embodiments, at least one R^a is C7 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0776] In some embodiments, at least one R^a is C8 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0777] In some embodiments, at least one R^a is C₈ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0778] In some embodiments, at least one R^a is C9 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0779] In some embodiments, at least one R^a is C₉ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0780] In some embodiments, at least one R^a is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [0781] In some embodiments, at least one R^a is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0782] In some embodiments, at least one R^a is C₄-C₁₀ fused bicyclic cycloalkyl. [0783] In some embodiments, at least one R^a is C₄-C₁₀ fused bicyclic cycloalkyl substituted with one or more R^Tb. [0784] In some embodiments, at least one R^a is . [0785] In some embodiments, at least one R^a is substituted with one or more R^Tb. [0786] In some embodiments, at least one R^a is C₅-C₁₀ bridged bicyclic cycloalkyl. [0787] In some embodiments, at least one R^a is C5-C10 bridged bicyclic cycloalkyl substituted with one or more R^Tb. [0788] In some embodiments, at least one R^a is , , . [0789] In some embodiments, at least one R^a is , , substituted with one or more R^Tb. 65 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0790] In some embodiments, at least one R^a is C₅-C₁₀ spiro bicyclic cycloalkyl. [0791] In some embodiments, at least one R^a is C5-C10 spiro bicyclic cycloalkyl substituted with one or more R^Tb. [0792] In some embodiments, at least one R^a 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. [0793] In some embodiments, at least one R^a 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, substituted with one or more R^Tb. [0794] In some embodiments, at least one R^a is . [0795] In some embodiments, at least one R^a is substituted with one or more R^Tb. [0796] In some embodiments, at least one R^a is . [0797] In some embodiments, at least one R^a is substituted with one or more R^Tb. [0798] In some embodiments, at least one R^a is 4- to 10-membered heterocyclyl. [0799] In some embodiments, at least one R^a is 4- to 10-membered heterocyclyl substituted with one or more R^Tb. [0800] In some embodiments, at least one R^a is 4-membered monocyclic heterocyclyl. [0801] In some embodiments, at least one R^a is 4-membered monocyclic heterocyclyl substituted with one or more R^Tb. [0802] In some embodiments, at least one R^a is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0803] In some embodiments, at least one R^a is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0804] In some embodiments, at least one R^a is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0805] In some embodiments, at least one R^a is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. 66 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0806] In some embodiments, at least one R^a is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0807] In some embodiments, at least one R^a is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0808] In some embodiments, at least one R^a is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0809] In some embodiments, at least one R^a is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0810] In some embodiments, at least one R^a is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0811] In some embodiments, at least one R^a is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0812] In some embodiments, at least one R^a is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [0813] In some embodiments, at least one R^a is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tb. [0814] In some embodiments, at least one R^a is 4- to 10-membered fused bicyclic heterocyclyl. [0815] In some embodiments, at least one R^a is 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more R^Tb. [0816] In some embodiments, at least one R^a is 5- to 10-membered bridged bicyclic heterocyclyl. [0817] In some embodiments, at least one R^a is 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more R^Tb. [0818] In some embodiments, at least one R^a is 5- to 10-membered spiro bicyclic heterocyclyl. [0819] In some embodiments, at least one R^a is 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more R^Tb. [0820] In some embodiments, at least one R^a is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S. [0821] In some embodiments, at least one R^a is 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 R^Tb. 67 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0822] In some embodiments, at least one R^a is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S. [0823] In some embodiments, at least one R^a is 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 R^Tb. [0824] In some embodiments, at least one R^a is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). [0825] In some embodiments, at least one R^a is 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 R^Tb. [0826] In some embodiments, at least one R^a is 4- to 10-membered fused bicyclic heterocyclyl containing one N. [0827] In some embodiments, at least one R^a is 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 R^Tb. [0828] In some embodiments, at least one R^a is 5- to 10-membered bridged bicyclic heterocyclyl containing one N. [0829] In some embodiments, at least one R^a is 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more R^Tb. [0830] In some embodiments, at least one R^a is 5- to 10-membered spiro bicyclic heterocyclyl containing one N. [0831] In some embodiments, at least one R^a is 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more R^Tb. [0832] In some embodiments, at least one R^a is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl). [0833] In some embodiments, at least one R^a is 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 R^Tb. [0834] In some embodiments, at least one R^a is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O. 68 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0835] In some embodiments, at least one R^a is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O, wherein the 5- to 10-membered bridged heterocyclyl is substituted with one or more R^Tb. [0836] In some embodiments, at least one R^a is 4- to 10-membered monocyclic heterocyclyl containing one S. [0837] In some embodiments, at least one R^a is 4- to 10-membered monocyclic heterocyclyl containing one S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more R^Tb. [0838] In some embodiments, at least one R^a is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S. [0839] In some embodiments, at least one R^a is 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 R^Tb. [0840] In some embodiments, at least one R^a is . [0841] In some embodiments, at least one R^a is substituted with one or more R^Tb. [0842] In some embodiments, at least one R^a is . [0843] In some embodiments, at least one R^a is substituted with one or more R^Tb. [0844] In some embodiments, at least one R^a is . [0845] In some embodiments, at least one R^a is substituted with one or more R^Tb. [0846] In some embodiments, at least one R^a is . [0847] In some embodiments, at least one R^a is substituted with one or more R^Tb. 69 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0848] In some embodiments, at least one R^a is C₆-C₁₀ aryl (e.g., phenyl or naphthalenyl). [0849] In some embodiments, at least one R^a is C6-C10 aryl (e.g., phenyl or naphthalenyl) substituted with one or more R^Tb. [0850] In some embodiments, at least one R^a is phenyl. [0851] In some embodiments, at least one R^a is phenyl substituted with one or more R^Tb. [0852] In some embodiments, at least one R^a is naphthalenyl. [0853] In some embodiments, at least one R^a is naphthalenyl substituted with one or more R^Tb. [0854] In some embodiments, at least one R^a is 5- to 10-membered heteroaryl. [0855] In some embodiments, at least one R^a is 5- to 10-membered heteroaryl substituted with one or more R^Tb. [0856] In some embodiments, at least one R^a is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0857] In some embodiments, at least one R^a is 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 R^Tb. [0858] In some embodiments, at least one R^a is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0859] In some embodiments, at least one R^a is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tb. [0860] In some embodiments, at least one R^a is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). [0861] In some embodiments, at least one R^a is 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 R^Tb. [0862] In some embodiments, at least one R^a is pyrrolyl. [0863] In some embodiments, at least one R^a is pyrrolyl substituted with one or more R^Tb. [0864] In some embodiments, at least one R^a is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl). [0865] In some embodiments, at least one R^a is 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 R^Tb. 70 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0866] In some embodiments, at least one R^a is oxazolyl. [0867] In some embodiments, at least one R^a . [0868] In some embodiments, at least one R^a [0869] In some embodiments, at least one R^a . [0870] In some embodiments, at least one R^a . [0871] In some embodiments, at least one R^a . [0872] In some embodiments, at least one R^a is pyrazolyl. [0873] In some embodiments, at least one R^a . [0874] In some embodiments, at least one R^a . [0875] In some embodiments, at least one R^a is isoxazolyl. [0876] In some embodiments, at least one R^a is isothiazolyl. [0877] In some embodiments, at least one R^a is imidazolyl. [0878] In some embodiments, at least one R^a is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl). [0879] In some embodiments, at least one R^a is 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 R^Tb. [0880] In some embodiments, at least one R^a is triazolyl. [0881] In some embodiments, at least one R^a i . [0882] In some embodiments, at least one R^a i . [0883] In some embodiments, at least one R^a i . 71 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0884] In some embodiments, at least one R^a is oxadiazolyl. [0885] In some embodiments, at least one R^a is . [0886] In some embodiments, at least one R^a is thiadiazolyl. [0887] In some embodiments, at least one R^a is . [0888] In some embodiments, at least one R^a is . [0889] In some embodiments, at least one R^a is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl). [0890] In some embodiments, at least one R^a is 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 R^Tb. [0891] In some embodiments, at least one R^a is tetrazolyl. [0892] In some embodiments, at least one R^a . [0893] In some embodiments, at least one R^a is oxatriazolyl. [0894] In some embodiments, at least one R^a is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [0895] In some embodiments, at least one R^a is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tb. [0896] In some embodiments, at least one R^a is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl). [0897] In some embodiments, at least one R^a is 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 R^Tb. [0898] In some embodiments, at least one R^a is pyridinyl. [0899] In some embodiments, at least one R^a is . [0900] In some embodiments, at least one R^a is . 72 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0901] In some embodiments, at least one . [0902] In some embodiments, at least one R^a is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl). [0903] In some embodiments, at least one R^a is 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 R^Tb. [0904] In some embodiments, at least one R^a is pyrimidinyl. [0905] In some embodiments, at least one R^a is . [0906] In some embodiments, at least one . [0907] In some embodiments, at least one R^a is . [0908] In some embodiments, at least one R^a is pyridazinyl. [0909] In some embodiments, at least one R^a is . [0910] In some embodiments, at least one R^a is . [0911] In some embodiments, at least one R^a is pyrazinyl. [0912] In some embodiments, at least one R^a is . [0913] In some embodiments, at least one R^a is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S. [0914] In some embodiments, at least one R^a is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tb. [0915] In some embodiments, at least one R^a is . 73 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0916] In some embodiments, at least one R^a is substituted with one or more R^Tb. [0917] In some embodiments, at least one R^a is . [0918] In some embodiments, at least one R^a is substituted with one or more R^Tb. Variables R^Tb [0919] In some embodiments, at least one R^Tb is oxo, halogen, cyano, -OH, -OR^b, -SR^b, - NH₂, -NHR^b, -N(R^b)₂, -NH-C(=O)-R^b, -NH-C(=O)-O-R^b, -NH-S(=O)₂-R^b, -N(C₁-C₆ alkyl)- C(=O)-R^b, -N(C1-C6 alkyl)-C(=O)-O-R^b, -N(C1-C6 alkyl)-S(=O)2-R^b, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂- C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc. [0920] In some embodiments, at least one R^Tb is oxo, halogen, cyano, -OH, -OR^b, -SR^b, - NH₂, -NHR^b, -N(R^b)₂, -NH-C(=O)-R^b, -NH-C(=O)-O-R^b, -NH-S(=O)₂-R^b, -N(C₁-C₆ alkyl)- C(=O)-R^b, -N(C1-C6 alkyl)-C(=O)-O-R^b, -N(C1-C6 alkyl)-S(=O)2-R^b, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl. [0921] In some embodiments, at least one R^Tb is oxo, halogen, cyano, -OH, -OR^b, -SR^b, - NH2, -NHR^b, -N(R^b)2, -NH-C(=O)-R^b, -NH-C(=O)-O-R^b, -NH-S(=O)2-R^b, -N(C1-C6 alkyl)- C(=O)-R^b, -N(C₁-C₆ alkyl)-C(=O)-O-R^b, -N(C₁-C₆ alkyl)-S(=O)₂-R^b, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2- C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is substituted with one or more R^Tc. [0922] In some embodiments, at least one R^Tb independently is oxo, halogen, cyano, -OH, - NH2, C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered 74 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc. [0923] In some embodiments, at least one R^Tb is oxo. [0924] In some embodiments, at least one R^Tb is halogen. [0925] In some embodiments, at least one R^Tb is -F. [0926] In some embodiments, at least one R^Tb is -Cl. [0927] In some embodiments, at least one R^Tb is -Br. [0928] In some embodiments, at least one R^Tb is -I. [0929] In some embodiments, at least one R^Tb is cyano. [0930] In some embodiments, at least one R^Tb is -OH. [0931] In some embodiments, at least one R^Tb is -OR^b. [0932] In some embodiments, at least one R^Tb is -SR^b. [0933] In some embodiments, at least one R^Tb is -NH2. [0934] In some embodiments, at least one R^Tb is -NHR^b. [0935] In some embodiments, at least one [0936] In some embodiments, at least one [0937] In some embodiments, at least one [0938] In some embodiments, at least one [0939] In some embodiments, at least one R^Tb is -N(C1-C6 alkyl)-C(=O)-R^b. [0940] In some embodiments, at least one R^Tb is -N(C₁ alkyl)-C(=O)-R^b. [0941] In some embodiments, at least one R^Tb is -N(C₂ alkyl)-C(=O)-R^b. [0942] In some embodiments, at least one R^Tb is -N(C3 alkyl)-C(=O)-R^b. [0943] In some embodiments, at least one R^Tb is -N(C4 alkyl)-C(=O)-R^b. [0944] In some embodiments, at least one R^Tb is -N(C₅ alkyl)-C(=O)-R^b. [0945] In some embodiments, at least one R^Tb is -N(C₆ alkyl)-C(=O)-R^b. [0946] In some embodiments, at least one R^Tb is -N(C1-C6 alkyl)-C(=O)-O-R^b. [0947] In some embodiments, at least one R^Tb is -N(C₁ alkyl)-C(=O)-O-R^b. [0948] In some embodiments, at least one R^Tb is -N(C₂ alkyl)-C(=O)-O-R^b. [0949] In some embodiments, at least one R^Tb is -N(C3 alkyl)-C(=O)-O-R^b. [0950] In some embodiments, at least one R^Tb is -N(C4 alkyl)-C(=O)-O-R^b. [0951] In some embodiments, at least one R^Tb is -N(C₅ alkyl)-C(=O)-O-R^b. [0952] In some embodiments, at least one R^Tb is -N(C6 alkyl)-C(=O)-O-R^b. [0953] In some embodiments, at least one R^Tb is -N(C1-C6 alkyl)-S(=O)2-R^b. [0954] In some embodiments, at least one R^Tb is -N(C₁ alkyl)-S(=O)₂-R^b. 75 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0955] In some embodiments, at least one R^Tb is -N(C₂ alkyl)-S(=O)₂-R^b. [0956] In some embodiments, at least one R^Tb is -N(C3 alkyl)-S(=O)2-R^b. [0957] In some embodiments, at least one R^Tb is -N(C4 alkyl)-S(=O)2-R^b. [0958] In some embodiments, at least one R^Tb is -N(C₅ alkyl)-S(=O)₂-R^b. [0959] In some embodiments, at least one R^Tb is -N(C6 alkyl)-S(=O)2-R^b. [0960] In some embodiments, at least one R^Tb is C1-C6 alkyl. [0961] In some embodiments, at least one R^Tb is C₁-C₆ alkyl substituted with one or more R^Tc. [0962] In some embodiments, at least one R^Tb is C1 alkyl. [0963] In some embodiments, at least one R^Tb is C₂ alkyl. [0964] In some embodiments, at least one R^Tb is C₃ alkyl. [0965] In some embodiments, at least one R^Tb is C4 alkyl. [0966] In some embodiments, at least one R^Tb is C5 alkyl. [0967] In some embodiments, at least one R^Tb is C₆ alkyl. [0968] In some embodiments, at least one R^Tb is C1-C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0969] In some embodiments, at least one R^Tb is C₁-C₆ haloalkyl substituted with one or more R^Tc. [0970] In some embodiments, at least one R^Tb is C1 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0971] In some embodiments, at least one R^Tb is C₂ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0972] In some embodiments, at least one R^Tb is C3 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0973] In some embodiments, at least one R^Tb is C₄ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0974] In some embodiments, at least one R^Tb is C₅ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0975] In some embodiments, at least one R^Tb is C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [0976] In some embodiments, at least one R^Tb is C₂-C₆ alkenyl. [0977] In some embodiments, at least one R^Tb is C2-C6 alkenyl substituted with one or more R^Tc. [0978] In some embodiments, at least one R^Tb is C₂ alkenyl. 76 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [0979] In some embodiments, at least one R^Tb is C₃ alkenyl. [0980] In some embodiments, at least one R^Tb is C4 alkenyl. [0981] In some embodiments, at least one R^Tb is C5 alkenyl. [0982] In some embodiments, at least one R^Tb is C₆ alkenyl. [0983] In some embodiments, at least one R^Tb is C2-C6 alkynyl. [0984] In some embodiments, at least one R^Tb is C2-C6 alkynyl substituted with one or more R^Tc. [0985] In some embodiments, at least one R^Tb is C2 alkynyl. [0986] In some embodiments, at least one R^Tb is C3 alkynyl. [0987] In some embodiments, at least one R^Tb is C₄ alkynyl. [0988] In some embodiments, at least one R^Tb is C₅ alkynyl. [0989] In some embodiments, at least one R^Tb is C6 alkynyl. [0990] In some embodiments, at least one R^Tb is C3-C10 cycloalkyl. [0991] In some embodiments, at least one R^Tb is C₃-C₁₀ cycloalkyl substituted with one or more R^Tc. [0992] In some embodiments, at least one R^Tb is C3-C10 monocyclic cycloalkyl. [0993] In some embodiments, at least one R^Tb is C₃-C₁₀ monocyclic cycloalkyl substituted with one or more R^Tc. [0994] In some embodiments, at least one R^Tb is C3 monocyclic cycloalkyl. [0995] In some embodiments, at least one R^Tb is C₃ monocyclic cycloalkyl substituted with one or more R^Tc. [0996] In some embodiments, at least one R^Tb is C4 monocyclic cycloalkyl. [0997] In some embodiments, at least one R^Tb is C4 monocyclic cycloalkyl substituted with one or more R^Tc. [0998] In some embodiments, at least one R^Tb is C₅ monocyclic cycloalkyl. [0999] In some embodiments, at least one R^Tb is C5 monocyclic cycloalkyl substituted with one or more R^Tc. [1000] In some embodiments, at least one R^Tb is C₆ monocyclic cycloalkyl. [1001] In some embodiments, at least one R^Tb is C6 monocyclic cycloalkyl substituted with one or more R^Tc. [1002] In some embodiments, at least one R^Tb is C₇ monocyclic cycloalkyl. [1003] In some embodiments, at least one R^Tb is C7 monocyclic cycloalkyl substituted with one or more R^Tc. [1004] In some embodiments, at least one R^Tb is C₈ monocyclic cycloalkyl. 77 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1005] In some embodiments, at least one R^Tb is C₈ monocyclic cycloalkyl substituted with one or more R^Tc. [1006] In some embodiments, at least one R^Tb is C9 monocyclic cycloalkyl. [1007] In some embodiments, at least one R^Tb is C₉ monocyclic cycloalkyl substituted with one or more R^Tc. [1008] In some embodiments, at least one R^Tb is C10 monocyclic cycloalkyl. [1009] In some embodiments, at least one R^Tb is C₁₀ monocyclic cycloalkyl substituted with one or more R^Tc. [1010] In some embodiments, at least one R^Tb is C4-C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1011] In some embodiments, at least one R^Tb is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1012] In some embodiments, at least one R^Tb is C4 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1013] In some embodiments, at least one R^Tb is C4 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1014] In some embodiments, at least one R^Tb is C₅ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1015] In some embodiments, at least one R^Tb is C5 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1016] In some embodiments, at least one R^Tb is C₆ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1017] In some embodiments, at least one R^Tb is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1018] In some embodiments, at least one R^Tb is C₇ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1019] In some embodiments, at least one R^Tb is C₇ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1020] In some embodiments, at least one R^Tb is C8 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1021] In some embodiments, at least one R^Tb is C₈ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1022] In some embodiments, at least one R^Tb is C9 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). 78 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1023] In some embodiments, at least one R^Tb is C₉ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1024] In some embodiments, at least one R^Tb is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1025] In some embodiments, at least one R^Tb is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1026] In some embodiments, at least one R^Tb is C₄-C₁₀ fused bicyclic cycloalkyl. [1027] In some embodiments, at least one R^Tb is C4-C10 fused bicyclic cycloalkyl substituted with one or more R^Tc. [1028] In some embodiments, at least one R^Tb is . [1029] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1030] In some embodiments, at least one R^Tb is C5-C10 bridged bicyclic cycloalkyl. [1031] In some embodiments, at least one R^Tb is C5-C10 bridged bicyclic cycloalkyl substituted with one or more R^Tc. [1032] In some embodiments, at least one R^Tb is , , . [1033] In some embodiments, at least one R^Tb is , , substituted with one or more R^Tc. [1034] In some embodiments, at least one R^Tb is C₅-C₁₀ spiro bicyclic cycloalkyl. [1035] In some embodiments, at least one R^Tb is C5-C10 spiro bicyclic cycloalkyl substituted with one or more R^Tc. [1036] In some embodiments, at least one R^Tb 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. [1037] In some embodiments, at least one R^Tb 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, substituted with one or more R^Tc. [1038] In some embodiments, at least one R^Tb is . 79 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1039] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1040] In some embodiments, at least one R^Tb is . [1041] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1042] In some embodiments, at least one R^Tb is 4- to 10-membered heterocyclyl. [1043] In some embodiments, at least one R^Tb is 4- to 10-membered heterocyclyl substituted with one or more R^Tc. [1044] In some embodiments, at least one R^Tb is 4-membered monocyclic heterocyclyl. [1045] In some embodiments, at least one R^Tb is 4-membered monocyclic heterocyclyl substituted with one or more R^Tc. [1046] In some embodiments, at least one R^Tb is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1047] In some embodiments, at least one R^Tb is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1048] In some embodiments, at least one R^Tb is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1049] In some embodiments, at least one R^Tb is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1050] In some embodiments, at least one R^Tb is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1051] In some embodiments, at least one R^Tb is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1052] In some embodiments, at least one R^Tb is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1053] In some embodiments, at least one R^Tb is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1054] In some embodiments, at least one R^Tb is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). 80 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1055] In some embodiments, at least one R^Tb is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1056] In some embodiments, at least one R^Tb is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1057] In some embodiments, at least one R^Tb is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1058] In some embodiments, at least one R^Tb is 4- to 10-membered fused bicyclic heterocyclyl. [1059] In some embodiments, at least one R^Tb is 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more R^Tc. [1060] In some embodiments, at least one R^Tb is 5- to 10-membered bridged bicyclic heterocyclyl. [1061] In some embodiments, at least one R^Tb is 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more R^Tc. [1062] In some embodiments, at least one R^Tb is 5- to 10-membered spiro bicyclic heterocyclyl. [1063] In some embodiments, at least one R^Tb is 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more R^Tc. [1064] In some embodiments, at least one R^Tb is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S. [1065] In some embodiments, at least one R^Tb is 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 R^Tc. [1066] In some embodiments, at least one R^Tb is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S. [1067] In some embodiments, at least one R^Tb is 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 R^Tc. [1068] In some embodiments, at least one R^Tb is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). [1069] In some embodiments, at least one R^Tb is 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 R^Tc. 81 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1070] In some embodiments, at least one R^Tb is 4- to 10-membered fused bicyclic heterocyclyl containing one N. [1071] In some embodiments, at least one R^Tb is 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 R^Tc. [1072] In some embodiments, at least one R^Tb is 5- to 10-membered bridged bicyclic heterocyclyl containing one N. [1073] In some embodiments, at least one R^Tb is 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more R^Tc. [1074] In some embodiments, at least one R^Tb is 5- to 10-membered spiro bicyclic heterocyclyl containing one N. [1075] In some embodiments, at least one R^Tb is 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more R^Tc. [1076] In some embodiments, at least one R^Tb is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl). [1077] In some embodiments, at least one R^Tb is 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 R^Tc. [1078] In some embodiments, at least one R^Tb is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O. [1079] In some embodiments, at least one R^Tb is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O, wherein the 5- to 10-membered bridged heterocyclyl is substituted with one or more R^Tc. [1080] In some embodiments, at least one R^Tb is 4- to 10-membered monocyclic heterocyclyl containing one S. [1081] In some embodiments, at least one R^Tb is 4- to 10-membered monocyclic heterocyclyl containing one S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more R^Tc. [1082] In some embodiments, at least one R^Tb is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S. 82 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1083] In some embodiments, at least one R^Tb is 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 R^Tc. [1084] In some embodiments, at least one R^Tb is . [1085] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1086] In some embodiments, at least one R^Tb is . [1087] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1088] In some embodiments, at least one R^Tb is . [1089] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1090] In some embodiments, at least one R^Tb is . [1091] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1092] In some embodiments, at least one R^Tb is C6-C10 aryl (e.g., phenyl or naphthalenyl). [1093] In some embodiments, at least one R^Tb is C6-C10 aryl (e.g., phenyl or naphthalenyl) substituted with one or more R^Tc. [1094] In some embodiments, at least one R^Tb is phenyl. [1095] In some embodiments, at least one R^Tb is phenyl substituted with one or more R^Tc. [1096] In some embodiments, at least one R^Tb is naphthalenyl. [1097] In some embodiments, at least one R^Tb is naphthalenyl substituted with one or more R^Tc. [1098] In some embodiments, at least one R^Tb is 5- to 10-membered heteroaryl. 83 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1099] In some embodiments, at least one R^Tb is 5- to 10-membered heteroaryl substituted with one or more R^Tc. [1100] In some embodiments, at least one R^Tb is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1101] In some embodiments, at least one R^Tb is 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 R^Tc. [1102] In some embodiments, at least one R^Tb is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1103] In some embodiments, at least one R^Tb is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tc. [1104] In some embodiments, at least one R^Tb is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). [1105] In some embodiments, at least one R^Tb is 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 R^Tc. [1106] In some embodiments, at least one R^Tb is pyrrolyl. [1107] In some embodiments, at least one R^Tb is pyrrolyl substituted with one or more R^Tc. [1108] In some embodiments, at least one R^Tb is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl). [1109] In some embodiments, at least one R^Tb is 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 R^Tc. [1110] In some embodiments, at least one R^Tb is oxazolyl. [1111] In some embodiments, at least one R^Tb is . [1112] In some embodiments, at least one R^Tb is thiazolyl. [1113] In some embodiments, at least one R^Tb is . 84 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1114] In some embodiments, at least one R^T . [1115] In some embodiments, at least one R^Tb is . [1116] In some embodiments, at least one R^Tb i [1117] In some embodiments, at least one R^Tb is . [1118] In some embodiments, at least one R^Tb is . [1119] In some embodiments, at least one R^Tb is isoxazolyl. [1120] In some embodiments, at least one R^Tb is isothiazolyl. [1121] In some embodiments, at least one R^Tb is imidazolyl. [1122] In some embodiments, at least one R^Tb is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl). [1123] In some embodiments, at least one R^Tb is 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 R^Tc. [1124] In some embodiments, at least one R^Tb is triazolyl. [1125] In some embodiments, at least one R^Tb is . [1126] In some embodiments, at least one R^Tb is . [1127] In some embodiments, at least one R^Tb is . [1128] In some embodiments, at least one R^Tb is oxadiazolyl. [1129] In some embodiments, at least one R^Tb is . [1130] In some embodiments, at least one R^Tb is thiadiazolyl. [1131] In some embodiments, at least one R^Tb is . 85 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1132] In some embodiments, at least one R^Tb is . [1133] In some embodiments, at least one R^Tb is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl). [1134] In some embodiments, at least one R^Tb is 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 R^Tc. [1135] In some embodiments, at least one R^Tb is tetrazolyl. [1136] In some embodiments, at least one R^Tb is . [1137] In some embodiments, at least one R^Tb is oxatriazolyl. [1138] In some embodiments, at least one R^Tb is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1139] In some embodiments, at least one R^Tb is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tc. [1140] In some embodiments, at least one R^Tb is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl). [1141] In some embodiments, at least one R^Tb is 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 R^Tc. [1142] In some embodiments, at least one R^Tb is pyridinyl. [1143] In some embodiments, at least one R^Tb is . [1144] In some embodiments, at least one R^Tb is . [1145] In some embodiments, at least one . [1146] In some embodiments, at least one R^Tb is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl). 86 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1147] In some embodiments, at least one R^Tb is 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 R^Tc. [1148] In some embodiments, at least one R^Tb is pyrimidinyl. [1149] In some embodiments, at least one R^Tb is . [1150] [1151] In some embodiments, at least one R^Tb is . [1152] In some embodiments, at least one R^Tb is pyridazinyl. [1153] In some embodiments, at least one R^Tb is . [1154] In some embodiments, at least one R^Tb is . [1155] In some embodiments, at least one R^Tb is [1156] In some embodiments, at least one R^Tb is . [1157] In some embodiments, at least one R^Tb is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S. [1158] In some embodiments, at least one R^Tb is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S, wherein the heteroaryl is substituted with one or more . [1159] In some embodiments, at least one R^Tb is . [1160] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. [1161] In some embodiments, at least one R^Tb is . 87 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1162] In some embodiments, at least one R^Tb is substituted with one or more R^Tc. Variables R^b [1163] In some embodiments, at least one R^b is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc. [1164] In some embodiments, at least one R^b is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl. [1165] In some embodiments, at least one R^b is C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, or C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂- C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is substituted with one or more R^Tc. [1166] In some embodiments, at least one R^b is C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10- membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc. [1167] In some embodiments, at least one R^b is C₁-C₆ alkyl. [1168] In some embodiments, at least one R^b is C₁-C₆ alkyl substituted with one or more R^Tc. [1169] In some embodiments, at least one R^b is C1 alkyl. [1170] In some embodiments, at least one R^b is C₂ alkyl. [1171] In some embodiments, at least one R^b is C3 alkyl. [1172] In some embodiments, at least one R^b is C4 alkyl. [1173] In some embodiments, at least one R^b is C₅ alkyl. [1174] In some embodiments, at least one R^b is C6 alkyl. [1175] In some embodiments, at least one R^b is C1-C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). 88 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1176] In some embodiments, at least one R^b is C₁-C₆ haloalkyl substituted with one or more R^Tc. [1177] In some embodiments, at least one R^b is C1 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1178] In some embodiments, at least one R^b is C2 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1179] In some embodiments, at least one R^b is C₃ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1180] In some embodiments, at least one R^b is C4 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1181] In some embodiments, at least one R^b is C₅ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1182] In some embodiments, at least one R^b is C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1183] In some embodiments, at least one R^b is C2-C6 alkenyl. [1184] In some embodiments, at least one R^b is C2-C6 alkenyl substituted with one or more R^Tc. [1185] In some embodiments, at least one R^b is C₂ alkenyl. [1186] In some embodiments, at least one R^b is C3 alkenyl. [1187] In some embodiments, at least one R^b is C₄ alkenyl. [1188] In some embodiments, at least one R^b is C₅ alkenyl. [1189] In some embodiments, at least one R^b is C6 alkenyl. [1190] In some embodiments, at least one R^b is C2-C6 alkynyl. [1191] In some embodiments, at least one R^b is C₂-C₆ alkynyl substituted with one or more R^Tc. [1192] In some embodiments, at least one R^b is C2 alkynyl. [1193] In some embodiments, at least one R^b is C₃ alkynyl. [1194] In some embodiments, at least one R^b is C₄ alkynyl. [1195] In some embodiments, at least one R^b is C5 alkynyl. [1196] In some embodiments, at least one R^b is C6 alkynyl. [1197] In some embodiments, at least one R^b is C₃-C₁₀ cycloalkyl. [1198] In some embodiments, at least one R^b is C3-C10 cycloalkyl substituted with one or more R^Tc. [1199] In some embodiments, at least one R^b is C₃-C₁₀ monocyclic cycloalkyl. 89 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1200] In some embodiments, at least one R^b is C₃-C₁₀ monocyclic cycloalkyl substituted with one or more R^Tc. [1201] In some embodiments, at least one R^b is C3 monocyclic cycloalkyl. [1202] In some embodiments, at least one R^b is C₃ monocyclic cycloalkyl substituted with one or more R^Tc. [1203] In some embodiments, at least one R^b is C4 monocyclic cycloalkyl. [1204] In some embodiments, at least one R^b is C₄ monocyclic cycloalkyl substituted with one or more R^Tc. [1205] In some embodiments, at least one R^b is C5 monocyclic cycloalkyl. [1206] In some embodiments, at least one R^b is C₅ monocyclic cycloalkyl substituted with one or more R^Tc. [1207] In some embodiments, at least one R^b is C6 monocyclic cycloalkyl. [1208] In some embodiments, at least one R^b is C6 monocyclic cycloalkyl substituted with one or more R^Tc. [1209] In some embodiments, at least one R^b is C7 monocyclic cycloalkyl. [1210] In some embodiments, at least one R^b is C7 monocyclic cycloalkyl substituted with one or more R^Tc. [1211] In some embodiments, at least one R^b is C₈ monocyclic cycloalkyl. [1212] In some embodiments, at least one R^b is C8 monocyclic cycloalkyl substituted with one or more R^Tc. [1213] In some embodiments, at least one R^b is C₉ monocyclic cycloalkyl. [1214] In some embodiments, at least one R^b is C9 monocyclic cycloalkyl substituted with one or more R^Tc. [1215] In some embodiments, at least one R^b is C₁₀ monocyclic cycloalkyl. [1216] In some embodiments, at least one R^b is C₁₀ monocyclic cycloalkyl substituted with one or more R^Tc. [1217] In some embodiments, at least one R^b is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1218] In some embodiments, at least one R^b is C4-C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1219] In some embodiments, at least one R^b is C₄ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1220] In some embodiments, at least one R^b is C4 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. 90 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1221] In some embodiments, at least one R^b is C₅ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1222] In some embodiments, at least one R^b is C5 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1223] In some embodiments, at least one R^b is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1224] In some embodiments, at least one R^b is C₆ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1225] In some embodiments, at least one R^b is C7 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1226] In some embodiments, at least one R^b is C₇ bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1227] In some embodiments, at least one R^b is C8 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1228] In some embodiments, at least one R^b is C8 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1229] In some embodiments, at least one R^b is C₉ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1230] In some embodiments, at least one R^b is C9 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1231] In some embodiments, at least one R^b is C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1232] In some embodiments, at least one R^b is C10 bicyclic cycloalkyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1233] In some embodiments, at least one R^b is C₄-C₁₀ fused bicyclic cycloalkyl. [1234] In some embodiments, at least one R^b is C4-C10 fused bicyclic cycloalkyl substituted with one or more R^Tc. [1235] In some embodiments, at least one R^b is . [1236] In some embodiments, at least one R^b is substituted with one or more R^Tc. [1237] In some embodiments, at least one R^b is C5-C10 bridged bicyclic cycloalkyl. 91 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1238] In some embodiments, at least one R^b is C₅-C₁₀ bridged bicyclic cycloalkyl substituted with one or more R^Tc. [1239] In some embodiments, at least one R^b is , , . [1240] In some embodiments, at least one R^b is , , substituted with one or more R^Tc. [1241] In some embodiments, at least one R^b is C5-C10 spiro bicyclic cycloalkyl. [1242] In some embodiments, at least one R^b is C₅-C₁₀ spiro bicyclic cycloalkyl substituted with one or more R^Tc. [1243] In some embodiments, at least one R^b 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. [1244] In some embodiments, at least one R^b 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, substituted with one or more R^Tc. [1245] In some embodiments, at least one R^b is . [1246] In some embodiments, at least one R^b is substituted with one or more R^Tc. [1247] In some embodiments, at least one R^b is . [1248] In some embodiments, at least one R^b is substituted with one or more R^Tc. [1249] In some embodiments, at least one R^b is 4- to 10-membered heterocyclyl. [1250] In some embodiments, at least one R^b is 4- to 10-membered heterocyclyl substituted with one or more R^Tc. [1251] In some embodiments, at least one R^b is 4-membered monocyclic heterocyclyl. [1252] In some embodiments, at least one R^b is 4-membered monocyclic heterocyclyl substituted with one or more R^Tc. 92 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1253] In some embodiments, at least one R^b is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1254] In some embodiments, at least one R^b is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1255] In some embodiments, at least one R^b is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1256] In some embodiments, at least one R^b is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1257] In some embodiments, at least one R^b is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1258] In some embodiments, at least one R^b is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1259] In some embodiments, at least one R^b is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1260] In some embodiments, at least one R^b is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1261] In some embodiments, at least one R^b is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1262] In some embodiments, at least one R^b is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1263] In some embodiments, at least one R^b is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1264] In some embodiments, at least one R^b is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) substituted with one or more R^Tc. [1265] In some embodiments, at least one R^b is 4- to 10-membered fused bicyclic heterocyclyl. [1266] In some embodiments, at least one R^b is 4- to 10-membered fused bicyclic heterocyclyl substituted with one or more R^Tc. [1267] In some embodiments, at least one R^b is 5- to 10-membered bridged bicyclic heterocyclyl. [1268] In some embodiments, at least one R^b is 5- to 10-membered bridged bicyclic heterocyclyl substituted with one or more R^Tc. [1269] In some embodiments, at least one R^b is 5- to 10-membered spiro bicyclic heterocyclyl. 93 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1270] In some embodiments, at least one R^b is 5- to 10-membered spiro bicyclic heterocyclyl substituted with one or more R^Tc. [1271] In some embodiments, at least one R^b is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S. [1272] In some embodiments, at least one R^b is 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 R^Tc. [1273] In some embodiments, at least one R^b is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S. [1274] In some embodiments, at least one R^b is 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 R^Tc. [1275] In some embodiments, at least one R^b is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). [1276] In some embodiments, at least one R^b is 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 R^Tc. [1277] In some embodiments, at least one R^b is 4- to 10-membered fused bicyclic heterocyclyl containing one N. [1278] In some embodiments, at least one R^b is 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 R^Tc. [1279] In some embodiments, at least one R^b is 5- to 10-membered bridged bicyclic heterocyclyl containing one N. [1280] In some embodiments, at least one R^b is 5- to 10-membered bridged bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered bridged bicyclic heterocyclyl is substituted with one or more R^Tc. [1281] In some embodiments, at least one R^b is 5- to 10-membered spiro bicyclic heterocyclyl containing one N. [1282] In some embodiments, at least one R^b is 5- to 10-membered spiro bicyclic heterocyclyl containing one N, wherein the 4- to 10-membered spiro bicyclic heterocyclyl is substituted with one or more R^Tc. [1283] In some embodiments, at least one R^b is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl). 94 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1284] In some embodiments, at least one R^b is 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 R^Tc. [1285] In some embodiments, at least one R^b is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O. [1286] In some embodiments, at least one R^b is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O, wherein the 5- to 10-membered bridged heterocyclyl is substituted with one or more R^Tc. [1287] In some embodiments, at least one R^b is 4- to 10-membered monocyclic heterocyclyl containing one S. [1288] In some embodiments, at least one R^b is 4- to 10-membered monocyclic heterocyclyl containing one S, wherein the 4- to 10-membered monocyclic heterocyclyl is substituted with one or more R^Tc. [1289] In some embodiments, at least one R^b is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S. [1290] In some embodiments, at least one R^b is 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 R^Tc. [1291] In some embodiments, at least one R^b is . [1292] In some embodiments, at least one R^b is substituted with one or more R^Tc. [1293] In some embodiments, at least one R^b is . [1294] In some embodiments, at least one R^b is substituted with one or more . [1295] In some embodiments, at least one R^b is . [1296] In some embodiments, at least one R^b is substituted with one or more R^Tc. 95 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1297] In some embodiments, at least one R^b is . [1298] In some embodiments, at least one R^b is substituted with one or more R^Tc. [1299] In some embodiments, at least one R^b is C6-C10 aryl (e.g., phenyl or naphthalenyl). [1300] In some embodiments, at least one R^b is C₆-C₁₀ aryl (e.g., phenyl or naphthalenyl) substituted with one or more R^Tc. [1301] In some embodiments, at least one R^b is phenyl. [1302] In some embodiments, at least one R^b is phenyl substituted with one or more R^Tc. [1303] In some embodiments, at least one R^b is naphthalenyl. [1304] In some embodiments, at least one R^b is naphthalenyl substituted with one or more R^Tc. [1305] In some embodiments, at least one R^b is 5- to 10-membered heteroaryl. [1306] In some embodiments, at least one R^b is 5- to 10-membered heteroaryl substituted with one or more R^Tc. [1307] In some embodiments, at least one R^b is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1308] In some embodiments, at least one R^b is 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 R^Tc. [1309] In some embodiments, at least one R^b is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1310] In some embodiments, at least one R^b is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tc. [1311] In some embodiments, at least one R^b is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). [1312] In some embodiments, at least one R^b is 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 R^Tc. [1313] In some embodiments, at least one R^b is pyrrolyl. [1314] In some embodiments, at least one R^b is pyrrolyl substituted with one or more R^Tc. 96 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1315] In some embodiments, at least one R^b is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl). [1316] In some embodiments, at least one R^b is 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 R^Tc. [1317] In some embodiments, at least one R^b is oxazolyl. [1318] In some embodiments, at least one R^b is . [1319] In some embodiments, at least one R^b is thiazolyl. [1320] In some embodiments, at least one R^b is . [1321] In some embodiments, at least one R^b is . [1322] In some embodiments, at least one R^b is . [1323] In some embodiments, at least one R^b is pyrazolyl. [1324] In some embodiments, at least one R^b is . [1325] In some embodiments, at least one R^b is . [1326] In some embodiments, at least one R^b is isoxazolyl. [1327] In some embodiments, at least one R^b is isothiazolyl. [1328] In some embodiments, at least one R^b is imidazolyl. [1329] In some embodiments, at least one R^b is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl). [1330] In some embodiments, at least one R^b is 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 R^Tc. [1331] In some embodiments, at least one R^b is triazolyl. 97 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1332] In some embodiments, at least one R^b is . [1333] In some embodiments, at least one R^b is . [1334] In some embodiments, at least one R^b is . [1335] In some embodiments, at least one R^b is oxadiazolyl. [1336] In some embodiments, at least one R^b is . [1337] In some embodiments, at least one R^b is thiadiazolyl. [1338] In some embodiments, at least one R^b is . [1339] In some embodiments, at least one R^b is . [1340] In some embodiments, at least one R^b is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl). [1341] In some embodiments, at least one R^b is 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 R^Tc. [1342] In some embodiments, at least one R^b is tetrazolyl. [1343] In some embodiments, at least one R^b is . [1344] In some embodiments, at least one R^b is oxatriazolyl. [1345] In some embodiments, at least one R^b is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1346] In some embodiments, at least one R^b is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S, wherein the heteroaryl is substituted with one or more R^Tc. [1347] In some embodiments, at least one R^b is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl). 98 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1348] In some embodiments, at least one R^b is 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 R^Tc. [1349] In some embodiments, at least one R^b is pyridinyl. [1350] In some embodiments, at least one R^b is . [1351] In some embodiments, at least one R^b is . [1352] In some embodiments, at least one . [1353] In some embodiments, at least one R^b is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl). [1354] In some embodiments, at least one R^b is 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 R^Tc. [1355] In some embodiments, at least one R^b is pyrimidinyl. [1356] In some embodiments, at least one R^b is . [1357] [1358] In some embodiments, at least one R^b is . [1359] In some embodiments, at least one R^b is pyridazinyl. [1360] In some embodiments, at least one R^b is . [1361] In some embodiments, at least one . [1362] In some embodiments, at least one R^b is pyrazinyl. 99 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1363] In some embodiments, at least one R^b is . [1364] In some embodiments, at least one R^b is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S. [1365] In some embodiments, at least one R^b is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S, wherein the heteroaryl is substituted with one or more . [1366] In some embodiments, at least one R^b is . [1367] In some embodiments, at least one R^b is substituted with one or more R^Tc. [1368] In some embodiments, at least one R^b is . [1369] In some embodiments, at least one R^b is substituted with one or more R^Tc. Variables R^Tc [1370] In some embodiments, at least one R^Tc is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -O(C₁-C₆ haloalkyl), -S(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -NH- C(=O)-(C1-C6 alkyl), -NH-C(=O)-O-(C1-C6 alkyl), -NH-S(=O)2-(C1-C6 alkyl), -N(C1-C6 alkyl)-C(=O)-(C1-C6 alkyl), -N(C1-C6 alkyl)-C(=O)-O-(C1-C6 alkyl), -N(C1-C6 alkyl)-S(=O)2- (C₁-C₆ alkyl), C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl. [1371] In some embodiments, at least one R^Tc is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, or 5- to 10- membered heteroaryl. [1372] In some embodiments, at least one R^Tc is oxo. [1373] In some embodiments, at least one R^Tc is halogen. [1374] In some embodiments, at least one R^Tc is cyano. [1375] In some embodiments, at least one R^Tc is -OH. 100 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1376] In some embodiments, at least one R^Tc is -O(C₁-C₆ alkyl). [1377] In some embodiments, at least one R^Tc is -O(C1 alkyl). [1378] In some embodiments, at least one R^Tc is -O(C2 alkyl). [1379] In some embodiments, at least one R^Tc is -O(C₃ alkyl). [1380] In some embodiments, at least one R^Tc is -O(C4 alkyl). [1381] In some embodiments, at least one R^Tc is -O(C5 alkyl). [1382] In some embodiments, at least one R^Tc is -O(C₆ alkyl). [1383] In some embodiments, at least one R^Tc is -O(C1-C6 haloalkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1384] In some embodiments, at least one R^Tc is -O(C₁ haloalkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1385] In some embodiments, at least one R^Tc is -O(C2 haloalkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1386] In some embodiments, at least one R^Tc is -O(C₃ haloalkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1387] In some embodiments, at least one R^Tc is -O(C4 haloalkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1388] In some embodiments, at least one R^Tc is -O(C₅ haloalkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1389] In some embodiments, at least one R^Tc is -O(C₆ haloalkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1390] In some embodiments, at least one R^Tc is -S(C1-C6 alkyl) (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1391] In some embodiments, at least one R^Tc is -S(C₁ alkyl). [1392] In some embodiments, at least one R^Tc is -S(C₂ alkyl). [1393] In some embodiments, at least one R^Tc is -S(C3 alkyl). [1394] In some embodiments, at least one R^Tc is -S(C₄ alkyl). [1395] In some embodiments, at least one R^Tc is -S(C₅ alkyl). [1396] In some embodiments, at least one R^Tc is -S(C6 alkyl). [1397] In some embodiments, at least one R^Tc is -NH2. [1398] In some embodiments, at least one R^Tc is -NH(C₁-C₆ alkyl). [1399] In some embodiments, at least one R^Tc is -NH(C1 alkyl). [1400] In some embodiments, at least one R^Tc is -NH(C2 alkyl). [1401] In some embodiments, at least one R^Tc is -NH(C₃ alkyl). 101 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1402] In some embodiments, at least one R^Tc is -NH(C₄ alkyl). [1403] In some embodiments, at least one R^Tc is -NH(C5 alkyl). [1404] In some embodiments, at least one R^Tc is -NH(C6 alkyl). [1405] In some embodiments, at least one R^Tc is -N(C₁-C₆ alkyl)₂. [1406] In some embodiments, at least one R^Tc is -N(C1 alkyl)2. [1407] In some embodiments, at least one R^Tc is -N(C2 alkyl)2. [1408] In some embodiments, at least one R^Tc is -N(C₃ alkyl)₂. [1409] In some embodiments, at least one R^Tc is -N(C4 alkyl)2. [1410] In some embodiments, at least one R^Tc is -N(C5 alkyl)2. [1411] In some embodiments, at least one R^Tc is -N(C₆ alkyl)₂. [1412] In some embodiments, at least one R^Tc is -NH-C(=O)-(C₁-C₆ alkyl). [1413] In some embodiments, at least one R^Tc is -NH-C(=O)-(C1 alkyl). [1414] In some embodiments, at least one R^Tc is -NH-C(=O)-(C2 alkyl). [1415] In some embodiments, at least one R^Tc is -NH-C(=O)-(C₃ alkyl). [1416] In some embodiments, at least one R^Tc is -NH-C(=O)-(C4 alkyl). [1417] In some embodiments, at least one R^Tc is -NH-C(=O)-(C5 alkyl). [1418] In some embodiments, at least one R^Tc is -NH-C(=O)-(C₆ alkyl). [1419] In some embodiments, at least one R^Tc is -NH-C(=O)-O-(C₁-C₆ alkyl). [1420] In some embodiments, at least one R^Tc is -NH-C(=O)-O-(C1 alkyl). [1421] In some embodiments, at least one R^Tc is -NH-C(=O)-O-(C₂ alkyl). [1422] In some embodiments, at least one R^Tc is -NH-C(=O)-O-(C₃ alkyl). [1423] In some embodiments, at least one R^Tc is -NH-C(=O)-O-(C4 alkyl). [1424] In some embodiments, at least one R^Tc is -NH-C(=O)-O-(C5 alkyl). [1425] In some embodiments, at least one R^Tc is -NH-C(=O)-O-(C₆ alkyl). [1426] In some embodiments, at least one R^Tc is -NH-S(=O)₂-(C₁-C₆ alkyl). [1427] In some embodiments, at least one R^Tc is -NH-S(=O)2-(C1 alkyl). [1428] In some embodiments, at least one R^Tc is -NH-S(=O)₂-(C₂ alkyl). [1429] In some embodiments, at least one R^Tc is -NH-S(=O)₂-(C₃ alkyl). [1430] In some embodiments, at least one R^Tc is -NH-S(=O)2-(C4 alkyl). [1431] In some embodiments, at least one R^Tc is -NH-S(=O)2-(C5 alkyl). [1432] In some embodiments, at least one R^Tc is -NH-S(=O)₂-(C₆ alkyl). [1433] In some embodiments, at least one R^Tc is -N(C1-C6 alkyl)-C(=O)-(C1-C6 alkyl). [1434] In some embodiments, at least one R^Tc is -N(C1-C6 alkyl)-C(=O)-O-(C1-C6 alkyl). [1435] In some embodiments, at least one R^Tc is -N(C₁-C₆ alkyl)-S(=O)₂-(C₁-C₆ alkyl). 102 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1436] In some embodiments, at least one R^Tc is C₁-C₆ alkyl. [1437] In some embodiments, at least one R^Tc is C1 alkyl. [1438] In some embodiments, at least one R^Tc is C2 alkyl. [1439] In some embodiments, at least one R^Tc is C₃ alkyl. [1440] In some embodiments, at least one R^Tc is C4 alkyl. [1441] In some embodiments, at least one R^Tc is C5 alkyl. [1442] In some embodiments, at least one R^Tc is C₆ alkyl. [1443] In some embodiments, at least one R^Tc is C1-C6 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1444] In some embodiments, at least one R^Tc is C₁ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1445] In some embodiments, at least one R^Tc is C2 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1446] In some embodiments, at least one R^Tc is C₃ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1447] In some embodiments, at least one R^Tc is C4 haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1448] In some embodiments, at least one R^Tc is C₅ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1449] In some embodiments, at least one R^Tc is C₆ haloalkyl (e.g., fluoroalkyl, chloroalkyl, bromoalkyl, and iodoalkyl). [1450] In some embodiments, at least one R^Tc is C2-C6 alkenyl. [1451] In some embodiments, at least one R^Tc is C2 alkenyl. [1452] In some embodiments, at least one R^Tc is C₃ alkenyl. [1453] In some embodiments, at least one R^Tc is C₄ alkenyl. [1454] In some embodiments, at least one R^Tc is C5 alkenyl. [1455] In some embodiments, at least one R^Tc is C₆ alkenyl. [1456] In some embodiments, at least one R^Tc is C₂-C₆ alkynyl. [1457] In some embodiments, at least one R^Tc is C2 alkynyl. [1458] In some embodiments, at least one R^Tc is C3 alkynyl. [1459] In some embodiments, at least one R^Tc is C₄ alkynyl. [1460] In some embodiments, at least one R^Tc is C5 alkynyl. [1461] In some embodiments, at least one R^Tc is C6 alkynyl. [1462] In some embodiments, at least one R^Tc is C₃-C₁₀ cycloalkyl. 103 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1463] In some embodiments, at least one R^Tc is C₃-C₁₀ monocyclic cycloalkyl. [1464] In some embodiments, at least one R^Tc is C3 monocyclic cycloalkyl. [1465] In some embodiments, at least one R^Tc is C4 monocyclic cycloalkyl. [1466] In some embodiments, at least one R^Tc is C₅ monocyclic cycloalkyl. [1467] In some embodiments, at least one R^Tc is C6 monocyclic cycloalkyl. [1468] In some embodiments, at least one R^Tc is C7 monocyclic cycloalkyl. [1469] In some embodiments, at least one R^Tc is C₈ monocyclic cycloalkyl. [1470] In some embodiments, at least one R^Tc is C9 monocyclic cycloalkyl. [1471] In some embodiments, at least one R^Tc is C10 monocyclic cycloalkyl. [1472] In some embodiments, at least one R^Tc is C₄-C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1473] In some embodiments, at least one R^Tc is C4 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1474] In some embodiments, at least one R^Tc is C₅ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1475] In some embodiments, at least one R^Tc is C6 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1476] In some embodiments, at least one R^Tc is C₇ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1477] In some embodiments, at least one R^Tc is C₈ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1478] In some embodiments, at least one R^Tc is C9 bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1479] In some embodiments, at least one R^Tc is C₁₀ bicyclic cycloalkyl (e.g., fused, bridged, or spiro). [1480] In some embodiments, at least one R^Tc is C4-C10 fused bicyclic cycloalkyl. [1481] In some embodiments, at least one R^T . [1482] In some embodiments, at least one R^T [1483] In some embodiments, at least one R^T , , . [1484] In some embodiments, at least one R^Tc is C5-C10 spiro bicyclic cycloalkyl. 104 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1485] In some embodiments, at least one R^Tc 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. [1486] In some embodiments, at least one R^Tc is . [1487] In some embodiments, at least one R^Tc is . [1488] In some embodiments, at least one R^Tc is 4- to 10-membered heterocyclyl. [1489] In some embodiments, at least one R^Tc is 4-membered monocyclic heterocyclyl. [1490] In some embodiments, at least one R^Tc is 5-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1491] In some embodiments, at least one R^Tc is 6-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1492] In some embodiments, at least one R^Tc is 7-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1493] In some embodiments, at least one R^Tc is 8-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1494] In some embodiments, at least one R^Tc is 9-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1495] In some embodiments, at least one R^Tc is 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro). [1496] In some embodiments, at least one R^Tc is 4- to 10-membered fused bicyclic heterocyclyl. [1497] In some embodiments, at least one R^Tc is 5- to 10-membered bridged bicyclic heterocyclyl. [1498] In some embodiments, at least one R^Tc is 5- to 10-membered spiro bicyclic heterocyclyl. [1499] In some embodiments, at least one R^Tc is 4- to 10-membered heterocyclyl containing at least one heteroatom selected from N, O, and S. [1500] In some embodiments, at least one R^Tc is 4- to 10-membered monocyclic heterocyclyl containing at least one heteroatom selected from N, O, and S. [1501] In some embodiments, at least one R^Tc is 4- to 10-membered monocyclic heterocyclyl containing one N (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). 105 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1502] In some embodiments, at least one R^Tc is 4- to 10-membered fused bicyclic heterocyclyl containing one N. [1503] In some embodiments, at least one R^Tc is 5- to 10-membered bridged bicyclic heterocyclyl containing one N. [1504] In some embodiments, at least one R^Tc is 5- to 10-membered spiro bicyclic heterocyclyl containing one N. [1505] In some embodiments, at least one R^Tc is 4- to 10-membered monocyclic heterocyclyl containing one O (e.g., oxeTcnyl, tetrahydrofuranyl, or tetrahydropyranyl). [1506] In some embodiments, at least one R^Tc is 4- to 10-membered bicyclic heterocyclyl (e.g., fused, bridged, or spiro) containing one O. [1507] In some embodiments, at least one R^Tc is 4- to 10-membered monocyclic heterocyclyl containing one S. [1508] In some embodiments, at least one R^Tc is 4- to 10-membered monocyclic heterocyclyl containing two heteroatoms selected from N, O, and S. [1509] In some embodiments, at least one R^Tc is . [1510] In some embodiments, at least one R^Tc . [1511] In some embodiments, at least one R^Tc is . [1512] In some embodiments, at least one R^Tc is . [1513] In some embodiments, at least one R^Tc is C₆-C₁₀ aryl (e.g., phenyl or naphthalenyl). [1514] In some embodiments, at least one R^Tc is phenyl. [1515] In some embodiments, at least one R^Tc is naphthalenyl. [1516] In some embodiments, at least one R^Tc is 5- to 10-membered heteroaryl. [1517] In some embodiments, at least one R^Tc is 5- to 10-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1518] In some embodiments, at least one R^Tc is 5-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1519] In some embodiments, at least one R^Tc is 5-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyrrolyl, furanyl, or thiophenyl). [1520] In some embodiments, at least one R^Tc is pyrrolyl. 106 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1521] In some embodiments, at least one R^Tc is . [1522] In some embodiments, at least one R^Tc is . [1523] In some embodiments, at least one R^Tc is 5-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, or imidazolyl). [1524] In some embodiments, at least one R^Tc is oxazolyl. [1525] In some embodiments, at least one R^Tc is . [1526] In some embodiments, at least one R^Tc is thiazolyl. [1527] In some embodiments, at least one R^Tc is . [1528] In some embodiments, at least one R^Tc is . [1529] In some embodiments, at least one R^Tc is . [1530] In some embodiments, at least one R^Tc is pyrazolyl. [1531] In some embodiments, at least one R^Tc is . [1532] In some embodiments, at least one R^Tc . [1533] In some embodiments, at least one R^Tc is isoxazolyl. [1534] In some embodiments, at least one R^Tc is isothiazolyl. [1535] In some embodiments, at least one R^Tc is imidazolyl. [1536] In some embodiments, at least one R^Tc is 5-membered heteroaryl containing three heteroatoms selected from N, O, and S (e.g., triazolyl, oxadiazolyl, thiadiazolyl, or oxathiadiazolyl). [1537] In some embodiments, at least one R^Tc is triazolyl. [1538] In some embodiments, at least one R^Tc is . 107 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1539] In some embodiments, at least one R is . [1540] In some embodiments, at least one R^Tc is . [1541] In some embodiments, at least one R^Tc is oxadiazolyl. [1542] In some embodiments, at least one R^Tc is . [1543] In some embodiments, at least one R^Tc is thiadiazolyl. [1544] In some embodiments, at least one R^Tc is . [1545] In some embodiments, at least one R^Tc is . [1546] In some embodiments, at least one R^Tc is 5-membered heteroaryl containing four heteroatoms selected from N, O, and S (e.g., tetrazolyl or oxatriazolyl). [1547] In some embodiments, at least one R^Tc is tetrazolyl. [1548] In some embodiments, at least one R^Tc is . [1549] In some embodiments, at least one R^Tc is oxatriazolyl. [1550] In some embodiments, at least one R^Tc is 6-membered heteroaryl containing at least one heteroatom selected from N, O, and S. [1551] In some embodiments, at least one R^Tc is 6-membered heteroaryl containing one heteroatom selected from N, O, and S (e.g., pyridinyl, pyranyl, or thiopyranyl). [1552] In some embodiments, at least one R^Tc is pyridinyl. [1553] In some embodiments, at least one R^Tc . [1554] In some embodiments, at least one R^Tc is . [1555] In some embodiments, at least one . 108 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1556] In some embodiments, at least one R^Tc is 6-membered heteroaryl containing two heteroatoms selected from N, O, and S (e.g., pyrimidinyl, pyridazinyl, or pyrazinyl). [1557] In some embodiments, at least one R^Tc is pyrimidinyl. [1558] In some embodiments, at least one R^Tc is . [1559] In some embodiments, at least one . [1560] In some embodiments, at least one R^Tc is . [1561] In some embodiments, at least one R^Tc is pyridazinyl. [1562] In some embodiments, at least one R^Tc is . [1563] In some embodiments, at least one R^Tc is . [1564] In some embodiments, at least one R^Tc is pyrazinyl. [1565] In some embodiments, at least one R^Tc is . [1566] In some embodiments, at least one R^Tc is 9-membered heteroaryl containing two heteroatoms selected from N, O, and S. [1567] In some embodiments, at least one R^Tc is . [1568] In some embodiments, at least one R^Tc is . Variables m, n, and ring A [1569] In some embodiments, m is 1, 2, or 3. [1570] In some embodiments, m is 1. [1571] In some embodiments, m is 2. [1572] In some embodiments, m is 3. [1573] In some embodiments, n is 1, 2, or 3. 109 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1574] In some embodiments, n is 1. [1575] In some embodiments, n is 2. [1576] In some embodiments, n is 3. [1577] In some embodiments, ring A is C₃-C₁₀ cycloalkyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl. [1578] In some embodiments, ring A is C3-C10 cycloalkyl. [1579] In some embodiments, ring A is C₆-C₁₀ aryl. [1580] In some embodiments, ring A is 5- to 10-membered heteroaryl. [1581] In some embodiments, ring A is phenyl, cyclohexyl, , , , , pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. , Exemplary Embodiments of the Compounds [1582] In some embodiments, R¹ is H and R² is H. [1583] In some embodiments, R¹ is methyl and R² is H. [1584] In some embodiments, R¹ and R² together form -CH2-. [1585] In some embodiments, R⁵ is H and R⁶ is CF₃. [1586] In some embodiments, R⁵ and R⁶ together form oxo. [1587] In some embodiments, Ar¹ is C6-C10 aryl optionally substituted with one or more R^t, and each R^t is independently halogen, -O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -NO₂, or C₁- C₆ alkyl. [1588] In some embodiments, Ar¹ is C6-C10 aryl optionally substituted with one or more R^t, and each R^t is independently -F, -Br, -O(CH₃), -NH₂, -NH(CH₃), -NO₂, or -CH₃. 110 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1589] In some embodiments, Ar¹ is phenyl optionally substituted with one or more R^t, and each R^t is independently halogen, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NO2, or C1-C6 alkyl. [1590] In some embodiments, Ar¹ is phenyl optionally substituted with one or more R^t, and each R^t is independently -F, -Br, -O(CH3), -NH2, -NH(CH3), -NO2, or -CH3. [1591] In some embodiments, Ar¹ is 5- to 10-membered heteroaryl optionally substituted with one or more R^t, and each R^t is independently halogen, -O(C₁-C₆ alkyl), -NH₂, -NH(C₁- C6 alkyl), -NO2, or C1-C6 alkyl. [1592] In some embodiments, Ar¹ is 5- to 10-membered heteroaryl optionally substituted with one or more R^t, and each R^t is independently -F, -Br, -O(CH₃), -NH₂, -NH(CH₃), -NO₂, or -CH₃. [1593] In some embodiments, Ar¹ is isoxazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, optionally substituted with one or more R^t, and each R^t is independently halogen, -O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -NO₂, or C₁-C₆ alkyl. [1594] In some embodiments, Ar¹ is isoxazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, optionally substituted with one or more R^t, and each R^t is independently -F, -Br, -O(CH₃), -NH₂, -NH(CH₃), -NO₂, or -CH₃. [1595] In some embodiments, T is -N(R^T1)₂; one R^T1 is C1-C3 alkyl substituted with one R^Ta; R^Ta is -OR^a; and R^a is C₆ aryl or 5- to 6- membered heteroaryl, wherein the C₆ aryl or 5- to 6- membered heteroaryl is optionally substituted with 1 or 2 R^Tb. [1596] In some embodiments, T is -N(R^T2)2; two R^T2, together with the atom to which they are attached, form 4- to 6-membered heterocyclyl substituted with one or more R^Ta; R^Ta is -OR^a; and R^a is C₆ aryl or 5- to 6- membered heteroaryl, wherein the C₆ aryl or 5- to 6- membered heteroaryl is optionally substituted with 1 or 2 R^Tb. [1597] In some embodiments, T is -N(R^T2)2; two R^T2, together with the atom to which they are attached, form 4- to 6-membered heterocyclyl substituted with one or more R^Ta; at least one R^Ta is C1-C6 alkyl substituted with one or more R^Tb; at least one R^Tb is -OR^b; and 111 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 R^b is C₃-C₆ cycloalkyl, 4- to 6-membered heterocyclyl, C₆ aryl, or 5- to 6- membered heteroaryl, wherein the C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C6 aryl, or 5- to 6- membered heteroaryl is optionally substituted with one or more R^Tc. [1598] In some embodiments, T is -N(R^T1)2; one R^T1 is C1-C6 alkyl or C3-C10 cycloalkyl, wherein the C1-C6 alkyl or C3-C10 cycloalkyl is optionally substituted with one or more R^Ta, and the other R^T1 is C₁-C₆ alkyl substituted with one or more R^Ta; at least one R^Ta is oxo, halogen, cyano, -OH, -NH2, C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; at least one R^Tb independently is oxo, halogen, cyano, -OH, -NH2, C1-C6 alkyl, C3- C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and at least one R^Tc is oxo, halogen, cyano, -OH, -O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or 5- to 10- membered heteroaryl. [1599] In some embodiments, T is -N(R^T1)2; one R^T1 is C₁-C₆ alkyl or C₃-C₁₀ cycloalkyl (e.g., C₃ cycloalkyl), wherein the C₁-C₆ alkyl or C₃-C₁₀ cycloalkyl is optionally substituted with one or more R^Ta, and the other R^T1 is C1-C6 alkyl substituted with one or more R^Ta; at least one R^Ta is -OR^a, -SR^a, -NHR^a, -N(R^a)2, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, - NH-S(=O)₂-R^a, -N(C₁-C₆ alkyl)-C(=O)-R^a, -N(C₁-C₆ alkyl)-C(=O)-O-R^a, or -N(C₁-C₆ alkyl)- S(=O)₂-R^a; at least one R^a is C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; at least one R^Tb independently is oxo, halogen, cyano, -OH, -NH2, C1-C6 alkyl, C3- C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and 112 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 at least one R^Tc is oxo, halogen, cyano, -OH, -O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, or 5- to 10- membered heteroaryl. [1600] In some embodiments, T is -N(R^T2)2; two R^T2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more R^Ta; at least one R^Ta is oxo, halogen, cyano, -OH, -NH2, or C1-C6 alkyl, wherein the C1- C₆ alkyl is optionally substituted with one or more R^Tb; at least one R^Tb is -OR^b; at least one R^b is C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and at least one R^Tc is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. [1601] In some embodiments, the compound is selected from the compounds described in Tables 1-2, and pharmaceutically acceptable salts thereof, racemic form thereof, or stereoisomer thereof. [1602] In some embodiments, the compound is selected from the compounds described in Tables 1-2, and pharmaceutically acceptable salts thereof. [1603] In some embodiments, the compound is selected from the compounds described in Tables 1-2. [1604] In some embodiments, the compound is selected from the compounds described in Table 1, and pharmaceutically acceptable salts thereof. [1605] In some embodiments, the compound is selected from the compounds described in Table1. [1606] In some embodiments, the compound is selected from the compounds described in Table 2, and pharmaceutically acceptable salts thereof. [1607] In some embodiments, the compound is selected from the compounds described in Table2. 113 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Table 1 114 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 115 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 116 319794142 v2

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Attorney Docket No. PRTE-020/01WO 345214-2086 118 319794142 v2

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Attorney Docket No. PRTE-020/01WO 345214-2086 120 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 121 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 122 319794142 v2

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Attorney Docket No. PRTE-020/01WO 345214-2086 124 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 125 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Table 2 126 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 127 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 128 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 129 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 130 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 131 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 132 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 133 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 134 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Additional Exemplary Embodiments of the Compounds [1608] In one embodiment, provided herein is a compound for use in the compositions and methods provided herein having Formula I: 135 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 or a pharmaceutically acceptable derivative thereof, where R¹ is H or alkyl and R² is H; or R¹ and R² together form (CH₂)x where x is 1, 2, or 3; R³ and R⁴ are selected from (i) and (ii): (i) R³ is optionally substituted alkyl and R⁴ is H; or (ii) R³ and R⁴ together form (CH2)y where y is 1, 2, 3 or 4; R⁵ is H and R⁶ is haloalkyl; or R⁵ and R⁶ together form =O; X¹ is O or NR⁷ where R⁷ is H or alkyl; X² is CH or N; and Ar¹ and Ar² are each independently optionally substituted aryl or optionally substituted heteroaryl. [1609] In another embodiment, the compound for use in the compositions and methods provided herein has Formula I, where: R¹ is H or methyl and R² is H; or R¹ and R² together form -CH₂-; R³ and R⁴ are selected from (i) and (ii): (i) R³ is optionally substituted alkyl and R⁴ is H; or (ii) R³ and R⁴ together form –(CH₂)₃-; R⁵ and R⁶ together form =O; X¹ is O or NR⁷ where R⁷ is H or methyl; X² is CH; and Ar¹ is optionally substituted heteroaryl; and Ar² is optionally substituted aryl. [1610] In another embodiment, R⁵ is H and R⁶ is trifluoromethyl. [1611] In another embodiment, the compound for use in the compositions and methods provided herein has Formula II: or a pharmaceutically acceptable derivative thereof. 136 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1612] In another embodiment, the compound for use in the compositions and methods provided herein has Formula II, where: R¹ is H or methyl and R² is H; or R¹ and R² together form -CH2-; R³ and R⁴ are selected from (i) and (ii): (i) R³ is optionally substituted alkyl and R⁴ is H; or (ii) R³ and R⁴ together form –(CH2)3-; X¹ is O or NR⁷ where R⁷ is H or methyl; X² is CH; and Ar¹ is optionally substituted heteroaryl; and Ar² is optionally substituted aryl. [1613] In another embodiment, Ar¹ is phenyl or optionally substituted heteroaryl. In another embodiment, Ar¹ is optionally substituted heteroaryl. In another embodiment, Ar¹ is optionally substituted pyrimidinyl, pyridyl, isoxazolyl, triazolyl or thiadiazolyl. In another embodiment, Ar¹ is pyrimidinyl, pyridyl, isoxazolyl, triazolyl or thiadiazolyl, each optionally substituted with NR⁸R⁹, OR¹⁰, alkyl, nitro or halo, where R⁸, R⁹ and R¹⁰ are each independently H or alkyl. In another embodiment, Ar¹ is pyrimidinyl, pyridyl, isoxazolyl, triazolyl or thiadiazolyl, each optionally substituted with fluoro, bromo, nitro, methoxy, NH₂, methyl or NHMe. In another embodiment, Ar¹ is selected from 2-amino-4-pyrimidinyl, 2- methoxy-4-pyridyl, 2-methoxy-4-pyrimidinyl, 2-fluoro-4-pyrimidinyl, 2-amino-4- pyrimidinyl, 4-pyridyl, 2-amino-4-pyridyl, 3-methyl-5-isoxazolyl, 1-methyl-3- bromo[1,2,4]triazol-5-yl, 1,3-dimethyl[1,2,4]triazol-5-yl, 3-methyl[1,2,4]thiadiazol-5-yl, 2- nitro-4-pyridyl or 2-methylamino-4-pyrimidinyl. [1614] In another embodiment, Ar² is optionally substituted phenyl or optionally substituted pyridyl. In another embodiment, Ar² is phenyl or pyridyl, each optionally substituted with alkyl or haloalkyl. In another embodiment, Ar² is phenyl or pyridyl, each optionally substituted with methyl or trifluoromethyl. In another embodiment, Ar² is 4- methylphenyl. In another embodiment, Ar² is 5-trifluoromethyl-2-pyridyl. [1615] In another embodiment, X¹ is O. In another embodiment, X¹ is NH. In another embodiment, X¹ is NR⁷ where R⁷ is alkyl. In another embodiment, X¹ is NMe. [1616] In another embodiment, X² is CH. In another embodiment, X² is N. [1617] In another embodiment, R¹ is H or methyl. In another embodiment, R¹ is methyl. In another embodiment, R¹ is H. [1618] In another embodiment, R² is H. In another embodiment, R¹ and R² together form -CH₂-. 137 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1619] In another embodiment, R³ is alkyl optionally substituted with hydroxy, alkoxy, aralkoxy or amino. In another embodiment, R³ is alkyl optionally substituted with hydroxy, methoxy, benzyloxy or amino. In another embodiment, R³ is methyl, isopropyl, cyanomethyl, 2-methoxy-1-ethyl, 3-methoxy-1-propyl, 2-amino-1-ethyl, 2-benzyloxy-1-ethyl or 2-hydroxy- 1-ethyl. [1620] In another embodiment, R⁴ is H. In another embodiment, R³ and R⁴ together form –(CH₂)₃-. [1621] In one embodiment, the compound for use in the compositions and methods provided herein is the (±)-trans isomer: . [1622] In one embodiment, the compound for use in the compositions and methods provided herein is the enantiomerically pure trans isomer: . [1623] In one embodiment, the compound for use in the compositions and methods provided herein is the (±)-trans isomer: . [1624] In one embodiment, the compound for use in the compositions and methods provided herein is the enantiomerically pure trans isomer: 138 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 . [1625] In another embodiment, the compound for use in the compositions and methods provided herein is selected from those shown in the table below. The indicated stereochemistry (i.e., “trans”, “(2R,4S)” or “(2S,4R)”) refers to the 2- and 4-positions of the tetrahydrofuranyl ring. The designation “(±)-trans” means the compound is a racemic mixture of the trans isomers. Synthesis of the Compounds [1626] The compounds provided herein may be prepared according to the synthetic procedures in the Examples and by methods well known to those of skill in the art. See, e.g., WO 2022/251533 and WO 2021/007594. Pharmaceutical Compositions [1627] The pharmaceutical compositions provided herein contain therapeutically effective amounts of one or more of compounds provided herein and a pharmaceutically acceptable carrier, diluent or excipient. [1628] The compounds can be formulated into suitable pharmaceutical preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for ophthalmic or parenteral administration, as well as transdermal patch preparation and dry powder inhalers. Typically, the compounds described above are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Seventh Edition 1999). [1629] In the compositions, effective concentrations of one or more compounds or pharmaceutically acceptable salts is (are) mixed with a suitable pharmaceutical carrier or vehicle. In certain embodiments, the concentrations of the compounds in the compositions are 139 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms and/or progression of a disease or disorder disclosed herein. [1630] Typically, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved or ameliorated. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. [1631] In addition, the compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. Liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as known in the art. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. [1632] The active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems described herein and then extrapolated therefrom for dosages for humans. In some embodiments, the active compound is administered in a method to achieve a therapeutically effective concentration of the drug. In some embodiments, a companion diagnostic (see, e.g., Olsen D and Jorgensen J T, Front. Oncol., 2014 May 16, 4:105, doi: 10.3389/fonC.2014.00105) is used to determine the therapeutic concentration and safety profile of the active compound in specific subjects or subject populations. [1633] The concentration of active compound in the pharmaceutical composition will depend on absorption, tissue distribution, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, 140 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 the amount that is delivered is sufficient to ameliorate one or more of the symptoms of a disease or disorder disclosed herein. [1634] In certain embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/mL to about 50-100 µg/mL. In one embodiment, the pharmaceutical compositions provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Pharmaceutical dosage unit forms are prepared to provide from about 1 mg to about 1000 mg and in certain embodiments, from about 10 to about 500 mg of the essential active ingredient or a combination of essential ingredients per dosage unit form. [1635] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions. [1636] Thus, effective concentrations or amounts of one or more of the compounds described herein or pharmaceutically acceptable salts thereof are mixed with a suitable pharmaceutical carrier or vehicle for systemic, topical or local administration to form pharmaceutical compositions. Compounds are included in an amount effective for ameliorating one or more symptoms of, or for treating, retarding progression, or preventing. The concentration of active compound in the composition will depend on absorption, tissue distribution, inactivation, excretion rates of the active compound, the dosage schedule, amount administered, particular formulation as well as other factors known to those of skill in the art. [1637] The compositions are intended to be administered by a suitable route, including but not limited to oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, mucosal, dermal, transdermal, buccal, rectal, topical, local, nasal or inhalation. For oral administration, capsules and tablets can be formulated. The compositions are in 141 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 liquid, semi-liquid or solid form and are formulated in a manner suitable for each route of administration. [1638] Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerin, propylene glycol, dimethyl acetamide or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose. Parenteral preparations can be enclosed in ampules, pens, disposable syringes or single or multiple dose vials made of glass, plastic or other suitable material. [1639] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate. [1640] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. [1641] The pharmaceutical compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil water emulsions containing suitable quantities of the compounds or pharmaceutically acceptable salts thereof. The pharmaceutically therapeutically active compounds and salts thereof are formulated and administered in unit dosage forms or multiple dosage forms. Unit dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier, vehicle or diluent. Examples of unit dose forms include ampules and syringes and individually packaged tablets or capsules. Unit dose forms may be administered in fractions or multiples thereof. A multiple dose form is a plurality of identical unit dosage forms packaged in a single container to be administered 142 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 in segregated unit dose form. Examples of multiple dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit doses which are not segregated in packaging. [1642] Sustained-release preparations can also be prepared. Suitable examples of sustained- release preparations include semipermeable matrices of solid hydrophobic polymers containing the compound provided herein, which matrices are in the form of shaped articles, e.g., films, or microcapsule. Examples of sustained-release matrices include iontophoresis patches, polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and ethyl-L-glutamate, non- degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated compound remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in their structure. Rational strategies can be devised for stabilization depending on the mechanism of action involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions. [1643] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from non-toxic carrier may be prepared. For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium croscarmellose, glucose, sucrose, magnesium carbonate or sodium saccharin. Such compositions include solutions, suspensions, tablets, capsules, powders and sustained release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain about 0.001%-100% active ingredient, in certain 143 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 embodiments, about 0.1-85% active ingredient, or, in other embodiments, about 75-95% active ingredient. [1644] The active compounds or pharmaceutically acceptable salts may be prepared with carriers that protect the compound against rapid elimination from the body, such as time release formulations or coatings. [1645] The compositions may include other active compounds to obtain desired combinations of properties. The compounds provided herein, or pharmaceutically acceptable salts thereof as described herein, may also be advantageously administered for therapeutic or prophylactic purposes together with another pharmacological agent known in the general art to be of value in treating one or more of the diseases or medical conditions referred to hereinabove, such as diseases related to oxidative stress. It is to be understood that such combination therapy constitutes a further aspect of the compositions and methods of treatment provided herein. [1646] Lactose-free compositions provided herein can contain excipients that are well known in the art and are listed, for example, in the U.S. Pharmacopeia (USP) SP (XXI)/NF (XVI). In general, lactose-free compositions contain an active ingredient, a binder/filler, and a lubricant in pharmaceutically compatible and pharmaceutically acceptable amounts. Exemplary lactose-free dosage forms contain an active ingredient, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate. [1647] Further encompassed are anhydrous pharmaceutical compositions and dosage forms containing a compound provided herein. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. See, e.g., Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp.379-80. In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment and use of formulations. [1648] Anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms that comprise lactose and at least one active ingredient that comprises a primary or secondary amine are anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. 144 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1649] An anhydrous pharmaceutical composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs and strip packs. Oral Dosage Forms [1650] Oral pharmaceutical dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric coated, sugar coated or film coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art. [1651] In certain embodiments, the formulations are solid dosage forms, such as capsules or tablets. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder; a diluent; a disintegrating agent; a lubricant; a glidant; a sweetening agent; and a flavoring agent. [1652] Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water-soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Emetic coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate. 145 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1653] If oral administration is desired, the compound could be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient. [1654] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. [1655] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action, such as antacids, H2 blockers, and diuretics. The active ingredient is a compound or pharmaceutically acceptable salt thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included. [1656] Pharmaceutically acceptable carriers included in tablets are binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, and wetting agents. Enteric coated tablets, because of the enteric coating, resist the action of stomach acid and dissolve or disintegrate in the neutral or alkaline intestines. Sugar coated tablets are compressed tablets to which different layers of pharmaceutically acceptable substances are applied. Film coated tablets are compressed tablets which have been coated with a polymer or other suitable coating. Multiple compressed tablets are compressed tablets made by more than one compression cycle utilizing the pharmaceutically acceptable substances previously mentioned. Coloring agents may also be used in the above dosage forms. Flavoring and sweetening agents are used in compressed tablets, sugar coated, multiple compressed and chewable tablets. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges. [1657] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil in-water or water in oil. In some 146 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles. [1658] Elixirs are clear, sweetened, hydroalcoholic preparations. Pharmaceutically acceptable carriers used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid. Pharmaceutically acceptable carriers used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use pharmaceutically acceptable suspending agents and preservatives. Pharmaceutically acceptable substances used in non- effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Pharmaceutically acceptable substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms. [1659] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluents include lactose and sucrose. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic adds include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water-soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such fruits, and synthetic blends of compounds which produce a pleasant taste sensation. [1660] For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos.4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be easily measured for administration. 147 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1661] Alternatively, liquid or semi solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells. Other useful formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550- dimethyl ether, polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates. [1662] Other formulations include, but are not limited to, aqueous alcoholic solutions including a pharmaceutically acceptable acetal. Alcohols used in these formulations are any pharmaceutically acceptable water-miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal. [1663] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenylsalicylate, waxes and cellulose acetate phthalate. Injectables, Solutions and Emulsions [1664] Parenteral administration, generally characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. In some embodiments, the suspension is a suspension of microparticles or nanoparticles. In some embodiments, the emulsion is an emulsion of microparticles or nanoparticles. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, 148 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 sorbitan monolaurate, triethanolamine oleate and cyclodextrins. Implantation of a slow release or sustained release system, such that a constant level of dosage is maintained is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. [1665] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or nonaqueous. [1666] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof. [1667] Pharmaceutically acceptable carriers used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other pharmaceutically acceptable substances. 149 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1668] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Pharmaceutical carriers also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. [1669] The concentration of the pharmaceutically active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the subject or animal as is known in the art. [1670] The unit dose parenteral preparations are packaged in an ampule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. [1671] Illustratively, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect. [1672] Injectables are designed for local and systemic administration. Typically, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1% w/w up to about 90% w/w or more, such as more than 1% w/w of the active compound to the treated tissue(s). The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the tissue being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with 150 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 the age of the individual treated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed formulations. [1673] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined. Lyophilized Powders [1674] Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels. [1675] The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable salt thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose or other suitable agent. The solvent may also contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at, in one embodiment, about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. Generally, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage (including but not limited to 10-1000 mg or 100-500 mg) or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4° C. to room temperature. [1676] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, about 1-50 mg, about 5- 35 mg, or about 9-30 mg of lyophilized powder, is added per mL of sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined. 151 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Topical Administration [1677] Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsion or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration. [1678] The compounds or pharmaceutically acceptable salts thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Pat. Nos.4,044,126, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will have diameters of less than 50 microns or less than 10 microns. [1679] The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered. [1680] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01%-10% isotonic solutions, pH about 5-7, with appropriate salts. Compositions for Other Routes of Administration [1681] Other routes of administration, such as topical application, transdermal patches, and rectal administration are also contemplated herein. [1682] For example, pharmaceutical dosage forms for rectal administration are rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories are used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Pharmaceutically acceptable substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono, di and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to 152 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. An exemplary weight of a rectal suppository is about 2 to 3 grams. [1683] Tablets and capsules for rectal administration are manufactured using the same pharmaceutically acceptable substance and by the same methods as for formulations for oral administration. Sustained Release Compositions [1684] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; and U.S. Pat. Nos.4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, 5,639,480, 5,733,566, 5,739,108, 5,891,474, 5,922,356, 5,972,891, 5,980,945, 5,993,855, 6,045,830, 6,087,324, 6,113,943, 6,197,350, 6,248,363, 6,264,970, 6,267,981, 6,376,461, 6,419,961, 6,589,548, 6,613,358, 6,699,500 and 6,740,634, each of which is incorporated herein by reference. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. [1685] All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. In one embodiment, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. In certain embodiments, advantages of controlled- release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance. In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects. [1686] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of 153 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds. [1687] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In one embodiment, a pump may be used (see, Sefton, CRC Crit. Ref. Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med.321:574 (1989). In another embodiment, polymeric materials can be used. In yet another embodiment, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol.2, pp.115-138 (1984). [1688] In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor. Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. 154 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Targeted Formulations [1689] The compounds provided herein, or pharmaceutically acceptable salts thereof, may also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non- limiting examples of targeting methods, see, e.g., U.S. Pat. Nos.6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. [1690] In one embodiment, the antibody-based delivery system is an antibody-drug conjugate ("ADC"), e.g., as described in Hamilton G S, Biologicals, 2015 September, 43(5):318-32; Kim E G and Kim K M, Biomol. Ther. (Seoul), 2015 November, 23(6):493- 509; and Peters C and Brown S, Biosci. Rep., 2015 Jun.12, 35(4) pii: e00225, each of which is incorporated herein by reference. [1691] In one embodiment, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine (7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. Articles of Manufacture [1692] The compounds or pharmaceutically acceptable salts can be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable salt thereof provided herein, which is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein, and a label that indicates that the compound or pharmaceutically acceptable salt thereof is used for treatment, prevention or amelioration of one or more symptoms or progression of a disease or disorder disclosed herein. [1693] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products are well known to those of skill in the 155 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, pens, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated. [1694] In certain embodiments, provided herein also are kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject. In certain embodiments, the kit provided herein includes a container and a dosage form of a compound provided herein, or a pharmaceutically acceptable derivative thereof. [1695] In certain embodiments, the kit includes a container comprising a dosage form of the compound provided herein, or a pharmaceutically acceptable derivative thereof, in a container comprising one or more other therapeutic agent(s) described herein. [1696] Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needle- less injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients. [1697] Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients. For example, if an active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Dosing [1698] The compounds and pharmaceutical compositions provided herein may be dosed in certain therapeutically or prophylactically effective amounts, certain time intervals, certain dosage forms, and certain dosage administration methods as described below. 156 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1699] In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about 0.005 to about 1,000 mg per day, from about 0.01 to about 500 mg per day, from about 0.01 to about 250 mg per day, from about 0.01 to about 100 mg per day, from about 0.1 to about 100 mg per day, from about 0.5 to about 100 mg per day, from about 1 to about 100 mg per day, from about 0.01 to about 50 mg per day, from about 0.1 to about 50 mg per day, from about 0.5 to about 50 mg per day, from about 1 to about 50 mg per day, from about 0.02 to about 25 mg per day, from about 0.05 to about 10 mg per day, from about 0.05 to about 5 mg per day, from about 0.1 to about 5 mg per day, or from about 0.5 to about 5 mg per day. [1700] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.5, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, or about 150 mg per day. [1701] In one embodiment, the recommended daily dose range of the compound provided herein, or a derivative thereof, for the conditions described herein lie within the range of from about 0.5 mg to about 50 mg per day, in one embodiment given as a single once-a-day dose, or in divided doses throughout a day. In some embodiments, the dosage ranges from about 1 mg to about 50 mg per day. In other embodiments, the dosage ranges from about 0.5 to about 5 mg per day. Specific doses per day include 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50 mg per day. [1702] In a specific embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25 or 50 mg per day. In another embodiment, the recommended starting dosage may be 0.5, 1, 2, 3, 4, or 5 mg per day. The dose may be escalated to 15, 20, 25, 30, 35, 40, 45 and 50 mg/day. In a specific embodiment, the compound can be administered in an amount of about 25 mg/day. In a particular embodiment, the compound can be administered in an amount of about 10 mg/day. In a particular embodiment, the compound can be administered in an amount of about 5 mg/day. In a particular embodiment, the compound can be administered in an amount of about 4 mg/day. In a particular embodiment, the compound can be administered in an amount of about 3 mg/day. [1703] In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 100 mg/kg/day, from about 0.01 to about 50 mg/kg/day, from about 0.01 to about 25 mg/kg/day, from about 0.01 to about 10 mg/kg/day, from about 0.01 to about 9 mg/kg/day, 0.01 to about 8 mg/kg/day, from about 0.01 to about 7 mg/kg/day, 157 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 from about 0.01 to about 6 mg/kg/day, from about 0.01 to about 5 mg/kg/day, from about 0.01 to about 4 mg/kg/day, from about 0.01 to about 3 mg/kg/day, from about 0.01 to about 2 mg/kg/day, from about 0.01 to about 1 mg/kg/day, or from about 0.01 to about 0.05 mg/kg/day. [1704] The administered dose can also be expressed in units other than mg/kg/day. For example, doses for parenteral administration can be expressed as mg/m²/day. One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m²/day to given either the height or weight of a subject or both (see, www.fda.gov/cder/cancer/animalframe.htm). For example, a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m²/day. [1705] In certain embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM, or from about 1 to about 20 µM. [1706] In other embodiments, the amount of the compound administered is sufficient to provide a plasma concentration of the compound at steady state, ranging from about 5 to about 100 nM, about 5 to about 50 nM, about 10 to about 100 nM, about 10 to about 50 nM or from about 50 to about 100 nM. [1707] As used herein, the term "plasma concentration at steady state" is the concentration reached after a period of administration of a compound provided herein, or a derivative thereof. Once steady state is reached, there are minor peaks and troughs on the time dependent curve of the plasma concentration of the compound. [1708] In certain embodiments, the amount of the compound administered is sufficient to provide a maximum plasma concentration (peak concentration) of the compound, ranging from about 0.001 to about 50 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.02 to about 25 µM, from about 0.05 to about 20 µM, from about 0.1 to about 20 µM, from about 0.5 to about 20 µM, or from about 1 to about 20 µM. [1709] In certain embodiments, the amount of the compound administered is sufficient to provide a minimum plasma concentration (trough concentration) of the compound, ranging from about 0.001 to about 500 µM, about 0.002 to about 200 µM, about 0.005 to about 100 µM, about 0.01 to about 50 µM, from about 1 to about 50 µM, about 0.01 to about 25 µM, 158 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 from about 0.01 to about 20 µM, from about 0.02 to about 20 µM, from about 0.02 to about 20 µM, or from about 0.01 to about 20 µM. [1710] In certain embodiments, the amount of the compound administered is sufficient to provide an area under the curve (AUC) of the compound, ranging from about 100 to about 100,000 ng*hr/mL, from about 1,000 to about 50,000 ng*hr/mL, from about 5,000 to about 25,000 ng*hr/mL, or from about 5,000 to about 10,000 ng*hr/mL. [1711] The methods provided herein encompass treating a patient regardless of subject's age, although some diseases or disorders are more common in certain age groups. [1712] Depending on the disease to be treated and the subject's condition, the compound provided herein, or a derivative thereof, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. The compound provided herein, or a derivative thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration. [1713] In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered parenterally. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously. [1714] The compound provided herein, or a derivative thereof, can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compound can be administered repeatedly if necessary, for example, until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity. For example, stable disease for solid tumors generally means that the perpendicular diameter of measurable lesions has not increased by 25% or more from the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3): 205216 (2000). Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities. [1715] The compound provided herein, or a derivative thereof, can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily 159 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as the compound provided herein, or a derivative thereof, is administered once or more than once each day, for example, for a period of time. The term "continuous" is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily for an uninterrupted period of at least 10 days to 52 weeks. The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compound provided herein or a derivative thereof is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term "cycling" as used herein is intended to mean that a therapeutic compound, such as the compound provided herein or a derivative thereof, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days. [1716] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once a day. In another embodiment, the compound provided herein, or a derivative thereof, is administered twice a day. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered three times a day. In still another embodiment, the compound provided herein, or a derivative thereof, is administered four times a day. [1717] In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day from one day to six months, from one week to three months, from one week to four weeks, from one week to three weeks, or from one week to two weeks. In certain embodiments, the compound provided herein, or a derivative thereof, is administered once per day for one week, two weeks, three weeks, or four weeks. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 4 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for 5 days. In one embodiment, the compound provided herein, or a derivative 160 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 thereof, is administered once per day for 6 days. In one embodiment, the compound provided herein, or a derivative thereof, is administered once per day for one week. In another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for two weeks. In yet another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for three weeks. In still another embodiment, the compound provided herein, or a derivative thereof, is administered once per day for four weeks. Methods of Treatment [1718] As disclosed herein and well known in the art, IRE1 promotes adaptive remodeling of cellular physiology to alleviate ER stress and enhance cellular proteostasis in response to acute ER insults. Thus, compounds that increase IRE1/XBP1s activity should ameliorate pathologic imbalances in ER proteostasis, and therefore be useful in treatment of diverse diseases. For example, stress-independent activation of a ligand-regulated IRE1 promotes cellular survival in response to chronic chemical ER insults. (Lin, et al. Science 2007, 318 (5852), 944-9) This suggests that IRE1 activation can mitigate ER-stress associated apoptosis implicated in many neurodegenerative diseases. Consistent with this, overexpressing the activated IRE1-regulated transcription factor XBP1s promotes neuroprotection in multiple animal models of neurodegenerative disease including Parkinson’s disease, Huntington’s disease, and peripheral nerve injury. (Valdes, et al. PNAS 2014, 111(18) 6804-9; Zuleta, et al. Biochem. Biophys. Res. Commun.2012, 420(3), 558-63; Valenzuela, et al. Cell Death Dis.2012, 3, e272) Furthermore, stress-independent, chemical genetic activation of IRE1/XBP1s signaling reduces the toxic intracellular aggregation of destabilized, aggregation-prone variants of rhodopsin and ^1-anti-trypsin (A1AT) implicated in retinitis pigmentosa and A1AT deficiency, respectively. (Shoulders et al. Cell Rep.2013, 3(4), 1279- 92; Chiang et al. Mol. Biol. Cell 2012, 23(5), 758-70; Sifers Proc. Am. Thorac. Soc.2010, 7(6), 376-80) Increasing XBP1s activity also promotes the degradation of destabilized amyloid precursor protein (APP) mutants, reducing extracellular populations of the APP cleavage product Aβ that are genetically and pathologically implicated in Alzheimer’s disease. (Cui et al. Neurochem. Res.2018, 43(3), 669-80; Kaneko et al. J. Neurosci.2010, 30(11), 3924-32) IRE1/XBP1s activation is also advantageous in cellular and animal models of multiple other disorders including diabetes and myocardial infarction, further highlighting the potential for enhancing IRE1 signaling to improve pathologic outcomes in multiple 161 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 diseases. (Ozcan et al. Science 2004, 306(5695), 457-61; Bi et al. Circ. Res.2018, 122(11), 1545-54). See also, WO 2021/007594. XBP1 is important for retinal neuronal function. Reduced levels of XBP1 and XBP1s accelerate the decline in retinal function and age-related retinal neurodegeneration in mice (McLaughlin et al.2018, Molecular Neurodegeneration, 13, 16) and deletion of XBP1 leads to early-onset retinal neurodegeneration in mouse model of Type I diabetes (McLaughlin et al. J. Clin. Med.2019, 8, 906-920), suggesting a role in diabetic retinopathy (Ma et al. J. Diabetic Res.2014, Article ID 160140). Deletion of XBP1 from chondrocytes in a mouse model of chondrodysplasia resulted in a dramatic increase in disease severity (shorter limbs, deformed ribcages and disrupted cartilage growth plates), suggesting an important role of XBP1 in response to abnormal protein aggregation in proliferating chondrocytes (Pirog et al. PLoS Genet.2019, 15, 1008215). Reduced levels of XBP1s have also been associated with cardiovascular diseases. For example, XBP1s levels are reduced in human endomyocardial biopsies in patients with heart failure with preserved ejection fraction (Schiattarella, et al. Nature 2019, 568(7752), 351-356). Overexpression of XBP1s ameliorates the HFpEF phenotype in mice (Schiattarella, supra; Schiattarella, et al. Nat. Commun.2021, 12, 1684). Reduced levels of XBP1s have also been associated with sensitivity of multiple melanoma cells to the proteasome inhibitor bortezomib (Borjan, et al. Frontiers Onc.2020, 9, 1530). Over expression of XBP1s has been shown to sensitize multiple melanoma cell lines to bortezomib (Ling, et al. Haematologica 2012, 97(1), 64-72). About one-third of the eukaryotic proteins, including all membrane proteins, enter the endoplasmic reticulum (ER) for their protein folding. Many mutations in ion channel proteins result in their misfolding and the mutant proteins are retained in the ER. Consequently, fewer ion channels reach their working destination. This leads to loss of their function and corresponding disease phenotypes. The ER proteostasis network regulates the ER folding capacity to assure that newly synthesized proteins achieve their native three-dimensional structures in the crowded, oxidative folding environments. The ER proteostasis is mainly monitored by the unfolded protein response (UPR). Examples of such conformational diseases include cystic fibrosis resulting from cystic fibrosis transmembrane conductance regulator (CFTR) misfolding, type 2 long QT syndrome resulting from trafficking deficiency of human ether-à-go-go-related gene (hERG) channels, congenital myasthenic syndromes resulting from misfolding of nicotinic acetylcholine receptors, and idiopathic epilepsy resulting from misfolding of γ-aminobutyric acid type A (GABAA) receptors or sodium channels such as NaV1.1. For example, XBP1s overexpression has been shown to restore trafficking and surface expression of variant of GABAA receptors linked to idiopathic 162 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 epilepsy (Fu, et al. PLoS ONE 2018, 13(11), e0207948). Osteogenesis Imperfecta (OI) is typically caused by mutations in collagen type-I that disrupt collagen folding and/or stability. XBP1s overexpression increases folding and secretion of variant collagen type-I in primary fibroblast cells of OI patients (DiChiara, et al. bioRxiv 2021, doi.org/10.1101/2021.04.15.439909). [1719] Thus, in some aspects, provided herein is a method of treating diseases and disorders that may be ameliorated by increasing IRE1/XBP1s activity in a subject by administering to the subject a compound or composition provided herein. [1720] In some aspects, provided herein is a compound or composition provided herein for treating diseases and disorders that may be ameliorated by increasing IRE1/XBP1s activity in a subject. [1721] In some aspects, provided herein is use of a compound provided herein in the manufacture of a medicament for treating diseases and disorders that may be ameliorated by increasing IRE1/XBP1s activity in a subject. [1722] In some embodiments, the disease or disorder is a cardiovascular disease, neurodegenerative disease, metabolic disorder, hepatic disorder, protein misfolding disorder or gastrointestinal disorder. [1723] In some embodiments, the disease is a cardiovascular disease, such as myocardial infarction or atherosclerosis. [1724] In some embodiments, the disease is a neurodegenerative disease, including peripheral nerve injury, Creutzfeldt–Jakob disease, Parkinson's disease, and Huntington's disease. [1725] In some embodiments, the disorder is a metabolic disorder, such as diabetes, including type II diabetes, and Gaucher disease. [1726] In some embodiments, the disease is a hepatic disorder, including non‐alcoholic fatty liver disease (NAFLD). In another embodiment, the disease is a hepatic disorder selected from Progressive familial intrahepatic cholestasis (PFIC), Benign recurrent intrahepatic cholestasis (BRIC) and Wilson’s disease. [1727] In some embodiments, the disorder is a protein misfolding disorder, including amyloid diseases, Alzheimer’s disease, ocular diseases such as retinal degeneration, lysosomal storage diseases, and alpha-1 antitrypsin deficiency, including alpha-1 antitrypsin associated emphysema and alpha-1 antitrypsin associated liver disease. 163 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1728] In some embodiments, the disease is an amyloid disease, including atrial amyloidosis, spongiform encephalopathies, senile systemic amyloidosis, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy I and II, and familial amyloidosis. [1729] In some embodiments, the disease is a gastrointestinal disorder, including Crohn’s disease. [1730] In some embodiments, the disease is retinitis pigmentosa, achromatopsia, diabetic retinopathy or retinal neurodegeneration. In another embodiment, the disease is idiopathic epilepsy. In another embodiment, the disease is chondrodysplasia. Combination Therapy with a Second Active Agent [1731] The compound provided herein, or a derivative thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and/or prevention of diseases and disorders that may be ameliorated by increasing IRE1/XBP1s activity in a subject. [1732] In one embodiment, provided herein is a method of treating, preventing, or managing diseases and disorders that may be ameliorated by increasing IRE1/XBP1s activity in a subject, comprising administering to a subject a compound provided herein, or a pharmaceutically acceptable derivative thereof, in combination with one or more second active agents. [1733] As used herein, the term "in combination" includes the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein, a compound provided herein, e.g., the compound provided herein, or a derivative thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein. [1734] Administration of the compound provided herein, or a derivative thereof and one or more second active agents to a subject can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration 164 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream) and the disease or disorder being treated. [1735] The route of administration of the compound provided herein, or a derivative thereof, is independent of the route of administration of a second therapy. In one embodiment, the compound provided herein, or a derivative thereof, is administered orally. In another embodiment, the compound provided herein, or a derivative thereof, is administered intravenously. Thus, in accordance with these embodiments, the compound provided herein, or a derivative thereof, is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, the compound provided herein, or a derivative thereof, and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, the compound provided herein, or a derivative thereof, is administered by one mode of administration, e.g., by IV, whereas the second agent is administered by another mode of administration, e.g., orally. [1736] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of disease being treated or managed, the severity and stage of disease, and the amount of the compound provided herein, or a derivative thereof, and any optional additional active agents concurrently administered to the subject. [1737] One or more second active ingredients or agents can be used together with the compound provided herein, or a derivative thereof, in the methods and compositions provided herein. Second active agents can be large molecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). [1738] Examples of large molecule active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Typical large molecule active agents are biological molecules, such as naturally occurring or synthetic or recombinant proteins. 165 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1739] In one embodiment, the compound provided herein, or a derivative thereof, can be administered in an amount ranging from about 0.1 to about 150 mg, from about 1 to about 25 mg, or from about 2 to about 10 mg orally and daily alone, or in combination with a second active agent, prior to, during, or after the use of conventional therapy. [1740] In certain embodiments, second active agents for use herein include other modulators of the UPR, such as but not limited to ATF6 activators and PERK modulators including those disclosed in US 2019/0008809, Fu et al. PLoS ONE 2018, 13(11), e0207948, Fu et al. Science Transl. Med.2015, 7(292), 292ra98, Ke et al. Cell Death and Disease 2020, 11, 130-143, Halliday 2015 Cell Death and Disease 2015, 6, e1672. [1741] In another embodiment, the second active agent is a pharmacological chaperone, defined as an agent able to bind a protein or protein variant and stabilize it, such as tafamidis (a transthyretin chaperone), 1-deoxygalactonojirimicin (DGJ)(a chaperone of alpha- galactosidase A (AGAL)), SR121463A and VPA-985 (chaperones of the V2 vasopressin receptor), E-4031 (a chaperone of HerG channel) (see, e.g., Liguori et al. International Journal of Molecular Sciences 2020, 21, 489-508, Morello et al. J. Clin. Invest.2000, 105, 887-895, Zhou et al. J. Biol. Chem.1999, 274(44), 31123-31126). Numerated Exemplary Embodiments Exemplary Embodiment No.1. A compound of Formula I: or a pharmaceutically acceptable derivative thereof, where R¹ is H or alkyl and R² is H; or R¹ and R² together form (CH2)x where x is 1, 2 or 3; R³ and R⁴ are selected from (i) and (ii): (i) R³ is optionally substituted alkyl and R⁴ is H; or (ii) R³ and R⁴ together form (CH2)y where y is 1, 2, 3 or 4; R⁵ is H and R⁶ is haloalkyl; or R⁵ and R⁶ together form =O; X¹ is O or NR⁷ where R⁷ is H or alkyl; X² is CH or N; and Ar¹ and Ar² are each independently optionally substituted aryl or optionally substituted heteroaryl. 166 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Exemplary Embodiment No.2. The compound of Exemplary Embodiment No.1, wherein: R¹ is H or methyl and R² is H; or R¹ and R² together form -CH2-; R³ and R⁴ are selected from (i) and (ii): (i) R³ is optionally substituted alkyl and R⁴ is H; or (ii) R³ and R⁴ together form –(CH2)3-; R⁵ and R⁶ together form =O; X¹ is O or NR⁷ where R⁷ is H or methyl; X² is CH; and Ar¹ is optionally substituted heteroaryl; and Ar² is optionally substituted aryl. Exemplary Embodiment No.3. The compound of Exemplary Embodiment No.1 or Exemplary Embodiment No.2, wherein R⁵ is H and R⁶ is trifluoromethyl. Exemplary Embodiment No.4. The compound of Exemplary Embodiment No.1 or Exemplary Embodiment No.2 that has Formula II: or a pharmaceutically acceptable derivative thereof. Exemplary Embodiment No.5. The compound of Exemplary Embodiment No.4, wherein: R¹ is H or methyl and R² is H; or R¹ and R² together form -CH2-; R³ and R⁴ are selected from (i) and (ii): (i) R³ is optionally substituted alkyl and R⁴ is H; or (ii) R³ and R⁴ together form –(CH₂)₃-; X¹ is O or NR⁷ where R⁷ is H or methyl; X² is CH; and Ar¹ is optionally substituted heteroaryl; and Ar² is optionally substituted aryl. Exemplary Embodiment No.6. The compound of Exemplary Embodiment No.1, wherein Ar¹ is phenyl or optionally substituted heteroaryl. Exemplary Embodiment No.7. The compound of Exemplary Embodiment No.1, wherein Ar¹ is optionally substituted heteroaryl. 167 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Exemplary Embodiment No.8. The compound of any one of Exemplary Embodiment Nos.1-7, wherein Ar¹ is optionally substituted pyrimidinyl, pyridyl, isoxazolyl, triazolyl or thiadiazolyl. Exemplary Embodiment No.9. The compound of any one of Exemplary Embodiment Nos.1-8, wherein Ar¹ is pyrimidinyl, pyridyl, isoxazolyl, triazolyl or thiadiazolyl, each optionally substituted with NR⁸R⁹, OR¹⁰, alkyl, nitro or halo, where R⁸, R⁹ and R¹⁰ are each independently H or alkyl. Exemplary Embodiment No.10. The compound of any one of Exemplary Embodiment Nos.1-9, wherein Ar¹ is pyrimidinyl, pyridyl, isoxazolyl, triazolyl or thiadiazolyl, each optionally substituted with fluoro, bromo, nitro, methoxy, NH₂, methyl or NHMe. Exemplary Embodiment No.11. The compound of any one of Exemplary Embodiment Nos.1-10, wherein Ar¹ is selected from 2-amino-4-pyrimidinyl, 2-methoxy-4-pyridyl, 2- methoxy-4-pyrimidinyl, 2-fluoro-4-pyrimidinyl, 2-amino-4-pyrimidinyl, 4-pyridyl, 2- amino-4-pyridyl, 3-methyl-5-isoxazolyl, 1-methyl-3-bromo[1,2,4]triazol-5-yl, 1,3- dimethyl[1,2,4]triazol-5-yl, 3-methyl[1,2,4]thiadiazol-5-yl, 2-nitro-4-pyridyl or 2- methylamino-4-pyrimidinyl. Exemplary Embodiment No.12. The compound of any one of Exemplary Embodiment Nos.1-11, wherein Ar² is optionally substituted phenyl or optionally substituted pyridyl. Exemplary Embodiment No.13. The compound of any one of Exemplary Embodiment Nos.1-12, wherein Ar² is phenyl or pyridyl, each optionally substituted with alkyl or haloalkyl. Exemplary Embodiment No.14. The compound of any one of Exemplary Embodiment Nos.1-13, wherein Ar² is phenyl or pyridyl, each optionally substituted with methyl or trifluoromethyl. Exemplary Embodiment No.15. The compound of any one of Exemplary Embodiment Nos.1-14, wherein Ar² is 4-methylphenyl. In another embodiment, Ar² is 5- trifluoromethyl-2-pyridyl. Exemplary Embodiment No.16. The compound of any one of Exemplary Embodiment Nos.1-15, wherein X¹ is O. Exemplary Embodiment No.17. The compound of any one of Exemplary Embodiment Nos.1-15, wherein X¹ is NH. Exemplary Embodiment No.18. The compound of any one of Exemplary Embodiment Nos.1-15, wherein X¹ is NR⁷ where R⁷ is alkyl. 168 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Exemplary Embodiment No.19. The compound of any one of Exemplary Embodiment Nos.1-15, wherein X¹ is NMe. Exemplary Embodiment No.20. The compound of any one of Exemplary Embodiment Nos.1-19, wherein X² is CH. Exemplary Embodiment No.21. The compound of any one of Exemplary Embodiment Nos.1-19, wherein X² is N. Exemplary Embodiment No.22. The compound of any one of Exemplary Embodiment Nos.1-21, wherein R¹ is H or methyl. Exemplary Embodiment No.23. The compound of any one of Exemplary Embodiment Nos.1-22, wherein R¹ is methyl. Exemplary Embodiment No.24. The compound of any one of Exemplary Embodiment Nos.1-22, wherein R¹ is H. Exemplary Embodiment No.25. The compound of any one of Exemplary Embodiment Nos.1-24, wherein R² is H. Exemplary Embodiment No.26. The compound of any one of Exemplary Embodiment Nos.1-21, wherein R¹ and R² together form -CH2-. Exemplary Embodiment No.27. The compound of any one of Exemplary Embodiment Nos.1-26, wherein R³ is alkyl optionally substituted with hydroxy, alkoxy, aralkoxy or amino. Exemplary Embodiment No.28. The compound of any one of Exemplary Embodiment Nos.1-27, wherein R³ is alkyl optionally substituted with hydroxy, methoxy, benzyloxy or amino. Exemplary Embodiment No.29. The compound of any one of Exemplary Embodiment Nos.1-28, wherein R³ is methyl, isopropyl, cyanomethyl, 2-methoxy-1-ethyl, 3-methoxy- 1-propyl, 2-amino-1-ethyl, 2-benzyloxy-1-ethyl or 2-hydroxy-1-ethyl. Exemplary Embodiment No.30. The compound of any one of Exemplary Embodiment Nos.1-29, wherein R⁴ is H. Exemplary Embodiment No.31. The compound of any one of Exemplary Embodiment Nos.1-26, wherein R³ and R⁴ together form –(CH2)3-. Exemplary Embodiment No.32. The compound of any one of Exemplary Embodiment Nos.1-31 that is the (±)-trans isomer: 169 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 . Exemplary Embodiment No.33. The compound of any one of Exemplary Embodiment Nos.1-32 that is the enantiomerically pure trans isomer: . Exemplary Embodiment No.34. The compound of any one of Exemplary Embodiment Nos.1, 2 and 4-33 that is the (±)-trans isomer: . Exemplary Embodiment No.35. The compound of any one of Exemplary Embodiment Nos.1, 2 and 4-34 that is the enantiomerically pure trans isomer: . Exemplary Embodiment No.36. A compound selected from Compounds 1-25 and 27-38. 170 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Exemplary Embodiment No.37. A pharmaceutical composition, comprising the compound of any one of Exemplary Embodiment Nos.1-36 and a pharmaceutically acceptable carrier. Exemplary Embodiment No.38. A method of treating a disease or disorder selected from a cardiovascular disease, neurodegenerative disease, metabolic disorder, hepatic disorder, protein misfolding disorder or gastrointestinal disorder in a subject, comprising administering to the subject the compound of any one of Exemplary Embodiment Nos.1- 36 or the pharmaceutical composition of Exemplary Embodiment No.37. Exemplary Embodiment No.39. The method of Exemplary Embodiment No.39, wherein the cardiovascular disease is myocardial infarction or atherosclerosis. Exemplary Embodiment No.40. The method of Exemplary Embodiment No.39, wherein the neurodegenerative disease is peripheral nerve injury, Creutzfeldt–Jakob disease, Parkinson's disease or Huntington's disease. Exemplary Embodiment No.41. The method of Exemplary Embodiment No.39, wherein the metabolic disorder is diabetes, type II diabetes or Gaucher disease. Exemplary Embodiment No.42. The method of Exemplary Embodiment No.39, wherein the hepatic disorder is non‐alcoholic fatty liver disease (NAFLD). Exemplary Embodiment No.43. The method of Exemplary Embodiment No.39, wherein the hepatic disorder is Progressive familial intrahepatic cholestasis (PFIC), Benign recurrent intrahepatic cholestasis (BRIC) or Wilson’s disease. Exemplary Embodiment No.44. The method of Exemplary Embodiment No.39, wherein the protein misfolding disorder is an amyloid disease, Alzheimer’s disease, an ocular disease, retinal degeneration, a lysosomal storage disease or alpha-1 antitrypsin deficiency, including alpha-1 antitrypsin associated emphysema and alpha-1 antitrypsin associated liver disease. Exemplary Embodiment No.45. The method of Exemplary Embodiment No.44, wherein the amyloid disease is atrial amyloidosis, spongiform encephalopathies, senile systemic amyloidosis, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy I and II, or familial amyloidosis. Exemplary Embodiment No.46. The method of Exemplary Embodiment No.39, wherein the gastrointestinal disorder is Crohn’s disease. Exemplary Embodiment No.47. A method of treating retinitis pigmentosa, achromatopsia, diabetic retinopathy or retinal neurodegeneration in a subject, comprising 171 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 administering to the subject the compound of any one of Exemplary Embodiment Nos.1- 36 or the pharmaceutical composition of Exemplary Embodiment No.37. Exemplary Embodiment No.48. A method of treating idiopathic epilepsy in a subject, comprising administering to the subject the compound of any one of Exemplary Embodiment Nos.1-36 or the pharmaceutical composition of Exemplary Embodiment No.37. Exemplary Embodiment No.49. A method of treating chondrodysplasia in a subject, comprising administering to the subject the compound of any one of Exemplary Embodiment Nos.1-36 or the pharmaceutical composition of Exemplary Embodiment No.37. Exemplary Embodiment No.50. A method of increasing IRE1 or XBP1s activity in a subject, comprising administering to the subject a compound of any one of Exemplary Embodiment Nos.1-36 or a pharmaceutical composition of Exemplary Embodiment No. 37. Exemplary Embodiment No.51. A method of treating idiopathic epilepsy, Dravet syndrome or Lennox-Gastaut syndrome in a subject, comprising administering to the subject the compound of any one of Exemplary Embodiment Nos.1-36 or the pharmaceutical composition of Exemplary Embodiment No.37. Exemplary Embodiment No.52. A method of treating genetic epilepsy in a subject, comprising administering to the subject the compound of any one of Exemplary Embodiment Nos.1-36 or the pharmaceutical composition of Exemplary Embodiment No.37. Exemplary Embodiment No.53. A method of treating genetic epilepsy due to at least one variant in GABAA receptor subunits in a subject, comprising administering to the subject the compound of any one of Exemplary Embodiment Nos.1-36 or the pharmaceutical composition of Exemplary Embodiment No.37. EXAMPLES [1742] The examples below are meant to illustrate certain embodiments provided herein, and not to limit the scope of this disclosure. [1743] Abbreviations: CDI – carbonyldiimidazole; DCM – Dichloromethane; DIAD Diisopropyl azodicarboxylate; DIEA – diisopropylethylamine; DMAP – 4- dimethylaminopyridine; DMF – dimethylformamide; EA – ethyl acetate; h – hour; hrs – hours; HPLC – high pressure liquid chromatography; MPLC – medium pressure liquid 172 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 chromatography; NMR – nuclear magnetic resonance; PE – petroleum ether; RT – room temperature; TEA- Triethylamine; TBAF – Tetra-n-butylammonium fluoride; THF – tetrahydrofuran; TLC – thin layer chromatography. EXAMPLE 1 [1744] 4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2- oxoethyl)-1H-pyrazol-4-yl)-2-oxabicyclo[2.1.1]hexane-1-carboxamide [1745] Step 1: tert-butyl 2-oxabicyclo[2.1.1]hexane-1-carboxylate [1746] To a solution of 2-oxabicyclo[2.1.1]hexane-1-carboxylic acid (1.00 g, 7.80 mmol, 1 eq) in t-BuOH (10 mL) was added Boc₂O (8.52 g, 39.02 mmol, 8.97 mL, 5 eq) and DMAP (953.49 mg, 7.80 mmol, 1 eq), Py (617.36 mg, 7.80 mmol, 629.96 μL, 1 eq) at 25 °C. The mixture was stirred at 35 °C for 2 h. The reaction solution was filtered, and the filtrate was concentrated under the reduced pressure to give the residue. The residue was purified by column chromatography on silica get eluted with petroleum ether/ethyl acetate =10/1 to 3/1 to give the title compound (720 mg, 50% yield) as yellow oil. 173 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1747] ¹H NMR (400 MHz, CDCl3) δ 3.87 (s, 2H), 2.91 (t, J = 3.3 Hz, 1H), 2.16-2.09 (m, 2H), 1.74-1.68 (m, 3H), 1.49 (s, 10H), 1.46 (s, 47H). [1748] Step 2: tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- oxabicyclo[2.1.1]hexane -1-carboxylate [1749] A mixture of tert-butyl 2-oxabicyclo[2.1.1]hexane-1-carboxylate (600 mg, 3.26 mmol, 1 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.24 g, 4.89 mmol, 1.5 eq), (1Z,5Z)- cycloocta-1,5- diene;2,4- dimethyl-bicyclo[1.1.0]butane (107.94 mg, 162.84 μmol, 0.05 eq) cycloocta-1,5- (63.26 mg, 325.68 μmol, 0.1 eq) in cyclooctane (4 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 2 h under N₂ atmosphere. The reaction was quenched by addition of 5 mL of methanol. The reaction solution was concentrated under the reduced pressure to give the residue. The residue was purified by column chromatography on silica get eluted with petroleum ether/ethyl acetate =10/1 to 1/2 to give the title compound (400 mg, crude) as yellow oil. [1750] ¹H NMR (400 MHz, CDCl3) δ 3.97 (s, 2H), 2.23 (dd, J = 1.4, 4.7 Hz, 2H), 1.79 (dd, J = 1.6, 4.6 Hz, 2H), 1.51 (s, 9H), 1.28 (s, 22H). [1751] Step 3: tert-butyl 4-hydroxy-2-oxabicyclo[2.1.1]hexane-1-carboxylate [1752] To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- oxabicyclo[2.1.1]hexane-1-carboxylate (400 mg, 1.29 mmol, 1 eq) in THF (12 mL) was added hydrogen peroxide;urea (1.21 g, 12.90 mmol, 10 eq) and potassium;acetate (1.27 g, 12.90 mmol, 10 eq) at 0 °C. and then H₂O (6 mL) was added dropwise at 0 °C. After addition, the mixture was stirred at this temperature for 0.15 h. The resulting mixture was stirred at 20 °C for 11.85 h. The mixture was diluted with ethyl acetate (2 mL) and washed with saturated ammonium chloride (4 mL). The aqueous layer was extracted with ethyl acetate (4 mL x 2). The combined organic layers were washed with saturated aqueous sodium thiosulfate (2 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica get eluted with petroleum ether/ethyl acetate =10/1 to 1/2 to give the title compound (300 mg, crude) as a yellow solid. [1753] ¹H NMR (400 MHz, CDCl3): δ 3.75-3.69 (m, 2H), 2.18 (s, 4H), 1.50 (s, 9H). [1754] Step 4: tert-butyl 4-((2-fluoropyrimidin-4-yl)oxy)-2-oxabicyclo[2.1.1]hexane-1- carboxylate [1755] To a stirred mixture of 2,4-difluoropyrimidine (208.68 mg, 1.80 mmol, 1.2 eq) and Cs₂CO₃ (976.33 mg, 3.00 mmol, 2 eq) in ACN (5 mL) was added tert-butyl 4-hydroxy-2- oxabicyclo[2.1.1]hexane-1-carboxylate (300 mg, 1.50 mmol, 1 eq) and the reaction mixture 174 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 was stirred at 50 °C for 5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (Petroleum ether /Ethyl acetate=3/1) to give the title compound (46 mg, 10% yield). [1756] ¹H NMR (400 MHz, CDCl₃) δ 8.37 (dd, J = 2.0, 5.6 Hz, 1H), 6.68 (dd, J = 3.1, 5.6 Hz, 1H), 4.07 (s, 2H), 2.68-2.53 (m, 4H), 1.53 (s, 9H). [1757] Step 5: tert-butyl 4-((2-aminopyrimidin-4-yl)oxy)-2-oxabicyclo[2.1.1]hexane-1- carboxylate [1758] To a stirred mixture of tert-butyl 4-(2-fluoropyrimidin-4-yl)oxy-2- oxabicyclo[2.1.1]hexane-1-carboxylate (46 mg, 155.25 μmol, 1 eq) in ACN (1 mL) was added NH₃.H₂O (85.64 mg, 659.82 μmol, 94.11 μL, 27% purity, 4.25 eq) at 25 °C, and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (Petroleum ether /Ethyl acetate=4/1) to give the title compound (40 mg, 87% yield) as a yellow solid. [1759] LC-MS [ESI, M+1]: 294.1 [1760] ¹H NMR (400 MHz, CDCl3) δ 1.51 (s, 9 H) 2.50 (dt, J = 13.10, 4.52 Hz, 4 H) 4.04 (s, 2 H) 5.10-5.23 (m, 2 H) 6.07 (d, J = 5.63 Hz, 1 H) 8.03 (d, J = 5.63 Hz, 1 H). [1761] Step 6: 4-((2-aminopyrimidin-4-yl)oxy)-2-oxabicyclo[2.1.1]hexane-1-carboxylic acid [1762] To a solution of tert-butyl 4-(2-aminopyrimidin-4-yl)oxy-2- oxabicyclo[2.1.1]hexane-1-carboxylate (40 mg, 136.37 μmol, 1 eq) in DCM (1 mL) was added the TFA (777.45 mg, 6.82 mmol, 506.48 μL, 50 eq) with stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent to give the title compound (45 mg, crude) as a yellow solid. [1763] ¹H NMR (400 MHz, CDCl₃) δ 2.60 (br dd, J = 4.50, 1.63 Hz, 11 H) 2.77 (br d, J = 4.75 Hz, 4 H) 4.11 (s, 2 H) 6.32 (d, J = 6.88 Hz, 1 H) 8.02 (d, J = 6.75 Hz, 1 H). [1764] LC-MS [ESI, M+1]: 238.1 [1765] Step 7: 4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-2-oxabicyclo[2.1.1]hexane-1- carboxamide [1766] A solution of 4-(2-aminopyrimidin-4-yl)oxy-2-oxabicyclo[2.1.1]hexane-1- carboxylic acid (15 mg, 63.23 μmol, 1 eq) and 2-(4-aminopyrazol-1-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]acetamide (21.88 mg, 75.88 μmol, 1.2 eq) in DMF (2 mL) was added the DIEA (24.52 mg, 189.70 μmol, 33.04 μL, 3 eq) at 0 °C. To the mixture was added the T4P (68.34 mg, 94.85 μmol, 50% purity, 1.5 eq) with stirred at 0 °C for 15 min. The mixture 175 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 was stirred at 25 °C for 1 h. The reaction mixture was washed with HCl (1 M, 10 ml X3) and washed with saturated NaHCO3 (30 ml), extracted with ethyl acetate (50 mL × 2). The combined organic layer was washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)-ACN];gradient:15%-45% B over 10 min) to give the title compound (7.37 mg, 23% yield) as a white solid. [1767] LC-MS [ESI, M+1]: 508.2 [1768] ¹H NMR (400 MHz, DMSO-d₆) δ 2.21-2.26 (m, 3 H) 2.41 (d, J = 4.25 Hz, 2 H) 2.47-2.49 (m, 2 H) 2.89 (s, 1 H) 3.10 (s, 2 H) 3.62 (t, J = 5.75 Hz, 1 H) 3.72-3.79 (m, 1 H) 3.99-4.08 (m, 3 H) 4.10-4.15 (m, 1 H) 5.07-5.21 (m, 2 H) 6.04 (d, J = 5.50 Hz, 1 H) 6.65 (s, 2 H) 6.80-6.92 (m, 2 H) 7.09 (dd, J = 12.13, 8.50 Hz, 2 H) 7.58 (d, J = 5.00 Hz, 1 H) 7.90 (s, 1 H) 8.01 (d, J = 5.63 Hz, 1 H) 10.04 (s, 1 H). EXAMPLE 2 [1769] (±)-trans-4-((2-methoxypyridin-4-yl) oxy)-N-(1-(2-(methyl(2-(p-tolyloxy) ethyl) amino)-2-oxoethyl)-1H-pyrazol-4-yl) tetrahydrofuran-2-carboxamide [1770] Step 1: ethyl (±)-trans-4-((2-methoxypyridin-4-yl) oxy) tetrahydrofuran-2- carboxylate 176 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1771] To a solution of NaH (613.55 mg, 15.34 mmol, 60% purity, 1.3 eq) in THF (50 mL) was added ethyl 4-hydroxytetrahydrofuran-2-carboxylate (2.27 g, 14.16 mmol, 1.2 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. Then to the reaction mixture was added 4-fluoro-2-methoxy-pyridine (1.5 g, 11.80 mmol, 1 eq) at 0°C, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (40 mL × 2). The combined organic layer was washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography on silica get eluted with petroleum ether/ethyl acetate =20/1 to 3/1 to give the title compound (190 mg, 710.87 μmol, 6.02% yield) as a white solid. [1772] Step 2: (±)-trans-4-((2-methoxypyridin-4-yl) oxy) tetrahydrofuran-2-carboxylic acid [1773] To a mixture of ethyl (2S,4R)-4-[(2-methoxy-4-pyridyl) oxy] tetrahydrofuran-2- carboxylate (188 mg, 703.39 μmol, 1 eq) in THF (0.7 mL) and MeOH (0.7 mL) and H₂O (0.7 mL) was added LiOH.H2O (88.55 mg, 2.11 mmol, 3 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to give the title compound (160 mg, 668.83 μmol, 95.09% yield) was obtained as a brown solid. [1774] Step 3: (±)-trans-4-((2-methoxypyridin-4-yl) oxy)-N-(1-(2-(methyl(2-(p-tolyloxy) ethyl) amino)-2-oxoethyl)-1H-pyrazol-4-yl) tetrahydrofuran-2-carboxamide [1775] To a mixture of (2S,4R)-4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2-carboxylic acid (20 mg, 83.60 μmol, 1 eq) and 2-(4-aminopyrazol-1-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]acetamide (24.11 mg, 83.60 μmol, 1 eq) in DMF (0.5 mL) was added DIEA (32.42 mg, 250.81 μmol, 43.69 μL, 3 eq) and T₄P (90.36 mg, 125.41 μmol, 50% purity, 1.5 eq) in one portion at 0 °C. The mixture was stirred at 25 °C for 1 hours. The reaction mixture was washed with 1 M HCl and NaHCO3 solution and water (1 mL) and extracted with ethyl acetate (1 mL*3). The combined organic layers were washed with brine (1 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was further purification by prep-HPLC (column: Phenomenex luna C18 250*50mm*15um; mobile phase: [water(FA)-ACN];gradient:22%-52% B over 9 min) and lyophilized to give the title compound (5.41 mg, 10.62 μmol, 12.70% yield) as yellow gum. [1776] LC-MS [ESI, M+1]: 510.3. [1777] ¹H NMR (400 MHz, DMSO-d6) δ = 10.07 (s, 1H), 8.00 (d, J = 6.0 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.10 (dd, J = 8.4, 11.8 Hz, 2H), 6.86 (dd, J = 177 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 8.6, 20.0 Hz, 2H), 6.62 (dd, J = 2.0, 6.0 Hz, 1H), 6.36 (d, J = 2.0 Hz, 1H), 5.27-5.04 (m, 3H), 4.60 (t, J = 8.0 Hz, 1H), 4.19-4.10 (m, 2H), 4.07-3.98 (m, 2H), 3.83 (s, 3H), 3.76 (br t, J = 4.8 Hz, 1H), 3.63 (t, J = 5.7 Hz, 1H), 3.13-2.88 (m, 3H), 2.40-2.33 (m, 2H), 2.24 (d, J = 4.8 Hz, 3H) EXAMPLE 3 [1778] (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-((5-(trifluoro methyl)pyridin-2-yl)oxy)ethyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)tetrahydrofuran-2- carboxamide [1779] Step 1: (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid [1780] To a solution of ethyl (2S,4R)-4-((2-methoxypyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxylate (450.00 mg, 1.68 mmol, 1 eq) in THF (2 mL), MeOH (2 mL), H2O (2 mL) was added LiOH.H₂O (211.17 mg, 5.03 mmol, 3 eq). The mixture was stirred at 25 °C for 3 hr. 178 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 The PH was adjusted to 7, the reaction mixture was concentrated under reduced pressure to remove solvent to give the title compound (402 mg, 99.77% yield) as yellow oil. [1781] LC-MS [ESI, M+1]: 241.1. [1782] ¹H NMR (400 MHz, DMSO-d6) δ 8.29 (d, J = 5.8 Hz, 1H), 6.55 (d, J = 5.6 Hz, 1H), 4.22-4.08 (m, 5H), 3.86 (s, 3H), 2.22-2.14 (m, 2H) [1783] Step 2: tert-butyl 2-(4-((±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)tetrahydrofuran- 2-carboxamido)-1H-1,2,3-triazol-1-yl)acetate [1784] To a solution of (2S,4R)-4-((2-methoxypyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxylic acid (402.00 mg, 1.67 mmol, 1 eq), tert-butyl 2-(4-amino-1H-1,2,3-triazol-1- yl)acetate (331.73 mg, 1.67 mmol, 1 eq) in DMF (1 mL) was added DIEA (648.87 mg, 5.02 mmol, 874.49 μL, 3 eq), T₄P (1.81 g, 2.51 mmol, 50% purity, 1.5 eq) at 0 °C for 0.25 hr. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into water (20 mL), extracted with Ethyl acetate (60 mL × 2). The combined organic layers were washed with brine (80 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (SiO2; Petroleum ether : Ethyl acetate = 1:2, Rf = 0.56) to give the title compound (370 mg, 880.07 μmol, 52.59% yield) as yellow oil. [1785] LC-MS [ESI, M+1]: 421.2. [1786] ¹H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 6.60 (d, J = 5.6 Hz, 1H), 5.65 (s, 1H), 5.25 (s, 2H), 4.69 (t, J = 7.7 Hz, 1H), 4.21 (dd, J = 4.0, 10.5 Hz, 1H), 3.88 (s, 3H), 2.89-2.71 (m, 3H), 1.44 (s, 9H) [1787] Step 3: 2-(4-((±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxamido)-1H-1,2,3-triazol-1-yl)acetic acid [1788] To a solution of tert-butyl 2-(4-((2S,4R)-4-((2-methoxypyrimidin-4- yl)oxy)tetrahydrofuran-2-carboxamido)-1H-1,2,3-triazol-1-yl)acetate (370 mg, 880.07 μmol, 1 eq) in DCM (0.2 mL) was added TFA (6.14 g, 53.85 mmol, 4 mL, 61.19 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent to give the title compound (608 mg, crude) as yellow oil. [1789] LC-MS [ESI, M+1]: 365.1. [1790] ¹H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.33 (d, J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 6.61 (d, J = 5.8 Hz, 1H), 5.69-5.62 (m, 1H), 5.25 (s, 2H), 4.69 (t, J = 7.8 Hz, 2H), 4.21 (dd, J = 4.0, 10.4 Hz, 1H), 3.89 (s, 3H), 2.91-2.70 (m, 3H) 179 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1791] Step 4: (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-((5- (trifluoromethyl)pyridin-2-yl)oxy)ethyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4- yl)tetrahydrofuran-2-carboxamide [1792] To a solution of 2-(4-((2S,4R)-4-((2-methoxypyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxamido)-1H-1,2,3-triazol-1-yl)acetic acid (50 mg, 137.24 μmol, 1 eq), N-methyl-2-((5- (trifluoromethyl)pyridin-2-yl)oxy)ethan-1-amine (30.22 mg, 117.75 μmol, 8.58e-1 eq, HCl) in DMF (1 mL) was added T₄P (148.33 mg, 205.87 μmol, 50% purity, 1.5 eq), DIEA (53.21 mg, 411.73 μmol, 71.72 μL, 3 eq) at 0 °C for 0.25 hr. The mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into water (20 mL), extracted with Ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:33%-63% B over 15 min) to give the title compound (29.76 mg, 36.75% yield, 96.0% purity). [1793] LC-MS [ESI, M+1]: 567.3. [1794] ¹H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.60 (dd, J = 0.9, 11.9 Hz, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.16-8.11 (m, 1H), 8.10-8.05 (m, 1H), 7.18-6.98 (m, 1H), 6.60 (d, J = 5.8 Hz, 1H), 5.65 (s, 1H), 5.54-5.40 (m, 2H), 4.74-4.54 (m, 2H), 4.47 (t, J = 5.6 Hz, 1H), 4.22 (ddd, J = 1.8, 3.9, 10.3 Hz, 1H), 3.98 (d, J = 10.4 Hz, 1H), 3.88 (s, 3H), 3.84 (t, J = 5.4 Hz, 1H), 3.71 (t, J = 5.6 Hz, 1H), 3.17-2.89 (m, 3H), 2.45-2.33 (m, 2H) EXAMPLE 4 [1795] trans-4-((2-methoxypyrimidin-4-yl)oxy)-N-(1-(2-oxo-2-((S)-3-(p- tolyloxy)piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide 180 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1796] Step 1: (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid [1797] To a solution of ethyl (±)-trans-4-(2-methoxypyrimidin-4-yl)oxytetrahydrofuran-2- carboxylate (0.1 g, 372.77 μmol, 1 eq) in THF(1 mL), MeOH(1 mL) and H2O(0.1 mL) was added LiOH.H₂O (31.28 mg, 745.53 μmol, 2 eq) at 25 °C, and the reaction mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely and 100% with desired compound mass was detected. The reaction mixture was concentrated under reduced pressure to afford the title compound (90 mg, crude) was obtained as a white solid. [1798] LC-MS [ESI, M+1]: 241.0 [1799] Step 2: trans-4-((2-methoxypyrimidin-4-yl)oxy)-N-(1-(2-oxo-2-((S)-3-(p- tolyloxy)piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1800] To a solution of (±)-trans-4-(2-methoxypyrimidin-4-yl)oxytetrahydrofuran-2- carboxylic acid (50.00 mg, 208.15 μmol, 1 eq), 2-(4-aminopyrazol-1-yl)-1-[(3S)-3-(4- methylphenoxy)-1-piperidyl]ethanone (65.44 mg, 208.15 μmol, 1 eq), DIEA (80.71 mg, 624.45 μmol, 108.77 μL, 3 eq) in DMF (0.5 mL) was added T4P (224.96 mg, 312.22 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. LCMS showed 83.7% peak of desired mass. The reaction mixture was poured into water (2 ml), extracted with Ethyl acetate (2 mL × 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (NH4HCO3 condition) to afford the title compound (26.38 mg, 49.16 μmol, 23.62% yield) as white solid. 181 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1801] LC-MS [ESI, M+1]: 559.3 [1802] ¹H NMR (400 MHz, DMSO-d6) δ = 10.08 (d, J = 3.2 Hz, 1H), 8.33 (d, J = 5.6 Hz, 1H), 8.03-7.79 (m, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.20-6.99 (m, 2H), 6.94-6.77 (m, 2H), 6.60 (d, J = 5.6 Hz, 1H), 5.65-5.58 (m, 1H), 5.16-4.78 (m, 2H), 4.61 (t, J = 7.6 Hz, 1H), 4.53-4.21 (m, 1H), 4.21-4.15 (m, 1H), 4.04-3.95 (m, 1H), 3.88 (s, 3H), 3.73-3.37 (m, 3H), 3.23-3.15 (m, 1H), 2.45-2.36 (m, 2H), 2.22 (d, J = 5.2 Hz, 3H), 2.03-1.90 (m, 1H), 1.80-1.64 (m, 2H), 1.59-1.39 (m, 1H) EXAMPLE 5 [1803] (±)-trans-4-((2-fluoropyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1804] Step 1: (±)-trans-4-((2-fluoropyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1805] To a solution of 2,4-difluoropyrimidine (34.61 mg, 298.18 μmol, 1.2 eq) and Cs2CO3 (161.92 mg, 496.96 μmol, 2 eq) in DMF (1 mL) was added (±)-trans-4- hydroxy-N-[1-[2-[methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4- yl]tetrahydrofuran-2-carboxamide (100.00 mg, 248.48 μmol, 1 eq). The mixture was stirred at 25 °C for 16 hr. LCMS showed the starting material was remained and 97% desired compound mass was detected. The reaction mixture was filtered and the mother solution was concentrated under reduced pressure, the residue was added into water (1 ml) and extracted with DCM/ethyl acetate (1 mL × 2). The combined organic layers were washed with brine (1 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:20%-50% B over 15 min) and the mobile phase was lyophilized to remove solvent to afford the (2S,4R)-4-(2-fluoropyrimidin- 182 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 4-yl)oxy-N-[1-[2-[methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4- yl]tetrahydrofuran-2-carboxamide (16 mg, 31.74 μmol, 12.77% yield, 98.88% purity) as yellow gum. [1806] LC-MS [ESI, M-84+1]: 499.3 [1807] ¹H NMR (400 MHz, DMSO-d6) δ = 10.08 (s, 1H), 8.77-8.41 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 4.8 Hz, 1H), 7.13-7.04 (m, 2H), 7.04-6.97 (m, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.65 (t, J = 4.0 Hz, 1H), 5.18 (s, 1H), 5.08 (s, 1H), 4.62 (t, J = 8.0 Hz, 1H), 4.21-4.15 (m, 1H), 4.12 (t, J = 5.2 Hz, 1H), 4.10-4.06 (m, 1H), 4.02 (t, J = 5.6 Hz, 1H), 3.75 (br t, J = 5.2 Hz, 1H), 3.63 (t, J = 5.6 Hz, 1H), 3.12-2.89 (m, 3H), 2.46 (br d, J = 7.6 Hz, 1H), 2.43-2.36 (m, 1H), 2.23 (d, J = 5.2 Hz, 3H) EXAMPLE 6 [1808] (±)-trans-4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1809] Step 1: (±)-trans-4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1810] To a solution of (±)-trans-4-(2-fluoropyrimidin-4-yl)oxy-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (5 183 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 mg, 10.03 μmol, 1 eq) in ACN (0.1 mL) was added NH3.H2O (91.00 mg, 778.98 μmol, 0.1 mL, 30% purity, 77.67 eq). And the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:15%-45% B over 15 min) and the mobile phase was lyophilized to afford (±)-trans-4-(2-aminopyrimidin-4-yl)oxy-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (3.39 mg, 6.76 μmol, 33.68% yield, 98.751% purity) as a white solid. [1811] LC-MS [ESI, M-84+1]: 496.3 [1812] ¹H NMR (400 MHz, DMSO-d6) δ = 10.06 (s, 1H), 7.98 (d, J = 5.6 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.14-7.04 (m, 2H), 6.93-6.78 (m, 2H), 6.64- 6.52 (m, 2H), 6.02 (d, J = 5.6 Hz, 1H), 5.59-5.49 (m, 1H), 5.17 (s, 1H), 5.08 (s, 1H), 4.59 (t, J = 8.0 Hz, 1H), 4.22-4.10 (m, 2H), 4.05-4.00 (m, 1H), 3.95 (d, J = 10.4 Hz, 1H), 3.75 (t, J = 4.8 Hz, 1H), 3.62 (t, J = 5.6 Hz, 1H), 3.11-2.88 (m, 3H), 2.38-2.32 (m, 2H), 2.23 (d, J = 4.8 Hz, 3H) EXAMPLE 7 [1813] (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)-2-methyl-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide 184 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1814] Step 1: ethyl 4-((tert-butyldiphenylsilyl)oxy)tetrahydrofuran-2-carboxylate [1815] To a solution of ethyl 4-hydroxytetrahydrofuran-2-carboxylate (10 g, 62.43 mmol) and imidazole (8.50 g, 124.87 mmol) in DCM (100 mL) was added TBDPSCl (22.31 g, 81.17 mmol, 20.77 mL) at 0 °C, and the reaction mixture was stirred at 20 °C for 16 h. LCMS showed 60% of desired compound mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC (0.1% FA condition) and the mobile phase was extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (500 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to remove solvent to give the title compound (20 g, 50.18 mmol, 80.37% yield, 100% purity) as a light yellow oil. [1816] LC-MS [ESI, M+23]: 413.3. [1817] Step 2: ethyl 4-((tert-butyldiphenylsilyl)oxy)-2-methyltetrahydrofuran-2- carboxylate [1818] To a stirred solution of ethyl 4-((tert-butyldiphenylsilyl)oxy)tetrahydrofuran-2- carboxylate (2 g, 5.02 mmol) in THF (20 mL) was added LDA (1 M, 5.64 mL) dropwise at - 78 °C under N2. The mixture was stirred at -78 °C for 0.5 h. Then, to the reaction mixture was added MeI (2.67 g, 18.81 mmol, 1.17 mL) dropwise at -78 °C under N₂, and the mixture 185 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 was stirred at 20 °C for 16 h. LCMS showed 48% of desired compound mass was detected. The reaction mixture was poured into sat. NH4Cl (20 ml) and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: UniSil 10-120 C1870x250mm;mobile phase: [water(FA)-ACN];gradient:53%-83% B over 20 min) and the mobile phase was lyophilized to remove solvent to give the title compound (1.07 g, 2.59 mmol, 51.68% yield, 100% purity) as a brown gum, and the title compound (0.7 g, 848.29 μmol, 16.91% yield, 50% purity) as a brown gum. [1819] LC-MS [ESI, M+1]: 222.1. [1820] Step 3: ethyl 4-hydroxy-2-methyltetrahydrofuran-2-carboxylate [1821] To a stirred solution of ethyl 4-((tert-butyldiphenylsilyl)oxy)-2- methyltetrahydrofuran-2-carboxylate (0.4 g, 969.48 μmol) in THF (3 mL) was added TBAF (1 M, 1.16 mL) at 20 °C, and the mixture was stirred at 20 °C for 1 h. TLC (Petroleum ether/Ethyl acetate=2:1) indicated the starting material was consumed completely and one major new spot was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, Eluent of 0-40-60% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give the title compound (170 mg, 927.13 μmol, 95.63% yield, 95% purity) as a colorless oil. [1822] Step 4: ethyl (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)-2-methyltetrahydrofuran- 2-carboxylate [1823] To a solution of NaH (42.94 mg, 1.07 mmol, 60% purity, 1.1 eq) in THF (3 mL) was added ethyl 4-hydroxy-2-methyltetrahydrofuran-2-carboxylate (170 mg, 975.92 μmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.1 h. Then to the reaction mixture was added 4-chloro-2-methoxy-pyrimidine (150 mg, 1.04 mmol) at 0 °C, and the reaction mixture was stirred at 20 °C for 1 h. LCMS showed 40% of desired compound mass was detected. The reaction mixture was quenched by sat. NH₄Cl (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL × 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-TLC (Petroleum ether/Ethyl acetate=2/1) to give the title compound (110 mg, 370.18 μmol, 37.93% yield, 95% purity) as a colorless oil. [1824] LC-MS [ESI, M+1]: 283.1. [1825] Step 5: (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)-2-methyltetrahydrofuran-2- carboxylic acid [1826] To a solution of ethyl (2S,4R)-4-((2-methoxypyrimidin-4-yl)oxy)-2- methyltetrahydrofuran-2-carboxylate (50.00 mg, 177.12 μmol) in MeOH (1 mL) and H₂O 186 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 (0.1 mL) was added LiOH.H₂O (14.87 mg, 354.24 μmol). The mixture was stirred at 25 °C for 1 h. LCMS showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to remove solvent to give the title compound (50 mg, crude) as a white solid. [1827] LC-MS [ESI, M+1]: 255.1. [1828] Step 6: (±)-trans-4-((2-methoxypyrimidin-4-yl)oxy)-2-methyl-N-(1-(2-(methyl(2- (p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1829] To a solution of (2S,4R)-4-((2-methoxypyrimidin-4-yl)oxy)-2- methyltetrahydrofuran-2-carboxylic acid (40.00 mg, 157.33 μmol) and 2-(4-amino-1H- pyrazol-1-yl)-N-methyl-N-(2-(p-tolyloxy)ethyl)acetamide (49.90 mg, 173.07 μmol) in DMF (1 mL) was added DIEA (61.00 mg, 472.00 μmol, 82.21 μL) and T₄P (170.04 mg, 236.00 μmol, 50% purity) . The mixture was stirred at 25 °C for 2 h. LCMS showed 54% of desired compound mass was detected. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate (20 mL × 2). The combined organic layer was washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:35%- 65% B over 9 min) and the mobile phase was lyophilized to remove solvent to give the title compound (18 mg, 33.96 μmol, 21.58% yield, 98.965% purity) as a white solid. [1830] LC-MS [ESI, M+1]: 525.4. [1831] ¹H NMR (400 MHz, DMSO-d₆) δ = 10.01 (s, 1H), 8.32 (d, J = 5.6 Hz, 1H), 7.92 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 4.8 Hz, 1H), 7.14-7.04 (m, 2H), 6.91-6.77 (m, 2H), 6.60 (d, J = 5.6 Hz, 1H), 5.57-5.48 (m, 1H), 5.24-5.01 (m, 2H), 4.18-3.99 (m, 4H), 3.87 (s, 3H), 3.79-3.60 (m, 2H), 3.11 (s, 2H), 2.89 (s, 1H), 2.83-2.75 (m, 1H), 2.23 (d, J = 5.2 Hz, 3H), 2.07 (d, J = 14.4 Hz, 1H), 1.49 (s, 3H). EXAMPLE 8 [1832] (±)-trans-4-(pyridin-4-yloxy)-N-(1-(3,3,3-trifluoro-2-(methyl(2-(p- tolyloxy)ethyl)amino)propyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide 187 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1833] Step 1: 3,3,3-trifluoro-2-(methyl(2-(p-tolyloxy)ethyl)amino)propan-1-ol [1834] To a solution of 2-bromo-3,3,3-trifluoro-propan-1-ol (300 mg, 1.55 mmol, 1 eq) and N-methyl-2-(4-methylphenoxy)ethanamine (256.89 mg, 1.55 mmol, 1 eq) in DMF (10 mL) was added K₂CO₃ (429.74 mg, 3.11 mmol, 2 eq). The mixture was stirred at 60 °C for 16 hr. LCMS showed 10% of desired compound mass was detected.100 °C, 4 h, LCMS showed 58% of desired compound mass was detected. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water(NH4HCO3)-ACN];gradient:36%-66% B over 28 min) and the mobile phase was lyophilized to remove solvent. to afford the 3,3,3-trifluoro-2-[methyl-[2-(4- methylphenoxy)ethyl]amino]propan-1-ol (100 mg, 339.01 μmol, 21.81% yield, 94% purity) as a yellow solid. [1835] LC-MS [ESI, M+1]: 278.1 [1836] ¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.09 (d, J = 8.0 Hz, 2H), 6.88-6.74 (m, 2H), 4.20-3.96 (m, 3H), 3.06-2.89 (m, 2H), 2.85-2.79 (m, 2H), 2.48 (s, 3H), 2.30 (s, 3H) 188 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1837] Step 2: 1,1,1-trifluoro-N-methyl-3-(4-nitro-1H-pyrazol-1-yl)-N-(2-(p-tolyloxy) ethyl)propan-2-amine [1838] To a solution of 3,3,3-trifluoro-2-[methyl-[2-(4- methylphenoxy)ethyl]amino]propan-1-ol (100 mg, 360.64 μmol, 1 eq) ,4-nitro-1H-pyrazole (40.78 mg, 360.64 μmol, 1 eq) in THF (2 mL) was added PPh3 (141.89 mg, 540.97 μmol, 1.5 eq) . DIAD (87.51 mg, 432.77 μmol, 83.90 μL, 1.2 eq) was added dropwise under 0 °C. The mixture was stirred at 20 °C for 16 h. LCMS showed 20% desired compound mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/1) and the eluent was concentrated under reduced pressure to remove solvent to afford the 1,1,1-trifluoro-N-methyl-N-[2-(4-methylphenoxy)ethyl]-3-(4-nitropyrazol-1- yl)propan-2-amine (30 mg, 48.34 μmol, 13.40% yield, 60% purity) as colorless oil. [1839] LC-MS [ESI, M+1]: 373.1 [1840] Step 3: 1-(3,3,3-trifluoro-2-(methyl(2-(p-tolyloxy)ethyl)amino)propyl)-1H-pyrazol- 4-amine [1841] To a solution of 1,1,1-trifluoro-N-methyl-N-[2-(4-methylphenoxy)ethyl]-3-(4- nitropyrazol-1-yl)propan-2-amine (30 mg, 80.57 μmol, 1 eq) in MeOH (1 mL) was added wet Pd/C (10 mg, 9.40 μmol, 10% purity, 1.17e-1 eq) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 2 hr under H₂(15 psi). LCMS showed 43% desired compound mass was detected. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove solvent to afford the 1-[3,3,3-trifluoro-2-[methyl-[2-(4- methylphenoxy)ethyl]amino]propyl]pyrazol-4-amine (25 mg, 73.02 μmol, 90.63% yield) as colorless oil. [1842] LC-MS [ESI, M+1]: 343.1 [1843] Step 4: (±)-trans-4-(pyridin-4-yloxy)-N-(1-(3,3,3-trifluoro-2-(methyl(2-(p- tolyloxy)ethyl)amino)propyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1844] To a solution of 1-[3,3,3-trifluoro-2-[methyl-[2-(4-methylphenoxy)ethyl]amino] propyl]pyrazol-4-amine (25 mg, 73.02 μmol, 1 eq) ,4-(4-pyridyloxy)tetrahydrofuran-2- carboxylic acid (18.94 mg, 87.63 μmol, 1.2 eq, Li) in DMF (1 mL) was added DIEA (28.31 mg, 219.07 μmol, 38.16 μL, 3 eq) and T₄P (39.46 mg, 109.53 μmol, 1.5 eq). The mixture was stirred at 25 °C for 0.5 hr. LCMS showed 46% of desired compound mass was detected. The reaction mixture was poured into water (1 ml) and extracted with ethyl acetate (1 mL × 2). The combined organic layer was washed with brine (1 mL × 2), dried over anhydrous sodium 189 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: YMC-Actus Triart C18150*30mm*7um;mobile phase: [water(FA)-ACN];gradient:25%-55% B over 10 min) and the mobile phase was lyophilized to remove solvent to afford the (2S,4R)-4-(4-pyridyloxy)-N-[1-[3,3,3-trifluoro-2-[methyl-[2- (4-methylphenoxy)ethyl]amino]propyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (1.52 mg, 2.68 μmol, 3.67% yield, 94.0% purity) as an off-white solid. [1845] LC-MS [ESI, M+1]: 534.2 [1846] ¹H NMR (400 MHz, DMSO-d6) δ = 10.11 (s, 1H), 8.43-8.39 (m, 2H), 8.08 (s, 1H), 7.60 (s, 1H), 7.07-7.04 (m, 2H), 7.01-6.98 (m, 2H), 6.76-6.72 (m, 2H), 5.25 (d, J = 3.6 Hz, 1H), 4.64-4.26 (m, 4H), 4.20-4.00 (m, 4H), 3.84-3.72 (m, 3H), 2.47 (s, 3H), 2.38-2.36 (m, 1H), 2.21 (s, 3H) EXAMPLE 9 [1847] trans-4-((2-aminopyridin-4-yl)oxy)-N-(1-(2-oxo-2-((S)-3-(p-tolyloxy)piperidin-1- yl)ethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1848] Step 1: trans-4-hydroxy-N-(1-(2-oxo-2-((S)-3-(p-tolyloxy)piperidin-1-yl)ethyl)-1H- pyrazol-4-yl)tetrahydrofuran-2-carboxamide 190 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1849] To a solution of 2-(4-aminopyrazol-1-yl)-1-[(3S)-3-(4-methylphenoxy)-1- piperidyl]ethanone (1.5 g, 4.77 mmol, 1 eq) in DMF (20 mL) was added DIEA (3.08 g, 23.86 mmol, 4.16 mL, 5 eq), T4P (5.16 g, 7.16 mmol, 50% purity, 1.5 eq) and 4- hydroxytetrahydrofuran-2-carboxylic acid (630.35 mg, 4.77 mmol, 1 eq). The mixture was stirred at 25 °C for 1 hr. After the mixture was cooled to room temperature, the reaction mixture was diluted with H2O (50 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:15%-45% B over 20 min) and lyophilized. The title compound (800 mg, 1.87 mmol, 39.13% yield) was obtained as a white solid. [1850] Step 2: trans-4-((2-nitropyridin-4-yl)oxy)-N-(1-(2-oxo-2-((S)-3-(p- tolyloxy)piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1851] To a mixture of (2S,4R)-4-hydroxy-N-[1-[2-[(3S)-3-(4-methylphenoxy)-1- piperidyl]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (100 mg, 233.38 μmol, 1 eq) and 4-fluoro-2-nitro-pyridine (39.79 mg, 280.06 μmol, 1.2 eq) in DMF (1 mL) was added Cs₂CO₃ (152.08 mg, 466.77 μmol, 2 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 4 hours. The suspension was filtered and the filtrated was concentrated under reduced pressure. The residue was further purification by pre-HPLC (column: YMC- Actus Triart C18150*30mm*7um;mobile phase: [water(FA)-ACN];gradient:38%-68% B over 10 min) and lyophilized. The title compound (20 mg, 36.33 μmol, 15.57% yield) was obtained as a white solid. [1852] Step 3: trans-4-((2-aminopyridin-4-yl)oxy)-N-(1-(2-oxo-2-((S)-3-(p- tolyloxy)piperidin-1-yl)ethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1853] To a solution of (2S,4R)-N-[1-[2-[(3S)-3-(4-methylphenoxy)-1-piperidyl]-2-oxo- ethyl]pyrazol-4-yl]-4-[(2-nitro-4-pyridyl)oxy]tetrahydrofuran-2-carboxamide (20 mg, 36.33 μmol, 1 eq) in MeOH (2 mL) was added Pd/C (20 mg, 18.79 μmol, 10% purity, 5.17e- 1 eq) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 2 hrs under H2(15 psi). The suspension was filtered and the filtrated was concentrated under reduced pressure. The residue was further purification by pre-HPLC (column: YMC-Actus Triart C18150*30mm*7um;mobile phase: [water(FA)-ACN];gradient:18%-48% B over 10 min) and lyophilized. The title compound (4.73 mg, 9.08 μmol, 24.99% yield, 99.9% purity) was obtained as a white solid. 191 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1854] LC-MS [ESI, M+1]: 521.3 [1855] ¹H NMR (400 MHz, DMSO-d6) δ = 10.07 (d, J = 3.2 Hz, 1H), 8.14 (s, 1H), 7.96- 7.80 (m, 1H), 7.73 (d, J = 5.6 Hz, 1H), 7.52 (d, J = 5.2 Hz, 1H), 7.17-6.99 (m, 2H), 6.95- 6.77 (m, 2H), 6.18-6.08 (m, 1H), 5.94 (d, J = 2.0 Hz, 1H), 5.85 (s, 2H), 5.15-4.78 (m, 3H), 4.58 (t, J = 7.6 Hz, 1H), 4.52-4.19 (m, 1H), 4.17-4.08 (m, 1H), 3.98 (d, J = 10.5 Hz, 1H), 3.75-3.64 (m, 1H), 3.62-3.47 (m, 2H), 3.22-3.15 (m, 1H), 2.36-2.32 (m, 2H), 2.22 (d, J = 5.2 Hz, 3H), 2.03-1.90 (m, 1H), 1.80-1.64 (m, 2H), 1.59-1.39 (m, 1H) EXAMPLE 10 [1856] (±)-trans-4-((2-aminopyrimidin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide 192 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1857] Step 1: (±)-trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)-4-(methylamino)tetrahydrofuran-2-carboxamide [1858] To a solution of 4-iodo-N-[1-[2-[methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo- ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (300 mg, 585.55 μmol, 1 eq) and methanamine;hydrochloride (197.67 mg, 2.93 mmol, 5 eq) in ACN (3 mL) was added DIEA (605.42 mg, 4.68 mmol, 815.93 μL, 8 eq). The mixture was stirred at 80 °C for 16 h under N₂. The suspension was filtered and the filtrated was concentrated under reduced pressure. The residue was further purification by pre-HPLC (column: YMC-Actus Triart C18 150*30mm*7um;mobile phase: [water(FA)-ACN];gradient:15%-45% B over 10 min) and lyophilized. The title compound (50 mg, 120.34 μmol, 20.55% yield) was obtained as a white solid. [1859] Step 2: (±)-trans-4-((2-fluoropyrimidin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1860] To a solution of (±)-trans-4-(methylamino)-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (20 mg, 48.14 μmol, 1 eq) in ACN (1 mL) was added Cs2CO3 (31.37 mg, 96.27 μmol, 2 eq) and 2,4-difluoropyrimidine (6.70 mg, 57.76 μmol, 1.2 eq). The mixture was stirred at 40 °C for 16 h under N₂. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:25%-55% B over 9 min) and lyophilized. The title compound (10 mg, 19.55 μmol, 40.61% yield) was obtained as yellow oil. [1861] Step 3: (±)-trans-4-((2-aminopyrimidin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1862] A solution of (2S,4R)-4-[(2-fluoropyrimidin-4-yl)-methyl-amino]-N-[1-[2-[methyl- [2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (5 mg, 9.77 μmol, 1 eq) in ACN (0.5 mL) and NH₃.H₂O (0.5 mL) was stirred at 60 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue The residue was further purification by pre-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:20%-50% B over 9 min) and lyophilized. The title compound (2.32 mg, 4.55 μmol, 46.58% yield, 99.8% purity) was obtained as a white solid. [1863] LC-MS [ESI, M+1]: 509.3 193 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1864] ¹H NMR (400 MHz, DMSO-d6) δ = 10.09-9.97 (m, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 6.0 Hz, 1H), 7.57-7.50 (m, 1H), 7.14-7.01 (m, 2H), 6.93-6.74 (m, 2H), 5.97 (s, 2H), 5.93-5.87 (m, 1H), 5.46-5.29 (m, 1H), 5.20-5.03 (m, 2H), 4.46-4.35 (m, 1H), 4.11 (t, J = 4.8 Hz, 1H), 4.02 (t, J = 6.0 Hz, 1H), 3.97-3.88 (m, 1H), 3.87-3.80 (m, 1H), 3.75 (t, J = 4.8 Hz, 1H), 3.65-3.58 (m, 1H), 3.11-2.88 (m, 3H), 2.87-2.79 (m, 3H), 2.46-2.41 (m, 1H), 2.22 (d, J = 4.8 Hz, 3H) EXAMPLE 11 [1865] (±)-trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4- yl)-4-((3-methylisoxazol-5-yl)oxy)tetrahydrofuran-2-carboxamide [1866] Step 1: (±)-trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)-4-((3-methylisoxazol-5-yl)oxy)tetrahydrofuran-2-carboxamide [1867] To a mixture of 3-methylisoxazol-5-ol (50 mg, 504.60 μmol), 4-hydroxy-N-[1-[2- [methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2- carboxamide (203.07 mg, 504.60 μmol) and PPh3 (198.53 mg, 756.90 μmol) in THF (2 mL) was added DIAD (122.44 mg, 605.52 μmol, 117.39 μL) at 0 °C under N₂, and the reaction mixture was stirred at 30 °C for 16 h. LCMS showed 4% peak of desired mass. The reaction mixture was poured into water (1 ml), extracted with Ethyl acetate (1 mL × 2). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 194 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:28%- 58% B over 9 min) and lyophilized to afford the title compound (18.26 mg, 36.73 μmol, 7.28% yield, 97.263% purity) as a white solid. [1868] LC-MS [ESI, M+1]: 484.2 [1869] 1H NMR (400 MHz, DMSO-d6) δ = 10.11 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 4.4 Hz, 1H), 7.16-7.03 (m, 2H), 6.94-6.75 (m, 2H), 5.54 (s, 1H), 5.18 (s, 2H), 5.08 (s, 1H), 4.62 (t, J = 8.0 Hz, 1H), 4.15-3.99 (m, 4H), 3.80-3.57 (m, 2H), 3.17-2.83 (m, 3H), 2.47- 2.30 (m, 2H), 2.23 (d, J = 5.2 Hz, 3H), 2.14 (s, 3H) EXAMPLE 12 [1870] (2R,4S)-N-(1-(2-((2-hydroxyethyl)(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)-4-((2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2-carboxamide [1871] Step 1: tert-butyl (2-methoxyethyl)(2-(p-tolyloxy)ethyl)carbamate [1872] To a solution of tert-butyl N-[2-(4-methylphenoxy)ethyl]carbamate (0.15 g, 596.85 μmol, 1 eq) in DMF (3 mL) was added NaH (28.65 mg, 716.22 μmol, 60% purity, 1.2 eq) at 0 °C under N₂. After 0.5 h, was added1-bromo-2-methoxy-ethane (99.55 mg, 716.22 μmol, 67.31 μL, 1.2 eq). The mixture was stirred at 20 °C for 1 h. LCMS showed 58% desired compound mass was detected. The reaction mixture was poured into NH₄Cl (3 ml) and extracted with ethyl acetate (3 mL × 2). The combined organic layer was washed with brine (2 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:48%- 195 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 78% B over 15 min) and the mobile phase was lyophilized to remove solvent to afford tert- butyl (2-methoxyethyl)(2-(p-tolyloxy)ethyl)carbamate (210 mg, 671.95 μmol) as yellow oil. [1873] LC-MS [ESI, M-100]: 210.0 [1874] ¹H NMR (400 MHz, DMSO-d₆) δ = 7.07 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.00 (s, 2H), 3.51 (t, J = 6.0 Hz, 2H), 3.44-3.33 (m, 4H), 3.24 (s, 3H), 2.22 (s, 3H), 1.38 (d, J = 4.4 Hz, 9H) [1875] Step 2: 2-methoxy-N-(2-(p-tolyloxy)ethyl)ethan-1-amine [1876] To a solution of tert-butyl N-(2-methoxyethyl)-N-[2-(4-methylphenoxy)ethyl] carbamate (100 mg, 323.21 μmol, 1 eq) in HCl/dioxane (1 mL) was stirred at 20 °C for 16 hr . LCMS showed 99% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent to afford 2-methoxy-N-(2-(p- tolyloxy)ethyl)ethan-1-amine (79 mg, crude, HCl) as a yellow oil. [1877] LC-MS [ESI, M+1]: 210.0 [1878] Step 3: (2R,4S)-N-(1-(2-((2-hydroxyethyl)(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)- 1H-pyrazol-4-yl)-4-((2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2-carboxamide [1879] To a solution of 2-methoxy-N-[2-(4-methylphenoxy)ethyl]ethanamine (40 mg, 162.77 μmol, 1 eq, HCl) and 2-[4-[[(2R,4S)-4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2- carbonyl]amino]pyrazol-1-yl]acetic acid (58.42 mg, 146.49 μmol, 0.9 eq, HCl) in DMF (1 mL) was added DIEA (63.11 mg, 488.31 μmol, 85.05 μL, 3 _eq) and T₄P (175.92 mg, 244.16 μmol, 50% purity, 1.5 eq). The mixture was stirred at 20 °C for 1 hr. LCMS showed 80% desired compound mass. The reaction mixture was poured into water (1 ml) and extracted with ethyl acetate (1 mL × 2). The combined organic layer was washed with brine (1 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:28%-58% B over 10 min) and the mobile phase was lyophilized to remove solvent to afford (2R,4S)-N-[1-[2-[2- methoxyethyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]-4-[(2-methoxy- 4-pyridyl)oxy]tetrahydrofuran-2-carboxamide (23.68 mg, 42.55 μmol, 26.14% yield, 99.47% purity) as a white solid. [1880] LC-MS [ESI, M+1]: 554.3 [1881] ¹H NMR (400 MHz, DMSO-d6) δ = 10.09 (s, 1H), 8.02-7.87 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.13-7.02 (m, 2H), 6.90-6.77 (m, 2H), 6.65-6.57 (m, 1H), 6.36 (s, 1H), 5.32-5.05 (m, 3H), 4.65-4.53 (m, 1H), 4.19-4.08 (m, 2H), 4.05-3.97 (m, 2H), 3.86-3.73 (m, 4H), 3.69- 196 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 3.60 (m, 2H), 3.57-3.46 (m, 2H), 3.42 (t, J = 5.2 Hz, 1H), 3.31-3.19 (m, 3H), 2.39-2.33 (m, 2H), 2.23 (d, J = 6.4 Hz, 3H) EXAMPLE 13 [1882] (2R,4S)-4-((2-aminopyrimidin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 39) 197 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1883] Step 1: tert-butyl methyl(2-(p-tolyloxy)ethyl)carbamate [1884] To a solution of p-cresol (20 g, 184.95 mmol, 1 eq), tert-butyl (2-hydroxyethyl) (methyl) carbamate (32.41 g, 184.95 mmol, 1 eq) and PPh3 (72.77 g, 277.42 mmol, 1.5 eq) in THF (200 mL) was added DIAD (44.88 g, 221.94 mmol, 1.3 eq) dropwise at 0 °C under N₂. The mixture was stirred at 25 °C for 12 hrs under N₂. LCMS showed 21% peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um);mobile phase: [water(FA)-ACN];gradient:60%-90% B over 20 min) and lyophilized to give the title compound (30 g, 113.06 mmol, 61.13% yield) as a white solid. [1885] LC-MS [ESI, M-Boc +1]: 166.0 198 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1886] ¹H NMR (400 MHz, CDCl₃) δ = 7.27 (s, 2H), 7.00-6.94 (m, 2H), 4.29-4.18 (m, 2H), 3.77 (s, 2H), 3.16 (s, 3H), 2.47 (s, 3H), 1.65 (s, 9H) [1887] Step 2：N-methyl-2-(p-tolyloxy)ethan-1-amine hydrochloride [1888] To a stirred mixture of tert-butyl methyl(2-(p-tolyloxy)ethyl)carbamate (25 g, 94.22 mmol, 1 eq) in DCM (100 mL) was added HCl/dioxane (4 M, 208.33 mL) at 0 °C, and the reaction mixture was stirred at 20 °C for 1 h. TLC (Petroleum ether : Ethyl acetate=5:1) showed tert-butyl methyl(2-(p-tolyloxy)ethyl)carbamate (Rf=0.5) was consumed completely and one new spot was detected. The mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with MeCN (80 ml) for 0.5 h. The turbid liquid was filtered and the filter cake was washed with MeCN (50 ml), and then, the filtrate cake was concentrated under reduced pressure to give the title compound (16.3 g, 84.24% yield, HCl) as a white solid. [1889] LC-MS [ESI, M+1]: 166.0 [1890] ¹H NMR (400 MHz, DMSO-d6) δ = 9.32 (br s, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.27 (t, J = 5.2 Hz, 2H), 2.58 (s, 3H), 2.23 (s, 3H). [1891] Step 3: 2-chloro-N-methyl-N-(2-(p-tolyloxy)ethyl)acetamide [1892] To a stirred mixture of N-methyl-2-(p-tolyloxy)ethan-1-amine hydrochloride (15.5 g, 76.85 mmol, HCl, 1 eq) in DCM (150 mL) was added TEA (23.33 g, 230.55 mmol, 3 eq) at 0°C, and then, 2-chloroacetyl chloride (11.28 g, 99.90 mmol, 1.3 eq) was added to the reaction mixture at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. LCMS showed N-methyl-2-(p-tolyloxy)ethan-1-amine hydrochloride was consumed completely and one main peak with desired mass was detected. The reaction mixture was poured into water (300 mL), extracted with DCM (200 mL × 2). The combined organic layer was washed with water (300 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 3/1) to give the title compound (16.2 g, 85.02% yield) as light brown oil. [1893] LC-MS [ESI, M+1]: 242.1 [1894] Step 4: N-methyl-2-(4-nitro-1H-pyrazol-1-yl)-N-(2-(p-tolyloxy)ethyl) acetamide [1895] To a mixture of 2-chloro-N-methyl-N-(2-(p-tolyloxy)ethyl)acetamide (16.2 g, 67.02 mmol, 1 eq) and 4-nitro-1H-pyrazole (7.58 g, 67.02 mmol, 1 eq) in MeCN (150 mL) was added K₂CO₃ (13.89 g, 100.53 mmol, 1.5 eq) at 15 °C, and the reaction mixture was stirred at 199 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 60 °C for 16 h. LCMS showed 2-chloro-N-methyl-N-(2-(p-tolyloxy)ethyl)acetamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was poured into water (500 mL), extracted with ethyl acetate (200 mL × 3). The combined organic layer was washed with brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (21.3 g, 97.89% yield) as a white solid. [1896] LC-MS [ESI, M+1]: 319.2 [1897] Step 5: 2-(4-amino-1H-pyrazol-1-yl)-N-methyl-N-(2-(p-tolyloxy)ethyl) acetamide hydrochloride [1898] To a solution of N-methyl-2-(4-nitro-1H-pyrazol-1-yl)-N-(2-(p-tolyloxy) ethyl) acetamide (10.6 g, 33.30 mmol, 1 eq) in EtOH (600 mL) was added wet Pd/C (1.5 g, 5% purity) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 20 h under H2 (15 psi). LCMS showed N-methyl- 2-(4-nitro-1H-pyrazol-1-yl)-N-(2-(p-tolyloxy) ethyl) acetamide was consumed completely and one main peak with desired mass was detected. The reaction mixture was combined with another batch work-up. The combined reaction mixture was concentrated under reduced pressure to remove solvent to give residue. The residue was added in H₂O (400 mL) and MeCN (40 mL), then dropped in 12M HCl (5.58ml), stirred and lyophilized to give the title compound (19.7 g, 87.90% yield, HCl salt) as red solid. [1899] LC-MS [ESI, M+1]: 189.0. [1900] ¹H NMR (400 MHz, DMSO-d₆) δ = 9.32 (br s, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.22 (t, J = 5.2 Hz, 2H), 3.27 (t, J = 5.2 Hz, 2H), 2.58 (s, 3H), 2.23 (s, 3H) [1901] Step 6: ethyl 4-(benzyl(methyl)amino)tetrahydrofuran-2-carboxylate [1902] To a solution of ethyl 4-oxotetrahydrofuran-2-carboxylate (3 g, 18.97 mmol, 1 eq) and N-methyl-1-phenyl-methanamine (2.30 g, 18.97 mmol, 2.45 mL, 1 eq) in EtOH (40 mL) was added NaBH(OAc)₃ (8.04 g, 37.94 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed 93% of peak with desired mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/1) to afford ethyl 4-[benzyl(methyl)amino]tetrahydrofuran-2-carboxylate (3 g, 60.06% yield) as yellow oil. [1903] LC-MS [ESI, M+1]: 264.2 200 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1904] ¹H NMR (400 MHz, DMSO-d6) δ = 7.36 - 7.19 (m, 5H), 4.45 (t, J = 8.0 Hz, 1H), 4.17 - 4.06 (m, 2H), 4.01 - 3.88 (m, 1H), 3.76 - 3.66 (m, 1H), 3.51 - 3.45 (m, 1H), 3.42 - 3.36 (m, 1H), 3.18 - 3.07 (m, 1H), 2.48 - 2.38 (m, 1H), 2.04 - 1.96 (m, 3H), 1.91 (s, 2H), 1.25 - 1.15 (m, 3H) [1905] Step 7: 4-(benzyl(methyl)amino)tetrahydrofuran-2-carboxylic acid [1906] To a solution of ethyl 4-[benzyl(methyl)amino]tetrahydrofuran-2-carboxylate (600 mg, 2.28 mmol, 1 eq) in MeOH (2 mL) THF (2 mL) H₂O (1 mL) was added LiOH.H₂O (286.84 mg, 6.84 mmol, 3 eq) and the reaction mixture was stirred at 20 °C for 1 h. LCMS showed 69% of peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue to afford 4-[benzyl(methyl)amino] tetrahydrofuran-2- carboxylic acid (800 mg, crude) as a white solid. [1907] LC-MS [ESI, M+1]: 236.1 [1908] Step 8: trans-4-(benzyl(methyl)amino)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)- 2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1909] To a solution of 2-(4-aminopyrazol-1-yl)-N-methyl-N-[2-(4-methylphenoxy) ethyl]acetamide (980.44 mg, 3.40 mmol, 1 eq) 4-[benzyl(methyl)amino]tetrahydrofuran-2- carboxylic acid (800 mg, 3.40 mmol, 1 eq) in DMF (10 mL) was added DIEA (1.32 g, 10.20 mmol, 1.78 mL, 3 eq) and T₄P (3.67 g, 5.10 mmol, 50% purity, 1.5 eq) at 0 °C, and the reaction was continue at 20 °C for 1 h. LCMS showed 93% of peak with desired mass. After the mixture was cooled to room temperature, the reaction mixture was diluted with H₂O (50 mL), and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water (ammonia hydroxide v/v)- ACN];gradient:28%-58% B over 12 min) and lyophilized to afford trans-4- (benzyl(methyl)amino)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol- 4-yl)tetrahydrofuran-2-carboxamide (760 mg, 44.21% yield) as yellow gum. [1910] LC-MS [ESI, M+1]: 506.3 [1911] ¹H NMR (400 MHz, DMSO-d6) δ = 9.96 - 9.89 (m, 1H), 7.91 (s, 1H), 7.54 (d, J = 4.0 Hz, 1H), 7.32 - 7.20 (m, 5H), 7.13 - 7.06 (m, 2H), 6.90 - 6.80 (m, 2H), 5.21 - 5.03 (m, 2H), 4.42 (t, J = 8.0 Hz, 1H), 4.12 (t, J = 5.2 Hz, 1H), 4.06 - 3.97 (m, 2H), 3.86 - 3.72 (m, 2H), 3.63 (t, J = 5.6 Hz, 1H), 3.55 - 3.48 (m, 1H), 3.44 - 3.37 (m, 1H), 3.21 - 3.12 (m, 1H), 3.11 - 2.88 (m, 3H), 2.48 - 2.39 (m, 1H), 2.23 (d, J = 4.0 Hz, 3H), 2.08 - 2.01 (m, 3H), 1.99 - 1.89 (m, 1H) 201 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1912] Step 9: trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol- 4-yl)-4-(methylamino)tetrahydrofuran-2-carboxamide [1913] To a solution of trans-4-[benzyl (methyl) amino]-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (660.00 mg, 1.31 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (200 mg, 187.93 μmol, 10% purity, 1.44e-1 eq) under Ar. The mixture was stirred at 25 °C for 2 h under H2 (15 Psi). LCMS showed 43% of peak with desired mass.43% reactant 1. The mixture was stirred at 25 °C for 4 h. LCMS showed 93% of peak with desired mass. The combined reaction mixture was concentrated under reduced pressure to remove solvent to afford trans-N-(1-(2- (methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-4- (methylamino)tetrahydrofuran-2-carboxamide (500 mg, 92.19% yield) was obtained as yellow gum. [1914] LC-MS [ESI, M+1]: 416.1 [1915] Step 10: trans-4-((2-aminopyrimidin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1916] To a solution of trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)-4-(methylamino)tetrahydrofuran-2-carboxamide (200 mg, 481.37 μmol, 1 eq), 4-chloropyrimidin-2-amine (62.36 mg, 481.37 μmol, 1 eq) in DMF (2 mL) was added DIEA (186.63 mg, 1.44 mmol, 251.53 μL, 3 eq) and the reaction mixture was stirred at 120 °C for 16 h. LCMS showed 70% of peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:15%-45% B over 15 min) and lyophilized to afford trans-4-((2- aminopyrimidin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2- oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (130 mg, 50.45% yield, 95% purity) as a white solid. [1917] LC-MS [ESI, M+1]: 509.2 [1918] ¹H NMR (400 MHz, DMSO-d6) δ = 10.14 - 10.00 (m, 1H), 7.92 (d, J = 2.8 Hz, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.61 - 7.48 (m, 1H), 7.16 - 7.04 (m, 2H), 6.92 - 6.77 (m, 2H), 6.01 (s, 2H), 5.91 (d, J = 6.0 Hz, 1H), 5.50 - 5.29 (m, 1H), 5.24 - 5.02 (m, 2H), 4.73 - 4.35 (m, 1H), 4.12 (t, J = 5.2 Hz, 1H), 4.02 (t, J = 6.0 Hz, 1H), 3.98 - 3.90 (m, 1H), 3.87 - 3.80 (m, 1H), 3.78 - 3.59 (m, 2H), 3.11 - 2.89 (m, 3H), 2.88 - 2.79 (m, 3H), 2.23 (d, J = 4.8 Hz, 3H), 2.04 - 1.89 (m, 1H) 202 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1919] Step 11: (2R,4S)-4-((2-aminopyrimidin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1920] The residue was further purification by pre-HPLC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO₂-ACN/EtOH(0.1% NH3H2O)];B%:40%, isocratic elution mode) and lyophilized to afford (2S,4R)-4-[(2-aminopyrimidin-4-yl)-methyl- amino]-N-[1-[2-[methyl-[2-(4-methylphenoxy)ethyl] amino]-2-oxo-ethyl]pyrazol-4- yl]tetrahydrofuran-2-carboxamide (7.13 mg, 6.99% yield, 98.0% purity) as a white solid. [1921] LC-MS [ESI, M+1]: 509.3 [1922] ¹H NMR (400 MHz, CHLOROFORM-d) δ = 8.35 (s, 1H), 8.05 - 7.98 (m, 1H), 7.86 (d, J = 6.4 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.12 - 7.06 (m, 2H), 6.82 - 6.76 (m, 2H), 5.92 (d, J = 6.4 Hz, 1H), 5.52 - 5.39 (m, 1H), 5.14 (d, J = 1.6 Hz, 1H), 5.03 - 4.94 (m, 3H), 4.74 - 4.68 (m, 1H), 4.14 - 4.08 (m, 3H), 3.95 - 3.89 (m, 1H), 3.81 - 3.75 (m, 2H), 3.23 - 3.04 (m, 3H), 2.96 (s, 3H), 2.61 - 2.51 (m, 1H), 2.44 - 2.34 (m, 1H), 2.30 (d, J = 4.0 Hz, 3H) EXAMPLE 14 [1923] (2R,4S)-N-(1-(2-(isopropyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4- yl)-4-((2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2-carboxamid (Compound 40) 203 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1924] Step 1: tert-butyl 2-(4-nitropyrazol-1-yl) acetate 204 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1925] To a solution of 4-nitro-1H-pyrazole (40 g, 353.75 mmol, 1 eq), tert-butyl 2- bromoacetate (69.00 g, 353.75 mmol, 52.23 mL, 1 eq) in ACN (600 mL) was added K2CO3 (146.67 g, 1.06 mol, 3 eq). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was poured into H₂O (aq) (300 ml) and extracted with ethyl acetate (400 mL × 2). The combined organic layer was washed with brine (200mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC ([water (FA)-ACN]) and the mobile phase was lyophilized to remove solvent to give tert-butyl 2-(4-nitropyrazol-1-yl) acetate (63.86 g, 77.86% yield) as white solid. [1926] LC-MS [ESI, M+1]: 172.0 [1927] Step 2: tert-butyl 2-(4-amino-1H-pyrazol-1-yl)acetate [1928] To a solution of tert-butyl 2-(4-nitropyrazol-1-yl)acetate (6 g, 26.41 mmol, 1 eq) in MeOH (100 mL) was added Pd/C (5.62 g, 5.28 mmol, 10% purity, 0.2 eq) under Ar. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred at 25 °C for 2 h under H2 (15psi). LCMS showed the starting material was consumed completely and 98% of desired compound mass was detected. The mixture was to filter, and the mixture was concentrated under reduced pressure to remove solvent to give tert-butyl 2-(4-amino-1H-pyrazol-1-yl)acetate (5.2 g, 99.84% yield) as a red solid. [1929] Step 3: trans-tert-butyl 2-(4-(4-((2-methoxypyridin-4-yl)oxy)tetrahydrofuran -2- carboxamido)-1H-pyrazol-1-yl)acetate [1930] To a solution of trans-4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2-carboxylic acid (20 g, 83.60 mmol, 1 eq) and tert-butyl 2-(4-aminopyrazol-1-yl)acetate (16.49 g, 83.60 mmol, 1 eq) in DMF (250 mL) was added DIEA (32.42 g, 250.81 mmol, 43.69 mL, 3 eq) and T₄P (90.36 g, 125.41 mmol, 50% purity, 1.5 eq) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 hr. LCMS showed the starting material was consumed completely and 53.5% of desired compound mass was detected. The reaction mixture was poured into water (3000 ml) and extracted with DCM/ethyl acetate (1000 mL × 2). The combined organic layer was washed with brine (1000 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(FA)-ACN];gradient:13%-43% B over 60 min) and the mobile phase was lyophilized to remove solvent to afford tert-butyl 2-[4-[[4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2- carbonyl]amino]pyrazol-1-yl]acetate (22 g, 29.87% yield) as a red solid. 205 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1931] Step 4: tert-butyl 2-(4-((2R,4S)-4-((2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2- carboxamido)-1H-pyrazol-1-yl)acetate [1932] The residue was separated by SFC (column: DAICEL CHIRALPAK AD(250mm*30mm,10um);mobile phase: [CO₂-ACN/EtOH(0.1% NH3H2O)];B%:60%, isocratic elution mode) and the mobile phase was concentrated under reduced pressure to remove solvent to afford tert-butyl 2-[4-[[(2R,4S)-4-[(2-methoxy-4- pyridyl)oxy]tetrahydrofuran-2-carbonyl]amino]pyrazol-1-yl]acetate (9 g, 21.40 mmol, 48.41% yield, 99.5% purity) as yellow gum. [1933] Column: Chiralpak AD-350×4.6mm I.D., 3um; Mobile phase: Phase A for CO2, and Phase B for EtOH(0.05%DEA); Gradient elution: EtOH(0.05%DEA) in CO2 from 20% to 60%; Flow rate: 3mL/min; Detector: PDA; Column Temp: 35C; Back Pressure: 100Bar. Retention time: 1.320 min. [1934] Step 5: 2-(4-((2R,4S)-4-((2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2- carboxamido)-1H-pyrazol-1-yl)acetic acid [1935] To a solution of tert-butyl 2-[4-[[(2R,4S)-4-[(2-methoxy-4- pyridyl)oxy]tetrahydrofuran-2-carbonyl]amino]pyrazol-1-yl]acetate (5 g, 11.95 mmol, 1 eq) in DCM (25 mL) was added HCl/dioxane (2 M, 280 mL, 46.87 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed 94% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent to afford 2-[4-[[(2R,4S)- 4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2-carbonyl]amino]pyrazol-1-yl]acetic acid (8.66 g, crude, HCl) was obtained as white solid . [1936] LC-MS [ESI, M+1]: 363.2 [1937] Step 6: N-(2-(p-tolyloxy)ethyl)propan-2-amine [1938] To a solution of 2-(4-methylphenoxy)ethanamine (200 mg, 1.32 mmol, 1 eq) in ACN (2 mL) was added DIEA (341.90 mg, 2.65 mmol, 2 eq) and 2-iodopropane (202.36 mg, 1.19 mmol, 0.9 eq). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water( NH4HCO3)-ACN]; gradient: 20%-50% B over 15 min ) and lyophilized. The N-(2-(p-tolyloxy)ethyl)propan-2-amine (50 mg, 19.56% yield) was obtained as a white solid. [1939] Step 7: (2R,4S)-N-(1-(2-(isopropyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)-4-((2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2-carboxamide 206 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1940] To a solution of 2-[4-[[(2R,4S)-4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2- carbonyl]amino]pyrazol-1-yl]acetic acid (35 mg, 87.76 μmol, 1 eq, HCl), N-[2-(4- methylphenoxy)ethyl]propan-2-amine (16.96 mg, 87.76 μmol, 1 eq) in DMF (1 mL) was added T₄P (94.85 mg, 131.65 μmol, 50% purity, 1.5 eq) and DIEA (34.03 mg, 263.29 μmol, 3 eq). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was poured into water (1 ml) and extracted with DCM (1 mL × 2). The combined organic layer was washed with brine (1 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was further purification by pre-HPLC (column: YMC-Actus Triart C18150*30mm*7um; mobile phase: [water (FA)-ACN]; gradient: 25%-55% B over 15 min) and lyophilized. The (2R,4S)-N-(1-(2-(isopropyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)-4-((2-methoxypyridin-4-yl)oxy) tetrahydrofuran-2-carboxamide (4.45 mg, 100%) was obtained as a white solid. [1941] ¹H NMR (400 MHz, DMSO-d6) δ = 10.06 (s, 1H), 8.02 - 7.88 (m, 2H), 7.53 (s, 1H), 7.17 - 7.00 (m, 2H), 6.91 - 6.77 (m, 2H), 6.66 - 6.57 (m, 1H), 6.35 (d, J = 2.0 Hz, 1H), 5.35 - 5.01 (m, 3H), 4.59 (t, J = 8.0 Hz, 1H), 4.33 - 4.04 (m, 3H), 4.03 - 3.95 (m, 2H), 3.82 (s, 3H), 3.72 - 3.45 (m, 2H), 2.39 - 2.32 (m, 2H), 2.22 (d, J = 8.8 Hz, 3H), 1.23 - 1.10 (m, 6H) 207 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 208 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 209 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 210 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 EXAMPLE 15 [1942] (2R,4S)-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 46) [1943] (2R,4S)-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 58) [1944] (2S,4R)-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 59) 211 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 212 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1945] Step 1: 2-(4-amino-1H-pyrazol-1-yl)-1-(3-methyl-3-((p-tolyloxy)methyl)azetidin-1- yl)ethan-1-one [1946] To a mixture of tert-butyl 3-(hydroxymethyl)-3-methyl-azetidine-1-carboxylate (1 g, 4.97 mmol, 1 eq), p-cresol (591.03 mg, 5.47 mmol, 571.59 μL, 1.1 eq) and PPh₃ (1.95 g, 7.45 mmol, 1.5 eq) in THF (6 mL) was added DIAD (1.21 g, 5.96 mmol, 1.16 mL, 1.2 eq) in one portion at 0 °C under N2. The mixture was stirred at 25 °C 16 h. LCMS showed starting material consumed and desired product mass was formed. The reaction was filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) and lyophilized directly to afford (800 mg, 49.73% yield, 90% purity) as a light yellow oil. [1947] LC-MS [ESI, M-55]: 236.0 [1948] ¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.09 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 3.92 - 3.86 (m, 4H), 3.64 (d, J = 8.4 Hz, 2H), 2.30 (s, 3H), 1.46 (s, 9H), 1.39 (s, 3H) [1949] Step 2: 3-methyl-3-((p-tolyloxy)methyl)azetidine [1950] To a solution of tert-butyl 3-methyl-3-[(4-methylphenoxy)methyl]azetidine-1- carboxylate (750 mg, 2.57 mmol, 1 eq) in DCM (3.75 mL) was added TFA (5.76 g, 50.48 mmol, 3.75 mL, 19.61 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed 92% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solventto afford product 3-methyl-3-[(4-methylphenoxy)methyl]azetidine (785 mg, 99.90% yield, TFA) was obtained as yellow oil [1951] LC-MS [ESI, M+1]: 192.1 [1952] Step 3: 1-(3-methyl-3-((p-tolyloxy)methyl)azetidin-1-yl)-2-(4-nitro-1H-pyrazol-1- yl)ethan-1-one [1953] To a solution of 3-methyl-3-[(4-methylphenoxy)methyl]azetidine (785 mg, 4.10 mmol, 1 eq), 2-(4-nitropyrazol-1-yl)acetic acid (702.27 mg, 4.10 mmol, 1 eq) in DMF (8 mL) was added DIEA (1.59 g, 12.31 mmol, 2.14 mL, 3 eq) and T₄P (4.44 g, 6.16 mmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed 64% peak of desired compound mass. The reaction mixture was poured into water (20 mL), extracted with Ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)-ACN];gradient:40%-70% B over 10 min) to afford (0.6 g, 42.45% yield) as yellow solid. 213 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1954] LC-MS [ESI, M+1]: 345.1 [1955] ¹H NMR (400 MHz, DMSO-d6) δ = 8.81 (s, 1H), 8.27 (s, 1H), 7.10 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.00 (s, 2H), 4.13 (d, J = 8.4 Hz, 1H), 4.02 - 3.88 (m, 3H), 3.86 - 3.59 (m, 2H), 2.23 (s, 3H), 1.36 (s, 3H) [1956] Step 4: 2-(4-amino-1H-pyrazol-1-yl)-1-(3-methyl-3-((p-tolyloxy)methyl)azetidin-1- yl)ethan-1-one [1957] To a solution of 1-[3-methyl-3-[(4-methylphenoxy)methyl]azetidin-1-yl]-2-(4- nitropyrazol-1-yl)ethanone (50 mg, 145.20 μmol, 1 eq) in MeOH (0.5 mL) was added Pd/C (20 mg, 18.79 μmol, 10% purity, 1.29e-1 eq) under N2 atmosphere. The suspension was degassed and purged with H₂ for 3 times. The mixture was stirred under (15 Psi) at 25 °C for 12 h. LCMS showed 96% peak of desired compound mass. The mixture was to filter, the reaction mixture was concentrated under reduced pressure to remove solvent to afford 2-(4- aminopyrazol-1-yl)-1-[3-methyl-3-[(4-methylphenoxy) methyl]azetidin-1-yl]ethanone (45 mg, 98.58% yield) as yellow oil. [1958] LC-MS [ESI, M+1]: 315.1 [1959] ¹H NMR (400 MHz, DMSO-d6) δ = 7.11 - 6.82 (m, 6H), 4.64 (s, 2H), 3.97 - 3.75 (m, 6H), 3.69 (d, J = 8.4 Hz, 1H), 3.57 (d, J = 9.6 Hz, 1H), 2.23 (s, 3H), 1.31 (s, 3H) [1960] Step 5: trans-ethyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)tetrahydrofuran-2- carboxylate [1961] To a solution of ethyl 4-hydroxytetrahydrofuran-2-carboxylate (2 g, 12.49 mmol, 1 eq) in THF (20 mL) was added NaH (749.22 mg, 18.73 mmol, 60% purity, 1.5 eq) at 0 °C for 0.5 h, the mixture was added 5-chloro-3-methyl-1,2,4-thiadiazole (1.68 g, 12.49 mmol, 1 eq) at 0 °C, then the mixture was stirred at 25 °C for 16 h under N2 atmosphere. LCMS showed 20% peak of desired compound mass and 7% peak of desired compound mass.The reaction mixture was quenched by NH₄Cl (30 mL), extracted with Ethyl acetate (120 mL× 2). The combined organic layers were washed with brine (130 mL ×2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(FA)- ACN];gradient:15%-45% B over 15 min) to afford trans-ethyl-4-((3-methyl-1,2,4-thiadiazol- 5-yl)oxy)tetrahydrofuran-2-carboxylate (50 mg, 1.53% yield) as yellow oil. [1962] LC-MS [ESI, M+23]: 281.1 [1963] Step 6: trans-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)tetrahydrofuran-2-carboxylic acid 214 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1964] To a solution of trans-ethyl-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)tetrahydrofuran- 2-carboxylate (30 mg, 116.15 μmol, 1 eq) in MeCN (0.4 mL), H2O (0.04 mL) was added TEA (21.16 mg, 209.06 μmol, 29.10 μL, 1.8 eq), LiBr (27.23 mg, 313.60 μmol, 7.87 μL, 2.7 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed 96% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent to afford trans-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)tetrahydrofuran-2-carboxylic acid (26 mg, 97.23% yield) as a yellow solid [1965] LC-MS [ESI, M+1]: 231.1 [1966] Step 7: trans-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1967] To a solution of trans-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)tetrahydrofuran-2- carboxylic acid (22.00 mg, 95.55 μmol, 1 eq), 2-(4-aminopyrazol-1-yl)-1-[3-methyl-3-[(4- methylphenoxy)methyl]azetidin-1-yl]ethanone (30.04 mg, 95.55 μmol, 1 eq) in DMF (0.5 mL) was added DIEA (37.05 mg, 286.66 μmol, 49.93 μL, 3 eq) and T₄P (103.27 mg, 143.33 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed 85% peak of desired compound mass. The reaction mixture was poured into water (5 mL), extracted with Ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:25%-55% B over 10 min) to afford trans-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (24.04 mg, 45.86% yield, 96% purity) as white solid. [1968] LC-MS [ESI, M+1]: 527.3 [1969] ¹H NMR (400 MHz, DMSO-d6) δ = 10.10 (s, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.09 (d, J = 8.3 Hz, 2H), 6.92 - 6.79 (m, 2H), 5.58 (d, J = 2.0 Hz, 1H), 4.82 (s, 2H), 4.64 (t, J = 8.0 Hz, 1H), 4.19 - 4.13 (m, 2H), 4.04 - 3.88 (m, 3H), 3.83 - 3.74 (m, 2H), 3.59 (d, J = 9.6 Hz, 1H), 2.61 - 2.53 (m, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.33 (s, 3H) [1970] Step 8: (2R,4S)-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1971] (2S,4R)-4-((3-methyl-1,2,4-thiadiazol-5-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1972] The residue was purified by column(column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO₂-EtOH:ACN=4:1 (0.1% NH₃H₂O)];B%:75%, 215 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 isocratic elution mode) to afford (2R,4S)-N-[1-[2-[3-methyl-3-[(4-methylphenoxy) methyl]azetidin-1-yl]-2-oxo-ethyl]pyrazol-4-yl]-4-[(3-methyl-1,2,4-thiadiazol-5- yl)oxy]tetrahydrofuran-2-carboxamide (3.12 mg, 20.59% yield, 99% purity) as yellow solid. [1973] LC-MS [ESI, M+1]: 527.1 [1974] ¹H NMR (400 MHz, DMSO-d6) δ = 10.11 (s, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.58 (s, 1H), 4.82 (s, 2H), 4.64 (t, J = 8.0 Hz, 1H), 4.20 - 4.09 (m, 2H), 4.05 - 3.86 (m, 3H), 3.83 - 3.74 (m, 2H), 3.59 (d, J = 9.6 Hz, 1H), 2.61 - 2.53 (m, 2H), 2.40 (s, 3H), 2.23 (s, 3H), 1.33 (s, 3H) EXAMPLE 16 [1975] trans-N-(1-(2-(3-methyl-3-((p-tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H- pyrazol-4-yl)-4-((2-(methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxamide (Compound 53) [1976] Step 1: trans-ethyl-4-((2-chloropyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylate 216 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1977] To a solution of ethyl 4-hydroxytetrahydrofuran-2-carboxylate (500 mg, 3.12 mmol, 1 eq), 2-chloropyrimidin-4-ol (407.49 mg, 3.12 mmol, 1 eq) in THF (5 mL) was added PPh3 (982.54 mg, 3.75 mmol, 1.2 eq) and DIAD (757.49 mg, 3.75 mmol, 726.26 μL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed 13% peak of desired compound mass and 29% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*50mm*10um;mobile phase: [H₂O(10mM HCOONH₄)- ACN];gradient:22%-52% B over 15.0 min) to afford trans-ethyl-4-((2-chloropyrimidin-4- yl)oxy)tetrahydrofuran-2-carboxylate (230 mg, 27.02% yield) as yellow oil. [1978] LC-MS [ESI, M+1]: 273.0 [1979] ¹H NMR (400 MHz, DMSO-d6) δ = 8.48 (d, J = 6.0 Hz, 1H), 7.01 (d, J = 6.0 Hz, 1H), 5.62 (d, J = 3.2 Hz, 1H), 4.64 (t, J = 7.6 Hz, 1H), 4.17 - 4.09 (m, 2H), 4.03 (d, J = 7.2 Hz, 2H), 2.46 - 2.36 (m, 2H), 1.20 (d, J = 7.2 Hz, 3H) [1980] Step 2: trans-ethyl-4-((2-(methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxylate [1981] To a solution of trans-ethyl-4-((2-chloropyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxylate (100 mg, 366.72 μmol, 1 eq) in MeCN (1 mL) was added MeNH₂ (2 M, 916.81 μL, 5 eq). The mixture was stirred at 70 °C for 16 h under N₂. LCMS showed 81% peak of desired compound mass. The suspension was filtered and the filtrated was concentrated under reduced pressure to afford trans-ethyl-4-((2-(methylamino)pyrimidin-4- yl)oxy)tetrahydrofuran-2-carboxylate (98 mg, 99.98% yield) as yellow solid [1982] LC-MS [ESI, M+1]: 268.1 [1983] Step 3: trans-4-((2-(methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid [1984] To a solution of trans-ethyl-4-((2-(methylamino)pyrimidin-4- yl)oxy)tetrahydrofuran-2-carboxylate (49 mg, 183.33 μmol, 1 eq) in MeOH (0.5 mL), H2O (0.1 mL) was added LiOH.H₂O (23.08 mg, 549.98 μmol, 3 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed 90% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent to afford trans-4-((2- (methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid (43 mg, 98.05% yield) as yellow solid [1985] LC-MS [ESI, M+1]: 240.1 [1986] Step 4: trans-N-(1-(2-(3-methyl-3-((p-tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)- 1H-pyrazol-4-yl)-4-((2-(methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxamide 217 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1987] To a solution of trans-4-((2-(methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxylic acid (33 mg, 137.94 μmol, 1 eq), 2-(4-aminopyrazol-1-yl)-1-[3-methyl-3-[(4- methylphenoxy)methyl]azetidin-1-yl]ethanone (43.37 mg, 137.94 μmol, 1 eq) in DMF (0.5 mL) was added DIEA (53.48 mg, 413.83 μmol, 72.08 μL, 3 eq) and T₄P (149.09 mg, 206.92 μmol, 50% purity, 1.5 eq). The mixture was stirred at 25 °C for 1 h. LCMS showed 89% peak of desired compound mass. The reaction mixture was poured into water (10 mL), extracted with Ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*25mm*5um;mobile phase: [H₂O(10mM NH₄HCO₃)-ACN];gradient:23%-53% B over 15.0 min) to afford trans-N-(1-(2-(3-methyl-3-((p-tolyloxy)methyl)azetidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)-4-((2-(methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxamide (46.94 mg, 62.90% yield, 99% purity) as white solid. [1988] LC-MS [ESI, M+1]: 536.4 [1989] ¹H NMR (400 MHz, DMSO-d6) δ = 10.06 (s, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.12 - 6.96 (m, 3H), 6.91 - 6.82 (m, 2H), 6.02 (d, J = 5.6 Hz, 1H), 5.56 (s, 1H), 4.82 (s, 2H), 4.59 (t, J = 8.0 Hz, 1H), 4.22 - 4.13 (m, 1H), 4.04 - 3.88 (m, 4H), 3.84 - 3.75 (m, 2H), 3.59 (d, J = 9.6 Hz, 1H), 2.76 (d, J = 4.8 Hz, 3H), 2.42 - 2.32 (m, 2H), 2.23 (s, 3H), 1.33 (s, 3H) EXAMPLE 17 [1990] trans-4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 54) 218 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1991] Step 1: trans-ethyl-4-((2-aminopyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylate [1992] To a solution of trans-ethyl 4-(2-chloropyrimidin-4-yl)oxytetrahydrofuran-2- carboxylate (30 mg, 110.02 μmol, 1 eq) was added NH3/MeOH (7 M, 0.5 mL, 31.81 eq). The mixture was stirred at 60 °C for 1 h. LCMS showed 79% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent to afford trans-ethyl-4-((2-aminopyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylate (27 mg, crude) as yellow solid. [1993] ¹H NMR (400 MHz, DMSO-d6) δ = 8.48 (d, J = 6.0 Hz, 1H), 7.01 (d, J = 6.0 Hz, 1H), 5.62 (d, J = 3.2 Hz, 1H), 4.64 (t, J = 7.6 Hz, 1H), 4.17 - 4.09 (m, 2H), 4.03 (d, J = 7.2 Hz, 2H), 2.46 - 2.36 (m, 2H), 1.20 (d, J = 7.2 Hz, 3H) [1994] Step 2: trans-4-((2-aminopyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid [1995] To a solution of methyl 4-(2-aminopyrimidin-4-yl)oxytetrahydrofuran-2- carboxylate (27 mg, 112.86 μmol, 1 eq) in MeOH (0.4 mL), H2O (0.1 mL) was added LiOH.H₂O (14.21 mg, 338.59 μmol, 3 eq) at 25 °C for 16 h. LCMS showed 20% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent to afford trans-4-((2-aminopyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid (25 mg, 98.36% yield) as yellow solid. [1996] LC-MS [ESI, M+1]: 226.0 219 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [1997] Step 3: trans-4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [1998] To a solution of trans-4-((2-aminopyrimidin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid (25 mg, 111.01 μmol), 2-(4-aminopyrazol-1-yl)-1-[3-methyl-3-[(4-methylphenoxy) methyl]azetidin-1-yl]ethanone (34.90 mg, 111.01 μmol, 1 eq) in DMF (0.1 mL) was added DIEA (43.04 mg, 333.04 μmol, 58.01 μL, 3 eq), T4P (119.98 mg, 166.52 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed there was 5% of desired compound formed. The reaction mixture was poured into water (5 mL), extracted with Ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*25mm*5um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:20%-50% B over 15.0 min) to afford trans-4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (1.35 mg, 2.28% yield, 98% purity) as white solid. [1999] LC-MS [ESI, M+1]: 522.2 [2000] ¹H NMR (400 MHz, DMSO-d6) δ = 9.93 (s, 1H), 7.92 (s, 1H), 7.54 (s, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.92 - 6.82 (m, 2H), 5.03 (d, J = 3.6 Hz, 1H), 4.81 (s, 2H), 4.48 (d, J = 2.0 Hz, 1H), 4.34 (d, J = 2.0 Hz, 1H), 4.02 - 3.86 (m, 4H), 3.84 - 3.75 (m, 2H), 3.73 - 3.68 (m, 1H), 3.59 (d, J = 9.6 Hz, 1H), 2.23 (s, 3H), 2.15 - 2.08 (m, 1H), 1.99 - 1.89 (m, 1H), 1.32 (s, 3H) EXAMPLE 18 [2001] trans-4-((2-aminopyrimidin-4-yl)oxy)-N-(1-(2-(3-methyl-3-((p- tolyloxy)methyl)azetidin-1-yl)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 55) 220 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2002] Step 1: tert-butyl 2-(4-nitro-1H-pyrazol-1-yl)acetate [2003] To a solution of tert-butyl 2-bromoacetate (3.45 g, 17.69 mmol, 2.61 mL, 1 eq) and 4-nitro-1H-pyrazole (2 g, 17.69 mmol, 1 eq) in ACN (20 mL) was added Cs₂CO₃ (11.53 g, 35.37 mmol, 2 eq), the mixture was stirred at 25 °C for 2 h. LCMS showed starting material consumed and desired product mass was formed. The resulting product was dissolved in ACN (20 mL) and filtered to removed the insoluble. The filter liquor was concentrated in vacuo to afford tert-butyl 2-(4-nitropyrazol-1-yl)acetate (4 g, crude) as a brown oil. [2004] LC-MS [ESI, M-99]: 171.9 [2005] Step 2: 2-(4-nitro-1H-pyrazol-1-yl)acetic acid 221 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2006] To a solution of tert-butyl 2-(4-nitropyrazol-1-yl)acetate (4 g, 13.20 mmol, 1 eq) in TFA (15.35 g, 134.62 mmol, 10 mL, 10.2 eq) and DCM (10 mL), the mixture was stirred at 25 °C for 12 h. LCMS showed starting material consumed and desired product mass was formed. The filter liquor was concentrated in vacuo. The crude product was purified by re-crystallization from PE (10 mL) and EA (4mL) at 25 °C to afford 2-(4- nitropyrazol-1-yl)acetic acid (2.34 g, 59.05% yield, TFA) as a brown solid. [2007] ¹H NMR (400 MHz, DMSO-d6) δ = 8.87 (s, 1H), 8.29 (s, 1H), 5.07 (s, 2H) [2008] Step 3: tert-butyl 3-[(4-chlorophenoxy) methyl]-3-methyl-azetidine-1-carboxylat [2009] To a solution of 4-chlorophenol (638.75 mg, 4.97 mmol, 489.09 μL, 1 eq), tert-butyl 3-(hydroxymethyl)-3-methyl-azetidine-1-carboxylate (1 g, 4.97 mmol, 1 eq) in THF (10 mL) was added PPh₃ (1.56 g, 5.96 mmol, 1.2 eq) and DIAD (1.21 g, 5.96 mmol, 1.16 mL, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS showed reactant was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep- HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH4HCO3)- ACN];gradient:60%-90% B over 10 min) to afford tert-butyl 3-[(4-chlorophenoxy) methyl]- 3-methyl-azetidine-1-carboxylate (705 mg, 44.60% yield) as a white solid. [2010] LC-MS [ESI, M-55]: 256.0 [2011] ¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.26 - 7.22 (m, 2H), 6.86 - 6.81 (m, 2H), 3.91 - 3.83 (m, 4H), 3.65 (d, J = 8.4 Hz, 2H), 1.46 (s, 9H), 1.39 (s, 3H) [2012] Step 4: 3-((4-chlorophenoxy)methyl)-3-methylazetidine [2013] To a solution of tert-butyl 3-[(4-chlorophenoxy)methyl]-3-methyl-azetidine-1- carboxylate (200 mg, 641.43 μmol, 1 eq) in DCM (2 mL) was added TFA (2.30 g, 20.19 mmol, 1.5 mL, 31.48 eq). The mixture was stirred at 25 °C for 0.5 h. LCMS showed 94% peak of desired compound mass. The reaction mixture was concentrated under reduced pressure to remove solvent to afford 3-[(4-chlorophenoxy)methyl]-3-methyl-azetidine (208 mg, 99.56% yield, TFA) as yellow solid. [2014] LC-MS [ESI, M+1]: 212.1 [2015] Step 5: 1-(3-((4-chlorophenoxy)methyl)-3-methylazetidin-1-yl)-2-(4-nitro-1H- pyrazol-1-yl)ethan-1-one [2016] To a solution of 3-[(4-chlorophenoxy)methyl]-3-methyl-azetidine (198 mg, 607.90 μmol, TFA, 1 eq), 2-(4-nitropyrazol-1-yl)acetic acid (104.02 mg, 607.90 μmol, 1 eq) in DMF (2 mL) was added DIEA (235.70 mg, 1.82 mmol, 317.65 μL, 3 eq) and T4P (657.01 mg, 911.85 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS 222 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 showed 65% peak of desired compound mass. The mixture was stirred at 25 °C for 12 h. LCMS showed 85% peak of desired compound mass. TLC (Petroleum ether: Ethyl acetate=1:1, UV) showed the starting material was consumed completely and one new spots was formed. The reaction mixture was poured into water (20 mL), extracted with Ethyl acetate (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The reaction water phase (20 ml), extracted with DCM (20 mL × 2). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 1:1) to afford 1-[3-[(4-chlorophenoxy)methyl]-3- methyl-azetidin-1-yl]-2-(4-nitropyrazol-1-yl)ethanone (210 mg, 94.70% yield) as yellow oil. [2017] LC-MS [ESI, M+1]: 365.0 [2018] ¹H NMR (400 MHz, DMSO-d6) δ = 8.81 (s, 1H), 8.27 (s, 1H), 7.35 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.00 (s, 2H), 4.14 (d, J = 8.4 Hz, 1H), 4.07 - 4.00 (m, 2H), 3.94 - 3.82 (m, 2H), 3.64 (d, J = 9.6 Hz, 1H), 1.36 (s, 3H) [2019] Step 6: 2-(4-amino-1H-pyrazol-1-yl)-1-(3-((4-chlorophenoxy)methyl)-3- methylazetidin-1-yl)ethan-1-one [2020] To a solution of 1-[3-[(4-chlorophenoxy)methyl]-3-methyl-azetidin-1-yl]-2-(4- nitropyrazol-1-yl)ethanone (170 mg, 466.03 μmol, 1 eq) in EtOH (2 mL), H2O (0.4 mL) was added Fe (130.13 mg, 2.33 mmol, 5 eq) and NH₄Cl (249.29 mg, 4.66 mmol, 10 eq). The mixture was stirred at 80 °C for 1 h. LCMS showed 21% peak of desired compound mass. The mixture was stirred at 80 °C for 16 h. LCMS showed 51% peak of desired compound mass. The mixture was to filter.The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purifiied by prep-HPLC(column: Waters Xbridge C18150*25mm*5um;mobile phase: [H₂O(10mM NH₄HCO₃)-ACN];gradient:20%- 50% B over 15.0 min) to afford 2-(4-aminopyrazol-1-yl)-1-[3-[(4-chlorophenoxy)methyl]-3- methyl-azetidin-1-yl]ethanone (47 mg, 30.12% yield) as yellow oil. [2021] LC-MS [ESI, M+1]: 335.1 [2022] ¹H NMR (400 MHz, DMSO-d6) δ = 7.42 - 7.27 (m, 2H), 7.02 - 6.94 (m, 3H), 6.91 (d, J = 0.8 Hz, 1H), 4.63 (s, 2H), 4.01 - 3.88 (m, 3H), 3.85 - 3.75 (m, 3H), 3.70 - 3.64 (m, 1H), 3.61 - 3.52 (m, 1H), 1.30 (s, 3H) [2023] Step 7: trans-N-(1-(2-(3-((4-chlorophenoxy)methyl)-3-methylazetidin-1-yl)-2- oxoethyl)-1H-pyrazol-4-yl)-4-((2-(methylamino)pyrimidin-4-yl)oxy)tetrahydrofuran-2- carboxamide 223 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2024] To a solution of 2-(4-aminopyrazol-1-yl)-1-[3-[(4-chlorophenoxy)methyl]-3- methyl-azetidin-1-yl]ethanone (42 mg, 125.45 μmol, 1 eq), 4-[2-(methylamino)pyrimidin-4- yl]oxytetrahydrofuran-2-carboxylic acid (30.01 mg, 125.45 μmol, 1 eq) in DMF (0.5 mL) was added DIEA (48.64 mg, 376.34 μmol, 65.55 μL, 3 eq) and T₄P (135.58 mg, 188.17 μmol, 50% purity, 1.5 eq) at 0 °C .The mixture was stirred at 25 °C for 1 h. LCMS showed 90% peak of desired compound mass. The reaction mixture was poured into water (8 ml), extracted with Ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*25mm*5um;mobile phase: [H₂O(10mM NH₄HCO₃)-ACN];gradient:23%-53% B over 15.0 min) to afford trans-N-[1-[2-[3-[(4-chlorophenoxy)methyl]-3-methyl-azetidin-1-yl]-2- oxo-ethyl]pyrazol-4-yl]-4-[2-(methylamino)pyrimidin-4-yl]oxy-tetrahydrofuran-2- carboxamide (29.14 mg, 41.36% yield, 99% purity) as white solid. [2025] LC-MS [ESI, M+1]: 556.2 [2026] ¹H NMR (400 MHz, DMSO-d6) δ = 10.07 (s, 1H), 8.02 (s, 1H), 7.94 (s, 1H), 7.55 (s, 1H), 7.38 - 7.30 (m, 2H), 7.08 - 6.93 (m, 3H), 6.02 (d, J = 5.6 Hz, 1H), 5.62 - 5.50 (m, 1H), 4.82 (s, 2H), 4.59 (t, J = 8.0 Hz, 1H), 4.23 - 4.12 (m, 1H), 4.06 - 3.92 (m, 4H), 3.84 - 3.74 (m, 2H), 3.60 (d, J = 9.6 Hz, 1H), 2.76 (d, J = 4.8 Hz, 3H), 2.40 - 2.30 (m, 2H), 1.33 (s, 3H) EXAMPLE 19 [2027] trans-4-((3-amino-1-methyl-1H-1,2,4-triazol-5-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 112) 224 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 225 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2028] Step 1: 4-hydroxytetrahydrofuran-2-carboxylic acid [2029] To a mixture of ethyl 4-hydroxytetrahydrofuran-2-carboxylate (500 mg, 3.12 mmol, 1 eq) in THF (3 mL), H2O (3 mL) and MeOH (3 mL) added LiOH.H2O (393.00 mg, 9.37 mmol, 3 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture pH was adjusted to 6 by adding 1M HCl and freeze-dried to give 4- hydroxytetrahydrofuran-2-carboxylic acid (500 mg, crude) as an off-white oil. [2030] 1H NMR (400 MHz, DMSO-d6) δ ppm 4.30-4.17 (m, 4H), 4.09 (dd, J = 5.2, 8.9 Hz, 3H), 3.69-3.62 (m, 3H), 2.25-2.15 (m, 1H), 2.06-1.98 (m, 1H), 1.84-1.71 (m, 2H) [2031] LC-MS [ESI, M+1]: 133.1 [2032] Step 2: 4-hydroxy-N-(1-(2-(methyl (2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)tetrahydrofuran-2-carboxamide [2033] To a mixture of 4-hydroxytetrahydrofuran-2-carboxylic acid (500 mg, 3.78 mmol, 1 eq) and 2-(4-amino-1H-pyrazol-1-yl)-N-methyl-N-(2-(p-tolyloxy)ethyl)acetamide (1.09 g, 3.78 mmol, 1 eq) in DMF (5 mL) was added DIEA (1.47 g, 11.35 mmol, 3 eq) and T4P (4.09 g, 5.68 mmol, 50% purity, 1.5 eq) in one portion at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was washed with 1 M HCl and NaHCO3 solution and water (5 mL) and extracted with ethyl acetate (5 mL*3). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was further purification by prep-HPLC (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water (FA)-ACN];gradient:25%-55% B over 15 min) and freeze-dried to give 4-hydroxy-N-(1-(2-(methyl (2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4- yl)tetrahydrofuran-2-carboxamide (260 mg, 17.07% yield) as a brown solid. [2034] 1H NMR (400 MHz, DMSO-d6) δ ppm 9.76 (s, 1H), 10.00-9.68 (m, 1H), 7.98-7.81 (m, 1H), 7.60-7.49 (m, 1H), 7.09 (dd, J = 8.4, 11.6 Hz, 2H), 6.85 (dd, J = 8.4, 20 Hz, 2H), 5.16 (s, 1H), 5.07 (s, 1H), 4.52-4.27 (m, 2H), 4.16-4.08 (m, 1H), 4.02 (t, J = 5.6 Hz, 1H), 3.97-3.83 (m, 1H), 3.83-3.68 (m, 2H), 3.62 (t, J = 5.6 Hz, 1H), 3.13-2.87 (m, 3H), 2.38-2.27 (m, 1H), 2.23 (d, J = 4.8 Hz, 3H), 2.06-1.90 (m, 1H) [2035] LC-MS [ESI, M+1]: 4.3.2. [2036] Step 3: 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole [2037] To a solution of 3,5-dibromo-1H-1,2,4-triazole (3 g, 13.22 mmol, 1 eq) in THF (30 mL) was added NaH (1.06 g, 26.45 mmol, 60% purity, 2 eq) at 0 °C for 30 min.2- (chloromethoxy)ethyl-trimethyl-silane (3.09 g, 18.51 mmol, 1.4 eq) was added at 0 °Cand the reaction was continue at 25 °C for 16 hr. The reaction mixture was quenched by NH4Cl (30 mL), extracted with Ethyl acetate (30 mL× 2). The combined organic layers were washed 226 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 with brine (30 mL ×2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1) and the eluent was concentrated under reduced pressure to remove solvent. The 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazole (4 g, 84.70% yield) was obtained as yellow liquid. [2038] Step 4: 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-ol [2039] To a solution of 2-[(3,5-dibromo-1,2,4-triazol-1-yl)methoxy]ethyl-trimethyl-silane (2 g, 5.60 mmol, 1 eq) in MeOH (20 mL) was added NaOH (10 M, 40.00 mL, 71.42 eq). The mixture was stirred at 100 °C for 16 hr. The mixture was cooled to room temperature. The reaction mixture was concentrated down to 7.5 mL, and the pH was adjusted to 6 by adding HCl in water. The residue was further purification by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water( NH4HCO3)- ACN];gradient:3%-33% B over 15 min) and lyophilized.5-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-ol (930 mg, 56.44% yield) was obtained as a white solid. [2040] Step 5: trans-4-((3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5- yl)oxy)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4- yl)tetrahydrofuran-2-carboxamide [2041] To a solution of 5-bromo-1-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-ol (400.00 mg, 1.36 mmol, 9.12e-1 eq) , 4-hydroxy-N-[1-[2-[methyl-[2-(4-methylphenoxy) ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (600 mg, 1.49 mmol, 1 eq) in Tol. (8 mL) was added 2-(tributyl-phosphanylidene)acetonitrile (539.74 mg, 2.24 mmol, 1.5 eq). The mixture was stirred at 100 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(FA)- ACN];gradient:52%-82% B over 15 min) and lyophilized. The trans-4-((3-bromo-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (260 mg, 25.70% yield) was obtained as a brown solid. [2042] Step 6: trans-4-((3-bromo-1H-1,2,4-triazol-5-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [2043] A solution of 4-[[5-bromo-2-(2-trimethylsilylethoxymethyl)-1,2,4-triazol-3-yl]oxy]- N-[1-[2-[methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4- yl]tetrahydrofuran-2-carboxamide (800 mg, 1.18 mmol, 1 eq) in DCM (10 mL) was 227 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 added TFA (13.06 g, 114.57 mmol, 8.51 mL, 97.19 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. Then was added MeOH (10 mL) and NH3.H2O (7.28 g, 62.32 mmol, 8 mL, 30% purity, 52.87 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(FA)- ACN];gradient:28%-58% B over 15 min) and lyophilized. The trans-4-((3-bromo-1H-1,2,4- triazol-5-yl)oxy)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl) amino)-2-oxoethyl)-1H-pyrazol-4- yl)tetrahydrofuran-2-carboxamide (300 mg, 46.41% yield) was obtained as a white solid. [2044] Step 7: trans-4-((3-bromo-1-methyl-1H-1,2,4-triazol-5-yl)oxy)-N-(1-(2-(methyl(2- (p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [2045] To a mixture of 4-[(3-bromo-1H-1,2,4-triazol-5-yl)oxy]-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (150 mg, 273.53 μmol, 1 eq) and K₂CO₃ (56.71 mg, 410.29 μmol, 1.5 eq) in DMF (8 mL) was added MeI (77.65 mg, 547.06 μmol, 34.06 μL, 2 eq) in one portion at 25 °C under N2. The mixture was stirred at 60 °C for 16 hours. The reaction mixture was poured into water (15 ml) and extracted with ethyl acetate (10 mL × 2). The combined organic layer was washed with brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was further purification by pre-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)- ACN];gradient:20%-50% B over 10 min) and lyophilized. The trans-4-((3-bromo-1-methyl- 1H-1,2,4-triazol-5-yl)oxy)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)tetrahydrofuran-2-carboxamide (100 mg, 32.50% yield) was obtained as a white solid. [2046] Step 8: trans-tert-butyl (1-methyl-5-((5-((1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)- 2-oxoethyl)-1H-pyrazol-4-yl)carbamoyl)tetrahydrofuran-3-yl)oxy)-1H-1,2,4-triazol-3- yl)carbamate [2047] A mixture of 4-[(5-bromo-2-methyl-1,2,4-triazol-3-yl)oxy]-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (80 mg, 142.24 μmol, 1 eq), tert-butyl carbamate (24.99 mg, 213.37 μmol, 1.5 eq), tBuONa (41.01 mg, 426.73 μmol, 3 eq), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy- palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (11.30 mg, 14.22 μmol, 0.1 eq) in dioxane (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16hr under N₂ atmosphere. The reaction mixture was 228 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water(NH4HCO3)- ACN];gradient:25%-55% B over 10 min) and lyophilized. The trans-tert-butyl (1-methyl-5- ((5-((1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4- yl)carbamoyl)tetrahydrofuran-3-yl)oxy)-1H-1,2,4-triazol-3-yl)carbamate (15 mg, 17.62% yield) was obtained as a white solid. [2048] Step 9: trans-4-((3-amino-1-methyl-1H-1,2,4-triazol-5-yl)oxy)-N-(1-(2-(methyl(2- (p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [2049] A solution of tert-butyl N-[1-methyl-5-[5-[[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]carbamoyl]tetrahydrofuran-3-yl]oxy- 1,2,4-triazol-3-yl]carbamate (7 mg, 11.69 μmol, 1 eq) in TFA (1.07 g, 9.42 mmol, 700.00 μL, 805.91 eq). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: YMC-Actus Triart C18150*30mm*7um;mobile phase: [water(FA)- ACN];gradient:20%-50% B over 15 min) and lyophilized. The trans-4-((3-amino-1-methyl- 1H-1,2,4-triazol-5-yl)oxy)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H- pyrazol-4-yl)tetrahydrofuran-2-carboxamide (8.06 mg, 68.86% yield, 99.6% purity) was obtained as a white solid. [2050] LC-MS [ESI, M + 1]: 499.3 [2051] ¹H NMR (400 MHz, DMSO-d₆) δ = 10.06 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 4.8 Hz, 1H), 7.14 - 7.02 (m, 2H), 6.93 - 6.77 (m, 2H), 5.30 (br d, J = 4.0 Hz, 1H), 5.20 - 5.05 (m, 4H), 4.62 (t, J = 8.0 Hz, 1H), 4.15 - 3.99 (m, 4H), 3.78 - 3.58 (m, 2H), 3.36 (br d, J = 4.0 Hz, 3H), 3.12 - 2.87 (m, 3H), 2.48 - 2.43 (m, 1H), 2.34 - 2.26 (m, 1H), 2.23 (d, J = 4.8 Hz, 3H) EXAMPLE 20 [2052] trans-4-((2-methoxypyridin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 113) 229 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2053] Step 1: ethyl 4-(benzyl(methyl)amino)tetrahydrofuran-2-carboxylate [2054] To a solution of ethyl 4-oxotetrahydrofuran-2-carboxylate (3 g, 18.97 mmol, 1 eq) and N-methyl-1-phenyl-methanamine (2.30 g, 18.97 mmol, 1 eq) in EtOH (40 mL) was added NaBH(OAc)₃ (8.04 g, 37.94 mmol, 2 eq). The mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = 1/1). The ethyl 4-(benzyl(methyl)amino)tetrahydrofuran-2-carboxylate (3 g, 60.06% yield) was obtained as yellow oil. [2055] Step 2: 4-(benzyl(methyl)amino)tetrahydrofuran-2-carboxylic acid [2056] To a solution of ethyl 4-[benzyl(methyl)amino]tetrahydrofuran-2-carboxylate (2.4 g, 9.11 mmol, 1 eq) in MeOH (10 mL), THF (10 mL), H₂O (4 mL) was added LiOH.H₂O (1.15 g, 27.34 mmol, 3 eq). and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The 4- 230 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 (benzyl(methyl)amino)tetrahydrofuran-2-carboxylic acid(3.6 g, crude) was obtained as yellow gum. [2057] Step 3: trans-4-(benzyl(methyl)amino)-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl) amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide [2058] To a solution of 2-(4-aminopyrazol-1-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]acetamide (122.55 mg, 425.03 μmol, 1 eq), 4-[benzyl(methyl) amino]tetrahydrofuran-2-carboxylic acid (100 mg, 425.03 μmol, 1 eq) in DMF (2 mL) was added DIEA (164.79 mg, 1.28 mmol, 3 eq) and T4P (459.36 mg, 637.54 μmol, 50% purity, 1.5 eq) at 0 °C, and the reaction was continue at 20 °C for 1 hr. After the mixture was cooled to room temperature, the reaction mixture was diluted with H₂O (5 mL), and then extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was further purification by pre-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:30%-60% B over 10 min) and lyophilized. The trans-4-(benzyl(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (130 mg, 58.38% yield) was obtained as a white solid. [2059] ¹H NMR (400 MHz, DMSO-d₆) δ = 9.94 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 4.4 Hz, 1H), 7.35 - 7.22 (m, 5H), 7.14 - 7.05 (m, 2H), 6.91 - 6.79 (m, 2H), 5.21 - 5.02 (m, 2H), 4.55 (t, J = 6.0 Hz, 1H), 4.18 - 3.97 (m, 3H), 3.80 - 3.70 (m, 2H), 3.63 (t, J = 5.6 Hz, 1H), 3.54 - 3.38 (m, 2H), 3.21 - 3.12 (m, 1H), 3.11 - 2.86 (m, 3H), 2.26 - 2.18 (m, 5H), 2.03 (s, 3H) [2060] Step 4: trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol- 4-yl)-4-(methylamino)tetrahydrofuran-2-carboxamide [2061] To a solution of 4-[benzyl(methyl)amino]-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (660.00 mg, 1.31 mmol) in MeOH (10 mL) was added Pd/C (200 mg, 187.93 μmol, 10% purity) under Ar. The mixture was stirred at 25 °C for 6 h under H₂ (15 psi). The combined reaction mixture was concentrated under reduced pressure to remove solvent to give the trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)- 4-(methylamino)tetrahydrofuran-2-carboxamide (500 mg, 92.19% yield) as yellow gum. [2062] Step 5: trans-4-((2-methoxypyridin-4-yl)(methyl)amino)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide 231 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2063] To a solution of 4-(methylamino)-N-[1-[2-[methyl-[2-(4-methylphenoxy)ethyl] amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (100.00 mg, 240.68 μmol, 1 eq) in DMF (1 mL) was added Cs2CO3 (235.26 mg, 722.05 μmol, 3 eq) and 4-fluoro-2- methoxy-pyridine (45.89 mg, 361.02 μmol, 1.5 eq). The mixture was stirred at 120 °C for 16 h under N2. The suspension was filtered and the filtrated was concentrated under reduced pressure. The residue was further purification by pre-HPLC (column: Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:23%-53% B over 10 min) and lyophilized. The trans-4-((2-methoxypyridin-4-yl)(methyl)amino)-N-(1-(2- (methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2- carboxamide (1.23 mg, 2.33 μmol, 0.97% yield, 99.2% purity) was obtained as a white solid. [2064] LC-MS [ESI, M + 1]: 523.2 [2065] ¹H NMR (400 MHz, DMSO-d6) δ = 10.10 - 9.97 (m, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.79 - 7.73 (m, 1H), 7.57 - 7.50 (m, 1H), 7.13 - 7.05 (m, 2H), 6.90 - 6.80 (m, 2H), 6.50 - 6.45 (m, 1H), 6.02 - 5.97 (m, 1H), 5.20 - 5.03 (m, 2H), 4.76 - 4.38 (m, 2H), 4.16 - 3.99 (m, 3H), 3.95 - 3.90 (m, 1H), 3.78 - 3.73 (m, 4H), 3.63 (br t, J = 5.2 Hz, 1H), 3.11 - 2.89 (m, 3H), 2.85 - 2.78 (m, 3H), 2.43 - 2.34 (m, 1H), 2.28 - 2.24 (m, 1H), 2.23 (d, J = 4.8 Hz, 3H) EXAMPLE 21 [2066] (2R,4S)-4-[(2-methoxy-4-pyridyl)oxy]-N-[1-[1-methyl-2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (Compound 115) 232 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2067] Step 1: ethyl 4-hydroxytetrahydrofuran-2-carboxylate [2068] To a mixture of ethyl 4-oxotetrahydrofuran-2-carboxylate (2.5 g, 15.81 mmol, 1 eq) in EtOH (25.5 mL) was added Pd/C (1.5 g, 1.41 mmol, 10% purity), the mixture was 233 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 stirred at 25 °C for 16 hr under H₂ (40Psi). TLC (Petroleum ether : Ethyl acetate=3:1, UV)showed the starting material was consumed completely and one new spot was formed (Rf=0.43). The reaction mixture was concentrated under reduced pressure to remove solvent to give the title compound (2 g, 98.58% yield) as yellow oil. [2069] ¹H NMR (400 MHz, DMSO-d6) δ 5.07-4.83 (m, 1H), 4.52-4.38 (m, 1H), 4.36-4.24 (m, 1H), 4.19-3.96 (m, 3H), 3.84-3.75 (m, 1H), 3.68-3.60 (m, 1H), 2.36-1.83 (m, 2H), 1.26- 1.13 (m, 3H) [2070] Step 2: ethyl-4-((2-methoxypyridin-4-yl) oxy) tetrahydro fura-2-carboxylate [2071] To a solution of NaH (613.55 mg, 15.34 mmol, 60% purity, 1.3 eq) in THF (50 mL) was added ethyl 4-hydroxytetrahydrofuran-2-carboxylate (2.27 g, 14.16 mmol, 1.2 eq) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. Then to the reaction mixture was added 4-fluoro-2-methoxy-pyridine (1.5 g, 11.80 mmol, 1 eq) at 0 °C, and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (40 mL × 2). The combined organic layer was washed with brine (80 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography on silica get eluted with petroleum ether/ethyl acetate =20/1 to 3/1 to give trans-ethyl-4-((2- methoxypyridin-4-yl) oxy) tetrahydro fura-2-carboxylate (190 mg, 6.02% yield) as a white solid. [2072] Step 3: trans-4-((2-methoxypyridin-4-yl)oxy) tetrahydrofuran-2-carboxylic acid [2073] To a mixture of trans-ethyl-4-[(2-methoxy-4-pyridyl) oxy] tetrahydrofuran-2- carboxylate (188 mg, 703.39 μmol, 1 eq) in THF (0.7 mL) and MeOH (0.7 mL) and H2O (0.7 mL) was added LiOH.H2O (88.55 mg, 2.11 mmol, 3 eq) in one portion at 25 °C. The mixture was stirred at 25 °C for 1 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to give the title compound (160 mg, 95.09% yield) was obtained as a brown solid. [2074] Step 4: (2R,4S)-4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2-carboxylic acid [2075] The residue was purified by column(column: DAICEL CHIRALCEL OX (250mm*30mm,10um);mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to obtained the product (2R,4S)-4-[(2-methoxy-4-pyridyl)oxy] tetrahydrofuran-2-carboxylic acid (890 mg, 3.50 mmol, 41.83% yield, 94% purity) as yellow solid. 234 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2076] ¹H NMR (400 MHz, DMSO-d₆) δ = 7.95 (d, J = 6.0 Hz, 1H), 6.65 - 6.49 (m, 1H), 6.29 (d, J = 2.0 Hz, 1H), 5.16 - 5.04 (m, 1H), 4.32 (t, J = 7.6 Hz, 1H), 4.06 - 4.00 (m, 1H), 3.84 (br s, 1H), 3.80 (s, 3H), 2.33 - 2.16 (m, 2H) [2077] Step 5: methyl 2-(4-nitropyrazol-1-yl)propanoate [2078] To a stirred mixture of 4-nitro-1H-pyrazole (1 g, 8.84 mmol, 1 eq) and K2CO3 (3.67 g, 26.53 mmol, 3 eq) in ACN (10 mL) was added methyl 2-bromopropanoate (1.48 g, 8.84 mmol, 985.26 μL, 1 eq), then the reaction mixture was stirred at 20 °C for 16 hr. LCMS showed 88% peak of desired mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. Methyl 2-(4-nitropyrazol-1- yl)propanoate (1.7 g, 96.52%) was obtained as yellow oil. [2079] LC-MS [ESI, M + 1]: 200.1. [2080] Step 6: 2-(4-nitropyrazol-1-yl)propanoic acid [2081] To a solution of methyl 2-(4-nitropyrazol-1-yl)propanoate (0.3 g, 1.51 mmol, 1 eq) in MeOH (2 mL) and H₂O (0.2 mL) was added LiOH.H₂O (126.42 mg, 3.01 mmol, 2 eq). The mixture was stirred at 20 °C for 1 hr. LCMS showed 100% peak of desired mass. The reaction mixture was concentrated under reduced pressure to remove solvent.2-(4- nitropyrazol-1-yl)propanoic acid (280 mg, 96.78%) was obtained as a white solid. [2082] LC-MS [ESI, M + 1]: 186.1. [2083] Step 7: N-methyl-N-[2-(4-methylphenoxy)ethyl]-2-(4-nitropyrazol-1- yl)propanamide [2084] To a solution of 2-(4-nitropyrazol-1-yl)propanoic acid (100 mg, 520.62 μmol, 1 eq, Li), N-methyl-2-(4-methylphenoxy)ethanamine (105.01 mg, 520.62 μmol, 1 eq, HCl) in DMF (1 mL) was added DIEA (201.86 mg, 1.56 mmol, 272.05 μL, 3 eq) and T4P (281.34 mg, 780.93 μmol, 1.5 eq) at 0 °C. The mixture was stirred at 20 °C for 1 hr. LCMS showed 40% peak of desired mass. The reaction mixture was poured into water (2 ml) and extracted with DCM (2 mL × 2). The combined organic layer was washed with brine (2 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 33%-63% B over 15 min) and the mobile phase was lyophilized to remove solvent. N-methyl-N-[2-(4- methylphenoxy) ethyl]-2-(4-nitropyrazol-1-yl) propanamide (80 mg, 96%) was obtained as a yellow solid. [2085] LC-MS [ESI, M + 1]: 333.2 235 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2086] Step 8: 2-(4-aminopyrazol-1-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]propanamide [2087] To a solution of N-methyl-N-[2-(4-methylphenoxy)ethyl]-2-(4-nitropyrazol-1- yl)propanamide (80 mg, 240.71 μmol, 1 eq) in MeOH (2 mL) was added Pd/C (20 mg, 18.79 μmol, 10% purity, 7.81e-2 eq) under Ar. The mixture was stirred at 30 °C for 16hr under H2 (15Psi). LCMS showed 96% peak of desired mass. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent.2-(4-aminopyrazol-1-yl)- N-methyl-N-[2-(4-methylphenoxy)ethyl]propanamide (70 mg, 96.18% yield) was obtained as yellow oil. [2088] LC-MS [ESI, M - 55]: 303.2. [2089] Step 9: (2R,4S)-4-[(2-methoxy-4-pyridyl)oxy]-N-[1-[1-methyl-2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide [2090] To a solution of 2-(4-aminopyrazol-1-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]propanamide (25.28 mg, 83.60 μmol, 1 eq), (2R,4S)-4-[(2-methoxy-4- pyridyl)oxy]tetrahydrofuran-2-carboxylic acid (20 mg, 83.60 μmol, 1 eq) in DMF (1 mL) was added DIEA (32.42 mg, 250.81 μmol, 43.69 μL, 3 eq) and T4P (90.36 mg, 125.41 μmol, 50% purity, 1.5 eq). The mixture was stirred at 20 °C for 1hr. LCMS showed 97% peak of desired mass. The reaction mixture was poured into water (1 ml) and extracted with DCM (1 mL × 2). The combined organic layer was washed with brine (1 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: YMC-Actus Triart C18 150*30mm*7um; mobile phase: [water (FA)-ACN]; gradient:23%-53% B over 15 min) and the mobile phase was lyophilized to remove solvent. (2R,4S)-4-[(2-methoxy-4-pyridyl)oxy]- N-[1-[1-methyl-2-[methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4- yl]tetrahydrofuran-2-carboxamide (9.38 mg, 17.83 μmol, 21.33% yield, 99.53% purity) was obtained as a white solid. [2091] LC-MS [ESI, M - 55]: 524.2. [2092] ¹H NMR (400 MHz, DMSO-d₆) δ = 10.10 (s, 1H), 8.04 - 7.91 (m, 2H), 7.59 - 7.43 (m, 1H), 7.07 (t, J = 9.2 Hz, 2H), 6.81 (t, J = 8.4 Hz, 2H), 6.65 - 6.57 (m, 1H), 6.35 (d, J = 2.0 Hz, 1H), 5.67 - 5.47 (m, 1H), 5.21 (s, 1H), 4.58 (t, J = 7.6 Hz, 1H), 4.17 - 4.09 (m, 1H), 4.02 - 3.96 (m, 3H), 3.82 (s, 3H), 3.67 - 3.58 (m, 2H), 3.04 - 2.88 (m, 3H), 2.35 (br d, J = 7.6 Hz, 2H), 2.22 (d, J = 3.6 Hz, 3H), 1.55 - 1.44 (m, 3H). 236 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 EXAMPLE 22 [2093] (2R,4S)-4-((2-methoxypyridin-4-yl)oxy)-N-(2-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-2H-1,2,3-triazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 118) [2094] Step 1: tert-butyl 2-(4-nitro-2H-1,2,3-triazol-2-yl)acetate [2095] To a stirred mixture of 4-nitro-1H-triazole (1 g, 8.77 mmol, 1 eq) and K₂CO₃ (3.63 g, 26.30 mmol, 3 eq) in ACN (10 mL) was added tert-butyl 2-bromoacetate (1.71 g, 8.77 mmol, 1.29 mL, 1 eq) at 0 °C, and then the reaction mixture was stirred at 25 °C for 12 hr. LCMS showed 52% peak 1 and 47% peak 2 of desired compound mass was detected and the starting material was consumed completely. The reaction mixture was filtered and the filtrate 237 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 was concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC(Waters Xbridge Prep OBD C18150*40mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:23%-53% B over 15 min) and the mobile phase was lyophilized to remove solvent to give Compound tert-butyl 2-(4-nitrotriazol-1-yl)acetate (819 mg, 40.94% yield) was obtained as a white solid. [2096] LC-MS [ESI, M+1]: 229.1. [2097] ¹H NMR (400 MHz, DMSO-d₆) δ = 8.78 (s, 1H), 5.57 (s, 2H), 1.43 (s, 9H) [2098] Step 2: 2-(4-nitro-2H-1,2,3-triazol-2-yl)acetic acid [2099] To a solution of tert-butyl 2-(4-nitrotriazol-2-yl)acetate (372 mg, 1.63 mmol, 1 eq) in TFA (3 mL). The mixture was stirred at 25 °C for 12 hr. The reaction mixture was concentrated under reduced pressure to remove solvent to afford 2-(4-nitrotriazol-2-yl)acetic acid (223 mg, crude) [2100] ¹H NMR (400 MHz, DMSO-d6) δ = 8.77 (s, 1H), 5.56 (s, 2H) [2101] Step 3: N-methyl-2-(4-nitro-2H-1,2,3-triazol-2-yl)-N-(2-(p- tolyloxy)ethyl)acetamide [2102] To a solution of 2-(4-nitrotriazol-2-yl)acetic acid (100 mg, 581.06 μmol, 1 eq), N- methyl-2-(4-methylphenoxy)ethanamine (96.01 mg, 581.06 μmol, 1 eq) in DMF (2 mL) was added T₄P (628.00 mg, 871.59 μmol, 50% purity, 1.5 eq) and DIEA (375.49 mg, 2.91 mmol, 5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed the starting material was consumed completely and showed there was 97% of desired compound mass was detected. The reaction mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL × 2). The combined organic layer was washed with NaHCO3.aq (5 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC(Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:38%-68% B over 10 min) and the mobile phase was lyophilized to remove solvent to afford N-methyl-N-[2-(4- methylphenoxy)ethyl]-2-(4-nitrotriazol-2-yl)acetamide (103 mg, 55.51% yield) as a brown solid. [2103] ¹H NMR (400 MHz, DMSO-d6) δ = 8.76 (d, J = 4.8 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.92 - 6.81 (m, 2H), 5.89 - 5.79 (m, 2H), 4.20 - 4.00 (m, 2H), 3.80 - 3.62 (m, 2H), 3.15 (s, 1H), 2.92 (s, 2H), 2.23 (d, J = 6.4 Hz, 3H) [2104] Step 4: 2-(4-amino-2H-1,2,3-triazol-2-yl)-N-methyl-N-(2-(p- tolyloxy)ethyl)acetamide 238 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2105] To a solution of N-methyl-N-[2-(4-methylphenoxy)ethyl]-2-(4-nitrotriazol-2- yl)acetamide (103 mg, 322.57 μmol, 1 eq) in MeOH (3 mL) was added wet Pd/C (103 mg, 96.79 μmol, 10% purity, 0.3 eq) under Ar. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred at 25 °C for 12 hrs under H₂ (15 psi). LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent to give 2-(4-aminotriazol-2-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]acetamide (93 mg, crude) as a white oil. [2106] LC-MS [ESI, M+1]: 290.2 [2107] ¹H NMR (400 MHz, DMSO-d₆) δ = 7.14 - 7.03 (m, 2H), 6.93 - 6.73 (m, 3H), 5.31 - 5.12 (m, 2H), 4.97 (br d, J = 4.8 Hz, 2H), 4.14 - 3.97 (m, 2H), 3.76 - 3.58 (m, 2H), 3.11 - 3.05 (m, 1H), 2.90 - 2.83 (m, 2H), 2.23 (br d, J = 4.4 Hz, 3H) [2108] Step 5: (2R,4S)-4-((2-methoxypyridin-4-yl)oxy)-N-(2-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-2H-1,2,3-triazol-4-yl)tetrahydrofuran-2-carboxamide [2109] To a solution of 2-(4-aminotriazol-2-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]acetamide (24.19 mg, 83.60 μmol, 1 eq), (2R,4S)-4-[(2-methoxy-4- pyridyl)oxy]tetrahydrofuran-2-carboxylic acid (20 mg, 83.60 μmol, 1 eq) in DMF (2 mL) was added DIEA (43.22 mg, 334.41 μmol, 4 eq) and T₄P (90.36 mg, 125.41 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was poured into water (5 ml) and extracted with ethyl acetate (5 mL × 2). The combined organic layer was washed with NaHCO3.aq (3 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC(Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:25%-55% B over 9 min) and the mobile phase was lyophilized to remove solvent to give Compound (2R,4S)-4-[(2-methoxy-4- pyridyl)oxy]-N-[2-[2-[methyl-[2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]triazol-4- yl]tetrahydrofuran-2-carboxamide (14.47 mg, 33.04% yield, 97.467% purity) as a off-white solid. [2110] LC-MS [ESI, M + 1]: 511.2 [2111] ¹H NMR (400 MHz, DMSO-d₆) δ = 10.86 (d, J = 8.4 Hz, 1H), 8.00 - 7.88 (m, 2H), 7.12 - 7.06 (m, 2H), 6.88 - 6.80 (m, 2H), 6.64 - 6.58 (m, 1H), 6.36 (s, 1H), 5.54 - 5.40 (m, 2H), 5.24 (br d, J = 2.8 Hz, 1H), 4.70 - 4.62 (m, 1H), 4.18 - 4.10 (m, 2H), 4.04 - 3.94 (m, 239 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 2H), 3.82 (s, 3H), 3.76 (br t, J = 4.8 Hz, 1H), 3.62 (t, J = 5.6 Hz, 1H), 3.12 (s, 1H), 2.88 (s, 2H), 2.40 - 2.34 (m, 2H), 2.22 (d, J = 5.6 Hz, 3H) EXAMPLE 23 [2112] trans-4-((5-fluoro-2-methoxypyridin-4-yl)oxy)-N-(1-(2-(methyl(2-(p- tolyloxy)ethyl)amino)-2-oxoethyl)-1H-pyrazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 133) [2113] Step 1: trans ethyl-4-((5-fluoro-2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2- carboxylate [2114] To a stirred mixture of 5-fluoro-2-methoxy-pyridin-4-ol (150 mg, 1.05 mmol, 1 eq), ethyl 4-hydroxytetrahydrofuran-2-carboxylate (167.87 mg, 1.05 mmol, 1 eq), PPh3 (357.37 mg, 1.36 mmol, 1.3 eq) in THF (3 mL) was added DIAD (254.32 mg, 1.26 mmol, 1.2 eq). The reaction mixture was stirred at 25 °C for 12 h. LCMS showed starting material was consumed and two peaks with desired mass were detected. The reaction was concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC(Phenomenex luna C18150*25mm* 10um;mobile phase: [water(TFA)- ACN];gradient:15%-45% B over 10 min) and the mobile phase was lyophilized to remove solvent to give trans ethyl 4-[(5-fluoro-2-methoxy-4-pyridyl)oxy] tetrahydrofuran-2- carboxylate (160 mg, 26.46% yield) was obtained as a white solid. [2115] LC-MS [ESI, M + 1]: 286.1 240 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2116] ¹H NMR (400 MHz, DMSO-d₆) δ = 8.02 (d, J = 3.2 Hz, 1H), 6.59 (d, J = 6.0 Hz, 1H), 5.25 (br d, J = 3.2 Hz, 1H), 4.64 (t, J = 7.6 Hz, 1H), 4.16 - 4.10 (m, 2H), 4.06 - 3.99 (m, 2H), 3.80 (s, 3H), 2.44 - 2.40 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H) [2117] Step 2: trans-4-((5-fluoro-2-methoxypyridin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid [2118] To a solution of ethyl 4-[(5-fluoro-2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2- carboxylate (55 mg, 192.80 μmol, 1 eq) in H₂O (0.2 mL), MeOH (1 mL) was added LiOH.H2O (24.27 mg, 578.40 μmol, 3 eq). The mixture was stirred at 25 °C for 1 hr. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent to give trans-4-[(5-fluoro-2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2-carboxylic acid (64 mg, crude) was obtained as a white solid. [2119] LC-MS [ESI, M + 1]: 258.1 [2120] Step 3: trans-4-[(5-fluoro-2-methoxy-4-pyridyl)oxy]-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide [2121] To a solution of 4-[(5-fluoro-2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2- carboxylic acid (32.11 mg, 124.85 μmol, 1.2 eq), 2-(4-aminopyrazol-1-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]acetamide (30 mg, 104.04 μmol, 1 eq) in DMF (1 mL) was added DIEA (67.23 mg, 520.21 μmol, 5 eq) and T4P (112.45 mg, 156.06 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was poured into water (6 ml) and extracted with ethyl acetate (6 mL × 2). The combined organic layer was washed with NaCl.aq (5 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC(Waters Xbridge 150*25mm* 5um;mobile phase: [water( NH₄HCO₃)- ACN];gradient:28%-58% B over 10 min) and the mobile phase was lyophilized to remove solvent to afford trans-4-[(5-fluoro-2-methoxy-4-pyridyl)oxy]-N-[1-[2-[methyl-[2-(4- methylphenoxy)ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]tetrahydrofuran-2-carboxamide (3.77 mg, 7.12 μmol, 6.84% yield, 99.608% purity) was obtained as a white solid. [2122] LC-MS [ESI, M + 1]: 528.2 [2123] ¹H NMR (400 MHz, DMSO-d₆) δ = 10.09 (s, 1H), 8.04 (d, J = 3.2 Hz, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 4.4 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.89 - 6.81 (m, 2H), 6.63 (d, J = 6.0 Hz, 1H), 5.29 (br s, 1H), 5.19 - 5.06 (m, 2H), 4.61 (t, J = 8.0 Hz, 1H), 4.18 - 4.10 (m, 241 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 2H), 4.08 - 4.01 (m, 2H), 3.81 (s, 3H), 3.75 (br t, J = 5.2 Hz, 1H), 3.63 (br t, J = 5.2 Hz, 1H), 3.10 (s, 2H), 2.89 (s, 1H), 2.43 - 2.37 (m, 2H), 2.23 (d, J = 4.8 Hz, 3H) EXAMPLE 24 [2124] trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4- yl)-4-((2-(methylamino)pyridin-4-yl)oxy)tetrahydrofuran-2-carboxamide (Compound 136) [2125] Step 1: trans-ethyl-4-((2-bromopyridin-4-yl)oxy)tetrahydrofuran-2-carboxylate [2126] To a solution of ethyl -4-hydroxytetrahydrofuran-2-carboxylate (9.10 g, 56.82 mmol, 1 eq) in DMF (100 mL) was added NaH (3.41 g, 85.23 mmol, 60% purity, 1.5 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then the solution of 2-bromo-4-fluoro- pyridine (10 g, 56.82 mmol, 1 eq) in DMF (20 mL) was added dropwise at 0 °C. After this, the mixture was stirred at 20 °C for 3 h under N₂. LCMS showed starting material was consumed and two main peaks with desired mass were detected. The mixture was poured into 300 mL saturated NH4Cl aq., extracted with EtOAc(150 mL*3). The combined organic layers were washed with brine (100 mL*2), dried over Na2SO4 and filtered. The filtrate was concentrated to give a residue. The residue was purified by the chromatography column on silica gel, eluting with EtOAc/PE(0-35%), to give the trans-ethyl-4-[(2-bromo-4- 242 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 pyridyl)oxy]tetrahydrofuran-2-carboxylate (9.82 g, 54.12% yield) was obtained as a light yellow oil. [2127] LC-MS [ESI, M + 1]: 315.9 [2128] ¹H NMR (400 MHz, DMSO-d₆) δ = 8.23 (d, J = 6.0 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.07 (m, 1H), 5.32 (br d, J = 2.8 Hz, 1H), 4.67 (t, J = 7.6 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 4.11 - 3.98 (m, 2H), 2.49 - 2.34 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H) [2129] Step 2: trans-4-((2-(methylamino)pyridin-4-yl)oxy)tetrahydrofuran-2-carboxylic acid [2130] A mixture of trans-ethyl-4-[(2-bromo-4-pyridyl)oxy]tetrahydrofuran-2-carboxylate (300.00 mg, 948.92 μmol, 1 eq), tert-butyl N-methylcarbamate (186.71 mg, 1.42 mmol, 1.5 eq), Pd(OAc)₂ (21.30 mg, 94.89 μmol, 0.1 eq), Cs₂CO₃ (618.36 mg, 1.90 mmol, 2 eq) and Xantphos (109.81 mg, 189.78 μmol, 0.2 eq) in DMF (4 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 °C for 16hr under N₂ atmosphere. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. the residue was added into water (2 ml) and extracted with ethyl acetate (3 mL × 2). The combined organic layers were washed with brine (3 mL × 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC(column: Phenomenex luna C18150*40mm* 15um;mobile phase: [water(FA)-ACN];gradient:12%-42% B over 15 min) and the mobile phase was lyophilized to remove solvent to give trans-4-[[2-(methylamino)-4-pyridyl]oxy]tetrahydrofuran-2- carboxylic acid (20 mg, 8.85% yield) was obtained as a yellow solid. [2131] LC-MS [ESI, M + 1]: 239.1 [2132] Step 3: trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-1,2,3- triazol-4-yl)-4-((2-(methylamino)pyridin-4-yl)oxy)tetrahydrofuran-2-carboxamide [2133] To a solution of trans-4-[[2-(methylamino)-4-pyridyl]oxy]tetrahydrofuran-2- carboxylic acid (13 mg, 54.57 μmol, 1 eq) and 2-(4-aminotriazol-1-yl)-N-methyl-N-[2-(4- methylphenoxy)ethyl]acetamide (15.79 mg, 54.57 μmol, 1 eq) in DMF (0.5 mL) was added T4P (58.97 mg, 81.85 μmol, 50% purity, 1.5 eq) and DIEA (21.16 mg, 163.70 μmol, 28.51 μL, 3 eq). The mixture was stirred at 25 °C for 0.2 hr. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was poured into water (1 ml) and extracted with DCM (1 mL × 2). The combined organic layer was washed with brine (1 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by prep- 243 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 HPLC(column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)- ACN];gradient:13%-43% B over 11 min) and the mobile phase was lyophilized to remove solvent to afford trans-N-(1-(2-(methyl(2-(p-tolyloxy)ethyl)amino)-2-oxoethyl)-1H-1,2,3- triazol-4-yl)-4-((2-(methylamino)pyridin-4-yl)oxy)tetrahydrofuran-2-carboxamide (1.21 mg, 2.33 μmol, 4.26% yield, 97.93% purity) was obtained as an off-white solid. [2134] LC-MS [ESI, M + 1]: 510.2 [2135] ¹H NMR (400 MHz, DMSO-d₆) δ = 10.84 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.17 - 7.03 (m, 2H), 6.95 - 6.79 (m, 2H), 6.32 (br d, J = 4.8 Hz, 1H), 6.18 - 6.09 (m, 1H), 5.89 (d, J = 1.6 Hz, 1H), 5.58 - 5.39 (m, 2H), 5.11 (br d, J = 2.4 Hz, 1H), 4.72 - 4.63 (m, 1H), 4.23 - 4.11 (m, 2H), 4.09 - 4.00 (m, 1H), 3.94 (d, J = 10.0 Hz, 1H), 3.79 (br t, J = 5.2 Hz, 1H), 3.65 (t, J = 5.6 Hz, 1H), 3.15 - 2.92 (m, 3H), 2.73 (d, J = 4.8 Hz, 3H), 2.36 - 2.33 (m, 2H), 2.23 (d, J = 5.6 Hz, 3H) EXAMPLE 25 [2136] (2R,4S)-4-((2-methoxypyridin-4-yl)oxy)-N-(1-(2-(methyl(1-(p-tolyloxy)propan-2- yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)tetrahydrofuran-2-carboxamide (Compound 137) 244 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2137] Step 1: 1-(p-tolyloxy)propan-2-one [2138] To a solution of p-cresol (2 g, 18.49 mmol, 1.93 mL, 1 eq), K2CO3 (12.78 g, 92.47 mmol, 5 eq), KI (1.23 g, 7.40 mmol, 0.4 eq) in ACN (20 mL).The mixture was added 1- chloropropan-2-one (2.05 g, 22.19 mmol, 1.2 eq) at 25 °C. The mixture was stirred at 80 °C for 16 hr. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent. The residue was purified by column chromatography (SiO2/300 mesh, Petroleum ether/Ethyl acetate=10:1) and the eluent was concentrated under reduced pressure to remove solvent to give 1-(4-methylphenoxy)propan-2-one (2.193 g, 71.49% yield) as a light yellow liquid. [2139] LC-MS [ESI, M + 1]: 165.1 245 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2140] ¹H NMR (400 MHz, DMSO-d6) δ = 7.07 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 4.73 (s, 2H), 2.22 (s, 3H), 2.14 (s, 3H) [2141] Step 2: N-methyl-1-(p-tolyloxy)propan-2-amine [2142] To a solution of 1-(4-methylphenoxy)propan-2-one (500 mg, 3.05 mmol, 1 eq) in MeNH2 (1.39 g, 15.23 mmol, 5 eq) was added wet Pd/C (500.00 mg, 469.84 μmol, 10% purity, 1.54e-1 eq) under Ar. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred at 25 °C for 12 hrs under H₂. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent to give N-methyl-1-(4-methylphenoxy)propan-2-amine (375 mg, crude) was obtained as a colourless oil. [2143] LC-MS [ESI, M + 1]: 180.1 [2144] ¹H NMR (400 MHz, DMSO-d6) δ = 7.06 (br d, J = 8.4 Hz, 2H), 6.94 (br d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 8.4 Hz, 1H), 3.82 - 3.66 (m, 2H), 2.86 - 2.77 (m, 1H), 2.31 (s, 3H), 2.22 (s, 3H), 2.17 (s, 2H), 1.03 (d, J = 6.4 Hz, 3H) [2145] Step 3: N-methyl-2-(4-nitro-1H-1,2,3-triazol-1-yl)-N-(1-(p-tolyloxy)propan-2- yl)acetamide [2146] To a solution of N-methyl-1-(4-methylphenoxy)propan-2-amine (100 mg, 557.85 μmol, 1 eq), 2-(4-nitrotriazol-1-yl)acetic acid (96.01 mg, 335.54 μmol, 6.01e-1 eq, TFA) in DMF (1 mL) was added DIEA (360.49 mg, 2.79 mmol, 5 eq) and T₄P (602.92 mg, 836.78 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was poured into water (6 ml) and extracted with ethyl acetate (6 mL × 2). The combined organic layer was washed with NaHCO₃.aq (5 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC( Phenomenex luna C18 150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:35%-65% B over 10 min) and the mobile phase was lyophilized to remove solvent to give N-methyl-N-[1-methyl-2-(4- methylphenoxy)ethyl]-2-(4-nitrotriazol-1-yl)acetamide (40 mg, 21.51% yield) was obtained as a white solid. [2147] LC-MS [ESI, M + 1]: 334.1 [2148] ¹H NMR (400 MHz, DMSO-d6) δ = 9.32 - 9.17 (m, 1H), 7.14 - 6.80 (m, 4H), 5.81 - 5.55 (m, 2H), 4.80 - 4.33 (m, 1H), 4.11 - 3.88 (m, 2H), 2.99 (s, 2H), 2.77 (s, 1H), 2.23 (d, J = 5.2 Hz, 3H), 1.32 - 1.15 (m, 3H) 246 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 [2149] Step 4: 2-(4-amino-1H-1,2,3-triazol-1-yl)-N-methyl-N-(1-(p-tolyloxy)propan-2- yl)acetamide [2150] To a solution of N-methyl-N-[1-methyl-2-(4-methylphenoxy)ethyl]-2-(4- nitrotriazol-1-yl)acetamide (30 mg, 90.00 μmol, 1 eq) in MeOH (10 mL) was added wet Pd/C (30.00 mg, 28.19 μmol, 10% purity, 3.13e-1 eq) under Ar. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 12 hrs under 50 Psi H₂. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove solvent to give 2-(4-aminotriazol-1-yl)-N-methyl-N-[1- methyl-2-(4-methylphenoxy)ethyl]acetamide (36 mg, crude) as a colourless oil. [2151] LC-MS [ESI, M + 1]: 304.2 [2152] Step 5: (2R,4S)-4-((2-methoxypyridin-4-yl)oxy)-N-(1-(2-(methyl(1-(p- tolyloxy)propan-2-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)tetrahydrofuran-2- carboxamide [2153] To a solution of 2-(4-aminotriazol-1-yl)-N-methyl-N-[1-methyl-2-(4- methylphenoxy)ethyl]acetamide (33.01 mg, 108.82 μmol, 1 eq), 4-[(2-methoxy-4- pyridyl)oxy]tetrahydrofuran-2-carboxylic acid (30 mg, 108.82 μmol, 1 eq) in DMF (1 mL) was added DIEA (70.32 mg, 544.10 μmol, 94.77 μL, 5 eq) and T₄P (117.61 mg, 163.23 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 12 hr. LCMS showed starting material was consumed and one main peak with desired mass was detected. The reaction mixture was poured into water (6 ml) and extracted with ethyl acetate (6 mL × 2). The combined organic layer was washed with NaCl.aq (5 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to remove solvent. The residue was purified by reversed-phase HPLC(Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN];gradient:22%-52% B over 9 min) and the mobile phase was lyophilized to remove solvent to give 4-[(2-methoxy-4-pyridyl)oxy]-N-[1-[2- [methyl-[1-methyl-2-(4-methylphenoxy)ethyl]amino]-2-oxo-ethyl]triazol-4- yl]tetrahydrofuran-2-carboxamide (3.08 mg, 5.57 μmol, 5.12% yield, 94.842% purity) as a off-white solid. [2154] LC-MS [ESI, M + 1]: 525.2 [2155] ¹H NMR (400 MHz, DMSO-d₆) δ = 10.86 (s, 1H), 8.09 (d, J = 4.8 Hz, 1H), 7.99 (d, J = 5.6 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.92 - 6.81 (m, 2H), 6.65 - 6.59 (m, 1H), 6.36 (d, J = 1.6 Hz, 1H), 5.59 - 5.37 (m, 2H), 5.24 (br d, J = 2.4 Hz, 1H), 4.79 - 4.32 (m, 2H), 4.22 - 4.14 (m, 247 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 1H), 4.06 - 3.92 (m, 3H), 3.82 (s, 3H), 2.96 (s, 2H), 2.75 (s, 1H), 2.40 - 2.35 (m, 2H), 2.23 (d, J = 4.4 Hz, 3H), 1.28 - 1.15 (m, 3H) EXAMPLE 27 [2156] (2R,4S)-N-[1-[2-[3-[(4-chlorophenoxy)methyl]-3-methyl-azetidin-1-yl]-2-oxo- ethyl]-3-fluoro-pyrazol-4-yl]-4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2-carboxamide (Compound 164) [2157] Step 1: 3-fluoro-4-nitro-1H-pyrazole [2158] The reaction was conducted by Flowchemistry. TLC (Petroleum ether: Ethyl acetate=1:1, UV) showed the starting material was consumed completely and one new spot was formed. The reaction mixture was poured into water (50 ml), extracted with Ethyl acetate 248 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 1:1) The product3-fluoro-4-nitro-1H-pyrazole (1.82 g, 100% yield) was obtained as yellow solid. [2159] 1H NMR (400 MHz, DMSO-d6) δ = 13.75 (s, 1H), 8.85 (d, J = 0.8 Hz, 1H) [2160] Step 2: tert-butyl 2-(3-fluoro-4-nitro-pyrazol-1-yl)acetate [2161] To a solution of 3-fluoro-4-nitro-1H-pyrazole (0.793 g, 6.05 mmol, 1 eq), tert-butyl 2-bromoacetate (1.06 g, 5.45 mmol, 0.9 eq) in MeCN (8 mL) was added Cs2CO3 (2.96 g, 9.08 mmol, 1.5 eq). The mixture was stirred at 60 °C for 12 hr. TLC (Petroleum ether: Ethyl acetate=5:1, UV) showed the starting material was consumed completely and three new spots was formed. The mixture was to foltre, the reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified byThe residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 5:1). The product tert-butyl 2- (3-fluoro-4-nitro-pyrazol-1-yl) acetate (0.8 g, 53.92%) was obtained as yellow solid. [2162] 1H NMR (400 MHz, CHLOROFORM-d) δ = 8.15 (s, 1H), 4.70 (s, 2H), 1.50 (s, 9H) [2163] Step 3: 2-(3-fluoro-4-nitro-pyrazol-1-yl) acetic acid [2164] To a solution fo tert-butyl 2-(3-fluoro-4-nitro-pyrazol-1-yl)acetate (200 mg, 815.64 μmol, 1 eq) in DCM (2 mL) was added TFA (3.07 g, 26.92 mmol, 2 mL, 33.01 eq) at 25 °C for 0.5 hr. TLC (Petroleum ether : Ethyl acetate=5:1, UV) showed the starting material was consumed completely and one new spot was formed. The reaction mixture was concentrated under reduced pressure to remove solvent. The product 2-(3-fluoro-4-nitro-pyrazol-1-yl) acetic acid (247 mg, 99.90% yield, TFA) was obtained as yellow oil. [2165] Step 4: 1-[3-[(4-chlorophenoxy) methyl ]-3-methyl-azetidin-1-yl]-2-(3-fluoro-4- nitro-pyrazol-1-yl)ethanone [2166] To a solution of 2-(3-fluoro-4-nitro-pyrazol-1-yl)acetic acid (247 mg, 814.85 μmol, 1 eq, TFA), 3-[(4-chlorophenoxy)methyl]-3-methyl-azetidine (145.97 mg, 448.17 μmol, 0.55 eq, TFA) in DMF (3 mL) was added DIEA (315.94 mg, 2.44 mmol, 425.79 μL, 3 eq), T4P (880.67 mg, 1.22 mmol, 50% purity, 1.5 eq) at 0 °C. The mixture ws stirred at 25 °C for 0.5 hr. LCMS showed 86% peak of desired compound mass. The reaction mixture was poured into water (10 ml), extracted with Ethyl acetate (20mL × 2). The combined organic layers were washed with brine (20mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (Petroleum ether: 249 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Ethyl acetate=1:2, UV). The product 1-[3-[(4-chlorophenoxy) methyl ]-3-methyl-azetidin-1- yl]-2-(3-fluoro-4-nitro-pyrazol-1-yl)ethanone (170 mg, 99%) was obtained as yellow solid. [2167] LC-MS [ESI, M +1]: 383.1. [2168] Step 5: 3-[(3-amino-2-pyridyl)oxy]-N-[1-[2-[methyl-[2-(4-methylphenoxy) ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]propanamide [2169] To a solution of 1-[3-[(4-chlorophenoxy)methyl]-3-methyl-azetidin-1-yl]-2-(3- fluoro-4-nitro-pyrazol-1-yl)ethanone (60 mg, 156.75 μmol, 1 eq) in EtOH (1 mL), H₂O (0.2 mL) was added Fe (43.77 mg, 783.75 μmol, 5 eq) and NH4Cl (83.85 mg, 1.57 mmol, 10 eq). The mixture was stirred at 80 °C for 1 hr. LCMS showed there was 91% of desired compound formed. The mixture was to filter. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was purified by prep-HPLC (column: Waters Xbridge C18150*25mm*5um; mobile phase: [H2O (10mM NH4HCO3)-ACN]; gradient: 25%-55% B over 15.0 min). The product 2-(4-amino-3-fluoro-pyrazol-1-yl)-1-[3- [(4-chlorophenoxy) methyl]-3-methyl-azetidin-1-yl]ethanone (50 mg, 90.42%) was obtained as yellow solid. [2170] LC-MS [ESI, M +1]: 353.1. [2171] Step 6: 3-[(3-amino-2-pyridyl)oxy]-N-[1-[2-[methyl-[2-(4-methylphenoxy) ethyl]amino]-2-oxo-ethyl]pyrazol-4-yl]propanamide [2172] To a solution of 2-(4-amino-3-fluoro-pyrazol-1-yl)-1-[3-[(4- chlorophenoxy)methyl]-3-methyl-azetidin-1-yl]ethanone (20 mg, 56.69 μmol, 1 eq), (2R,4S)- 4-[(2-methoxy-4-pyridyl)oxy]tetrahydrofuran-2-carboxylic acid (13.56 mg, 56.69 μmol, 1 eq) in DMF (0.5 mL) was added DIEA (21.98 mg, 170.07 μmol, 3 eq) and T4P (61.27 mg, 85.04 μmol, 50% purity, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 1 hr. LCMS showed 80% peak of desired compound mass. The reaction mixture was poured into water (5 ml), extracted with Ethyl acetate (8 mL × 2). The combined organic layers were washed with brine (8mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*25mm*5um; mobile phase: [H₂O(10Mm NH₄HCO₃)-ACN]; gradient: 38%-68% B over 15.0 min). The product (2R,4S)-N-[1-[2-[3-[(4-chlorophenoxy)methyl]-3-methyl-azetidin-1- yl]-2-oxo-ethyl]-3-fluoro-pyrazol-4-yl]-4-[(2-methoxy-4-pyridyl)oxy] tetrahydrofuran-2- carboxamide (11.01 mg, 99%) was obtained as white solid. [2173] LC-MS [ESI, M +1]: 574.1. [2174] 1H NMR (400 MHz, DMSO-d6) δ = 9.78 (s, 1H), 7.98 (d, J = 6.0 Hz, 1H), 7.87 (d, J = 2.0 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.66 - 6.57 (m, 1H), 6.35 (d, J 250 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 = 2.0 Hz, 1H), 5.22 (br s, 1H), 4.73 (s, 2H), 4.62 (s, 1H), 4.18 - 3.94 (m, 5H), 3.88 - 3.77 (m, 4H), 3.61 (d, J = 9.6 Hz, 1H), 2.39 - 2.30 (m, 2H), 1.34 (s, 3H) EXAMPLE 28 [2175] IRE1–XBP1s activation Assay: HEK293 T-REx cells stably expressing the XBP1- RLuc splicing reporter were treated with an IRE1–XBP1s activator provided herein (10 µM) in the presence or absence of the IRE1 active site inhibitor 4µ8C (32 µM) for 18 h. Luminescence was shown as the percentage signal relative to thapsigargin (Tg) (500 nM, 18 h). Results are shown in Table A below. [2176] Table A: IRE1–XBP1s Activation Data *++: %Tg>=50%, +: 30%=<%Tg<50%; +/-: %Tg%<30% 251 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 EXAMPLE 29 [2177] IRE1–XBP1s activation Assay: HEK293 T-REx cells stably expressing the XBP1- RLuc splicing reporter were treated with an IRE1–XBP1s activator provided herein (10 µM) in the presence or absence of the IRE1 active site inhibitor 4µ8C (32 µM) for 18 h. Luminescence was shown as the percentage signal relative to thapsigargin (Tg) (1 µM, 18 h). Results are shown in Table B below. [2178] Table B: IRE1–XBP1s Activation Data 252 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 *++: %Tg>=50%, +: 30%=<%Tg<50%; +/-: %Tg%<30% EQUIVALENTS [2179] This disclosure is not to be limited in scope by the embodiments disclosed in the examples which are intended as single illustrations of individual aspects, and any equivalents are within the scope of this disclosure. Various modifications in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. [2180] Various references such as patents, patent applications, and publications are cited herein, the disclosures of which are hereby incorporated by reference herein in their entireties. 253 319794142 v2

Claims

Attorney Docket No. PRTE-020/01WO 345214-2086 WHAT IS CLAIMED IS: 1. A compound of Formula A-I: , or a pharmaceutically acceptable salt thereof, wherein R¹ is H or C1-C6 alkyl and R² is H; or R¹ and R² together form (CH2)x wherein x is 1, 2, or 3; R⁵ is H and R⁶ is C₁-C₆ haloalkyl; or R⁵ and R⁶ together form oxo; R⁷ is H or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more -OH or -O(C1-C6 alkyl); X² is CR^s or N; R^s is H or halogen; X¹ is O or NR⁸, wherein R⁸ is H or C1-C6 alkyl; Ar¹ is C6-C10 aryl or 5- to 10-membered heteroaryl, wherein the C6-C10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more R^t; each R^t independently is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1- C6 alkyl), -N(C1-C6 alkyl)2, -NO2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 haloalkoxy; T is -NHR^T1, -N(R^T1)₂, or -N(R^T2)₂; each R^T1 independently is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ 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-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10-membered heteroaryl is optionally substituted with one or more R^Ta; two R^T2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more R^Ta; each R^Ta independently is oxo, halogen, cyano, -OH, -OR^a, -SR^a, -NH₂, -NHR^a, - N(R^a)2, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, -NH-S(=O)2-R^a, -N(C1-C6 alkyl)-C(=O)-R^a, - N(C₁-C₆ alkyl)-C(=O)-O-R^a, -N(C₁-C₆ alkyl)-S(=O)₂-R^a, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 254 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; each R^a independently is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; each R^Tb independently is oxo, halogen, cyano, -OH, -OR^b, -SR^b, -NH2, -NHR^b, - N(R^b)2, -NH-C(=O)-R^b, -NH-C(=O)-O-R^b, -NH-S(=O)2-R^b, -N(C1-C6 alkyl)-C(=O)-R^b, - N(C₁-C₆ alkyl)-C(=O)-O-R^b, -N(C₁-C₆ alkyl)-S(=O)₂-R^b, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; each R^b independently is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and each R^Tc independently is oxo, halogen, cyano, -OH, -O(C₁-C₆ alkyl), -O(C₁-C₆ haloalkyl), -S(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, -NH-C(=O)-(C₁-C₆ alkyl), -NH-C(=O)-O-(C1-C6 alkyl), -NH-S(=O)2-(C1-C6 alkyl), -N(C1-C6 alkyl)-C(=O)-(C1- C6 alkyl), -N(C1-C6 alkyl)-C(=O)-O-(C1-C6 alkyl), -N(C1-C6 alkyl)-S(=O)2-(C1-C6 alkyl), C1- C₆ alkyl, C₁-C₆ haloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀ cycloalkyl, 4- to 10- membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl. 2. The compound of claim 1, wherein the compound has the structure of Formula B: Formula B, or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 or 2, wherein the compound has the structure of Formula C: 255 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 4. The compound of any one of claims 1-3, wherein the compound has the structure of Formula D: Formula D, or a pharmaceutically acceptable salt thereof. 5. The compound of any one of claims 1-4, wherein the compound has the structure of Formula E: , or a pharmaceutically acceptable salt thereof, wherein ring A is C3-C10 cycloalkyl or C6-C10 aryl. 6. The compound of any one of claims 1-5, wherein the compound has the structure of Formula E-a, Formula E-b, Formula E-c, or Formula E-d: - , 256 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 Formula E-d, or a pharmaceutically acceptable salt thereof, wherein ring A is C3-C10 cycloalkyl or C6-C10 7. The compound of any one of claims 1-3, wherein the compound has the structure of Formula F: Formula F, or a pharmaceutically acceptable salt thereof. 8. The compound of any one of claims 1-3 and 7, wherein the compound has the structure of Formula G: Formula G, or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; and m is 1, 2, or 3. 9. The compound of any one of claims 1-3, 7, and 8, wherein the compound has the structure of Formula H: Formula H, or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; and ring A is C₃-C₁₀ cycloalkyl or C₆-C₁₀ aryl. 10. The compound of any one of claims 1-3 and 7-9, wherein the compound has the structure of Formula H-a, Formula H-b, Formula H-c, or Formula H-d: 257 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 - , or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, or 3; and ring A is C₃-C₁₀ cycloalkyl or C₆-C₁₀ aryl. 11. The compound of claim 1, wherein R¹ is H or C1-C6 alkyl and R² is H. 12. The compound of claim 1, wherein R⁵ and R⁶ together form oxo. 13. The compound of claim 1, wherein R⁷ is H. 14. The compound of claim 1 or 2, wherein X² is CH, CF, or N. 15. The compound of claim 1 or 2, wherein X¹ is O. 16. The compound of claim 1 or 2, wherein X¹ is NR⁸, wherein R⁸ is H or C1-C3 alkyl. 17. The compound of any one of claims 1-16, wherein Ar¹ is phenyl optionally substituted with one or more R^t. 18. The compound of any one of claims 1-16, wherein Ar¹ is isoxazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each optionally substituted with one or more R^t. 258 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 19. The compound of any one of claims 1-18, wherein Ar¹ is substituted with 1 or 2 R^t. 20. The compound of any one of claims 1-19, wherein each R^t is independently halogen, - O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NO2, or C1-C6 alkyl. 21. The compound of any one of claims 1-20, wherein each R^t is independently halogen, - NH2, methyl or -OCH3. 22. The compound of any one of claims 1-3 and 11-21, wherein T is -N(R^T1)₂. 23. The compound of any one of claims 1-3 and 11-21, wherein T is -N(R^T2)2. 24. The compound of any one of claims 1-4 and 11-22, wherein one R^T1 is C₁-C₆ alkyl or C3-C10 cycloalkyl, wherein the C1-C6 alkyl or C3-C10 cycloalkyl is optionally substituted with one or more R^Ta, and the other R^T1 is C1-C6 alkyl substituted with one or more R^Ta. 25. The compound of any one of claims 1-3, 7, 11-21, and 23, wherein two R^T2, together with the atom to which they are attached, form 4- to 6-membered heterocyclyl substituted with one or more R^Ta. 26. The compound of any one of claims 1-3, 7, 11-21, 23, and 25, wherein two R^T2, together with the atom to which they are attached, form 4- to 6-membered heterocyclyl having at least one nitrogen as the ring atom and wherein the heterocyclyl is substituted with one or more R^Ta. 27. The compound of any one of claims 1-8 and 11-26, wherein at least one R^Ta is oxo, halogen, cyano, -OH, -NH₂, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb. 259 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 28. The compound of any one of claims 1-8 and 11-27, wherein at least one R^Ta is oxo, halogen, cyano, -OH, -NH2, or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with one or more R^Tb. 29. The compound of any one of claims 1-8 and 11-27, wherein at least one R^Ta is -OR^a, - SR^a, -NHR^a, -N(R^a)2, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, -NH-S(=O)2-R^a, -N(C1-C6 alkyl)- C(=O)-R^a, -N(C₁-C₆ alkyl)-C(=O)-O-R^a, or -N(C₁-C₆ alkyl)-S(=O)₂-R^a. 30. The compound of any one of claims 1-8 and 11-27, wherein at least one R^a is C1-C6 alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆- C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb. 31. The compound of any one of claims 1-3, 11-22, 24, 29, and 30, wherein: T is -N(R^T1)2; one R^T1 is C1-C3 alkyl substituted with one R^Ta; R^Ta is -OR^a; and R^a is C₆ aryl or 5- to 6- membered heteroaryl, wherein the C₆ aryl or 5- to 6- membered heteroaryl is optionally substituted with 1 or 2 R^Tb. 32. The compound of any one of claims 1-3, 11-21, 23, 25, 29, and 30, wherein: T is -N(R^T2)2; two R^T2, together with the atom to which they are attached, form 4- to 6-membered heterocyclyl substituted with one or more R^Ta; R^Ta is -OR^a; and R^a is C6 aryl or 5- to 6- membered heteroaryl, wherein the C6 aryl or 5- to 6- membered heteroaryl is optionally substituted with 1 or 2 R^Tb. 33. The compound of any one of claims 1-7 and 11-32, wherein at least one R^Tb independently is oxo, halogen, cyano, -OH, -NH2, C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10- membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc. 260 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 34. The compound of any one of claims 1-7 and 11-32, wherein at least one R^Tb is -OR^b. 35. The compound of any one of claims 1-7, 11-32, and 34, wherein at least one R^b is C1- C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc. 36. The compound of any one of claims 1-3, 11-21, 23, 25, 29, 30, 34, and 35, wherein: T is -N(R^T2)₂; two R^T2, together with the atom to which they are attached, form 4- to 6-membered heterocyclyl substituted with one or more R^Ta; at least one R^Ta is C1-C6 alkyl substituted with one or more R^Tb; at least one R^Tb is -OR^b; and R^b is C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C6 aryl, or 5- to 6- membered heteroaryl, wherein the C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, C6 aryl, or 5- to 6- membered heteroaryl is optionally substituted with one or more R^Tc. 37. The compound of any one of claims 1-36, wherein at least one R^Tc is oxo, halogen, cyano, -OH, -O(C₁-C₆ alkyl), -NH₂, -NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or 5- to 10- membered heteroaryl. 38. The compound of any one of claims 1-3, 11-22, 24, 27, and 33, wherein T is -N(R^T1)₂; one R^T1 is C₁-C₆ alkyl or C₃-C₁₀ cycloalkyl, wherein the C₁-C₆ alkyl or C₃-C₁₀ cycloalkyl is optionally substituted with one or more R^Ta, and the other R^T1 is C1-C6 alkyl substituted with one or more R^Ta; at least one R^Ta is oxo, halogen, cyano, -OH, -NH₂, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1- C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; at least one R^Tb independently is oxo, halogen, cyano, -OH, -NH2, C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, 261 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and at least one R^Tc is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or 5- to 10- membered heteroaryl. 39. The compound of any one of claims 1-3, 11-22, 24, 29, 30, 33, and 37, wherein T is -N(R^T1)₂; one R^T1 is C1-C6 alkyl or C3-C10 cycloalkyl (e.g., C3 cycloalkyl), wherein the C1-C6 alkyl or C3-C10 cycloalkyl is optionally substituted with one or more R^Ta, and the other R^T1 is C₁-C₆ alkyl substituted with one or more R^Ta; at least one R^Ta is -OR^a, -SR^a, -NHR^a, -N(R^a)₂, -NH-C(=O)-R^a, -NH-C(=O)-O-R^a, - NH-S(=O)2-R^a, -N(C1-C6 alkyl)-C(=O)-R^a, -N(C1-C6 alkyl)-C(=O)-O-R^a, or -N(C1-C6 alkyl)- S(=O)2-R^a; at least one R^a is C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆- C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tb; at least one R^Tb, when present, independently is oxo, halogen, cyano, -OH, -NH₂, C₁- C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl, wherein the C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆-C₁₀ aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; and at least one R^Tc, when present, is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, - NH(C₁-C₆ alkyl), -N(C₁-C₆ alkyl)₂, C₁-C₆ alkyl, C₁-C₆ haloalkyl, or 5- to 10- membered heteroaryl. 40. The compound of any one of claims 1-3, 11-21, 23, 27, 34, 35, and 37, wherein T is -N(R^T2)₂; two R^T2, together with the atom to which they are attached, form 4- to 10-membered heterocyclyl optionally substituted with one or more R^Ta; at least one R^Ta is oxo, halogen, cyano, -OH, -NH₂, or C₁-C₆ alkyl, wherein the C₁-C₆ alkyl is optionally substituted with one or more R^Tb; at least one R^Tb is -OR^b; 262 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 at least one R^b is C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, 4- to 10-membered heterocyclyl, C₆- C10 aryl, or 5- to 10- membered heteroaryl, wherein the C1-C6 alkyl, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl is optionally substituted with one or more R^Tc; at least one R^Tc is oxo, halogen, cyano, -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, or C1-C6 haloalkyl. 41. The compound of any one of claims 5, 6, 9, and 10, wherein ring A is phenyl, cyclohexyl, , , , , pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. 42. A compound selected from the compounds described in Tables 1 and 2, and pharmaceutically acceptable salts thereof, racemic form thereof, or stereoisomer thereof. 43. A compound selected from the compounds described in Table 1, and pharmaceutically acceptable salts thereof. 44. A compound selected from the compounds described in Table 2, and pharmaceutically acceptable salts thereof. 45. A pharmaceutical composition comprising a compound of any one of claims 1-44, and one or more pharmaceutically acceptable carriers or excipients. 46. A method of treating a disease or disorder selected from a cardiovascular disease, neurodegenerative disease, metabolic disorder, hepatic disorder, protein misfolding disorder or gastrointestinal disorder in a subject, comprising administering to the subject the compound of any one of claims 1-44 or the pharmaceutical composition of claim 45. 47. The method of claim 46, wherein the cardiovascular disease is myocardial infarction or atherosclerosis. 263 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 48. The method of claim 46, wherein the neurodegenerative disease is peripheral nerve injury, Creutzfeldt–Jakob disease, Parkinson's disease or Huntington's disease. 49. The method of claim 46, wherein the metabolic disorder is diabetes, type II diabetes or Gaucher disease. 50. The method of claim 46, wherein the hepatic disorder is non‐alcoholic fatty liver disease (NAFLD). 51. The method of claim 46, wherein the hepatic disorder is progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC) or Wilson’s disease. 52. The method of claim 46, wherein the protein misfolding disorder is an amyloid disease, Alzheimer’s disease, an ocular disease, retinal degeneration, a lysosomal storage disease or alpha-1 antitrypsin deficiency. 53. The method of claim 52, wherein the alpha-1 antitrypsin deficiency is alpha-1 antitrypsin associated emphysema or alpha-1 antitrypsin associated liver disease. 54. The method of claim 52, wherein the amyloid disease is atrial amyloidosis, spongiform encephalopathies, senile systemic amyloidosis, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy I and II, or familial amyloidosis. 55. The method of claim 46, wherein the gastrointestinal disorder is Crohn’s disease. 56. A method of treating retinitis pigmentosa, achromatopsia, diabetic retinopathy or retinal neurodegeneration in a subject, comprising administering to the subject the compound of any one of claims 1-44 or the pharmaceutical composition of claim 45. 57. A method of treating idiopathic epilepsy in a subject, comprising administering to the subject the compound of any one of claims 1-44 or the pharmaceutical composition of claim 45. 264 319794142 v2

Attorney Docket No. PRTE-020/01WO 345214-2086 58. A method of treating chondrodysplasia in a subject, comprising administering to the subject the compound of any one of claims 1-44 or the pharmaceutical composition of claim 45. 59. A method of increasing IRE1 or XBP1s activity in a subject, comprising administering to the subject a compound of any one of claims 1-44 or a pharmaceutical composition of claim 45. 60. A method of treating idiopathic epilepsy, Dravet syndrome or Lennox-Gastaut syndrome in a subject, comprising administering to the subject the compound of any one of claims 1-44 or the pharmaceutical composition of claim 45. 61. A method of treating genetic epilepsy in a subject, comprising administering to the subject the compound of any one of claims 1-44 or the pharmaceutical composition of claim 45. 62. The method of claim 61, wherein the genetic epilepsy is due to at least one variant in GABAA receptor subunits. 265 319794142 v2