WRN helicase modulators and methods of using the same

Abstract

The present disclosure relates to compounds of Formula (I') and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating Werner Helicase (WRN) activity and may be used in the treatment of disorders in which WRN activity is implicated, such as cancer.

Description

Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) WRN HELICASE MODULATORS AND METHODS OF USING THE SAME REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S Provisional Application No. 63 / 666,584, filed July 1, 2024 and U.S. Provisional Application No. 63 / 738,161, filed December 23, 2024, the entire contents of each of which is incorporated herein by reference. INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on June 26, 2025, is named MOMA-008-001WO-ST26.xml and is 1,932 bytes in size. BACKGROUND

[0003] The present disclosure relates to small molecule modulators of Werner helicase (WRN), designed for the treatment of a disease or disorder (e.g., cancer).

[0004] Genome instability is a hallmark of cancer, achieved through loss of DNA mismatch repair in numerous tumor types such as colorectal, gastric, endometrial, neuroendocrine, breast, ovarian, cervical, uterine, liver, prostate, cholangiocarcinoma, thyroid, pancreatic, uveal melanoma, esophageal, glioblastoma, and lung cancers identified as deficient in these pathways. This DNA mismatch repair deficiency (dMMR) leads to a high mutational burden genome-wide, but it is mainly characterized by insertions and deletions at repetitive DNA sequences across the genome known as microsatellites. The resulting phenotype is known as microsatellite instability, and the most severe of which is graded as microsatellite instability high (MSI-H). Tumor status of dMMR is determined by presence / absence of MMR proteins MLH1, MSH2, MSH6, and / or PMS2 via immunohistochemistry, while MSI is determined by targeted molecular diagnostics of tumor DNA.

[0005] Standard of care for dMMR / MSI-H solid tumors includes 5-Fluorouracil-containing chemotherapeutic regimens and / or checkpoint inhibitors. These chemotherapeutic regimens have modest long term response rates and can be poorly tolerated by patients. Anti-PD1 therapies have been approved as a first-line therapy in MSI-H cancers, taking advantage of tumor-specific neoantigens created by high mutation levels. Despite treatment with anti-PD-1 checkpoint inhibitors, about half of dMMR / MSI tumors do not respond, thus alternative therapies are needed.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0006] In parallel, functional genomics screens identified the essentiality of the WRN helicasein MSI-H cells. Furthermore, the mechanism of WRN helicase essentiality in MSI-H cancer cells has been elucidated, as WRN resolves repetitive large-scale TA dinucleotide expansions that uniquely occur in MSI-H cells at recurrent locations in the genome. These expanded TA dinucleotide repeats form secondary DNA structures that must be resolved by the WRN helicase during DNA replication in order for the cell to duplicate its DNA and divide properly. In the absence of WRN helicase activity, these toxic DNA structures persist, leading to chromosomal breakage at these sites and subsequent cell cycle arrest and cell death. As such, in the absence of WRN helicase activity, a DNA damage-mediated anti-proliferative and pro- apoptotic effect is observed exclusively in MSI-H tumors but not in normal tissues with functioning mismatch repair (MMR). Thus, inhibition of the WRN helicase is an ideal strategy for the treatment of MMR-deficient and / or MSI-H tumors.

[0007] The disclosure arises from a need to provide further compounds for the modulation ofWRN activity with improved therapeutic potential. In particular, compounds with improved physicochemical, pharmacological and / or pharmaceutical properties. SUMMARY

[0008] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is -O-, -NH-, or -S-; A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl);Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; and R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0009] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl); RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl;Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; and R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0010] In some aspects, the present disclosure provides a compound of Formula (I-a):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0011] In some aspects, the present disclosure provides a compound of Formula (I-a):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0012] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing a compound as described herein (e.g., a method comprising one or more steps described in any one of Schemes 1-6).

[0013] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient, diluent, or carrier, or a combination thereof.

[0014] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in the Examples).

[0015] In some aspects, the present disclosure provides a method of modulating Werner helicase (WRN) activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0016] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0017] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0018] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating WRN activity (e.g., in vitro or in vivo).

[0019] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0020] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0021] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating WRN activity (e.g., in vitro or in vivo).

[0022] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0023] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0024] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.

[0025] In some aspects, the present disclosure provides a method of preparing a compound, comprising one or more steps described herein.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0027] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[0028] The present disclosure relates to pyridyl-amide derivatives, prodrugs, and pharmaceutically acceptable salts thereof, which may modulate Werner helicase (WRN) activity and are accordingly useful in methods of treatment of the human or animal body. The present disclosure also relates to processes for the preparation of these compounds, toAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) pharmaceutical compositions comprising them and to their use in the treatment of disorders in which WRN is implicated, such as cancer. Definitions

[0029] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0030] Without wishing to be limited by this statement, it is understood that, while various options for variables are described herein, the disclosure intends to encompass operable embodiments having combinations of the options. The disclosure may be interpreted as excluding the non-operable embodiments caused by certain combinations of the options. For example, while various options for variables X, A1, A2, RA1, RA2, R1, R2, R2a, R3, and R4are described herein, the disclosure may be interpreted as excluding structures for non-operable compound caused by certain combinations of variables X, A1, A2, RA1, RA2, R1, R2, R2a, R3, and R4.

[0031] As used herein, “alkyl”, “C1, C2, C3, C4, C5or C6alkyl” or “C1-C6alkyl” is intended to include C1, C2, C3, C4, C5or C6straight chain (linear) saturated aliphatic hydrocarbon groups and C3, C4, C5or C6branched saturated aliphatic hydrocarbon groups. For example, C1-C6alkyl is intends to include C1, C2, C3, C4, C5and C6alkyl groups. Examples of alkyl include, moieties having from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight chain or branched alkyl has six or fewer carbon atoms (e.g., C1-C6for straight chain, C3-C6for branched chain), and in another embodiment, a straight chain or branched alkyl has four or fewer carbon atoms.

[0032] As used herein, the term “optionally substituted alkyl” refers to unsubstituted alkyl or alkyl having designated substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0033] As used herein, the term “alkenyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond. For example, the term “alkenyl” includes straight chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), and branched alkenyl groups. In certain embodiments, a straight chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6for straight chain, C3-C6for branched chain). The term “C2-C6” includes alkenyl groups containing two to six carbon atoms. The term “C3-C6” includes alkenyl groups containing three to six carbon atoms.

[0034] As used herein, the term “optionally substituted alkenyl” refers to unsubstituted alkenyl or alkenyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0035] As used herein, the term “alkynyl” includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, “alkynyl” includes straight chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), and branched alkynyl groups. In certain embodiments, a straight chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6for straight chain, C3-C6for branched chain). The term “C2-C6” includes alkynyl groups containing two to six carbon atoms. The term “C3- C6” includes alkynyl groups containing three to six carbon atoms. As used herein, “C2-C6alkenylene linker” or “C2-C6alkynylene linker” is intended to include C2, C3, C4, C5or C6chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2- C6alkenylene linker is intended to include C2, C3, C4, C5and C6alkenylene linker groups.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0036] As used herein, the term “optionally substituted alkynyl” refers to unsubstituted alkynyl or alkynyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0037] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl) include both the unsubstituted moieties and the moieties having one or more of the designated substituents. For example, substituted heterocyclyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl- piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0038] 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.

[0039] As used herein, the term “heterocyclyl” refers to a saturated or partially unsaturated 3- 8 membered monocyclic, 7-12 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 sulfur, 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-Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) 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-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, 5,6-dihydro-4H- cyclopenta[b]thiophenyl, and the like. In the case of multicyclic heterocyclyl, only one of the rings in the heterocyclyl needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0040] It is understood that when a variable has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the variable. For example, when a variable (e.g., variable X) is cycloalkyl or heterocyclyl, and has two attachments to the rest of the formula of the compound, the two attachments could be at the same atom or different atoms of the cycloalkyl or heterocyclyl.

[0041] As used herein, the term “aryl” includes groups with aromaticity, including “conjugated,” or multicyclic systems with one or more aromatic rings and do not contain any heteroatom in the ring structure. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like.

[0042] As used herein, the term “heteroaryl” is intended to include a stable 5-, 6-, or 7- membered monocyclic or 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, 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 sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or other substituents, as defined). The nitrogen andsulfur heteroatoms may optionally be oxidized (i.e., N O and S(O)p, where p = 1 or 2). It isto be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like. Heteroaryl groups can also be fused or bridged withAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0043] Furthermore, the terms “aryl” and “heteroaryl” include multicyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthrydine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.

[0044] The cycloalkyl, heterocyclyl, aryl, or heteroaryl ring can be substituted at one or more ring positions (e.g., the ring-forming carbon or heteroatom such as N) with such substituents as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings, which are not aromatic so as to form a multicyclic system (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxole-5-yl).

[0045] As used herein, the term “about” refers to a recited amount, value, or duration ± 10 % or less of said amount, value, or duration. In some embodiments, “about” refers to a recited amount, value, or duration ± 10 %, ± 8 %, ± 6 %, ± 5 %, ± 4 %, ± 2 %, ± 1 %, or ± 0.5 %. In other embodiments, “about” refers to a recited amount, value, or duration ± 10 %, ± 8 %, ± 6 %, ± 5 %, ± 4 %, or ± 2 %. In other embodiments, “about” refers to a recited amount, value, or duration ± 5 %. In some embodiments, “about” refers to a listed amount, value, or duration ± 2 % or ± 1 %. For example, in some embodiments, when the term “about” is used when reciting a temperature or temperature range, these terms refer to the recited temperature or temperature range ± 5 °C, ± 2 °C, or ± 1 °C. In other embodiments, the term “about” refers to the recited temperature or temperature range ± 2 °C.

[0046] As used herein, the term “substituted,” means that any one or more hydrogen atoms on the designated atom is replaced with a selection from the indicated groups, provided that the designated atom’s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =O), then 2 hydrogen atoms on the atom areAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) replaced. Keto substituents are not present on aromatic moieties. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C=C, C=N or N=N). “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0047] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0048] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may optionally be substituted with up to two R moieties and R at each occurrence is selected independently from the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0049] As used herein, the term “hydroxy” or “hydroxyl” includes groups with an -OH or -O- .

[0050] As used herein, the term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0051] The term “haloalkyl” or “haloalkoxyl” refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0052] As used herein, the term “optionally substituted haloalkyl” refers to unsubstituted haloalkyl having designated substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0053] As used herein, the term “alkoxy” or “alkoxyl” includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

[0054] As used herein, the expressions “one or more of A, B, or C,” “one or more A, B, or C,” “one or more of A, B, and C,” “one or more A, B, and C,” “selected from the group consisting of A, B, and C”, “selected from A, B, and C”, and the like are used interchangeably and all refer to a selection from a group consisting of A, B, and / or C, i.e., one or more As, one or more Bs, one or more Cs, or any combination thereof, unless indicated otherwise.

[0055] It is to be understood that the present disclosure provides methods for the synthesis of the compounds of any of the Formulae described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0056] It is to be understood that, throughout the description, where compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0057] It is to be understood that the synthetic processes of the disclosure can tolerate a wide variety of functional groups, therefore various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof.

[0058] It is to be understood that compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or which will be apparent to the skilled artisan in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as Smith, M. B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for organic Synthesis, John Wiley and Sons (1995), incorporated by reference herein, are useful and recognized reference textbooks of organic synthesis known to those in the art

[0059] One of ordinary skill in the art will note that, during the reaction sequences and synthetic schemes described herein, the order of certain steps may be changed, such as the introduction and removal of protecting groups. One of ordinary skill in the art will recognize that certain groups may require protection from the reaction conditions via the use of protecting groups. Protecting groups may also be used to differentiate similar functional groups in molecules. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rdedition, John Wiley & Sons: New York, 1999.

[0060] It is to be understood that, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to provide such treatment or prevention as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment or prevention includes use of the compounds to prepare a medicamentAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) to treat or prevent such condition. The treatment or prevention includes treatment or prevention of human or non-human animals including rodents and other disease models.

[0061] It is to be understood that, unless otherwise stated, any description of a method of treatment includes use of the compounds to provide such treatment as is described herein. It is to be further understood, unless otherwise stated, any description of a method of treatment includes use of the compounds to prepare a medicament to treat such condition. The treatment includes treatment of human or non-human animals including rodents and other disease models.

[0062] As used herein, the term “subject” includes human and non-human animals, as well as cell lines, cell cultures, tissues, and organs. In some embodiments, the subject is 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 some embodiments, the subject is a human.

[0063] As used herein, the term “subject in need thereof” refers to a subject having a disease or having an increased risk of developing the disease. A 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 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 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.

[0064] 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. It is to be appreciated that references to “treating” or “treatment” include the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing orAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0065] It is to be understood that a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph or solvate thereof, can or may also be used to prevent a relevant disease, condition or disorder, or used to identify suitable candidates for such purposes.

[0066] 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.

[0067] It is to be understood that one skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rdedition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18thedition (1990). These texts can, of course, also be referred to in making or using an aspect of the disclosure.

[0068] It is to be understood that the present disclosure also provides pharmaceutical compositions comprising any compound described herein in combination with one or more pharmaceutically acceptable excipient, diluent, adjuvant, carrier, or a combination thereof.

[0069] As used herein, the term “pharmaceutical composition” is a formulation containing the compounds of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial. The quantity of active ingredient (e.g., a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved. One skilled in the art will appreciate that it is sometimes necessary to make routine variationsAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0070] 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.

[0071] 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.

[0072] It is to be understood that a pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0073] It is to be understood that a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment. For example, a compound of the disclosure may be injected intoAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) the blood stream or body cavities or taken orally or applied through the skin with patches. The dose chosen should be sufficient to constitute effective treatment but not so high as to cause unacceptable side effects. The state of the disease condition (e.g., a disease or disorder disclosed herein) and the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.

[0074] 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. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0075] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0076] The pharmaceutical compositions containing active compounds of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and / or auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen.

[0077] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, Cremophor EL (BASF, Parsippany,N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile andAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), cyclodextrins and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0078] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0079] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules or sachets. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such asAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0080] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0081] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays, powders or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0082] The active compounds can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811.

[0083] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.

[0084] It is to be understood that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0085] It is to be 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.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0086] 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. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral organic acid salts of basic residues such as amines, alkali 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 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.

[0087] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0088] 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 ratio other than 1:1, e.g., 3:1, 2:1, 1:2, or 1:3.

[0089] The compounds, or pharmaceutically acceptable salts thereof, are administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperitoneally,Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally.

[0090] 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.

[0091] Techniques for formulation and administration of the disclosed compounds of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19thedition, 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 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.

[0092] 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.

[0093] In the synthetic schemes described herein, compounds may be drawn with one particular configuration for simplicity. Such particular configurations are not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it will be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

[0094] 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.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0095] As use herein, the phrase “compound of the disclosure” refers to those compoundswhich are disclosed herein, both generically and specifically. Compounds of the Present Disclosure

[0096] In some aspects, the present disclosure provides a compound of Formula (I’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is -O-, -NH-, or -S-; A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl); RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo;Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; and R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0097] In some aspects, the present disclosure provides a compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl); RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl,haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo;Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; and R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0098] In some aspects, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is CRA1; A2is N or CRA2; RA1is H, C1-C6alkyl, -NH2, or -S(C1-C6alkyl); RA2is H or halo; R1is H, halo, or C1-C6haloalkyl; R2is C1-C6haloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, or - N(R2a)2; each R2aindependently is C1-C6alkyl or C1-C6alkoxy; R3is C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, or -N(C1-C6alkyl)2or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is C3-C10cycloalkyl optionally substituted with one or more halo; and R5is C1-C6alkyl or C3-C10cycloalkyl.

[0099] In some aspects, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is CRA1; A2is N or CRA2; RA1is H, C1-C6alkyl, -NH2, or -S(C1-C6alkyl); RA2is H or halo; R1is H, halo, or C1-C6haloalkyl; R2is C1-C6haloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, or - N(R2a)2; each R2aindependently is C1-C6alkyl or C1-C6alkoxy; R3is C6-C10aryl; and R4is C3-C10cycloalkyl.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0100] In some aspects, the present disclosure provides a compound of Formula (II), or apharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is halo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; and R4is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0101] It is understood that, for a compound of the present disclosure, variables X, A1, A2,RA1, RA2, R1, R2, R2a, R3, and R4can each be, where applicable, selected from the groups described herein, and any group described herein for any of variables X, A1, A2, RA1, RA2, R1, R2, R2a, R3, and R4 can be combined, where applicable, with any group described herein for one or more of the remainder of variables X, A1, A2, RA1, RA2, R1, R2, R2a, R3, and R4.

[0102] In some embodiments, X is -O-, -NH-, or -S-.

[0103] In some embodiments, X is -O- or -S-.

[0104] In some embodiments, X is -O-.

[0105] In some embodiments, X is -NH-.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0106] In some embodiments, X is -S-.

[0107] In some embodiments, A1is N or CRA1.

[0108] In some embodiments, A1is N.

[0109] In some embodiments, A1is CRA1.

[0110] In some embodiments, A2is N or CRA2.

[0111] In some embodiments, A2is N.

[0112] In some embodiments, A2is CRA2.

[0113] In some embodiments, RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1- C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl).

[0114] In some embodiments, RA1is H.

[0115] In some embodiments, RA1is halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl).

[0116] In some embodiments, RA1is H, C1-C6alkyl, -NH2, or -S(C1-C6alkyl).

[0117] In some embodiments, RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0118] In some embodiments, RA1is halo.

[0119] In some embodiments, RA1is F, Cl, Br, or I. In some embodiments, RA1is F, Cl, or Br. In some embodiments, RA1is F or Cl.

[0120] In some embodiments, RA1is F. In some embodiments, RA1is Cl. In some embodiments, RA1is Br. In some embodiments, RA1is I.

[0121] In some embodiments, RA1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0122] In some embodiments, RA1is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0123] In some embodiments, RA1is C1-C6alkyl.

[0124] In some embodiments, RA1is methyl. In some embodiments, RA1is ethyl. In some embodiments, RA1is propyl. In some embodiments, RA1is butyl. In some embodiments, RA1is pentyl. In some embodiments, RA1is hexyl. In some embodiments, RA1is isopropyl. In some embodiments, RA1is isobutyl. In some embodiments, RA1is isopentyl. In some embodiments, RA1is isohexyl. In some embodiments, RA1is secbutyl. In some embodiments, RA1is secpentyl. In some embodiments, RA1is sechexyl. In some embodiments, RA1is tertbutyl.

[0125] In some embodiments, RA1is C2-C6alkenyl.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0126] In some embodiments, RA1is C2-C6alkynyl.

[0127] In some embodiments, RA1is C1-C6haloalkyl.

[0128] In some embodiments, RA1is halomethyl. In some embodiments, RA1is haloethyl. In some embodiments, RA1is halopropyl. In some embodiments, RA1is halobutyl. In some embodiments, RA1is halopentyl. In some embodiments, RA1is halohexyl.

[0129] In some embodiments, RA1is C1-C6alkoxy.

[0130] In some embodiments, RA1is methoxy. In some embodiments, RA1is ethoxy. In some embodiments, RA1is propoxy. In some embodiments, RA1is butoxy. In some embodiments, RA1is pentoxy. In some embodiments, RA1is hexoxy.

[0131] In some embodiments, RA1is C1-C6haloalkoxy.

[0132] In some embodiments, RA1is halomethoxy. In some embodiments, RA1is haloethoxy. In some embodiments, RA1is halopropoxy. In some embodiments, RA1is halobutoxy. In some embodiments, RA1is halopentoxy. In some embodiments, RA1is halohexoxy.

[0133] In some embodiments, RA1is -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1- C6alkyl).

[0134] In some embodiments, RA1is -NH2.

[0135] In some embodiments, RA1is -NH(C1-C6alkyl).

[0136] In some embodiments, RA1is -N(C1-C6alkyl)2.

[0137] In some embodiments, RA1is -SH.

[0138] In some embodiments, RA1is -S(C1-C6alkyl).

[0139] In some embodiments, RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0140] In some embodiments, RA2is H or halo.

[0141] In some embodiments, RA2is H.

[0142] In some embodiments, RA2is halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6haloalkyl.

[0143] In some embodiments, RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0144] In some embodiments, RA2is halo.

[0145] In some embodiments, RA2is F, Cl, Br, or I. In some embodiments, RA2is F, Cl, or Br. In some embodiments, RA2is F or Cl.

[0146] In some embodiments, RA2is F. In some embodiments, RA2is Cl. In some embodiments, RA2is Br. In some embodiments, RA2is I.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0147] In some embodiments, RA2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0148] In some embodiments, RA2is C1-C6alkyl.

[0149] In some embodiments, RA2is methyl. In some embodiments, RA2is ethyl. In some embodiments, RA2is propyl. In some embodiments, RA2is butyl. In some embodiments, RA2is pentyl. In some embodiments, RA2is hexyl. In some embodiments, RA2is isopropyl. In some embodiments, RA2is isobutyl. In some embodiments, RA2is isopentyl. In some embodiments, RA2is isohexyl. In some embodiments, RA2is secbutyl. In some embodiments, RA2is secpentyl. In some embodiments, RA2is sechexyl. In some embodiments, RA2is tertbutyl.

[0150] In some embodiments, RA2is C2-C6alkenyl.

[0151] In some embodiments, RA2is C2-C6alkynyl.

[0152] In some embodiments, RA2is C1-C6haloalkyl.

[0153] In some embodiments, RA2is halomethyl. In some embodiments, RA2is haloethyl. In some embodiments, RA2is halopropyl. In some embodiments, RA2is halobutyl. In some embodiments, RA2is halopentyl. In some embodiments, RA2is halohexyl.

[0154] In some embodiments, R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1- C6haloalkyl.

[0155] In some embodiments, R1is H, halo, or C1-C6haloalkyl.

[0156] In some embodiments, R1is H.

[0157] In some embodiments, R1is halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl.

[0158] In some embodiments, R1is halo.

[0159] In some embodiments, R1is F, Cl, Br, or I. In some embodiments, R1is F, Cl, or Br. In some embodiments, R1is F or Cl.

[0160] In some embodiments, R1is F. In some embodiments, R1is Cl. In some embodiments, R1is Br. In some embodiments, R1is I.

[0161] In some embodiments, R1is C1-C6alkyl.

[0162] In some embodiments, R1is methyl. In some embodiments, R1is ethyl. In some embodiments, R1is propyl. In some embodiments, R1is butyl. In some embodiments, R1is pentyl. In some embodiments, R1is hexyl. In some embodiments, R1is isopropyl. In some embodiments, R1is isobutyl. In some embodiments, R1is isopentyl. In some embodiments, R1is isohexyl. In some embodiments, R1is secbutyl. In some embodiments, R1is secpentyl. In some embodiments, R1is sechexyl. In some embodiments, R1is tertbutyl.

[0163] In some embodiments, R1is C2-C6alkenyl.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0164] In some embodiments, R1is C2-C6alkynyl.

[0165] In some embodiments, R1is C1-C6haloalkyl.

[0166] In some embodiments, R1is halomethyl. In some embodiments, R1is haloethyl. In some embodiments, R1is halopropyl. In some embodiments, R1is halobutyl. In some embodiments, R1is halopentyl. In some embodiments, R1is halohexyl.

[0167] In some embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2.

[0168] In some embodiments, R2is C1-C6haloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3- C10cycloalkyl, or -N(R2a)2.

[0169] In some embodiments, R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0170] In some embodiments, R2is C1-C6alkyl.

[0171] In some embodiments, R2is methyl. In some embodiments, R2is ethyl. In some embodiments, R2is propyl. In some embodiments, R2is butyl. In some embodiments, R2is pentyl. In some embodiments, R2is hexyl. In some embodiments, R2is isopropyl. In some embodiments, R2is isobutyl. In some embodiments, R2is isopentyl. In some embodiments, R2is isohexyl. In some embodiments, R2is secbutyl. In some embodiments, R2is secpentyl. In some embodiments, R2is sechexyl. In some embodiments, R2is tertbutyl.

[0172] In some embodiments, R2is C2-C6alkenyl.

[0173] In some embodiments, R2is C2-C6alkynyl.

[0174] In some embodiments, R2is C1-C6haloalkyl.

[0175] In some embodiments, R2is halomethyl. In some embodiments, R2is haloethyl. In some embodiments, R2is halopropyl. In some embodiments, R2is halobutyl. In some embodiments, R2is halopentyl. In some embodiments, R2is halohexyl.

[0176] In some embodiments, R2is C1-C6alkoxy.

[0177] In some embodiments, R2is methoxy. In some embodiments, R2is ethoxy. In some embodiments, R2is propoxy. In some embodiments, R2is butoxy. In some embodiments, R2is pentoxy. In some embodiments, R2is hexoxy.

[0178] In some embodiments, R2is C1-C6haloalkoxy.

[0179] In some embodiments, R2is halomethoxy. In some embodiments, R2is haloethoxy. In some embodiments, R2is halopropoxy. In some embodiments, R2is halobutoxy. In some embodiments, R2is halopentoxy. In some embodiments, R2is halohexoxy.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0180] In some embodiments, R2is -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3- C10cycloalkyl, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0181] In some embodiments, R2is -(C1-C6alkyl)-C3-C10cycloalkyl.

[0182] In some embodiments, R2is -(C1-C6haloalkyl)-C3-C10cycloalkyl.

[0183] In some embodiments, R2is -(C1haloalkyl)-C3-C10cycloalkyl. In some embodiments, R2is -(C2haloalkyl)-C3-C10cycloalkyl. In some embodiments, R2is -(C3haloalkyl)-C3-C10cycloalkyl. In some embodiments, R2is -(C4haloalkyl)-C3-C10cycloalkyl. In some embodiments, R2is -(C5haloalkyl)-C3-C10cycloalkyl. In some embodiments, R2is -(C6haloalkyl)-C3-C10cycloalkyl.

[0184] In some embodiments, R2is -(C1-C6alkyl)-C3cycloalkyl. In some embodiments, R2is -(C1-C6alkyl)-C4cycloalkyl. In some embodiments, R2is -(C1-C6alkyl)-C5cycloalkyl. In some embodiments, R2is -(C1-C6alkyl)-C6cycloalkyl. In some embodiments, R2is -(C1-C6alkyl)- C7cycloalkyl. In some embodiments, R2is -(C1-C6alkyl)-C8cycloalkyl. In some embodiments, R2is -(C1-C6alkyl)-C9cycloalkyl. In some embodiments, R2is -(C1-C6alkyl)-C10cycloalkyl.

[0185] In some embodiments, R2is -(C1haloalkyl)-C3cycloalkyl. In some embodiments, R2is -(C1haloalkyl)-C4cycloalkyl. In some embodiments, R2is -(C1haloalkyl)-C5cycloalkyl. In some embodiments, R2is -(C1haloalkyl)-C6cycloalkyl. In some embodiments, R2is -(C1haloalkyl)-C7cycloalkyl. In some embodiments, R2is -(C1haloalkyl)-C8cycloalkyl. In some embodiments, R2is -(C1haloalkyl)-C9cycloalkyl. In some embodiments, R2is -(C1haloalkyl)- C10cycloalkyl.

[0186] In some embodiments, R2is -(C2haloalkyl)-C3cycloalkyl. In some embodiments, R2is -(C2haloalkyl)-C4cycloalkyl. In some embodiments, R2is -(C2haloalkyl)-C5cycloalkyl. In some embodiments, R2is -(C2haloalkyl)-C6cycloalkyl. In some embodiments, R2is -(C2haloalkyl)-C7cycloalkyl. In some embodiments, R2is -(C2haloalkyl)-C8cycloalkyl. In some embodiments, R2is -(C2haloalkyl)-C9cycloalkyl. In some embodiments, R2is -(C2haloalkyl)- C10cycloalkyl.

[0187] In some embodiments, R2is -(C3haloalkyl)-C3cycloalkyl. In some embodiments, R2is -(C3haloalkyl)-C4cycloalkyl. In some embodiments, R2is -(C3haloalkyl)-C5cycloalkyl. In some embodiments, R2is -(C3haloalkyl)-C6cycloalkyl. In some embodiments, R2is -(C3haloalkyl)-C7cycloalkyl. In some embodiments, R2is -(C3haloalkyl)-C8cycloalkyl. In some embodiments, R2is -(C3haloalkyl)-C9cycloalkyl. In some embodiments, R2is -(C3haloalkyl)- C10cycloalkyl.

[0188] In some embodiments, R2is -(C4haloalkyl)-C3cycloalkyl. In some embodiments, R2is -(C4haloalkyl)-C4cycloalkyl. In some embodiments, R2is -(C4haloalkyl)-C5cycloalkyl. InAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) some embodiments, R2is -(C4haloalkyl)-C6cycloalkyl. In some embodiments, R2is -(C4haloalkyl)-C7cycloalkyl. In some embodiments, R2is -(C4haloalkyl)-C8cycloalkyl. In some embodiments, R2is -(C4haloalkyl)-C9cycloalkyl. In some embodiments, R2is -(C4haloalkyl)- C10cycloalkyl.

[0189] In some embodiments, R2is -(C5haloalkyl)-C3cycloalkyl. In some embodiments, R2is -(C5haloalkyl)-C4cycloalkyl. In some embodiments, R2is -(C5haloalkyl)-C5cycloalkyl. In some embodiments, R2is -(C5haloalkyl)-C6cycloalkyl. In some embodiments, R2is -(C5haloalkyl)-C7cycloalkyl. In some embodiments, R2is -(C5haloalkyl)-C8cycloalkyl. In some embodiments, R2is -(C5haloalkyl)-C9cycloalkyl. In some embodiments, R2is -(C5haloalkyl)- C10cycloalkyl.

[0190] In some embodiments, R2is -(C6haloalkyl)-C3cycloalkyl. In some embodiments, R2is -(C6haloalkyl)-C4cycloalkyl. In some embodiments, R2is -(C6haloalkyl)-C5cycloalkyl. In some embodiments, R2is -(C6haloalkyl)-C6cycloalkyl. In some embodiments, R2is -(C6haloalkyl)-C7cycloalkyl. In some embodiments, R2is -(C6haloalkyl)-C8cycloalkyl. In some embodiments, R2is -(C6haloalkyl)-C9cycloalkyl. In some embodiments, R2is -(C6haloalkyl)- C10cycloalkyl.

[0191] In some embodiments, R2is C3-C10cycloalkyl.

[0192] In some embodiments, R2is C3cycloalkyl. In some embodiments, R2is C4cycloalkyl. In some embodiments, R2is C5cycloalkyl. In some embodiments, R2is C6cycloalkyl. In some embodiments, R2is C7cycloalkyl. In some embodiments, R2is C8cycloalkyl. In some embodiments, R2is C9cycloalkyl. In some embodiments, R2is C10cycloalkyl.

[0193] In some embodiments, R2is 3- to 10-membered heterocyclyl.

[0194] In some embodiments, R2is 3-membered heterocyclyl. In some embodiments, R2is 4- membered heterocyclyl. In some embodiments, R2is 5-membered heterocyclyl. In some embodiments, R2is 6-membered heterocyclyl. In some embodiments, R2is 7-membered heterocyclyl. In some embodiments, R2is 8-membered heterocyclyl. In some embodiments, R2is 9-membered heterocyclyl. In some embodiments, R2is 10-membered heterocyclyl.

[0195] In some embodiments, R2is -N(R2a)2.

[0196] In some embodiments, each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0197] In some embodiments, each R2aindependently is H.

[0198] In some embodiments, each R2aindependently is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0199] In some embodiments, each R2aindependently is C1-C6alkyl or C1-C6alkoxy.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0200] In some embodiments, R2ais C1-C6alkyl.

[0201] In some embodiments, R2ais methyl. In some embodiments, R2ais ethyl. In some embodiments, R2ais propyl. In some embodiments, R2ais butyl. In some embodiments, R2ais pentyl. In some embodiments, R2ais hexyl. In some embodiments, R2ais isopropyl. In some embodiments, R2ais isobutyl. In some embodiments, R2ais isopentyl. In some embodiments, R2ais isohexyl. In some embodiments, R2ais secbutyl. In some embodiments, R2ais secpentyl. In some embodiments, R2ais sechexyl. In some embodiments, R2ais tertbutyl.

[0202] In some embodiments, R2ais C2-C6alkenyl.

[0203] In some embodiments, R2ais C2-C6alkynyl.

[0204] In some embodiments, R2ais C1-C6haloalkyl.

[0205] In some embodiments, R2ais halomethyl. In some embodiments, R2ais haloethyl. In some embodiments, R2ais halopropyl. In some embodiments, R2ais halobutyl. In some embodiments, R2ais halopentyl. In some embodiments, R2ais halohexyl.

[0206] In some embodiments, R2ais C1-C6alkoxy.

[0207] In some embodiments, R2ais methoxy. In some embodiments, R2ais ethoxy. In some embodiments, R2ais propoxy. In some embodiments, R2ais butoxy. In some embodiments, R2ais pentoxy. In some embodiments, R2ais hexoxy.

[0208] In some embodiments, R2ais C1-C6haloalkoxy.

[0209] In some embodiments, R2ais halomethoxy. In some embodiments, R2ais haloethoxy. In some embodiments, R2ais halopropoxy. In some embodiments, R2ais halobutoxy. In some embodiments, R2ais halopentoxy. In some embodiments, R2ais halohexoxy.

[0210] In some embodiments, R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo.

[0211] In some embodiments, R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl, or 5- to 10-membered heteroaryl.

[0212] In some embodiments, R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy.

[0213] In some embodiments, R3is C1-C6alkyl.

[0214] In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is propyl. In some embodiments, R3is butyl. In some embodiments, R3isAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) pentyl. In some embodiments, R3is hexyl. In some embodiments, R3is isopropyl. In some embodiments, R3is isobutyl. In some embodiments, R3is isopentyl. In some embodiments, R3is isohexyl. In some embodiments, R3is secbutyl. In some embodiments, R3is secpentyl. In some embodiments, R3is sechexyl. In some embodiments, R3is tertbutyl.

[0215] In some embodiments, R3is C2-C6alkenyl.

[0216] In some embodiments, R3is C2-C6alkynyl.

[0217] In some embodiments, R3is C1-C6haloalkyl.

[0218] In some embodiments, R3is halomethyl. In some embodiments, R3is haloethyl. In some embodiments, R3is halopropyl. In some embodiments, R3is halobutyl. In some embodiments, R3is halopentyl. In some embodiments, R3is halohexyl.

[0219] In some embodiments, R3is C1-C6alkoxy.

[0220] In some embodiments, R3is methoxy. In some embodiments, R3is ethoxy. In some embodiments, R3is propoxy. In some embodiments, R3is butoxy. In some embodiments, R3is pentoxy. In some embodiments, R3is hexoxy.

[0221] In some embodiments, R3is C1-C6haloalkoxy.

[0222] In some embodiments, R3is halomethoxy. In some embodiments, R3is haloethoxy. In some embodiments, R3is halopropoxy. In some embodiments, R3is halobutoxy. In some embodiments, R3is halopentoxy. In some embodiments, R3is halohexoxy.

[0223] In some embodiments, R3is C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6- C10aryl, or 5- to 10-membered heteroaryl.

[0224] In some embodiments, R3is C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0225] In some embodiments, R3is C3-C10cycloalkyl.

[0226] In some embodiments, R3is C3cycloalkyl. In some embodiments, R3is C4cycloalkyl. In some embodiments, R3is C5cycloalkyl. In some embodiments, R3is C6cycloalkyl. In some embodiments, R3is C7cycloalkyl. In some embodiments, R3is C8cycloalkyl. In some embodiments, R3is C9cycloalkyl. In some embodiments, R3is C10cycloalkyl.

[0227] In some embodiments, R3is 3- to 10-membered heterocyclyl.

[0228] In some embodiments, R3is 3-membered heterocyclyl. In some embodiments, R3is 4- membered heterocyclyl. In some embodiments, R3is 5-membered heterocyclyl. In some embodiments, R3is 6-membered heterocyclyl. In some embodiments, R3is 7-membered heterocyclyl. In some embodiments, R3is 8-membered heterocyclyl. In some embodiments, R3is 9-membered heterocyclyl. In some embodiments, R3is 10-membered heterocyclyl.

[0229] In some embodiments, R3is C6-C10aryl or 5- to 10-membered heteroaryl.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0230] In some embodiments, R3is C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0231] In some embodiments, R3is C6-C10aryl.

[0232] In some embodiments, R3is C6-C10aryl substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0233] In some embodiments, R3is C6-C10aryl optionally substituted with one or more halo.

[0234] In some embodiments, R3is C6-C10aryl substituted with one or more halo.

[0235] In some embodiments, R3is C6-C10aryl substituted with one or more F, Cl, Br, or I. In some embodiments, R3is C6-C10aryl substituted with one or more F, Cl, or Br. In some embodiments, R3is C6-C10aryl substituted with one or more F or Cl.

[0236] In some embodiments, R3is C6-C10aryl substituted with one or more F. In some embodiments, R3is C6-C10aryl substituted with one or more Cl. In some embodiments, R3is C6-C10aryl substituted with one or more Br. In some embodiments, R3is C6-C10aryl substituted with one or more I.

[0237] In some embodiments, R3is C6-C10aryl optionally substituted with one or more C1-C6alkyl.

[0238] In some embodiments, R3is C6-C10aryl substituted with one or more C1-C6alkyl.

[0239] In some embodiments, R3is C6-C10aryl substituted with one or more methyl. In some embodiments, R3is C6-C10aryl substituted with one or more ethyl. In some embodiments, R3is C6-C10aryl substituted with one or more propyl. In some embodiments, R3is C6-C10aryl substituted with one or more butyl. In some embodiments, R3is C6-C10aryl substituted with one or more pentyl. In some embodiments, R3is C6-C10aryl substituted with one or more hexyl. In some embodiments, R3is C6-C10aryl substituted with one or more isopropyl. In some embodiments, R3is C6-C10aryl substituted with one or more isobutyl. In some embodiments, R3is C6-C10aryl substituted with one or more isopentyl. In some embodiments, R3is C6-C10aryl substituted with one or more isohexyl. In some embodiments, R3is C6-C10aryl substituted with one or more secbutyl. In some embodiments, R3is C6-C10aryl substituted with one or more secpentyl. In some embodiments, R3is C6-C10aryl substituted with one or more sechexyl. In some embodiments, R3is C6-C10aryl substituted with one or more tertbutyl.

[0240] In some embodiments, R3is C6-C10aryl optionally substituted with one or more C1-C6haloalkyl.

[0241] In some embodiments, R3is C6-C10aryl substituted with one or more C1-C6haloalkyl.

[0242] In some embodiments, R3is C6-C10aryl substituted with one or more halomethyl. In some embodiments, R3is C6-C10aryl substituted with one or more haloethyl. In someAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) embodiments, R3is C6-C10aryl substituted with one or more halopropyl. In some embodiments, R3is C6-C10aryl substituted with one or more halobutyl. In some embodiments, R3is C6-C10aryl substituted with one or more halopentyl. In some embodiments, R3is C6-C10aryl substituted with one or more halohexyl.

[0243] In some embodiments, R3is C6-C10aryl optionally substituted with one or more -NH2.

[0244] In some embodiments, R3is C6-C10aryl optionally substituted with one or more - NH(C1-C6alkyl).

[0245] In some embodiments, R3is C6-C10aryl optionally substituted with one or more -N(C1- C6alkyl)2.

[0246] In some embodiments, R3is C6-C10aryl substituted with one or more -NH2.

[0247] In some embodiments, R3is C6-C10aryl substituted with one or more -NH(C1-C6alkyl).

[0248] In some embodiments, R3is C6-C10aryl substituted with one or more -N(C1-C6alkyl)2.

[0249] In some embodiments, R3is C6aryl.

[0250] In some embodiments, R3is C8aryl. In some embodiments, R3is C10aryl.

[0251] In some embodiments, R3is 5- to 10-membered heteroaryl optionally substituted with one or more halo.

[0252] In some embodiments, R3is 5- to 10-membered heteroaryl.

[0253] In some embodiments, R3is 5- to 10-membered heteroaryl optionally substituted with one or more halo.

[0254] In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more halo.

[0255] In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more F, Cl, Br, or I. In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more F, Cl, or Br. In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more F or Cl.

[0256] In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more F. In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more Cl. In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more Br. In some embodiments, R3is 5- to 10-membered heteroaryl substituted with one or more I.

[0257] In some embodiments, R3is 5-membered heteroaryl. In some embodiments, R3is 6- membered heteroaryl. In some embodiments, R3is 7-membered heteroaryl. In some embodiments, R3is 8-membered heteroaryl. In some embodiments, R3is 9-membered heteroaryl. In some embodiments, R3is 10-membered heteroaryl.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0258] In some embodiments, R4is R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl.

[0259] In some embodiments, R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0260] In some embodiments, R4is H.

[0261] In some embodiments, R4is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0262] In some embodiments, R4is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0263] In some embodiments, R4is C1-C6alkyl.

[0264] In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is propyl. In some embodiments, R4is butyl. In some embodiments, R4is pentyl. In some embodiments, R4is hexyl. In some embodiments, R4is isopropyl. In some embodiments, R4is isobutyl. In some embodiments, R4is isopentyl. In some embodiments, R4is isohexyl. In some embodiments, R4is secbutyl. In some embodiments, R4is secpentyl. In some embodiments, R4is sechexyl. In some embodiments, R4is tertbutyl.

[0265] In some embodiments, R4is C2-C6alkenyl.

[0266] In some embodiments, R4is C2-C6alkynyl.

[0267] In some embodiments, R4is C1-C6haloalkyl.

[0268] In some embodiments, R4is halomethyl. In some embodiments, R4is haloethyl. In some embodiments, R4is halopropyl. In some embodiments, R4is halobutyl. In some embodiments, R4is halopentyl. In some embodiments, R4is halohexyl.

[0269] In some embodiments, R4is C1-C6alkoxy.

[0270] In some embodiments, R4is methoxy. In some embodiments, R4is ethoxy. In some embodiments, R4is propoxy. In some embodiments, R4is butoxy. In some embodiments, R4is pentoxy. In some embodiments, R4is hexoxy.

[0271] In some embodiments, R4is C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0272] In some embodiments, R4is C3-C10cycloalkyl optionally substituted with one or more halo.

[0273] In some embodiments, R4is C3-C10cycloalkyl.

[0274] In some embodiments, R4is C3-C10cycloalkyl substituted with one or more halo.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0275] In some embodiments, R4is C3-C10cycloalkyl substituted with one or more F, Cl, Br, or I. In some embodiments, R4is C3-C10cycloalkyl substituted with one or more F, Cl, or Br. In some embodiments, R4is C3-C10cycloalkyl substituted with one or more F or Cl.

[0276] In some embodiments, R4is C3-C10cycloalkyl substituted with one or more F. In some embodiments, R4is C3-C10cycloalkyl substituted with one or more Cl. In some embodiments, R4is C3-C10cycloalkyl substituted with one or more Br. In some embodiments, R4is C3-C10cycloalkyl substituted with one or more I.

[0277] In some embodiments, R4is C3cycloalkyl. In some embodiments, R4is C4cycloalkyl. In some embodiments, R4is C5cycloalkyl. In some embodiments, R4is C6cycloalkyl. In some embodiments, R4is C7cycloalkyl. In some embodiments, R4is C8cycloalkyl. In some embodiments, R4is C9cycloalkyl. In some embodiments, R4is C10cycloalkyl.

[0278] In some embodiments, R4is 3- to 10-membered heterocyclyl.

[0279] In some embodiments, R4is 3-membered heterocyclyl. In some embodiments, R4is 4- membered heterocyclyl. In some embodiments, R4is 5-membered heterocyclyl. In some embodiments, R4is 6-membered heterocyclyl. In some embodiments, R4is 7-membered heterocyclyl. In some embodiments, R4is 8-membered heterocyclyl. In some embodiments, R4is 9-membered heterocyclyl. In some embodiments, R4is 10-membered heterocyclyl.

[0280] In some embodiments, R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0281] In some embodiments, R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, or C1-C6alkoxy.

[0282] In some embodiments, R5is C1-C6alkyl.

[0283] In some embodiments, R5is methyl. In some embodiments, R5is ethyl. In some embodiments, R5is propyl. In some embodiments, R5is butyl. In some embodiments, R5is pentyl. In some embodiments, R5is hexyl. In some embodiments, R5is isopropyl. In some embodiments, R5is isobutyl. In some embodiments, R5is isopentyl. In some embodiments, R5is isohexyl. In some embodiments, R5is secbutyl. In some embodiments, R5is secpentyl. In some embodiments, R5is sechexyl. In some embodiments, R5is tertbutyl.

[0284] In some embodiments, R5is C2-C6alkenyl.

[0285] In some embodiments, R5is C2-C6alkynyl.

[0286] In some embodiments, R5is C1-C6haloalkyl.

[0287] In some embodiments, R5is halomethyl. In some embodiments, R5is haloethyl. In some embodiments, R5is halopropyl. In some embodiments, R5is halobutyl. In some embodiments, R5is halopentyl. In some embodiments, R5is halohexyl.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0288] In some embodiments, R5is C1-C6alkoxy.

[0289] In some embodiments, R5is methoxy. In some embodiments, R5is ethoxy. In some embodiments, R5is propoxy. In some embodiments, R5is butoxy. In some embodiments, R5is pentoxy. In some embodiments, R5is hexoxy.

[0290] In some embodiments, R5is C3-C10cycloalkyl or 3- to 10-membered heterocyclyl.

[0291] In some embodiments, R5is C3-C10cycloalkyl.

[0292] In some embodiments, R5is C3cycloalkyl. In some embodiments, R5is C4cycloalkyl. In some embodiments, R5is C5cycloalkyl. In some embodiments, R5is C6cycloalkyl. In some embodiments, R5is C7cycloalkyl. In some embodiments, R5is C8cycloalkyl. In some embodiments, R5is C9cycloalkyl. In some embodiments, R5is C10cycloalkyl.

[0293] In some embodiments, R5is 3- to 10-membered heterocyclyl.

[0294] In some embodiments, R5is 3-membered heterocyclyl. In some embodiments, R5is 4- membered heterocyclyl. In some embodiments, R5is 5-membered heterocyclyl. In some embodiments, R5is 6-membered heterocyclyl. In some embodiments, R5is 7-membered heterocyclyl. In some embodiments, R5is 8-membered heterocyclyl. In some embodiments, R5is 9-membered heterocyclyl. In some embodiments, R5is 10-membered heterocyclyl.

[0295] In some embodiments, each R3ais independently halo.

[0296] In some embodiments, each R3ais independently F, Cl, Br, or I. In some embodiments, each R3ais independently F, Cl, or Br. In some embodiments, each R3ais independently F or Cl.

[0297] In some embodiments, each R3ais independently F. In some embodiments, each R3ais independently Cl. In some embodiments, each R3ais independently Br. In some embodiments, each R3ais independently I.

[0298] In some embodiments, each R3ais independently C1-C6alkyl.

[0299] In some embodiments, each R3ais independently methyl. In some embodiments, each R3ais independently ethyl. In some embodiments, each R3ais independently propyl. In some embodiments, each R3ais independently butyl. In some embodiments, each R3ais independently pentyl. In some embodiments, each R3ais independently hexyl. In some embodiments, each R3ais independently isopropyl. In some embodiments, each R3ais independently isobutyl. In some embodiments, each R3ais independently isopentyl. In some embodiments, each R3ais independently isohexyl. In some embodiments, each R3ais independently secbutyl. In some embodiments, each R3ais independently secpentyl. In some embodiments, each R3ais independently sechexyl. In some embodiments, each R3ais independently tertbutyl.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0300] In some embodiments, each R3a is independently C1-C6 haloalkyl.

[0301] In some embodiments, each R3a is independently halomethyl. In some embodiments,each R3ais independently haloethyl. In some embodiments, each R3ais independently halopropyl In some embodiments, each R3ais independently halobutyl. In some embodiments, each R3ais independently halopentyl. In some embodiments, each R3ais independently halohexyl.

[0302] In some embodiments, each R3a is independently -NH2.

[0303] In some embodiments, each R3a is independently -NH(C1-C6 alkyl).

[0304] In some embodiments, each R3a is independently -N(C1-C6 alkyl)2.

[0305] In some embodiments, the compound of Formula (I’) or Formula (I) has 0 R3a. Insome embodiments, the compound of Formula (I’) or Formula (I) has 1 R3a.In some embodiments, the compound of Formula (I’) or Formula (I) has 2 R3a.In some embodiments, the compound of Formula (I’) or Formula (I) has 3 R3a.

[0306] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I”):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0307] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula(I”’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0308] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I’-a):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0309] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-a):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0310] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I’-a’):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0311] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-a’):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0312] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I’-a”):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0313] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-a”):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0314] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-b):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0315] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-b’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0316] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-b”):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0317] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ab’):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0318] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ab):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0319] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-c):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0320] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ac’):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0321] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ac):ac), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0322] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-bc):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0323] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-abc):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)abc), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0324] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-d):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0325] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ad’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0326] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ad):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)ad), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0327] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-bd):bd), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0328] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-abd): O S H O HN OA1N A2OR2(I-abd), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0329] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ae):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0330] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0331] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ag):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0332] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-ah):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0333] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-e):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0334] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-f):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0335] In some embodiments, the compound of Formula (I’) or Formula (I) is of Formula (I-g):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0336] In some embodiments, the compound is selected from the compounds described inTable 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0337] In some embodiments, the compound is selected from the compounds described inTable 1, or a pharmaceutically acceptable salt thereof.

[0338] In some embodiments, the compound is selected from the prodrugs of compoundsdescribed in Table 1, or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the compound is selected from the compounds described inTable 1.

[0340] In some embodiments, the compound is selected from the compounds described inTable 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the compound is selected from the compounds described inTable 2, or a pharmaceutically acceptable salt thereof.

[0342] In some embodiments, the compound is selected from the prodrugs of compoundsdescribed in Table 2, or a pharmaceutically acceptable salt thereof.

[0343] In some embodiments, the compound is selected from the compounds described inTable 2.

[0344] In some embodiments, the compound is selected from the compounds described inTable 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0345] In some embodiments, the compound is selected from the compounds described inTable 3, or a pharmaceutically acceptable salt thereof.

[0346] In some embodiments, the compound is selected from the prodrugs of compoundsdescribed in Table 3, or a pharmaceutically acceptable salt thereof.

[0347] In some embodiments, the compound is selected from the compounds described inTable 3.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Table 1Compound No. Example No. Name Structure(S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 1 1a 5-(ethyl(methyl)amino)- 6-phenoxypyrazine-2- carboxamide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 2 2a 5- (methoxy(methyl)amino) -6-phenoxypyrazine-2- carboxamide (S,E)-5-cyclopentyl-N- (1-cyclopropyl-3- 3 3a (methylsulfonyl)allyl)-6- phenoxypyrazine-2- carboxamide (S,E)-3-amino-5- cyclopentyl-N-(1- 4 4a cyclopropyl-3- (methylsulfonyl)allyl)-6- phenoxypyrazine-2- carboxamide (S,E)-3-amino-N-(1- cyclopropyl-3- 5 5a (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6- phenoxypyrazine-2- carboxamide (S,E)-5-cyclopentyl-N- 6 6a (1-cyclopropyl-3- (methylsulfonyl)allyl)-6- phenoxypicolinamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)Compound No. Example No. Name Structure(S,E)-3-amino-5- cyclopentyl-N-(1- 7 7a cyclopropyl-3- (methylsulfonyl)allyl)-6- phenoxypicolinamide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 8 8a 5-(1,1-difluoroethyl)-6- phenoxypyrazine-2- carboxamide (S,E)-N-(1-cyclopropyl- 9 9a 3-(methylsulfonyl)allyl)- 5-(1,1-difluoroethyl)-6- phenoxypicolinamide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 10 5-(1,1-difluoroethyl)-4- fluoro-6- phenoxypicolinamide (S,E)-N-(1-cyclopropyl- 3-fluoro-3- O F (methylsulfonyl)al O 11 11a lyl)-5-O N(1,1-difluoroethyl)-6- N S H phenoxypyrazine-2- O N carboxamide F F (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 12 12a (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6- phenoxypicolinamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)Compound No. Example No. Name Structure(S,E)-N-(1-cyclopropyl- 3-fluoro-3- 13 (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-4- fluoro-6- phenoxypicolinamide (S,E)-3-amino-5- cyclopentyl-N-(1- 14 cyclopropyl-3- (methylsulfonyl)allyl)-6- (phenylthio)pyrazine-2- carboxamide (S,E)-5-cyclopentyl-N- (1-cyclopropyl-3- 15 15a (methylsulfonyl)allyl)-3- methyl-6- phenoxypyrazine-2- carboxamide (S,E)-5-cyclopentyl-N- (1-cyclopropyl-3- 16 (methylsulfonyl)allyl)-3- (methylthio)-6- phenoxypyrazine-2- carboxamide (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 17 (methylsulfonyl)allyl)-5- (cyclopropyldifluoromet hyl)-6-phenoxypyrazine- 2-carboxamide Table 2Compound No. Example No. Name Structure(S,E)-N-(1-cyclopropyl- 3-fluoro-3- 18 1b (methylsulfonyl)allyl)-2- (1,1-difluoroethyl)-4- phenoxypyrimidine-5- carboxamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)Compound No. Example No. Name Structure(S,E)-N-(1-cyclopropyl- 3-fluoro-3- (methylsulfonyl)allyl)-2- 19 2b (cyclopropyldifluoromet hyl)-4- phenoxypyrimidine-5- carboxamide (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 20 3b (methylsulfonyl)allyl)-6- (1,1-difluoroethyl)-5- fluoro-2- phenoxynicotinamide Table 3 Compound Example No.NamStructureNo.e(S,E)-5-cyclopentyl-N- 21 18a (1-cyclopropyl-3-fluoro- 3-(methylsulfonyl)allyl)- 6-phenoxypicolinamide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 22 19a 5-(1,1-difluoroethyl)-6- (4- fluorophenoxy)picolina mide (S,E)-6-(4- chlorophenoxy)-N-(1- cyclopropyl-3- 23 20a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami deAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Compound Example No. StructureNo.Name(S,E)-6-(4- bromophenoxy)-N-(1- cyclopropyl-3- 24 21a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-N-(1-cyclopropyl- 25 22a 3-(methylsulfonyl)allyl)- 5-(1,1-difluoroethyl)-6- (p-tolyloxy)picolinamide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 26 23a 5-(1,1-difluoroethyl)-6- (3,4- difluorophenoxy)picolin amide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 27 24a 5-(1,1-difluoroethyl)-6- (4- (trifluoromethyl)phenox y)picolinamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Compound Example No.NamStructureNo.e(S,E)-N-(1-cyclopropyl- 3-fluoro-3- 28 25a (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6-(4- fluorophenoxy)picolina mide (S,E)-6-(4- bromophenoxy)-N-(1- cyclopropyl-3-fluoro-3- 29 26 (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 30 27a (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6-(4- (trifluoromethyl)phenox y)picolinamide (S,E)-6-(3- bromophenoxy)-N-(1- cyclopropyl-3- 31 28a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-6-(3- bromophenoxy)-N-(1- cyclopropyl-3-fluoro-3- 32 29a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami deAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Compound Example No.NaStructureNo.me(S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 33 30a 5-(1,1-difluoroethyl)-6- (m- tolyloxy)picolinamide (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 34 31a(methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6-(m- tolyloxy)picolinamide (S,E)-6-(3- chlorophenoxy)-N-(1- cyclopropyl-3- 35 32a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-6-(3- chlorophenoxy)-N-(1- cyclopropyl-3-fluoro-3- 36 33a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-6-(benzo[d]thiazol- 6-yloxy)-N-(1- cyclopropyl-3-fluoro-3- 37 34a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami deAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Compound Example No.NamStructureNo.e(S,E)-6-(benzo[d]thiazol- 6-yloxy)-N-(1- cyclopropyl-3- 38 35a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 39 36a (methylsulfonyl)allyl)-5- (cyclopropyldifluoromet hyl)-6- phenoxypicolinamide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 40 37a 5- (cyclopropyldifluoromet hyl)-6- phenoxypicolinamide (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 41 38a (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6-(4- (dimethylamino)phenoxy )picolinamide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 42 39a 5-(1,1-difluoroethyl)-6- (pyridin-4- yloxy)picolinamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Compound Example No. StructureNo.Name(S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 43 40a 5-(1,1-difluoroethyl)-6- (pyridin-3- yloxy)picolinamide (S,E)-6-((1H- benzo[d]imidazol-6- yl)oxy)-N-(1- 44 41a cyclopropyl-3-fluoro-3- (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-6-((2- chloropyridin-4-yl)oxy)- N-(1-cyclopropyl-3- 45 42a (methylsulfonyl)allyl)-5- (1,1- difluoroethyl)picolinami de (S,E)-N-(1-cyclopropyl- 3-fluoro-3- (methylsulfonyl)allyl)-5- 46 43a (1,1-difluoroethyl)-6- (3,4- difluorophenoxy)picolin amide (S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 44a 47 5-(1,1-difluoroethyl)-6- (3,4- difluorophenoxy)pyrazin e-2-carboxamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Compound Example No.NStructureNo.ame(S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 45a 48 5-(1,1-difluoroethyl)-6- (4- fluorophenoxy)pyrazine- 2-carboxamide (S,E)-N-(1-cyclopropyl- 3-fluoro-3- (methylsulfonyl)allyl)-5- 49 46a (1,1-difluoroethyl)-6- (3,4- difluorophenoxy)pyrazin e-2-carboxamide (S,E)-N-(1-cyclopropyl- 3-fluoro-3- 50 47a (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6-(4- fluorophenoxy)pyrazine- 2-carboxamide (S,E)-N-(1-cyclopropyl- 3- 51 48a (cyclopropylsulfonyl)all yl)-5-(1,1-difluoroethyl)- 6-phenoxypyrazine-2- carboxamide (S,E)-N-(1-(3,3- difluorocyclobutyl)-3- 52 49a (methylsulfonyl)allyl)-5- (1,1-difluoroethyl)-6- phenoxypyrazine-2- carboxamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Compound Example No.NaStructureNo.me(S,E)-N-(1-cyclopropyl- 3-(methylsulfonyl)allyl)- 53 5- (cyclopropyldifluoromet hyl)-6-phenoxypyrazine- 2-carboxamide

[0348] In some embodiments, the compound is a pharmaceutically acceptable salt of any oneof the compounds described in Table 1.

[0349] In some aspects, the present disclosure provides a compound being an isotopicderivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0350] In some embodiments, the compound is an isotopic derivative of any one of thecompounds described in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the compound is an isotopic derivative of any one of thecompounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0352] In some embodiments, the compound is an isotopic derivative of any one of prodrugsof the compounds described in Table 1, or a pharmaceutically acceptable salt thereof.

[0353] In some embodiments, the compound is an isotopic derivative of any one of thecompounds described in Table 1.

[0354] In some embodiments, the compound is a pharmaceutically acceptable salt of any oneof the compounds described in Table 2.

[0355] In some embodiments, the compound is an isotopic derivative of any one of thecompounds described in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0356] In some embodiments, the compound is an isotopic derivative of any one of thecompounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0357] In some embodiments, the compound is an isotopic derivative of any one of prodrugsof the compounds described in Table 2, or a pharmaceutically acceptable salt thereof.

[0358] In some embodiments, the compound is an isotopic derivative of any one of thecompounds described in Table 2.

[0359] In some embodiments, the compound is a pharmaceutically acceptable salt of any oneof the compounds described in Table 3.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0360] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3, or a prodrug or pharmaceutically acceptable salt thereof.

[0361] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3, or a pharmaceutically acceptable salt thereof.

[0362] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 3, or a pharmaceutically acceptable salt thereof.

[0363] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 3.

[0364] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0365] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0366] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0367] The term “isotopic derivative,” as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I’), Formula (I), or Formula (II) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I’), Formula (I), or Formula (II). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,18O,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof). In some embodiments, the compound is a18F labeled compound. In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof. In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0368] It is understood that the18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S labeled reagent for a non-isotope labeled reagent.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0369] A compound of the invention or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,125I,129I,131I,135I,32S,34S,35S, and36S atom(s) is within the scope of the invention. Further, substitution with isotope (e.g,,18F,123I,124I,125I,129I,131I,135I,3S,34S,35S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0370] For the avoidance of doubt it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0371] The various functional groups and substituents making up the compounds of the Formula (I’), Formula (I), or Formula (II) are typically chosen such that the molecular weight of the compound does not exceed 1000 daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 daltons or less.

[0372] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0373] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0374] It will be understood that while compounds disclosed herein may be presented in one particular configuration. Such particular configuration is not to be construed as limiting the disclosure to one or another isomer, tautomer, regioisomer or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regioisomers or stereoisomers. In some embodiments, the presentation of a compound herein in a particular configuration intends to encompass, and to refer to, each of the available isomers, tautomers, regioisomers, and stereoisomers of theAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) compound, or any mixture thereof; while the presentation further intends to refer to the specific configuration of the compound.

[0375] It will be understood that while compounds disclosed herein may be presented without specified configuration (e.g., without specified stereochemistry). Such presentation intends to encompass all available isomers, tautomers, regioisomers, and stereoisomers of the compound. In some embodiments, the presentation of a compound herein without specified configuration intends to refer to each of the available isomers, tautomers, regioisomers, and stereoisomers of the compound, or any mixture thereof.

[0376] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0377] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0378] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0379] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0380] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compoundsAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0381] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0382] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0383] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0384] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0385] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and thoseAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0386] The compounds of this disclosure may possess one or more asymmetric centers; such compounds can therefore be produced as individual I- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”,4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centers (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess WRN inhibitory activity.

[0387] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0388] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0389] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. TheAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0390] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or anhydrous form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0391] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0392] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure origin to the reference compound.

[0393] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0394] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0395] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understood that the disclosure encompasses all such solvated forms that possess WRN activity.

[0396] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, orAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) mixtures thereof, which possess WRN activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0397] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (I’), Formula (I), or Formula (II) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (I’), Formula (I), or Formula (II). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate

[0398] Compounds of any one of the Formulae disclosed herein containing an amine function may also form N-oxides. A reference herein to a compound of Formula (I’), Formula (I), or Formula (II) that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidized to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0399] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed whenAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) the compound of the disclosure contains a suitable group or substituent to which a property- modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0400] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically-produced compound or a metabolically-produced compound.

[0401] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard- Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0402] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include C1-C10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoylAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) and phenylacetyl groups, C1-C10alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(C1-C6alkyl)2carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4- (C1-C4alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include -acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0403] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4alkylamine such as methylamine, a (C1-C4alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-C4alkoxy-C2-C4alkylamine such as 2-methoxyethylamine, a phenyl-C1- C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0404] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-C4alkyl)piperazin-1- ylmethyl.

[0405] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).

[0406] Suitably, the present disclosure excludes any individual compounds not possessing the biological activity defined herein. Methods of Synthesis

[0407] In some aspects, the present disclosure provides a method of preparing a compound of the present disclosure.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0408] In some aspects, the present disclosure provides a method of a compound, comprising one or more steps as described herein.

[0409] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, or directly obtained by a method for preparing a compound as described herein.

[0410] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein.

[0411] The compounds of the present disclosure can be prepared by any suitable technique known in the art. Particular processes for the preparation of these compounds are described further in the accompanying examples.

[0412] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0413] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilized.

[0414] It will be appreciated that during the synthesis of the compounds of the disclosure in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed. For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule. Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0415] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with theAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a tert-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0416] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0417] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a tert-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0418] Once a compound of Formula (I’), Formula (I), or Formula (II) has been synthesized by any one of the processes defined herein, the processes may then further comprise the additional steps of: (i) removing any protecting groups present; (ii) converting the compound Formula (I’), Formula (I), or Formula (II) into another compound of Formula (I’), Formula (I), or Formula (II); (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) forming a prodrug thereof.

[0419] The resultant compounds of Formula (I’), Formula (I), or Formula (II) can be isolated and purified using techniques well known in the art.

[0420] In some embodiments, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. ExamplesAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) of suitable solvents comprise but are not limited to hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2- dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone, methylisobutylketone (MIBK) or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate or methyl acetate, or mixtures of the said solvents or mixtures with water.

[0421] The reaction temperature is suitably between about -100 °C and 300 °C, depending on the reaction step and the conditions used.

[0422] Reaction times are generally in the range between a fraction of a minute and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in the art, for example reaction monitoring. Based on the reaction temperatures given above, suitable reaction times generally lie in the range between 10 minutes and 48 hours.

[0423] Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

[0424] As will be understood by the person skilled in the art of organic synthesis, compounds of the present disclosure are readily accessible by various synthetic routes, some of which are exemplified in the accompanying examples. The skilled person will easily recognize which kind of reagents and reactions conditions are to be used and how they are to be applied and adapted in any particular instance – wherever necessary or useful – in order to obtain the compounds of the present disclosure. Furthermore, some of the compounds of the present disclosure can readily be synthesized by reacting other compounds of the present disclosure under suitable conditions, for instance, by converting one particular functional group being present in a compound of the present disclosure, or a suitable precursor molecule thereof, into another one by applying standard synthetic methods, like reduction, oxidation, addition or substitution reactions; those methods are well known to the skilled person. Likewise, the skilledAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) person will apply – whenever necessary or useful – synthetic protecting (or protective) groups; suitable protecting groups as well as methods for introducing and removing them are well- known to the person skilled in the art of chemical synthesis and are described, in more detail, in, e.g., P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4thedition (2006) (John Wiley & Sons).

[0425] General routes for the preparation of a compound of the application are described inSchemes 1-6 herein. Scheme 1

[0426] Compounds of the formula Gen-A may be prepared by the synthetic route depicted inScheme 1, wherein A2is CRA2or N and Xzis a halide. In some cases, RA1is an amine, and in some cases RA1is H. In cases wherein RA1is an amine, a protecting group may need to be introduced and removed later in the synthesis. For example, the amine may be protected with one or two Boc groups, which may be removed through the use of acid. In some cases, R2is a nucleophile, for example an amine, which can be added to an intermediate Gen-A-1 to afford Gen-A-2. In cases wherein A2is N, this amine R2can be introduced via an SNAr reaction. In some cases, R2can be introduced via a cross coupling reaction. Gen-A-2 can then be converted to Gen-A-3 by the addition of a functionalized alcohol, for example in an SNAr reaction. In some cases, the alcohol can undergo a cross-coupling reaction to afford Gen-A-3. In some cases, the ester of Gen-A-2 is saponified during the course of the reaction in affording Gen-A- 3 and in some cases, the ester is subsequently saponified via treatment with a base, for example lithium hydroxide, to afford Gen-A-3. Carboxylic acid Gen-A-3 can then undergo an amide couple reaction with an amine Gen-A-4 using standard amide coupling conditions to afford compounds of the formula Gen-A.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Scheme 2

[0427] In some cases, Gen-A-1 may be functionalized with a boronic acid or ester to afforda cross-coupled product Gen-B-2, which can then undergo a coupling reaction or an SNAr reaction with a suitable alcohol to afford Gen-B-3 as described in Scheme 1. Gen-B-3 can then be subjected to hydrogenation conditions to afford Gen-B-4, which can undergo anamide coupling reaction to afford Gen-B. In some embodiments, RZ is halo, C1-C6 alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl. Scheme 3

[0428] In some cases, an aryl ester of the formula Gen-C-1 may undergo a reaction with anucleophile R2, for example when R2is an amine it can react via an SNAr reaction, to afford Gen-C-2. Gen-C-2 can then be subjected to halogenation conditions. For example, ester Gen- C-2 can undergo a reaction with NCS to afford Gen-A-2 where Xz= halo (e.g., Cl). Gen-A-2 can then be further elaborated as described in Scheme 1.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Scheme 4

[0429] In some cases, Gen-A-1 may undergo a cross-coupling reaction with a vinyl stannaneto afford a compound of the formula Gen-E-2, which can then be converted to Gen-E-3 via exposure to an acid, for example TsOH. The resulting ketone Gen-E-3 can be treated with DAST to afford Gen-E-3, which can then undergo further functionalization analogous to Gen-E-4. Scheme 5

[0430] In some cases, a pyridine ester Gen-F-1 may be first functionalized with an alcohol toafford Gen-F-2, via an SNAr reaction. Gen-F-2 can then be further functionalized via a cross- coupling reaction with a group R2bearing a suitable functional group. For example, R2—FG can be an alkyl halide and can undergo a nickel-catalyzed cross-electrophile coupling reaction to afford Gen-F-3. Gen-F-3 can then be saponified to the corresponding acid through the use of a base, and the resulting acid can be further functionalized in a manner analogous to Gen-A-3.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Scheme 6

[0431] In some cases, compounds of the formula Gen-A-3 or a similar intermediate canundergo amide coupling with an amino alcohol Gen-A-5 to provide alcohol Gen-A-6. Gen-A- 6 can then be oxidized to the corresponding aldehyde Gen-A-7, for example through the use of the Dess-Martin periodinane, to provide aldehyde Gen-A-7. This aldehyde can then engage in an olefination reaction with a suitable alkyl phosphate of the formula Gen-A-8 to provide compounds of the generic formula Gen-A. Biological Assays

[0432] Compounds designed, selected and / or optimized by methods described above, onceproduced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0433] Furthermore, high-throughput screening can be used to speed up analysis using suchassays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0434] Various in vitro or in vivo biological assays are may be suitable for detecting the effectof the compounds of the present disclosure. These in vitro or in vivo biological assays canAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0435] In some embodiments, the biological assay is described in the Examples herein.

[0436] In some embodiments, the Werner helicase construct is produced and purified for use in the biological assay.

[0437] In some embodiments, WRN activity may be measured using an ATPase assay.

[0438] In some embodiments, Full length WRN protein (aa 2-1432) may be used in the ATPase assay.

[0439] In some embodiments, the compound may be incubated with the protein under optimized conditions.

[0440] In some embodiments, control wells may be utilized to included compounds which show no inhibition of WRN and compounds which show maximum inhibition of WRN.

[0441] In some embodiments, the inhibition may be observed with luminescence was (e.g., on a PHERAstar) followed by a data fit to obtain AC50values.

[0442] In some embodiments, the compounds may be incubated with a cancer cell line (e.g., a colon carcinoma line). In some embodiments, the incubation may take place for a period of time at a specified temperature. In some embodiments, luminescence quantification of activity may be performed followed by a fit (e.g., linear least squares fit) to provide AC50values.

[0443] In some embodiments, the biological assay is completed more than one time (e.g., in duplicate) and the reported AC50is an average. Pharmaceutical Compositions

[0444] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier or diluent. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable saltAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) thereof, and a pharmaceutically acceptable diluent or carrier. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carrier, diluent, adjuvant, excipient, or a combination thereof. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound described in Tables 1-3. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Tables 1-3.

[0445] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0446] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in- fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0447] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0448] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated-γ-cyclodextrin, and trimethyl-γ- cyclodextrin, and mixtures thereof.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0449] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenediaminetetraacetic acid and metal salts thereof, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0450] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, erthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0451] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0452] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols – such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0453] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent is typically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base – depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0454] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0455] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0456] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, orange flavoring.

[0457] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with one or more pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, or a combination thereof.

[0458] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous orAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0459] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0460] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a WRN related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0461] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat a WRN related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0462] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (I’), Formula (I), or Formula (II) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine. Methods of Use

[0463] In some aspects, the present disclosure provides a method of modulating WRN activity, comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0464] In some aspects, the present disclosure provides a method of modulating WRN activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0465] In some aspects, the present disclosure provides a method of modulating WRN activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0466] In some aspects, the present disclosure provides a method of modulating WRN activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0467] In some aspects, the present disclosure provides a method of modulating WRN activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0468] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0469] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0470] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0471] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0472] In some aspects, the present disclosure provides a method for inhibiting DNA repair by WRN in a cancer cell comprising contacting the cell with an effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0473] In some embodiments, the cancer is a microsatellite instability-high (MSI-H) and / or mismatch repair deficient (dMMR) cancer.

[0474] In some embodiments, the cancer is a microsatellite instability-high (MSI-H) cancer. In some embodiments, the cancer is a mismatch repair deficient (dMMR) cancer.

[0475] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MMR gene expression, in which MMR genes include: MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, PMS1, and EPCAM, the absence of MMR genes, or reduced function of MMR proteins, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0476] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MMR gene expression, in which MMR genes include: MLH1, PMS2, MSH2, MSH3,Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) MSH6, MLH3, PMS1, and EPCAM, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0477] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by the absence of MMR genes, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0478] In some aspects, the present disclosure provides a method for treating and / or preventing a cancer in a patient, wherein the cancer is characterized by a reduced function of MMR proteins, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0479] In some embodiments, the disease or disorder is associated with an implicated WRN activity. In some embodiments, the disease or disorder is a disease or disorder in which WRN activity is implicated.

[0480] In some embodiments, the disease or disorder is associated with an implicated WRN activity. In some embodiments, the disease or disorder is a disease or disorder in which WRN activity is implicated.

[0481] In some embodiments, the disease or disorder is cancer.

[0482] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0483] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0484] In some aspects, the present disclosure provides a method of treating or preventing cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0485] In some aspects, the present disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of the present disclosureAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0486] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in modulating WRN activity.

[0487] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating WRN activity (e.g., in vitro or in vivo).

[0488] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in modulating WRN activity (e.g., in vitro or in vivo).

[0489] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for inhibiting DNA repair by WRN in a cell. In some embodiments, the cell is an MSI-H and / or MMR-deficient cell.

[0490] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease in a patient, wherein the disease is characterized by overexpression of WRN.

[0491] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a cancer in a patient, wherein the cancer is characterized by a reduction or absence of MMR gene expression, the absence of MMR genes, or reduced function of MMR proteins, in which MMR genes include: MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, PMS1, and EPCAM.

[0492] In some embodiments, the MMR gene is MLH1.

[0493] In some embodiments, the MMR gene is PMS2.

[0494] In some embodiments, the MMR gene is MSH2.

[0495] In some embodiments, the MMR gene is MSH3.

[0496] In some embodiments, the MMR gene is MSH6.

[0497] In some embodiments, the MMR gene is MLH3.

[0498] In some embodiments, the MMR gene is PMS1.

[0499] In some embodiments, the MMR gene is EPCAM.

[0500] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of an MSI-H and / or MMR-deficient cancer in a patient.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0501] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in treating or preventing a disease or disorder.

[0502] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0503] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0504] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing cancer in a subject in need thereof.

[0505] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof.

[0506] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for modulating WRN activity (e.g., in vitro or in vivo).

[0507] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0508] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0509] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0510] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0511] The present disclosure provides compounds that function as modulators of WRN activity.

[0512] In some embodiments, modulation is inhibition.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0513] Effectiveness of compounds of the disclosure can be determined by industry-accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0514] The present disclosure also provides a method of treating a disease or disorder in which WRN activity is implicated in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0515] In some embodiments, an MSI-H and / or MMR-deficient cancer is colorectal cancer. Colorectal cancer includes, but is not limited to, adenocarcinoma, mucinous adenocarcinoma, and signet-ring cell carcinoma. In some embodiments, an MSI-H and / or MMR-deficient cancer is gastric cancer. Gastric cancer includes, but is not limited to, adenocarcinoma, diffuse adenocarcinoma, intestinal adenocarcinoma, mixed adenosquamous carcinoma, signet ring adenocarcinoma, small cell adenocarcinoma, tubular adenocarcinoma, undifferentiated adenocarcinoma.

[0516] In some embodiments, the cancer is MSI and / or MMR-deficient cancer.

[0517] In some embodiments, an MSI and / or MMR-deficient cancer is colorectal cancer. In some embodiments, an MSI-H and / or MMR-deficient cancer is colorectal cancer. Colorectal cancer includes, but is not limited to, adenocarcinoma, mucinous adenocarcinoma, and signet- ring cell carcinoma. In some embodiments, an MSI and / or MMR-deficient cancer is gastric cancer. In some embodiments, an MSI-H and / or MMR-deficient cancer is gastric cancer. Gastric cancer includes, but is not limited to, adenocarcinoma, diffuse adenocarcinoma, intestinal adenocarcinoma, mixed adenosquamous carcinoma, signet ring adenocarcinoma, small cell adenocarcinoma, tubular adenocarcinoma, undifferentiated adenocarcinoma.

[0518] In some embodiments, the cancer is selected from colorectal, gastric, endometrial, neuroendocrine, breast, ovarian, cervical, uterine, liver, prostate, cholangiocarcinoma, thyroid, pancreatic, uveal melanoma, esophageal, glioblastoma, and lung cancer.

[0519] In some embodiments, the cancer is selected from colorectal, gastric, endometrial, neuroendocrine, breast, ovarian, cervical, uterine, liver, prostate, cholangiocarcinoma, thyroid, pancreatic, uveal melanoma, esophageal, glioblastoma, and lung cancer.

[0520] In some embodiments, the cancer is colorectal cancer.

[0521] In some embodiments, the cancer is gastric cancer.

[0522] In some embodiments, the cancer has a deficiency in a DNA damage repair process.

[0523] In some embodiments, the cancer is sensitive to WRN inhibition.

[0524] In some embodiments, the cancer has evidence of elevated WRN activity.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0525] In some embodiments, the cancer has elevated expression of WRN mRNA or protein.

[0526] In some embodiments, the cancer has elevated expression of WRN mRNA.

[0527] In some embodiments, the cancer has elevated expression of WRN protein.

[0528] In some embodiments, the cancer is classified by a genotype.

[0529] In some embodiments, the genotype has a modulated function.

[0530] In some embodiments, the modulated function is an inactivating mutation, deletion, or other genomic alteration.

[0531] In some embodiments, the genotype is loss of mRNA or protein expression.

[0532] In some embodiments, the cancer has modulated function of at least one gene.

[0533] In some embodiments, the gene is selected from MLH1, PMS2, MSH2, MSH4, MSH6, MLH3, PMS1, and EPCAM.

[0534] In some embodiments, the cancer is MSI and / or MMR-deficient cancer.

[0535] In some embodiments, the cancer is MSI-H and / or MMR-deficient cancer.

[0536] In some embodiments, the cancer is classified as an MSI and / or MMR-deficient cancer because the tumor is unable to accurately repair mismatches or small insertions or deletions in DNA via mismatch repair.

[0537] In some embodiments, the cancer is classified as an MSI-H and / or MMR-deficient cancer because the tumor is unable to accurately repair mismatches or small insertions or deletions in DNA via mismatch repair.

[0538] In some embodiments, the mutation is in a gene that, when lost, causes MMR- deficiency.

[0539] In some embodiments, the cancer is characterized by a reduction or absence of MMR gene expression, the absence of MMR genes, or reduced function of MMR proteins, in which MMR genes include: MLH1, PMS2, MSH2, MSH3, MSH6, MLH3, PMS1, and EPCAM.

[0540] In some embodiments, the MMR gene is MLH1.

[0541] In some embodiments, the MMR gene is PMS2.

[0542] In some embodiments, the MMR gene is MSH2.

[0543] In some embodiments, the MMR gene is MSH3.

[0544] In some embodiments, the MMR gene is MSH6.

[0545] In some embodiments, the MMR gene is MLH3.

[0546] In some embodiments, the MMR gene is PMS1.

[0547] In some embodiments, the MMR gene is EPCAM.

[0548] In some embodiments, the cancer has a compromised mismatch repair pathway.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0549] In some embodiments, the cancer with a compromised MMR is dependent on WRN activity.

[0550] In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a solid tumor.

[0551] In some embodiments, the cancer is an advanced solid tumor.

[0552] In some embodiments, the cancer is metastatic.

[0553] In some embodiments, the cancer is a tumor with microsatellite instability (e.g., colorectal, gastric, endometrial cancers). In some embodiments, the cancer is a TA-repeat expanded tumor.

[0554] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and chemotherapy and immunotherapy for the treatment of tumors with microsatellite instability (e.g., colorectal, gastric, endometrial cancers).

[0555] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and chemotherapy for the treatment of tumors with microsatellite instability (e.g., colorectal, gastric, endometrial cancers).

[0556] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and immunotherapy for the treatment of tumors with microsatellite instability (e.g., colorectal, gastric, endometrial cancers).

[0557] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and chemotherapy or immunotherapy for the treatment of tumors with microsatellite instability (e.g., colorectal, gastric, endometrial cancers).

[0558] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and chemotherapy and immunotherapy for the treatment of TA-repeat expanded tumors.

[0559] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and chemotherapy for the treatment of TA-repeat expanded tumors.

[0560] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and immunotherapy for the treatment of TA-repeat expanded tumors.

[0561] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and chemotherapy or immunotherapy for the treatment of TA-repeat expanded tumors.

[0562] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and chemotherapy for the treatment of TA-repeat expanded tumors.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0563] In some aspects, the present disclosure provides a combination of a compound of the present disclosure and immunotherapy for the treatment of TA-repeat expanded tumors.

[0564] In some embodiments, the compound of the present disclosure and chemotherapy or immunotherapy are administered in temporal proximity, sequentially, or in alternation.

[0565] In some embodiments, the compound of the present disclosure and chemotherapy or immunotherapy are administered in temporal proximity.

[0566] In some embodiments, the compound of the present disclosure and chemotherapy or immunotherapy are administered sequentially.

[0567] In some embodiments, the compound of the present disclosure and chemotherapy or immunotherapy are administered in alternation.

[0568] In some embodiments, the compound of the present disclosure and chemotherapy or immunotherapy are administered as different formulations.

[0569] In some aspects, the present disclosure provides a combination therapy comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second therapeutic agent.

[0570] In some aspects, the present disclosure provides a combination therapy comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second chemotherapeutic agent, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0571] In some aspects, the present disclosure provides a combination therapy comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) an immunotherapy, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0572] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, and a second therapeutic agent, for use in combination for treating or preventing cancer in a subject.

[0573] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, and a second chemotherapeutic agent, or a pharmaceuticallyAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0574] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, and an immunotherapy, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, for use in combination for treating or preventing cancer in a subject.

[0575] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second therapeutic agent.

[0576] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second chemotherapeutic agent, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0577] In some aspects, the present disclosure provides a method of treating or preventing cancer, comprising administering to a subject: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) an immunotherapy, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0578] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, and a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0579] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, and a second chemotherapuetic agent, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0580] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, and an immunotherapy, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0581] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, in combination with a second therapeutic agent, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0582] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, in combination with a second chemotherapuetic agent, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0583] In some aspects, the present disclosure provides use of a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, in combination with an immunotherapy, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, in the manufacture of a medicament for a combinatorial therapy for the treatment or prevention of cancer in a subject.

[0584] In some aspects, the present disclosure provides a kit comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second therapeutic agent.

[0585] In some aspects, the present disclosure provides a kit comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second chemotherapuetic agent, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0586] In some aspects, the present disclosure provides a kit comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; andAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) (b) an immunotherapy, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0587] In some aspects, the present disclosure provides a pharmaceutical package comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second therapeutic agent.

[0588] In some aspects, the present disclosure provides a pharmaceutical package comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) a second chemotherapeutic agent, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0589] In some aspects, the present disclosure provides a pharmaceutical package comprising: (a) a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof; and (b) an immunotherapy, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0590] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, is a compound of Formula (I’), or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof.

[0591] In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof, is a compound of Formula (I), or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, tautomer, or isotopic derivative thereof.

[0592] In some embodiments, the second therapeutic agent is a chemotherapeutic agent.

[0593] In some embodiments, the second therapeutic agent is an immunotherapy.

[0594] In some embodiments, the second therapeutic agent is SN38, 5-fluorouracil, doxorubicin, carboplatin, paclitaxel, or irinotecan.

[0595] In some embodiments, the second therapeutic agent is irinotecan.

[0596] In some embodiments, the second therapeutic agent is topotecan.

[0597] In some embodiments, the subject is a human. Routes of AdministrationAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0598] Compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be administered alone as a sole therapy or can be administered in addition with one or more other substances and / or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.

[0599] For example, therapeutic effectiveness may be enhanced by administration of an adjuvant (i.e. by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering the compound of Formula (I’), Formula (I), or Formula (II) with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0600] In the instances where the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the disclosure need not be administered via the same route as other therapeutic agents, and may, because of different physical and chemical characteristics, be administered by a different route. For example, the compound of the disclosure may be administered orally to generate and maintain good blood levels thereof, while the other therapeutic agent may be administered intravenously. The initial administration may be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0601] The particular choice of other therapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the individual and the appropriate treatment protocol. According to this aspect of the disclosure there is provided a combination for use in the treatment of a disease in which WRN activity is implicated comprising a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0602] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carrier, diluent, adjuvant, or excipient, or a combination thereof.

[0603] In addition to its use in therapeutic medicine, compounds of Formula (I’), Formula (I), or Formula (II) and pharmaceutically acceptable salts thereof are also useful as pharmacological tools in the development and standardization of in vitro and in vivo testAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) systems for the evaluation of the effects of modulators of WRN activity in laboratory animals such as dogs, rabbits, monkeys, mini-pigs, rats and mice, as part of the search for new therapeutic agents.

[0604] In any of the above-mentioned pharmaceutical composition, process, method, use,medicament, and manufacturing features of the instant disclosure, any of the alternate embodiments of macromolecules of the present disclosure described herein also apply.

[0605] The compounds of the disclosure or pharmaceutical compositions comprising thesecompounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0606] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal;sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray or powder); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. Exemplary Embodiments

[0607] Exemplary Embodiment 1. A compound of Formula (I):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is -O-, -NH-, or -S-; A1is N or CRA1; A2is N or CRA2;Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl); RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; and R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0608] Exemplary Embodiment 2. A compound of Formula (I) :or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is N or CRA1; A2 is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl);Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; and R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0609] Exemplary Embodiment 3. The compound of Exemplary Embodiment 1 or Exemplary Embodiment 2, wherein A1is CRA1; A2is N or CRA2; RA1is H, C1-C6alkyl, -NH2, or -S(C1-C6alkyl); RA2is H or halo; R1is H, halo, or C1-C6haloalkyl; R2is C1-C6haloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, or - N(R2a)2; each R2aindependently is C1-C6alkyl or C1-C6alkoxy; R3is C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl,alkyl)2or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is C3-C10cycloalkyl optionally substituted with one or more halo; and R5is C1-C6alkyl or C3-C10cycloalkyl.

[0610] Exemplary Embodiment 4. The compound of any one of the preceding Exemplary Embodiments, wherein X is -O- or -S-.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0611] Exemplary Embodiment 5. The compound of any one of the preceding ExemplaryEmbodiments, wherein X is -O-.

[0612] Exemplary Embodiment 6. The compound of any one of the preceding ExemplaryEmbodiments, wherein A1is CRA1.

[0613] Exemplary Embodiment 7. The compound of any one of the preceding ExemplaryEmbodiments, wherein A2is N.

[0614] Exemplary Embodiment 8. The compound of any one of the preceding ExemplaryEmbodiments, wherein A2is CRA1.

[0615] Exemplary Embodiment 9. The compound of any one of the preceding ExemplaryEmbodiments, wherein RA1is H, C1-C6alkyl, -NH2, or -S(C1-C6alkyl).

[0616] Exemplary Embodiment 10. The compound of any one of the preceding ExemplaryEmbodiments, wherein RA2is H or halo.

[0617] Exemplary Embodiment 11. The compound of any one of the preceding ExemplaryEmbodiments, wherein R1is H, halo, or C1-C6haloalkyl.

[0618] Exemplary Embodiment 12. The compound of any one of the preceding ExemplaryEmbodiments, wherein C1-C6haloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, or -N(R2a)2.

[0619] Exemplary Embodiment 13. The compound of any one of the preceding ExemplaryEmbodiments, wherein each R2aindependently is C1-C6alkyl or C1-C6alkoxy.

[0620] Exemplary Embodiment 14. The compound of any one of the preceding ExemplaryEmbodiments, wherein R3is C6aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or -N(C1-C6alkyl)2.

[0621] Exemplary Embodiment 15. The compound of any one of the preceding ExemplaryEmbodiments, wherein R4is C3-C10cycloalkyl optionally substituted with one or more halo.

[0622] Exemplary Embodiment 16. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I’-a), (I’-a’), or (I’-a”):a”),Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1- C6alkyl), or -N(C1-C6alkyl)2.

[0623] Exemplary Embodiment 17. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-b), (I-b’), or (I-b”):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0624] Exemplary Embodiment 18. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of (I-ab’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1- C6 alkyl), or -N(C1-C6 alkyl)2.

[0625] Exemplary Embodiment 19. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0626] Exemplary Embodiment 20. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-ac’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1- C6alkyl), or -N(C1-C6alkyl)2.

[0627] Exemplary Embodiment 21. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-bc):bc), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0628] Exemplary Embodiment 22. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-abc):abc), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0629] Exemplary Embodiment 23. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-d):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0630] Exemplary Embodiment 24. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-ad’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1- C6alkyl), or -N(C1-C6alkyl)2.

[0631] Exemplary Embodiment 25. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-bd):bd), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0632] Exemplary Embodiment 26. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-abd):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)abd), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0633] Exemplary Embodiment 27. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-ae):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo.

[0634] Exemplary Embodiment 28. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-af):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3a is independently halo.

[0635] Exemplary Embodiment 29. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-ag):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0636] Exemplary Embodiment 30. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-ah):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0637] Exemplary Embodiment 31. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-e):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0638] Exemplary Embodiment 32. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-f):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0639] Exemplary Embodiment 33. The compound of any one of the preceding ExemplaryEmbodiments, wherein the compound is of Formula (I-g):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0640] Exemplary Embodiment 34. A compound of Formula (II):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is halo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2;Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; and R4is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

[0641] Exemplary Embodiment 35. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is selected from a compound described in Table 1, or a pharmaceutically acceptable salt thereof.

[0642] Exemplary Embodiment 36. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is selected from a compound described in Table 2, or a pharmaceutically acceptable salt thereof.

[0643] Exemplary Embodiment 37. The compound of any one of the preceding Exemplary Embodiments, wherein the compound is selected from a compound described in Table 3, or a pharmaceutically acceptable salt thereof.

[0644] Exemplary Embodiment 38. A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in any one of Schemes 1-6.

[0645] Exemplary Embodiment 39. A pharmaceutical composition comprising the compound of any one of the preceding Exemplary Embodiments or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient, diluent, adjuvant, carrier, or a combination thereof.

[0646] Exemplary Embodiment 40. The pharmaceutical composition of Exemplary Embodiment 39, wherein the compound is selected from a compound described in Table 1.

[0647] Exemplary Embodiment 41. The pharmaceutical composition of Exemplary Embodiment 39, wherein the compound is selected from a compound described in Table 2.

[0648] Exemplary Embodiment 42. The pharmaceutical composition of Exemplary Embodiment 39, wherein the compound is selected from a compound described in Table 3.

[0649] Exemplary Embodiment 43. A method of modulating WRN activity, comprising contacting a cell with a compound of any one of Exemplary Embodiments 1-38 or a pharmaceutical composition of any one of Exemplary Embodiments 39-42.

[0650] Exemplary Embodiment 44. The compound of any one of Exemplary Embodiments 1- 38 or a pharmaceutical composition of any one of Exemplary Embodiments 39-42 for use in modulating WRN activity.

[0651] Exemplary Embodiment 45. Use of the compound of any one of Exemplary Embodiments 1-38 in the manufacture of a medicament for modulating WRN activity.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0652] Exemplary Embodiment 46. A method of treating or preventing a disease or disorder in a subject, comprising administering to the subject a compound of any one of Exemplary Embodiments 1-38 or a pharmaceutical composition of any one of Exemplary Embodiments 39-42.

[0653] Exemplary Embodiment 47. The compound of any one of Exemplary Embodiments 1- 38 or a pharmaceutical composition of any one of Exemplary Embodiments 39-42 for use in treating or preventing a disease or disorder.

[0654] Exemplary Embodiment 48. Use of the compound of any one of Exemplary Embodiments 1-38 in the manufacture of a medicament for treating or preventing a disease or disorder.

[0655] Exemplary Embodiment 49. The method, compound, pharmaceutical composition, or use of any one of Exemplary Embodiments 46-48, wherein the disease or disorder is associated with an implicated WRN activity.

[0656] Exemplary Embodiment 50. The method, compound, pharmaceutical composition, or use of any one of Exemplary Embodiments 46-49, wherein the disease or disorder is cancer.

[0657] Exemplary Embodiment 51. The method, compound, pharmaceutical composition, or use of any one of Exemplary Embodiments 46-50, wherein the subject is human. EXAMPLES AbbreviationsAc2O acetic anhydride AcOH Acetic acid AcOH acetic acid AUC area under the concentration-time curve AUC Last AUC from dosing (time 0) to the last measurable concentration AUC Inf AUC from dosing (time 0) extrapolated to infinity Cbz-OSu N-(Benzyloxycarbonyloxy)succinimide CDI carbonyldiimide CL_obs observed plasma clearance CMPI 2-chloro-1-methyl-pyridin-1-ium iodide DAST diethylaminosulfur trifluoride dba dibenzylideneacetone DCMDichloromethaneDIBAL-H Diisobutylaluminium hydride DIEA, DIPEAN,N-DiisopropylethylamineDMF dimethyl formamide dppf 1,1′-Ferrocenediyl-bis(diphenylphosphine) EA, EtOAc ethyl acetate EDC(1-ethyl-3-(3-dimethylaminopropyl)carbodiimideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) EtOAcEthyl acetateETOH ethanol FA formic acid h hour(s) HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHEX Hexanes HOBTHydroxybenzotriazoleIV intravenous LCMS liquid chromatography-coupled mass spectrometry LED Light-emitting diodes LHMDS Lithium bis(trimethylsilyl)amide MeCN acetonitrile MeCN Acetonitrile MeOH methanol Ms2O methylsulfonyl methanesulfonate NaOH sodium hydroxide NMO N-Methylmorpholine N-oxide NMR nuclear magnetic resonance spectrometry PE petroleum ether PEG polyethylene glycol PIDA (Diacetoxyiodo)benzene PK pharmacokinetic PO oral PPh3triphenylphosphine rt room temperature t1 / 2half-life T3P Propylphosphonic anhydride TBAF tetrabutylazanium;fluoride TBAI tetrabutylammonium iodide tbbpy 4,4′-Di-tert-butyl-2,2′-dipyridyl TBP tributyl phosphate t-Bu XPhos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl TEA Triethylamine TEMPO 2,2,6,6-Tetramethylpiperidine 1-Oxyl Free Radical THF Tetrahydrofuran TLC thin-layer chromatography TMAD Tetramethylazodicarboxamide TMSCN trimethylsilyl cyanide Ts-OH p-toluenesulfonic acid Wt Weight General analytical methods:

[0658] As depicted in the Examples below, in some exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, althoughAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0659] The symbols and conventions used in the following descriptions of processes, schemes, and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0660] Unless otherwise indicated, all temperatures are expressed inoC.

[0661] All solvents used were commercially available and were used without further purification.

[0662] Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen. Flash column chromatography was generally carried out using Silica gel 60 (0.035- 0.070 mm particle size). Compounds and intermediates were analyzed by one of the LCMS methods listed below. In cases where the compound contains a bromine, either both or one of the common isotope masses (79Br and81Br) are reported. LCMS Method 1:

[0663] MS instrument type: SHIMADZU LCMS-2020; column: XBridge C182.1 * 30 mm, 3.5 um; mobile phase A: 0.025% NH3•water in water (v / v), B: MeCN; gradient: 0.00 min 5% B→ 0.80 min 95% B→ 0.94 min 95% B→ 0.95 min 5% B→ 1.00 min 5% B; flow rate: 2.0 mL / min; oven temperature: 40 °C; UV detection: PDA (220 nm & 254 nm). LCMS Method 2:

[0664] MS instrument type: SHIMADZU LCMS-2020; column: Kinetex® EVO C18 2.1 * 30 mm 5 um; mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in MeCN (v / v); gradient: 0.00 0.80 min 95% B→ 0.95 min 95% B→ 0.96 min 5% B→ 1.00 min 5% B; flow rate: 2.0 mL / min; oven temperature: 50 °C; UV detection: PDA (220 nm & 254 nm). LCMS Method 3:

[0665] MS instrument type: Shimadzu LCMS-2020; Column: Poroshell HPH-C18, 30*3.0mm, 2.7 μm; Mobile phase A: water / 5mM NH4HCO3, Mobile phase B: MeCN; Flow rate: 1.2ml / min; Gradient:10% B to 95% B in 0.7 min, hold 0.4 min; oven temperature: 40 °C; UV detection: PDA (220 nm & 254 nm). LCMS Method 4:

[0666] MS instrument type: Shimadzu LCMS-2020; Column: Shim-pack XR-ODS, 3.0*50 mm, 2.2 μm; Mobile Phase A:water / 0.05% TFA, Mobile Phase B: MeCN / 0.05% TFA; FlowAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) rate: 1.5 ml / min; Gradient:5%B to 100%B in 1.1min, hold 0.6 min; oven temperature: 40 °C; UV detection: PDA (220 nm & 254 nm). LCMS Method 5:

[0667] MS instrument type: Shimadzu LCMS-2020; Column: L-column, 3.0*30 mm, 2.7 μm;Mobile Phase A: water / 0.07% FA; Mobile Phase B: MeCN / 0.1% FA; Flow rate: 1.5 ml / min; Gradient: 5% B to 100% B in 1.1min, hold 0.6 min; oven temperature: 40 °C; UV detection: PDA (220 nm & 254 nm). Instrument Parameters

[0668] NMR and 13C NMR spectra were recorded on a 400 MHz Varian spectrometer;chemical shifts (δ) are reported relative to residual proton solvent signals. Data for NMR spectra are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, brs = broad singlet, d = doublet, hept = heptet, p = pentet, t = triplet, q = quartet, dd = doublet of doublets, td = triplet of doublets, m = multiplet), coupling constant (Hz), integration. In some embodiments, the compounds of the instant disclosure may exist as one or more rotamers in solution, and as such the analytical NMR data may represent several rotameric mixtures. Most deuterated solvents contained typically 0.03% to 0.05% v / v tetramethylsilane, which was used as the reference signal (set at d 0.00 for both 1H andIn cases where the deuterated solvents did not contain tetramethylsilane, the residual non- deuterated solvent peaks were used as a reference signal, as per published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997). Example 1. Synthesis of the Compounds of the Present Disclosure Example 1a: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(ethyl(methyl)amino)-6- phenoxypyrazine-2-carboxamideStep 1: Synthesis of methyl 5-(ethyl(methyl)amino)pyrazine-2-carboxylate

[0669] To a stirred solution of methyl 5-chloropyrazine-2-carboxylate (500 mg, 1 Eq, 2.90mmol) in MeCN (5 mL) was added K2CO3(2.00 g, 5 Eq, 14.5 mmol) and N-methylethanamineAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) hydrochloride (831 mg, 3 Eq, 8.69 mmol) at 25 °C and stirred at 80 °C for 12 hours. The reaction progress was monitored by LCMS. After completion of reaction, the reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:3) to afford methyl 5-(ethyl(methyl)amino) pyrazine-2-carboxylate (500 mg, 2.56 mmol, 88.4 %) as a white solid.

[0670] LCMS ( ESI, m / z): 196 [M+H]+.1H: (400 MHz, Chloroform-d) δ 8.80 (d, J = 1.4 Hz, 1H), 8.02 (d, J = 1.4 Hz, 1H), 3.95 (s, 3H), 3.67 (q, J = 7.1 Hz, 2H), 3.17 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). Step 2: Synthesis of methyl 6-chloro-5-(ethyl(methyl)amino)pyrazine-2-carboxylate

[0671] To a stirred solution of methyl 5-(ethyl(methyl)amino) pyrazine-2-carboxylate (500 mg, 1 Eq, 2.56 mmol) in DMF (5 mL) was added NCS (410 mg, 1.2 Eq, 3.07 mmol) at 25 °C and stirred for 12 hours. The reaction progress was monitored by LCMS. After completion of reaction, the reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:9) to afford methyl 6-chloro-5-(ethyl(methyl)amino) pyrazine-2-carboxylate (440 mg, 1.92 mmol, 74.8 %) as a yellow oil.

[0672] LCMS ( ESI, m / z): 230 [M+H]+.1H NMR: (400 MHz, Chloroform-d) δ 8.70 (s, 1H), 3.95 (s, 3H), 3.70 (q, J = 7.0 Hz, 2H), 3.22 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). Step 3: Synthesis of methyl 5-(ethyl(methyl)amino)-6-phenoxypyrazine-2-carboxylate

[0673] To a stirred solution of methyl 6-chloro-5-(ethyl(methyl)amino) pyrazine-2- carboxylate (200 mg, 1 Eq, 871 μmol) in NMP (1 mL) was added phenol (164 mg, 2 Eq, 1.74 mmol) and Cs2CO3(284 mg, 1 Eq, 871 μmol) at 25°C and stirred at 120 °C for 2 hours. The reaction progress was monitored by LCMS. After completion of reaction, the reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was extracted with EA (2 x 50 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:4) to afford 5-(ethyl(methyl)amino)-6-phenoxypyrazine-2-carboxylic acid (130 mg, 476 μmol, 54.6 %) as a white solid.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0674] LCMS ( ESI, m / z): 288 [M+H]+.1H NMR: (400 MHz, Chloroform-d) δ 8.56 (s, 1H), 7.45 – 7.33 (m, 2H), 7.23 – 7.11 (m, 3H), 3.83 – 3.76 (m, 5H), 3.29 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H). Step 4: Synthesis of 5-(ethyl(methyl)amino)-6-phenoxypyrazine-2-carboxylic acid

[0675] To a stirred solution of methyl 5-(ethyl(methyl)amino)-6-phenoxypyrazine-2- carboxylate (60 mg, 1 Eq, 0.21 mmol) in THF (1 mL) and water (0.25 mL) was added LiOH (10 mg, 2 Eq, 0.42 mmol) at 25 °C and stirred at 40 °C for 3 hours. The reaction progress was monitored by LCMS. After completion of reaction, the reaction was quenched by the addition of water (20 mL) and acidified to pH 4 with 1M H2SO4at 0 °C. The resulting mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-(ethyl(methyl)amino)-6-phenoxypyrazine-2-carboxylic acid (70 mg, crude) as white solid. The crude product was used in the next step directly without further purification.

[0676] LCMS ( ESI, m / z): 274 [M+H]+. Step 5: Synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(ethyl(methyl)amino)-6- phenoxypyrazine-2-carboxamide

[0677] To a stirred solution of 5-(ethyl(methyl)amino)-6-phenoxypyrazine-2-carboxylic acid (55.0 mg, 1 Eq, 201 μmol) in THF (1 mL) was added (S,E)-1-cyclopropyl-3- (methylsulfonyl)prop-2-en-1-amine (70.5 mg, 2 Eq, 403 μmol), DIEA (78.0 mg, 105 μL, 3 Eq, 604 μmol) and HATU (115 mg, 1.5 Eq, 302 μmol) at 25 °C and stirred for 2 hours. The reaction progress was monitored by LCMS. After completion of reaction, the reaction was quenched by the addition of water (20 mL) at room temperature. The resulting mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B in 1 min, 5% B to 38% B in 2 min, 38% to 55% B in 11 min; Wave Length: 254nm / 220nm nm; RT1 (min: 9.32) to afford (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5- (ethyl(methyl)amino)-6-phenoxypyrazine-2-carboxamide (29.6 mg, 68.6 μmol, 34.1 %) as a white semi-solid.

[0678] LCMS (ESI, m / z): 431 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.50 – 7.42 (m, 3H), 7.28 – 7.20 (m, 3H), 6.75 (dd, J = 15.3, 5.1 Hz, 1H), 6.62 (dd, J = 15.3, 1.5 Hz,Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) 1H), 4.12 – 3.94 (m, 1H), 3.73 (t, J = 7.0 Hz, 2H), 3.21 (s, 3H), 2.99 (s, 3H), 1.24 – 1.15 (m, 3H), 1.04 – 0.93 (m, 1H), 0.54 – 0.44 (m, 1H), 0.44 – 0.35 (m, 1H), 0.35 – 0.26 (m, 1H), 0.21 – 0.13 (m, 1H). Example 2a: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5- (methoxy(methyl)amino)-6-phenoxypyrazine-2-carboxamideStep 1: Synthesis of methyl 6-chloro-5-(methoxy(methyl)amino)pyrazine-2-carboxylate

[0679] To a stirred solution of methyl 6-chloro-5-fluoropyrazine-2-carboxylate (200 mg, 1Eq, 1.05 mmol) in ACN (4 mL) was added N,O-dimethylhydroxylamine (64.1 mg, 1 Eq, 1.05 mmol) and K2CO3(435 mg, 3 Eq, 3.15 mmol) at 25 °C and stirred for 1 hour. The reaction progress was monitored by LCMS. After completion of reaction, the reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EA (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:2) to afford methyl 6-chloro-5-(methoxy(methyl)amino)pyrazine-2-carboxylate (175 mg, 755 μmol, 72.0 %) as a white solid.

[0680] LCMS m / z 232 [M+H]+.Step 2: Synthesis of 5-(methoxy(methyl)amino)-6-phenoxypyrazine-2-carboxylic acid

[0681] To a stirred solution of methyl 6-chloro-5-(methoxy(methyl)amino)pyrazine-2-carboxylate (162 mg, 1 Eq, 699 μmol) in NMP (3 mL) was added Cs2CO3(684 mg, 3 Eq, 2.10 mmol) and phenol (79.0 mg, 1.2 Eq, 839 μmol) at 25°C. This reaction mixture was stirred for 2 hours at 100 °C. The reaction progress was monitored by LCMS. After completion of reaction, the reaction was quenched by the addition of water (3 mL) and then 5 mL 0.5 M H2SO4was added to adjusted PH to 3-4 at 0oC. Then, the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the conditions (column, C18 silica gel; mobile phase, MeCN in water (FA 0.1%) , 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 5-(methoxy(methyl)amino)-6- phenoxypyrazine-2-carboxylic acid (100 mg, 363 μmol, 51.9 %) as a white solid.

[0682] LCMS m / z 276 [M+H]+.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Step 3: Synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5- (methoxy(methyl)amino)-6-phenoxypyrazine-2-carboxamide

[0683] To a stirred solution of methyl 5-(methoxy(methyl)amino)-6-phenoxypyrazine-2-carboxylate (50 mg, 1 Eq, 0.17 mmol) in DMA (2 mL) was added CMPI (88 mg, 2 Eq, 0.35mmol) (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (61 mg, 2 Eq, 0.35 mmol)and DIEA (89 mg, 4 Eq, 0.69 mmol) at 25 °C and stirred for 2 hours. The reaction progress was monitored by LCMS. After completion, the reaction was quenched by the addition of water (10 mL) at room temperature. The resulting mixture was extracted with EA (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the conditions (Column: XBridge Prep OBD C18 Column 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 34% B in 2 min, 34% to 54% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.23) to afford (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(methoxy(methyl)amino)-6- phenoxypyrazine-2-carboxamide (34.8 mg, 79.3 μmol, 46 %, 98.5) as a white solid.

[0684] 1H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.73-7.36 (m, 2H), 7.30 (d, J = 7.4Hz, 1H), 7.22 – 7.16 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.88 (dd, J = 15.2, 4.6 Hz, 1H), 6.33 (dd, J = 15.2, 1.7 Hz, 1H), 4.23-4.01 (m, 1H), 3.90 (s, 3H), 3.32 (s, 3H), 2.91 (s, 3H), 0.99 - 0.72 (m, 1H), 0.71-0.53 (m, 1H), 0.52-0.42 (m, 1H), 0.41-0.17 (m, 2H).

[0685] LCMS m / z 433 [M+H]+.Example 3a: (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypyrazine-2-carboxamideStep 1: Synthesis of methyl 5,6-dichloropyrazine-2-carboxylate

[0686] To a solution of methyl 5,6-dichloropyrazine-2-carboxylate (600 mg, 1 Eq, 2.90 mmol)in a 5:1 mixture of 1,4-Dioxane: H2O (18 mL) were added Na2CO3(614 mg, 2 Eq, 5.80 mmol),Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Cyclopenten-1-ylboronicacid, pinacolester (450 mg, 0.8 Eq, 2.32 mmol) and Pd(dppf)Cl2(170 mg, 0.08 Eq, 232 μmol). The reaction system was purged with N2replacement three times. The resulting mixture was stirred for 3 hours at 80 °C. The reaction was complete detected by LCMS. The mixture was diluted with water (20 mL) and EA (20 mL), the aqueous layer was extracted with EA (2 x 40 mL). The organic layer was combined and washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by reverse phase chromatography (column: C18 column; Gradient: MeCN in water with 0.1% formic acid) to afford methyl 6-chloro-5-(cyclopent-1-en-1-yl) pyrazine-2- carboxylate (260 mg, 1.09 mmol, 37.6 %) as a brown solid.

[0687] LCMS (ESI, m / z): 239 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 7.18 – 7.16 (m, 1H), 3.92 (s, 3H), 2.95 – 2.81 (m, 2H), 2.70 – 2.62 (m, 2H), 1.99 – 1.91 (m, 2H). Step 2: Synthesis of 5-(cyclopent-1-en-1-yl)-6-phenoxypyrazine-2-carboxylic acid

[0688] To a solution of methyl 6-chloro-5-(cyclopent-1-en-1-yl) pyrazine-2-carboxylate (250 mg, 1 Eq, 1.05 mmol) in 1,4-Dioxane (5 mL) were added Cs2CO3(1.02 g, 3 Eq, 3.14 mmol), Phenol (493 mg, 439 μL, 5 Eq, 5.24 mmol), N, N-Dimethylglycine (21.6 mg, 0.02 mL, 0.2 Eq, 209 μmol) and CuI (39.9 mg, 0.2 Eq, 209 μmol). Reaction system was purged with N2replacement three times. The resulting mixture was stirred for 2 hours at 110 °C. The reaction was complete detected by LCMS. The mixture was acidified to pH=3 with 1 M Sulfuric acid, then diluted with EA (20 mL) and water (15 mL), the aqueous layer was extracted with EA (2 x 20 mL). The organic layers were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by reverse phase chromatography (column: C18 column; Gradient: MeCN in water with 0.1% formic acid) to afford 5-(cyclopent-1-en-1-yl)-6-phenoxypyrazine-2-carboxylic acid (200 mg, 708 μmol, 67.6 %) as a brown solid.

[0689] LCMS (ESI, m / z): 283 [M-H]-.1H NMR (400 MHz, DMSO-d6) δ 13.47 (s, 1H), 8.87 (s, 1H), 7.49 – 7.44 (m, 2H), 7.29 – 7.25 (m, 3H), 7.21 – 7.19 (m, 1H), 2.94 – 2.89 (m, 2H), 2.75 – 2.64 (m, 2H), 1.95 (p, J = 7.6 Hz, 2H). Step 3: Synthesis of 5-cyclopentyl-6-phenoxypyrazine-2-carboxylic acid

[0690] To a solution of 5-(cyclopent-1-en-1-yl)-6-phenoxypyrazine-2-carboxylic acid (160 mg, 1 Eq, 567 μmol) in THF (3.2 mL) were added Pd / C (32 mg, 10% Wt, 0.053 Eq, 30 μmol). The reaction system was purged with H2replacement three times. The resulting mixture was stirred for 2 hours at 25 °C under H2atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with THF (3 x 10 mL). The filtrate was concentrated under reduced pressure to afford crude product 5-cyclopentyl-6-Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) phenoxypyrazine-2-carboxylic acid (180 mg) as a brown oil. The crude product was used in the next step directly without further purification.

[0691] LCMS (ESI, m / z): 285 [M+H]+.Step 4: Synthesis of (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypyrazine-2-carboxamide

[0692] To a solution of (S, E)-1-cyclopropyl-3-(methylsulfonyl) prop-2-en-1-amine (46.23mg, 1.5 Eq, 263.8 μmol) in DMF (2.5 mL) were added 2-chloro-1-methyl-pyridin-1-ium iodide (67.39 mg, 1.5 Eq, 263.8 μmol), DIEA (136.4 mg, 6 Eq, 1.055 mmol) and 5-cyclopentyl-6- phenoxypyrazine-2-carboxylic acid (50.00 mg, 1 Eq, 175.9 μmol). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. The mixture was diluted with water (20 mL) and EA (20 mL), the aqueous layer was extracted with EA (2 x 20 mL). The organic layer was combined and washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 50% B to 63% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.42) to afford (S, E)-5-cyclopentyl- N-(1-cyclopropyl-3-(methylsulfonyl) allyl)-6-phenoxypyrazine-2-carboxamide (12.4 mg, 28.0 μmol, 15.9 %) as a white solid.

[0693] LCMS (ESI, m / z): 442 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.08(d, J = 8.4 Hz, 1H), 7.47 – 7.43 (m, 2H), 7.28 – 7.23 (m, 3H), 6.81 – 6.68 (m, 2H), 4.06 – 4.05 (m, 1H), 3.64 – 3.60 (m, 1H), 2.98 (s, 3H), 2.04 – 2.01 (m, 2H), 1.91 – 1.88 (m, 2H), 1.77 – 1.65 (m, 4H), 1.07 – 1.05 (m, 1H), 0.42 – 0.41 (m, 1H), 0.36 – 0.34 (m, 2H), 0.23 – 0.22 (m, 1H). Example 4a: (S,E)-3-amino-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypyrazine-2-carboxamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Step 1: Synthesis of methyl 3-amino-6-chloro-5-(cyclopent-1-en-1-yl)pyrazine-2-carboxylate

[0694] To a solution of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5 g, 1 Eq, 0.02 mol) in 1,4-Dioxane (40 mL) and H2O (8 mL) and was added [1,1'- Bis(diphenylphosphino)ferrocene] dichloropalladium(II) Complex with Dichloromethane (2 g, 0.1 Eq, 2 mmol)2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3 g, 0.8 Eq, 0.02 mol) K2CO3(6 g, 2 Eq, 0.05 mol). The reaction system was purged with N2replacement three times. The resulting mixture was stirred for 2 hours at 80 °C. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature. The mixture was filtered and rinsed with EA (3 x 100 mL), the aqueous layer was extracted with EA (2 x 100 mL). The organic layer was combined and washed with saturated brine (3 x 100 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash column chromatography, eluted with EA / PE (2:5) to afford methyl 3-amino- 6-chloro-5-(cyclopent-1-en-1-yl)pyrazine-2-carboxylate (4.4 g, 17 mmol, 80 %) as a yellow solid.

[0695] LCMS (ESI, m / z):254 [M+1]+. Step 2: Synthesis of 3-amino-5-(cyclopent-1-en-1-yl)-6-phenoxypyrazine-2-carboxylic acid

[0696] To a solution of methyl 3-amino-6-chloro-5-(cyclopent-1-en-1-yl) pyrazine-2- carboxylate (1 g, 1 Eq, 4 mmol) in 1,4-Dioxane (10 mL) was added Cuprous iodide (0.2 g, 0.03 mL, 0.2 Eq, 0.8 mmol) N, N-Dimethylglycine (0.08 g, 0.08 mL, 0.2 Eq, 0.8 mmol), Cs2CO3(3 g, 2 Eq, 8 mmol), phenol (0.7 g, 2 Eq, 8 mmol). The reaction system was pursed with N2 replacement three times. The resulting mixture was stirred for 12 hours at 110 °C. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature. The mixture was filtered and rinsed with EA (3 x 30 mL), the aqueous layer was extracted with EA (2 x 30 mL). The organic layer was combined and washed with saturated brine (3 x 30 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by reverse phase chromatography (column: C18 column; Gradient: MeCN in water with 0.2% formic acid) to afford 3-amino-5-(cyclopent-1-en-1-yl)-6- phenoxypyrazine-2-carboxylic acid (150 mg, 505 μmol, 10 %) as white oil.

[0697] LCMS (ESI, m / z):298 [M+1]+. Step 3: Synthesis of 3-amino-5-cyclopentyl-6-phenoxypyrazine-2-carboxylic acid

[0698] To a solution of 3-amino-5-(cyclopent-1-en-1-yl)-6-phenoxypyrazine-2-carboxylic acid (150 mg, 1 Eq, 505 μmol) in MeOH (10 mL) were added Pd / C (161 mg, 50% Wt, 757 μmol). The mixture was purged with nitrogen for three times and then was pressurized 7 atm with hydrogen at 25 °C for 12 hours. The reaction was monitored by LCMS. The mixture wasAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) filtered and rinsed with MeOH (3 x 10 mL). The solvent was removed under reduced pressure. This resulted in 3-amino-5-cyclopentyl-6-phenoxypyrazine-2-carboxylic acid (120 mg, crude) as a crude white oil. The crude product was used in the next step directly without further purification.

[0699] LCMS (ESI, m / z):300 [M+1]+. Step 4: Synthesis of (S,E)-3-amino-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypyrazine-2-carboxamide

[0700] To a solution of 3-amino-5-cyclopentyl-6-phenoxypyrazine-2-carboxylic acid (80 mg, 1 Eq, 0.27 mmol) in THF (4 mL) and was added HATU (0.15 g, 1.5 Eq, 0.40 mmol), (S, E)-1- cyclopropyl-3-(methylsulfonyl) prop-2-en-1-amine (94 mg, 2 Eq, 0.53 mmol), DIEA (0.35 g, 0.47 mL, 10 Eq, 2.7 mmol). The reaction system was purged with N2 replacement three times. The resulting mixture was stirred for 1 hour at 25 °C. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature, the mixture was filtered and rinsed with EA (3 x 10 mL), the aqueous layer was extracted with EA (2 x 10 mL). The organic layer was combined and washed with saturated brine (3 x 10 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by Column: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 47% B in 2 min, 47% to 67% B in 12 min; Wave Length: 254nm / 220 nm; RT1(min): 10.1 to afford (S,E)-3-amino-5-cyclopentyl-N-(1-cyclopropyl-3- (methylsulfonyl)allyl)-6-phenoxypyrazine-2-carboxamide (14.5 mg, 31.7 μmol, 12 %) as a white solid.

[0701] LCMS: 457 [M+1]+.1H NMR: (400 MHz, Chloroform-d, ppm) δ 7.42 – 7.33 (m, 3H), 7.20 – 7.14 (m, 1H), 7.08 – 7.02 (m, 2H), 6.99 – 6.85 (m, 1H), 6.45 – 6.14 (m, 3H), 4.21 – 3.98 (m, 1H), 3.61 – 3.33 (m, 1H), 2.91 (s, 3H), 2.09 – 1.95 (m, 2H), 1.94 – 1.77 (m, 4H), 1.73 – 1.65 (m, 2H), 0.93 – 0.82 (m, 1H), 0.67 – 0.57 (m, 1H), 0.55 – 0.47 (m, 1H), 0.49 – 0.25 (m, 2H).

[0702] Chiral HPLC: Column: CHIRAL (R, R) Whelk-O1; Column Size: 0.46*50mm, 3μm; Co-Solvent: Hex(0.1%DEA): EtOH=50:50, Flow: 1.67 mL / min; RT=1.524 min

[0703] Chiral HPLC: Column: CHIRAL PAK IK-3; Column Size: 0.46*50mm, 3μm; Co- Solvent: Hex(0.1%DEA): EtOH=50:50 Flow: 1.67 mL / min; RT=0.781 min

[0704] Chiral HPLC: Column: CHIRAL Cellulose-SZ; Column Size: 0.46*50mm, 3μm; Co- Solvent: Hex(0.1%DEA): EtOH=50:50 Flow: 1.67 mL / min; RT=0.798 min Example 5a: (S,E)-3-amino-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) difluoroethyl)-6-phenoxypyrazine-2-carboxamideStep 1: Synthesis of methyl 3-amino-6-chloro-5-(1-ethoxyvinyl)pyrazine-2-carboxylate

[0705] To a stirred solution of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (2 g, 1 Eq,9 mmol) and Bis-(triphenylphosphino)-palladous chloride (0.6 g, 0.1 Eq, 0.9 mmol) and Lithium chloride (1 g, 0.5 mL, 3.5 Eq, 0.03 mol) in DMF (40 mL) was added tributyl(1- ethoxyvinyl)stannane (3 g, 1 Eq, 9 mmol) dropwise at 25 °C. The resulting mixture was stirred at 80 °C for 4 hours under N2atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4 / 1) to afford methyl 3-amino-6-chloro-5-(1-ethoxyvinyl)pyrazine-2-carboxylate (1 g, 4 mmol, 40 %) as a yellow solid.

[0706] LCMS (ES,m / z): 258 [M+H]+.Step 2: Synthesis of methyl 5-acetyl-3-amino-6-chloropyrazine-2-carboxylate

[0707] To a stirred solution of methyl 3-amino-6-chloro-5-(1-ethoxyvinyl)pyrazine-2-carboxylate (1 g, 1 Eq, 4 mmol) in THF (20 mL) was added p-Toluene sulfonic acid monohydrate (1 g, 1 mL, 2 Eq, 8 mmol) dropwise at 25 °C. The resulting mixture was stirred at 25 °C for 1 hour. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford methyl 5-acetyl-3-amino-6- chloropyrazine-2-carboxylate (700 mg, 3.05 mmol, 80 %) as a yellow solid. LCMS (ES,m / z): 230 [M+H]+. Step 3: Synthesis of methyl 3-amino-6-chloro-5-(1,1-difluoroethyl)pyrazine-2-carboxylate

[0708] A solution of methyl 5-acetyl-3-amino-6-chloropyrazine-2-carboxylate (200 mg, 1 Eq,871 μmol) in DAST (2 mL) was stirred at 40 °C for 16 hour. Desired product could be detectedAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) by LCMS. The reaction was quenched with NaHCO3(aq.) at 0 °C. The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford methyl 3-amino-6-chloro-5-(1,1-difluoroethyl)pyrazine-2-carboxylate (140 mg, crude) as a yellow solid.

[0709] LCMS (ES,m / z): 252 [M+H]+. Step 4: Synthesis of 3-amino-5-(1,1-difluoroethyl)-6-phenoxypyrazine-2-carboxylic acid

[0710] A mixture of methyl 3-amino-6-chloro-5-(1,1-difluoroethyl)pyrazine-2-carboxylate (130.00 mg, 1 Eq, 516.65 μmol), Cs2CO3(336.67 mg, 2 Eq, 1.03 mmol), phenol (72.93 mg, 1.5 Eq, 774.98 μmol), CuI (19.679 mg, 0.2 Eq, 103.33 μmol) and dimethylglycine (21.311 mg, 0.02 mL, 0.4 Eq, 206.66 μmol) in 1,4-Dioxane (4 mL) was stirred for 12 hour at 100 °C under N2atmosphere. The resulting mixture was diluted with water (10 mL). The mixture / residue was acidified to pH 4 with HCl (2N). The resulting mixture was extracted with EA (2 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-amino-5-(1,1-difluoroethyl)-6-phenoxypyrazine-2-carboxylic acid (50 mg, 0.17 mmol, 33 %) as a yellow solid.

[0711] LCMS (ES,m / z): 296 [M+H]+. Step 5: Synthesis of (S,E)-3-amino-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1- difluoroethyl)-6-phenoxypyrazine-2-carboxamide

[0712] A mixture of 3-amino-5-(1,1-difluoroethyl)-6-phenoxypyrazine-2-carboxylic acid (40.00 mg, 1 Eq, 135.5 μmol), 2-chloro-1-methyl-pyridin-1-ium iodide (51.92 mg, 1.5 Eq, 203.2 μmol), (S,E)-1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (35.61 mg, 1.5 Eq, 203.2 μmol) and DIEA (52.53 mg, 70.8 μL, 3 Eq, 406.4 μmol) in THF (2 mL) was stirred for 1 hour at 25 °C under air atmosphere. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (2 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: Welch Ultimate LP-C1830*150, 10μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 45% B to 75 % B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.17) to afford (S,E)-3-Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) amino-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6-phenoxypyrazine- 2-carboxamide (28.30 mg, 62.0 μmol, 45.8 %) as a yellow solid.

[0713] LCMS (ES,m / z): 453 [M+H]+. 1F-NMR (400 MHz, DMSO-d6) -89.927. 1H-NMR(400 MHz, DMSO-d6) δ 8.39 (d, J = 8.6 Hz, 1H), 7.62 (s, 2H), 7.43 – 7.28 (m, 2H), 7.16-7.08 (m, 1H), 7.08 – 7.00 (m, 2H), 6.81 (dd, J = 14.2, 5.0 Hz, 1H), 6.73 (dd, J = 14.2, 1.0 Hz, 1H), 4.05-3.92 (m, 1H), 2.99 (s, 3H), 1.99 (t, J = 16.0 Hz, 3H), 1.20-1.02 (m, 1H), 0.58-0.48 (m, 1H), 0.47-0.39 (m, 1H), 0.39-0.30 (m, 1H), 0.29-0.19 (m, 1H). Example 6a: (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypicolinamideStep 1: Synthesis of methyl 5-bromo-6-phenoxypicolinate

[0714] To a solution of methyl 5-bromo-6-fluoropicolinate (1.8 g, 1 Eq, 7.7 mmol) in ACN(18 mL) was added Cs2CO3 (7.5 g, 3 Eq, 23 mmol) and phenol (0.36 g, 0.5 Eq, 3.8 mmol) was stirred for 2 h at 80 °C under N2atmosphere. The reaction was monitored by LCMS. The mixture was diluted with ice water (50 mL) and EA (50 mL), the aqueous layer was extracted with EA (2 x 50 mL). The combined organic layer was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash column chromatography, eluted with EA / PE (1:5) to afford methyl 5-bromo- 6-phenoxypicolinate (800 mg, 2.60 mmol, 34 %) as a yellow solid.

[0715] LCMS (ESI, m / z): 308 [M+1]+.Step 2: Synthesis of methyl 5-cyclopentyl-6-phenoxypicolinate

[0716] To a solution of methyl 5-bromo-6-phenoxypicolinate (800 mg, 1 Eq, 2.60 mmol) inDMA (16 mL) was added N-(phenyl(pyridin-2-yl) methyl) picolinamide (90.1 mg, 0.12 Eq, 312 μmol), Bis(tricyclohexylphosphine)nickel(II)chloride (179 mg, 0.1 Eq, 260 μmol), bromocyclopentane (387 mg, 1 Eq, 2.60 mmol), Zinc (560 mg, 107 μL, 3.3 Eq, 8.57 mmol) and Magnesium chloride (247 mg, 149 μL, 1 Eq, 2.60 mmol) was stirred for 16h at 80 °C under N2atmosphere. The reaction was monitored by LCMS. The mixture was diluted with ice waterAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) (50 mL) and EA (50 mL), the aqueous layer was extracted with EA (2 x 50 mL). The combined organic layer was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash column chromatography, eluted with EA / PE (1:5) to afford methyl 5-cyclopentyl-6-phenoxypicolinate (100 mg, 336 μmol, 13.0 %) as a white solid.

[0717] LCMS (ESI, m / z): 298 [M+H]+. Step 3: Synthesis of 5-cyclopentyl-6-phenoxypicolinic acid

[0718] To a solution of methyl 5-cyclopentyl-6-phenoxypicolinate (80 mg, 1 Eq, 0.27 mmol) in THF (2 mL) and H2O (0.5 mL) were added LiOH (9.7 mg, 1.5 Eq, 0.40 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction was monitored by LCMS. The mixture was diluted with ice water (20 mL) and EA (20 mL), the aqueous layer was extracted with EA (2 x 20 mL). The combined organic layer was washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash column chromatography, eluted with EA / PE (1:1) to afford 5-cyclopentyl-6-phenoxypicolinic acid (45 mg, 0.16 mmol, 59 %) as a white solid.

[0719] LCMS (ESI, m / z): 284 [M+H]+. Step 4: Synthesis of (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypicolinamide

[0720] To a solution of 5-cyclopentyl-6-phenoxypicolinic acid (35 mg, 1 Eq, 0.12 mmol) in THF (1.75 mL) were added DIEA (96 mg, 0.13 mL, 6 Eq, 0.74 mmol), (S, E)-1-cyclopropyl- 3-(methylsulfonyl) prop-2-en-1-amine (22 mg, 1 Eq, 0.12 mmol) and HATU (70 mg, 1.5 Eq, 0.19 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. The mixture was diluted with water (20 mL) and EA (20 mL), the aqueous layer was extracted with EA (2 x 20 mL). The organic layer was combined and washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 54% B in 2 min, 54% to 70% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.73) to afford (S, E)-5-cyclopentyl- N-(1-cyclopropyl-3-(methylsulfonyl) allyl)-6-phenoxypicolinamide (7.9 mg, 18 μmol, 14 %) as a yellow oil. LCMS (ESI, m / z): 441[M+H]+.1H NMR (400 MHz, Chloroform-d) δ 7.81 –7.71 (m, 2H), 7.50 –7.49 (m, 1H), 7.47 – 7.41 (m, 2H), 7.24 – 7.21 (m, 1H), 7.18 – 7.12 (m, 2H), 6.99 –6.77 (m, 1H), 6.30 (dd, J = 15.2, 1.7 Hz, 1H), 4.35 – 4.11 (m, 1H), 3.50 – 3.36 (m, 1H), 2.90 (s, 3H),Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) 2.26 – 2.12 (m, 2H), 2.01 – 1.82 (m, 2H), 1.81 – 1.64 (m, 4H), 0.86 – 0.77 (m, 1H), 0.62 – 0.41 (m, 2H), 0.33 – 0.23 (m, 2H).

[0721] Chiral HPLC: Column: CHIRAL Cellulose-IDA-3; Column Size: 0.46*50mm, 3μm;Co-Solvent: Hex(0.1%DEA): EtOH=70:30, Flow: 1.67 mL / min; RT=1.631 min

[0722] Chiral HPLC: Column: CHIRAL Cellulose-SB; Column Size: 0.46*50mm, 3μm; Co-Solvent: Hex(0.1%DEA): EtOH=70:30 Flow: 1.67 mL / min; RT=0.805 min

[0723] Chiral HPLC: Column: CHIRAL Cellulose-SZ; Column Size: 0.46*50mm, 3μm; Co-Solvent: Hex(0.1%DEA): EtOH=50:50 Flow: 1.67 mL / min; RT=0.893 min Example 7a: (S,E)-3-amino-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypicolinamideStep 1: Synthesis of methyl 3-amino-5-bromo-6-chloropicolinate

[0724] To a solution of methyl 3-amino-5-bromopicolinate (5 g, 1 Eq, 0.02 mol) in DMF (50mL) was added NCS (4 g, 1.5 Eq, 0.03 mol). The mixture was warmed to 50 °C and stirred for 2 hours. The reaction was monitored by LCMS. The mixture was diluted with ice water (500 mL) and EA (500 mL), the aqueous layer was extracted with EA (2 x 500 mL). The combined organic layer was washed with saturated brine (2 x 500 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash column chromatography, eluted with EA / PE (1:1) to afford methyl 3-amino-5-bromo-6- chloropicolinate (3.5 g, 13 mmol, 60 %) as a white solid.

[0725] LCMS (ESI, m / z): 265 [M+H]+.Step 2: Synthesis of methyl 3-amino-6-chloro-5-(cyclopent-1-en-1-yl)picolinate

[0726] To a solution of methyl 3-amino-5-bromo-6-chloropicolinate (1.5 g, 1 Eq, 5.6 mmol)in 1,4-Dioxane (15 mL) and Water (3 mL) was added Pd(dppf)Cl2 (0.46 g, 0.1 Eq, 0.56 mmol), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 1.1 Eq, 6.2 mmol) and K2CO3(2.3 g, 3 Eq, 17 mmol). The reaction system was purged with N2replacement three times. The resulting mixture was warmed to 80 °C and stirred for 2 hours. The reaction wasAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) monitored by LCMS. The reaction was monitored by LCMS. The mixture was diluted with ice water (50 mL) and EA (50 mL), the aqueous layer was extracted with EA (2 x 50 mL). The combined organic layer was washed with saturated brine (2 x 50 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash column chromatography, eluted with EA / PE (1:2) to afford methyl 3-amino-6-chloro-5-(cyclopent-1- en-1-yl)picolinate (920 mg, 3.64 mmol, 64 %) as a yellow solid.

[0727] LCMS (ESI, m / z): 253 [M+H]+. Step 3: Synthesis of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-(cyclopent-1-en-1- yl)picolinate

[0728] To a solution of methyl 3-amino-6-chloro-5-(cyclopent-1-en-1-yl)picolinate (800 mg, 1 Eq, 3.17 mmol) in DCM (8 mL) were added Di-tert-butyl dicarbonate (2.76 g, 2.83 mL, 4 Eq, 12.7 mmol) ,4-Dimethylaminopyridine (387 mg, 1 Eq, 3.17 mmol) and TEA (961 mg, 3 Eq, 9.50 mmol). The resulting mixture was stirred for 2 hours at 50 °C. The reaction was complete detected by LCMS. The mixture was diluted with ice water (80 mL) and EA (80 mL), the aqueous layer was extracted with EA (2 x 80 mL). The combined organic layer was washed with saturated brine (2 x 80 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash column chromatography, eluted with EA / PE (1:3) to afford methyl 3-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-(cyclopent-1-en-1- yl)picolinate (850 mg, 1.88 mmol, 59.3 %) as a white solid.

[0729] LCMS (ESI, m / z): 453 [M+H]+. Step 4: Synthesis of 3-amino-5-(cyclopent-1-en-1-yl)-6-phenoxypicolinic acid

[0730] To a solution of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-chloro-5-(cyclopent-1- en-1-yl)picolinate (800 mg, 1 Eq, 1.77 mmol) in 1,4-Dioxane (8 mL) were added Cuprous iodide (67.3 mg, 12.0 μL, 0.2 Eq, 353 μmol), Phenol (332 mg, 296 μL, 2 Eq, 3.53 mmol), N,N- Dimethylglycine (36.4 mg, 0.04 mL, 0.2 Eq, 353 μmol) and Cesium carbonate (1.73 g, 424 μL, 3 Eq, 5.30 mmol). The reaction system was purged with N2replacement three times. The resulting mixture was stirred for 12 hours at 110°C under N2atmosphere. The reaction was complete detected by LCMS. The residue was purified by reverse phase chromatography (column: C18 column; Gradient: MeCN in water with 0.5% formic acid) to afford methyl 3- (bis(tert-butoxycarbonyl)amino)-5-cyclopentyl-6-phenoxypicolinate (180 mg, 351 μmol, 19.9 %) as a yellow solid.

[0731] LCMS (ESI, m / z): 297 [M+H]+. Step 5: Synthesis of 3-amino-5-cyclopentyl-6-phenoxypicolinic acidAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0732] To a solution of 3-amino-5-(cyclopent-1-en-1-yl)-6-phenoxypicolinic acid (170 mg, 1 Eq, 574 μmol) in MeOH (3.4 mL) were added Pd / C (170 mg, 10% Wt, 0.278 Eq, 160 μmol). The mixture was purged with hydrogen for three times and stirred at 25 °C for 2 hours. The reaction mixture was cooled to room temperature. The reaction was monitored by LCMS. The mixture was filtered and rinsed with EA (5 x 20 mL), the filtrate was concentrated under vacuum to give a residue. This resulted in 3-amino-5-cyclopentyl-6-phenoxypicolinic acid (110 mg, crude) as a crude white solid. The crude product was used in the next step directly without further purification.

[0733] LCMS (ESI, m / z): 299 [M+H]+. Step 6: Synthesis of (S,E)-3-amino-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenoxypicolinamide

[0734] To a solution of 3-amino-5-cyclopentyl-6-phenoxypicolinic acid (40 mg, 1 Eq, 0.13 mmol) in THF (0.8 mL) were added DIEA (52 mg, 3 Eq, 0.40 mmol), (S,E)-1-cyclopropyl-3- (methylsulfonyl)prop-2-en-1-amine (35 mg, 1.5 Eq, 0.20 mmol) and HATU (61 mg, 1.2 Eq, 0.16 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. The mixture was diluted with water (20 mL) and EA (20 mL), the aqueous layer was extracted with EA (2 x 20 mL). The organic layer was combined and washed with saturated brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 5% B in 1 min, 5% B to 49% B in 2 min, 49% to 67% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.63 ) to afford (S,E)-3-amino-5- cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenoxypicolinamide (15.5 mg, 33.6 μmol, 25 %) as an off-white solid.

[0735] LCMS (ESI, m / z): 456.25 [M+H]NMR: (400 MHz, Chloroform-d, ppm) δ 7.51 (d, J = 8.3 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.21 – 7.12 (m, 1H), 7.12 – 7.05 (m, 2H), 7.01 (s, 1H), 6.90 (dd, J = 15.1, 4.4 Hz, 1H), 6.32 (dd, J = 15.2, 1.8 Hz, 1H), 4.11 – 4.04 (m, 1H), 3.34 – 3.21 (m, 1H), 2.90 (s, 3H), 2.17 – 2.05 (m, 2H), 1.88 – 1.57 (m, 6H), 0.86 – 0.76 (m, 1H), 0.63 – 0.52 (m, 1H), 0.50 – 0.42 (m, 1H), 0.34 – 0.20 (m, 2H).

[0736] Chiral HPLC: Column: CHIRALCEL OD-3; Column Size: 0.46*5cm,3μm; Mobile Phase: Hex(0.1%DEA):EtOH=70:30; Flow: 1.67 mL / min; Temperature: Ambient; RT=0.703 min.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0737] Chiral HPLC: Column: Opti-Chiral A2-3; Column Size: 0.46*5cm,3μm; MobilePhase: Hex(0.1%DEA):EtOH=70:30; Flow: 1.67 mL / min; Temperature: Ambient; RT=1.27 min.

[0738] Chiral HPLC: Column: CHIRALPAK IH-3; Column Size: 0.46*5cm,3μm; MobilePhase: Hex(0.1%DEA):EtOH=70:30; Flow: 1.67 mL / min; Temperature: Ambient; RT=1.818 min. Example 1b: (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamideStep 1: Synthesis of ethyl 2-(1,1-difluoroethyl)-4-hydroxypyrimidine-5-carboxylate

[0739] To a stirred solution of 2,2-difluoropropanimidamide (6.00 g, 1 Eq, 55.5 mmol) inEtOH (120 mL) were added K2CO3(11.5 g, 1.5 Eq, 83.3 mmol) and diethyl 2- (ethoxymethylene) malonate (18.0 g, 1.5 Eq, 83.3 mmol) dropwise at room temperature. The resulting mixture was stirred for 12 hours at 90 °C under N2atmosphere. Desired product could be detected by LCMS. The solvent was removed under reduced pressure to give a residue. The crude product was purified by silica gel chromatography eluted with MeOH / DCM (5 / 1) to give ethyl 2-(1,1-difluoroethyl)-4-hydroxypyrimidine-5-carboxylate (6.6 g, 28 mmol, 51 %) as a yellow solid.

[0740] LCMS (ESI, m / z): 233 [M+ H] +.Step 2: Synthesis of ethyl 4-chloro-2-(1,1-difluoroethyl)pyrimidine-5-carboxylate

[0741] The solution of ethyl 2-(1,1-difluoroethyl)-4-hydroxypyrimidine-5-carboxylate (11.56g, 1 Eq, 49.79 mmol) in POCl3(231 mL) was stirred at 80 °C for 2 hours. The reaction was monitored by LCMS. The solvent was removed under reduced pressure. The mixture wasAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) quenched with sat. NaHCO3(aq.) and extracted with EA (3 x 700 mL). The organic layer was combined and washed with saturated brine (2 x 700 mL), dried over anhydrous sodium sulfate and concentrated to afford ethyl 4-chloro-2-(1,1-difluoroethyl) pyrimidine-5-carboxylate (6.63 g, 26.5 mmol, 53.1 %) as a crude yellow oil. The crude product was used in the next step directly without further purification.

[0742] LCMS (ESI, m / z):251 [M+1]+. Step 3: Synthesis of ethyl 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylate

[0743] To a solution of ethyl 4-chloro-2-(1,1-difluoroethyl)pyrimidine-5-carboxylate (500 mg, 1 Eq, 1.99 mmol) in MeCN (10 mL) were added K2CO3(827 mg, 3 Eq, 5.98 mmol) and phenol (207 mg, 1.1 Eq, 2.19 mmol). The resulting mixture was stirred for 2 hours at 80 °C. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EA (2 x 50 mL). The organic layer was combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. The crude product was purified by silica gel chromatography eluted with PE: EA=6:1 to give ethyl 2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxylate (600 mg, 1.95 mmol, 97.6 %) as a yellow oil.

[0744] LCMS (ES,m / z): 309 [M+1]+.1H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 7.46 – 7.41 (m, 2H), 7.31 – 7.27 (m, 1H), 7.21 – 7.16 (m, 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.83 (t, J = 18.5 Hz, 3H), 1.43 (t, J = 7.1 Hz, 3H). Step 4: Synthesis of 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid

[0745] To a solution of ethyl 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylate (600 mg, 1 Eq, 1.95 mmol) in THF (10 mL) were added LiOH (140 mg, 3 Eq, 5.84 mmol) in Water (2.5 mL). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. The mixture was acidified to pH 3 with 1M H2SO4at 0℃. The aqueous layer was extracted with EA (2 x 50 mL). The organic layer was combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give a residue. This resulted in 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid (600 mg, crude) as a crude light- yellow solid. The crude product was used in the next step directly without further purification.

[0746] LCMS (ES,m / z): 281[M+1]+. Step 5: Synthesis of (S)-N-(1-cyclopropyl-2-hydroxyethyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0747] To a solution of 2-(1,1-difluoroethyl)-4-phenoxypyrimidine-5-carboxylic acid (600 mg, 1 Eq, 2.14 mmol) in DMF (12 mL) were added CMPI (1.09 g, 2 Eq, 4.28 mmol), (S)-2-Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) amino-2-cyclopropylethan-1-ol, HCl (354 mg, 1.2 Eq, 2.57 mmol) and DIEA (2.77 g, 3.73 mL, 10 Eq, 21.4 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (50 mL). The resulting mixture was extracted with EA (2 x 50 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluted with PE: EA=1:2 to give (S)-N-(1-cyclopropyl-2-hydroxyethyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (600 mg, 1.65 mmol, 77.1 %) as a white solid.

[0748] LCMS (ES,m / z):364 [M+1](400 MHz, Chloroform-d) δ 9.48 (s, 1H), 7.96 (d, J = 7.1 Hz, 1H), 7.54 – 7.44 (m, 2H), 7.40 – 7.31 (m, 1H), 7.28 – 7.21 (m, 2H), 3.95 (dd, J = 11.1, 3.3 Hz, 1H), 3.85 (dd, J = 11.1, 5.6 Hz, 1H), 3.60 – 3.49 (m, 1H), 1.85 (t, J = 18.5 Hz, 3H), 1.10-0.96 (m, 1H), 0.70 – 0.34 (m, 4H). Step 6: Synthesis of (S)-N-(1-cyclopropyl-2-oxoethyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0749] To a solution of (S)-N-(1-cyclopropyl-2-hydroxyethyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide (200 mg, 1 Eq, 550 umol) in DCM (4 mL) was added DMP (280 mg, 1.2 Eq, 660 umol) at 0℃. The mixture was warmed to 25 ℃ and stirred for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA= 1:1 to afford (S)-N-(1-cyclopropyl-2-oxoethyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (190 mg, 526 μmol, 95.5 %) as a white solid.

[0750] LCMS (ES,m / z): 362 [M+1]+.1H NMR (400 MHz, Chloroform-d) δ 9.77 (s, 1H), 9.48 (s, 1H), 8.26 (d, J = 6.6 Hz, 1H), 7.53 – 7.29 (m, 5H), 4.25 (dd, J = 9.1, 6.6 Hz, 1H), 1.86 (t, J = 18.5 Hz, 3H), 1.01 (ddt, J = 12.9, 8.1, 4.0 Hz, 1H), 0.82 – 0.65 (m, 4H) Step 7: Synthesis of (S)-N-(1-cyclopropyl-2-oxoethyl)-2-(1,1-difluoroethyl)-4- phenoxypyrimidine-5-carboxamide

[0751] To a solution of diethyl (fluoro(methylsulfonyl)methyl)phosphonate (0.14 g, 3 Eq, 0.58 mmol) in THF (1.4 mL) was added NaH (31 mg, 60% Wt, 4 Eq, 0.77 mmol) at 0℃ .The mixture was warmed to 25 °C and stirred for 1 hour. (S)-N-(1-cyclopropyl-2-oxoethyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (70 mg, 1 Eq, 0.19 mmol) was added to the mixture at 0 °C and stirred for 0.5 hour at 0 °C. The reaction was monitored by LCMS. TheAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) reaction was quenched with water (20 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: YMC-Actus Triart C18 ExRS 30*150 mm, 5μm; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 44% B to 64% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.98) to afford (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-2-(1,1- difluoroethyl)-4-phenoxypyrimidine-5-carboxamide (12 mg, 26 μmol, 14 %) as a white solid.

[0752] LCMS (ES,m / z): 456 [M+1]+. 1H NMR (400 MHz, Chloroform-d) δ 9.46 (s, 1H), 7.88(d, J = 6.9 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.42 – 7.33 (m, 1H), 7.29 – 7.19 (m, 2H), 6.22 (dd, J = 32.4, 8.5 Hz, 1H),4.42 (td, J = 8.7, 6.7 Hz, 1H), 3.06 (s, 3H), 1.84 (t, J = 18.5 Hz, 3H), 1.28 – 1.11 (m, 1H), 0.75 – 0.60 (m, 2H), 0.56 – 0.42 (m, 2H).19F NMR (376 MHz, Chloroform-d) δ -93.80, -125.21.Example 8a: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6-phenoxypyrazine-2-carboxamideStep 1: Synthesis of methyl 6-chloro-5-(1-ethoxyvinyl)pyrazine-2-carboxylate

[0753] To a solution of methyl 5,6-dichloropyrazine-2-carboxylate (100 mg, 1 Eq, 483 μmol)in DMF (2 mL) were added bis(triphenylphosphine)palladium(II) dichloride (33.9 mg, 0.1 Eq, 48.3 μmol), tributyl(1-ethoxyvinyl) stannane (140 mg, 0.8 Eq, 386 μmol) and lithium chloride (71.7 mg, 27.8 μL, 3.5 Eq, 1.69 mmol). The reaction system was purged with argon (x3). The resulting mixture was stirred for 3 h at 80 °C under an argon atmosphere. The mixture was diluted with ice water (10 mL) and EA (10 mL), the aqueous layer was extracted with EA (2 x 20 mL). The combined organic layers were washed with saturated brine (2 x 20 mL) and dried over anhydrous sodium sulfate, and concentrated to give a residue. The residue was purified by reverse phase chromatography (column: C18 column; Gradient: MeCN in water with 0.1% formic acid) to afford methyl 6-chloro-5-(1-ethoxyvinyl) pyrazine-2-carboxylate (34 mg) as a yellow oil.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0754] 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 4.80 – 4.74 (m, 2H), 3.98 (q, J = 7.0 Hz, 2H), 3.94 (s, 3H), 1.40 – 1.29 (m, 3H). LCMS (ESI, m / z):243 [M+H]+Step 2: Synthesis of methyl 5-acetyl-6-chloropyrazine-2-carboxylate

[0755] To a solution of methyl 6-chloro-5-(1-ethoxyvinyl) pyrazine-2-carboxylate (550 mg, 1 Eq, 2.27 mmol) in THF (11 mL) was added p-toluenesulfonic acid monohydrate (862 mg, 695 μL, 2 Eq, 4.53 mmol). The mixture was stirred at rt for 3 h. After completion the resulting mixture was concentrated to give a residue. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to afford methyl 5-acetyl-6-chloropyrazine-2- carboxylate (450 mg, 2.10 mmol, 92.5 %) as a white solid.

[0756] 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 3.96 (s, 3H), 2.67 (s, 3H). LCMS (ESI, m / z): 215 [M+H]+Step 3: Synthesis of methyl 6-chloro-5-(1,1-difluoroethyl)pyrazine-2-carboxylate

[0757] A solution of methyl 5-acetyl-6-chloropyrazine-2-carboxylate (550 mg, 1 Eq, 2.56 mmol) in DAST (5.5 mL) was stirred at 40 °C for 2 h. The reaction was quenched with NaHCO3(sat., aq.) at 0 °C. The resulting mixture was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (2 x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to afford methyl 6-chloro-5-(1,1- difluoroethyl) pyrazine-2-carboxylate (500 mg) as a yellow oil.

[0758] 1H NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 3.96 (s, 3H), 2.11 (t, J = 19.4 Hz, 3H). LCMS (ESI, m / z): 237 [M+H]+Step 4: Synthesis of 5-(1,1-difluoroethyl)-6-phenoxypyrazine-2-carboxylic acid

[0759] To a solution of methyl 6-chloro-5-(1,1-difluoroethyl) pyrazine-2-carboxylate (500 mg, 1 Eq, 2.11 mmol) in 1,4-dioxane (10 mL) were added Cs2CO3(2.07 g, 3 Eq, 6.34 mmol), phenol (994 mg, 885 μL, 5 Eq, 10.6 mmol), N, N-dimethylglycine (43.6 mg, 0.04 mL, 0.2 Eq, 423 μmol) and CuI (80.5 mg, 0.2 Eq, 423 μmol). The reaction system was purged with nitrogen (x 3). The resulting mixture was stirred for 2 h at 80 °C. The reaction was complete detected by LCMS. The mixture was then acidified to pH=3 with the addition of 1M Sulfuric acid (aqueous), then diluted with EA (20 mL) and water (20 mL). The aqueous layer was extracted with EA (2 x 20 mL) and the combined organic layers were washed with saturated brine (aqueous, 20 mL) and dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by reverse phase chromatography (column: C18 column; Gradient: MeCN in water with 0.1% formic acid) to afford 5-(1,1-difluoroethyl)-6- phenoxypyrazine-2-carboxylic acid (400 mg) as a yellow solid.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0760] 1H NMR (300 MHz, DMSO-d6) δ 13.92 (s, 1H), 8.94 (s, 1H), 7.55 – 7.41 (m, 2H),7.37 – 7.20 (m, 3H), 2.14 (t, J = 19.3 Hz, 3H). LCMS (ESI, m / z): 281 [M+H]+Step 5: Synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6- phenoxypyrazine-2-carboxamide

[0761] To a stirred solution of 5-(1,1-difluoroethyl)-6-phenoxypyrazine-2-carboxylic acid (40mg, 1 Eq, 0.14 mmol) in DMF (0.4 mL) was added (S,E)-1-cyclopropyl-3- (methylsulfonyl)prop-2-en-1-amine (38 mg, 1.5 Eq, 0.21 mmol), DIEA (55 mg, 75 μL, 3 Eq, 0.43 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (81 mg, 1.5 Eq, 0.21 mmol) at rt and stirred for 2 h. After completion of reaction, the reaction was quenched by the addition of water (20 mL) at rt. The resulting mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 40% B to 50% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.1) to afford (S,E)- N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6-phenoxypyrazine-2- carboxamide (16.5 mg, 37.6 μmol, 26 %) as an off-white semi-solid.

[0762] 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.53 – 7.41(m, 2H), 7.38 – 7.21 (m, 3H), 6.87 – 6.67 (m, 2H), 4.16 – 3.99 (m, 1H), 2.99 (s, 3H), 2.14 (t, J = 19.2 Hz, 3H), 1.14 – 1.02 (m, 1H), 0.58 – 0.48 (m, 1H), 0.47 – 0.33 (m, 2H), 0.30 – 0.20 (m, 1H). LCMS ( ESI, m / z): 436 [M-H]- Example 9a: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6- phenoxypicolinamideStep 1: Synthesis of methyl 5-(1-ethoxyvinyl)-6-fluoropicolinateAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0763] To a solution of methyl 5-bromo-6-fluoropicolinate (300 mg, 1 Eq, 1.28 mmol) in DMF (6 mL) were added bis(triphenylphosphine)palladium(II) dichloride(90.0 mg, 0.1 Eq, 128 μmol), tributyl(1-ethoxyvinyl) stannane (556 mg, 1.2 Eq, 1.54 mmol) and lithium chloride (190 mg, 73.7 μL, 3.5 Eq, 4.49 mmol). The mixture was placed under a positive pressure of nitrogen and subjected to three backfilling cycles under high vacuum. The resulting mixture was stirred for 100 °C at 3 h under a nitrogen atmosphere.. After the reaction mixture was cooled to rt, the mixture was filtered and rinsed with EA (3 x 100 mL), then diluted with water (100 mL). The aqueous layer was extracted with EA (2 x 100 mL), and the combined organic layers were washed with saturated brine (3 x 60 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The crude product was purified by silica gel chromatography, eluting with PE: EA=10:1 to afford methyl 5-(1-ethoxyvinyl)-6- fluoropicolinate (258 mg) as a bright yellow oil.

[0764] LCMS (ES, m / z): 226 [M+1]+Step 2: Synthesis of methyl 5-acetyl-6-fluoropicolinate

[0765] To a stirred solution of methyl 5-(1-ethoxyvinyl)-6-fluoropicolinate (258 mg, 1 Eq, 1.15 mmol) in THF (5.16 mL) was added Ts-OH (436 mg, 2 Eq, 2.29 mmol) at rt and the resulting mixture was stirred for 2 h. After completion of reaction, the reaction was quenched by the addition of water (100 mL) at rt. The resulting mixture was extracted with EA (2 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE (1:5) to afford methyl 5-acetyl-6-fluoropicolinate (187 mg) as a grey solid.

[0766] LCMS (ES, m / z): 198 [M+1]+Step 3: Synthesis of methyl 5-(1,1-difluoroethyl)-6-fluoropicolinate

[0767] A stirred solution of methyl 5-acetyl-6-fluoropicolinate (187 mg, 1 Eq, 948 μmol) in DAST (1.87 mL) was stirred for 2 h at 40 °C. After completion of reaction, the reaction was quenched by the addition of aqueous solution of sodium bicarbonate (200 mL) at rt. The resulting mixture was extracted with EA (2 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with EA / PE (1:5) to afford methyl 5-(1,1-difluoroethyl)-6- fluoropicolinate (172 mg) as a yellow oil.

[0768] LCMS (ES, m / z): 220 [M+1]+Step 4: Synthesis of methyl 5-(1,1-difluoroethyl)-6-phenoxypicolinateAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0769] To a solution of methyl 5-(1,1-difluoroethyl)-6-fluoropicolinate (172 mg, 1 Eq, 785 μmol) in DMF (3.4 mL) was added K2CO3(325 mg, 3 Eq, 2.35 mmol) and phenol (111 mg, 1.5 Eq, 1.18 mmol). The mixture was stirred at 80 °C for 2 h, after which the mixture was cooled to rt and diluted with EA (100 mL) and water (15 mL). The aqueous layer was then extracted with EA (2 x 100 mL). The organic layers were combined and washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford methyl 5-(1,1-difluoroethyl)-6-phenoxypicolinate (250 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification.

[0770] LCMS (ES, m / z): 294 [M+1]+Step 5: Synthesis of 5-(1,1-difluoroethyl)-6-phenoxypicolinic acid

[0771] To a stirred solution of methyl 5-(1,1-difluoroethyl)-6-phenoxypicolinate (250 mg, 1 Eq, 852 μmol) in THF (2.5 mL) and water (1.25 mL) was added LiOH (61.2 mg, 3 Eq, 2.56 mmol) at rt, and the resulting mixture was and stirred for 2 h. The mixture was then acidified to pH=3 with the addition of 1 M Sulfuric acid (aqueous), after which the reaction mixture was diluted with EA (100 mL) and water (50 mL), the aqueous layer was extracted with EA (2 x 100 mL). The organic layers were combined and washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford 5-(1,1- difluoroethyl)-6-phenoxypicolinic acid (200 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification.

[0772] LCMS (ES, m / z): 280 [M+1]+Step 6: Synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6- phenoxypicolinamide

[0773] To a solution of 5-(1,1-difluoroethyl)-6-phenoxypicolinic acid (40 mg, 1 Eq, 0.14 mmol) in THF (0.8 mL) were added DIEA (0.11 g, 0.15 mL, 6 Eq, 0.86 mmol), (S, E)-1- cyclopropyl-3-(methylsulfonyl) prop-2-en-1-amine (30 mg, 1.2 Eq, 0.17 mmol) and HATU (82 mg, 1.5 Eq, 0.21 mmol). The mixture was stirred at rt for 2 h. . The mixture was diluted with water (20 mL) and EA (20 mL), and the aqueous layer was extracted with EA (2 x 20 mL). The combined organic layers were washed with saturated brine (2 x 20 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by Prep-HPLC (Column: Xselect CSH Prep C18, 30*150mm 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 42% B to 60% B in 8 min; Wave Length: 254nm / 220nm nm; RT1(min): 9.93) to afford (S, E)-N-(1-cyclopropyl-3-(methylsulfonyl) allyl)-5-(1,1-difluoroethyl)-6- phenoxypicolinamide (9.3 mg, 21 μmol, 15 %) as a colorless oil.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0774] 1H NMR (400 MHz, Chloroform-d) δ 8.12 (d, J = 7.7 Hz, 1H), 7.87 (d, J = 7.6 Hz,1H), 7.51 – 7.39 (m, 3H), 7.32 – 7.28 (m, 1H), 7.21 – 7.15 (m, 2H), 6.86 (dd, J = 15.2, 4.7 Hz, 1H), 6.31 (dd, J = 15.2, 1.7 Hz, 1H), 4.12 – 4.03 (m, 1H), 2.91 (s, 3H), 2.16 (t, J = 12.6 Hz, 3H), 0.78 – 0.89 (m, 1H),0.72–0.61 (m, 1H), 0.56 – 0.46 (m, 1H), 0.36 – 0.22 (m, 2H). LCMS (ESI, m / z): 437 [M+ H]+

[0775] ChiralHPLC: Column Name: Cellulose SB; Column Size :0.46*5cm.3um; MobilePhase: Hex(0.1%FA): EtOH=70:30; Flow Rate :1.67ml / min; Temperature: Ambient; RT=2.078 min. Example 11a: (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(1,1- difluoroethyl)-6-phenoxypyrazine-2-carboxamide

[0776] To a solution of (S, E)-1-cyclopropyl-3-fluoro-3-(methylsulfonyl) prop-2-en-1-amine(31.0 mg, 1.5 Eq, 161 μmol) in DMF (0.6 mL) were added 5-(1,1-difluoroethyl)-6- phenoxypyrazine-2-carboxylic acid (30.0 mg, 1 Eq, 107 μmol), 2-chloro-1-methyl-pyridin-1- ium iodide (41.0 mg, 1.5 Eq, 161 μmol) and DIEA (69.2 mg, 5 Eq, 535 μmol). The mixture was stirred at 40 °C for 2 h . The mixture was diluted with water (20 mL) and EA (20 mL), and the aqueous layer was extracted with EA (2 x 20 mL). The organic layers were combined and washed with saturated brine (2 x 20 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by Prep-HPLC (Column: Xbridge Phenyl OBD Column, 30*150mm 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 46% B to 60% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.65) to afford (S, E)-N-(1- cyclopropyl-3-fluoro-3-(methylsulfonyl) allyl)-5-(1,1-difluoroethyl)-6-phenoxypyrazine-2- carboxamide (7.3 mg, 16 μmol, 15 %) as a white solid.

[0777] 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.41 (d, J = 8.2 Hz, 1H), 7.49 – 7.45(m, 2H), 7.29 – 7.27 (m, 3H), 6.35 (dd, J = 34.6, 9.0 Hz, 1H), 4.27 (q, J = 8.7 Hz, 1H), 3.23 (s, 3H), 2.12 (t, J = 19.3 Hz, 3H), 1.21 – 1.18 (m, 1H), 0.51 – 0.44 (m, 2H), 0.31 – 0.30 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -90.15, -126.89. LCMS (ESI, m / z):456 [M+H]+Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) Example 12a: (S,E)-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(1,1- difluoroethyl)-6-phenoxypicolinamide

[0778] To a solution of 5-(1,1-difluoroethyl)-6-phenoxypicolinic acid (40 mg, 1 Eq, 0.14mmol) in THF (0.8 mL) were added DIEA (0.11 g, 0.15 mL, 6 Eq, 0.86 mmol), (S, E)-1- cyclopropyl-3-fluoro-3-(methylsulfonyl) prop-2-en-1-amine (33 mg, 1.2 Eq, 0.17 mmol) and HATU (82 mg, 1.5 Eq, 0.21 mmol). The mixture was stirred at rt for 2 h. . The mixture was diluted with water (20 mL) and EA (20 mL) and the aqueous layer was extracted with EA (2 x 20 mL). The organic layers were combined and washed with saturated brine (2 x 20 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by Prep-HPLC (Column: Xbridge Phenyl OBD Column, 30*150mm 5μm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 45% B to 65% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.85) to afford (S, E)-N-(1-cyclopropyl-3-fluoro-3- (methylsulfonyl) allyl)-5-(1,1-difluoroethyl)-6-phenoxypicolinamide (3.9 mg, 8.2 μmol, 5.8 %) as a colorless oil.

[0779] 1H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 7.7 Hz,1H), 7.50 – 7.43 (m, 3H), 7.32 – 7.27 (m, 1H), 7.21 – 7.12 (m, 2H), 6.02 (dd, J = 32.4, 8.5Hz, 1H), 4.26 (q, J = 8.1 Hz, 1H), 3.02 (s, 3H), 2.15 (t, J = 18.6 Hz, 3H), 0.97 – 0.83 (m, 1H), 0.59 – 0.44 (m, 2H), 0.31 – 0.19 (m, 2H). LCMS (ESI, m / z): 455 [M+ H]+

[0780] Chiral HPLC: Column Name: Cellulose SZ; Column Size :0.46*5cm.3um; MobilePhase: Hex(0.1%FA): EtOH=70:30; Flow Rate :1.67ml / min; Temperature: Ambient; RT=1.680 min Example 15a: (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-6- phenoxypyrazine-2-carboxamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)Step 1: Synthesis of ethyl 2-(2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetamido)-3- oxobutanoate

[0781] To a solution of 2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid (3 g, 1 Eq,0.01 mol) in DCM (60 mL) were added HATU (4 g, 0.9 Eq, 0.01 mol) ,ethyl 2-amino-3- oxobutanoate (2 g, 1.2 Eq, 0.01 mol) and DIEA (0.02 kg, 0.03 L, 15 Eq, 0.2 mol). The resulting mixture was stirred for 1 hour at rt. . The reaction was quenched with water (100mL). The aqueous layer was extracted with DCM (2 x 100 mL) and the combined organic layers were washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The crude product was purified by silica gel chromatography, eluting with PE: EA=3:1 to give ethyl 2-(2-((tert-butoxycarbonyl)amino)-2- cyclopentylacetamido)-3-oxobutanoate (2.7 g) as a white solid.

[0782] 1H NMR (400 MHz, Chloroform-d) δ 7.06 (s, 1H), 5.21 (dd, J = 6.3, 2.4 Hz, 1H), 4.99(s, 1H), 4.30 – 4.23 (m, 2H), 4.11 – 4.02 (m, 1H), 2.38 (d, J = 3.4 Hz, 3H), 2.26 (dt, J = 16.2, 8.0 Hz, 1H), 1.83 – 1.51 (m, 8H), 1.45 (d, J = 2.3 Hz, 9H), 1.31 (t, J = 7.1 Hz, 3H). LCMS (ES,m / z): 371[M+1]+Step 2: Synthesis of ethyl 5-cyclopentyl-6-hydroxy-3-methylpyrazine-2-carboxylate

[0783] To a solution of ethyl 2-(2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetamido)-3-oxobutanoate (2.7 g, 1 Eq, 7.3 mmol) in DCE (54 mL) was added TFA (8.3 g, 5.6 mL, 10 Eq, 73 mmol) and the resulting solution was stirred at 60 °C for 2 hour. . The solvent was then removed under reduced pressure, and to the crude mixture in DCE (54 mL) was added AcOH (4.4 g, 4.2 mL, 10 Eq, 73 mmol). The resulting mixture was stirred for 0.5 hour at rt. . The reaction was quenched with water (200 mL) and the aqueous layer was extracted with DCM (2 x 200 mL). The organic layers were combined and washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The crude product was purified by silica gel chromatography, eluting with PE: EA=3:1 to give ethyl 5-cyclopentyl-6-hydroxy-3-methylpyrazine-2-carboxylate (450 mg) as a yellow solid.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)

[0784] 1H NMR (400 MHz, Chloroform-d) δ 9.51 (s, 1H), 4.43 (qd, J = 7.1, 1.0 Hz, 2H), 3.63 (p, J = 7.9 Hz, 1H), 2.66 – 2.61 (m, 3H), 2.05 – 1.65 (m, 8H), 1.41 (td, J = 7.1, 1.0 Hz, 3H). LCMS (ES,m / z): 251[M+1]+Step 3: Synthesis of ethyl 6-chloro-5-cyclopentyl-3-methylpyrazine-2-carboxylate Ethyl 5-cyclopentyl-6-hydroxy-3-methylpyrazine-2-carboxylate (450 mg, 1 Eq, 1.80 mmol) in POCl3(9 mL) was stirred for 6 h at 80 °C. . The reaction mixture was then cooled to rt, and the solvent was removed under reduced pressure. The reaction was quenched with sat. aqueous NaHCO3(50mL) at 0 ℃. The aqueous layer was extracted with DCM (2 x 50 mL). The organic layer was combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The crude product was purified by silica gel chromatography, eluting with PE: EA=10:1 to give ethyl 6-chloro-5-cyclopentyl-3-methylpyrazine-2-carboxylate (400 mg) as a yellow oil.

[0785] 1H NMR (400 MHz, Chloroform-d) δ 4.45 (q, J = 7.1 Hz, 2H), 3.62 (p, J = 7.9 Hz, 1H), 2.78 (s, 3H), 2.12 – 1.67 (m, 7H), 1.43 (t, J = 7.1 Hz, 3H). LCMS (ES,m / z): 269 [M+1]+Step 4: Synthesis of 5-cyclopentyl-3-methyl-6-phenoxypyrazine-2-carboxylic acid

[0786] To a solution of ethyl 6-chloro-5-cyclopentyl-3-methylpyrazine-2-carboxylate (260 mg, 1 Eq, 967 μmol) in toluene (5.2 mL) were added K3PO4(513 mg, 2.5 Eq, 2.42 mmol) , phenol (273 mg, 3 Eq, 2.90 mmol), t-Bu Xphos (82.2 mg, 0.2 Eq, 193 μmol) and Pd2(dba)3.CHCl3(100 mg, 0.1 Eq, 96.7 μmol). The reaction vessel was placed under a positive pressure of nitrogen and subjected to three backfilling cycles under high vacuum. The resulting mixture was stirred for 16 h at 110 °C under a nitrogen atmosphere. The reaction mixture was then cooled to rt and was quenched with water (50 mL). The aqueous layer was extracted with DCM (2 x 20 mL) and the combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, water (0.1%FA) in ACN, 10% to 100% gradient in 20 min; detector, UV 254 nm) to give 5- cyclopentyl-3-methyl-6-phenoxypyrazine-2-carboxylic acid (260 mg, crude) as a yellow oil.

[0787] LCMS (ES,m / z): 299 [M+1]+Step 5: Synthesis of (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-6- phenoxypyrazine-2-carboxamide

[0788] To a solution of 5-cyclopentyl-3-methyl-6-phenoxypyrazine-2-carboxylic acid (70 mg, 1 Eq, 0.23 mmol) in DMF (1.4 mL) were added CMPI (90 mg, 1.5 Eq, 0.35 mmol), (S,E)- 1-cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (62 mg, 1.5 Eq, 0.35 mmol) and DIEAAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) (0.15 g, 0.20 mL, 5 Eq, 1.2 mmol). The resulting mixture was stirred for 2 h at rt.. The reaction was quenched with water (20 mL) and the aqueous layer was extracted with EA (2 x 20 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 58% B to 70% B in 11 min; Wave Length: 254nm / 220nm nm; RT1(min): 8.33) to afford (S,E)-5-cyclopentyl-N-(1- cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-6-phenoxypyrazine-2-carboxamide (24.8 mg, 53.1 μmol, 23 %) as a white solid.

[0789] 1H NMR (400 MHz, Chloroform-d) δ 7.53-7.40 (m, 3H), 7.31 – 7.22 (m, 1H), 7.20 –7.10 (m, 2H), 6.86 (dd, J = 15.1, 4.6 Hz, 1H), 6.30 (dd, J = 15.1, 1.7 Hz, 1H), 4.19-4.03 (m, 1H), 3.80-3.45 (m, 1H), 2.90 (s, 3H), 2.86 (s, 3H), 2.18 – 2.10 (m, 2H), 2.09 – 1.94 (m, 2H), 1.94-1.84 (m, 2H), 1.83 – 1.68 (m, 2H), 0.88-0.70 (m, 1H), 0.65-0.52 (m, 1H), 0.51 – 0.40 (m, 1H), 0.33 – 0.18 (m, 2H). LCMS (ES,m / z): 456 [M+1]+Example 18a: (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-6- phenoxypyrazine-2-carboxamideStep 1: Synthesis of tert-butyl (S)-(1-cyclopropyl-2-oxoethyl)carbamate

[0790] To a solution of tert-butyl (S)-(1-cyclopropyl-2-hydroxyethyl)carbamate (2.6 g, 1 Eq,13 mmol) in DCM (26 mL) was added DMP (11 g, 2 Eq, 26 mmol) and the resulting mixture was stirred at 25°C for 2 h. TLC indicated material was consumed completely and one new spot formed. The mixture was diluted with ice water (50 mL) and DCM (50 mL), and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash columnAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) chromatography, eluting with EA / PE (1:2) to afford tert-butyl (S)-(1-cyclopropyl-2- oxoethyl)carbamate (5 g, crude) as a white solid. Step 2: Synthesis of tert-butyl (S,E)-(1-cyclopropyl-3-fluoro-3- (methylsulfonyl)allyl)carbamate

[0791] To a solution of diethyl (fluoro(methylsulfonyl)methyl)phosphonate (2 g, 2 Eq, 0.01 mol) in THF (20 mL) was added NaH (0.6 g, 60% Wt, 3 Eq, 0.02 mol) and the resulting mixture was stirred 0.5 hour at 0°C. Tert-butyl (S)-(1-cyclopropyl-2-oxoethyl)carbamate (1 g, 1 Eq, 5 mmol) was then added dropwise to the above mixture at 0°C under a nitrogen atmosphere. The mixture was warmed to 25°C and stirred for 2 h. . The mixture was then diluted with ice water (50 mL) and EA (50 mL), and the aqueous layer was extracted with EA (2 x 50 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by flash column chromatography, eluting with EA / PE (1:5) to afford tert- butyl (S,E)-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)carbamate (550 mg) as a yellow oil.

[0792] LCMS (ESI, m / z): 294 [M+H]+Step 3: Synthesis of (S,E)-1-cyclopropyl-3-fluoro-3-(methylsulfonyl)prop-2-en-1-amine

[0793] To a solution of tert-butyl (S,E)-(1-cyclopropyl-3-fluoro-3- (methylsulfonyl)allyl)carbamate (350 mg, 1 Eq, 1.19 mmol) in acetonitrile (3.5 mL) was added p-toluenesulfonic acid (247 mg, 222 μL, 1.2 Eq, 1.43 mmol) and the resulting mixture was stirred at 50 °C for 4 h. . The solvent was then removed under reduced pressure to afford(S,E)- 1-cyclopropyl-3-fluoro-3-(methylsulfonyl)prop-2-en-1-amine (650 mg, crude) as a crude yellow oil. The crude product was used in the next step directly without further purification. Step 4: Synthesis of (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-6- phenoxypyrazine-2-carboxamide

[0794] To a solution of 5-cyclopentyl-6-phenoxypyrazine-2-carboxylic acid (66 mg, 1.5 Eq, 0.23 mmol) in THF (1.3 mL) were added HATU (71 mg, 1.2 Eq, 0.19 mmol), (S,E)-1- cyclopropyl-3-fluoro-3-(methylsulfonyl)prop-2-en-1-amine (30 mg, 1 Eq, 0.16 mmol) and DIEA (60 mg, 3 Eq, 0.47 mmol). The resulting mixture was stirred at rt for 2 h. . The mixture was then diluted with water (20 mL) and EA (20 mL), and the aqueous layer was extracted with EA (2 x 20 mL). The combined organic layers were washed with saturated brine (2 x 20 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The residue was purified by Prep-HPLC (Column: Xbridge Phenyl OBD Column, 30*150mm 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B:Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) ACN; Flow rate: 60 mL / min mL / min; Gradient: 41% B to 61% B in 11 min; Wave Length: 254nm / 220nm nm; RT1 (min): 8.87) to afford (S,E)-5-cyclopentyl-N-(1-cyclopropyl-3-fluoro- 3-(methylsulfonyl)allyl)-6-phenoxypyrazine-2-carboxamide (2.2 mg, 4.8 μmol, 4.5 %) as a white solid.

[0795] 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.90 (d, J = 1.0 Hz, 1H), 7.46 (t, J = 7.7Hz, 2H), 7.34 – 7.28 (m, 2H), 7.16 (dd, J = 8.3, 1.4 Hz, 2H), 6.01 (dd, J = 32.4, 9.0 Hz, 1H), 4.28 (q, J = 8.2 Hz, 1H), 3.76 – 3.66 (m, 1H), 3.02 (s, 3H), 2.19 – 2.10 (m, 2H), 2.03 – 1.92 (m, 2H), 1.91 – 1.83 (m, 2H), 1.81 – 1.71 (m, 2H), 0.99 – 0.88 (m, 1H), 0.59 – 0.45 (m, 2H),0.35 – 0.23 (m, 2H).19F NMR (376 MHz, Chloroform-d, ppm) δ -125.42, -125.56. LCMS (ESI,m / z): 460.10 [M+H]+

[0796] Chiral HPLC: Column: Cellulose-SB; Column Size: 0.46*5cm,3μm; Mobile Phase:Hex(0.1%DEA):EtOH=50:50; Flow: 1.67 mL / min; Temperature: Ambient; RT=3.326 min. Example 19a: (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6-(4- fluorophenoxy)picolinamideStep 1: Synthesis of methyl 5-(1,1-difluoroethyl)-6-(4-fluorophenoxy)picolinate

[0797] To a solution of methyl 5-(1,1-difluoroethyl)-6-fluoropicolinate (100 mg, 1 Eq, 456μmol) in DMF (2 mL) was added K2CO3(189 mg, 3 Eq, 1.37 mmol) and 4-fluorophenol (76.7 mg, 1.5 Eq, 684 μmol). The mixture was stirred at 80 °C for 2 h.. The reaction was then diluted with EA (100 mL) and water (50 mL), and the aqueous layer was extracted with EA (2 x 100 mL). The organic layers were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford methyl 5- (1,1-difluoroethyl)-6-(4-fluorophenoxy)picolinate (140 mg) as a yellow solid. The crude product was used in the next step directly without further purification.

[0798] LCMS (ES, m / z): 312 [M+H]+Step 2: Synthesis of 5-(1,1-difluoroethyl)-6-(4-fluorophenoxy)picolinic acid

[0799] To a solution of methyl 5-(1,1-difluoroethyl)-6-(4-fluorophenoxy)picolinate (130 mg,1 Eq, 418 μmol) in water (0.65 mL) and THF (1.95 mL) was added LiOH (30.0 mg, 3 Eq, 1.25 mmol). The mixture was stirred at rt for 2 h. . The mixture was acidified to pH=5 with the addition of 1 M Sulfuric acid (aq.), then diluted with EA (50 mL) and water (45 mL), and the aqueous layer was extracted with EA (2 x 50 mL). The organic layers were combined andAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford 5-(1,1-difluoroethyl)-6-(4-fluorophenoxy)picolinic acid (130 mg) as a yellow solid. The crude product was used in the next step directly without further purification.

[0800] LCMS (ES, m / z): 298 [M+H]+Step 3: Synthesis of (S,E)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6-

[0801] To a stirred solution of 5-(1,1-difluoroethyl)-6-(4-fluorophenoxy)picolinic acid (30 mg, 1 Eq, 0.10 mmol) in THF (0.6 mL) was added HATU (58 mg, 1.5 Eq, 0.15 mmol), (S,E)-1- cyclopropyl-3-(methylsulfonyl)prop-2-en-1-amine (21 mg, 1.2 Eq, 0.12 mmol) and DIEA (78 mg, 0.11 mL, 6 Eq, 0.61 mmol) at rt. The resulting mixture was stirred for 2 h. The reaction was quenched by the addition of water (20 mL) at rt and the resulting mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (Column: YMC- Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 35% B to 48% B in 10 min; Wave Length: 254nm / 220 nm; RT1(min): 8.37min) to afford (S,E)-N-(1-cyclopropyl-3- (methylsulfonyl)allyl)-5-(1,1-difluoroethyl)-6-(4-fluorophenoxy)picolinamide (9.7 mg) as a white solid.

[0802] LCMS (ES, m / z): 455 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 7.7 Hz, 1H), 7.89 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 6.2 Hz, 4H), 6.87 (dd, J = 15.2, 4.7 Hz, 1H), 6.35 (dd, J = 15.2, 1.7 Hz, 1H), 4.18 – 4.05 (m, 1H), 2.15 (t, J = 18.6 Hz, 3H), 1.61 (s, 3H), 0.89 – 0.81 (m, 1H), 0.67 – 0.59 (m, 1H), 0.53 – 0.44 (m, 1H), 0.31 – 0.20 (m, 1H).19F NMR: (376 MHz, Chloroform-d, ppm) δ -88.93, -116.85

[0803] Chiral HPLC: Column Name: CHIRALPAK IA‐3; Column Size: 3.0*50mm.3um; Mobile phase: MeOH (0.1%DEA ):10% to 50% in 2.0 min, hold 1.0 min at 50%; Flow: 2.0 mL / min; Temperature: Ambient; RT= 0.951 min. Example 20a: (S,E)-6-(4-chlorophenoxy)-N-(1-cyclopropyl-3-(methylsulfonyl)allyl)-5- (1,1-difluoroethyl)picolinamideAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO)Step 1: Synthesis of methyl 6-(4-chlorophenoxy)-5-(1,1-difluoroethyl)picolinate

[0804] To a solution of methyl 5-(1,1-difluoroethyl)-6-fluoropicolinate (100 mg, 1 Eq, 456μmol) in DMF (1 mL) were added 4-chlorophenol (88.0 mg, 1.5 Eq, 684 μmol) and K2CO3(189 mg, 3 Eq, 1.37 mmol). The mixture was stirred at 80 °C for 2 h.. The mixture was diluted with ice water (100 mL) and EA (100 mL), and the aqueous layer was extracted with EA (2 x 100 mL). The combined organic layers were washed with saturated brine (2 x 100 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford methyl 6-(4-chlorophenoxy)-5-(1,1-difluoroethyl)picolinate 100 mg as a crude white solid. The crude product was used in the next step directly without further purification.

[0805] LCMS (ESI, m / z): 328 [M+H]+Step 2: Synthesis of 6-(4-chlorophenoxy)-5-(1,1-difluoroethyl)picolinic acid

[0806] To a solution of methyl 6-(4-chlorophenoxy)-5-(1,1-difluoroethyl)picolinate (100 mg,1 Eq, 305 μmol) in THF (0.4 mL) and H2O (0.1 mL) was added LiOH (36.5 mg, 5 Eq, 1.53 mmol). The mixture was stirred at rt for 2 h. . The mixture was then diluted with ice water (50 mL) and EA (50 mL), and the aqueous layer was extracted with EA (2 x 50 mL). The combined organic layers were washed with saturated brine (2 x 50 mL) and dried over anhydrous sodium sulfate, filtered, a...

Claims

Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) CLAIMS:or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is -O-, -NH-, or -S-; A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl); RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; andAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

2. A compound of Formula (I) :or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: A1is N or CRA1; A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -SH, or -S(C1-C6alkyl); RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; R3is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2, or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3- C10 cycloalkyl optionally substituted with one or more halo, or 3- to 10-membered heterocyclyl; andAttorney Docket No.: 43705-02053 (MOMA-008 / 001WO) R5is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

3. The compound of claim 1 or claim 2, wherein A1is CRA1; A2is N or CRA2; RA1is H, C1-C6alkyl, -NH2, or -S(C1-C6alkyl); RA2is H or halo; R1is H, halo, or C1-C6haloalkyl; R2is C1-C6haloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, or - N(R2a)2; each R2aindependently is C1-C6alkyl or C1-C6alkoxy; R3is C6-C10aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, or -N(C1-C6alkyl)2or 5- to 10-membered heteroaryl optionally substituted with one or more halo; R4is C3-C10cycloalkyl optionally substituted with one or more halo; and R5is C1-C6alkyl or C3-C10cycloalkyl.

4. The compound of any one of the preceding claims, wherein X is -O- or -S-.

5. The compound of any one of the preceding claims, wherein X is -O-.

6. The compound of any one of the preceding claims, wherein A1is CRA1.

7. The compound of any one of the preceding claims, wherein A2is N.

8. The compound of any one of the preceding claims, wherein A2is CRA1.

9. The compound of any one of the preceding claims, wherein RA1is H, C1-C6alkyl, -NH2, or -S(C1-C6alkyl).

10. The compound of any one of the preceding claims, wherein RA2is H or halo.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) 11. The compound of any one of the preceding claims, wherein R1is H, halo, or C1-C6haloalkyl.

12. The compound of any one of the preceding claims, wherein C1-C6haloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, or -N(R2a)2.

13. The compound of any one of the preceding claims, wherein each R2aindependently is C1- C6alkyl or C1-C6alkoxy.

14. The compound of any one of the preceding claims, wherein R3is C6aryl optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), or - N(C1-C6alkyl)2.

15. The compound of any one of the preceding claims, wherein R4is C3-C10cycloalkyl optionally substituted with one or more halo.

16. The compound of any one of the preceding claims, wherein the compound is of Formula (I’-a), (I’-a’), or (I’-a”):a”), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3a is independently halo, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1- C6alkyl), or -N(C1-C6alkyl)2.

17. The compound of any one of the preceding claims, wherein the compound is of Formula (I-b), (I-b’), or (I-b”):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

18. The compound of any one of the preceding claims, wherein the compound is of (I-ab’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1- C6alkyl), or -N(C1-C6alkyl)2.

19. The compound of any one of the preceding claims, wherein the compound is of Formula (I-c):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

20. The compound of any one of the preceding claims, wherein the compound is of Formula (I-ac’):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo, C1-C6alkyl, C1-C6haloalkyl, --NH(C1- C6alkyl), or -N(C1-C6alkyl)2.

21. The compound of any one of the preceding claims, wherein the compound is of Formula (I-bc):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

22. The compound of any one of the preceding claims, wherein the compound is of Formula (I-abc):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

23. The compound of any one of the preceding claims, wherein the compound is of Formula (I-d):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

24. The compound of any one of the preceding claims, wherein the compound is of Formula (I-ad’):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo, C1-C6alkyl, C1-C6haloalkyl, --NH(C1- C6alkyl), or -N(C1-C6alkyl)2.

25. The compound of any one of the preceding claims, wherein the compound is of Formula (I-bd):bd), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

26. The compound of any one of the preceding claims, wherein the compound is of Formula (I-abd):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)abd), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

27. The compound of any one of the preceding claims, wherein the compound is of Formula (I-ae):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo.

28. The compound of any one of the preceding claims, wherein the compound is of Formula (I-af):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein each R3ais independently halo.

29. The compound of any one of the preceding claims, wherein the compound is of Formula (I-ag):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)ag), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

30. The compound of any one of the preceding claims, wherein the compound is of Formula (I-ah):ah), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

31. The compound of any one of the preceding claims, wherein the compound is of Formula (I-e):or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

32. The compound of any one of the preceding claims, wherein the compound is of Formula (I-f) or Formula (I-g):Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO)or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

33. A compound of Formula (II):or a pharmaceutically acceptable salt, oxide, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:A2is N or CRA2; RA1is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; RA2is H, halo, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, or C1-C6haloalkyl; R1is halo; R2is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, -(C1-C6alkyl)-C3-C10cycloalkyl, -(C1-C6haloalkyl)-C3-C10cycloalkyl, C3-C10cycloalkyl, 3- to 10-membered heterocyclyl, or -N(R2a)2; each R2aindependently is H, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6haloalkoxy; and R4is C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6haloalkyl, C1-C6alkoxy, C3-C10cycloalkyl, or 3- to 10-membered heterocyclyl.

34. The compound of any one of the preceding claims, wherein the compound is selected from a compound described in Table 1, or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) 35. The compound of any one of the preceding claims, wherein the compound is selected from a compound described in Table 2, or a pharmaceutically acceptable salt thereof.

36. The compound of any one of the preceding claims, wherein the compound is selected from a compound described in Table 3, or a pharmaceutically acceptable salt thereof.

37. A compound obtainable by, or obtained by, a method described herein; optionally, the method comprises one or more steps described in any one of Schemes 1-6.

38. A pharmaceutical composition comprising the compound of any one of the preceding claims or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient, diluent, adjuvant, carrier, or a combination thereof.

39. The pharmaceutical composition of claim 38, wherein the compound is selected from a compound described in Table 1.

40. The pharmaceutical composition of claim 38, wherein the compound is selected from a compound described in Table 2.

41. The pharmaceutical composition of claim 38, wherein the compound is selected from a compound described in Table 3.

42. A method of modulating WRN activity, comprising contacting a cell with a compound of any one of claims 1-37 or a pharmaceutical composition of any one of claims 39-42.

43. The compound of any one of claims 1-37 or a pharmaceutical composition of any one of claims 39-42 for use in modulating WRN activity.

44. Use of the compound of any one of claims 1-37 in the manufacture of a medicament for modulating WRN activity.

45. A method of treating or preventing a disease or disorder in a subject, comprising administering to the subject a compound of any one of claims 1-37 or a pharmaceutical composition of any one of claims 39-42.Attorney Docket No.: 43705-02053 (MOMA-008 / 001WO) 46. The compound of any one of claims 1-37 or a pharmaceutical composition of any one of claims 39-42 for use in treating or preventing a disease or disorder.

47. Use of the compound of any one of claims 1-37 in the manufacture of a medicament for treating or preventing a disease or disorder.

48. The method, compound, pharmaceutical composition, or use of any one of claims 45-47, wherein the disease or disorder is associated with an implicated WRN activity.

49. The method, compound, pharmaceutical composition, or use of any one of claims 45-48, wherein the disease or disorder is cancer.

50. The method, compound, pharmaceutical composition, or use of any one of claims 45-49, wherein the subject is human.

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