Modulators of beta catenin and uses thereof

Abstract

Provided are compounds of the Formula I: (I), or pharmaceutically acceptable salts thereof, which are useful for the modulation of beta catenin condensates and in the treatment of a variety of conditions or diseases associated therewith.

Description

MODULATORS OF BETA CATENIN AND USES THEREOFRELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 710,194, filed on October 22, 2024. The entire contents of the foregoing application are expressly incorporated herein by reference.BACKGROUND

[0002] Biomolecular condensates are ubiquitous spatiotemporal organizers of biology, compartmentalizing and integrating a wide variety of regulatory pathways within cells. See Banani, S. F. et al. Nat Rev Mol Cell Bio 18, 285-298 (2017); and Hyman, A. A. et al. Annu Rev Cell Dev Bi 30, 39-58 (2014). Aberrant condensates, or condensatopathies, act as central nodes of dysfunction in disease, representing a new class of targets for drug discovery. See Alberti, S. et al. Nat Rev Mol Cell Bio 22, 196-213 (2021); Boija, A. et al. Cancer Cell 39, 174-192 (2021); Mitrea, D. M. et al. Nat Rev Drug Discov 1-22 (2022); Martin, E. W. et al. J. Mol. Biol. 168380 (2023); and Patel, A. et al. Frontiers Mol Biosci 9, 1007744 (2022). This new perspective expands the target space and enables new strategies for pursuing targets historically considered ‘undruggable’; these strategies include but are not limited to modifying the condensates these targets associate to, or targeting structural states that are selectively adopted by the ‘undruggable’ target inside the condensate. See Mitrea, D. et al. Nat Rev Drug Discov 1-22 (2022). Due to their integrative role, dysfunction of condensates leads to complex defects in multiple biological processes, explaining the root cause of complex diseases, such as cancer and neurodegeneration. This central role in pathophysiology also opens opportunities to discover broad-acting drugs that are active across large patient populations with a shared condensatopathy but of diverse genetic background.

[0003] Beta catenin is a validated anti -neoplastic target, known to be a driver of overproliferation and aberrant transcriptional programming in a broad spectrum of cancers, including, but not limited to colorectal, breast, skin and pancreatic cancer. See Liu, J. et al. Signal Transduct Target Ther. (2022); and Zhang, Y. et al. J Hematol Oncol 13, 165 (2020). The cancer-driving activity of beta catenin is attributed to its constitutively active transcriptional promoting function, which results from several mutations and other aberrations along the dysregulated Wnt-pathway. Transcriptionally active beta catenin drives the expression of dozens of genes including NOTUM, MYC, AXIN2 and LEFT See Nusse, R. et al. Nature 519, 163 (2015) and Herbst, A. et al. BMC Genomics 15, 74 (2014). Thus,what is needed is novel small molecules that modulate beta catenin’s aberrant transcriptional activation and cell proliferation through its sequestration into nuclear condensates.SUMMARY

[0004] Provided herein are compounds having the Formula I:R2and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, X, z1, z2, and z3are as described herein. In one aspect, the described compounds of Formula I and pharmaceutically acceptable salts thereof modulate beta catenin (e.g., sequester beta catenin in nuclear condensates), and are useful in a variety of therapeutic applications such as, for example, in treating cancer. See for example the cancer cell-line derived xenograft study and related data shown in the exemplification section below.

[0005] Pharmaceutical compositions comprising the described compounds and pharmaceutically acceptable salts of the described compounds, as well as methods for their preparation are also included.BRIEF DESCRIPTION OF THE DRAWINGS

[0006] Figure 1 shows the beta catenin condensate modulation in DLD-1 cells treated with Example 1 orDMSO.

[0007] Figure 2 shows tumor volumes for mice treated with Example 1 and mice provided vehicle.

[0008] Figure 3 shows the gene expression changes in DLD-1 cells treated with Example 1 or DMSO.DETAILED DESCRIPTION1. General Description of Compounds

[0009] In a first embodiment, provided herein are compounds having the Formula I:or a pharmaceutically acceptable salt thereof, wherein:z1is N or -CR3;z2is N or -CR5;z3is N or -CR4;R1is hydrogen, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, or (C i-C4)alkylene[OP(O)(OH)2] ;R2is aryl, heteroaryl, heterocyclyl, or cycloalkyl, each of which are optionally substituted with 1 to 3 groups selected from R1A;R3and R4are each independently hydrogen, halo, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (C2-C4)alkenyl, (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heteroaryl], (Ci-C4)alkylene[cycloalkyl], -S(O)2(Ci-C4)alkyl, or -S(0)(Ci-C4)alkyl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano;R5is hydrogen, halo, or (Ci-C4)alkyl;X is -OR6or -NR7R8;R6is cycloalkyl, heterocyclyl, (Ci-C4)alkylene(Ci-C4alkoxy), (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heteroaryl], (Ci-C4)alkylene[heterocyclyl], or (Ci-C4)alkylene[cycloalkyl], wherein the aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from R2A;R7and R8are taken together to form a heterocyclyl optionally substituted with 1 to 3 groups selected from R2A;each R1Ais independently selected from halo, cyano, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, hydroxy[halo(Ci-C4)alkyl], cyano(Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, (Ci-C4)alkoxyO(Ci-C4)alkyl, (Ci-C4)alkoxyO[deuterated(Ci-C4)alkyl], halo(Ci-C4)alkoxy, (Ci-C4)alkoxyO[halo(Ci-C4)alkyl], oxo, hydroxy, -O[hydroxy(Ci-C4)alkyl], -Ofcycloalkyl], -Ofheterocyclyl], -Ofaryl], -O [heteroaryl], (Ci-C4)alkylene[cycloalkyl], (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[heteroaryl], -O(Ci-C4)alkylene[NRaRb], -O(Ci-C4)alkylene[NRaC(O)Rb], -O(Ci-C4)alkylene[cycloalkyl], -0(Ci-C4)alkylene[aryl], -O(Ci-C4)alkylene[heterocyclyl], -O(Ci-C4)alkylene[heteroaryl], cycloalkyl, heterocyclyl, aryl, heteroaryl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], (Ci-C4)alkoxyO[cycloalkyl], (Ci-C4)alkoxyO[heterocyclyl], (Ci-C4)alkoxyO[heteroaryl], (Ci-C4)alkoxyO[phenyl], -C(O)[heterocyclyl], -SRa, -S(O)Ra, -SO2Ra, -S(0)(NRa)Rb, -NRbS02Rb, -SO2NRa, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)NRb, -NRaRb, -NH(Ci-C4)alkylene[heterocyclyl], and (Ci-C4)alkyleneNRaRb, where each occurrence of cycloalkyl, heterocyclyl, aryl, and heteroaryl alone, or as part of another group, is optionally substituted with 1 to 3 groups selected from halo, oxo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxy, -NH2, -NH(Ci-C4)alkyl, -N((Ci-C4)alkyl)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, and cyano;each R2Ais independently selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, deuterated(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], oxo, -Ofcycloalkyl], cyano, hydroxy, S(0)(Ci-C4)alkyl, -S(O)2(Ci-C4)alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, (Ci-C4)alkylene[cycloalkyl], (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[heteroaryl], -C(0)Ral, -C(0)0Ral, -C(0)NRalRbl, -NRalC(0)Rbl, -NRalC(0)NRbl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano; andeach Ra, Ral, Rb, and Rblis each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkyleneNH2, (Ci-C4)alkyleneNH((Ci-C4alkyl), (Ci-C4)alkyleneN((Ci-C4alkyl)2, cycloalkyl, and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each optionally substituted with (Ci-C4)alkyl, hydroxy, or hydroxy (Ci-C4)alkyl;provided that:(i) if R7and R8, taken together with the N to which they are attached, form pyrrolidinyl, then R2Ais not -C(0)NH2;(ii) if R7and R8, taken together with the N to which they are attached, form piperidinyl, then R2Ais not benzyl; and(iii) if R7and R8, taken together with the N to which they are attached, form 6- to 12- membered heterocyclyl, then R2is substituted by 1 to 3 groups selected from R1A2. Definitions

[0010] 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 pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[0011] As used in the structure herein a hyphen (-) or squiggly line “ “ indicates the point of attachment of the particular depicted structure or substituent group to the appropriate atom(s) in the remainder of the molecule.

[0012] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0013] The term “alkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-C12”), for example 1 to 6 carbons atoms (“Ci-Ce”), or 1 to 4 carbons atoms (“C1-C4”) in the group. Examples of alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3 -pentyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), hexyl (Ce) (e.g., n-hexyl), heptyl (C7) (e.g., n-heptyl), octyl (Cs) (e.g., n-octyl), and the like. In some embodiments, the alkyl group is a Ci-Cealkyl; in other embodiments, it is a Ci-C4alkyl; and in other embodiments, it is a Ci-Csalkyl.

[0014] As used herein, the term “alkenyl” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-C12”) in the group, wherein the group includes at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl (-CEUCH2;C2alkenyl), allyl (-CH2-CEUCH2; Csalkenyl), propenyl (-CH=CHCH3; Csalkenyl), isopropenyl (-C(CH3)=CH2; Csalkenyl), butenyl (-CEUCHCH2CH3; C4alkenyl), sec-butenyl (-C(CH3)=CHCH3; C4alkenyl), iso-butenyl (-CH=C(CH3)2; C4alkenyl), 2-butenyl (-CH2CFUCHCH3; C4alkyl), pentenyl (-CEUCElCEkCEhCEE; Csalkenyl), and the like.

[0015] When a range of carbon atoms is used herein, for example, Ci-Ce, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-C3” includes Cn C3, C1-C2, C2-C3, Ci, C2, and C3.

[0016] The term “cycloalkyl” when used alone or as part of a substituent group refers to cyclic-containing, saturated or partially unsaturated hydrocarbon groups having from 3 to 10carbon atoms (“C3-C10”), for example from 3 to 7 carbon atoms (“C3-C7”). Examples of cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (Ce), cycloheptyl (C7), and the like. In some embodiments, the cycloalkyl group is a C3-4cycloalkyl; in other embodiments, it is a Cs-Cecycloalkyl; and in other embodiments, it is C3-Cscycloalkyl.

[0017] The term “alkylene” refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C2-C12”) in the group which is further substituted by a separate group. Examples of alkylene include (Ci-C4)alkylene[heterocyclyl], which is a Ci-C4alkyl substituted with a heterocyclyl, (Ci-C4)alkylene[aryl], which is a Ci-C4alkyl substituted with an aryl, (Ci-C4)alkylene[cycloalkyl], which is a Ci-C4alkyl substituted with a cycloalkyl, and (Ci-C4)alkylene[heteroaryl], which is a Ci-C4alkyl substituted with a heteroaryl.

[0018] The term “halo” or “halogen,” as used by itself or as part of another group refers to a fluorine, chlorine, bromine, or iodine atom.

[0019] As used herein, the term “haloalkyl” and “haloalkenyl” refer to an alkyl or alkenyl group, respectively, wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms which may be the same or different.

[0020] The term “alkoxy” as used by itself or as part of another group refers to an oxygen radical attached to an alkyl group by a single bond. Examples of alkoxyl groups include methoxy (OCH3), ethoxy (OCH2CH3), propoxy (e.g., -OnPr, -O'Pr), or butoxy (e.g., -OnBu, -O'Bu, -OsBu, -0‘Bu), and the like. In other embodiments, the alkoxy group is a Ci-ealkoxy. In further embodiments, the alkoxy group is a Ci-4alkoxy. In further embodiments, the alkoxy group is a Ci-3alkoxy.

[0021] As used herein, the term “haloalkoxy” refers to an alkoxy group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms which may be the same or different.

[0022] A “deuterated” alkyl or alkoxy group means that one or more hydrogen atoms is replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen has been replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98% or 99%.Deuterium enrichment is a mole percent and is obtained by dividing the number of deuterium atoms at all sites of enrichment with the number of hydrogen plus deuterium atoms at all of the sites of enrichment. For example, a compound with two deuterated methyl groups has a 98.0% enrichment when 98.0% of the hydrogen atoms on the two methyl groups have been replaced with deuterium.

[0023] The term “aryl” used alone or as part of a larger moiety refers to, unless otherwise specified, a 6- or 10-membered aromatic hydrocarbon ring. An aryl group may be mono- or bi-cyclic, e.g.,. phenyl or naphthyl.

[0024] The term “heteroaryl” used alone or as part of a larger moiety refers to, unless otherwise specified, a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, triazinyl, tetrazinyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, imidazopyridinyl, benzooxazolyl, benzooxodi azolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position.

[0025] The term “heterocyclyl” means, unless otherwise specified, a 5- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. It can be monocyclic, bicyclic (e.g., a bridged, fused, or spiro bicyclic ring), or tricyclic. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyridinonyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, oxetanyl, azetidinyl and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclyl” also includes, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aryl or heteroaryl ring, such as for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position.

[0026] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0027] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0028] The term “bridged” refers to two rings that share three ring atoms with one another.

[0029] The term “optionally substituted,” as used herein to describe a chemical moiety defined herein, means that the moiety may, but is not required to be, substituted with one or more suitable functional groups or other substituents as provided herein.

[0030] As used herein, the term “oxo” refers to a “=O” functional group.

[0031] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

[0032] The term “about” when used in combination with a numeric value or range of values means the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art.

[0033] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including supercritical fluid chromatography (SFC), chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972).

[0034] Exemplary compounds of the disclosure including a chiral center may be depicted herein as having particular stereochemistries, but for which absolute stereochemistry has not been obtained. Absolute configurations can be obtained using methods known in the art.

[0035] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution and connectivity but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers or diastereomers.

[0036] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by dashed or wedge bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a molepercent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0037] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0038] It will be understood that certain compounds disclosed herein may exist in tautomeric forms. Such forms are included as part of the present disclosure. Thus, when a compound herein is represented by a structural formula or designated by a chemical name herein, all tautomeric forms which may exist for the compound are encompassed by the structural formula.

[0039] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers.

[0040] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0041] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0042] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, / .< ., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), z.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0043] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0044] For use in medicines, the salts of the compounds described herein refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, iodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0045] In some embodiments, the pharmaceutically acceptable salt of a compound described herein is a mono or di-sodium salt e.g., when R1is (Ci-C4)alkylene[OP(O)(OH)2].

[0046] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in a country other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans .

[0047] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that is sufficient to achieve the desired therapeutic effect (such as treatment of a condition recited herein) under the conditions of administration.

[0048] The use of any and all examples, or exemplary language (e.g., “such as” and “e.g.”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. Phrases such as “in one aspect”, “in one embodiment”, “in another aspect”, “in another embodiment”, “in embodiments”, and the likeshould not be construed as indicating that such elements occur or exist in isolation or that such elements are not shared by other aspects or embodiments of the disclosure. Rather, it should be understood that all aspects and embodiments may be freely combined with any and all other aspects and embodiments of the disclosure as described herein. No language in the specification should be construed as indicating that any non-claimed element is essential to the practice of the disclosure.3. Compounds

[0049] As part of a second embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, z3is -CR4; and each R2Ais independently selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, deuterated(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], oxo, cyano, hydroxy, S(O)(Ci-C4)alkyl, -S(O)2(Ci-C4)alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, (Ci-C4)alkylene[cycloalkyl], (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[heteroaryl], -C(O)Ral, -C(O)ORal, -NRalC(0)Rbl, -NRalC(0)NRbl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano, and wherein the remaining variables are as described above for Formula I.

[0050] As part of a third embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, (i) z1is N, z2is -CR5, and z3is -CR4; (ii) z1is -CR3, z3is -CR4, and z2is N; or (iii) z1is -CR3, z2is -CR5, and z3is -CR4, wherein the remaining variables are as described above for Formula I or the second embodiment. Alternatively, as part of the third embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, z1is -CR3, z2is -CR5, and z3is -CR, and wherein the remaining variables are as described above for Formula I or the second embodiment.

[0051] As part of a fourth embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R3is hydrogen, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkoxy, cyano, -S(O)2(Ci-C4)alkyl, or (Ci-C4)alkylene[heterocyclyl], wherein said heterocyclyl is optionally substituted by 1 halo, and wherein the remaining variables are as described above for Formula I or any one of the second or third embodiments. Alternatively, as part of the fourth embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R3is hydrogen, -F, -O Cl, -CH3, -CF3, -CH=CH2, -OCH3, cyano, -S(O)2CH3, , or, and wherein the remaining variables are as described above for Formula I or any one of the second or third embodiments.

[0052] As part of a fifth embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R4is hydrogen, halo, or (Ci-C4)alkyl, and wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments. Alternatively, as part of the fifth embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R4is hydrogen, -F, or -CH3, and wherein the remaining variables are as described above for Formula I or any one of the second to fourth embodiments.

[0053] As part of a sixth embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R5is hydrogen, halo, or (Ci-C4)alkyl, and wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments. Alternatively, as part of the sixth embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R5is hydrogen, -F, or -CH3, and wherein the remaining variables are as described above for Formula I or any one of the second to fifth embodiments.

[0054] As part of a seventh embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R1is hydrogen or (Ci-C4)alkylene[OP(O)(OH)2], and wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments. Alternatively, as part of the seventh embodiment, for the compounds of Formula I, or a pharmaceutically acceptable salt thereof, R1is hydrogen, and wherein the remaining variables are as described above for Formula I or any one of the second to sixth embodiments.

[0055] As part of an eighth embodiment, the compounds of Formula I have the structural Formula II:O'(II);or a pharmaceutically acceptable salt thereof, and wherein the remaining variables are as described above for Formula I.

[0056] As part of a ninth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, R2is phenyl, cyclohexyl, azetidinyl, morpholinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, piperdinyl, azaspirohexanyl, azaspiroheptanyl, oxaazaspiroheptanyl, oxaazaspirooctanyl, oxaazaspirononanyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, dihydropyrazolooxazinyl, dihydrodioxinopyridinyl, or hexahydropyrazinopyridooxazinyl, each of which is optionally substituted with 1 to 3 groups selected from R1A, and wherein the remaining variables are as described above for Formula I or II or any one of the second to eighth embodiments. Alternatively, as part of the ninth embodiment, for the compounds ofFormula Ior II, or a salt thereof, R2iN-NHN-N, each of which is optionally substituted with 1 or 2 groups selected from R1A, and wherein the remaining variables are as described above for Formula I or II or any one of the second to eighth embodiments. Alternatively, as part of the ninth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable R1AR1AR1Asalt thereof, R2is:and wherein the remaining variables are as described above for Formula I or II or any one of the second to eighth embodiments.

[0057] As part of a tenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, each R1Ais independently halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, hydroxy[halo(Ci-C4)alkyl], (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], hydroxy, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkoxyO(Ci-C4)alkyl, (Ci-C4)alkoxy O [deuterated(C i -C4)alkyl], (C i -C4)alkoxy O [halo(C i -C4)alkyl] , -O(C i -C4)alkylene[NRaRb], -NRaRb, -NH(Ci-C4)alkylene[heterocyclyl], cyano, -C(O)Ra, -C(0)NRaRb, -SC>2Ra, cycloalkyl, heterocyclyl, (Ci-C4)alkylene[heterocyclyl], -O(Ci-C4)alkylene[cycloalkyl], -O(Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkoxyO[cycloalkyl], -Ofcycloalkyl], or -Ofheterocyclyl], where each occurrence of cycloalkyl and heterocyclyl, alone, or as part of another group, is optionally substituted with 1 to 3 groups selected from oxo, (Ci-C4)alkyl, hydroxy, -NH(Ci-C4alkyl), and heterocyclyl, and wherein the remaining variables are as described above for Formula I or II or any one of the second to ninth embodiments.

[0058] As part of an eleventh embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, Raand Rbare each independently hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, cycloalkyl, or heterocyclyl, wherein the cycloalkyl and heterocyclyl are each optionally substituted with (Ci-C4)alkyl, hydroxy, or hydroxy(Ci-C4)alkyl, and wherein the remaining variables are as described above for Formula I or II or any one of the second to tenth embodiments.

[0059] As part of a twelfth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, each R1Ais independently -F, -Cl, -CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CF3, -CF2CH2OH, -CH2OCH3, -CH2OCD3, -CH2OCHF2, -CH2OCF3, -CH2CH2OCH3, -C(OH)(CH3)2, -CH2C(OH)(CH3)2, hydroxy, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2OCD3, -OCH2CH2OCHF2, -OCH2CH2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, cyano, -C(O)CH3, -C(0)NH2, -C(0)NHCH3, -C(O)N(CH3)2, -C(O)NHCH2CH2OCH3, -S(O)2CH3, cyclopropyl,O?N JD HN, or , and wherein the remaining variables are as described above for Formula I or II or any one of the second to eleventh embodiments.

[0060] As part of a thirteenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, X is -OR6, and wherein the remaining variables are as described above for Formula I or II or any one of the second to twelfth embodiments.

[0061] As part of a fourteenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, R6is (Ci-C4)alkylene[heteroaryl], and wherein the remaining variables are as described above for Formula I or II or any one of the second to thirteenth embodiments. Alternatively, as part of the fourteenth embodiment, for thecompounds of Formula I or II, or a pharmaceutically acceptable salt thereof, R6is, and wherein the remaining variables are as described above for Formula I or II or any one of the second to thirteenth embodiments.

[0062] As part of a fifteenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, X is -NR7R8, and wherein the remaining variables are as described above for Formula I or II or any one of the second to twelfth embodiments.

[0063] As part of a sixteenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, R7and R8, together with the N to which they are attached, form azetidinyl, azaspirohexanyl, azaspiroheptanyl, oxaazaspiroheptanyl, thiaazaspiroheptanyl, diazaspirooctanyl, oxaazaspirooctanyl, oxaazaspirononanyl, diazaspirononanyl, oxadiazaspirononanyl, or dioxaazaspirononanyl, each of which are optionally substituted with 1 to 3 groups selected from R2A, and wherein the remaining variables are as described above for Formula I or II or any one of the second to twelfth or fifteenth embodiments. Alternatively, as part of the sixteenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, R7and R8, together with theN■K>Qu>OuKX / +N u5 , or +O0 , eachHofFwhich are optionally substituted with 1 to 3 groups selected from R2A, and wherein the remaining variables are as described above for Formula I or II or any one of the second to twelfth or fifteenth embodiments. Alternatively, as part of the sixteenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, R7and R8,R2AR2Aor +O0 , each of which are optionally substituted with 1 to 3 groups selected from R2A, and wherein the remaining variables are as described above for Formula I or II or any one of the second to twelfth or fifteenth embodiments.

[0064] As part of a seventeenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, each R2Ais independently halo, (Ci-C4)alkyl, deuterated(Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci- C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], hydroxy(Ci- C4)alkyl, hydroxy, (Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, -S(O)2(Ci-C4)alkyl, cyano, or cycloalky, and wherein the remaining variables are as described above for Formula I or II or any one of the second to twelfth, fifteenth, or sixteenth embodiments. Alternatively, as part of the seventeenth embodiment, for the compounds of Formula I or II, or a pharmaceutically acceptable salt thereof, R2Ais independently -F, -CH3, -CD3, -CH2F, -CF3, -CH2CF3, - CH2OCH3, -CH2OCH2CH3, -CH2OCD3, -CH2OCHF2, -CH2OCF3, -C(OH)(CH3)2, - C(CH3)2OCH3, hydroxy, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -S(O)2CH3, cyano, orcyclopropyl, and wherein the remaining variables are as described above for Formula I or II or any one of the second to twelfth, fifteenth, or sixteenth embodiments.

[0065] As part of an eighteenth embodiment, the compounds of Formula I have the structural Formula III:R1AR2A□2A(HI);or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered nitrogen containing heteroaryl, and wherein the remaining variables are as described above for Formula I.

[0066] As part of a nineteenth embodiment, for the compounds of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, Ring A is pyrazolyl, pyridinyl, or pyrimidinyl, and wherein the remaining variables are as described above for Formula I, II, or III or the eighteenth embodiment. Alternatively, as part of the nineteenth embodiment, for the compounds of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, Ring A is:, each of which is substituted by R1A, and wherein the remaining variables are as described above for Formula I, II, or III or the eighteenth embodiment. Alternatively, as part of the nineteenth embodiment, for the compounds of Formula I, II, orHI, or a pharmaceutically acceptable salt thereof, Ring A is:and wherein the remaining variables are as described above for Formula I, II, or III or the eighteenth embodiment.

[0067] As part of a twentieth embodiment, for the compounds of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R1Ais (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkoxyO(Ci-C4)alkyl, -O[cycloalkyl], or -O[heterocyclyl], and wherein the remaining variables are as described above for Formula I, II, or III or the eighteenth or nineteenth embodiment. Alternatively, as part of the twentieth embodiment, for the compounds ofFormula I, II, or III, or a pharmaceutically acceptable salt thereof, R1Ais -OCH3, -OCHF2, -OCH2CH3, -OCH(CH3)2, -O-cyclopropyl, -OCH2CH2OCH3, oran(jwherejnthe remaining variables are as described above for Formula I, II, or III or the eighteenth or nineteenth embodiment.

[0068] As part of a twenty-first embodiment, for the compounds of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R2Ais independently halo, (Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkoxy, or deuterated(Ci-C4)alkoxy, and wherein the remaining variables are as described above for Formula I, II, or III or one of the eighteenth to twentieth embodiments. Alternatively, as part of the twenty-first embodiment, for the compounds of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R2Ais -F, -CH3, -CH2OCH3, -CH2OCH2CH3, -CH2OCD3, or -OCD3, and wherein the remaining variables are as described above for Formula I, II, or III or one of the eighteenth to twentieth embodiments.

[0069] As part of a twenty-second embodiment, for the compounds of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R1Ais (Ci-C4)alkoxy; and each R2Ais independently halo, (Ci-C4)alkylene(Ci-C4)alkoxy, or (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], and wherein the remaining variables are as described above for Formula I, II, or III or the eighteenth embodiment. Alternatively, as part of the twenty-second embodiment, for the compounds of Formula I, II, or III, or a pharmaceutically acceptable salt thereof, R1Ais -OCH3 or -OCH2CH3; and each R2Ais independently -F, -CH2OCH3, or -CH2OCD3, and wherein the remaining variables are as described above for Formula I, II, or III or the eighteenth embodiment.

[0070] Additional compounds are described and exemplified herein, and are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms of such compounds are included.4. Uses, Formulation and Administration

[0071] The compounds and compositions described herein are generally useful for modulating the activity of beta catenin. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein sequester beta catenin in nuclear condensates. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein modulate beta catenin condensates.

[0072] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disease or condition associated with beta catenin function. Thus, provided herein are methods of treating a disease or condition associated with beta catenin function, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof. In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disease or condition associated with the modulation of beta catenin condensates. Thus, provided herein are methods of treating a disease or condition associated with the modulation of beta catenin condensates, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.

[0073] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition associated with beta catenin function. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a disease or condition associated with beta catenin. Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition associated with the modulation of beta catenin condensates. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a disease or condition associated with the modulation of beta catenin condensates.

[0074] In one aspect, the disease or condition associated with beta catenin or the modulation of beta catenin condensates is cancer. In embodiments, the cancer is bladder cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, leukemia, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, or a solid tumor. In embodiments, the breast cancer is triple negative breast cancer. In embodiments,the leukemia is chronic lymphocytic leukemia or acute myeloid leukemia. In embodiments, the lung cancer is non-small cell lung cancer.

[0075] In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein modulate the function of beta catenin. In some aspects, modulating beta catenin comprises modulating beta catenin partitioning into condensates. In some aspects, modulating beta catenin comprises modulating transcription of beta catenin-dependent genes. In some aspects, modulating beta catenin comprises modulating beta catenin association with chromatin. In some aspects, modulating beta catenin comprises modulating beta catenin interaction network. In some aspects, modulating beta catenin comprises modulating beta catenin posttranscriptional modification status. In some aspects, modulating beta catenin comprises modulating direct and indirect regulators of beta catenin and the WNT pathway. In some aspects, modulating beta catenin comprises modulating the cell cycle.

[0076] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0077] In some aspects, the pharmaceutical compositions are administered orally.

[0078] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.EXEMPLIFICATION

[0079] While there is described herein a number of embodiments, it is apparent that the basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0080] The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one with ordinary skill in the art.

[0081] Synthetic procedure A

[0082] Example 1: 3-Fluoro-3-(methoxymethyl)-N-(7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)azetidine-l-carboxamide

[0083] Step 1

[0084] A mixture of 7-bromobenzo[d]thiazol-2-amine (50.0 g, 218 mmol), (2-methoxypyrimidin-5-yl)boronic acid (40.3 g, 261 mmol), dioxane (750 mL) and water (250 mL) was degassed and purged with nitrogen three times. SPhos Pd G3 (13.6 g, 17.4 mmol) and potassium phosphate (139 g, 654 mmol) were added and the reaction mixture was stirred at 100 °C for 12 h under a nitrogen atmosphere. Additional water (50 mL) was added and stirring continued at room temperature for 30 min. The precipitate was filtered and then triturated with dichloromethane (1 L, 25 °C, 2 h) to afford 7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-amine (41.0 g, 158 mmol, 73%) as a gray solid; 5H (400 MHz; DMSO-d6) 8.86 (2H, s), 7.59 (2H, s), 7.41-7.31 (2H, m), 7.14 (1H, dd, J7.2, 1.2 Hz), 3.99 (3H, s); ES-MS [M+H]+: 259.0.

[0085] Step 2

[0086] Phenyl chloroformate (40.8 mL, 325 mmol) was added to a solution of 7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-amine (56.0 g, 216 mmol) and pyridine (35.0 mL, 433 mmol) in THF (900 mL) at 25 °C. The resulting solution was stirred at 25 °C for 12 h. The precipitate was filtered and then triturated with acetonitrile (2 x 500 mL, 25 °C, 2 h) to afford phenyl (7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamate (61.0 g, 157 mmol, 73%) as a gray solid; 5H (400 MHZ; DMSO-d6) 12.82 (1H, br s), 8.98 (2H, s), 7.86 (1H, d, J 8.00 Hz), 7.63 (1H, t, J 8.00 Hz), 7.57-7.46 (3H, m), 7.42-7.26 (3H, m), 4.04 (3H, s); ES-MS [M+H]+: 379.0.

[0087] Step 3

[0088] Triethylamine (66.2 mL, 475 mmol) was added to a solution of phenyl (7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamate (60.0 g, 158 mmol) and 3-fluoro-3-(methoxymethyl)azetidine hydrochloride (37.0 g, 238 mmol) in dichloromethane (1.2 L). The resulting solution was stirred at 25 °C for 12 h, then filtered and concentrated in vacuo. Trituration was first carried out with a mixture of water (1.8 L) and acetonitrile (600 mL), then ethanol (1 L). Dichloromethane (2 L) and Silicycle SiliaMetS thiol metal scavenger (30.0 g) were added and the resulting mixture was stirred at 30 °C for 30 min, then filtered. Additional scavenger (30.0 g) was added to the filtrate and the resulting mixture was stirred at 30 °C for 30 min, filtered, then concentrated in vacuo. The residue was recrystallized from PE:EtOAc (5: 1, 300 mL). Acetonitrile (20 mL) and water (200 mL) were added and the resulting mixture was stirred for 10 min. Concentration in vacuo and lyophilization afforded 3-fluoro-3-(methoxymethyl)-N-(7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)azetidine-1-carboxamide (30.0 g, 77.2 mmol, 49%) as a white solid; 5H (400 MHz; DMSO-d6); 11.69-11.43 (1H, m), 8.93 (2H, s), 7.70 (1H, s), 7.52 (1H, t, J7.80 Hz), 7.38 (1H, d, J 7.20 Hz), 4.30-4.04 (4H, m), 4.01 (3H, s), 3.78-3.64 (2H, m), 3.34 (3H, s); 5F(400 MHz; DMS0-d6) -155.48; ES-MS [M+H]+: 404.0.

[0089] Other examples prepared using procedures similar to synthetic procedure A are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).IntermediatesEx. ES-MS Name Structure requiringNo. [M+H]+synthesis3 - (methoxym ethyl) -N- (7- H [NHZK2 phenylbenzo [d]thiazol-2- 1S^ 0N\vZ — \ OMe n / a 354.1 yl)azetidine- 1 -carboxamide03 - (methoxym ethyl) -N- (7- f| | 'X_NH(6-methoxypyridin-3 - 1 OvOMe3 n / a 385.1 yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamideOMe3 -methoxy -3- (methoxymethyl)-N-(7-(6- 4 methoxypyridin-3 - 1 n / a 415.1Mli °yl)benzo[d]thiazol-2-Meyl)azetidine- 1 -carboxamide OMeN-(7-(6-methoxypyridin-3- H \ NH 0—FFyl)benzo [d]thiazol-2-yl)-3 - 5 n / a 439.1 ((trifluoromethoxy )methyl)Qazetidine- 1 -carboxamideOMe3 -(2-hydroxypropan-2-yl)- (I I NH / N-(7 -(6-methoxypyridin-3 - — \OH6 n / a 399.1 yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamideOMe3-(2-methoxypropan-2-yl)- f| | 'X—NH IN-(7 -(6-methoxypyridin-3 - T 1s0vOMen / a 413.1 yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamideOMeN-(7-(6-methoxypyridin-3- H | ^NHyl)benzo[d]thiazol-2-yl)-2- j ~sn / a 383.2 oxa-6-azaspiro[3.3]heptane- 6-carboxamideOMeN-(7-(6-methoxypyridin-3- \\ \ NH Oyl)benzo [d]thiazol-2-yl)-3 - n / a 419.1 (methylsulfonyl)azetidine- 1 -carboxamideOMeN-(7-(6-methoxypyridin-3- f| | 'X_|\|Hyl)benzo [d]thiazol-2-yl)-3 - (2,2,2- Isn / a 423.0 trifluoroethyl)azetidine- 1 - carboxamide 0OMe3-(methoxy-d3)-N-(7-(6- H £ NHmethoxypyridin-3 - 3-(methoxy-d3)- ^N\XOCD3yl)benzo [d]thiazol-2-yl)-3 - 3- 388.1 methylazetidine- 1 - methylazetidine carboxamide OMe3 - (methoxym ethyl) -N- (7- (6-methoxypyridin-3 - [l lNH / Kyl)benzo [d]thiazol-2-yl)-3 -c^N0><^OMen / a 399.1 methylazetidine- 1 - carboxamide OMeN-(7-(6-methoxypyridin-3- H | 'X—NH ^NMeyl)benzo[d]thiazol-2-yl)-8- methyl-5 -oxa-2, 8 - n / a 426.2 diazaspiro[3.5]nonane-2- carboxamide OMe8-cyclopropyl-N-(7-(6- methoxypyridin-3 - \\ IXVNH 8-cyclopropyl-5- yl)benzo [d]thiazol-2-yl)-5 - oxa-2,8- 452.2 oxa-2, 8- diazaspiro[3.5]no diazaspiro[3.5]nonane-2- C)1nane carboxamide OMeN-(7-(6-methoxypyridin-3- yl)benzo[d]thiazol-2-yl)-6- methyl-2,6- n / a 424.2 diazaspiro[3.5]nonane-2- carboxamide OMeN-(7-(6-methoxypyridin-3- H r \^NHyl)benzo[d]thiazol-2-yl)-6- methyl-2,6- n / a 410.2 diazaspiro [3.4] octane-2 - carboxamide OMeN-(7-(6-methoxy-2- h V X^NHmethylpyridin-3 - J ~sdhfOv>yl)benzo[d]thiazol-2-yl)-2- n / a 397.2 oxa-6-azaspiro[3.3]heptane- 6-carboxamide OMe3 -(fluoromethyl) -N- (7- (6 - H | NHmethoxypyridin-3 - n / a 373.1 yl)benzo[d]thiazol-2- nsyl)azetidine- 1 -carboxamideOMe6-methoxy-N-(7-(6- [| T NHmethoxypyridin-3 - OMe1 oyl)benzo [d]thiazol-2-yl)-2-7n / a 411.2 azaspiro[3.3]heptane-2- carboxamide OMe6-hydroxy-N-(7-(6- ^^.Nmethoxypyridin-3 - [| I 5>— NHyl)benzo [d]thiazol-2-yl)-6- n / a 411.2 methyl-2- azaspiro[3.3]heptane-2- OMecarboxamide6,6-difluoro-N-(7-(6- methoxypyridin-3 - v-sZNOO<Fyl)benzo[d]thiazol-2-yl)-2- n / a 417.1 azaspiro[3.3]heptane-2- carboxamide OMe5,5-difluoro-N-(7-(6- f| I NHmethoxypyridin-3 - yl)benzo[d]thiazol-2-yl)-2- n / a 417.1 azaspiro[3.3]heptane-2- carboxamide OMe6 -fluoro -N- (7- (6 - methoxypyridin-3 - yl)benzo[d]thiazol-2-yl)-2- n / a 399.1 azaspiro[3.3]heptane-2- carboxamide OMe6-cyano-N-(7-(6- [l INH / Kmethoxypyridin-3 - yl)benzo [d]thiazol-2-yl)-2- n / a 406.1 azaspiro[3.3]heptane-2- carboxamide OMel-cyano-N-(7-(6- ^s_.NH [ NHmethoxypyridin-3 - yl)benzo [d]thiazol-2-yl)-5 - n / a 392.0 azaspiro[2.3]hexane-5- carboxamide $ 'OMe5-methoxy-N-(7-(6- fl I 5>— NHmethoxypyridin-3 - V'sdhN(>Oyl)benzo[d]thiazol-2-yl)-2- n / a 411.2A ll OMeazaspiro[3.3]heptane-2- carboxamide OMe6 - (difluoromethy 1)- 6 - / XNhy droxy -N - (7- (6 - H |XVNHLAs'methoxypyridin-3 - n / a 447.1 yl)benzo[d]thiazol-2-yl)-2- azaspiro[3.3]heptane-2- OM / / me _carboxamide3- ((difluoromethoxy)methyl)- ( JZ 3V Z\ F - 3 -fluoro -N- (7- (6 - ((difluoromethox 439.1 methoxypyridin-3 - y)methyl)-3- Ayl)benzo[d]thiazol-2- £o fluoroazetidine OMe oyl)azetidine- 1 -carboxamide u wN-(7-(6-methoxypyridin-3- [| I 'ANH Fyl)benzo [d]thiazol-2-yl)-6- Srsr<xnF(trifluoromethyl)-2- n / a 449.1 azaspiro[3.3]heptane-2- Qcarboxamide OMeN-(7-(2-ethoxypyrimidin-5- 3 -fluoro-3 - yl)benzo [d]thiazol-2-yl)-3 - ((methoxy- fluoro-3 -((methoxy- 421.2 d3 )methyl)azetidi d3)methyl)azetidine- 1 - ne carboxamide9,9-difluoro-N-(7-(6-FFmethoxypyridin-3 - n [ NH S — < 9,9-difluoro-6- yl)benzo [d]thiazol-2-yl)-6- T^SyN\ / \ ? methyl-2,6- 460.2 methyl-2,6- diazaspiro[3.5]no diazaspiro[3.5]nonane-2- Cy nane carboxamide OMeN-(7-(2-ethoxypyrimidin-5- yl)benzo[d]thiazol-2-yl)-6- n / a 412.2 oxa-2-azaspiro [3 ,4]octane- 2-carboxamideN-(7-(2-methoxypyrimidin- 5 -yl)benzo [d]thiazol-2-yl)- 6-oxa-2- LLJO n / a 398.2 azaspiro [3.4] octane-2 - carboxamideX / / ' m _ zAs iN-(7-(2-methoxypyrimidin- f| [ X? Z X As Z) i NH5 -yl)benzo [d]thiazol-2-yl)- a Y I _7 _ _ \D <J zoX^- zzZ) C zk zoo5-ox -2-T1 n / a 398.1 azaspiro [3.4] octane-2 - \ \ \ / zZ / \= / v_ Nz=0- carboxamide / OMeN-(7-(2-ethoxypyrimidin-5- f| | \X_ NH _yl)benzo [d]thiazol-2-yl)-5 - n / a 412.2 oxa-2-azaspiro [3 ,4]octane- N2-carboxamideOEt3-(ethoxymethyl)-N-(7-(2- ethoxypyrimidin-5 - 3- yl)benzo [d]thiazol-2-yl)-3 - (ethoxymethyl)- 432.2 fluoroazetidine- 1 - 3 -fluoroazetidine carboxamide3-fluoro-3- ^s_-N(methoxym ethyl) -N- (7- (6 - ( XXMHN z\ JX^ F OMemethoxypyridin-3 - n / a 403.2 yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamide OMe3 -fluoro-3 -((methoxy - 3 -fluoro-3 - d3 )met E XX^N^HN / ^\<^ Fhyl)-N -(7-(6- OCD3((methoxy- 406.1 methoxypyridin-3 - d3 )methyl)azetidi yl)benzo[d]thiazol-2- ne yl)azetidine- 1 -carboxamide OMeH [ NH 3-(methoxy-d3)-N-(7-(6- ZN>OCD3methoxypyridin-3 - 3-(methoxy- 374.1 yl)benzo[d]thiazol-2- d3)azetidine yl)azetidine- 1 -carboxamideOMe3-ethoxy-N-(7-(6- H [ ^>— NHmethoxypyridin-3 - J-|O<OEt399.2 yl)benzo [d]thiazol-2-yl)-3 - n / a methylazetidine- 1 - Cxcarboxamide OMe^^N[| I / >—NH / x 3-ethoxy-N-(7-(6- ^-N^0Etmethoxypyridin-3 - 385.2 n / a yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamideOMe3-methoxy-N-(7-(6- E 1 ^nhmethoxypyridin-3 - XN\><oMe385.2 yl)benzo [d]thiazol-2-yl)-3 - n / a methylazetidine- 1 - Cxcarboxamide OMeE [ / >—nh3-isopropoxy-N-(7-(6- methoxypyridin-3 - 399.1 n / a yl)benzo[d]thiazol-2- 0ryl)azetidine- 1 -carboxamideOMeN-(7-(6-methoxypyridin-3- H | ^NH , —yl)benzo[d]thiazol-2-yl)-6- n / a 411.2 oxa-2-azaspiro[3.5]nonane- 2-carboxamideOMeN-(7-(6-methoxypyridin-3- h [ ^NH , — .yl)benzo [d]thiazol-2-yl)-5 - Xsz<>0n / a 411.2 oxa-2-azaspiro[3.5]nonane- 2-carboxamide87 / O^ \M7= e\ CDN-(7-(6-methoxypyridin-3- yl)benzo[d]thiazol-2-yl)-2- C zkT1thia-6- z n / a 431.1 azaspiro[3.3]heptane-6- carboxamide 2,2-dioxideC / )\ / \ / o ol,l-difluoro-N-(7-(6- H \ \^NHmethoxypyridin-3 - xsrxFyl)benzo [d]thiazol-2-yl)-5 - n / a 403.1 azaspiro[2.3]hexane-5- i ll Fcarboxamide OMe3 -cyclopropyl-3 -hydroxy- N-(7 -(6-methoxypyridin-3 - ZN>‘v n / a 397.2 yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamideOMe6-hydroxy-N-(7-(6- methoxypyridin-3 - ( Z\ / \ OHyl)benzo [d]thiazol-2-yl)-6- ozn / a 465.1 (trifluoromethyl)-2- azaspiro[3.3]heptane-2- OMecarboxamideN-(7-(6-methoxypyridin-3- H [ NH > — .yl)benzo[d]thiazol-2-yl)-7- n / a 411.2 oxa-2-azaspiro[3.5]nonane- 2-carboxamideOMe3-hydroxy-N-(7-(6- methoxypyridin-3 - yl)benzo [d]thiazol-2-yl)-3 - n / a 425.1 (trifluoromethyl)azetidine- Z— A / =\1 -carboxamide O s—OMej y a>N-(7-(6-methoxypyridin-3- [| | V‘ NHyl)benzo [d]thiazol-2-yl)- 1 - V~sZN)X>n / a 383.1 oxa-6-azaspiro[3.3]heptane- 6-carboxamideI OMe osCD3-FH | \^NH o— ( ((difluoromethoxy)methyl)- — / FN-(7 -(6-methoxypyridin-3 - n / a 421.0 yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamide OMe3-fluoro-3- (methoxym ethyl) -N- (7- (2 - methoxypyrimidin-5 -yl)-4- n / a 418.2 methylbenzo [d]thiazol-2- yl)azetidine- 1 -carboxamideN- (6 -fluoro -7- (6 - fl \ X)— NHmethoxypyridin-3 - 7-bromo-6- yl)benzo [d]thiazol-2-yl)-5 - fluorobenzo [d] thi 415.1 oxa-2-azaspiro [3 ,4]octane- azol-2-amine2-carboxamide OMeN- (6 -fluoro -7- (6 - T '\_NHmethoxypyridin-3 - r 7-bromo-6- "sJ-N0Oyl)benzo[d]thiazol-2-yl)-6- fluorobenzo [d] thi 415.1 oxa-2-azaspiro [3 ,4]octane- azol-2-amine2-carboxamide Me3-(methoxy-d3)- N-(6-chloro-7-(6-(l,l- jT [ '\_NH 3- difluoroethyl)pyridin-3 - / \Z^OCD3methylazetidine yl)benzo [d]thiazol-2-yl)-3 - and 456.1 (methoxy-d3)-3- 7-bromo-6- methylazetidine- 1 -XF chlorobenzo [d] thi carboxamideazol-2-amineN-(6-chloro-7-(6- methoxypyridin-3 - jf T NHCl^\| 7-bromo-6- yl)benzo [d]thiazol-2-yl)-3 - \ / <OMechlorobenzo [d] thi 419.1 methoxy -3- azol-2-amine methylazetidine- 1 - )MecarboxamideN-(6-chloro-7-(6-(l,l- f | ^NHdifluoroethyl)pyridin-3 - Cl""^ f"s^N0>vo7-bromo-6- yl)benzo[d]thiazol-2-yl)-2- chlorobenzo [d] thi 451.1Noxa-6-azaspiro[3.3]heptane- azol-2-amine6-carboxamide SFN-(6-chloro-7-(6- | ^NHmethoxypyridin-3 - jfps^-N7-bromo-6- yl)benzo[d]thiazol-2-yl)-2- 0C° chlorobenzo [d] thi 417.2 oxa-6-azaspiro[3.3]heptane- azol-2-amine6-carboxamide JMeN-(6-chloro-7-(6- T '\_NHFmethoxypyridin-3 - r7-bromo-6- N^<^OMeyl)benzo [d]thiazol-2-yl)-3 - 437.1 chlorobenzo [d] thi fluoro-3- jJl azol-2-amine (methoxymethyl)azetidine- Me1 -carboxamide3-fluoro-N-(6-methoxy-7- (6-methoxypyridin-3 - 1 X z\ V^ F OMe 7-bromo-6- 62 yl)benzo [d]thiazol-2-yl)-3 - methoxybenzo [d] 433.2 (methoxymethyl)azetidine- thiazol-2-amine1 -carboxamide OMeN-(6-methoxy-7-(6- methoxypyridin-3 - 1 1 X"NHZ\ / \ 7-bromo-6- 63 yl)benzo[d]thiazol-2-yl)-2- methoxybenzo [d] 413.1 oxa-6-azaspiro[3.3]heptane- thiazol-2-amine6-carboxamide OMeN-(7-(6-methoxypyridin-3- yl)-6- H T ^NH7-bromo-6- methylbenzo [d]thiazol-2- 64 methylbenzo [d] th 397.2 yl)-2-oxa-6- iazol-2-amine azaspiro[3.3]heptane-6- carboxamide OMe[| INH3-(methoxy-d3)- N-(6-chloro-7-(5-ClJLsJ^N^<OCD3 3- methoxypyrazin-2-NXJ methylazetidine yl)benzo [d]thiazol-2-yl)-3 - 65 ^Me and 423.3(methoxy-d3)-3- (Stille coupling using 2-methoxy-5- 7-bromo-6- methylazetidine- 1 - (tributylstannyl)pyrazine for Step 1 : chlorobenzo [d] thi carboxamidePd2(dba)s, PCys, LiCl, dioxane, azol-2-amine110 °C)N- (6 -fluoro -7- (2 - isopropoxypyrimidin-5 - 7-bromo-6- yl)benzo [d]thiazol-2-yl)-3 - OMe345 fluorobenzo [d] thi 448.2 hydroxy-3- azol-2-amine (methoxymethyl)azetidine- 1 -carboxamide

[0090] Synthetic procedure B

[0091] Example 66: N-(7-(2-ethoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-fluoro-3- (methoxymethyl)azetidine-l -carboxamide

[0092] Step 1

[0093] Phenyl chloroformate (4.11 mL, 32.7 mmol) was added to a solution of 7-bromobenzo[d]thiazol-2-amine (5.00 g, 21.8 mmol) and pyridine (3.52 mL, 43.7 mmol) in THF (100 mL). The resulting mixture was stirred at 20 °C for 2 h and then concentrated in vacuo. Trituration (acetonitrile: water 1:1, 50 mL) afforded phenyl (7-bromobenzo[d]thiazol-2-yl)carbamate (7.00 g, 19.9 mmol, 91%) as an off-white solid; 5H(400 MHZ; DMSO-d6) 13.11-12.66 (1H, m), 7.81 (1H, d, . / 8 Hz), 7.57-7.44 (4H, m) 7.43-7.33 (3H, m); ES-MS [M+H]+: 351.0.

[0094] Step 2

[0095] 3 -Fluoro-3-(methoxymethyl)azetidine (2.77 g, 11.9 mmol) was added to a solution of phenyl (7-bromobenzo[d]thiazol-2-yl)carbamate (2.00 g, 5.73 mmol) and triethylamine (0.80 mL, 5.73 mmol) in THF (20 mL). The resulting solution was stirred at 20 °C for 2 h, then concentrated in vacuo. Trituration (acetonitrile: water 1:1, 20 mL) afforded N-(7-bromobenzo[d]thiazol-2-yl)-3-fluoro-3-(methoxymethyl)azetidine-l -carboxamide (2.00 g, 5.24 mmol, 91%) as a white solid; 5H (400 MHZ; DMSO-d6) 11.84-11.47 (1H, m), 7.69-7.61 (1H, m), 7.45 (1H, d, J7.75 Hz), 7.38-7.32 (1H, m), 4.27-4.07 (4H, m), 3.75 (1H, s), 3.69 (1H, s), 3.35 (3H, br s); ES-MS [M+H]+: 374.0.

[0096] Step 3

[0097] A mixture of N-(7-bromobenzo[d]thiazol-2-yl)-3-fluoro-3-(methoxymethyl)azetidine-l -carboxamide (200 mg, 0.53 mmol), (2-ethoxypyrimidin-5-yl)boronic acid (99 mg, 0.59 mmol), Pd(dppf)C12 (39 mg, 0.05 mmol), Na2CCh (170 mg, 1.60 mmol), dioxane (2 mL) and water (0.5 mL) was degassed and purged with nitrogen three times. The reaction mixture was stirred at 80 °C for 12 h under a nitrogen atmosphere, thencooled, diluted with water (2 mL) and extracted into EtOAc (2 x 2 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by preparative HPLC (Phenomenex Luna C18 150*25 10 pm column; acetonitrile: [water (0.1% formic acid)]; gradient: 37%-67% water (0.1% formic acid) over 10 min afforded N-(7-(2-ethoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-fluoro-3-(methoxymethyl)azetidine-l -carboxamide (66 mg, 0.16 mmol) as a white solid; 5H(400 MHz; CDCh) 8.83 (2H, s), 7.74 (1H, d, J 8.19 Hz), 7.54 (1H, m), 7.27 (1H, s), 4.53 (2H, m), 4.27 (4H, m), 3.70 (2H, d, J 17.61 Hz), 3.49 (3H, s), 1.51 (3H, m); 5F (400 MHz; DMSO-d6) -124.8, -155.5; ES-MS [M+H]+: 418.2.

[0098] Other examples prepared using synthetic procedure B are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).IntermediatesEx. ES-MS Name Structure requiring No. [M+H]+synthesis3-fluoro-3- N-(tetrahydro-2H- ( / \ F(methoxym ethyl) -N-(7-(6- T^~S / FNV^OMe pyran-4-yl)-5- ((tetrahydro-2H-pyran-4- (4, 4,5,5- 67 472.2 yl)amino)pyridin-3 - tetramethyl- 1,3,2- yl)benzo[d]thiazol-2- dioxaborolan-2- yl)azetidine- 1 -carboxamide yl)pyridin-2-amineN-methyl-N- 3-fluoro-3- (tetrahydro-2H- (methoxym ethyl) -N-(7-(6- [ T Z\ Fpyran-4-yl)-5- (methyl(tetrahydro-2H- 68 (4, 4,5,5- 486.1 pyran-4-yl)amino)pyridin- tetramethyl- 1,3,2- 3 -yl)benzo [d]thiazol-2- dioxaborolan-2- yl)azetidine- 1 -carboxamideyl)pyridin-2-amineN-(7-(6-(l,l-difhioro-2- 2,2-difluoro-2-(5- r yr / ^nhz\ Fhydroxyethyl)pyridin-3 - T ^SX / 0Me(4, 4,5,5- yl)benzo [d]thiazol-2-yl)-3 - tetramethyl- 1,3,2- 69 453.1 fluoro-3- dioxaborolan-2- (methoxymethyl)azetidine- L^F yl)pyridin-2- 1 -carboxamide OH yl)ethan-l-olN-(4- 3-fluoro-3- LIcH methyltetrahydro- t y V1(m o eNV^ Fe h x m thyl) -N-(7-(6- OMe2H-pyran-4-yl)-5- ((4-methyltetrahydro-2H- (4, 4,5,5- 486.1 pyran-4-yl)amino)pyridin- tetramethyl- 1,3,2- 3 -yl)benzo [d]thiazol-2- dioxaborolan-2- yl)azetidine- 1 -carboxamideyl)pyridin-2-amine f| J ^NHN-(7 -(6-(oxetan-3 - yl)pyridin-3- Z— A / =\yl)benzo[d]thiazol-2-yl)-2- / \ / / V 0)_ _ n / a 409.2XJ ' / V-7=oxa-6-azaspiro[3.3]heptane- 11 CD6-carboxamideex z1iznN-(7 -(6-(oxetan-3 - [ '\—NHyloxy)pyridin-3- T 's^N0Oyl)benzo[d]thiazol-2-yl)-2- n / a 425.1 oxa-6-azaspiro[3.3]heptane- 6-carboxamideN-(7-(6- h | ^NH(difluoromethoxy)pyridin- 3 -yl)benzo [d]thiazol-2-yl)- n / a 419.1 2-oxa-6- azaspiro[3.3]heptane-6-F^,ocarboxamideN-(7-(2-methoxypyrimidin- 5 -yl)benzo [d]thiazol-2-yl)- 2-oxa-6- n / a 384.1 azaspiro[3.3]heptane-6- carboxamideN-(7-(6- (difluoromethoxy)pyridin- C VU J^-SQ^N\ UHN V^FOMe3 -yl)benzo [d]thiazol-2-yl)- n / a 439.1 3-fluoro-3- (methoxymethyl)azetidine- 1 -carboxamide3 -(methoxy-d3 )-3 - methylazetidine5 - (2 - (3 - (methoxy -d3 ) -3 - and methylazetidine- 1 - Z\ N-(oxetan-3 -yl)-5 - carboxamido)benzo [d]thiaz °z / =\ / / \ \ (\ / \ _ _ 457.3(4, 4,5,5- ol-7 -yl)-N -(oxetan-3 - Otetramethyl- 1,3,2- yl)picolinamidedioxaborolan-2- yl)picolinamide3 -(methoxy-d3 )-3 - methylazetidine3 -(methoxy -d3)-3 -methyl- H \ U— ' NH ■oN-(7-(3-methyl-4-(oxetan- T ^OC oD3andw2-methyl-N- 3- (oxetan-3-yl)-4- 470.1 ylcarbamoyl)phenyl)benzo [(4, 4,5,5- d]thiazol-2-yl)azetidine- 1 - HN^UDtetramethyl- 1,3,2- carboxamidedioxaborolan-2- yl)benzamide3 -(methoxy-d3 )-3 - methylazetidine(R)-3 -(methoxy-d3 )-3 - H £ Mb! andmethyl-N-(7-(6- C^N\XOCD3(R)-N- ((tetrahydrofuran-3 - (tetrahydrofuran-3 - 443.2 yl)amino)pyridin-3 - yl)-5-(4, 4,5,5- yl)benzo[d]thiazol-2- tetramethyl- 1,3,2- yl)azetidine- 1 -carboxamideH^*X2)Ddioxaborolan-2- yl)pyridin-2-amine3 -(methoxy-d3 )-3 - methylazetidine(S)-3-(methoxy-d3)-3- N £ JH- NH andmethyl-N-(7-(6- Y'S^NXXOCD3(S)-N- ((tetrahydrofuran-3 - (tetrahydrofuran-3 - 443.2 yl)amino)pyridin-3 - yl)-5-(4, 4,5,5- yl)benzo[d]thiazol-2- tetramethyl- 1,3,2- yl)azetidine- 1 -carboxamidedioxaborolan-2- yl)pyridin-2-amineN-(7-(l-(2-hydroxy-2- Z— A / =\ Z— A / =A / \ / / V O)_ _methylpropyl)- 1 H-pyrazol- / \ / / V Q)_ _ / / s{ 1 CD f| T NH . 3 -(m ethoxy -d3 )-3 - 4-yl)benzo[d]thiazol-2-yl)- j \ CDT jZ X / SDCD3419.3 methylazetidine3 -(methoxy -d3)-3 - methylazetidine- 1 - HO^ _ / carboxamide3 -fluoro-3 -((methoxy - 1 yo 3 -fluoro-3 - d3 )methyl)-N -(7 o o -(2- o u w ((methoxy- w407.1 methoxypyrimidin-5 - d3 )methyl)azetidin yl)benzo[d]thiazol-2- eyl)azetidine- 1 -carboxamide3-(methoxy-d3)-N-(7-(2- methoxypyrimidin-5 - 3 -(methoxy -d3)-3 - yl)benzo [d]thiazol-2-yl)-3 - 389.1 methylazetidine methylazetidine- 1 - carboxamideN-(7-(6- [ JL z\ F (difluoromethoxy)pyridin- 3 -fluoro-3 - ^r ~s N^O00033 -yl)benzo [d]thiazol-2-yl)- ((methoxy- 442.2 3 -fluoro-3 -((methoxy - d3 )methyl)azetidin d3)methyl)azetidine- 1 - e carboxamide3-fluoro-N-(7-(l-(2- 3 -fluoro-3 - [ / I ^7 z\ F hydroxy-2-methylpropyl)-N_X^OCD3 ((methoxy- 437.2 lH-pyrazol-4- d3 )methyl)azetidin yl)benzo [d]thiazol-2-yl)-3 - HO^ _ / e((methoxy-d3)methyl)azetidine- 1 - carboxamideN-(7-(2- 3 -fluoro-3 - (difluoromethoxy)pyrimidi ((methoxy- n-5 -yl)benzo [d]thiazol-2- d3 )methyl)azetidin 443.1 yl)-3 -fluoro-3 -((methoxy - e d3)methyl)azetidine- 1 - carboxamide3 -(methoxy-d3 )-3 - ~n H | 'X—NHZ— A / =\ methylazetidine3 -(methoxy -d3)-3 -methyl- / \ / / Q T_ _ V^OCD3N-( - 4 ( x t n 3 # m and7 ( - o e a - - mz^ N-(oxetan-3-yl)-4- ylcarbamoyl)phenyl)benzo [ 0 456.3 v (4, 4,5,5- d]thiazol-2-yl)azetidine- 1 - exz.HN-^O tetramethyl- 1,3,2- carboxamidedioxaborolan-2- yl)benzamide 7 I X3 -fluoro-N -(7-(2- o o o o o o u u wisopropoxypyrimidin-5 - 3 -fluoro-3 - yl)benzo [d]thiazol-2-yl)-3 - ((methoxy- 435.2 ((methoxy- d3 )methyl)azetidin d3)methyl)azetidine- 1 - e carboxamideN-(7-(2-ethoxypyrimidin-5- yl)benzo [d]thiazol-2-yl)-3 - 3 -(methoxy -d3)-3 - (methoxy-d3)-3- 403.2 methylazetidine methylazetidine- 1 - carboxamideN-(7-(2- H INHisopropoxypyrimidin-5 - T \Z^OCD3yl)benzo [d]thiazol-2-yl)-3 - 3 -(m ethoxy -d3 )-3 - 417.2 (methoxy-d3)-3- methylazetidine methylazetidine- 1 - carboxamideh [ ^NHN-(7-(4- (difluoromethoxy)phenyl)benzo[d]thiazol-2-yl)-2-oxa- n / a 418.1 6-azaspiro[3.3]heptane-6- 0carboxamideN-(7-(2- 2-cyclopropoxy-5- cyclopropoxypyrimidin-5 - (4, 4,5,5- yl)benzo [d]thiazol-2-yl)-3 - z— A / =\ <D / \^ / ofluoro-3- Q_ _ tetramethyl- 1,3,2- 430.3 dioxaborolan-2- (methoxymethyl)azetidine- yl)pyrimidine1 -carboxamideZ'1l 3 -(methoxy-d3 )-3 - Il | 'X—NH zmethylazetidine3 -(methoxy -d3)-3 -methyl- T / \Z^OCD3andN-(7-(2-(oxetan-3-yl)-l- o 2-(oxetan-3-yl)-5- oxoisoindolin-5- A CDD ( 468.2(4, 4,5,5- yl)benzo[d]thiazol-2- tetramethyl- 1,3,2- yl)azetidine- 1 -carboxamidedioxaborolan-2- yl)isoindolin- 1 -one3-fluoro-N-(7-(2-(2- 2-(2- methoxyethoxy)pyrimidin- methoxyethoxy)-5- 5 -yl)benzo [d]thiazol-2-yl)- (4, 4,5,5- 448.2 3- tetramethyl- 1,3,2- (methoxymethyl)azetidine- dioxaborolan-2- 1 -carboxamide yl)pyrimidineOMe tert-butyl 3- 3-fluoro-N-(7- ° / \ J (4, 4,5,5- (6, 6a, 7, 8, 9,10- [ |Ftetramethyl- 1,3,2- hexahydropyrazino [1,2- dioxaborolan-2-yl)- d]pyrido[3,2-b][l,4]oxazin- 6a, 7, 9,10- 485.2 3 -yl)benzo [d]thiazol-2-yl)- XJ tetrahydropyrazino [3- l,2-d]pyrido[3,2- (methoxymethyl)azetidine- b][l,4]oxazine- 1 -carboxamide H 8(6H)-carboxylateN-(7-(2-ethoxypyrimidin-5- [| | V- NHyl)benzo[d]thiazol-2-yl)- 1 Ol,l-difluoro-5-Zn / a 418.1 azaspiro[2.3]hexane-5- NcarboxamideOEtN-(7-(l -isopropyl- 1H- H [ X- NHpyrazol-4- yl)benzo[d]thiazol-2-yl)-2- n / a 384.2 oxa-6-azaspiro[3.3]heptane- N N6-carboxamide3 -fluoro-3 -((m ethoxy - 3 -fluoro-3 - d3)methyl)-N-(7-(l- ((methoxy- ((tetrahydro-2H-pyran-4- d3 )methyl)azetidin 463.3 yl)methyl)- 1 H-pyrazol-4- syP e yl)benzo[d]thiazol-2- yl)azetidine- 1 -carboxamide3 -fluoro-3 - (methoxymethyl)-N-(7-(l - [ T YNXHFi ^sX / OMe(2 -morpholinoethyl)- 1 H- n / a 475.2 pyrazol-4- yl)benzo[d]thiazol-2- 0yl)azetidine- 1 -carboxamide(S)-N-(7-(l -((1 ,4-dioxan-2- (S)-l-((l,4-dioxan- |T y ' ^YNH / \yl)methyl)- 1 H-pyrazol-4- 0X-S \_N V F OMe 2-yl)methyl)-4- 1 Oyl)benzo [d]thiazol-2-yl)-3 - (4, 4,5,5- 462.2 fluoro-3 - k 1 tetramethyl- 1,3,2- (methoxymethyl)azetidine- dioxaborolan-2-yl)- 1 -carboxamide IH-pyr azole(R)-N-(7-(l -(( 1 ,4-dioxan-2- (R)- 1 -((1 ,4-dioxan- J X / \ Fyl)methyl)- 1 H-pyrazol-4- T^sYN / <0-OMe2-yl)methyl)-4- yl)benzo [d]thiazol-2-yl)-3 - (4, 4,5,5- 462.2 fluoro-3 - tetramethyl- 1,3,2- (methoxymethyl)azetidine- dioxaborolan-2-yl)- 1 -carboxamide IH-pyr azole°C3DN-(7-( 1 -methyl- 1H- pyrazol-5- yl)benzo[d]thiazol-2-yl)-2- n / a 356.1 oxa-6-azaspiro[3.3]heptane- 6-carboxamideN-(7-(6,7-dihydro-4H- pyrazolo [5 , 1 -c] [ 1 ,4]oxazin- H £ NH3 -yl)benzo [d]thiazol-2-yl)- r 's^OO n / a 398.2 2-oxa-6- azaspiro[3.3]heptane-6- / carboxamide / =\l,l-difluoro-N-(7-(l-(2- 2-methyl-l-(3- hydroxy-2-methylpropyl)- methyl-4-(4, 4,5,5 - 3 -methyl- 1 H-pyrazol-4- C Zk tetramethyl-1,3,2-T1 448.2 yl)benzo [d]thiazol-2-yl)-5 - z dioxaborolan-2-yl)- azaspiro[2.3]hexane-5- HO^ _ / IH-pyrazol-l- 5carboxamide oo yl)propan-2-ol ol,l-difluoro-N-(7-(l-(2- hydroxy-2-methylpropyl)- f| | NHlH-pyrazol-4- Xsn / a 434.1 yl)benzo [d]thiazol-2-yl)-5 - azaspiro[2.3]hexane-5- carboxamide3 -fluoro -3- ((methoxy- d3 )methyl)azetidin5 - (2 - (3 -fluoro -3 - ((methoxy - e d3)methyl)azetidine- 1 - and carboxamido)benzo [d]thiaz 475.3N-(oxetan-3 -yl)-5 - ol-7 -yl)-N -(oxetan-3 - (4, 4,5,5- yl)picolinamidetetramethyl- 1,3,2- dioxaborolan-2- yl)picolinamideN-(7-(3,6-dihydro-2H- pyran-4-yl)benzo [d]thiazol- [[ / ^nhz\ F2-yl)-3-fluoro-3- 1 Qi n / a 378.1 (methoxymethyl)azetidine- 1 -carboxamide3-fluoro-3- (methoxymethyl)-N -(7- (tetrahydro-2H-pyran-4- 380.1 yl)benzo[d]thiazol-2- °yl)azetidine- 1 -carboxamide (Hydrogenation of Example 106:H2, 50 PSI, EtOAc)*Boc removal required as additional final step (5 eq TFA, dichloromethane)

[0099] Synthetic procedure C

[0100] Example 108: 3-Fluoro-N-(7-(4-methoxy-lH-pyrazol-l-yl)benzo[d]thiazol-2-yl)~ 3-(melhoxymelhyl)azelidine-l -carboxamide

[0101] A mixture of N-(7-bromobenzo[d]thiazol-2-yl)-3-fluoro-3-(methoxymethyl)azetidine-l -carboxamide (see B Step 2; 100 mg, 0.27 mmol), DMSO (2 mL), cesium carbonate (435 mg, 1.34 mmol), bis[(tetrabutylammonium iodide)copper(I) iodide] (30 mg, 26.7 mmol), 4-methoxy-lH-pyrazole (52 mg, 0.53 mmol) andN,N-dimethylglycine (6 mg, 54 pmol) was stirred at 120 °C for 12 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Preparative HPLC purification (column: Phenomenex Luna Cis 150*25 mm 10 pm; acetonitrile: water (formic acid)]; gradient: 31%-61% B over 10 min) afforded 3-fluoro-N-(7-(4-methoxy-lH-pyrazol-l-yl)benzo[d]thiazol-2-yl)-3-(methoxymethyl)azetidine-l-carboxamide (17 mg, 45 pmol, 17%) as a white solid; 5H(400 MHZ; CDCh) 7.73 (1H, s), 7.60-7.52 (2H, m), 7.44 (1H, m), 7.29 (1H, d, J8.1 Hz), 4.29-4.21 (4H, m), 3.86 (3H, s), 3.66 (2H, m), 3.48-3.44 (3H, m); 5F (400 MHz; CDCh) -157.4; MS-MS [M+H]+: 392.1.

[0102] Other examples prepared using synthetic procedure C are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).Ex. Intermediates ES-MS Name StructureNo. requiring synthesis [M+H]+3-fluoro-N-(7-(4-(2- 3 -fluoro-3 - (methoxy-d3 )ethoxy)- ((methoxy- IH-pyrazol-l- d3 )methyl)azetidineN109 yl)benzo[d]thiazol-2- and 442.2 yl)-3-((methoxy- p 4-(2-(methoxy- d3)methyl)azetidine- 1 - d3)ethoxy)-lH- carboxamide *bcD3pyrazoleN-(7-(4-(2- 0(difluoromethoxy)ethr3 -fluoro-3 - ox ^FN\ / <F0CD3((methoxy- y)-lH-pyrazol-l- N d3 )methyl)azetidine yl)benzo[d]thiazol-2- 110 and 475.2 yl)-3 -fluoro-3 - F4-(2- ((methoxy- 10o (difluoromethoxy)et d3)methyl)azetidine- 1 - oohoxy)- 1 H-pyr azole carboxamide3 -fluoro-3 -((m ethoxy - 3 -fluoro-3 - d3)methyl)-N-(7-(4-(2- ((methoxy- morpholinoethoxy)- IH- d3 )methyl)azetidine111 pyrazol-l- and 494.1 yl)benzo[d]thiazol-2- 4-(2-((lH-pyrazol-4- yl)azetidine-l- yl)oxy)ethyl)morpho carboxamide line3-fluoro-3- (methoxymethyl)-N-(7- (4-(2- [| £ 'FNH .\FsZJ^NF<^>OMe 4-(2-((lH-pyrazol-4- morpholinoethoxy)- IH- N °112 yl)oxy)ethyl)morpho 491.2 pyrazol-l- line yl)benzo[d]thiazol-2- yl)azetidine-l- carboxamideN-(7-(4-ethoxy-lH- pyrazol-1- J [ V- NHyl)benzo[d]thiazol-2- N0n / a 406.2 yl)-3-fluoro-3- (methoxymethyl)azetidiOEtne- 1 -carboxamide(R)-3-fluoro-3- (methoxymethyl)-N-(7- (4-(2- [i inh(R)-4-(l-((lH- morpholinopropoxy)- N ° pyrazol-4- 505.2 IH-pyrazol-l- yl)oxy)propan-2- yl)benzo[d]thiazol-2- yl)morpholine yl)azetidine-l- carboxamide(S)-3-fluoro-3- (methoxymethyl)-N-(7- (4-(2- [i inh(S)-4-(l-((lH- morpholinopropoxy)- N ° pyrazol-4- 505.2 IH-pyrazol-l- yl)oxy)propan-2- yl)benzo[d]thiazol-2- yl)morpholine yl)azetidine-l- carboxamideN-(7-bromo-6- 3 -fluoro -N-(6 -fluoro - 7- fluorobenzo [d]thiazo(4-((tetrahydro-2H- l-2-yl)-3 -fluoro-3 - pyran-4-yl)amino)- 1 H- 1 X z\ F (methoxymethyl)azet pyrazol-1- N O idine- 1 -carboxamide 479.2 yl)benzo[d]thiazol-2- andyl)-3- M / "AN-(tetrahydro-2H- (methoxymethyl)azetidipyran-4-yl)-lH- ne- 1 -carboxamidepyrazol-4-amine4-(2-((lH-pyrazol-4- 3 -fluoro -N-(6 -fluoro - 7- O yl)oxy)ethyl)morpho(4-(2-(3- '^N / x'>OMefl q lin-3-one oxomorpholino)eFthoxy)- andIH-pyrazol-l- NN-(7-bromo-6- 523.3 yl)benzo[d]thiazol-2- fluorobenzo [d]thiazo yl)-3- l-2-yl)-3 -fluoro-3 - (methoxymethyl)azetidi(methoxymethyl)azet ne- 1 -carboxamideidine- 1 -carboxamide4-((l-methyl-2- 3 -fluoro -N-(6 -fluoro - 7- oxabicyclo [2.1.1 ]hex0 (4-((l-methyl-2- an-4-yl)methoxy)- oxabicyclo[2.1. l]hexan- [| | NHFIH-pyr azole4-yl)methoxy)- 1 H- and N506.3 pyrazol-1- N-(7-bromo-6- yl)benzo[d]thiazol-2- H fluorobenzo [d]thiazoyl)-3- l-2-yl)-3 -fluoro-3 - (methoxymethyl)azetidi(methoxymethyl)azet ne- 1 -carboxamideidine- 1 -carboxamideN-(7-(4-ethoxy-lH- o N-(7-bromo-6- 'VN / ><C'OMe pyrazol-l-yl)-6- [I 7Ffluorobenzo [d]thiazo fluorobenzo [d]thiazol-2- l-2-yl)-3 -fluoro-3 - 424.1 N yl)-3 -fluoro-3 - (methoxymethyl)azet (methoxymethyl)azetidiidine- 1 -carboxamide OEtne- 1 -carboxamideN-(7-bromo-6- fluorobenzo [d]thiazoN-(7-(4-(2-(6-oxa-3- l-2-yl)-3 -fluoro-3 - azabicyclo [3.1.1 ]heptan- O ((methoxy- 3 -yl)ethoxy)- 1 H- 'VN / \<'>OCD3d3 )methyl)azetidine- fi y \\_I / HFpyrazol-l-yl)-6- F^Y^S1 -carboxamide fluorobenzo [d]thiazol-2- N 524.2 andyl)-3 -fluoro-3 - 3-(2-((lH-pyrazol-4- ((methoxy- yl)oxy)ethyl)-6-oxa- d3 )methyl)azetidine- 1 - 3- carboxamideazabicyclo [3.1.1 ]hepfane3 -fluoro -N-(6 -fluoro - 7- O N-(7-bromo-6- (4-methoxy- IH-pyrazol- ^N / \<2'OMefl | \^NHFfluorobenzo [d]thiazo1 -yl)benzo [d]thiazol-2- l-2-yl)-3 -fluoro-3 - 410.1 yl)-3- N(methoxymethyl)azet (methoxymethyl)azetidiOMe idine- 1 -carboxamide ne- 1 -carboxamidetrans-4-(2-((lH- pyrazol-4- N-(7-(4-(2-(trans-2,6- 0V- N / VCxOMe yl)oxy)ethyl)-2,6- dimethylmorpholino)eth f| [ \\_|YHFdimethylmorpholine oxy)- 1 H-pyrazol- 1 -yl)- and6-fluorobenzo [d]thiazol- N 537.3N-(7-bromo-6- 2-yl)-3 -fluoro-3 - fluorobenzo [d]thiazo (methoxymethyl)azetidil-2-yl)-3 -fluoro-3 - ne- 1 -carboxamide(methoxymethyl)azet idine- 1 -carboxamide cis-4-(2-((lH- pyrazol-4- N-(7-(4-(2-(cis-2,6- 0yl)oxy)ethyl)-2,6- dimethylmorpholino)eth f| f \\_NHFdimethylmorpholine oxy)- 1 H-pyrazol- 1 -yl)- and6-fluorobenzo [d]thiazol- N 537.2N-(7-bromo-6- 2-yl)-3 -fluoro-3 - fluorobenzo [d]thiazo (methoxymethyl)azetidil-2-yl)-3 -fluoro-3 - ne- 1 -carboxamide(methoxymethyl)azet idine- 1 -carboxamide6-(2-((lH-pyrazol-4- N-(7-(4-(2-(2-oxa-6- yl)oxy)ethyl)-2-oxa- azaspiro[3.3]heptan-6- o 6- V- N / V7'OMeyl)ethoxy)- 1 H-pyrazol- fl | y- NHFazaspiro [3.3 ]heptanel-yl)-6- F^A5andN 521.1 fluorobenzo [d]thiazol-2- N-(7-bromo-6- yl)-3 -fluoro-3 - fluorobenzo [d]thiazo°-\ / \ / Y)(methoxymethyl)azetidi l-2-yl)-3 -fluoro-3 - ne- 1 -carboxamide (methoxymethyl)azet idine- 1 -carboxamide4-(2-(lH-pyrazol-4- 3-fluoro-N-(6-fluoro-7- 0^NZ\<'>OMe yl)ethyl)morpholine(4-(2-morpholinoethyl)- If I 'M” andIH-pyrazol-l- N N-(7-bromo-6- yl)benzo[d]thiazol-2- 493.1 v) fluorobenzo [d]thiazo yi)-3- l-2-yl)-3 -fluoro-3 - (methoxymethyl)azetidi N—(methoxymethyl)azet ne- 1 -carboxamideidine- 1 -carboxamide(S)-4-(l-((lH- (S)-3-fluoro-N-(6- pyrazol-4- fluoro-7-(4-(2- 0 yl)oxy)propan-2- morpholinopropoxy)- If T ^HFyl)morpholineIH-pyrazol-l- andN 523.2 yl)benzo[d]thiazol-2- N-(7-bromo-6- yi)-3- fluorobenzo [d]thiazo (methoxymethyl)azetidi °>c° l-2-yl)-3 -fluoro-3 - ne- 1 -carboxamide (methoxymethyl)azet idine- 1 -carboxamide(R)-4-(l-((lH- (R) -3 -fluoro -N- (6 - pyrazol-4- fluoro-7-(4-(2- o yl)oxy)propan-2- 'VN / \<>OMemorpholinopropoxy)- n \ NHFyl)morpholineIH-pyrazol-l- F-^Y^S andN 523.3 yl)benzo[d]thiazol-2- N-(7-bromo-6- yl)-3- fluorobenzo [d]thiazo (methoxymethyl)azetidi l-2-yl)-3 -fluoro-3 - ne- 1 -carboxamide (methoxymethyl)azet idine- 1 -carboxamideN-(7-bromo-6- N-(6-fluoro-7-(4-(2- O z\ fluorobenzo [d]thiazo morpholinoethoxy)- IH- N VN V ] 1-2-yl)-5-oxa-2- H | ^NH ^ V--1pyrazol-l- azaspiro[3.4]octane- yl)benzo[d]thiazol-2- N 2-carboxamide 503.2 yl)-5-oxa-2- andazaspiro [3.4] octane-2 - 4-(2-((lH-pyrazol-4- carboxamide yl)oxy)ethyl)morpholineN-(7-bromo-6- N-(6-fluoro-7-(4-(2- fluorobenzo [d]thiazo morpholinoethoxy)- IH- 1-2-yl)-6-oxa-2- pyrazol-l- azaspiro[3.4]octane- yl)benzo[d]thiazol-2- N 2-carboxamide 503.1 yl)-6-oxa-2- andazaspiro [3.4] octane-2 - 4-(2-((lH-pyrazol-4- carboxamide yl)oxy)ethyl)morpholineN-(7-bromo-6- fluorobenzo [d]thiazoN-(7-(4-(2-(8-oxa-3- l-2-yl)-3 -fluoro-3 - azabicyclo[3.2. l]octan- ((methoxy- 3 -yl)ethoxy)- 1 H- d3 )methyl)azetidine- pyrazol-l-yl)-6- 1 -carboxamide fluorobenzo [d]thiazol-2-6« 538.3 oyl - - l o o 3 o and) 3 f u r - - u3-(2-((lH-pyrazol-4- ((methoxy- yl)oxy)ethyl)- 8 -oxa- d3 )methyl)azetidine- 1 - 3- carboxamideazabicyclo[3.2. l]octane3-fluoro-N-(6-fluoro-7- (4-((l- o'^N / X>OMemorpholinocyclopropyl) f| q NHF4-(l-(((l H-pyrazol- methoxy)- 1 H-pyrazol- 1 - 4- N n 535.3 yl)benzo[d]thiazol-2- yl)oxy)methyl)cyclo oyi)-3- propyl)morpholine (methoxymethyl)azetidine- 1 -carboxamide3-fluoro-N-(6-fluoro-7- (4-(2-methyl-2- O'^N / \<CxOMemorpholinopropoxy)- l| | V- NHF4-(l-((lH-pyrazol-4- 1 H-pyrazol- 1 - yl)oxy)-2- N n 537.2 yl)benzo[d]thiazol-2- methylpropan-2- yl)-3- yl)morpholine (methoxymethyl)azetidine- 1 -carboxamide3-fluoro-N-(6-fluoro-7- O(4-(2-methoxyethoxy)- V- N / V^OMeIH-pyrazol-l- J jT NHFyl)benzo[d]thiazol-2- N n / a 454.1 yi)-3- (methoxymethyl)azetidi \— OMene- 1 -carboxamide3-fluoro-N-(6-fluoro-7- (4-(2- morpholinoethoxy)- IH- Jl ^nhN / \ \<^ F OMe 4-(2-((lH-pyrazol-4- pyrazol-l- N0yl)oxy)ethyl)morpho 509.1 yl)benzo[d]thiazol-2- lineyi)-3- (methoxymethyl)azetidine- 1 -carboxamideN-(7-bromo-6- 3 -fluoro -N-(6 -fluoro - 7- fluorobenzo [d]thiazo(4-(2- l-2-yl)-3 -fluoro-3 - morpholinoethoxy)- IH- ((methoxy- F^XJ^'S \-N X^0CD3pyrazol-l- N ° d3 )methyl)azetidine- 512.1 yl)benzo[d]thiazol-2- 1 -carboxamide yl)-3-((methoxy- and d3)methyl)azetidine- 1 - 4-(2-((lH-pyrazol-4- carboxamide yl)oxy)ethyl)morpholine3-fluoro-N-(6-fluoro-7- N-(7-bromo-6- (4-(2-methoxyethoxy)- fluorobenzo [d]thiazoIH-pyrazol-l- F" 1'\X X>^SX^NHZ\ \<^ F OCD3l-2-yl)-3 -fluoro-3 - yl)benzo[d]thiazol-2- N ° 457.2((methoxy- yl)-3-((methoxy- d3 )methyl)azetidine- d3)methyl)azetidine- 1 - OMe1 -carboxamide carboxamide3-fluoro-N-(7-(4-(2- m ethoxy ethoxy)- 1 H- pyrazol-1- L \z JL"S / ^NH / \ V^ F OMeyl)benzo[d]thiazol-2- N 0 n / a 436.2 yi)-3- (methoxymethyl)azetidi X^OMene- 1 -carboxamideoxazol-2-ylmethyl (7- ~ Nf| T Z^NH oxazol-2-ylmethyl(4-morpholino- 1 H- (7- pyrazol-1- N 427.1 bromobenzo [d]thiaz yl)benzo[d]thiazol-2- ol-2-yl)carbamate yl)carbamateQoxazol-2-ylmethyl (7- ~Noxazol-2-ylmethyl(4-(2-methoxyethoxy)- (l \ NH^x^^S (7- IH-pyrazol-l-7416.1 N bromobenzo [d]thiaz yl)benzo[d]thiazol-2- ol-2-yl)carbamate yl)carbamate^OMe0.oxazol-2-ylmethyl (7- / . .N oxazol-2-ylmethyl(4-methoxy- IH-pyrazol- \\ \XVNH (7- 372.1 1 -yl)benzo [d]thiazol-2- N bromobenzo [d]thiaz yl)carbamate ol-2-yl)carbamateOMeN-(7-bromo-4,6- N-(4,6-difluoro-7-(4-(2- F difluorobenzo [d] thi a morpholinoethoxy)- IH- zol-2-yl)-3-fluoro-3- pyrazol-l- Il [ NH (methoxymethyl)azet MIS SINyl)benzo[d]thiazol-2- N ° idine- 1 -carboxamideGyl)-3-fluoro-3- and (methoxymethyl)azetidi 4-(2-((lH-pyrazol-4- ne- 1 -carboxamide yl)oxy)ethyl)morpho lineN-(7-bromo-6- fluorobenzo [d]thiazoN-(7-(4-(azetidin-3- OMel-2-yl)-3 -fluoro-3 - yloxy)- 1 H-pyrazol- 1 - (methoxymethyl)azet yl)-6- A idine- 1 -carboxamide142 fluorobenzo [d]thiazol-2- 451.3 yl)-3 -fluoro-3 - tert-butyl 3-((lH- (methoxymethyl)azetidi (Boc removal required aspyrazol-4- ne- 1 -carboxamide additional final step (20 eq TFA,yl)oxy)azetidine- 1 - dichloromethane)carboxylateN-(7-bromo-6- 1 / Xo o LN z\3 - V^ F fluorobenzo [d]thiazo flu r -N-(6 -fluoro - 7- OMeN ° l-2-yl)-3 -fluoro-3 - (4-(( 1 -methylazetidin-3 - (methoxymethyl)azet yl)oxy)- 1 H-pyrazol- 1 - Hidine- 1 -carboxamide143 yl)benzo[d]thiazol-2- 465.3 andyl)-3- / tert-butyl 3-((lH- (methoxymethyl)azetidi (Prepared by methylation of pyrazol-4- ne- 1 -carboxamide Example 142 using formaldehyde, yl)oxy)azetidine- 1 - NaBHsCN, AcOH, MeOH, 25 °C) carboxylate

[0103] Synthetic procedure D

[0104] Example 144: 3-Fluoro-N-(6-fluoro-7-(6-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)benzo[d]thiazol-2-yl)-3-((methoxy-d3)methyl)azetidine-l-carboxamide

[0105] Pd(dppf)C12 (400mg, 0.55 mmol) was added to a solution of N-(7-bromo-6-fluorobenzo[d]thiazol-2-yl)-3-fluoro-3-((methoxy-d3)methyl)azetidine-l-carboxamide (2.00 g, 5.06 mmol), N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.3 g, 7.56 mmol), sodium carbonate (1.80 g, 17.0 mmol) in dioxane (20 mL) and water (0.5 mL). The mixture was degassed and purged with nitrogen three times, then stirred at 80 °C for 12 h. Water (40 mL) was added and the mixture was extracted intoethyl acetate (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 90:10 to 100:0) then preparative HPLC (column: Phenomenex Luna Cis 150*40mm 15 pm; acetonitrile:water(formic acid); gradient: 25%-55% B over 10 min) afforded 3-fluoro-N-(6-fluoro-7-(6-((tetrahydro-2H-pyran-4-yl)amino)pyridin-3-yl)benzo[d]thiazol-2-yl)-3-((methoxy-d3)methyl)azetidine-l -carboxamide (702 mg, 1.43 mmol, 28% yield) as a white solid; 5H (400 MHz; DMSO-d6) 11.79-11.17 (1H, m), 8.20 (1H, s), 7.58 (1H, br d, J 8.6 Hz), 7.51 (1H, m), 7.36-7.20 (1H, m), 6.89 (1H, d, J7.4 Hz), 6.62 (1H, d, J8.6 Hz), 4.19-3.95 (5H, m), 3.93-3.84 (2H, m), 3.75-3.64 (2H, m), 3.43 (2H, m), 1.92 (2H, m), 1.55-1.37 (2H,Xm); 5F (400 MHz; DMSO-d6) -125.7, -155.5; ES-MS [M+H]+: 493.2.

[0106] Other examples prepared using synthetic procedure D are shown in the following ttable. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).IntermediatesEx. ES-MS Name Structure requiringNo. [M+H]+synthesisN-(7-(2- N-(7-bromo-6- (difluoromethoxy)pyrimidin- fluorobenzo [d] thia5-yl)-6- zol-2-yl)-3-fluoro- 145 fluorobenzo [d]thiazol-2-yl)- 3-((methoxy- 461.1 3 -fluoro-3 -((methoxy - d3 )methyl)azetidin d3)methyl)azetidine- 1 - e-1 -carboxamide carboxamideN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3 -fluoro -N- (6 -fluoro -7- (2 - 3-((methoxy- ((tetrahydro-2H-pyran-4- d3 )methyl)azetidin yl)amino)pyrimidin-5 - e-1 -carboxamide146 yl)benzo [d]thiazol-2-yl)-3 - 494.3 and((methoxy- N-(tetrahydro-2H- d3)methyl)azetidine- 1 - pyran-4-yl)-5- carboxamide(4, 4,5,5- tetramethyl- 1,3,2- dioxaborolan-2-yl)pyrimidin-2- amineN-(7-(2- COQ N-(7-bromo-6- (difluoromethoxy)pyrimidin- Ofi rnhfluorobenzo [d] thi a5-yl)-6- T c / \Z^OCD36 zol-2-yl)-3- fluorobenzo [d]thiazol-2-yl)- z 443.2N. N (methoxy-d3)-3- 3 -(methoxy -d3)-3 - z X- IFI methylazetidine- 1 - methylazetidine- 1 - carboxamide carboxamide y)S CN-(7-bromo-6- fluorobenzo [d] thiazol-2-yl)-3- (methoxy-d3)-3- N- (6 -fluoro -7- (2 - methylazetidine- 1 - ((tetrahydro-2H-pyran-4- carboxamide yl)amino)pyrimidin-5 - andyl)benzo [d]thiazol-2-yl)-3 - N-(tetrahydro-2H- 476.3 (methoxy-d3)-3- pyran-4-yl)-5- methylazetidine- 1 - (4, 4,5,5- carboxamide tetramethyl- 1,3,2- dioxaborolan-2- yl)pyrimidin-2- amine3 -fluoro -N- (6 -fluoro -7- (6 - N-(7-bromo-6- (morpholinomethyl)pyridin- 1 X ^N\H_N / \ \<^ F,OCD3fluorobenzo [d] thi a3 -yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 493.2 ((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamide3 -fluoro -N- (6 -fluoro -7- (4 - N-(7-bromo-6- (morpholinomethyl)phenyl)b 1 X )-N Z\ F fluorobenzo [d] thi a enzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 492.2 ((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - 0 d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(7-bromo-6- N- (6 -fluoro -7- (6 - H T / *— NH . fluorobenzo [d] thia (morpholinomethyl)pyridin- F I S Y—I rO / \Z 'OCD3° zol-2-yl)-3- 3 -yl)benzo [d]thiazol-2-yl)-3 - (methoxy-d3)-3- 475.2 (methoxy-d3)-3- Cxmethylazetidine- 1 - methylazetidine- 1 - carboxamide carboxamideN- (6 -fluoro -7- (4 - N-(7-bromo-6- inomethyl)phenyl)b f| [ NH(morphol F I S Y—I rO / \Z ^OCD3fluorobenzo [d] thi a°enzo [d]thiazol-2-yl)-3 - zol-2-yl)-3- 474.2 (methoxy-d3)-3- (methoxy-d3)-3- methylazetidine- 1 - 0 methylazetidine- 1 - carboxamide carboxamideN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3- 3 -fluoro -N- (6 -fluoro -7- (2 - (methoxymethyl)az ((1- I XX^ Y- N / \ V^ F OMe etidine-1- (hydroxymethyl)cyclobutyl)acarboxamide mino)pyrimidin-5 - 491.2NxN andyl)benzo [d]thiazol-2-yl)-3 - (l-((5-(4, 4,5,5- (methoxymethyl)azetidine- 1 - HNHOO>\ / tetramethyl- 1,3,2- carboxamidedioxaborolan-2- yl)pyrimidin-2- yl)amino)cyclobut yl)methanolN-(7-bromo-6- N- (6 -fluoro -7- (2 - J I J*- NHfluorobenzo [d] thi a isopropoxypyrimidin-5 -Fc^N\ / <OMezol-2-yl)-3- yl)benzo [d]thiazol-2-yl)-3 - 432.2N^N methoxy-3- methoxy -3 -methylazetidine- methylazetidine- 1 - 1 -carboxamidecarboxamideN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3- 3 -fluoro -N- (6 -fluoro -7- (2 - (methoxymethyl)az (((3S,4R)-3- etidine-1- hydroxytetrahydro-2H-pyran- v carboxamide4-yl)amino)pyrimidin-5- and 507.1 yl)benzo [d]thiazol-2-yl)-3 - (3S,4R)-4-((5- (methoxymethyl)azetidine- 1 - I X (4, 4,5,5- o ocarboxamide 22 n n>> tetramethyl- 1,3,2- dioxaborolan-2- yl)pyrimidin-2- yl)amino)tetrahydr o-2H-pyran-3-olN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3- (methoxymethyl)az3 -fluoro -N- (6 -fluoro -7- (2 - etidine-1- ((l-methyl-2- carboxamide oxabicyclo[2.1. l]hexan-4- and yl)methoxy)pyrimidin-5 - 518.42-((l-Methyl-2- yl)benzo [d]thiazol-2-yl)-3 - oxabicyclo[2.1.1]h (methoxymethyl)azetidine- 1 - exan-4- carboxamideyl)methoxy)-5- (4, 4,5,5- tetramethyl-1,3- dioxolan-2- yl)pyrimidineN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3- (methoxymethyl)az 3-fluoro-N-(6-fluoro-7-(2-(2- etidine-1- morpholinoethoxy)pyrimidin- carboxamide5 -yl)benzo [d]thiazol-2-yl)-3 - 521.3D < and (methoxymethyl)azetidine- 1 - o4-(2-((5-(4, 4,5,5- carboxamidetetramethyl- 1,3,2- 2 <0 Tl zs xt I dioxaborolan-2- Zyl)pyrimidin-2- ZOC^GZO^ yl)oxy)ethyl)morp holineN-(7-bromo-6- Q fluorobenzo [d] thia I zol-2-yl)-3-fluoro- o<0 3- N-(7-(2- (methoxymethyl)az cyclopropoxypyrimidin-5 - I JL \-N Z\ V F OMeetidine-1- yl)-6-fluorobenzo[d]thiazol- carboxamide 448.2 2-yl)-3-fluoro-3- N . Nand (methoxymethyl)azetidine- 1 - 2-cyclopropoxy-5- carboxamide(4, 4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)pyrimidineN-(7-bromo-6- fluorobenzo [d] thia5-(6-fluoro-2-(3-fluoro-3- zol-2-yl)-3-fluoro- (methoxymethyl)azetidine- 1 - 3- 448.1 carboxamido)benzo [d]thiazol(methoxymethyl)az -7 -yl)-N -methylpicolin amideetidine-1- carboxamideN-(7-bromo-6- 3 -fluoro -N- (6 -fluoro -7- (6 - fluorobenzo [d] thia (morpholine-4- zol-2-yl)-3-fluoro- carbonyl)pyridin-3 - 3- 504.2 yl)benzo [d]thiazol-2-yl)-3 - (methoxymethyl)az (methoxymethyl)azetidine- 1 - etidine-1- carboxamidecarboxamide0) 0) N-(7-bromo-6- O Ofluorobenzo [d] thia zol-2-yl)-3-fluoro- X X 3- X X ZKk X X- 3 -fluoro -N- (6 -fluoro -7- (2 - D3 Z x Z > (methoxymethyl)az (morpholine-4- xw^ etidine-1- carbonyl)pyrimidin-5 - carboxamide505.2 yl)benzo [d]thiazol-2-yl)-3 - . w and (methoxymethyl)azetidine- 1 - 0 morpholino(5- carboxamide (4, 4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)pyrimidin-2- yl)methanoneN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 0F3- ><0Me(methoxymethyl)az5-(6-fluoro-2-(3-fluoro-3- I Xetidine-1- (methoxymethyl)azetidine- 1 - carboxamide carboxamido)benzo [d]thiazol CX 492.1 and-7-yl).N-(2- HN^O N-(2- methoxyethyl)picolinamidemethoxyethyl)-5 - ^Me (4, 4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)picolinamideN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3- (methoxymethyl)az3 -fluoro -N- (6 -fluoro -7- (2 - etidine-1- (((l-methyl-2- carboxamide oxabicyclo[2.1. l]hexan-4- D <D <yl)m t y ) m n ) y i i s s and e h l a i o p rm din- o o 517.22-((l-Methyl-2- 5 -yl)benzo [d]thiazol-2-yl)-3 - oxabicyclo[2.1.1]h (methoxymethyl)azetidine- 1 - z exan-4- carboxamidepI / Y)z. - yl)methoxy)-5- ZOT^ (4, 4,5,5- tetramethyl-1,3- \\l / z '== ' ^- — dioxolan-2- yl)pyrimidineN-(7-bromo-6- N-(7-(2- fluorobenzo [d] thia cyclobutoxypyrimidin-5 -yl)- zol-2-yl)-3-fluoro- 6-fluorobenzo [d]thiazol-2- 3- 462.1 yl)-3-fluoro-3- (methoxymethyl)az (methoxymethyl)azetidine- 1 - etidine-1- carboxamidecarboxamideN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-5,8- dioxa-2- N- (6 -fluoro -7- (6 - Il I NH ^0azaspiro [3.5 ]nonan ((tetrahydro-2H-pyran-4- ’Y1Y"X> e-2-carboxamide yl)amino)pyridin-3 - and 500.1 yl)benzo [d]thiazol-2-yl)-5 , 8 - N-(tetrahydro-2H- dioxa-2-azaspiro [3.5 ]nonane- pyran-4-yl)-5- 2-carboxamide(4, 4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)pyridin-2-amineN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3- (methoxymethyl)az3 -fluoro -N- (6 -fluoro -7- (2 - etidine-1- ((lr,3r)-3- carboxamide hydroxycyclobutoxy)pyrimidD <s Q and 478.1 in-5 -yl)benzo [d]thiazol-2-yl)- o O(lr,3r)-3-((5- 3 -(methoxymethyl)azetidine- a b is (4, 4,5,5- 1 -c r oxamidez z tetramethyl- 1,3,2- xs, zL xX Z) T o zi I dioxaborolan-2- 19ZO <5C^" yl)pyrimidin-2- yl)oxy)cyclobutan-z\= \ / l-olN-(6-fluoro-7-(2-(oxetan-3- N-(7-bromo-6- Xyloxy)pyrimidin-5 - oo fluorobenzo [d] thi a oyl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3- 449.1 (methoxy-d3)-3- (methoxy-d3)-3- methylazetidine- 1 - methylazetidine- 1 - carboxamide carboxamide3 -fluoro -N- (6 -fluoro -7- (2 - N-(7-bromo-6- (oxetan-3 -yloxy)pyrimidin-5 - fluorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 467.1 ((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(7-bromo-6- 3 -fluoro -N-(6 -fluoro - 7- fluorobenzo [d] thia (pyridazin-4- 1 JL UN z'\V F zol-2-yl)-3-fluoro- ,OMeyl)benzo [d]thiazol-2-yl)-3 - 3- 392.2 (methoxymethyl)azetidine- 1 - (methoxymethyl)az 6carboxamide etidine-1- carboxamideN-(7-bromo-6- fluorobenzo [d] thia zol-2-yl)-3-fluoro- 3- N-(7-(2-(2- (methoxymethyl)az cyclopropoxyethoxy)pyrimidietidine-1- n-5-yl)-6- carboxamide fluorobenzo fd]thiazol-2-yl)- 492.2D C3-fluoro-3- so 2-(2- (methoxymethyl)azetidine- 1 - cyclopropoxyethox carboxamide 2CDO -n z y)-5-(4, 4,5,5- xL. x- X Z) tetramethyl- 1,3,2- ZZ)i ^ dioxaborolan-2- yl)pyrimidineCk H11z N-(7-bromo-6- u.3-fluoro-N-(6-fluoro-7-(2-(2- fluorobenzo [d] thia methoxyethoxy)pyrimidin-5 - zol-2-yl)-3-fluoro- oyl)benzo [d]thiazol-2-yl)-3 - CD 3- 466.2 (methoxymethyl)azetidine- 1 - (methoxymethyl)az carboxamide etidine-1- carboxamideN-(6-chloro-7-(2, 3 -dihydroN-(7-bromo-6- fl, 4]dioxino[2,3-b]pyridin-7- CI-AJ-S^^N^<^0CD3 chlorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 468.2 fluoro-3 -((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(6-chloro-7-(2, 3 -dihydro°A / \ OCD3N-(7-bromo-6- N VN3fl, 4]dioxino[2,3-b]pyridin-7- fl 1 NHvchlorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - CI^X^~Szol-2-yl)-3- 450.1 (methoxy-d3)-3- (methoxy-d3)-3- methylazetidine- 1 - methylazetidine- 1 - carboxamide carboxamideN-(7-bromo-6- chlorobenzo [d] thia zol-2-yl)-3-fluoro- N-(6-chloro-7-(2-(2- 3-((methoxy- hydroxypropan-2- d3 )methyl)azetidin1 JjM" Z\ Fyl)pyrimidin-5- ^N^^OCD3e-1 -carboxamide yl)benzo [d]thiazol-2-yl)-3 - and 469.2Nfluoro-3 -((methoxy- N-(7-bromo-6- d3)methyl)azetidine- 1 - OH* fluorobenzo [d] thi a carboxamide zol-2-yl)-3-fluoro- 3-((methoxy- d3 )methyl)azetidin e-1 -carboxamideN-(7-(6- f| [ *>— NH N-(7-bromo-6- (difluoromethoxy)pyridin-3 - fluorobenzo [d] thi a yl)-6-fluorobenzo[d]thiazol- zol-2-yl)-2-oxa-6- 437.1 2-yl)-2-oxa-6- azaspiro [3.3 ]hepta azaspiro[3.3]heptane-6- F^One-6-carboxamide carboxamideN- (6 -fluoro -7- (6 - ff 1NHN-(7-bromo-6- ((tetrahydro-2H-pyran-4- <^NC>COfluorobenzo [d] thi a yl)amino)pyridin-3 - zol-2-yl)-2-oxa-6- 470.1 yl)benzo[d]thiazol-2-yl)-2- azaspiro [3.3 ]hepta oxa-6-azaspiro[3.3]heptane- ne-6-carboxamide6-carboxamideN- (6 -fluoro -7- (5 -fluoro -6 - N-(7-bromo-6- methoxypyridin-3 - f| | \\_NH fluorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - T / \Z^OCD3zol-2-yl)-3- 424.1 (methoxy-d3)-3- (methoxy-d3)-3- methylazetidine- 1 - FX) methylazetidine- 1 - OMecarboxamide carboxamideN- (6 -fluoro -7- (6 - N-(7-bromo-6- methoxypyridin-3 - J| | \V_ NH fluorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3- 406.1 (methoxy-d3)-3- (methoxy-d3)-3- methylazetidine- 1 - methylazetidine- 1 - OMecarboxamide carboxamidecoQJ| J J^NH ON-(6-chloro-7-(6- O N-(7-bromo-6- (difluor methoxy)pyridin-3 -ci s N\X / o0chlorobenzo [d] thi a yl)benzo[d]thiazol-2-yl)-2- Z zol-2-yl)-2-oxa-6- 453.1 oxa-6-azaspiro[3.3]heptane- AsX) Z azaspiro [3.3 ]hepta F^,06-carboxamide zzA> ne-6-carboxamideN-(6-chloro-7-(2- N-(7-bromo-6- oisopropoxypyrimidin-5 - chlorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 469.1 fluoro-3 -((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(6-chloro-7-(2- N-(7-bromo-6- ethoxypyrimidin-5 - chlorobenzo [d] thi a1 XX>“\HZ\ Fyl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 455.1 fluoro-3 -((methoxy- N. N 3-((methoxy- d3)methyl)azetidine- 1 - X. d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(6-chloro-7-(2- N-(7-bromo-6- ((tetrahydro-2H-pyran-4- £ T NHchlorobenzo [d] thi a yl)amino)pyrimidin-5 -Cl^N(X°CD3 zol-2-yl)-3- yl)benzo [d]thiazol-2-yl)-3 - 492.1X N (methoxy-d3)-3- (methoxy-d3)-3- methylazetidine- 1 - methylazetidine- 1 - carboxamide carboxamideN-(7-bromo-6- chlorobenzo [d] thia zol-2-yl)-3-fluoro- 3-((methoxy- N-(6-chloro-7-(2- d3 )methyl)azetidin ((tetrahydro-2H-pyran-4- e-1 -carboxamide yl)amino)pyrimidin-5 - yl)benzo [d]thiazol-2-yl)-3 - CO 510.2Q N-(tetrahydro-2H- fluoro-3 -((methoxy- O QO QO pyran-4-yl)-5- d3)methyl)azetidine- 1 - (4, 4,5,5- carboxamide oZ Z tetramethyl- 1,3,2- x A i Ax iX) Z X) Z dioxaborolan-2- ZOt ZW^^ yl)pyrimidin-2- amineN-(6-chloro-7-(6- o o N-(7-bromo-6- (difluoromethoxy)pyridin-3 - chlorobenzo [d] thi a Iyl)benzo [d]thiazol-2-yl)-3 - oo zol-2-yl)-3-fluoro- o w 476.1 fluoro-3 -((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(6-chloro-7-(2- N-(7-bromo-6- (difluoromethoxy)pyrimidin- chlorobenzo [d] thi a5 -yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 477.0 fluoro-3 -((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(6-chloro-7-(6-(2- N-(7-bromo-6- morpholinoethoxy)pyridin-3 - Cl'^Xj^S \^N^<J,OCD3chlorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 539.2 fluoro-3 -((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(6-chloro-7-(6-(l,l- N-(7-bromo-6- difluoroethyl)pyridin-3 - chlorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 474.1 fluoro-3 -((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideN-(6-chloro-7-(6- Q N-(7-bromo-6- ((tetrahydro-2H-pyran-4- QO chlorobenzo [d] thi a yl)amino)pyridin-3 - o zol-2-yl)-3-fluoro- yl)benzo [d]thiazol-2-yl)-3 - Z 509.23-((methoxy- fluoro-3 -((methoxy- XZ d3 )methyl)azetidin d3)methyl)azetidine- 1 - Z e-1 -carboxamide carboxamide &N-(6-chloro-7-(2- N-(7-bromo-6- d fl I / ^(difluoromethoxy)pyrimidin- C 1 / yz " SN\H— N chlorobenzo [d] thi a1 I I rO / \Z "OCD3- l b n o d t o °5 y ) e z [ ] hiazol-2-yl)-3 - o zol-2-yl)-3- o w 459.2 (methoxy-d3)-3- N . N (methoxy-d3)-3- methylazetidine- 1 -FX methylazetidine- 1 - carboxamide carboxamideN-(6-chloro-7-(2- N-(7-bromo-6- methoxypyrimidin-5 - H T J / - NH chlorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-Cl^N^X°CD3423.1 (methoxy-d3)-3- (methoxy-d3)-3- Nmethylazetidine- 1 - methylazetidine- 1 - OMecarboxamide carboxamideN-(6-chloro-7-(6- N-(7-bromo-6- H J Y— NH(difluoromethoxy)pyridin-3 - C 1 / s \ — N chlorobenzo [d] thi a1 I 4O \ / 'OCD3°yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3- 458.1 (methoxy-d3)-3- (methoxy-d3)-3- methylazetidine- 1 - methylazetidine- 1 - carboxamide carboxamideN-(6-chloro-7-(6- N-(7-bromo-6- methoxypyridin-3 - f INHchlorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3- 422.1 (methoxy-d3)-3-Cl[ 5<^N^<°CD3(methoxy-d3)-3- methylazetidine- 1 - methylazetidine- 1 - OMecarboxamide carboxamideoxazol-2-ylmethyl (7-(l- oxazol-2-ylmethyl methyl-6-oxo-l,6- \ ii y- NH(7- dihydropyridin-3 - 383.1 bromobenzo [d] thi a yl)benzo[d]thiazol-2- L NMe zol-2-yl)carbamate yl)carbamate0oxazol-2-ylmethyl (7-(6-oxo-Noxazol-2-ylmethylIl I NH1 ,6-dihydropyridin-3 - (7- 369.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate |l NH zol-2-yl)carbamateoxazol-2-ylmethyl (7-(3- ~ N oxazol-2-ylmethyl|| | NHchloro-4- (7- 416.0 methoxyphenyl)benzo [d] thia bromobenzo [d] thi azol-2-yl)carbamate JO zol-2-yl)carbamate OMeoxazol-2-ylmethyl (7-(3-Noxazol-2-ylmethyl fluoro-4- (7- 400.1 methoxyphenyl)benzo [d] thia bromobenzo [d] thi azol-2-yl)carbamate JO zol-2-yl)carbamateOMeoxazol-2-ylmethyl (7-(2,4- oxazol-2-ylmethyl dimethoxypyrimidin-5 - (7- 414.0 yl)benzo[d]thiazol-2- l .OMe bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate OMe0oxazol-2-ylmethyl (7-(6- / . ..N VcTiJ oxazol-2-ylmethyl methylpyridin-3 - ft \ (7- 367.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateoxazol-2-ylmethyl (7-(2,6-Noxazol-2-ylmethylIl \ NHdimethylpyridin-3 - (7- 381.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate0Noxazol-2-ylmethyl (7-(2- oxazol-2-ylmethyl\\ \ V- NHfluoro-6-methoxypyridin-3 - (7- 401.0 yl)benzo[d]thiazol-2- J\zFbromobenzo [d] thi a yl)carbamate C kl zol-2-yl)carbamate OMeoxazol-2-ylmethyl (7-(6- oxazol-2-ylmethyl methoxy-4-methylpyridin-3 - (7- 397.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateOMeooxazol-2-ylmethyl (7-(4,6- ~ N oxazol-2-ylmethylfl 1 NHdimethoxypyridin-3 - (7- 413.1 yl)benzo[d]thiazol-2- MeO^ l bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate OMeoxazol-2-ylmethyl (7-(4-Noxazol-2-ylmethyl methyl-6- NH(7- (trifluoromethyl)pyridin-3 - 435.0 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamateAF30oxazol-2-ylmethyl (7-(5- oxazol-2-ylmethylf| | V- NHfluoro-6-methoxypyridin-3 - (7- 401.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate 4OMeoxazol-2-ylmethyl (7-(5- N VcTiJ oxazol-2-ylmethylNHchloro-6-methoxypyridin-3 - (7- 417.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate CI^VOMe0oxazol-2-ylmethyl (7-(5- oxazol-2-ylmethyl[| | \^NHamino-6-methoxypyridin-3 - (7- 398.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate H2N'^Y^JOMe_Noxazol-2-ylmethyl (7-(6- NH oxazol-2-ylmethyl isopropoxypyridin-3 - (7- 411.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateo.Noxazol-2-ylmethyl (7-(6- Il I NH oxazol-2-ylmethyl cyanopyridin-3- (7- 378.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamatei0-.0 JVC>oxazol-2-ylmethyl (7-(6- oxazol-2-ylmethyl\\ 1XVNHcarbamoylpyridin-3 - (7- 396.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate H2N^ONoxazol-2-ylmethyl (7-(6- oxazol-2-ylmethyl (methylcarbamoyl)pyridin-3 - (7- 410.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate Csj'1zol-2-yl)carbamateHN^ONoxazol-2-ylmethyl (7-(6- NH oxazol-2-ylmethyl (dimethylcarbamoyl)pyridin- (7- 424.1 3 -yl)benzo [d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateo.oxazol-2-ylmethyl (7-(6-Noxazol-2-ylmethyl[| | V- NHaminopyridin-3- (7- 368.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate NH20oxazol-2-ylmethyl (7-(6-Noxazol-2-ylmethyl(I 1 NH(methylamino)pyridin-3 - (7- 382.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate NHMe0oxazol-2-ylmethyl (7-(6-Noxazol-2-ylmethyl[| | NH(dimethylamino)pyridin-3 - (7- 396.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate NMe20Noxazol-2-ylmethyl (7-(6- (f 1 NH oxazol-2-ylmethyl morpholinopyridin-3 - (7- 438.2 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateNu0.Noxazol-2-ylmethyl (7-(6- || [ \\_NH oxazol-2-ylmethyl (pyrrolidin- 1 -yl)pyridin-3 - (7- 422.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate CsJ'1zol-2-yl)carbamateNo0_Noxazol-2-ylmethyl (7-(6- oxazol-2-ylmethylIl I NHcyclopropylpyridin-3 - (7- 393.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate0~Noxazol-2-ylmethyl (7-(6- oxazol-2-ylmethylIl I / >— NH(methylsulfonyl)pyridin-3 - (7- 431.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate Cjii zol-2-yl)carbamate 0=8=010Noxazol-2-ylmethyl (7-(6- oxazol-2-ylmethylii i NHacetylpyridin-3- (7- 395.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate x^>00oxazol-2-ylmethyl (7-(6- , N oxazol-2-ylmethylIl T(trifluoromethoxy)pyridin-3 - (7- 437.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateOCF30Noxazol-2-ylmethyl (7-(6- [l I NH oxazol-2-ylmethyl (cyclopropylmethoxy)pyridin (7- 423.0 -3 -yl)benzo [d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamater0oxazol-2-ylmethyl (7-(6- l| | NH oxazol-2-ylmethyl (morpholinomethyl)pyridin- (7- 452.1 3 -yl)benzo [d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateo,oxazol-2-ylmethyl (7-(6-Nf| | ^NH oxazol-2-ylmethyl ((tetrahydro-2H-pyran-4- (7- yl)oxy)pyridin-3 - 453.1 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamate0oxazol-2-ylmethyl (7-(2,6-Noxazol-2-ylmethylIl Ix)— NHdimethoxypyridin-3 - (7- 413.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi aJ-y°Meyl)carbamate zol-2-yl)carbamateOMe0oxazol-2-ylmethyl (7-(6- N oxazol-2-ylmethylf| I / >— NHmethoxy-2-methylpyridin-3 - (7- 397.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate OMeoxazol-2-ylmethyl (7-(2- ~ N oxazol-2-ylmethyl|| | NHmethoxy-6-methylpyridin-3 - (7- 397.1 yl)benzo[d]thiazol-2- l oMe bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate„Noxazol-2-ylmethyl (7-(6-(2- oxazol-2-ylmethyl (dimethylamino)ethoxy)pyrid (7- 440.1 in-3 -yl)benzo [d]thiazol-2- bromobenzo [d] thi a 6yl)carbamate zol-2-yl)carbamate Me2N^~Noxazol-2-ylmethyl (7-(6-(2- |l | y- NH oxazol-2-ylmethyl methoxy ethoxy )pyridin-3 - (7- 427.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate MeO^oxazol-2-ylmethyl (7-(2,3- oxazol-2-ylmethyl dihydro-[ 1 ,4]dioxino [2,3 - (7- b]pyridin-7- 411.0 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamateoxazol-2-ylmethyl(7- bromobenzo [d] thi aNzol-2-yl)carbamate oxazol-2-ylmethyl (7-(6-(2- [| | V- NHandoxa-6-azaspiro[3.3]heptan-6- 6-(5-(4, 4,5,5- yl)pyridin-3- 450.1 tetramethyl- 1,3,2- yl)benzo[d]thiazol-2- dioxaborolan-2- yl)carbamate Nyl)pyridin-2-yl)-2- oxa-6- azaspiro [3.3 ]heptaneoxazol-2-ylmethyl (7-(l- N oxazol-2-ylmethyl methyl- 1 H-pyrazol-4- l| \ NH (7- 356.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateNoxazol-2-ylmethyl (7-(6-(l,l- [I I / >— NH oxazol-2-ylmethyl difluoroethyl)pyridin-3 - (7- 417.0 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate0~Noxazol-2-ylmethyl oxazol-2-ylmethyl (7-(2,4- fl T 7>— NH(7- dimethoxyphenyl)benzo [d] thi 412.0MeCi l bromobenzo [d] thi a azol-2-yl)carbamatezol-2-yl)carbamate U OMeoxazol-2-ylmethyl (7-(6- ~ N °prS3oxazol-2-ylmethyl (morpholine-4- (7- carbonyl)pyridin-3 - 466.1 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamateN N VO NHoxazol-2-ylmethyl (7-(6-((2- oxazol-2-ylmethyl methoxyethyl)carbamoyl)pyri (7- 454.0 din-3 -yl)benzo [d]thiazol-2- flTj bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate HN^O(Ceoxazol-2-ylmethyl(7- bromobenzo [d] thi a oxazol-2-ylmethyl (7-(6-(3- N zol-2-yl)carbamateNH(methylamino)oxetan-3 - andyl)pyridin-3- N-methyl-3-(5- 438.2 yl)benzo[d]thiazol-2- pCjlj (4, 4,5,5- yl)carbamate tetramethyl- 1,3,2- dioxaborolan-2- yl)pyridin-2- yl)oxetan-3 -amine ex oxazol-2-ylmethylJ — j] (7- oxazol-2-ylmethyl (7-(2- bromobenzo [d] thi a ((tetrahydro-2H-pyran-4- zol-2-yl)carbamate yl)oxy)pyrimidin-5 - and 454.2 yl)benzo[d]thiazol-2- 2-((tetrahydro-2H- yl)carbamate 9 pyran-4-yl)oxy)-5 - (4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)pyrimidineoxazol-2-ylmethyl(7- bromobenzo [d] thi a oxazol-2-ylmethyl (7-(6-Nzol-2-yl)carbamate[I [ NH((tetrahydro-2H-pyran-4- and yl)amino)pyridin-3 - N-(tetrahydro-2H- 452.1 yl)benzo[d]thiazol-2- pyran-4-yl)-5- yl)carbamate (4, 4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)pyridin-2-amineoxazol-2-ylmethyl (7-(l-(2-Noxazol-2-ylmethyl hydroxy-2-methylpropyl)- f| | NH(7- lH-pyrazol-4- 414.1 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamate HO-^ _ / ONo Joxazol-2-ylmethyl (7-(l-(2- N> oxazol-2-ylmethylH [ 8>— NHmethoxyethyl)- 1 H-pyrazol-4- (7- 400.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamateMet / Noxazol-2-ylmethyl (7-(l- f| f V^H oxazol-2-ylmethyl (oxetan-3 -yl)- 1 H-pyrazol-4- \Vs (7- 398.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate k 4 zol-2-yl)carbamateO_NvVoxazol-2-ylmethyl (7-(l- I oxazol-2-ylmethyl ( e h o a - \lr d u - l V It t a y r f r n 3 y )- 1 H- s (7- 412.1 pyrazol-4-yl)benzo [d]thiazol- bromobenzo [d] thi a2-yl)carbamate zol-2-yl)carbamate & oxazol-2-ylmethyl(7- 0 bromobenzo [d] thi aNzol-2-yl)carbamate oxazol-2-ylmethyl (7-(6-((2- I Vl W I V NH andoxa-6-azaspiro[3.3]heptan-6- 6-((5-(4, 4,5,5- yl)methyl)pyridin-3 - tetramethyl- 1,3,2- 464.1 yl)benzo[d]thiazol-2- dioxaborolan-2- yl)carbamate yl)pyridin-2- yl)methyl)-2-oxa- 6- azaspiro [3.3 ]heptaneO oxazol-2-ylmethyl(7- x. N Vo bromobenzo [d] thi a oxazol-2-ylmethyl (7-(6- H 1 V^VV-'S7 Hzol-2-yl)carbamate (oxetan-3- and ylcarbamoyl)pyridin-3 - 452.1N-(oxetan-3 -yl)-5 - yl)benzo[d]thiazol-2- Cv1(4, 4,5,5- yl)carbamate HN"VOtetramethyl- 1,3,2- dioxaborolan-2- yl)picolinamideoxazol-2-ylmethyl (7-(l- oxazol-2-ylmethyl ((tetrahydro-2H-pyran-4- H | NH(7- yl)methyl)- 1 H-pyrazol-4- 440.2 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamateCL01NNoxazol-2-ylmethyl oxazol-2-ylmethyl (7-(4- Il 1 NH (7- methoxyphenyl)thiazolo [4,5 - chlorothiazolo [4,5 - 383.1 b]pyridin-2-yl)carbamate b]pyridin-2- yl)carbamateOMe001NNW oxazol-2-ylmethyl oxazol-2-ylmethyl (7-(4- Il 1XVNH (7- chlorophenyl)thiazolo [4,5 - chlorothiazolo [4,5 - 387.0 b]pyridin-2-yl)carbamate b]pyridin-2- yl)carbamateClCL0oxazol-2-ylmethyl / — (\ 1oxazol-2-ylmethyl (7- (7- Il 1x)— NHphenylthiazolo [4,5 -b]pyridin- chlorothiazolo [4,5 - 353.1 2-yl)carbamate b]pyridin-2- yl)carbamateoxazol-2-ylmethyl (7-(3,6-NVcAJ1oxazol-2-ylmethyl dihydro-2H-pyran-4- |l ] / >— NH (7- 358.1 yl)benzo[d]thiazol-2- bromobenzo [d] thi a yl)carbamate zol-2-yl)carbamate0oxazol-2-ylmethyl (7-(l-Noxazol-2-ylmethyl acetyl-1,2,3,6- [l 1 / >— NH(7- tetrahydropyridin-4- 399.1 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamate0oxazol-2-ylmethyl (7-(l-Noxazol-2-ylmethyl methyl-1,2,3,6- Il \XVNH(7- tetrahydropyridin-4- 371.0 bromobenzo [d] thi a yl)benzo[d]thiazol-2- zol-2-yl)carbamate yl)carbamate10^N2-(4- oxazol-2-ylmethyl (7- Il I / >— NHmethoxycyclohex- ((ls,4s)-4- 1 -en-l-yl)-4, 4,5,5 - 388.0 methoxycyclohexyl)benzo [d]tetramethyl- 1,3,2- thiazol-2-yl)carbamateOMe dioxaborolane(Extra hydrogenation steprequired: H2, 15 PSI, THF / MeOH)0^N2-(4- oxazol-2-ylmethyl (7- Il I NHmethoxycyclohex- ((lr,4r)-4- 1 -en-l-yl)-4, 4,5,5 - 388.1 methoxycyclohexyl)benzo [d]tetramethyl- 1,3,2- thiazol-2-yl)carbamate^Me dioxaborolane(Extra hydrogenation steprequired: H2, 15 PSI, THF / MeOH)0NIl \ 'V NH tert-butyl 4- oxazol-2-ylmethyl (7-(l- (4, 4,5,5- acetylpiperidin-4- tetramethyl- 1,3,2- 401.1 yl)benzo[d]thiazol-2- dioxaborolan-2- yl)carbamate yl)piperidine-l- (Extra deBoc (HC1, EtOAc) and carboxylate acylation(acetic anhydride) stepsrequired70>VO V\\ \VW tert-butyl 4- oxazol-2-ylmethyl (7-(l- (4, 4,5,5- carbamoylpiperidin-4- tetramethyl- 1,3,2- 402.1 yl)benzo[d]thiazol-2- dioxaborolan-2- H2N"'KDyl)carbamate yl)piperidine-l- (Extra deBoc (HC1, EtOAc) andcarboxylateurea formation((trimethylsilyl)isocyanate stepsrequired)1 / I z\ FN-(7-bromo-6- V"N fluorobenzo [d] thi a3 -fluoro -N- (6 -fluoro -7- (6 - Lvzol-2-yl)-3-fhioro- methoxypyridazin-3 - OMe3- yl)benzo [d]thiazol-2-yl)-3 - 422.1(methoxymethyl)az (methoxymethyl)azetidine- 1 - (Stille coupling using 2-methoxy-5etidine-1- carboxamide 3-methoxy-6- (tributylstannyl)pyridazine : carboxamide Pd2(dba)s, PCys, LiCl, dioxane,90 °C)3 -fluoro -N- (4 -fluoro -7- (2 - N-(7-bromo-4- methoxypyrimidin-5 - fluorobenzo [d] thi a yl)benzo [d]thiazol-2-yl)-3 - zol-2-yl)-3-fluoro- 346 425.1((methoxy- 3-((methoxy- d3)methyl)azetidine- 1 - d3 )methyl)azetidin carboxamide e-1 -carboxamideCO QD <N-(4,6-difluoro-7-(2- N-(7-bromo-4,6- 10F Omethoxypyrimidin-5 - / L N M x O OCD3difluorobenzo [d] thi yl)benzo [d]thiazol-2-yl)-3 - Xz azol-2-yl)-3 -fluoro- 347 X 443.2 fluoro-3 -((methoxy- cr z z 3-((methoxy- d3)methyl)azetidine- 1 - NxN y Ar.c zr d3 )methyl)azetidin z,Acarboxamide OMe e-1 -carboxamideZo / ( A n=z~~ ~y7\ / D <Q ( _ / / \ \_N-(7-bromo-4,6- zz o \= / \ / A / / o u->——difluorobenzo [d] thi azol-2-yl)-3 -fluoro- oN-(4,6-difluoro-7-(6- oo 3-((methoxy- ((tetrahydro-2H-pyran-4- d3 )methyl)azetidin yl)amino)pyridin-3 - e-1 -carboxamide 348 yl)benzo [d]thiazol-2-yl)-3 - 511.2 fluoro-3 -((methoxy- N-(tetrahydro-2H- d3)methyl)azetidine- 1 - pyran-4-yl)-5- carboxamide (4, 4,5,5- tetramethyl- 1,3,2- dioxaborolan-2- yl)pyridin-2-amineN-(7-bromo-6- N-(6-chloro-7-(2- chlorobenzo [d] thi a isopropoxypyrimidin-5 - zol-2-yl)-3- 349 yl)benzo [d]thiazol-2-yl)-3 - 448.2 methoxy-3- methoxy -3 -methylazetidine- methylazetidine- 1 - 1 -carboxamidecarboxamide

[0107] Synthetic procedure E

[0108] Example 257: Oxazol-2-ylmethyl (7-(6-methoxy-2,4-dimethylpyridin-3-yl) benzo [ d]thiazol-2-y I) carbamate

[0109] Step 1

[0110] Pd(dppf)C12 (32 mg, 0.04 mmol) was added to a solution of 7-bromobenzo[d]thiazol-2-amine (100 mg, 0.44 mmol), bis(pinacolato)diboron (166 mg, 0.65 mmol) and potassium acetate (129 mg, 1.31 mmol) in dioxane (2 mL). The resulting mixture was stirred at 100 °C for 16 h, filtered, concentrated in vacuo and purified by flash column chromatography on silica (EtOAc:PE, 0:100 to 50:50) to afford 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (120 mg, 0.43, 100%) as a yellow gum; ES-MS [M+H]+: 277.1.

[0111] Step 2

[0112] Pd(dppf)C12 (10 mg, 0.014 mmol) was added to a solution of 3-bromo-6-methoxy- 2,4-dimethylpyridine (30 mg, 0.14 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (50 mg, 0.18 mmol) and potassium carbonate (58 mg, 0.42 mmol) in dioxane (1 mL) and water (0.1 mL). The resulting mixture was stirred at 80 °C for 16 h. Water (10 mL) was added at room temperature and the reaction mixture was extracted into ethyl acetate (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Preparative TLC (EtOAc:PE 1:1) afforded 7-(6-methoxy-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-amine (15 mg, 0.052 mmol, 37%) as a yellow solid; ES-MS [M+H]+: 286.0.

[0113] Step 3

[0114] CDI (142 mg, 0.88 mmol) was added to a solution of oxazol-2-ylmethanol (87 mg, 0.88 mmol) in THF and the resulting solution was stirred at 60°C for 2 h, then allowed to cool to 25 °C. The mixture was then added to a solution of 7-(6-methoxy-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-amine (50 mg, 0.18 mmol), triethylamine (122 pL, 0.88 pmol) and DMAP (2 mg, 0.18 mmol) in THF (1 mL). The reaction mixture was stirred at 60 °C for 12 h, then concentrated in vacuo. Purification by preparative HPLC (column: Phenomenex Luna C18 150*25mm 10 pm; acetonitrile: water(formic acid); gradient: 35%-65% B over 10 min) afforded oxazol-2-ylmethyl (7-(6-methoxy-2,4-dimethylpyridin-3-yl)benzo[d]thiazol-2-yl)carbamate (6 mg, 0.15 mmol, 9%) as a white solid; 5H (400 MHz; DMSO-d6) 12.60-12.24 (1H, m), 8.19-8.14 (1H, m), 7.76-7.69 (1H, m), 7.57-7.48 (1H, m), 7.28-7.24 (1H, m), 7.14-7.08 (1H, m), 6.70-6.64 (1H, m), 5.31 (2H, s), 3.88 (3H, s), 2.07 (3H, s), 1.91 (3H, s); ES-MS [M+H]+: 411.0.

[0115] Other examples prepared using synthetic procedure E are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).IntermediatesEx. ES-MS Name Structure requiringNo. [M+H]+synthesisoxazol-2-ylmethyl (7-(5-Nii r NH 2-bromo-5-(2- (2-methoxyethoxy)-3 - methoxyethoxy)- 258 methylpyrazin-2- 442.23- yl)benzo [d]thiazol-2- methylpyrazine yl)carbamate IMeO^ONoxazol-2-ylmethyl (R)-(7- Il 1 NH(6-((tetrahydrofuran-3 - ^X-J^S7259 yl)oxy)pyridin-3 - n / a 439.2 yl)benzo [d]thiazol-2- yl)carbamate0Nopn3oxazol-2-ylmethyl (S)-(7- || | NH(6-((tetrahydrofuran-3 - yl)oxy)pyridin-3 - n / a 439.1 yl)benzo [d]thiazol-2- yl)carbamateoxazol-2-ylmethyl (7-(5-N|l | y- NHmethoxypyridin-2- n / a 383.1 yl)benzo [d]thiazol-2- yl)carbamateQ OMeNoxazol-2-ylmethyl (7-(5- f| | ^NHmethoxy-3 -methylpyrazin- n / a 398.0 2-yl)benzo[d]thiazol-2- yl)carbamateNXi / leoxazol-2-ylmethyl (7-(3- ~Nmethyl-5- NH(methylcarbamoyl)pyrazin- n / a 425.1 2-yl)benzo[d]thiazol-2- yl)carbamateCONHMe0^Noxazol-2-ylmethyl (7-(6- [| | NH(oxetan-3 -yl)pyridin-3 - n / a 409.0 yl)benzo [d]thiazol-2- yl)carbamate

[0116] Synthetic procedure F

[0117] Example 264: Oxazol-2-ylmethyl (7 -(6-oxa-2 -azaspiro [3.4] octan-2-yl) benzo [ d]thiazol-2-y I) carbamate

[0118] Step 1

[0119] Boc anhydride (1.26 mL, 5.48 mmol) and DMAP (60 mg, 0.49 mmol) were added to a mixture of 7-bromo-l, 3-benzothiazol-2-amine (900 mg, 3.93 mmol) in dichloromethane (10 mL) at 0 °C. The mixture was stirred at 25 °C for 12 h, then water (50 mL) was added. The reaction mixture was extracted into ethyl acetate (3 x 50 mL) and the combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE 20:80) afforded tert-butyl (7-bromobenzo[d]thiazol-2-yl)carbamate (650 mg, 1.97 mmol, 72%) as a white solid: ES-MS [M+H]+: 329.0.

[0120] Step 2S

[0121] 6-Oxa-2-azaspiro[3.4]octane oxalate (216 mg, 683 pmol) and sodium tert-butoxide (131 mg, 1.37 mmol) were added to a solution of tert-butyl (7-bromobenzo[d]thiazol-2-yl)carbamate (150 mg, 0.46 mmol) in 2-methyl-2 -butanol (3 mL). tBuXPhos Pd G3 (36 mg, 0.046 mmol) was then added and the resulting mixture was stirred at 100 °C for 16 h under nitrogen. Water (10 mL) was added and the mixture was extracted into ethyl acetate (3 x 10 mL). The combined extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Trituration with methanol afforded tert-butyl (7-(6-oxa-2-azaspiro[3.4]octan-2-yl)benzo[d]thiazol-2-yl)carbamate (140 mg, 0.39 mmol, 85%) as an off-white solid; ES-MS [M+H]+: 362.2.

[0122] Step 3

[0123] TFA (0.3 mL, 4.04 mmol) was added to a solution of tert-butyl (7-(6-oxa-2-azaspiro[3.4]octan-2-yl)benzo[d]thiazol-2-yl)carbamate (140 mg, 0.39 mmol) indi chloromethane (1.5 mL) and the resulting mixture was stirred for 25 °C for 2 h. The reaction was adjusted to pH 7 with saturated sodium bicarbonate solution and extracted into EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Trituration with methanol afforded 7-(6-oxa-2-azaspiro[3.4]octan-2-yl)benzo[d]thiazol-2-amine (60 mg, 0.23 mmol, 59%) as a pink solid; ES-MS [M+H]+: 262.2.

[0124] Step 4

[0125] Oxazol-2-ylmethyl (7-(6-oxa-2-azaspiro[3.4]octan-2-yl)benzo[d]thiazol-2-yl)carbamate (41 mg, 0.098 mmol, 43%, white solid) was prepared using Step 3 from Synthetic procedure E; 5H (400 MHZ; DMSO-d6) 12.28 (1H, br d, J 1.2 Hz), 8.19 (1H, s), 7.29 (1H, s), 7.27-7.21 (1H, m), 7.11 (1H, d, J 8.0 Hz), 6.32 (1H, d, J 8.0 Hz), 5.36 (2H, s), 4.05-3.98 (4H, m), 3.86-3.81 (2H, m), 3.75 (2H, m), 2.21-2.14 (2H, m); ES-MS [M+H]+: 387.1.

[0126] Other examples prepared using synthetic procedure F are shown in the following table. All intermediates are commercially available.ES-MS Ex. No. Name Structure[M+H]+0Noxazol-2-ylmethyl (7-(4- [l I / >— NH\z^S7methoxypiperidin- 1 - 389.2Nyl)benzo[d]thiazol-2-yl)carbamate9OMeoz^° / — <\ 1NozWzw^oxazol-2-ylmethyl (7-(3- f| _ \ / D < I ^NH (methoxymethyl)azetidin- 1 - 375.2Nyl)benzo[d]thiazol-2-yl)carbamateMee Yroxazol-2-ylmethyl (7-(3- methoxyazetidin- 1 - 361.1 yl)benzo[d]thiazol-2-yl)carbamate0oxazol-2-ylmethyl (7-(2-oxa-6- [| | NHazaspiro [3.3 ]heptan-6- 373.1Nyl)benzo[d]thiazol-2-yl)carbamate0oxazol-2-ylmethyl (7-(3-NVM J1[I T NH ((trifluoromethoxy)methyl)azetidin- 429.1 1 -yl)benzo [d]thiazol-2- Nyl)carbamateYF3CCTVOoxazol-2-ylmethyl (7-(3-(2,2,2- \\ 1 VNH trifluoroethyl)azetidin- 1 - 413.1Nyl)benzo[d]thiazol-2-yl)carbamate. r 3^70Noxazol-2-ylmethyl (7-(l-oxa-6- f| \ NHazaspiro [3.3 ]heptan-6- 373.1 yl)benzo[d]thiazol-2-yl)carbamate N7Oyoxazol-2-ylmethyl (7-(3-(2- [I I / >— NHl\Ashydroxypropan-2-yl)azetidin- 1 - 389.0Nyl)benzo[d]thiazol-2-yl)carbamate^OH..Ny V 3oxazol-2-ylmethyl (7-(6-oxa-2- [| \ 'ANHAV'-'Sazaspiro [3.5]nonan-2- 401.1Nyl)benzo[d]thiazol-2-yl)carbamateo.Ny<\)oxazol-2-ylmethyl (7-(3- \\ I VNHcyclopropyl-3 -hydroxy azetidin- 1 - 387.1Nyl)benzo[d]thiazol-2-yl)carbamateNoxazol-2-ylmethyl (7-(3-hydroxy- 3 -(trifluoromethyl)azetidin- 1 - 415.1Nyl)benzo[d]thiazol-2-yl)carbamateF-^OH~Noxazol-2-ylmethyl (7-(5-oxa-2- [I I / >— NHazaspiro [3.5]nonan-2- 401.1Nyl)benzo[d]thiazol-2-yl)carbamate6~ Nu Ioxazol-2-ylmethyl (7-(3-XVNH (difluoromethoxy)azetidin- 1 - N 397.0 yl)benzo[d]thiazol-2-yl)carbamate7[| | \^NHoxazol-2-ylmethyl (7-(3- isopropoxy azetidin- 1 - 389.0 yl)benzo[d]thiazol-2-yl)carbamate..Noxazol-2-ylmethyl (7-(3-hydroxy- NH3 -methylazetidin- 1 - 361.0 yl)benzo[d]thiazol-2-yl)carbamate NHd^\oxazol-2-ylmethyl (7-(3-(2- 280 oxopyrrolidin- 1 -yl)azetidin- 1 - 414.1 yl)benzo[d]thiazol-2-yl)carbamateOoxazol-2-ylmethyl (7-(6-hydroxy- f| | \^NH6-(trifluoromethyl)-2- 281 455.1 azaspiro [3.3 ]heptan-2- o Nyl)benzo[d]thiazol-2-yl)carbamateF3d*bHNoxazol-2-ylmethyl (7-(l , 1 -difluoro- [l I NH282 5 -azaspiro [2.3 ]hexan-5 - 393.1Nyl)benzo[d]thiazol-2-yl)carbamate0Noxazol-2-ylmethyl (7-(3- 283 (fluoromethyl)azetidin- 1 - 363.1Nyl)benzo[d]thiazol-2-yl)carbamatey

[0127] Synthetic procedure G

[0128] Example 284: 3-Fluoro-3-(methoxymethyl)-N-(7-(5-methoxypyridin-2-yl)benzo[d]thiazol-2-yl)azetidine-l-carboxamideo oOPhN^N0<F'OMe

[0129] 3 -Fluoro-3-(methoxymethyl)azetidine (30 mg, 252 pmol) and tri ethylamine (55 pL, 395 pmol) were added to a solution of phenyl (7-(5-methoxypyridin-2-yl)benzo[d]thiazol-2-yl)carbamate* (50 mg, 132 pmol) in dichloromethane (1 mL) and the resulting mixture was stirred at 25 °C for 1 h. Water (20 mL) was added and the mixture was extracted into EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by preparative HPLC (column: Welch Xtimate C18 150*25mm 5 pm; acetonitrile:water(formic acid); gradient: 34%-64% B over 10 min)) afforded 3-fluoro-3-(methoxymethyl)-N-(7-(5-methoxypyridin-2-yl)benzo[d]thiazol-2-yl)azetidine-l -carboxamide (8 mg, 19.1 pmol) as a yellow solid; 5H (400 MHz; CD3OD) 8.45 (1H, d, J2.8 Hz), 8.07-8.04 (1H, m), 7.81 (1H, d, JIA Hz), 7.64 (1H, d, J7.7 Hz), 7.53-7.46 (2H, m), 4.36-4.12 (4H, m), 3.95 (3H, s), 3.73 (2H, d, J 19.7 Hz), 3.46 (3H, s); 5F (400 MHz; CD3OD) -159.0; ES-MS [M+H]+: 403.1.*prepared using Synthetic procedure E, steps 1 and 2, then Synthetic procedure A, step 2

[0130] Other examples prepared using synthetic procedure G are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).Ex. Intermediates ES-MS Name StructureNo. requiring synthesis [M+H]+N-(7-(5- methoxypyrazin-2- CXVNL A Ayl)benzo [d]thiazol-2- 285 n / a 384.1 yl)-2-oxa-6- azaspiro[3.3]heptane-6- 0OMecarboxamideN-(7-(3-chloro-5- methoxypyrazin-2- f| [ \^NHyl)benzo [d]thiazol-2- 2-bromo-3-chloro-5- 286 418.1 yl)-2-oxa-6- methoxypyr azine r?azaspiro[3.3]heptane-6- OMecarboxamideN-(7-(l-methyl-lH- l,2,3-triazol-5- n T NHyl)benzo [d]thiazol-2- r's / -<%> n / a 357.1 yl)-2-oxa-6- azaspiro[3.3]heptane-6- K1=Ncarboxamide3 -(methoxy-d3 )-3 - [i rnhmethyl-N-(7-(6-(oxetan- z Z— / =x.— A / =\ / \ / \ / V^ T / O)^ Q 1- __ r oV ^ X)CD3°3 -yloxy)pyridin-3 - 3 -(methoxy -d3)-3 - 430.2 yl)benzo [d]thiazol-2- methylazetidine yl)azetidine-l- o z<carboxamideTiz3 -fluoro-3 - I(methoxymethyl)-N-(7 - o oo o(5 -((tetrahydro-2H- u cow6-bromo-N- pyran-4- (tetrahydro-2H-pyran- 472.2 yl)amino)pyridin-2- Q4-yl)pyridin-3 -amine yl)benzo [d]thiazol-2- yl)azetidine-l- carboxamide3 -fluoro-3 -((methoxy - d3)methyl)-N-(7-(2- (oxetan-3- 3 -fluoro-3 -((methoxy- yloxy)pyrimidin-5 - 449.2 d3)methyl)azetidine yl)benzo [d]thiazol-2- yl)azetidine-l- carboxamide3 -(methoxy-d3 )-3 - methyl-N-(7-(2-(oxetan- 3 -yloxy)pyrimidin-5 - 3 -(methoxy -d3)-3 - 431.2 yl)benzo [d]thiazol-2- methylazetidine yl)azetidine-l- carboxamideN-(7-(5-methoxy-3- methylpyrazin-2- yl)benzo [d]thiazol-2- n / a 441.2 y 1) - 8 -methyl- 5 -oxa-2,8- diazaspiro [3.5 ]nonane- 2-carboxamideN-(7-(5-(l,l- difluoroethyl)-3- f X ^NHz\ Fmethylpyrazin-2- 2-chloro-5-(l,l- yl)benzo [d]thiazol-2- >1Ndifluoroethyl)-3- 452.1 yl)-3-fluoro-3- ZZ (^ methylpyrazine (methoxymethyl)azetidi C Z<Fne- 1 -carboxamide zN-(7-(5-methoxy-3- methylpyrazin-2- H [ NH L z<Dyl)benzo [d]thiazol-2- 'f ~sn / a 398.1 yl)-2-oxa-6- azaspiro[3.3]heptane-6- vOMecarboxamide3-fluoro-N-(7-(5- methoxy-3- methylpyrazin-2- ( X z\ FN?<^OMeyl)benzo[d]thiazol-2- n / a 418.0Nyl)-3- (methoxymethyl)azetidi OMene- 1 -carboxamide3-fluoro-3- (methoxymethyl)-N-(7 - 5 -methyl-3 ,6-dihydro- (5 -methyl-3 ,6-dihydro- ( XX\HZ\ F2H-pyran-4-yl2H-pyran-4- 392.2 trifluoromethanesulfon yl)benzo [d]thiazol-2- XT ateyl)azetidine-l- carboxamide3 -fluoro-3 -((m ethoxy - 3 -fluoro -N- (6 -fluoro -7- d3)methyl)azetidine(5 -methoxy -3- and methylpyrazin-2- phenyl (6-fluoro-7-(5- 297 yl)benzo [d]thiazol-2- methoxy-3- 439.2 yl)-3-((methoxy- methylpyrazin-2- d3 )methyl)azetidine- 1 - yl)benzo[d]thiazol-2- carboxamide yl)carbamate*QN-(6-fluoro-7-(5- OOmethoxy-3- phenyl (6-fluoro-7-(5- f| ] \\_NH „ s—Omethylpyrazin-2- methoxy-3- W O298 yl)benzo[d]thiazol-2- x Ik. methylpyrazin-2- 446.1D x Hyl)-5,8-dioxa-2- yl)benzo[d]thiazol-2- Yazaspiro [3.5]nonane-2- O \ _ _ / ?D \ <M■ - e yl)carbamate*carboxamide*Prepared using: (1) Procedure I, Step 1; (2) Procedure E, Step 1; (3) Procedure E, Step 2; (4) Procedure I, Step 3; (5) Procedure A, Step 2

[0131] Synthetic procedure H

[0132] Example 299: Oxazol-2-ylmethyl (7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamate

[0133] Step 1

[0134] Pd(dppf)C12 (80 mg, 109 pmol) was added to a solution of 7-bromobenzo[d]thiazol-2-amine (250 mg, 1.09 mmol), (2-methoxypyrimidin-5-yl)boronic acid (202 mg, 1.31 mmol) and sodium carbonate (231 mg, 2.18 mmol) in dioxane (3 mL) and water (0.6 mL) at 25 °C. The mixture was stirred at 80 °C for 16 h. Water (15 mL) was added and the mixture was extracted into EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE 0:100 to 80:20) afforded 7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-amine (80 mg, 310 pmol, 28%); ES-MS [M+H]+: 259.1.

[0135] Step 2

[0136] Oxazol-2-ylmethyl (7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)carbamate was prepared from 7-(2-methoxypyrimidin-5-yl)benzo[d]thiazol-2-amine using Synthetic procedure E, Step 3; SH(400 MHz; DMSO-d6) 12.71-12.14 (1H, m), 8.94 (2H, s), 8.18 (1H, s), 7.77 (1H, m), 7.56(1H, m), 7.43 (1H, m), 7.28 (1H, s), 5.37 (2H, s), 4.01 (3H, s, 3H); ESMS [M+H]+: 384.1.

[0137] Other examples prepared using synthetic procedure H are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).IntermediatesEx. ES-MS Name Structure requiring No. [M+H]+synthesisOoxazol-2-ylmethyl (7-(6-N[| | A— NH(trifluoromethyl)pyridin- 300 n / a 421.0 3 -yl)benzo [d]thiazol-2- yl)carbamateAF30_oxazol-2-ylmethyl (7-NIl I NH301 phenylbenzo [d]thiazol-2- n / a 352.1 yl)carbamate0N— x0i — 7pyridin-2-ylmethyl (7- Vo \= / H | NHphenylbenzo [d]thiazol-2- n / a 362.0 yl)carbamateoxazol-2-ylmethyl (7- _N(pyridin-3- n \ NHn / a 353.2 yl)benzo[d]thiazol-2- yl)carbamate0Noxazol-2-ylmethyl (7-(4- || | NHmethoxyphenyl)benzo [d] t n / a 382.2 hiazol-2-yl)carbamateOMe0oxazol-2-ylmethyl (7-(4- [l [ NHchlorophenyl)benzo [d] thi n / a 386.1 azol-2-yl)carbamateCl0oxazol-2-ylmethyl (7-(6-NIl I NHmethoxypyridin-3 - n / a 383.1 yl)benzo[d]thiazol-2- yl)carbamateOMeN°prS3oxazol-2-ylmethyl (7-(4- U I NHfluorophenyl)benzo [d] thia n / a 370.1 zol-2-yl)carbamateOoxazol-2-ylmethyl (7-(4- (trifluoromethyl)phenyl)b fl \ n / a 420.1 enzo[d]thiazol-2- yl)carbamate 0 AF3_Noxazol-2-ylmethyl (7-(4- (trifluoromethoxy)phenyl)n / a 436.1 benzo [d]thiazol-2- yl)carbamateACF3N— .pyridin-2-ylmethyl (7-(6- N Vo \= / f| [ x\_ | / Hmethoxypyridin-3 - n / a 393.1 yl)benzo[d]thiazol-2- yl)carbamateOMe0oxazol-2-ylmethyl (7-(6- f °V<VN3 7-bromo-6- [ VNHmethoxypyridin-3 -yl)-6- F3CVV-S (trifluoromethyl)be 451.1 (trifluoromethyl)benzo [d] t nzo[d]thiazol-2- hiazol-2-yl)carbamate amineOMe0oxazol-2-ylmethyl (6-NVCTUmethoxy-7-(6- Jl L NH 7-bromo-6- methoxypyridin-3 - MeO^Y^3methoxybenzo [d] th 413.0 yl)benzo[d]thiazol-2- iazol-2-amine yl)carbamateOMe0oxazol-2-ylm ethyl (5- N VcAJfluoro-7-(6- Z Z=\— A 11 [XVNH 7-bromo-5- methoxypyridin-3 - \ / / / Q __ fluorobenzo [d] thi a 401.0 / / \ / V - ) \ CDyl)benzo[d]thiazol-2- Z C / ^ zol-2-amine yl)carbamateO ZsOMeT1ooxazol-2-ylmethyl (4-(6- ^ O^z4- methoxypyridin-3 - chlorothiazolo [5 ,4- 384.1 yl)thiazolo [5 ,4-c]pyridin- c]pyridin-2-amine2-yl)carbamateoxazol-2-ylmethyl (4- J. rx^nh4- phenylthiazolo [5 ,4- Vschlorothiazolo [5 ,4- 353.1 c]pyridin-2-yl)carbamate c]pyridin-2-amine 0oxazol-2-ylmethyl (7-(6- iNIl T NHmethoxypyridin-3 -yl)-4- n / a 397.1 methylbenzo [d]thiazol-2- yl)carbamateOMeoxazol-2-ylmethyl (7-(6-NNH 7-bromo-5- methoxypyridin-3 -yl)-5 - methylbenzo [d] thi a 397.1 methylbenzo [d]thiazol-2- zol-2-amine yl)carbamateOMeoxazol-2-ylmethyl (7-(6- N[| | NHmethoxypyridin-3 -yl)-6- n / a 397.1 methylbenzo [d]thiazol-2- yl)carbamateOMeOIoxazol-2-ylmethyl (7-(4-N|| | V- NHchlorophenyl)-4- n / a 404.1 fluorobenzo [d]thiazol-2- yl)carbamateCloxazol-2-ylmethyl (6- ~ Nchloro-7-(6- J I NH 7-bromo-6- methoxypyridin-3 - chlorobenzo [d] thi a 417.0 yl)benzo[d]thiazol-2- zol-2-amine yl)carbamateOMe0oxazol-2-ylmethyl (6-N2-amino-7-(6- cyano-7-(6- JJ I NHmethoxypyridin-3 - methoxypyridin-3 - 408.1 yl)benzo [d]thiazole yl)benzo[d]thiazol-2- -6-carbonitrile yl)carbamateOMe(Step 2 only)oxazol-2-ylmethyl (6- oVofluoro-7-(6- J £ Jx- NH 7-bromo-6- 322 methoxypyridin-3 - fluorobenzo [d] thi a 401.1 yl)benzo[d]thiazol-2- zol-2-amine yl)carbamateOMe0O 7-(6- .^ N W N>oxazol-2-ylmethyl (7-(6- 1| £ ^—NfH methoxypyridin-3 - MeO2S^x£^methoxypyridin-3 -yl)-6-syl)-6- 323 461.1 (methylsulfonyl)benzo [d] t (methylsulfonyl)be hiazol-2-yl)carbamate nzo[d]thiazol-2- OMeamine(Step 2 only)ONHoxazol-2-ylmethyl (7- (pyridin-2- 324 L ij n / a 353.0 yl)benzo[d]thiazol-2- yl)carbamate (Stille coupling used in Step 1 : 2- (tributylstannyl)pyridine, Pd(Phs)4,DMF, 100 °C)~Nr IT NHoxazol-2-ylmethyl (6- chloro-7-(5- 351 methoxypyrazin-2- N^ Jl n / a 418.0 yl)benzo[d]thiazol-2- OMeyl)carbamate (Stille coupling used in Step 1 : 2- methoxy-5- (tributylstannyl)pyrazine, P(Cys) PdG3, EtOH, 90 °C)

[0138] Synthetic procedure I

[0139] Example 325: Oxazol-2-ylmethyl (7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)benzo[d]thiazol-2-yl)carbamate

[0140] Step 1

[0141] Titanium(IV) ethoxide (18.2 mL, 87.7 mmol) was added to a solution of 7-bromobenzo[d]thiazol-2-amine (10.0 g, 43.7 mmol) and 2,4-dimethoxybenzaldehyde (15.0 g, 90.3 mmol) in THF (100 mL) at 25 °C. The mixture was stirred at 60 °C for 16 h. Sodium cyanoborohydride (5.60 g, 89.1 mmol) was then added at 25 °C and stirring was continued for 12 h at this temperature. Water (300 mL) was added and the mixture was extracted into EtOAc (3 x 200 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by preparative HPLC (column: Welch Ultimate XB-NH2250*50 10 pm; hexane: ethanol (0.1% NH3 H2O)]; gradient: 10%-50% B over 15 min) afforded 7-bromo-N-(2,4-dimethoxybenzyl)benzo[d]thiazol-2-amine (8.00 g, 20.7 mmol, 47%) as a yellow solid; ES-MS [M+H]+381.0.

[0142] Step 2

[0143] SPhos Pd G3 (210 mg, 269 pmol) and sodium tert-butoxide (700 mg, 8.01 mmol) were added to a solution of 3 -((difluoromethoxy)methyl)-3 -fluoroazetidine (400 mg, 2.58 mmol) and 7-bromo-N-(2,4-dimethoxybenzyl)benzo[d]thiazol-2-amine (1.00 g, 2.64 mmol) in 2-methylbutan-2-ol (10 mL). The mixture was stirred at 110 °C for 12 h. Water (50 mL) was added and the mixture was extracted into EtOAc (3 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 30:70 to 40:60) afforded 7-(3- ((difluorom ethoxy )methyl)-3 -fluoroazeti din- l-yl)-N-(2, 4-dimethoxybenzyl)benzo[d]thiazol-2-amine (150 mg, 132 pmol, 5%) as a yellow oil; ES-MS [M+H]+454.2.

[0144] Step 3

[0145] TFA (5 mL) was added to 7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)-N-(2,4-dimethoxybenzyl)benzo[d]thiazol-2-amine (150 mg, 331 pmol) and the reaction mixture was stirred at 25 °C for 12 h. The mixture was adjusted to pH 7 with saturated aqueous bicarbonate solution and extracted into dichloromethane (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 30:70 to 40:60) afforded 7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)benzo[d]thiazol-2-amine (60 mg, 158 pmol, 48%) as a yellow oil; ES-MS [M+H]+304.0.

[0146]

[0147] Oxazol-2-ylmethyl (7-(3 -((difluoromethoxy)methyl)-3 -fluoroazetidin- 1 -yl)benzo[d]thiazol-2-yl)carbamatewas prepared from 7-(3 -((difluorom ethoxy )methyl)-3-fluoroazetidin-l-yl)benzo[d]thiazol-2-amine using Synthetic Procedure E, step 3; 6H (400 MHz; DMSO-d6) 12.3 (1H, br s), 8.19 (1H, m), 7.28 (2H, m), 7.17 (1H, m), 6.81 (1H, m), 6.42 (1H, m), 5.35 (2H, m), 4.40-4.00 (6H, m); SF(400 MHz; CD3OD) -85.9, -157.6; ES-MS [M+H]+: 429.1.

[0148] Other examples prepared using synthetic procedure I are shown in the following table.ES-MS Ex. No. Name Structure[M+H]+ooxazol-2-ylmethyl (7-(3-fluoro-3- 326 (methoxymethyl)azetidin- 1 - 393.1 yl)benzo[d]thiazol-2-yl)carbamate NMeO-^P

[0149] Synthetic procedure J

[0150] Example 327: Oxazol-2-ylmethyl (7 -morpholinobenzo [d]thiazol-2-yl)carbamate

[0151] SPhos Pd G3 (20 mg, 26 pmol) and potassium phosphate (180 mg, 0.85 mmol) were added to a solution of oxazol-2-ylmethyl (7-bromobenzo[d]thiazol-2-yl)carbamate (400 mg, 2.58 mmol) and morpholine (30 pL, 344 pmol) in 2-methylbutan-2-ol (2 mL). The mixture was stirred at 110 °C for 12 h. The reaction mixture was cooled, filtered and concentrated in vacuo. Purification by preparative HPLC ((column: Welch Xtimate Cis 150*25 mm 5 pm; acetonitrile: water(formic acid); gradient: 28%-48% B over 10 min) afforded oxazol-2-ylmethyl (7-morpholinobenzo[d]thiazol-2-yl)carbamate (5 mg, 13.6 pmol, 5 %) as a white solid; 5H (400 MHz; DMSO-d6) 8.18 (1H, s), 7.39-7.31 (2H, m), 7.28 (1H, s), 6.93-6.84 (1H, m), 5.33 (2H, s), 3.82-3.75 (4H, m), 3.14-3.06 (4H, m); ES-MS [M+H]+361.1.

[0152] Other examples prepared using synthetic procedure J are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).IntermediatesEx. ES-MS Name Structure requiringNo. [M+H]+synthesisNoxazol-2-ylmethyl (7-(3- NH((difluoromethoxy)methyl)a328 zetidin-1- N n / a 411.2 yl)benzo[d]thiazol-2- yl)carbamate yF^Foxazol-2-ylmethyl (7-(3- 3-fluoro-3- fluoro-3 -((methoxy- ((methoxy- 329 d3)methyl)azetidin- 1 - 396.1N d3)methyl)azetidi yl)benzo[d]thiazol-2- ne yl)carbamate D3CO—

[0153] Synthetic procedure K

[0154] Example 330: Sodium (N-(7-(2-ethoxypyrimidin-5-yl)benzo [d]thiazol-2-yl)-3-fluoro-3-( (methoxy-d3 ) melhy !)azelidine-l -car boxamido) methyl phosphate

[0155] Step 1

[0156] Di-tert-butyl chloromethyl phosphate (292 mg, 1.13 mmol) was added to a mixture of Example 30 (350 mg, 0.83 mmol), potassium iodide (292 mg, 1.76 mmol) and potassium carbonate (292 mg, 2.11 mmol) in DMF (8 mL). The resulting mixture was stirred at 60 °C for 12 h. Water (100 mL) was added and the mixture was extracted into EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by lash column chromatography on silica (EtOAc:PE, 0:100 to 80:20) then preparative HPLC (column: Welch Ultimate XB-CN 250*50 10 pm; hexane: ethanol; gradient: l%-40% B over 15 min) afforded di-tert-butyl ((N-(7-(2-ethoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-fluoro-3-((methoxy-d3)methyl)azetidine-l-carboxamido)methyl) phosphate (250 mg, 0.35 mmol, 42%) as a yellow oil; ES-MS [M+H]+: 643.4.

[0157] Step 2

[0158] TFA (0.7 mL, 8.97 mmol) was added to a solution of di-tert-butyl ((N-(7-(2-ethoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-fluoro-3-((methoxy-d3)methyl)azetidine-l-carboxamido)methyl) phosphate (200 mg, 0.31 mmol) in dichloromethane (2 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated and purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm 10 pm; acetonitrile:water(formic acid); gradient: 35%-65% B over 10 min) to afford (N-(7-(2-ethoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-fluoro-3-((methoxy-d3)methyl)azetidine-l-carboxamido)methyl dihydrogen phosphate as a white solid ES-MS [M+H]+: 531.2.

[0159] Step 3

[0160] A solution of (N-(7-(2-ethoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-fluoro-3-((methoxy-d3)methyl)azetidine-l-carboxamido)methyl dihydrogen phosphate (50 mg, 0.094 mmol) in water (10 mL) and acetonitrile (2 mL) was filtered through Dowex 50W X8 Ion Exchange Resin (sodium form, 100-200 mesh, strongly acidic, 500 mg). The filtrate was lyophilized to afford sodium (N-(7-(2-ethoxypyrimidin-5-yl)benzo[d]thiazol-2-yl)-3-fluoro-3-((methoxy-d3)methyl)azetidine-l-carboxamido)methyl phosphate (40 mg, 0.069 mmol, 99%) as a white solid; 5H (400 MHZ; CD3OD) 8.85-8.73 (2H, m), 7.84-7.73 (1H, m), 7.60-7.48 (1H, m), 7.37-7.27 (1H, m), 6.16-5.98 (2H, m), 4.58-4.48 (2H, m), 4.39-3.97 (4H, m), 3.76-3.63 (2H, m), 1.52-1.37 (3H, m); 5F (400 MHZ; CD3OD) -1.18; ES-MS [M+H]+: 531.0.

[0161] Other examples prepared using synthetic procedure K are shown in the following table.Ex. Starting ES-MS Name StructureNo. material [M+H]+sodium (N-(6-chloro-7-(6- methoxypyridin-3 -OW y— K N / \ v^rOCD33yl)benzo [d]thiazol-2-yl)-3 - f| T^OPO3Na2331 (methoxy-d3)-3- Example 192 532.1 methylazetidine- 1 - carboxamido)methylOMephosphatesodium (3-fluoro-3- o(methoxymethy 1)-N - (7- (2 - methoxypyrimidin-5 - OPO3Na2332 yl)benzo[d]thiazol-2- Example 1 514.2 yl)azetidine-l- Ncarboxamido)methylOMephosphate

[0162] Synthetic procedure L

[0163] Example 333: N-(7-(3-((Difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)benzo [d]thiazol-2-yl)-5-oxa-2-azaspiro [ 3.4 ]octane-2-carboxamide

[0164] Step 1NO2

[0165] 3 -((Difluorom ethoxy )methyl)-3 -fluoroazetidine TFA salt (3.50 g, 13.0 mmol) was added to a mixture of 7-floro-4-nitrobenzo[d]thiazol-2-amine* (2.50 g, 11.7 mmol) and potassium carbonate (5.39 g, 39.0 mmol) in DMF and the reaction mixture was stirred at 100 °C for 12 h. Water (80 mL) was added and the mixture was extracted into EtOAc (3 x 40 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Trituration with acetonitrile afforded 7-(3 -((difluorom ethoxy)methyl)-3-fluoroazetidin-l-yl)-4-nitrobenzo[d]thiazol-2-amine (2.50 g, 3.01 mmol, 23%) as a yellow solid; ES-MS [M+H]+: 349.1.*see ‘Intermediate synthesis’ section

[0166] Step 2F F

[0167] Phenyl (7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)-4-nitrobenzo[d]thiazol-2-yl)carbamate was prepared from 7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)-4-nitrobenzo[d]thiazol-2-amine using Synthetic Procedure E, Step 3 (600 mg, 1.28 mmol, 56%); ES-MS [M+H]+: 469.1.

[0168] Step 3

[0169] N-(7-(3 -((Difluoromethoxy )methyl)-3-fluoroazeti din-l-yl)-4-nitrobenzo[d]thiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxamide was prepared from phenyl (7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)-4-nitrobenzo[d]thiazol-2-yl)carbamate using Synthetic Procedure A, Step 3 (250 mg, 0.51 mmol, 48%); 6H(400 MHZ; DMSO-d6) 11.87 (1H, br s), 8.12 (1H, d, J 8.9 Hz), 7.05-6.62 (1H, m), 7.04-6.59 (1H, m), 6.38 (1H, d, J9.0 Hz), 4.57-4.33 (6H, m), 4.12 (2H, br s), 3.78 (2H, t, J6.8 Hz), 3.37 (2H, br s), 2.12-2.05 (2H, m), 1.87 (2H, m).

[0170] Step 4

[0171] A mixture of N-(7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)-4-nitrobenzo[d]thiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxamide (250 mg, 0.51 mmol) and 10% Pd / C (100 mg, 0.94 mmol) in THF (5 m ) was degassed and purged with hydrogen three times, and then stirred at 25 °C for 12 h under a hydrogen (15 psi). The mixture wasfiltered and concentrated in vacuo to afford N-(4-amino-7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)benzo[d]thiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxamide (200 mg, 0.44 mmol, 85%) as a white solid; 5H (400 MHz; DMSO-d6) 11.52-10.71 (1H, m), 7.03-6.62 (1H, m), 6.58 (1H, d, J 8.1 Hz), 6.30 (1H, d, J 8.2 Hz), 4.70 (2H, br s), 4.38-4.30 (2H, m), 4.11-3.96 (6H, m), 3.91-3.80 (2H, m), 3.77 (2H, m), 2.11-2.04 (2H, m), 1.86 (2H, m).

[0172] Step 5

[0173] A solution of tert-butyl nitrite (68 mg, 0.66 mmol) in THF (1 mL) was added to a mixture of N-(4-amino-7-(3 -((difluoromethoxy )methyl)-3-fluoroazeti din- 1-yl)benzo[d]thiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxamide (100 mg, 0.22 mmol) in THF (1 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 5 h then water (20 mL) was added. The mixture was extracted into EtOAc (3 x 10 mL) and the combined organic extracts were dried over anhydrous sodium sulfate, then concentrated in vacuo. Purification by preparative HPLC (column: Waters Xbridge 150*25mm 5 pm; acetonitrile:water(NH4CO3); gradient: 30%-60% B over 10 min) afforded N-(7-(3-((difluoromethoxy)methyl)-3-fluoroazetidin-l-yl)benzo[d]thiazol-2-yl)-5-oxa-2-azaspiro[3.4]octane-2-carboxamide (4 mg, 9 pmol, 4%) as a yellow solid; 5H (400 MHZ; DMSO-d6) 11.67-10.97 (1H, m), 7.28-7.21 (1H, m), 7.17-7.06 (1H, m), 6.82 (1H, m), 6.39 (1H, d, J7.9 Hz), 4.36 (2H, d, J 23.8 Hz), 4.23 (2H, m), 4.13-3.94 (6H, m), 3.76 (2H, m), 2.13-2.02 (2H, m), 1.86 (2H, m); 5F (400 MHZ; DMSO-d6) -82.7, -155.1; ES-MS [M+H]+: 443.2.

[0174] Other examples prepared using synthetic procedure L are shown in the following table.Ex. ES-MS Name StructureNo. [M+H]+V- JN-(7-(3-((difluoromethoxy)methyl)-3- H | V- NHfluoroazetidin- 1 -yl)benzo [d]thiazol-2-yl)- 334 N 443.26-oxa-2-azaspiro[3.4]octane-2- carboxamide O-^FF—OV- N / \<>OMeN-(7-(3-((difluoromethoxy)methyl)-3- [M^HFfluoroazetidin- 1 -yl)benzo [d]thiazol-2-yl)- 335 N 449.2 3 -fluoro-3 -(methoxymethyl)azetidine- 1 - carboxamide oXFS03 -fluoro-N -(7-(3 -fluoro-3 - 'XN / VC'OMeF(morpholinomethyl)azetidin- 1 - 336 N 468.1 yl)benzo [d]thiazol-2-yl)-3 - (methoxymethyl)azetidine- 1 -carboxamide0H | NHoxazol-2-ylmethyl (7-(3-fluoro-3- N337 (morpholinomethyl)azetidin- 1 - 448.1 yl)benzo[d]thiazol-2-yl)carbamate(Steps 2 and 3 replaced with Procedure E, step 3)

[0175] Synthetic procedure M

[0176] Example 338: Oxazol-2-ylmethyl (6-((3-fluoroazetidin-l-yl)methyl)-7-(6-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)carbamate

[0177] Step 1

[0178] Pd(PPh3)2Ch (2.09 g, 2.97 mmol) was added to a mixture of 6-bromo-7-(6-methoxypyridin-3-yl)benzo[d]thiazol-2-amine* (10.0 g, 29.7 mmol), potassium vinyltrifluoroborate (5.98 g, 44.6 mmol) and potassium carbonate (12.3 g, 89.2 mmol) in dioxane (200 mL) and water (20 mL). The reaction mixture was stirred at 80 °C for 16 h. Water (50 mL) was added and the mixture was extracted into EtOAc (3 x 50 mL) and the combined organic extracts were dried over anhydrous sodium sulfate, then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 50:50) afforded 7-(6-methoxypyridin-3-yl)-6-vinylbenzo[d]thiazol-2-amine (3.50 g, 11.2 mmol, 38% yield) as a yellow solid; ES-MS [M+H]+: 284.0.*see ‘Intermediate synthesis’ section

[0179] Step 2

[0180] Potassium osmate(VI) dihydrate (195 mg, 0.53 mmol) and sodium periodate (5.66 g, 26.5 mmol) were added to a solution of 7-(6-methoxypyridin-3-yl)-6-vinylbenzo[d]thiazol-2-amine (1.50 g, 5.29 mmol) in THF (60 mL) and water (15 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with saturated aqueous sodium bisulfite solution (30 mL) and extracted into EtOAc (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate, then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 60:40) afforded 2-amino-7-(6-methoxypyridin-3-yl)benzo[d]thiazole-6-carbaldehyde (930 mg, 2.57 mmol, 49%) as a white solid; ES-MS [M+H]+: 286.0.

[0181] Step 3

[0182] Sodium cyanoborohydride (165 mg, 2.63 mmol), 3 -fluoroazetidine HC1 salt (146 mg, 1.31 mmol) and acetic acid (50 pL, 876 pmol) were added to a solution of 2-amino-7-(6-methoxypyridin-3-yl)benzo[d]thiazole-6-carbaldehyde (250 mg, 876 pmol) in methanol (5 mL). The reaction mixture was stirred at 40 °C for 16 h then concentrated in vacuo. Water (10 mL) was added and the mixture was extracted into ethyl acetate (3 ^ 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 80:20) afforded 6-((3-fluoroazetidin-l-yl)methyl)-7-(6-methoxypyridin-3-yl)benzo[d]thiazol-2-amine (200 mg, 523 pmol, 60%) as a white solid; ES-MS [M+H]+: 345.1.

[0183] Step 4

[0184] Oxazol-2-ylmethyl (6-((3-fluoroazetidin-l-yl)methyl)-7-(6-methoxypyridin-3-yl)benzo[d]thiazol-2-yl)carbamate was prepared from 6-((3-fluoroazetidin-l-yl)methyl)-7-(6-methoxypyridin-3-yl)benzo[d]thiazol-2-amine using Synthetic Procedure E, step 3; 6H(400 MHz; DMSO-d6) 12.40-12.24 (1H, m), 8.31-8.23 (1H, m), 8.19-8.14 (1H, m), 7.87-7.79 (1H, m), 7.71-7.63 (1H, m), 7.57-7.49 (1H, m), 7.29-7.22 (1H, m), 7.03-6.95 (1H, m), 5.36-5.26 (2H, m), 5.23-5.01 (1H, m), 3.99-3.90 (3H, m), 3.58-3.41 (4H, m), 3.13-2.98 (2H, m); 5F (400 MHz, DMSO-d6), -178.0; CDCI3ES-MS [M+H]+: 470.1.

[0185] Other examples prepared using synthetic procedure M are shown in the following table.Ex. ES-MS Name StructureNo. [M+H]+oNoxazol-2-ylmethyl (7-(6-methoxypyridin-3- / 1 f| \ V- NH339 yl)-6-(pyrrolidin- 1 -ylmethyl)benzo [d]thiazol- 466.22-yl)carbamateOMe°. w;°jl oxazol-2-ylmethyl (7-(6-methoxypyridin-3- 340 yl)-6-(morpholinomethyl)benzo[d]thiazol-2- 482.2 yl)carbamateOMeOfl [oxazol-2-ylmethyl (7-(6-methoxypyridin-3- 341 409.2 yl)-6-vinylbenzo[d]thiazol-2-yl)carbamateOMeSteps 1 and 4 only

[0186] Synthetic procedure N

[0187] Example 342: 3-Fluoro-N-(6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol-2-yl)-3-(methoxymethyl)azetidine-l-carboxamide

[0188]

[0189] tert-Butyl (6,7-difluoro-4-nitrobenzo[d]thiazol-2-yl)carbamate was prepared from 6, 7-difluoro-4-nitrobenzo[d]thiazol-2-amine using Procedure F, Step 1; 6H (400 MHz; DMSO-d6) 13.20-12.23 (1H, m), 8.39 (1H, m), 1.51 (9H, s).

[0190] Step 2NHBocNHBoc

[0191] Cesium carbonate (1.73 g, 5.31 mmol) was added to a solution of tert-butyl (6,7-difluoro-4-nitrobenzo[d]thiazol-2-yl)carbamate (880 mg, 2.66 mmol) and lH-pyrazole-4-carbaldehyde (383 mg, 3.98 mmol) in DMF (9 mL). The resulting mixture was heated at 60 °C for 16 h. Water (20 mL) was added and the mixture was extracted into ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, then concentrated in vacuo. Trituration with acetonitrile afforded tert-butyl (6-fluoro-7-(4-formyl-lH-pyrazol-l-yl)-4-nitrobenzo[d]thiazol-2-yl)carbamate (900 mg, 2.21 mmol, 83%) as a light yellow solid; 5H (400 MHZ; DMSO-d6) 12.44 (1H, br s), 10.01 (1H, s), 9.19 (1H, d, J2.4 Hz), 8.52 (1H, s), 8.39 (1H, d, J 12.0 Hz), 1.51 (9H, s).

[0192] Step 3

[0193] Acetic acid (126 pL, 2.21 mmol) was added to a solution of tert-butyl (6-fluoro-7-(4-formyl-lH-pyrazol-l-yl)-4-nitrobenzo[d]thiazol-2-yl)carbamate (900 mg, 2.21 mmol) and morpholine (0.39 mL, 4.42 mmol) in DCE (18 mL). The mixture was stirred at 25 °C for 2 h, then sodium triacetoxyborohydride (0.94 g, 4.42 mmol) was added at 0 °C. Stirring was continued at 60 °C for 16 h. Water (20 mL) was added and the mixture extracted into ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Trituration with acetonitrile afforded tert-butyl (6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)-4-nitrobenzo[d]thiazol-2-yl)carbamate (1.00 g, 2.09 mmol, 95%) as a light yellow solid; ESMS [M+H]+: 479.2.

[0194] Step 4NHBoc

[0195] tert-Butyl (4-amino-6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol-2-yl)carbamatewas prepared from tert-butyl (6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)-4-nitrobenzo[d]thiazol-2-yl)carbamate using Procedure L, Step 4; ES-MS [M+H]+: 449.2.

[0196] Step 5NHBoc

[0197] tert-Butyl (6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol-2-yl)carbamate was prepared from tert-butyl (4-amino-6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol-2-yl)carbamate using Procedure L, step 5; ES-MS [M+H]+: 434.3.

[0198] Step 6

[0199] HC1 (2.0 M in dioxane, 10 mL, 20.0 mmol) was added to a solution of tert-butyl (6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol-2-yl)carbamate (550 mg, 1.27 mmol) in dioxane (2 mL). The mixture was stirred at 60 °C for 2 h, then concentrated in vacuo. Trituration with ethyl acetate afforded 6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol-2-amine (460 mg, 1.24 mmol, 98%) as an orange solid; ES-MS [M+H]+: 334.2.

[0200] Steps 7 and 8

[0201] 3 -Fluoro-N-(6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol- 2-yl)-3-(methoxymethyl)azetidine-l -carboxamide was prepared from 6-fluoro-7-(4-(morpholinomethyl)-lH-pyrazol-l-yl)benzo[d]thiazol-2-amine using Procedure A, Steps 2 and 3; 5H (400 MHZ; CDC13) 8.23 (1H, br s), 8.18 (1H, d, J2.4 Hz), 7.76 (1H, s), 7.46 (1H, m), 7.34-7.28 (1H, m), 4.30 (4H, d, J 19.2 Hz), 3.78-3.74 (4H, m), 3.69 (2H, d, J 18.0 Hz), 3.58 (2H, s), 3.47 (3H, s), 2.56 (4H, br s); 5F (400 MHZ; CDCI3) -130.1, -157.5; ES-MS [M+H]+: 479.2.

[0202] Other examples prepared using synthetic procedure N are shown in the following table. All intermediates are commercially available unless noted (see ‘Intermediate synthesis’ section).Ex. Intermediates ES-MS Name StructureNo. requiring synthesis [M+H]+3 -fluoro -3- OV- N / \<f^OMe(methoxymethyl)-N -F(7-(4- 7-fluoro-4- (morpholinomethyl)- N343 nitrobenzo [d]thiazol- 461.1IH-pyrazol-l- 2-amineyl)benzo [d]thiazol- g2-yl)azetidine-l- carboxamide3-fluoro-N-(7-(4- 0 3 -fluoro -3- V- N / \<f^0CD3methoxy-lH- fl [ / >— NHF((methoxy- pyrazol-1- d3 )methyl)azetidineN344 yl)benzo [d]thiazol- and 395.1 2-yl)-3-((methoxy- MeO F 7-fluoro-4- d3)methyl)azetidine- Prepared using these Steps in order nitrobenzo [d]thiazol- 1 -carboxamide shown: 1, 6, 7, 4, 5 2-amine

[0203] Intermediate synthesis

[0204] 3-(Methoxy-d3)-3-methylazetidine

[0205] Step 1

[0206] A mixture of tert-butyl 3 -hydroxy-3 -methylazetidine- 1 -carboxylate (0.50 g, 2.67 mmol) and iodomethane-d3 (0.33 mL, 5.34 mmol) in THF (10 mL) was degassed and purged with nitrogen three times. Sodium hydride (60% dispersion in oil, 160 mg, 4.01 mmol) was added at 0 °C under nitrogen and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted into ethyl acetate (3 ^ 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo to afford tert-butyl 3-(methoxy-d3)-3 -methylazetidine- 1 -carboxylate (0.60 g, 2.26 mmol, 85% yield, 77% purity) as a white solid; 5H (400 MHZ; DMSO-d6) 3.78-3.55 (4H, m), 1.39-1.34 (12H, m); ES-MS [M+H]+: 205.2.

[0207] Step 2OCD3> OCDBocN' HN3

[0208] Trifluoroacetic acid (0.55 mL, 7.34 mmol) was added to a solution of tert-butyl 3- (methoxy-d3)-3-methylazetidine-l-carboxylate (0.30, 1.47 mmol) in dichloromethane (5 mL)and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (50 mL) and then solid sodium bicarbonate was added in portions until the pH was ~8. The mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 3-(methoxy-d3)-3-methylazetidine (0.10 g, 0.77 mmol, 52% yield, 80% purity) as a white solid; ES-MS [M+H]+: 105.1.

[0209] 8-Cyclopropyl-5-oxa-2, 8-diazaspiro[ 3.5 ] nonane

[0210] Step 1NH KB0CN0O — BOCN^Q

[0211] Cyclopropylboronic acid (100 mg, 1.16 mmol), copper(II) acetate (60 mg, 0.33 mmol) and sodium carbonate (50 mg, 0.47 mmol) were added to a solution of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (50 mg, 0.22 mmol) in dichloromethane (3 mL). The resulting mixture was stirred at 35 °C for 12 h then filtered. The filtrate was concentrated in vacuo to afford tert-butyl 8-cyclopropyl-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (58 mg) as a yellow oil which was used without further purification.

[0212] Step 2HNO0

[0213] Trifluoroacetic acid (0.50 mL, 6.73 mmol) was added to a solution of tert-butyl 8-cyclopropyl-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (58 mg, 0.22 mmol) in di chloromethane (0.5 mL) and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to afford 8-cyclopropyl-5-oxa-2,8-diazaspiro[3.5]nonane (36 mg) as a yellow oil which used without further purification.

[0214] 3-((difluoromethoxy)methyl)-3-fluoroazetidine

[0215] Step 1FBocN OH >BocN O F

[0216] (Bromodifluoromethyl)trimethylsilane (495 mg, 2.44 mmol) was added to a mixture of tert-butyl 3 -fluoro-3-(hydroxymethyl)azetidine-l -carboxylate (200 mg, 0.97 mmol), potassium acetate (383 mg, 3.9 mmol), water (2 mL) and dichloromethane (2 mL). The resulting mixture was stirred at 20 °C for 12 h, then washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 10:90) afforded tert-butyl 3-((difluoromethoxy)methyl)-3-fluoroazetidine-1 -carboxylate (50 mg, 0.20 mmol, 20%) as a colorless oil; 5H(400 MHZ; DMSO-d6) 6.75 (1H, m), 4.22 (2H, d, J 22.5 Hz), 4.02-3.89 (4H, m), 1.39 (9H, s).

[0217] Step 2F FBocN^X^O^F HNQx^O^F

[0218] Trifluoroacetic acid (0.30 mL, 4.04 mmol) was added to a solution of tert-butyl 3-((difluorom ethoxy )methyl)-3-fluoroazeti dine- 1 -carboxylate (50 mg, 0.20 mmol) in dichloromethane (1 mL) and the resulting mixture was stirred at 20 °C for 1.5 h. The reaction mixture was concentrated in vacuo to afford 3 -((difluoromethoxy)methyl)-3 -fluoroazetidine (30 mg, TFA salt) as a colorless oil which used without further purification.

[0219] 3-Fluoro-3-((methoxy-d3)methyl)azetidine

[0220] Step 1Z\ F Z\ F BocN VJjDH - ► BocN / <O0CD3

[0221] tert-Butyl 3 -fluoro-3-(hydroxymethyl)azetidine-l -carboxylate (200 mg, 0.97 mmol) was added to a mixture of sodium hydride (60% dispersion in oil, 80 mg, 2.00 mmol) in THF (3 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 30 min. lodomethane-d3 (64 pL, 1.03 mmol) was added at 0 °C and the mixture was stirred at 25 °C for another 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted into EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo to afford tert-butyl 3-fluoro-3-((methoxy-d3)methyl)azetidine-l -carboxylate (200 mg) as a yellow oil which was used without further purification.

[0222] Step 2BOCNQ><^OCD3 — ► HNQX^,OCD3

[0223] Trifluoroacetic acid (1.00 mL, 13.5 mmol) was added to a solution of tert-butyl 3-fluoro-3-((methoxy-d3)methyl)azetidine-l-carboxylate (200 mg, 0.90 mmol) indichloromethane (2 mL) and the resulting mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo to afford 3-fluoro-3-((methoxy-d3)methyl)azetidine (200 mg) as a yellow oil which used without further purification.

[0224] 9, 9 -Difluor o-6-methyl-2, 6-diazaspiro[ 3.5 Jnonane

[0225] Step 1

[0226] Using a flow reactor, LDA (1 M in THF, 120 mL) was added to a solution of methyl l-benzhydrylazetidine-3 -carboxylate (30.0 g, 107 mmol) in THF (300 mL) at -40 °C.A solution of benzyl (3-oxopropyl)carbamate (10.0 g, 48.2 mmol) in THF (100 mL) was then added. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (200 mL) and extracted into EtOAc (3 x 500 mL). The combined organic extracts were washed with brine (3 x 300 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 50:50) afforded methyl 1 -benzhydryl-3 -(3 -(((benzyloxy)carbonyl)amino)- 1 -hydroxypropyl)azetidine-3-carboxylate (19.0 g, 33.1 mmol, 69%); 6H(400 MHZ; CDCh) 9.79 (1H, s), 7.40-7.33 (15H, m), 5.14-5.11 (1H, m), 5.09 (2H, s), 4.14-4.05 (1H, m), 3.79-3.63 (3H, m), 3.41-3.35 (4H, m), 2.76-2.68 (2H, m), 1.67-.49 (2H, m); ES-MS [M+H]+: 489.3.

[0227] NHCbz NHCbz

[0228] Dess-Martin periodinane (20.0 g, 47.2 mmol) was added to a solution of methyl 1-benzhydryl-3 -(3 -(((benzyloxy)carbonyl)amino)-l-hydroxypropyl)azetidine-3 -carboxylate (10.0 g, 20.5 mmol) in dichloromethane (100 mL). The resulting mixture was stirred at 20 °C for 12 h, then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 40:60) afforded methyl 1 -benzhydryl-3 -(3-(((benzyloxy)carbonyl)amino)propanoyl)azetidine-3-carboxylate (6.0 g, 9.25 mmol, 45%) asa yellow oil; 5H(400 MHz; CDCh) 7.47-7.27 (12H, m), 7.26-7.16 (3H, m), 5.09 (2H, s), 4.38 (1H, s), 3.74 (3H, s), 3.57-3.45 (6H, m), 2.86-2.77 (2H, m).

[0229] Step 3OMeNHCbz NHCbz

[0230] (Diethylamino)sulfur trifluoride (4 mL, 30.3 mmol) was added to a solution of methyl 1 -benzhy dryl-3 -(3 -(((benzyloxy)carbonyl)amino)propanoyl)azetidine-3 -carboxylate (5.80 g, 11.9 mmol) in dichloromethane (50 mL) at 0 °C and the resulting mixture was stirred at 20 °C for 12 h. The reaction was quenched with saturated sodium bicarbonate solution (100 mL) and extracted into EtOAc (3 x 500 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 40:60) afforded methyl l-benzhydryl-3-(3-(((benzyloxy)carbonyl)amino)-l,l-difluoropropyl)azetidine-3-carboxylate (2.30 g, 1.99 mmol, 17%) as a yellow oil; 5H(400 MHZ; CDCh) 7.47-7.28 (12H, m), 7.25-7.16 (3H, m), 5.18-5.05 (2H, m), 5.05-4.91 (1H, m), 4.46-4.34 (1H, m), 3.89-3.76 (3H, m), 3.65-3.54 (2H, m), 3.52-3.42 (2H, m), 3.35 (2H, m), 2.23-2.02 (2H, m); ES-MS [M+H]+: 509.2.

[0231] Step 4

[0232] Trifluoroacetic acid (4.40 mL, 59.2 mmol) was added to a solution of methyl 1-benzhy dryl-3 -(3 -(((benzyloxy)carbonyl)amino)-l,l-difluoropropyl)azetidine-3 -carboxylate (2.20 g, 4.33 mmol) in dichloromethane (30 mL) and the resulting mixture was stirred at 60 °C for 12 h. A solution of triethylamine (13.2 mL, 94.8 mmol) in dichloromethane (30 mL) was then added at 40 °C and stirring was continued at this temperature for 4 h. The reaction mixture was concentrated in vacuo and flash column chromatography on silica (EtOAc:PE, 0:100 to 100:0) afforded 2 -benzhy dryl-9,9-difluoro-2,6-diazaspiro[3.5]nonan-5-one (0.70 g, 1.94 mmol), 45%) as a yellow oil; ES-MS [M+H]+: 343.2.

[0233] Step 5

[0234] Sodium hydride (60% dispersion in oil, 70 mg, 1.75 mmol) was added at 0 °C under nitrogen to a solution of 2-benzhydryl-9,9-difluoro-2,6-diazaspiro[3.5]nonan-5-one (350 mg, 1.02 mmol) in DMF (5 mL). The resulting mixture was stirred at 25 °C for 30 min. lodomethane (123 pL, 1.97 mmol) was added at 0 °C and stirring was continued for another 2 h. The reaction was quenched with water (20 mL) and extracted into EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 60:40) afforded 2-benzhydryl-9,9-difluoro-6-methyl-2,6-diazaspiro[3.5]nonan-5-one (300 mg, 0.92 mmol, 90%) as a yellow oil; 5H (400 MHZ; CDCh) 7.51-7.44 (4H, m), 7.31-7.26 (4H, m), 7.21-7.14 (2H, m), 4.72-4.62 (1H, m), 3.59-3.50 (2H, m), 3.49-3.42 (2H, m), 3.36-3.24 (2H, m), 2.97 (3H, s), 2.29-2.16 (2H, m). ES-MS [M+H]+: 357.1.

[0235] Step 6

[0236] BH3.THF (1.0 M, 3.0 mL, 3 mmol) was added to a solution of 2-benzhydryl-9,9-difhioro-6-methyl-2,6-diazaspiro[3.5]nonan-5-one (300 mg, 0.84 mmol) in THF (10 mL) and the resulting mixture was stirred at 60 °C for 2 h. The reaction was quenched carefully with methanol (10 mL) and extracted concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 100:0) afforded 2-benzhydryl-9,9-difluoro-6-methyl-2,6-diazaspiro[3.5]nonane (250 mg, 0.37 mmol, 43%) as a yellow oil. ES-MS [M+H]+: 343.2.

[0237] Step 7

[0238] A mixture of 2-benzhydryl-9,9-difluoro-6-methyl-2,6-diazaspiro[3.5]nonane (220 mg, 0.64 mmol), 15% Pd / C (1.0 g, 1.41 mmol) and TFA (53 pL, 0.71 mmol) in ethanol (5mL) was degassed and purged with hydrogen three times, and then stirred at 35 °C for 12 h under a hydrogen atmosphere. Ethanol (20 mL) was added and the mixture was filtered. The filtrate was concentrated in vacuo to afford 9,9-difluoro-6-methyl-2,6-diazaspiro[3.5]nonane as a yellow gum that was used without further purification; ES-MS [M+H]+: 177.2.

[0239] 3-(Ethoxymethyl)-3-fluoroazetidine

[0240] Step 1BocN^V^OH - ► BocN^Xc^OEt\Z^F \Z^F

[0241] A mixture of tert-butyl 3 -hydroxy-3 -methylazetidine- 1 -carboxylate (2.00 g, 9.75 mmol) and iodoethane (1.56 mL, 19.5 mmol) in THF (20 mL) was degassed and purged with nitrogen three times. Sodium hydride (60% dispersion in oil, 585 mg, 14.6 mmol) was added at 0 °C under nitrogen and the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted into ethyl acetate (3 ^ 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo to afford tert-butyl 3-(ethoxymethyl)-3 -fluoroazetidine- 1 -carboxylate (2.40 g, 9.26 mmol, 95% yield) as a white solid; 5H (400 MHZ; DMSO-d6) 4.04-3.80 (4H, m), 3.75-3.62 (2H, m), 3.52 (2H, m), 1.38 (9H, s), 1.12 (3H, m); ES-MS [M-Boc+H]+: 134.3.

[0242] Step 2BocN^X^^OEt - ► HN^XX^OEt\Z^F \Z^F

[0243] HC1 (4.0 M in dioxane, 1 mL, 13.5 mmol) was added to a solution of tert-butyl tert-butyl 3 -(ethoxymethyl)-3-fluoroazeti dine- 1 -carboxylate (100 mg, 0.43 mmol) in dichloromethane (2 mL) and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to afford 3 -(ethoxymethyl)-3 -fluoroazetidine (60 mg) as a yellow oil which used without further purification; ES-MS [M+H]+: 134.2.

[0244] 3-(Methoxy-d3)azetidine

[0245] Step 1BochX>— OH - ► BOCNQ>— OCD3

[0246] tert-Butyl 3 -hydroxyazetidine-1 -carboxylate (500 mg, 2.89 mmol) was added to a mixture of sodium hydride (60% dispersion in oil, 254 mg, 6.35 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. Iodomethane-d3 (395 pL, 6.35 mmol) was added at 0 °C and the mixture was stirred at 25 °C for another 1.5 h. The reactionmixture was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted into EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford tertbutyl 3-(methoxy-d3)azetidine-l-carboxylate (550 mg) as a yellow oil which was used without further purification; 6H(400 MHZ; DMSO-d6) 4.16-4.08 (1H, m), 4.01-3.93 (2H, m), 3.63 (2H, m), 1.37 (9H, s).

[0247] Step 2BOCNQ>— OCD3- ► HN^— OCD3

[0248] Trifluoroacetic acid (2.00 mL, 27.0 mmol) was added to a solution of tert-butyl 3-(methoxy-d3)azetidine-l -carboxylate (550 mg, 2.90 mmol) in dichloromethane (6 mL) and the resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo to afford 3-(methoxy-d3)azetidine TFA salt (260 mg) as a yellow oil which used without further purification.

[0249] 7-Bromo-6-fluorobenzo [d]thiazol-2-amine

[0250] Step 1

[0251] A solution of benzoyl isothiocyanate (43.2 g, 264 mmol) in acetonitrile (500 mL) was slowly added to a solution of 3-bromo-2,4-difluoroaniline (50.0 g, 240 mmol) in acetonitrile (1 L) and the resulting mixture was stirred at 20 °C for 2 h. The solid was filtered and dried in vacuo to afford N-((3-bromo-2,4-difluorophenyl)carbamothioyl)benzamide (80.0 g. 216 mmol. 90%) as a light yellow solid which used without further purification; 6H(400 MHz; DMSO-d6) 12.32 (1H, s), 11.92 (1H, s), 8.04 (2H, d, JIA Hz), 7.86 (1H, m), 7.76-7.67 (1H, m), 7.65-7.55 (2H, m), 7.39 (1H, m).

[0252] Step 2

[0253] Aqueous sodium hydroxide (2.0 M, 161 mL, 3.23 mmol) was added to a solution of N-((3-bromo-2,4-difluorophenyl)carbamothioyl)benzamide (80.0 g, 216 mmol) inmethanol (800 mL) and the resulting mixture was stirred at 20 °C for 12 h. Aqueous hydrochloric acid (1.0 M) was added until the pH was ~5-6. The resulting solid was filtered, washed with water (100 mL) and dried in vacuo to afford l-(3-bromo-2,4- difluorophenyl)thiourea (50.0 g, 162 mmol, 75%) as a light yellow solid which used without further purification; 5H (400 MHZ; DMSO-d6) 9.41 (1H, s), 8.19-7.71 (1H, m), 7.56 (1H, m), 7.26 (1H, m).

[0254] Step 3

[0255] Sodium hydride (60% dispersion in oil, 11.2 g, 281 mmol) was added portion wise to a solution of l-(3-bromo-2,4-difluorophenyl)thiourea (50.0 g, 187 mmol) in NMP (500 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 30 min and then 80 °C for 12 h. The reaction mixture was cooled to room temperature and poured slowly into saturated aqueous ammonium chloride solution (1 L). Water was added (1 L) and the mixture was extracted into ethyl acetate (3 x 500 mL). The combined organic extracts were washed with brine (3 x 500 mL), dried over anhydrous sodium sulfate and concentrated in vacuo.Trituration with dichloromethane afforded 7-bromo-6-fluorobenzo[d]thiazol-2-amine (40.0 g, 155 mmol, 83%) as a brown solid; 5H (400 MHZ; DMSO-d6) 7.74 (2H, s), 7.35 (1H, m), 7.30-7.21 (1H, m); ES-MS [M+H]+: 248.9.

[0256] The following intermediates were prepared in an analogous manner:Name Structure Starting material Analytical data7-Bromo-6- fi I V- NH 3-bromo-4-chloro-2- chlorobenzo [d]thiazol-2-2CI^^S ES-MS [M+H]+: 264.9 fluoro anilineamine7-bromo-5- NHfl23-bromo-2,5- uorobenzo [d]thiazol-2- ES-MS [M+H]+: 248.9Br difluoroanilineamine4-chlorothiazolo [5 ,4- 3-bromo-2- ES-MS [M+H]+: 186.2 c]pyridin-2-amine chloropyridin-4-amine6-bromo-7-(6- || | \^NH24-bromo-2-fluoro-3-(6- methoxypyridin-3 - methoxypyridin-3 - ES-MS [M+H]+: 336.0 yl)benzo[d]thiazol-2-amine yl)anilineOMe

[0257] 4-Bromo-2-fluoro-3-(6-methoxypyridin-3-yl)anilme

[0258] Step 1NH2OMe

[0259] Pd(dppf)C12 (2.89 g, 3.95 mmol) was added to a solution of 3-bromo-2- fluoroaniline (15.0 g, 78.9 mmol), (6-methoxypyridin-3-yl)boronic acid (18.1 g, 118 mmol) and potassium carbonate (21.8 g, 158 mmol) in dioxane (150 mL) and water (30 mL). The resulting mixture was heated at 80 °C for 16 h. Water (150 mL) was added and the mixture was extracted into ethyl acetate (3 x 150 mL). The combined organic extracts were washed with brine (3 x 150 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 25:75) afforded 2-fluoro-3-(6-methoxypyridin-3-yl)aniline (16.8 g, 77.0 mmol, 98%) as a yellow solid; ES-MS [M+H]+: 219.4.

[0260] Step 2

[0261] NBS (13.7 g, 77.0 mmol) was added to a solution of 2-fluoro-3-(6-methoxypyri din-3 -yl)aniline (16.8 g, 77.0 mmol) in DMF (168 mL). The resulting mixture was stirred at 25 °C for 2 h. Water (150 mL) was added and the mixture was extracted into ethyl acetate (3 * 150 mL). The combined organic extracts were washed with brine (150 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 15:85) afforded 4-bromo-2-fluoro-3-(6-methoxypyri din-3 -yl)aniline (21.5 g, 72.4 mmol, 94%) as a yellow solid; ES-MS [M+H]+: 297.2.

[0262] 2-Amino-7-(6-methoxypyridin-3-yl)benzo[d]thiazole-6-carbonitrile

[0263] Tetrakis(triphenylphosphine)palladium(0) (172 mg, 0.15 mmol) was added to a mixture of 6-bromo-7-(6-methoxypyridin-3-yl)benzo[d]thiazol-2-amine (500 mg, 1.49 mmol), zinc cyanide (349 mg, 2.97 mmol) and zinc (19 mg, 0.30 mmol) in DMF (5 mL). The resulting mixture was stirred at 120 °C for 16 h. Water (5 mL) was added and the mixture was extracted into ethyl acetate (3 ^ 5 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Trituration (1:1 EtOAc:PE) afforded 2-amino-7-(6-methoxypyridin-3-yl)benzo[d]thiazole-6-carbonitrile (210 mg, 0.74 mmol, 50%) as a yellow solid; ES-MS [M+H]+: 283.1.

[0264] 7-(6-Methoxypyridin-3-yl)-6-(methylsulfonyl)benzo[d]thiazol-2-amine

[0265] DMEDA (262 mg, 2.97 mmol) and copper(II) tritiate (538mg, 1.49 mmol) were added to a solution of 6-bromo-7-(6-methoxypyridin-3-yl)benzo[d]thiazol-2-amine (500 mg, 1.49 mmol) and sodium methyl sulfinate (304 mg, 2.97 mmol) in DMSO (10 mL). The resulting mixture was heated at 120 °C for 16 h. Water (10 mL) was added and the mixture was extracted into ethyl acetate (3 ^ 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo.Purification by flash column chromatography on silica (EtOAc:PE, 0:100 to 95:5) afforded 7-(6-methoxypyridin-3-yl)-6-(methylsulfonyl)benzo[d]thiazol-2-amine (100 mg, 298 pmol, 20%) as a yellow solid; ES-MS [M+H]+: 336.1.

[0266] 7- bromo-6-methoxybenzo[d]thiazol-2-amine

[0267] Step 1MeOJj L J^CI / — <x )^°Me MeO-^Y^S- Jj JJBr

[0268] DIPEA (3.38 mL. 19.4 mmol) was added to a solution of 2,4-dimethoxybenzylamine (1.94 mL, 12.9 mmol) and 7-bromo-2-chloro-6-methoxybenzo[d]thiazole (1.8 g, 6.46 mmol) in dioxane (18 mL) at 25 °C and the resulting mixture was stirred at 120 °C for 16 h. The reaction mixture was concentrated in vacuo and triturated with ethyl acetate (15 mL) to afford 7-bromo-N-(2,4-dimethoxybenzyl)-6-methoxybenzo[d]thiazol-2-amine (2.60 g, 5.89 mmol, 91%) as a white solid; ES-MS [M+H]+: 409.0.

[0269] Step 2

[0270] A mixture of 7-bromo-N-(2,4-dimethoxybenzyl)-6-methoxybenzo[d]thiazol-2- amine (250 mg, 0.61 mmol) in TFA (10 mL) was stirred at 25 °C for 16 h, then saturated sodium carbonate aqueous solution was slowly added until the pH was ~8. The mixture was extracted into ethyl acetate (3 x 500 mL) and the combined organic extracts were dried over anhydrous sodium sulfate then concentrated in vacuo. Trituration with ethyl acetate (3 mL) afforded 7-bromo-6-methoxybenzo[d]thiazol-2-amine (100 mg, 374 mmol, 61%) as a yellow solid; 5H (400 MHZ; DMSO-d6) 7.50-7.40 (2H, m), 7.32-7.22 (1H, m), 7.04-6.94 (1H, m), 3.82 (3H, s); ES-MS [M+H]+: 258.9.

[0271] 7- bromo-6-methylbenzo[d]thiazol-2-amine

[0272] Bromine (462 pL, 8.97 mmol) was added to a solution of l-(3-bromo-4- methylphenyl)thiourea* (2.0 g, 8.16 mmol) in acetic acid (15 mL) at 0 °C. The resulting mixture was warmed to 20 °C then stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo, and triturated with ethyl acetate (10 mL). The solid was purified by preparative HPLC (column: Phenom enex Luna C 18 150*40 15 pm; acetonitrile: [water (0.1% TFA)]; gradient: 10%-40% water (0.1% TFA) over 12 min; flow rate 60 mL / min) to afford 7- bromo-6-methylbenzo[d]thiazol-2-amine (260 mg, 1.03 mmol) as a white solid; 5H (400 MHz; DMSO-d6) 8.07-7.82 (2H, m), 7.28-7.19 (2H, m), 2.36 (3H, s); ES-MS [M+H]+:244.9.*prepared in an analogous manner to l-(3-bromo-2,4-difluorophenyl)thiourea from 3-bromo- 4-methylaniline

[0273] The following intermediates were prepared in an analogous manner:Name Structure Starting material Analytical datal-(3-bromo-4- 7-bromo-6- (trifluoromethyl)phenyl)thiourea (trifluoromethyl)benzo [d] ES-MS [M+H]+: 297.2 thiazol-2-amine (prepared from 3-bromo-4- (trifluoromethyl)aniline)l-(3-bromo-5- 8H(400 MHZ; CDC13) 7-bromo-5- methylphenyl)thioureaNH2 9.74-8.68 (2H, m), methylbenzo [d]thiazol-2- 7.32 (1H, m), 7.26 amine (prepared from 3-bromo-5- (1H, s), 2.43 (3H, s) methylaniline)l-(5-fluoro-2- NO27-fluoro-4- nitrophenyl)thioureanitrobenzo [d]thiazol-2- ES-MS [M+H]+: 214.2 amine (prepared from 5-fluoro-2- nitroaniline)7-bromo-4,6- Fdifluorobenzo [d]thiazol- |l 1NH2 5-bromo-2,4-difluoroaniline ES-MS [M+H]+: 371.0 2-amine6,7-difluoro-4- NO2nitrobenzo [d]thiazol-2- [1 I NH24 , 5 -difluoro -2 -nitro aniline ES-MS [M+H]+: 232.1 amine

[0274] N-( tetrahydro-2H-pyran-4-yl)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyridin-2-amine

[0275] Step 1BrBr

[0276] 4-Aminotetrahydropyran (4.31 g, 42.6 mmol) was added to a solution of DIPEA (14.9 mL, 85.2 mmol) and 5-bromo-2-fluoropyridine (2.92 mL, 28.4 mmol) in DMSO (50 mL). The resulting mixture was stirred at 100 °C for 12 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 5-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (4.00 g, 15.6 mmol, 55%) as a white solid; 5H (400 MHZ; DMSO-d6) 8.00 (1H, d, J2.40 Hz), 7.48 (1H, m), 6.77 (1H, m), 6.47 (1H, d, J8.80 Hz), 3.90-3.79 (3H, m), 3.42-3.35 (2H, m), 1.84 (2H, m), 1.47- 1.32 (2H, m). ES-MS [M+H]+: 259.1.

[0277] Step 2

[0278] Pd(dppf)C12 (285 mg, 0.39 mmol) was added to a solution of 5-bromo-N- (tetrahydro-2H-pyran-4-yl)pyridin-2-amine (1.00 g, 3.89 mmol), bis(pinacolato)diboron (1.48 g, 5.83 mmol) and potassium acetate (1.15 g, 11.7 mmol) in dioxane (10 mL). The resulting mixture was stirred at 80 °C for 4 h, then concentrated in vacuo. The mixture was diluted with ethyl acetate (50 mL) and filtered. The filter cake was washed with ethyl acetate (2 x 30 mL) and the filtrate was concentrated in vacuo to afford N-(tetrahydro-2H-pyran-4-yl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1.00 g. 2.63 mmol, 68%) as a white solid; 5H(400 MHZ; DMSO-d6) 8.20 (1H, m), 7.50 (1H, m), 6.93 (1H, m), 6.48-6.40 (1H, m), 3.89-3.80 (2H, m), 3.44-3.34 (2H, m), 1.89-1.78 (3H, m), 1.46-1.37 (2H, m), 1.24 (12H, s). ES-MS [M+H]+: 305.2.

[0279] The following intermediates were prepared in an analogous manner:StartingName Structure Analytical datamaterial8H(400 MHZ; DMSO-d6) 8.30(1H, d, J 1.38 Hz), 7.67 (1H, m), N- N-methyl-N-(tetrahydro-2H-pyran- 6.63 (1H, d, J 8.75 Hz), 4.80-4.67 methyltetrahy4-yl)-5 -(4, 4, 5, 5 -tetramethyl- 1,3,2- (1H, m), 3.92 (2H, m), 3.49-3.46 dropyran-4- dioxaborolan-2-yl)pyridin-2-amine 3 (2H, m), 2.85 (3H, s), 1.85-1.69 amine(2H, m), 1.48 (2H, m); 1.26 (12H, s)8H(400 MHZ; DMSO-d6) 8.17 N-(4-methyltetrahydro-2H-pyran- 4- (1H, m), 7.48 (1H, m), 6.56-6.51 4-yl)-5 -(4, 4, 5, 5 -tetramethyl- 1,3,2- methyloxan- (2H, m), 3.57-3.54 (4H, m), 2.20 dioxaborolan-2-yl)pyridin-2-amine 4-amine (2H, m), 1.61-1.54 (2H, m), 1.41(3H, s), 1.24 (12H, s)""3

[0280] 2, 2-difluoro-2-(5-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridin-2-yl)ethan- l-ol

[0281] Pd(dppf)C12 (31 mg, 0.04 mol) was added to a solution of 2-(5-bromopyridin-2- yl)-2,2-difluoroethan-l-ol (100 mg, 0.42 mmol), bis(pinacolato)diboron (213 mg, 0.84 mmol) and potassium acetate (124 mg, 1.26 mmol) in dioxane (2 mL). The resulting mixture was stirred at 80 °C for 4 h, concentrated in vacuo and purified by flash column chromatography on silica (EtOAc:PE, 0:100 to 50:50) to afford 2,2-difhioro-2-(5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-yl)ethan-l-ol (80 mg, 224 pmol, 53%) as a yellow oil; ES-MS [M+H]+: 204.0 (boronic acid).

[0282] The following intermediates were prepared in an analogous manner:Name Structure Starting material Analytical data8H(400 MHZ; DMSO-d6) N-(oxetan-3-yl)-5-(4, 4,5,5- 9.57 (1H, d, J 6.75 Hz), 8.825-bromo-N-(oxetan- tetr amethyl- 1,3,2- (1H, s), 8.20 (1H, m), 8.033-yl)pyridine-2- dioxaborolan-2- 0 (1H, d, J 7.63 Hz), 5.11- carboxamideyl)picolinamide HN^O 4.98 (1H, m), 4.76-4.64(4H, m), 1.33 (12H, s) ■6CDo0O CD - - 2-cyclopropoxy-5 -(4,4,5 ,5 - 5-bromo-2- 8H(400 MHZ; CDC13) 8.83 tetr amethyl- 1,3 ,2- (cyclopropyloxy)pyri (2H, m), 4.40 (1H, m), 1.36Adioxaborolan-2-yl)pyrimidine midine (12H, s), 0.84 (1H, s) / r P2- m u b P — —7b ■ °2-(2-methoxyethoxy)-5- 5-bromo-2-(2- (4,4,5 ,5 -tetramethyl- 1,3,2- methoxyethoxy)pyri ES-MS [M+H]+: 281.2 dioxaborolan-2-yl)pyrimidine midine4-(2-((5-(4,4,5,5-tetramethyl- 4-(2-((5- 1 ,3 ,2-dioxaborolan-2- bromopyrimidin-2- ES-MS [M+H]+: 254.1 yl)pyrimidin-2- yl)oxy)ethyl)morphol (boronic acid) yl)oxy)ethyl)morpholine inemorpholino(5-(4,4,5,5- (5 -bromopyrimidin- tetr amethyl- 1,3,2- 2- ES-MS [M+H]+: 238.2 dioxaborolan-2-yl)pyrimidin- yl)(morpholino)meth (boronic acid)2-yl)methanone anone2-((tetrahydro-2H-pyran-4- 5-bromo-2- yl)oxy)-5 -(4,4,5 ,5 -tetramethyl- ES-MS [M+H]+: 225.2(tetrahydro-2h-pyran- 1 ,3 ,2-dioxaborolan-2- (boronic acid)4-yloxy)pyrimidineyl)pyrimidine

[0283] 2-Methyl-N-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzamide

[0284] 3 -Aminooxetane (84 mg, 1.14 mmol) was added to a solution of 2-methyl-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.76 mmol), DIPEA (399 pL, 2.29 mmol) and HATU (348 mg, 0.97 mmol) in DMF (3 mL) and the resulting mixture was stirred at 25 °C for 1 h. Water was added (10 mL) and the mixture was extracted into ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 60:40) afforded 2-methyl-N-(oxetan-3-yl)-4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (160 mg, 0.50 mmol, 65%) as a yellow oil; 5H(400 MHZ; CDC13) 7.71-7.62 (2H, m), 7.40-7.34 (1H, m), 6.41-6.30 (1H, m), 5.29-5.18 (1H, m), 5.07-4.97 (2H, m), 4.63-4.55 (2H, m), 2.44 (3H, s), 1.36 (12H, s); ES-MS [M+H]+: 318.0.

[0285] The following intermediate was prepared in an analogous manner:Name Structure Starting material Analytical data8H(400 MHZ; DMS0-d6)9.22 (1H, d, J 6.4 Hz), 4-(4, 4,5,5- N-(oxetan-3-yl)-4-(4, 4,5,5- 7.94 (2H, d, J8.1 Hz), tetramethyl- 1,3,2- tetramethyl- 1 ,3 ,2-dioxaborolan-2- 7.80 (2H, d, J8.1 Hz), dioxaborolan-2- yl)benzamide 5.12-4.99 (1H, m), 4.81 yl)benzoic acid(2H, m), 4.64 (2H, m), 1.35 (12H, s)

[0286] (R)-N-(T etrahydrofuran-3-yl)-5-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyridin-2-amine

[0287] (R)-3 -Aminotetrahydrofuran (0.59 g, 6.72 mmol) was added to a solution of DIPEA (2.34 mL, 13.5 mmol) and 2-fluoro-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyridine (1.00 g, 4.48 mmol) in DMSO (10 mL). The resulting mixture was stirred at 100 °C for 12 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (R)-N-(tetrahydrofuran-3-yl)- 5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridin-2-amine (1.00 g, 3.10 mmol, 69%) as a white solid; 5H (400 MHZ; DMSO-d6) 8.23 (s, 1H), 7.54 (1H, m), 7.11 (1H, d, J 6.4 Hz), 6.45 (1H, d, J 8.4 Hz), 4.46-4.34 (1H, m), 3.89-3.78 (2H, m), 3.70 (1H, m), 3.50 (1H, m), 2.15 (1H, m), 1.82-1.71 (m, 1H), 1.24 (12H, s); ES-MS [M+H]+: 291.2.

[0288] The following intermediates were prepared in an analogous manner:Analytical Name Structure Starting materialdata''B / (S)-N-(tetrahydrofuran-3-yl)-5-(4, 4,5,5- (S)-3- ES-MS tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyridin- aminotetrahydrofuran [M+H]+: 291.1 2-amine ■60— J6-(5-(4, 4, 5, 5-tetramethyl-l, 3,2- 2-oxa-6- ES-MS [M+H] dioxaborolan-2-yl)pyridin-2-yl)-2-oxa-6- azaspiro [3.3 ]heptane+: 303.3 azaspiro [3.3 ]heptane oxalate^z~— / \

[0289] 2-(Oxetan-3-yl)-5-( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)isoindolin-l-one

[0290] Step 1Br

[0291] 3 -Aminooxetane (522 mg, 7.14 mmol) was added to a solution of methyl 4- bromo-2-(bromomethyl)benzoate (2.00 g, 6.49 mmol) and DIPEA (3.39 mL, 19.48 mmol) in THF (20 mL) and the resulting mixture was stirred at 60 °C for 12 h. Water was added (20 mL) and the mixture was extracted into ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 100:0) afforded 5-bromo-2-(oxetan-3-yl)isoindolin-l-one (1.20 g,4.48 mmol, 69%) as a yellow solid; 5H (400 MHZ; DMSO-d6) 7.97 (1H, m), 7.76-7.71 (1H, m), 7.69-7.63 (1H, m), 5.59- 5.37 (1H, m), 4.91- 4.82 (6H, m); ES-MS [M+H]+: 268.1.

[0292] Step 2

[0293] 2-(Oxetan-3 -y 1 ) - 5 -(4,4, 5 , 5 -tetramethyl- 1 , 3 ,2-dioxaborolan-2-yl)i soindolin- 1 -one was prepared in an analogous manner to 2,2-difluoro-2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-l-ol from 5 -bromo-2-(oxetan-3-yl)i soindolin- 1 -one; 5H (400 MHz; DMSO-d6) 7.93 (1H, s), 7.78 (1H, d, J 7.70 Hz), 7.71-7.67 (1H, m), 5.43 (1H, m), 4.91-4.76 (6H, m), 1.33 (12H, s); ES-MS [M+H]+: 316.2.

[0294] Tert-Butyl 3-( 4, 4, 5, 5 -tetr ame thy l-l , 3, 2-dioxaborolan-2-yl)-6a, 7, 9, 10-tetrahydropyrazino[ 1, 2-d ]pyrido[ 3, 2-b ][ 1, 4 ] oxazine-8 ( 6H) -carboxylate

[0295] Step 1

[0296] DIPEA (2.42 mL, 13.9 mmol) was added to a solution of 5-bromo-2,3-difluoropyridine (2.69 g, 13.9 mmol) and tert-butyl 3-(hydroxymethyl)piperazine-l-carboxylate (2.00 g, 9.25 mmol) in DMSO (20 mL) and the resulting mixture was stirred at 100 °C for 16 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 30:70) afforded tert-butyl 4-(5-bromo-3-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-l -carboxylate (1.50 g, 3.73 mmol, 40%) as a colorless oil; ESMS [M+H]+: 392.1.

[0297] Step 2BrBoc

[0298] Sodium hydride (60% dispersion in oil, 37 mg, 0.92 mmol) was added to a solution of tert-butyl 4-(5-bromo-3-fluoropyridin-2-yl)-3-(hydroxymethyl)piperazine-l-carboxylate (300 mg, 0.77 mmol) in DMF (4 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 30 min and then 50 °C for 1 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride solution (30 mL). The mixture was extracted into ethyl acetate (3 ^ 30 mL) and the combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford tert-butyl 3 -brom o-6a, 7, 9, 10-tetrahydropyrazino[ 1 ,2-d]pyrido[3 ,2-b] [ 1 ,4]oxazine-8(6H)-carboxylate (280 mg, 0.75 mmol, 97%) as a yellow oil; 5H(400 MHZ; CDC13) 7.85-7.80 (1H, m), 7.12-7.08 (1H, m), 4.52-4.41 (1H, m), 4.30-4.21 (1H, m), 4.21-4.03 (2H, m), 4.00-3.89 (1H, m), 3.40-3.27 (1H, m), 2.96-2.90 (1H, m), 2.81-2.71 (1H, m), 2.68-2.53 (1H, m), 1.52-1.47 (9H, m); ESMS [M+H]+: 372.1.

[0299] Step 3

[0300] tert-Butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-6a,7,9,10-tetrahydropyrazino[l,2-d]pyrido[3,2-b][l,4]oxazine-8(6H)-carboxylate was prepared in an analogous manner to 2,2-difluoro-2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin- 2-yl)ethan-l-ol from tert-butyl 3-bromo-6a,7,9,10-tetrahydropyrazino[l,2-d]pyrido[3,2-b][l,4]oxazine-8(6H)-carboxylate; ES-MS [M+H]+: 336.2 (boronic acid).

[0301] (R)-l-((l, 4-Dioxan-2-yl)methyl)-4-(4, 4,5, 5 -tetramethyl- 1, 3, 2-dioxaborolan-2-yl)~ IH-pyrazole

[0302] DIAD (1.04 g, 5.16 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole (500 mg, 2.58 mmol), (R)-(l,4-dioxan-2-yl)methanol (370 mg, 3.13 mmol) and triphenylphosphine (1.35 g, 5.15 mmol) in THF (10 mL). The resulting mixture stirred at 20 °C for 12 h, then concentrated in vacuo. Preparative HPLC purification (column: Waters Xbridge Prep OBD Cis 150*40 mm 10 pm; acetonitrile:water(TFA); gradient: 15%-45% B over 20 min) afforded (R)-l-((l,4-dioxan-2- yl)methyl)-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (800 mg, 2.45 mmol.95%) as a white solid; 5H (400 MHZ; DMSO-d6) 8.87 (2H, s), 3.49 (3H, m), 3.32-3.21 (6H, m), 1.20-1.14 (12H, m); ES-MS [M+H]+: 213.1 (boronic acid).

[0303] The following intermediate was prepared in an analogous manner:Analytica Name Structure Starting material1 dataES-MS (S)-l-((l,4-Dioxan-2-yl)methyl)-4-(4, 4,5,5 - (S)-(l,4-dioxan-2- [M+H]+: tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-pyrazole yl)methanol294.9°vZyD

[0304] 2-Methyl-l-( 3-methyl-4-( 4, 4, 5, 5-tetramethyl-l , 3, 2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)propan-2-ol

[0305] Step 1Br

[0306] Cesium carbonate (15.2 g, 46.6 mmol) was added to a solution 4-bromo-3-methyl-IH-pyrazole (5.00 g, 31.1 mmol) in DMF (20 mL) and the resulting mixture was stirred at 25 °C for 10 min. 2,2-Dimethyloxirane (8.27 mL, 93.2 mmol) was added and stirring was continued at 25 °C for 16 h. Water was added (100 mL) and the mixture was extracted into ethyl acetate (3 * 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Preparative HPLC purification (Welch Ultimate XB-SiOH 250*70 10 pm; hexane: ethanol; B%: 10%, isocratic elution mode) afforded l-(4-bromo-3-methyl-lH-pyrazol-l-yl)-2-methylpropan-2-ol (4.50 g, 18.5 mmol, 60%) as a yellow oil; 5H(400 MHZ; CDC13) 7.48-7.44 (1H, m), 3.96 (2H, s), 2.24 (3H, s), 1.16 (6H, s); ES-MS [M+H]+: 232.9.

[0307] Step 2

[0308] 2-Methyl-l-(3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-2-ol was prepared in an analogous manner to 2,2-difluoro-2-(5-(4,4,5,5-tetram ethyl- 1 ,3 ,2-di oxaborolan-2-yl)pyri din-2 -yl)ethan- 1 -ol from 1 -(4-bromo-3 -methyl- 1H-pyrazol-l-yl)-2-methylpropan-2-ol; 5H (400 MHZ; CDC13) 7.72-7.70 (1H, m), 4.66-4.64 (1H, m), 3.93-3.91 (2H, m), 2.22 (3H, s), 1.24 (12H, s), 1.04-1.02 (6H, m); ES-MS [M+H]+:281.1.

[0309] 4-(2-(Methoxy-d3)ethoxy)-lH-pyrazole

[0310] Step 1OTBSHOTHPTHP

[0311] Cesium carbonate (7.43 g, 17.9 mmol) was added to a solution of l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-ol (3.00 g, 17.9 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (5.13 g, 21.6 mmol) in DMF (10 mL). The resulting mixture was stirred at 80 °C for 2 h. Water was added (100 mL) and the mixture was extracted into ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (5.00 g, 15.3 mmol, 85%) as a white solid.

[0312] Step 2^OTBS d^OHN" N"THP THP

[0313] TBAF (5.21 g, 19.9 mmol) was added to a solution of 4-(2-((tert- Butyldimethylsilyl)oxy)ethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (5.00 g, 15.3 mmol) in THF (30 mL) and the resulting mixture was stirred at 25 °C for 12 h. Water was added (20 mL) and the mixture was extracted into ethyl acetate (3 ^ 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 80:20) afforded 2-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)ethan-l-ol (2.00 g, 9.42 mmol, 62%) as a white solid; 5H (400 MHz; DMSO-d6) 7.59 (1H, s), 7.25 (1H, s), 5.24 (1H, m), 4.82 (1H, m), 3.93-3.84 (3H, m), 3.69-3.55 (3H, m), 2.10-1.97 (1H, m), 1.97-1.79 (2H, m), 1.73-1.57 (1H, m), 1.56-1.46 (2H, m).

[0314] Step 3

[0315] 4-(2-(Methoxy-d3 )ethoxy)- 1 -(tetrahy dro-2H-pyran-2-yl)- 1 H-pyrazole was prepared in an analogous manner to 3-(methoxy-d3)azetidine; 6H (400 MHZ; DMSO-d6) 7.60 (1H, s), 7.26 (1H, s), 5.23 (1H, m), 3.95 (2H, m), 3.92-3.84 (1H, m), 3.65-3.55 (3H, m), 2.10-1.98 (1H, m), 1.96-1.79 (2H, m), 1.72-1.58 (1H, m), 1.55-1.44 (2H, m).

[0316] Step 4

[0317] HC1 (1.0 M in dioxane, 8.72 mL, 8.72 mmol) was added to a solution of 4-(2-(methoxy-d3)ethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (400 mg, 1.74 mmol) in dichloromethane (5 mL). The mixture was stirred at 25 °C for 12 h, then adjusted to pH ~9 by addition of saturated aqueous sodium bicarbonate solution. Water was added (10 mL) and the mixture was extracted into ethyl acetate (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 75:25) afforded 4-(2-(methoxy-d3)ethoxy)-IH-pyrazole (100 mg, 0.69 mmol, 39%) as a white solid; 5H (400 MHZ; DMSO-d6) 12.35 (1H, br s), 7.57-7.05 (2H, m), 3.98-3.87 (2H, m), 3.63-3.55 (2H, m).

[0318] 4-(2-(Difluoromethoxy)ethoxy)-lH-pyrazoleOTBSBoc

[0319] Cesium carbonate (10.6 g, 32.6 mmol) was added to a solution of tert-butyl 4-hydroxy-lH-pyrazole-l-carboxylate (3.00 g, 16.3 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (4.68 g, 19.5 mmol) in DMF (30 mL). The resulting mixture was stirred at 80 °C for 1 h. Water was added (60 mL) and the mixture was extracted into ethyl acetate (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford tert-butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-lH-pyrazole-1 -carboxylate (3.00 g, 8.76 mmol, 54%) which was used without further purification.

[0320] Step 2OTBS OHH N" H KTBoc Boc

[0321] p-Toluenesulfonic acid (302 mg, 1.75 mmol) was added to a solution of tert-butyl 4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-lH-pyrazole-l-carboxylate (3.00 g, 8.76 mmol) in DMF (20 mL) and the resulting mixture was stirred at 20 °C for 12 h. Water was added (40 mL) and the mixture was extracted into ethyl acetate (2 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 100:0) afforded tert-butyl 4-(2-hydroxyethoxy)-lH-pyrazole-l-carboxylate (1.50 g, 6.24 mmol, 71%); ES-MS [M+H]+: 229.2.

[0322] Step 3^DH ^DCHF2H i\rBoc H Boc

[0323] (Bromodifluoromethyl)trimethylsilane (2.94 g, 14.5 mmol) was added to a mixture of tert-butyl 4-(2-hydroxyethoxy)-lH-pyrazole-l-carboxylate (1.50 g, 6.57 mmol), potassium acetate (1.93 g, 19.7 mmol), dichloromethane (10 mL) and water (10 mL). The resulting mixture was stirred at 20 °C for 12 h, then extracted into di chloromethane (3 x 5 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 100:0) afforded tert-butyl 4-(2-(difluoromethoxy)ethoxy)-lH-pyrazole-l -carboxylate (300 mg, 099 mmol, 15%) as a colorless oil; 5H (400 MHZ; DMSO-d6) 8.00 (1H, d, J 0.63 Hz), 7.74 (1H, d, J 0.75 Hz), 6.56-6.98 (1H, m), 4.13-4.22 (4H, m), 1.60 (9H, s).

[0324] Step 4

[0325] HC1 (1.0 M in dioxane, 2 mL, 2 mmol) was added to a solution of tert-butyl 4-(2-(difluoromethoxy)ethoxy)-lH-pyrazole-l-carboxylate (300 mg, 1.08 mmol). The resulting mixture was stirred at 20 °C for 1 h, then concentrated in vacuo to afford 4-(2-(difluoromethoxy)ethoxy)-lH-pyrazole (180 mg) which was used without further purification.

[0326] 4-(2-( ( lH-Pyrazol-4-yl)oxy)ethyl)morpholine

[0327] Step 1Boc

[0328] Cesium carbonate (2.30 g, 7.06 mmol) was added to a solution of tert-butyl 4-hydroxy-lH-pyrazole-l-carboxylate (0.65 g, 3.53 mmol) and 4-(2-bromoethyl)morpholine (821 mg, 4.23 mmol) in DMF (7 mL). The resulting mixture was stirred at 80 °C for 2 h. Water was added (20 mL) and the mixture was extracted into ethyl acetate (3 ^ 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 60:40) afforded tert-butyl 4-(2-morpholinoethoxy)-lH-pyrazole-l-carboxylate (800 mg, 2.69 mmol, 76%) as a yellow oil; 5H(400 MHZ; DMSO-d6) 7.91 (1H, d, J 0.75 Hz), 7.66 (1H, d, J=0.75), 4.03 (1H, m), 4.02 (1H, m), 3.60-3.52 (4H, m), 2.63 (2H, m), 2.48-2.39 (4H, m), 1.55 (s, 9 H).

[0329] Step 2

[0330] TFA (3 mL, 40.4 mmol) was added to a solution of tert-butyl 4-(2-morpholinoethoxy)-lH-pyrazole-l-carboxylate (800 mg, 2.69 mmol) in dichloromethane (9 mL) and the resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was thenadjusted to pH ~8 by the addition of sodium bicarbonate. Water was added (10 mL) and the mixture was extracted into ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 4-(2-((lH-pyrazol-4-yl)oxy)ethyl)morpholine (200 mg, 1.01 mmol, 38%) as a yellow solid; 5H(400 MHZ; DMSO-d6) 12.32 (1H, br s), 7.48-7.23 (2H, m), 3.93 (2H, m), 3.59-3.50 (4H, m), 2.61 (2H, m), 2.46-2.36 (4H, m).

[0331] The following intermediate was prepared in an analogous manner:Name Structure Starting material Analytical dataHN8H(400 MHZ; DMSO-d6) 11.67-10.64 (1H, 4-(l-(((lH-pyrazol-4- (1- m), 7.41 (2H, s), 4.12 (2H, br s), 3.89 (4H, yl)oxy)methyl)cyclop p morpholinocyclopbr s), 3.60-3.20 (2H, m), 1.88-1.19 (4H, ropyljmorpholine ropyljmethanolm), 0.99 (2H, br s)

[0332] (R)-4-( I -( (lH-Pyrazol-4-yl)oxy)propan-2-yl)morpholine

[0333] Step 1THPM

[0334] (Tributylphosphoranylidene)acetonitrile (6.89 g, 28.5 mmol) was added to a solution of l-(oxan-2-yl)-lH-pyrazol-4-ol (3.20 g, 19.0 mmol) and benzyl N-[(2R)-1- hydroxypropan-2-yl]carbamate (5.97 g, 28.5 mmol) in toluene (50 mL). The resulting mixture was stirred at 100 °C for 16 h then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 22:78) afforded benzyl ((2R)-1-((1- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)propan-2-yl)carbamate (1.00 g, 2.78 mmol, 15%) as a yellow oil; 5H(400 MHZ; DMSO-d6) 7.60 (1H, s), 7.38-7.33 (5H, m), 7.25 (1H, s), 5.22 (1H, m), 5.02 (2H, s), 3.92-3.74 (3H, m), 3.72-3.66 (1H, m), 3.63-3.51 (1H, m), 2.01 (1H, br s), 1.94-1.79 (2H, m), 1.70-1.58 (1H, m), 1.55-1.46 (2H, m), 1.11 (3H, d, J6.60 Hz).

[0335] Step 2CbzHN H2N

[0336] Benzyl ((2R)-l-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)propan-2-yl)carbamate (1.00 g, 2.78 mmol) was added to a suspension of 10% Pd / C (100 mg, 94 pmol) in THF (10 mL) under nitrogen. The resulting mixture was degassed and purged with hydrogen three times, then stirred under hydrogen (50 PSI) at 25 °C for 4.5 h. The mixture was then filtered through celite and concentrated in vacuo to afford (2R)-l-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)propan-2-amine (500 mg) as a yellow oil.

[0337] Step 3

[0338] Potassium carbonate (736 mg, 5.33 mmol) and l-bromo-2-(2-bromoethoxy)ethane (453 mg, 1.95 mmol) were added to a solution of (2R)-l-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)propan-2-amine (400 mg, 1.78 mmol) in ethanol (4 mL). The resulting mixture was stirred at 60 °C for 16 h, then filtered and concentrated in vacuo. Preparative HPLC purification (column: Welch Ultimate XB-CN 250*70 mm 10 pm; hexane: ethanol; gradient: l%-30% B over 15 min) afforded 4-((2R)-l-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)propan-2-yl)morpholine (535 mg, 1.47 mmol, 83%) as a yellow oil; ES-MS [M+H]+: 296.2.

[0339] Step 4

[0340] HC1 (2.0 M dioxane, 1 mL, 1 mmol) was added to a solution of 4-((2R)-l-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)propan-2-yl)morpholine (100 mg, 339 pmol) in dichloromethane (0.5 mL). The resulting mixture was stirred at 25 °C for 4 h. Water was added (2 mL) and the mixture was extracted into dichloromethane (3 2 mL). Thecombined organic extracts were washed with brine (6 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford (R)-4-(l-((lH-pyrazol-4-yl)oxy)propan-2- yl)morpholine (100 mg) as a white solid that was used without further purification; 6H (400 MHz; DMSO-d6) 12.32 (1H, m), 7.44 (1H, br s), 7.25 (1H, m), 3.91 (1H, m), 3.72 (1H, m), 3.55 (4H, m), 2.86-2.77 (1H, m), 2.52 (4H, m), 1.03 (3H, d, J 6.75 Hz).

[0341] The following intermediates were prepared in an analogous manner:StartingName Structure Analytical data materialbenzyl N- 8H(400 MHZ; DMSO-d6) 13.46-12.26 HN(S)-4-(l-((lH-pyrazol- [(2S)-1- (1H, m), 7.98-7.18 (2H, m), 3.92 (1H, m), 4-yl)oxy)propan-2- hydroxypropan 3.75-3.71 (1H, m), 3.58-3.53 (4H, m), yl)morpholine -2- 2.86-2.77 (1H, m), 2.73 (5H, m), 1.04 yl]carbamate (3H, d, 76.75 Hz); ES-MS [M+H]+: 212.2HN4-(2- 8H(400 MHZ; DMSO-d6) 12.36 (1H, br s), 4-(2-((lH-pyrazol-4- F hydroxyethyl) 7.60-7.08 (2H, m), 4.03 (2H, s), 3.98 (2H, yl)oxy)ethyl)morpholinmorpholin-3- m), 3.84-3.76 (2H, m), 3.62 (2H, m), -3 -one* N_F one 3.47-3.42 (2H, m)HN4-((l-methyl-2- (l-methyl-2- 8H(400 MHZ; DMSO-d6) 7.35 (2H, s) oxabicyclo [2.1.1 ]hexan F oxabicyclo[2.1.4.10 (2H, s) 3.61 (2H, s) 1.67 (2H, m) -4-yl)methoxy)- 1 H- l]hexan-4- 1.47 (2H, m) 1.35 (3H, s) pyrazole* yl)methanol*Prepared using steps 1 and 4 only

[0342] N-(7-bromo-6-fluorobenzo[d]thiazol-2-yl)-3-fluoro-3-(methoxymethyl)azetidine- 1-carboxamide

[0343] Step 1

[0344] Phenyl chloroformate (15.2 mL, 121 mmol) was added to a solution of 7-bromo- 6-fluorobenzo[d]thiazol-2-amine (see D, steps 2-4, 10.0 g, 40.5 mmol) and 2,6-lutidine (23.6 mL, 202 mmol) in di chloromethane (100 mL). The resulting mixture was stirred at 20 °C for 12 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (6 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Trituration with methanol afforded phenyl (7-bromo-6- fhiorobenzo[d]thiazol-2-yl)carbamate (10.0 g, 24.8 mmol, 61%) as a white solid; 5H(400 MHz; DMSO-d6) 12.86 (1H, br s), 7.78 (1H, m), 7.51-7.44 (3H, m), 7.36-7.29 (3H, m); ESMS [M+H]+: 369.0.

[0345] Step 2

[0346] 3 -Fluoro-3-(methoxymethyl)azetidine (1.17 g, 9.80 mmol) was added to a solution of phenyl (7-bromo-6-fluorobenzo[d]thiazol-2-yl)carbamate (2.40 g, 6.54 mmol) and triethylamine (0.91 mL, 6.54 mmol) in dichloromethane (30 mL). The resulting solution was stirred for at 40 °C for 12 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 40:60) afforded N-(7-bromo-6- fluorobenzo[d]thiazol-2-yl)-3-fluoro-3-(methoxymethyl)azetidine-l -carboxamide (2.50 g, 6.25 mmol, 96%) as a white solid; 5H (400 MHZ; DMSO-d6); 11.68 (1H, br s), 7.65 (1H, m), 7.40 (1H, m), 4.30-4.03 (4H, m), 3.77-3.65 (2H, m), 3.34 (3H, s); ES-MS [M+H]+: 392.0.

[0347] The following intermediates were prepared in an analogous manner:StartingName Structure Analytical datamaterial(s)8H(400 MHZ; DMSO-d6) 12.47- N-(7-bromo-6- 12.22 (1H, m), 7.60-7.15 (2H, m), fluorobenzo [d]thiaz5-oxa-2- 3.98-3.85 (4H, m) 2.57-2.55 (2H, ol-2-yl)-5-oxa-2- azaspiro [3.4]octane m), 2.48 (2H, m) 2.15 (2H, m) azaspiro [3.4]octane Br1.12 (6H, d, J 6.36 Hz); ES-MS -2-carboxamide[M+H]+: 388.0N-(7-bromo-6- fluorobenzo [d]thiaz6-oxa-2- ol-2-yl)-6-oxa-2- jpryl<>Cjo[M+H]+: 388.0azaspiro [3.4]octaneazaspiro [3.4]octane-2-carboxamideN-(7-bromo-6- fluorobenzo [d]thiaz3 -fluoro -3- ol-2-yl)-3 -fluoro-3 - NHF((methoxy- [M+H]+: 397.1 ((methoxy- d3)methyl)azetidined3 )methyl)azetidine-1 -carboxamideN-(7-bromo-6- fluorobenzo [d]thiaz 8H(400 MHZ; DMSO-d6) 11.53 ol-2-yl)-3- ii r y-nh3 -(methoxy -d3)-3 - (1H, br s), 7.71-7.56 (1H, m), 7.40 (methoxy-d3)-3- methylazetidine (1H, m), 4.07-3.93 (2H, m), 3.86 methylazetidine- 1 - (2H, m), 1.42 (3H, s) carboxamideN-(7-bromo-6- fluorobenzo [d]thiaz 8H(400 MHZ; DMSO-d6) 11.52 ol-2-yl)-3- 3-methoxy-3- (1H, br s), 7.64 (1H, m), 7.38 (1H, methoxy-3- methylazetidine m), 4.06-3.78 (4H, m), 3.18 (3H, methylazetidine- 1 - s), 1.42 (3H, s); [M+H]+: 374.1 carboxamide7-bromo-6- N-(7-bromo-6- chlorobenzo [d]thiazchlorobenzo [d] thi aol-2-amine 8H(400 MHZ; DMSO-d6) 11.97- zol-2-yl)-3-fluoro- C|X I^X~-sr ^ F 11.51 (1H, m), 7.69-7.54 (2H, m), 3-((methoxy- 4.29-4.11 (4H, m), 3.77-3.65 (2H,3 -fluoro -3- m); [M+H]+: 413.0d3 )methyl)azetidin((methoxy- e-1 -carboxamided3)methyl)azetidineN-(7-bromo-6- 7-bromo-6- chlorobenzo [d] thi a chlorobenzo [d]thiaz8H(400 MHZ; DMSO-d6) 11.61 zol-2-yl)-3- [I I y1—NHzx ol-2-amine(1H, br s), 7.68-7.54 (2H, m), (methoxy-d3)-3-C| / Br ~ ^ CX 4.02-3.93 (2H, m), 3.87 (2H, br s),1.42 (3H, s) methylazetidine- 1 - 3 -(methoxy -d3)-3 - carboxamide methylazetidineN-(7-bromo-6- fluorobenzo [d]thiaz x^^N|| [ X\— NH „ 2-oxa-6- ol-2-yl)-2-oxa-6- [M+H]+: 374.0azaspiro [3.3 ]heptaneazaspiro [3.3 ]heptane-6-carboxamide2-oxa-6- N-(7-bromo-6- azaspiro [3.3 ]heptane 8H(400 MHZ; DMSO-d6) 11.18- chlorobenzo [d] thi af| [ NH 11.95 (1H, m), 7.54-7.68 (2H, m), zol-2-yl)-2-oxa-6- 7-bromo-6- 4.67 (4H, s), 4.22 (4H, br s); azaspiro [3.3 ]heptanchlorobenzo [d]thiaz [M+H]+: 390.0e-6-carboxamideol-2-amineN-(7-bromo-4,6- difluorobenzo [d] thi8H(400 MHZ; DMSO-d6) 11.91 azol-2-yl)-3 -fluoro- 1 ° 7\ 7-bromo-4,6- xkN'^N^<~xOMe (1H, br d, J 1.38 Hz), 7.55 (1H, 3- difluorobenzo [d] thi am), 4.51-3.99 (4H, m), 3.84-3.59 (methoxymethyl)az zol-2-amine(2H, m), 3.34 (3H, s)etidine-1- carboxamide

[0348] N-(Tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-amineBocH2N'

[0349] Acetic acid (312 pL, 5.46 mmol) was added to a solution of tert-butyl 4-amino-IH-pyrazole-l -carboxylate (1.00 g, 5.46 mmol) and tetrahydropyran-4-one (1.09 g, 10.9 mmol) in DCE (10 mL). The mixture was stirred at 25 °C for 2 h, then sodium triacetoxyborohydride (2.31 g, 10.9 mmol) was added at 0 °C. Stirring was continued at 25 °C for 16 h. The mixture was adjusted to pH 7 with saturated aqueous bicarbonate solution and extracted into ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 50:50) followed by preparative HPLC (column: Waters Xbridge 150*25 mm 5 pm; acetonitrile: water(NH4COs); gradient: 22%-42% B over 42 min) afforded N-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-4-amine (250 mg, 1.50 mmol, 27%) as a yellow solid; 5H (400 MHZ; DMSO-d6); 12.06 (1H, br s), 7.07 (2H, s), 4.14 (1H, br d, J7.6 Hz), 3.83 (2H, m), 3.35-3.28 (2H, m), 3.05-2.91 (1H, m), 1.84 (2H, m), 1.33-1.24 (2H, m).

[0350] 3-(2-( ( lH-Pyrazol-4-yl)oxy)ethyl)-6-oxa-3-azabicyclo[ 3.1.1 ]heptane

[0351] Step 1

[0352] IBX (1.60 g, 5.71 mmol) was added to a solution of tert-butyl 4-(2-hydroxyethoxy)-lH-pyrazole-l-carboxylate* (410 mg, 1.80 mmol) in acetonitrile (5 mL) and the mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and washed with acetonitrile (5 mL). The resulting solution of tert-butyl 4-(2-oxoethoxy)-lH-pyrazole-l-carboxylate in acetonitrile (5 mL) was used directly in Step 2.*see Step 2 of 4-(2-(difluoromethoxy)ethoxy)-lH-pyrazole synthesis

[0353] Step 2H

[0354] Sodium cyanoborohydride (240 mg, 3.82 mmol), 6-oxa-3- azabicyclo[3.1.1]heptane (480 mg, 3.54 mmol) and acetic acid (20 mg, 333 pmol) were added to a solution of tert-butyl 4-(2-oxoethoxy)-lH-pyrazole-l-carboxylate (600 mg, 2.65 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at 25 °C for 16 h then quenched with water (50 mL). The mixture was extracted into ethyl acetate (3 x 20 mL) and 3:1 ethyl acetate:MeOH (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by preparative HPLC (column: Phenomenex Luna Cis 150*40 mm 15 pm; acetonitrile:water(NH4CC>3); gradient: 5%-35% B over 15 min) afforded 3-(2-((lH-pyrazol-4- yl)oxy)ethyl)-6-oxa-3-azabicyclo[3.1.1]heptane (44 mg, 210 pmol, 8%) as ayellow oil; 5H (400 MHz; CDC13) 7.32 (2H, s), 4.52 (2H, d, J 6.3 Hz), 4.11 (2H, m), 3.25 (2H, br d, J 11.3 Hz), 3.05 (3H, m), 2.95 (2H, br d, J 11.3 Hz), 2.39 (1H, br d, J 8.1 Hz); ES-MS [M+H]+: 210.1.

[0355] The following intermediate was prepared in an analogous manner:StartingName Structure Analytical data material_NH 8H(400 MHZ; DMSO-d6) 10.64 (1H, r .'N br s), 7.43 (2H, s), 4.46 (2H, br d, J 3-(2-((lH-pyrazol-4- 0^^ 8 -oxa-3 - 2.5 Hz), 4.32 (2H, t, 75.1 Hz), 3.39 yl)oxy)ethyl)- 8 -oxa-3 - azabicyclo[3.2.1](2H, br s), 3.31 (2H, brd, 712.4 azabicyclo [3.2. l]octane octaneHz), 3.21-3.15 (2H, m,), 2.28-2.19 4(2H, m), 1.98-1.86 (2H, m)

[0356] Cis-4-(2-( lH-Pyrazol-4-yl)oxy)ethyl)-2, 6-dimethylmorpholine

[0357] Step 1L?

[0358] Carbon tetrabromide (12.0 g, 36.2 mmol) was added to a mixture of 2-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)ethan-l-ol* (5.50 g, 25.9 mmol) and triphenylphosphine (10.0 g, 38.1 mmol) in dichloromethane (30 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 12 h, concentrated in vacuo and purified by flash column chromatography on silica (EtOAc:PE, 0:100 to 30:70) to afford 4-(2 -bromoethoxy)- 1-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (5.0 g, 18.0 mmol, 70%) as a yellow oil; 5H(400 MHz; CDC13) 7.36-7.28 (2H, m), 5.29 (1H, m), 4.21 (2H, m), 4.05 (1H, m), 3.71 (1H, m), 3.60 (2H, m), 2.06 (3H, m), 1.70 (3H, m); ES-MS [M-THP+H]+: 210.1.*see Step 2 of 4-(2-(methoxy-d3)ethoxy)-lH-pyrazole synthesis

[0359] Step 2THPN

[0360] A mixture of 4-(2-bromoethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (1.00 g, 3.63 mmol), cis-2,6-dimethylmorpholine (600 mg, 5.21 mmol) and potassium carbonate (1.20 g, 8.68 mmol) in DMF (10 mL) was stirred at 60 °C for 12 h, then concentrated in vacuo. Water was added (50 mL) and the mixture was extracted into ethyl acetate (2 x 50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford cis-2,6-dimethyl-4-(2-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)ethyl)morpholine (1.10 g) which was used without further purification; ES-MS [M+H]+: 310.1.

[0361] Step 3

[0362] HC1 (2.0 M dioxane, 2 mL, 4 mmol) was added to a solution of cis-2,6-dimethyl- 4-(2-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)ethyl)morpholine (1.10 g, 3.56 mmol) in dioxane (5 mL) and the resulting mixture was stirred at 25 °C for 12 h. Saturated sodium bicarbonate solution (20 mL) was added and the mixture was extracted into ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford cis-4-(2-((lH-pyrazol-4- yl)oxy)ethyl)-2,6-dimethylmorpholine (0.60 g, 2.53 mmol, 71%) as a yellow oil; ES-MS [M+H]+: 226.1.

[0363] The following intermediates were prepared in an analogous manner:Name Structure Starting material(s) Analytical data HN8H(400 MHZ; DMSO-d6) CN12.47-12.22 (1H, m), 7.60- trans-4-(2-((lH-pyrazol-4- atrans-2,6- 7.15 (2H, m), 3.98-3.85 (4H, yl)oxy)ethyl)-2,6- dimehylmorpholine m) 2.57-2.55 (2H, m), 2.48 dimethylmorpholine(2H, m) 2.15 (2H, m) 1.12 (6H, d, J 6.36 Hz) p .2-(l -(tetrahydro-2H- 8H(400 MHZ; DMSO-d6) HN pyran-2-yl)-lH- 12.72-12.24 (1H, m), 7.64- 4-(2-(lH-pyrazol-4- pyrazol-4-yl)ethan- 1 - 7.23 (2H, m), 3.61-3.54 (4H, yl)ethyl)morpholine ol m), 2.59-2.54 (2H, m), 2.49- — N 2.31 (6H, m); ES-MS morpholine [M+H]+: 182.1

[0364] 6-(2-( lH-Pyrazol-4-yl)oxy)ethyl)-2-oxa-6-azaspiro[ 3.3 ]heptane

[0365] Step 1

[0366] Cesium carbonate (3.87 g, 11.9 mmol) was added to a solution of l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-ol (1.00 g, 5.95 mmol) and 2-bromo- 1,1 -dimethoxy-ethane (1.51 g, 8.92 mmol) in DMF (10 mL). The mixture was stirred at 60 °C for 2 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 ^ 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 40:60) afforded 4-(2,2-dimethoxyethoxy)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole (800 mg, 3.12 mmol, 53%) as a yellow oil.

[0367] Step 2

[0368] HC1 (4.0 M in dioxane, 4 mL, 16 mmol) was added to a solution of 4-(2,2-dimethoxy ethoxy)- l-(tetrahydro-2H-pyran -2 -yl)-lH-pyrazole (800 mg, 3.12 mmol) in THF (4 mL) and the mixture was stirred at 25 °C for 2 h. Sodium bicarbonate was added until the pH was ~7 and the mixture was extracted into EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-((lH-pyrazol-4-yl)oxy)acetaldehyde (300 mg, 2.38 mmol, 76%) as a yellow oil which was used without further purification.

[0369] Step 3

[0370] Sodium cyanoborohydride (224 mg, 3.57 mmol), 2-oxa-6-azaspiro[3.3]heptane (283 mg, 2.85 mmol) and acetic acid (14 pL, 238 pmol) were added to a solution of 2-((lH-pyrazol-4-yl)oxy)acetaldehyde (300 mg, 2.38 mmol) in acetonitrile (3 mL). The reactionmixture was stirred at 25 °C for 16 h then quenched with water (3 mL). The mixture was extracted into ethyl acetate (3 x 2 mL). The aqueous phase was purified by preparative HPLC (column: Waters Xbridge 150*25mm 10 pm; acetonitrile:water(NH4OH); gradient: l%-29% B over 1 min) to 6-(2-((lH-pyrazol-4-yl)oxy)ethyl)-2-oxa-6-azaspiro[3.3]heptane (110 mg, 526 pmol, 22%) as a white solid; 5H(400 MHZ; DMSO-d6) 12.30 (1H, br d, J 1.22 Hz), 7.30 (2H, s), 4.58 (4H, s), 3.75 (2H, m), 3.30 (4H, s), 2.59 (2H, m).

[0371] 4-( l-(( lH-pyrazol-4-yl)oxy)-2-methylpropan-2-yl)morpholine

[0372] Step 1

[0373] DIAD (1.48 g, 7.33 mmol) was added to a solution of tert-butyl 4-hydroxy-lH-pyrazole-1 -carboxylate (900 mg, 4.89 mmol), 2-methyl-2-morpholinopropan-l-ol (856 mg, 5.37 mmol) and triphenylphosphine (1.92 g, 7.33 mmol) in THF (20 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 16 h. Water was added (30 mL) and the mixture was extracted into ethyl acetate (3 ^ 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 40:60) afforded tert-butyl 4-(2-methyl-2-morpholinopropoxy)-lH-pyrazole-1 -carboxylate (610 mg, 1.82 mmol, 37%) as a yellow oil; ES-MS [M+H]+: 326.1.

[0374] Step 2

[0375] HC1 (2.0 M in dioxane, 6 mL, 12 mmol) was added to tert-butyl 4-(2-methyl-2-morpholinopropoxy)-lH-pyrazole-l-carboxylate (400 mg, 1.23 mmol) and the mixture was stirred at 25 °C for 1 h. Saturated aqueous sodium bicarbonate solution (30 mL) was added and the mixture was extracted into EtOAc (3 x 30 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Preparative HPLC (Welch Ultimate XB-SiOH 250*50 mm 10 pm; hexane: ethanol; gradient: 1%-15% B over 15 min)afforded 4-(l-((lH-pyrazol-4-yl)oxy)-2-methylpropan-2-yl)morpholine (180 mg, 0.80 mmol, 65%) as a white solid; 5H(400 MHz; CD3OD) 7.49-7.14 (2H, m), 3.74-3.65 (4H, m), 2.68- 2.58 (4H, m), 2.48 (2H, s), 1.24 (6H, s).

[0376] N-( tetrahydro-2H-pyran-4-yl)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyrimidin-2-amineI° / ( () Z CD —— / ^1z-

[0377] DIPEA (9 mL, 51.6 mmol) was added to a solution of 2-fluoro-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (3.60 g, 35.5 mmol) and tetrahydropyran-4- amine (3.60 g, 35.5 mmol) in DMSO (30 mL). The resulting mixture was heated at 100 °C for 16 h. Water was added (50 mL) and the mixture was extracted into EtOAc (3 x 50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford N-(tetrahydro-2H-pyran-4-yl)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyrimidin-2-amine (3.3 g, 10.8 mmol, 67%) as a white solid; 5H (400 MHZ; DMSO-d6) 8.40 (2H, s), 7.58 (1H, br d, J7.8 Hz), 4.05-3.92 (1H, m), 3.85 (2H, br d, J 10.9 Hz), 3.41- 3.35 (2H, m), 1.78 (2H, m), 1.58-1.43 (2H, m), 1.26 (12H, s).

[0378] The following intermediates were prepared in an analogous manner:StartingName Structure Analytical data material(s)SH(400 MHz; DMSO-d6) 8.36 (2H, s), 7.48 (1H, s), ( 1 -((5 -(4,4,5 ,5 -tetramethyl- 1,3,2- 1- 4.84 (1H, br s), 3.62 (2H, dioxaborolan-2-yl)pyrimidin-2- Aminocyclobutane br s), 2.21-2.09 (4H, m), yl)amino)cyclobutyl)methanol methanol 1.77-1.60 (2H, m), 1.25 (12H, s); ES-MS [M+H]+: 306.28H(400 MHZ; DMS0-d6)8.39 (2H, s), 7.47 (1H, d, J (3S,4R)-4-((5-(4, 4,5,5- 8.2 Hz), 4.92 (1H, d,J5.5 tetramethyl- 1 ,3 ,2-dioxaborolan- (3S,4R)-4- Hz), 3.45 (1H, m), 3.17 2-yl)pyrimidin-2- aminotetrahydro- (1H, d, J 5.1 Hz), 3.11- yl)amino)tetrahydro-2H-pyran-3 - 2H-pyran-3-ol 2.92 (2H, m), 1.91-1.85 ol (1H, m), 1.35 (2H, brd, J 6.6 Hz), 1.26 (12H, s); ESMS [M+H]+: 322.2

[0379] 2-((l -Methyl-2-oxabicyclo[ 2.1.1 ]hexan-4-yl)methoxy)-5-(4, 4, 5, 5-tetramethyl-l, 3- dioxolan-2-yl)pyrimidine

[0380] Step 1Br

[0381] Sodium hydride (60% dispersion in oil, 125 mg, 3.12 mmol) was added to a solution of (l-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methanol (200 mg, 1.56 mmol) in THF (4 mL) at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. 5-Bromo-2- fluoropyrimidine (304 mg, 1.72 mmol) was added and the mixture was stirred at 25 °C for 90 min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 mL) and extracted into ethyl acetate (2 x 2 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 100:0 to 50:50) afforded 5-bromo-2-((l-methyl-2- oxabicyclo[2.1.1]hexan-4-yl)methoxy)pyrimidine (200 mg, 0.69 mmol, 45%) as a white solid; ES-MS [M+H]+: 258.1.

[0382] Step 2

[0383] 2-((l-Methyl-2-oxabicyclo[2.1.1]hexan-4-yl)methoxy)-5-(4,4,5,5-tetramethyl-l,3- dioxolan-2-yl)pyrimidine was prepared in an analogous manner to 2,2-difluoro-2-(5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-l-ol.

[0384] The following intermediates were prepared in an analogous manner:Q m — —V / r\x -°y V O CQ——StartingName ]< O S^tructure Analytical data X material(s)(lr,3r)-3-((5-(4, 4,5,5- (lr,3r)- tetramethyl- 1 ,3 ,2-dioxaborolan- cyclobutane-1,3- ES-MS [M+H]+: 293.1 2-yl)pyrimidin-2- diolyl)oxy)cyclobutan- 1 -olSH(400 MHz; DMSO-d6) 2-(2-cyclopropoxyethoxy)-5 - 2- 8.72 (2H, s), 4.44 (2H, m), (4, 4, 5, 5 -tetramethyl- 1,3,2- cyclopropoxyethan 3.77 (2H, m), 3.30 (lH, m), dioxaborolan-2-yl)pyrimidine -l-ol 1.30 (12H, s), 0.52-0.40(4H, m)

[0385] 2-Bromo-5-(2-methoxyethoxy)-3-methylpyrazineBr

[0386] 1 -Iodo-2-methoxyethane (236 mg, 1.27 mmol) and silver carbonate were added to a solution of 5-bromo-6-methylpyrazin-2-ol (200 mg, 1.06 mmol) in DMF (5 mL). The Z z—resulting mixture was stirred at d 6 o CD—0 °C for 12 h, then filtered and concentrated in vacuo.\ CDPurification by preparative HPLC (co olumn: Phenomenex Luna C18 150*25mm 10 pm; acetonitrile: water(formic acid); gradient: 35%-65% B over 10 min) afforded 2-bromo-5-(2- methoxyethoxy)-3 -methylpyrazine (60 mg, 0.24 mmol, 23%) as a yellow oil; ES-MS [M+H]+: 249.1.

[0387] The following intermediate was prepared in an analogous manner:Name Structure Starting material(s) Analytical data2-bromo-3 -chloro-5 - 5-bromo-6- SH(400 MHz; DMSO-d6) methoxypyrazine chloropyrazin-2-ol 8.23 (1H, s), 3.93 (3H, s)

[0388] 6-Bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine

[0389] Sodium cyanoborohydride (1.13 g, 18.0 mmol), 6-bromopyri din-3 -amine (1.04 g, 5.99 mmol) and acetic acid (343 pL, 5.99 mmol) were added to a solution of tetrahydropyran- 4-one (600 mg, 5.99 mmol) in methanol (15 mL). The reaction mixture was stirred at 40 °C for 12 h then quenched with water (20 mL). The mixture was extracted into ethyl acetate (3 x 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Preparative HPLC purification (column: Phenomenex Luna C18 150*25 mm 10 pm; acetonitrile:water(formic acid); gradient: 21%-51% B over 10 min)afforded 6-bromo-N-(tetrahydro-2H-pyran-4-yl)pyridin-3-amine (650 mg, 2.53 mmol, 42%) as a white solid; ES-MS [M+H]+: 258.9.

[0390] 2 -Chlor o-5-( 1, l-difluoroethyl)-3-methylpyr azineCl Cl

[0391] DAST (2.14 g, 9.67 mmol) was added to a solution of l-(5-chloro-6- methylpyrazin-2-yl)ethan-l-one (330 mg, 1.93 mmol) in di chloromethane (3.3 mL) at 0 °C and the resulting mixture was stirred at 25 °C for 16 h. The reaction quenched with saturated sodium bicarbonate solution (10 mL) and extracted into di chloromethane (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 8:92) afforded 2-chloro-5-(l,l-difluoroethyl)-3-methylpyrazine (120 mg, 0.62 mmol, 32%) as a colorless oil; 5H (400 MHZ; CDC13) 8.54 (1H, s), 2.71 (3H, s), 2.07-1.98 (3H, m). ES-MS [M+H]+: 193.2.

[0392] Oxazol-2-ylmethyl (7-bromobenzo[d]thiazol-2-yl)carbamate

[0393] Oxazol-2-ylmethyl (7-bromobenzo[d]thiazol-2-yl)carbamate was prepared from 7-bromobenzo[d]thiazol-2-amine using Synthetic Procedure E, step 3; ES-MS [M+H]+: 356.0.

[0394] The following intermediate was prepared in an analogous manner:Analytical Name Structure Starting materialdata* 7-Chlorothiazolo[4,5-b]pyridin-2-amine was prepared from 3 -bromo-4-chloropyri din-2- amine in an analogous manner to 7-bromo-6-fluorobenzo[d]thiazol-2-amine

[0395] N-Methyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetan- 3-amine

[0396] Step 1Br

[0397] n-BuLi (2.5 M, 9.29 mL, 3.70 mmol) was added to a solution of 2,5- dibromopyridine (5 g, 21.1 mmol) at -60 °C and stirred for 15 min at this temperature. A solution of 2-Methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (4.07 g, 23.2 mmol) in toluene (5 mL) was added and the mixture was stirred at -60 °C for a further 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted into ethyl acetate (3 ^ 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 50:50) afforded N-(3-(5- bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfinamide (4.10 g, 12.0 mmol, 57%) as a yellow solid; ES-MS [M+H]+: 334.9.

[0398] Step 2Br Br

[0399] Sodium hydride (60% dispersion in oil, 180 mg, 4.50 mmol) was added at 0 °C under nitrogen to a solution of N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-2-methylpropane-2-sulfmamide (1.0 g, 3.00 mmol) in THF (10 mL). The resulting mixture was stirred at 0 °C for 30 min. A solution of iodomethane (373 pL, 6.00 mmol) in THF (2 mL) was added at 0 °C and stirring was continued at 25 °C for another 12 h. The reaction was quenched with saturated aqueous ammonium chloride solution (15 mL) and extracted into EtOAc (2 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-N,2-dimethylpropane-2-sulfinamide (300 mg, 0.92 mmol, 90%) as a yellow oil; ES-MS [M+H]+: 348.9.

[0400] Step 3N

[0401] HC1 (4.0 M in dioxane, 8 mL, 2 mmol) was added to a solution of N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-N,2-dimethylpropane-2-sulfinamide (800 mg, 2.30 mmol) in THF (4 mL) at 0 °C and stirred for 1 h at this temperature. The mixture adjusted to pH 8 with saturated sodium bicarbonate at 0 °C and extracted into ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford N-(3-(5-bromopyridin-2-yl)oxetan-3-yl)-N,2-dimethylpropane-2-sulfmamide (500 mg, 2.13 mmol, 92% as a red oil; ES-MS [M+H]+: 242.9.

[0402] Step 4

[0403] N-Methyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)oxetan-3-amine was prepared from 3-(5-bromopyridin-2-yl)-N-methyloxetan-3-amine in an analogous manner to 2,2-difluoro-2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-l-ol; ES-MS [M+H]+: 209.1 (boronic acid).

[0404] 6-( (5-(4, 4, 5, 5-Tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-2-oxa-6-azaspiro[ 3.3 ] heptane

[0405] Step 1Br Br

[0406] Potassium carbonate was added to a solution of 5-bromo-2-(chloromethyl)pyridine (200 mg, 0.97 mmol) and 2-oxa-6-azaspiro[3.3]heptane (144 mg, 1.45 mmol) in acetonitrile (5 mL) and the resulting mixture was heated at 80 °C for 12 h. Water (5 mL) was added and the mixture was extracted into ethyl acetate (3 ^ 10 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-((5-bromopyridin-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane(200 mg, 0.74 mmol, 77%) as a white solid; ES-MS [M+H]+: 269.9.

[0407] Step 2Br 'Bx

[0408] 6-((5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane was prepared from 6-((5-bromopyridin-2-yl)methyl)-2-oxa-6-azaspiro[3.3]heptane in an analogous manner to 2,2-difluoro-2-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)ethan-l-ol; ES-MS [M+H]+: 235.1 (boronic acid).

[0409] 5-Methyl-3, 6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate

[0410] Step 1O OTMS

[0411] Trimethylsilyl trifluoromethanesulfonate (2.4 mL, 13.3 mmol) was slowly added to a solution of 3-methyltetrahydro-4H-pyran-4-one (2.00 g, 17.5 mmol) and triethylamine(2.40 mL, 17.24 mmol) in dichloromethane (20 mL) at 0 °C and stirred for 30 min at this temperature. Water (20 mL) was added and the reaction mixture was extracted into dichloromethane (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo to afford trimethyl((5-methyl-3,6-dihydro-2H-pyran-4-yl)oxy)silane (3.70 g) as a yellow oil which was used without further purification.

[0412] Step 2OTMS OTf

[0413] Methyl lithium (1.6 M in THF, 13 mL, 20.8 mmol) was slowly added to a solution of trimethyl((5-methyl-3,6-dihydro-2H-pyran-4-yl)oxy)silane (3.70 g, 19.9 mmol) in THF (30 mL) at 0 °C and stirred for 30 min at this temperature. Phenyl triflimide (14.0 g, 39.2 mmol) was then added and stirring was continued at 30 °C for 30 min. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and acetic acid was added until the pH was ~6. Water (20 mL) was added and the reaction mixture was extracted into EtOAc (3 x 20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica (EtOAc:PE, 0:100 to 5:95) afforded 5-methyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.6 g, 6.50 mmol, 33%) as a yellow oil; 5H(400 MHZ; CDC13) 4.13-4.10 (2H, m), 3.89 (2H, m), 2.46 (2H, m), 1.72 (3H, s).

[0414] tert-butyl 3-( lH-pyrazol-4-yl)oxy)azetidine-l -carboxylate

[0415] Step 1THP

[0416] Cesium carbonate (11.6 g, 35.7 mmol) was added to a solution of l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-ol (3.00 g, 17.8 mmol) and tert-butyl 3 -iodoazetidine- 1-carboxylate (7.57 g, 26.8 mmol) in DMF (30 mL). The mixture was stirred at 40 °C for Ih. Water (50 mL) was added and the reaction mixture was extracted into EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Flash column chromatography on silica(EtOAc:PE, 0:100 to 40:50) afforded tert-butyl 3-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)azetidine-l -carboxylate (3.60 g, 11.1 mmol, 62%) as a yellow oil.

[0417] Step 2

[0418] TFA (15 mL, 202 mmol) was added to a solution of tert-butyl 3-((l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)oxy)azetidine-l-carboxylate (3.40 g, 10.5 mmol) in di chloromethane (30 mL) and the mixture was stirred at 25 °C for Ih. The reaction mixture was concentrated in vacuo to afford 4-(azetidin-3-yloxy)-lH-pyrazole (1.40 g, 10.1 mmol, 96%) as a yellow oil.

[0419] Step 3^~NH ^NBoc

[0420] Di-tert-butyl decarbonate (2.20 g, 10.1 mmol) was added to a solution of 4-(azetidin-3-yloxy)-lH-pyrazole (1.40 g, 10.1 mmol) and triethylamine (7.00 mL, 50.3 mmol) in methanol (15 mL). The mixture was stirred at 25 °C for Ih, then concentrated in vacuo. Purification by preparative HPLC (column: Kromasil Eternity XT 250*80 mm 10 pm; acetonitrile:water(NH4HCC>3); gradient: 20%-50% B over 20 min) afforded tert-butyl 3-((lH-pyrazol-4-yl)oxy)azetidine-l -carboxylate as a yellow solid; 6H (400 MHZ; DMSO-d6) 12.47 (1H, br s), 7.44-7.24 (2H, m), 4.76-4.65 (1H, m), 4.26-4.10 (2H, m), 3.82-3.68 (2H, m), 1.41-1.35 (9H, m).

[0421] Biological Assays

[0422] DLD-1 Cell Viability Assay

[0423] Compound cytotoxicity in DLD-1 human colorectal adenocarcinoma cells (ATCC CCL-221) was gauged using the CellTiter Gio 2.0 Luminescent Cell Viability Assay (Promega). DLD-1 cells maintained in growth medium (RPMI, 10% FBS, 1% P / S) were seeded into 1536-well black clear bottom plates (Coming 3836) at a density of 400 cells / 5pL / well (0.08X10A6cells / mL) and incubated overnight in a 5% CO2 incubator at 37°C.Compounds in 10 point 1:3 serial dilution in DMSO (provided by compound management in 384-well Low Dead Volume Echo certified plates, Labcyte LP-0200) were stamped (15 nL) onto 1536-well plates containing DLD-1 cells (at about 30-40% cell density) for a final compound concentration ranging from 30 pM to 1.5 nM. 30 pM (final concentration) of Toxoflavin served as a low control while DMSO only served as a high control in these experiments. The final DMSO concentration in the assay plate is 0.3%. Each sample was tested in triplicate.

[0424] 72 hours post compound introduction, 5 pL of CellTiter Gio 2.0 at room temperature is added to the cells in media using a multidrop combi and incubated for 30 minutes at room temperature. Luminescence from the samples is recorded with a Clariostar Plus plate reader and all data is normalized to the average of DMSO treated group and expressed as the percentage of control. IC50 values based on curve classification for each compound were calculated from the concentration response curves (percentage inhibition) using Dotmatics data management software.

[0425] Immunofluorescence Nuclear Condensate Assay

[0426] An immunofluorescence (IF) assay was used to measure the sequestration of beta catenin into nuclear condensates. DLD-1 cells (ATCC CCL-221) were maintained in growth medium RPMI 1640 (ATCC modification) (Thermo, A1049101) supplemented with 10% fetal bovine serum (VWR, 89510-196). Twenty-four hours prior to compound treatment, cells were seeded into 1536-well black clear bottom plates (Greiner, GR 789866) at a density of 600 cells / 5 pL / well and incubated overnight in a 5% CO2 incubator at 37 °C for 24 hours. Compounds in 10 point 1:3 serial dilution in DMSO in 384-well Low Dead Volume Echo certified plates (Labcyte, LP-0200) were stamped (15 nL) onto 1536-well plates containing DLD-1 cells for a final compound concentration ranging from 30 pM to 1.5 nM. NCB-0846 (30 pM) (Selleck, S8392) served as a high control while DMSO served as a low control in these experiments. The final DMSO concentration in the assay plate is 0.3%. Each sample was tested in triplicate.

[0427] Twenty-four hours after compound treatment, cells were fixed with the addition of 2 pL of 12% formaldehyde (Sigma, 1.04003) at room temperature for 15 minutes, permeabilized in 0.1% Triton X-100 (Sigma, 93443) in PBS for 15 minutes, blocked in 0.2% gelatin from cold water fish (Sigma, G7765) in PBS for 1 hour, and then stained with a 1:1000 dilution of the phospho beta catenin antibody (Invitrogen, 703638) in 0.2% gelatin overnight at 4 °C followed by incubation with a 1 : 10000 dilution of Hoechst (Thermo,H3570) and with a 1 : 1000 dilution of secondary antibody (Thermo, A l 1070) for 1 hour at room temperature. Plates were then imaged (Opera Phenix, Perkin Elmer), and analyzed with the Harmony software quantitating the fraction of cells with bright phospho beta catenin depots (see Figure 1). The data was normalized to the high (NCB-0846, 30 pM) and low (DMSO) controls. ECso values based on curve classification for each compound were calculated from the concentration response curves (percentage response) using Dotmatics data management software.

[0428] The data from the viability IC50 and immunofluorescence (IF) EC50 values are shown in the table below:Ex. No. DLD-1 Cell Viability IC50 DLD-1 IF ECso1 A A2 A A3 A A4 A A5 B B6 C C7 A A8 A A9 C C10 A B11 A A12 A A13 B B14 C C15 B B16 C C17 B B18 B B19 A A20 C C21 A A22 A A23 A A24 B B25 B B26 B B27 C C28 A B29 C C30 A A31 C nd32 B A33 B BC B B A A A A A A A A A A A A A A A A A B B A A C C A A B B C C B B B B A A A A B B A A A A A B A A B B B B A A A A C C A A B B A A A A B B B B B B C CB nd B A B C A A B B C C B C A B C CA AB B A A B A A A C C A A B B B B B A A A C B B B C C B A C C A A B B A A A A B C C CC c B c B A A AB nd A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A B B A A A A A A A AA AA C A A B B A A A A A A A CA nd A A A A A A A A B B A A A A A A A A B B B B A A A A B B B B A B B A B B B B B B A A A A A A C C A A B B A AB nd A A B B A A A A B B A A A A A B B B B BB ndC ndA nd B A A A A A B B B B A A A A A A A A A A B B B B B B A A B B C C B B A A B B B B B B B A A B B C B B A A B C B C A A C C B B A B B B C B C B C C C C C C A A B B B B A B A B A A A A A AA AB B B C A A A A C C A A A A A A A B A A C C A A A A A A A A B A A A B C A B A A B A C B B B A A B B C C B B B B B B B B C B B B A A B BB nd A A A A C C B B B C A A B B C C B A B B A B C CB BA A B B A A B B B B B B B A C C B B B BA nd C C B BC nd B B B B A A B B C C B B B B A A B A A A B B A A A A A A B B B B A A A B A A B A A A A B A A A A A A A B B B C C B B B B A A B B A AA nd322 A A323 C B324 B B325 A A326 A A327 B B328 A A329 A A330 A A331 A B332 A A333 B B334 C C335 A A336 C C337 B C338 C c339 C c340 C nd341 A A342 A A343 B A344 A A345 C C346 B A347 B A348 A A349 B B350 A A351 A AA: IC50 orECso <0.1 pMB: IC50 or EC50 >0.1 and <1 pMC: IC50 or EC50 >1 and <10 pMnd: not determined

[0429] Mouse Pharmacokinetic Study

[0430] Example 1 was formulated in DMSO : PEG400 : water (1 :4:5) for IV dosing and Cremophor® RH 40 : 20% HP-P-CD (1:19) for PO dosing. Three female BALB / c mice were dosed IV (1 mg / kg) and serial bleed time-points were taken at 0 min, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h. Ten female BALB / c mice were dosed PO (10 mg / kg) and bleeds were taken at 0 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h across the group (maximum two samples per mouse). Samples were prepared by protein precipitation with acetonitrile and analyzed by quantitative LC / MS using a AB API 5500 LC / MS / MS. PK parameters wereestimated by non-compartmental model using WinNonlin 8.3. The PK data for Example 1 is shown in the table below:Route of Dose Parameter Value administrationTl / 2 7.7 hCmax 2.19 pMPO 10 mg / kgAUClast 3.18 h-pMF% 52%Cl 64 mL / min / kgIV 1 mg / kgVss 16.9 L / kg

[0431] Colorectal Cancer Cell-Line Derived Xenograft Study

[0432] HCT-116 cells (ATCC CCL-247) were cultured in McCoy’s %A media until sufficient cell numbers for implantation into mice were obtained. Cells were harvested and inoculated (5xl06in 100 pL in McCoy's 5a medium) subcutaneously into the right flank of nude mice and tumor growth was monitored by caliper measurement. When tumors reached -70-100 mm3, mice were randomized into treatment groups (5 groups, n=10 / group) and treatment was initiated. Example 1, formulated in Cremophor® RH 40 : 20% HP-P-CD (1:19) for PO dosing, was administered as follows: Vehicle; Example l-50mg / kg QD. Tumor volume measurements were captured twice weekly using digital calipers and the data is represented as the mean group tumor volume + / - S.E.M. Figure 2 shows the tumor volumes for mice treated with Example 1 and mice provided with vehicle.

[0433] qPCR Assay

[0434] Gene expression of beta catenin target genes was measured by duplexed Real- Time quantitative Polymerase Chain Reaction (RT- qPCR) in DLD-1 human colorectal adenocarcinoma cells (ATCC CCL-221). DLD-1 cells maintained in growth medium (RPMI ATCC formulation, 10% FBS) were seeded in 384-well black clear bottom plates (Revvity, Phenoplate) at a density of 2000 cells / 40 pL / well (5.0xl04cells / mL) and incubated overnight at 37°C with 5% CO2. The example compound diluted in DMSO at the indicated concentrations was added to the cells. The final DMSO concentration in each well was 0.1%.24 hours after compound addition, cells were washed once with lx Phosphate Buffered Saline (PBS) and lysed using 30 pL of cell lysis buffer (ThermoFisher #4391851C). Cell lysis occurs over an 8-minute period at room temperature while shaking the plate on a platform shaker. After cell lysis, 3 pL of stop solution (ThermoFisher #4391851C) was added. 4 pL of cell lysate was then transferred to 384-well qPCR-compatible plates (ThermoFisher #4483285). qPCR Master Mix (ThermoFisher #A15299) containing target and housekeeping TaqMan probes is then dispensed, and each reaction was assembledaccording to the manufacturer’s instructions. Transcript abundance was measured by qPCR using a Quantstudio 7 Flex thermocycler. Each sample was tested in duplicate across 4 beta catenin target genes: Axin2 (ThermoFisher Hs00610344_ml), Lefl (ThermoFisher Hs01547250_ml), Myc (ThermoFisher Hs00153408_ml), andNotum (ThermoFisher Hs00394510_ml). The housekeeping control gene, RNase P, was duplexed with one target gene per well. Quantification was performed by calculating the AACt and relative quantification (2'AACt) values. Figure 3 shows the gene expression changes in DLD-1 cells treated with Example 1 or DMSO.

Claims

CLAIMSWhat is claimed is:

1. A compound having the structural Formula I:or a pharmaceutically acceptable salt thereof, wherein:z1is N or -CR3;z2is N or -CR5;z3is N or -CR4;R1is hydrogen, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, or (C i-C4)alkylene[OP(O)(OH)2] ;R2is aryl, heteroaryl, heterocyclyl, or cycloalkyl, each of which are optionally substituted with 1 to 3 groups selected from R1A;R3and R4are each independently hydrogen, halo, cyano, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (C2-C4)alkenyl, (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heteroaryl], (Ci-C4)alkylene[cycloalkyl], -S(O)2(Ci-C4)alkyl, or -S(0)(Ci-C4)alkyl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano;R5is hydrogen, halo, or (Ci-C4)alkyl;X is -OR6or -NR7R8;R6is cycloalkyl, heterocyclyl, (Ci-C4)alkylene(Ci-C4alkoxy), (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heteroaryl], (Ci-C4)alkylene[heterocyclyl], or (Ci-C4)alkylene[cycloalkyl], wherein the aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from R2A;R7and R8are taken together to form a heterocyclyl optionally substituted with 1 to 3 groups selected from R2A;each R1Ais independently selected from halo, cyano, (Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, hydroxy[halo(Ci-C4)alkyl], cyano(Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, (Ci-C4)alkoxyO(Ci-C4)alkyl, (Ci-C4)alkoxyO[deuterated(Ci-C4)alkyl], halo(Ci-C4)alkoxy, (Ci-C4)alkoxyO[halo(Ci-C4)alkyl], oxo, hydroxy, -O[hydroxy(Ci-C4)alkyl], -Ofcycloalkyl], -Ofheterocyclyl], -Ofaryl], -O [heteroaryl], (Ci-C4)alkylene[cycloalkyl], (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[heteroaryl], -O(Ci-C4)alkylene[NRaRb], -O(Ci-C4)alkylene[NRaC(O)Rb], -O(Ci-C4)alkylene[cycloalkyl], -O(Ci-C4)alkylene[aryl], -O(Ci-C4)alkylene[heterocyclyl], -O(Ci-C4)alkylene[heteroaryl], cycloalkyl, heterocyclyl, aryl, heteroaryl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], (Ci-C4)alkoxyO[cycloalkyl], (Ci-C4)alkoxyO[heterocyclyl], (Ci-C4)alkoxyO[heteroaryl], (Ci-C4)alkoxyO[phenyl], -C(O)[heterocyclyl], -SRa, -S(O)Ra, -SO2Ra, -S(0)(NRa)Rb, -NRbS02Rb, -S02NRa, -C(0)Ra, -C(0)0Ra, -C(0)NRaRb, -NRaC(0)Rb, -NRaC(0)NRb, -NRaRb, -NH(Ci-C4)alkylene[heterocyclyl], and (Ci-C4)alkyleneNRaRb, where each occurrence of cycloalkyl, heterocyclyl, aryl, and heteroaryl alone, or as part of another group, is optionally substituted with 1 to 3 groups selected from halo, oxo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, hydroxy, -NH2, -NH(Ci-C4)alkyl, -N((Ci-C4)alkyl)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, and cyano;each R2Ais independently selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, deuterated(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], oxo, -Ofcycloalkyl], cyano, hydroxy, S(0)(Ci-C4)alkyl, -S(O)2(Ci-C4)alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, (Ci-C4)alkylene[cycloalkyl], (Ci-C4)alkylene[aryl], (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[heteroaryl], -C(0)Ral, -C(0)0Ral, -C(0)NRalRbl, -NRalC(0)Rbl, -NRalC(0)NRbl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano; andeach Ra, Ral, Rb, and Rblis each independently selected from hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkyleneNH2, (Ci-C4)alkyleneNH((Ci-C4alkyl), (Ci-C4)alkyleneN((Ci-C4alkyl)2, cycloalkyl, and heterocyclyl, wherein the cycloalkyl and heterocyclyl are each optionally substituted with (Ci-C4)alkyl, hydroxy, or hydroxy (Ci-C4)alkyl;provided that:(i) if R7and R8, taken together with the N to which they are attached, form pyrrolidinyl, then R2Ais not -C(0)NH2;(ii) if R7and R8, taken together with the N to which they are attached, form piperidinyl, then R2Ais not benzyl; and(iii) if R7and R8, taken together with the N to which they are attached, form 6- to 12- membered heterocyclyl, then R2is substituted by 1 to 3 groups selected from R1A2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein: z3is -CR4; andeach R2Ais independently selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, deuterated(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], oxo, cyano, hydroxy, S(O)(Ci-C4)alkyl, -S(O)2(Ci-C4)alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, (Ci-C4)alkylene[cycloalkyl], (Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkylene[heteroaryl], -C(O)Ral, -C(O)ORal, -NRalC(0)Rbl, -NRalC(0)NRbl, wherein said heterocyclyl, aryl, heteroaryl, and cycloalkyl are each optionally substituted with 1 to 3 groups selected from halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, and cyano.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein:(i) z1is N, z2is -CR5, and z3is -CR4;(ii) z1is -CR3, z3is -CR4, and z2is N; or(iii) z1is -CR3, z2is -CR5, and z3is -CR4.

4. The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein z1is -CR3, z2is -CR5, and z3is -CR4.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen, halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (C2-C4)alkenyl, (Ci-C4)alkoxy, cyano, -S(O)2(Ci-C4)alkyl, or (Ci-C4)alkylene[heterocyclyl], wherein said heterocyclyl is optionally substituted by 1 halo.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen, -F, -Cl, -CH3, -CF3, -CH=CH2, -OCH3, cyano, -S(O)2CH3,7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen, halo, or (Ci-C4)alkyl.

8. The compound of any one of Claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R4is hydrogen, -F, or -CH3.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, halo, or (Ci-C4)alkyl.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R5is hydrogen, -F, or -CH3.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen or (Ci-C4)alkylene[OP(O)(OH)2].

12. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R1is hydrogen.

13. The compound of Claim 1, having the structural Formula II:R2or a pharmaceutically acceptable salt thereof.

14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R2is phenyl, cyclohexyl, azetidinyl, morpholinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, piperdinyl, azaspirohexanyl, azaspiroheptanyl,oxaazaspiroheptanyl, oxaazaspirooctanyl, oxaazaspirononanyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, isoindolinyl, dihydropyrazolooxazinyl, dihydrodioxinopyridinyl, or hexahydropyrazinopyridooxazinyl, each of which is optionally substituted with 1 to 3 groups selected from R1A.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable saltof which is optionally substituted with 1 or 2 groups selected from R1A.

16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt D1A p1A D1A R1ARIA R1Athereof, wherein R2is:RIA RIARIAR1A17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each R1Ais independently halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, hydroxy(Ci-C4)alkyl, hydroxy[halo(Ci-C4)alkyl], (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], hydroxy, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkoxyO(Ci-C4)alkyl, (Ci-C4)alkoxyO[deuterated(Ci-C4)alkyl], (Ci-C4)alkoxyO[halo(Ci-C4)alkyl], -O(Ci-C4)alkylene[NRaRb], -NRaRb, -NH(Ci-C4)alkylene[heterocyclyl], cyano, -C(O)Ra, -C(0)NRaRb, -SC>2Ra, cycloalkyl, heterocyclyl, (Ci-C4)alkylene[heterocyclyl], -O(Ci-C4)alkylene[cycloalkyl], -O(Ci-C4)alkylene[heterocyclyl], (Ci-C4)alkoxyO[cycloalkyl], -Ofcycloalkyl], or -Ofheterocyclyl], where each occurrence of cycloalkyl and heterocyclyl, alone, or as part of another group, is optionally substituted with 1 to 3 groups selected from oxo, (Ci-C4)alkyl, hydroxy, -NH(Ci-C4alkyl), and heterocyclyl.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein Raand Rbare each independently hydrogen, (Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, cycloalkyl, or heterocyclyl, wherein the cycloalkyl and heterocyclyl are each optionally substituted with (Ci-C4)alkyl, hydroxy, or hydroxy(Ci-C4)alkyl.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein each R1Ais independently -F, -Cl, -CH3, -CH(CH3)2, -CH2F, -CHF2, -CF3, -CF2CH3, -CH2CF3, -CF2CH2OH, -CH2OCH3, -CH2OCD3, -CH2OCHF2, -CH2OCF3, - CH2CH2OCH3, -C(OH)(CH3)2, -CH2C(OH)(CH3)2, hydroxy, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2OCD3, -OCH2CH2OCHF2, -OCH2CH2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, cyano, -C(O)CH3, -C(O)NH2, -C(O)NHCH3, - OC(O)N(CH3)2, -C(O)NHCH2CH2OCH3, -S(O)2CH3, cyclopropyl, 'uw+w, ,20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein X is -OR6.

21. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R6is (Ci-C4)alkylene[heteroaryl].

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable saltthereof, whereinR6is23. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein X is -NR7R8.

24. The compound of any one of Claims 1 to 19 or 23, or a pharmaceutically acceptable salt thereof, wherein R7and R8, together with the N to which they are attached, form azetidinyl, azaspirohexanyl, azaspiroheptanyl, oxaazaspiroheptanyl, thiaazaspiroheptanyl, diazaspirooctanyl, oxaazaspirooctanyl, oxaazaspirononanyl, diazaspirononanyl, oxadiazaspirononanyl, or dioxaazaspirononanyl, each of which are optionally substituted with 1 to 3 groups selected from R2A.

25. The compound of any one of Claims 1 to 19, 23, or 24, or a pharmaceutically acceptable salt thereof, wherein R7and R8, together with the N to which they are attached,with 1 to 3 groups selected from R2A.

26. The compound of any one of Claims 1 to 19 or 23 to 25, or a pharmaceutically acceptable salt thereof, wherein R7and R8, together with the N to which they are attached,R2A R2A p2AR2AR2A27. The compound of any one of Claims 1 to 19 or 23 to 26, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently halo, (Ci-C4)alkyl, deuterated(Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkylene[halo(Ci-C4)alkoxy], hydroxy(Ci-C4)alkyl, hydroxy, (Ci-C4)alkoxy, deuterated(Ci-C4)alkoxy, -S(O)2(Ci-C4)alkyl, cyano, or cycloalkyl.

28. The compound of any one of Claims 1 to 19 or 23 to 27, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently -F, -CH3, -CD3, -CH2F, -CF3, -CH2CF3, -CH2OCH3, -CH2OCH2CH3, -CH2OCD3, -CH2OCHF2, -CH2OCF3, -C(OH)(CH3)2, -C(CH3)2OCH3, hydroxy, -OCH3, -OCD3, -OCH2CH3, -OCH(CH3)2, -S(O)2CH3, cyano, or cyclopropyl.

29. The compound of Claim 1, having the structural Formula III:R1ASor a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- to 6-membered nitrogen containing heteroaryl.

30. The compound of Claim 29, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl, pyridinyl, or pyrimidinyl.

31. The compound of Claim 29 or 30, or a pharmaceutically acceptable salt thereof,wherein Ring A is:, or , each of which is substituted by R1A.R1A32. The compound of any one of Claims 29 to 31, wherein Ring A is:'A^uv'R1A33. The compound of any one of Claims 29 to 32, or a pharmaceutically acceptable salt thereof, wherein R1Ais (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkoxyO(Ci-C4)alkyl, -Ofcycloalkyl], or -Ofheterocyclyl],34. The compound of any one of Claims 29 to 33, or a pharmaceutically acceptable salt thereof, wherein R1Ais -OCH3, -OCHF2, -OCH2CH3, -OCH(CH3)2, -O-cyclopropyl, -OCH2CH2OCH3, or35. The compound of any one of Claims 29 to 34, or a pharmaceutically acceptable salt thereof, wherein each R2Ais independently halo, (Ci-C4)alkyl, (Ci-C4)alkylene(Ci-C4)alkoxy, (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy], (Ci-C4)alkoxy, or deuterated(Ci-C4)alkoxy.

36. The compound of any one of Claims 29 to 35, or a pharmaceutically acceptable salt thereof, wherein R2Ais -F, -CH3, -CH2OCH3, -CH2OCH2CH3, -CH2OCD3, or -OCD3.

37. The compound of Claim 29, or a pharmaceutically acceptable salt thereof, wherein:R1Ais (Ci-C4)alkoxy; andeach R2Ais independently halo, (Ci-C4)alkylene(Ci-C4)alkoxy, or (Ci-C4)alkylene[deuterated(Ci-C4)alkoxy],38. The compound of Claim 29 or 37, or a pharmaceutically acceptable salt thereof, wherein:R1Ais -0CH3or -OCH2CH3; andeach R2Ais independently -F, -CH2OCH3, or -CH2OCD3.

39. The compound of Claim 1, wherein the compound is selected from any one of Examples 1 to 351, or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

41. A method of treating a disease or condition responsive to the modulation of beta catenin condensates, the method comprising administering to a subject in need an effective amount of a compound according to any one of Claims 1 to 39, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Claim 40.

42. The method of Claim 41, wherein the disease or condition is cancer.

43. The method of claim 42, wherein the cancer is bladder cancer, breast cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, leukemia, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, or a solid tumor.

44. The method of claim 43, wherein the breast cancer is triple negative breast cancer, the leukemia is chronic lymphocytic leukemia or acute myeloid leukemia, and the lung cancer is non-small cell lung cancer.

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