Process for preparing ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) inhibitors

Abstract

The present disclosure relates generally to processes for providing compounds that can be used as inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), which inhibitors can be useful in treating or preventing soft bone diseases, such as hypophosphatasia (HPP).

Description

PROCESS FOR PREPARING ECTONUCLEOTIDE PYROPHOSPHATASE / PHOSPHODIESTERASE 1 (ENPP1) INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U. S. C. §119(e) to U. S. Provisional Application Number 63 / 736,320, filed December 19, 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] The present disclosure relates generally to processes for providing compounds that can be used as inhibitors of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1). which inhibitors can be useful in treating or preventing soft bone diseases, such as hypophosphatasia (HPP).BACKGROUND

[0003] Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene, which encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Low TNSALP activity leads to the extracellular accumulation of phosphoethanolamine (PEA), inorganic pyrophosphate (PPi), and pyridoxal 5 phosphate (PLP) in blood or urine. PPi, an inhibitor of bone mineralization, is one of the key substrates involved in the pathogenesis of HPP. In HPP, excess PPi contributes to defective mineralization of bones (rickets or osteomalacia), premature loss of deciduous teeth, chronic bone and muscle pain, recurrent fractures, respiratory and muscle dysfunction and periodontal defects. Symptoms range from lethal or severe in the perinatal or infantile-onset forms of HPP, to modest or mild in the childhood and adult-onset forms. The incidence of severe HPP ranges from about 1: 100,000 to 1:300,000 live births. In certain populations the incidence is higher, such as in the Canadian Mennonites in whom the incidence is as high as about 1 in 2,500 births.

[0004] Hypophosphatasia presents a significant burden to affected individuals and their families.Therefore, there remains a need for improved or alternate processes for the efficient production of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) inhibitors that can be used to treat or prevent hypophosphatasia.SUMMARY

[0005] In one aspect, provided herein is a process for preparing a compound of Formula I:or a salt thereof, wherein R1, ml, m2, nl, and n2 are each independently as defined throughout; wherein the compound of Formula I is provided by contacting a compound of Formula IIA:H HAor a salt thereof, with Compound C:or a salt thereof, under suitable coupling conditions: wherein the compound of Formula IIA, or a salt thereof, and / or Compound C is prepared according to the present disclosure.DETAILED DESCRIPTIONDefinitions

[0006] As used herein, the term “contacting” refers to the process of bringing into contact at least two distinct species such that they can react. It should be appreciated, however, that the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

[0007] The term “reaction conditions” is intended to refer to the physical and / or environmental conditions under which a chemical reaction proceeds. Examples of reaction conditions include, but are not limited to, one or more of following: reaction temperature, solvent, pH, pressure, reaction time, moleratio of reactants, the presence of a base or acid, one or more protecting groups, catalyst, radiation, etc. Reaction conditions may be named after the particular chemical reaction in which the conditions are employed, such as, coupling conditions, hydrogenation conditions, acylation conditions, reduction conditions, etc. Reaction conditions for most reactions are generally known to those skilled in the art or can be readily obtained from the literature. Exemplary reaction conditions sufficient for performing the chemical transformations provided herein can be found throughout, and in particular, the examples below. It is also contemplated that the reaction conditions can include reagents in addition to those listed in the specific reaction.

[0008] “Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional moiety. “Deprotecting” or “deprotection” refers to a step removing the protecting group so as to restore the functional moiety to its original state. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See also Wuts, P. G. M. & Greene, T. W. (Wiley: 6th edition (March 5, 2025). Protecting groups are often utilized to mask the reactivity of certain functional moieties, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. For example, exemplary carboxylic acid protecting groups include alkyl or benzyl protecting groups, such as methyl, ethyl, benzyl, or tert-butyl; silyl groups such as 2-(trimethylsilyl)ethyl; and thioesters such as tert-butyl thioester. In some embodiments, the protecting group is tert-butyl. Exemplary amine protecting groups include carbamate protecting groups, such as tertbutyl carbamate (Boc), 9-fluorenylmethyl carbamate (Fmoc), or benzyl carbamate. In some embodiments, the protecting group is tert-butyl carbamate (Boc).

[0009] “Alkyl” refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “C1-C8 alkyl”). 3 to 8 carbon atoms (a “Cs-Cg alkyl”), 1 to 6 carbon atoms (a “Ci-Ce alkyl”), 1 to 5 carbon atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0010] “Alkenyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). The alkenyl group may be in "cis" or "trans" configurations, or alternatively in “£” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having2 to 4 carbon atoms (a “C2-C4 alkenyl”)- Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2 -enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta- 1,3 -dienyl, 2-methylbuta- 1,3 -dienyl, homologs and isomers thereof, and the like.

[0011] ‘‘Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a “Ci-Ce alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”).Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and the like. “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency.

[0012] “Alkynyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C) and having the number of carbon atoms designated (i.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl”), having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2 -ynyl (or propargyl), but-l-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.

[0013] “Aryl” refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and / or heterocyclyl rings. In one variation, the aryl group contains from 6 to 14 annular carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.

[0014] “Cycloalkyl” refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but excludes aryl groups. In certain embodiments, cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. In certain embodiments, cycloalkyl is a cyclic hydrocarbon having from 3 to 13 annular carbon atoms. In certain embodiments, cycloalkyl is a cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a "C3-C8 cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.

[0015] ‘ ‘Halo” refers to elements of the Group 17 series having atomic number 9 to 85. In certain embodiments, halo groups include fluoro, chloro, bromo, and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with twoC‘di”) or three (“tri”) halo groups, which may be but are not necessarily the same halo: thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” In certain embodiments, a perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0016] “Heteroaryl” refers to and includes unsaturated aromatic cyclic groups having from 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of tire molecule at an annular carbon or at an annular heteroatom. Heteroaryl may contain additional fused rings (e.g., from 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and / or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl, pyrazolyl, 1,2,4-triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzoimidazolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, purinyl. benzofuranyl, fiiropyridinyl, benzooxazolyl, benzothiophenyl, benzothiazolyl, oxazolopyridinyl, thiazolopyridinyl, thienopyridinyl, quinolinyl, quinolonyl, naphthyridinyl, quinazolinyl, pyridopyrimidinyl, cinnolinyl, or pyridopyridazinyl, and the like.

[0017] “Heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having from 1 to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. A heterocyclyl group may have a single ring or multiple condensed rings, but excludes heteroaryl groups. A heterocyclyl comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, azepanyl, tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

[0018] “Oxo” refers to the moiety =0.

[0019] Also provided are salts of compounds referred to herein, such as pharmaceutically acceptable salts. The disclosure also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds described.

[0020] Tire term “salt” is meant to include salts of the compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds describedherein. When compounds as disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds as disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzene sulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present disclosure may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., (1985) and Journal of Pharmaceutical Science, 66:2 (1977), each of which is incorporated herein by reference in its entirety.Processes

[0021] In one embodiment, provided is a compound of Formula I:Formula Ior a salt thereof, comprising contacting a compound of Formula IIA:H2NX 'P,sx_ R1NH HAor a salt thereof, with Compound C:ClyN-r?Cl cor a salt thereof, under suitable coupling conditions: provided that the compound of Formula IIA. or a salt thereof, is prepared by deprotecting a compound of Formula IA as prepared according to the present disclosure; or Compound C is prepared according to the present disclosure;wherein:R1is hydrogen, Ci-Ce alkyl. Cs-Ce cycloalkyl. -(Ci-Ce alkylene)Cs-C6 cycloalkyl. 3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)Ce-aryl, 5- to 6-membered heteroaryl, -(Ci-Ce alkylene)5-to 6-membered heteroaryl, Ci-Ce haloalkyl, -(Ci-Ce alkylene)OR13, -(Ci-C6alkylene)SR13, -(Ci-C6alkylene)S(O)2R13, -(Ci-C6alkylene)S(O)2NR14R15, -(Ci-Ce alkylene)NR13S(O)2R14, -(Ci-C6alkylene)NR14R15, -(Ci-C6alkylene)C(O)R13, -(Ci-C6alkylene)NR13C(O)R14, -(Ci-C6alkylene )NR13C(O)NR14R15, -(Ci-C6alkylene)C(O)OR13, -(C1-C6alkylene)C(O)ONR14R15, or -(C1-C6 alkylene)-C(O)NR14R15; wherein each may be optionally protected, and wherein each of which is optionally substituted with Rd;Rdis hydrogen, halo, -OH, oxo, -CN, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -COOH or Ci-Ce alkyl optionally substituted with -OH, halo, CN, or oxo;each R13, R14, and R15is independently hydrogen, Ci-Ce alkyl, C2-Cs alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Ci-Ce cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of R13, R14, and R15is independently optionally substituted by oxo, -OH, C2-Ce alkenyl, C2-Ce alkynyl, -CN, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH, or halo;or R14and R15are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH or halo; andeach ml, m2, nl, and n2 is independently 1, 2, 3, or 4.

[0022] In some embodiments, the coupling conditions comprise nucleophilic aromatic substitution reaction conditions.

[0023] In some embodiments, the coupling conditions comprise a polar aprotic solvent, such as DMSO (dimethyl sulfoxide), DMF (dimethylformamide), or acetonitrile (CH3CN), and the like.

[0024] In some embodiments, the coupling conditions comprise an organic base, such as an amine base (e g., DIPEA, DMIPA, TEA, TMA, NMP, DIPA, TMEDA, DBU. DIAPA, etc ).

[0025] It will be appreciated that where typical process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0026] Additionally, protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M. & Greene, T. W. (Wiley; 6th edition (March 5, 2025). For example, protecting groups for alcohols, such as hydroxy, include silyl ethers (including trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), and triisopropylsilyl (TIPS) ethers), which can be removed by acid or fluoride ion, such as NaF, TBAF (tetra-n-butylammonium fluoride), HF-Py, or HF-NEt3. Other protecting groups for alcohols include acetyl, removed by acid or base, benzoyl, removed by acid or base, benzyl, removed by hydrogenation, methoxyethoxymethyl ether, removed by acid, dimethoxytrityl, removed by acid, methoxymethyl ether, removed by acid, tetrahydropyranyl or tetrahydrofuranyl, removed by acid, and trityl, removed by acid. Examples of protecting groups for amines include carbobenzyloxy, removed by hydrogenolysis p-methoxybenzyl carbonyl, removed by hydrogenolysis, tert-butyloxycarbonyl, removed by concentrated strong acid (such as HC1 or CF3COOH), or by heating to greater than about 80 °C, 9-fluorenylmethyloxycarbonyl, removed by base, such as piperidine, acetyl, removed by treatment with a base, benzoyl, removed by treatment with a base, benzyl, removed by hydrogenolysis, carbamate group, removed by acid and mild heating, p-methoxybenzyl, removed by hydrogenolysis, 3,4-dimethoxybenzyl, removed by hydrogenolysis, p-methoxyphenyl, removed by ammonium cerium(IV) nitrate, tosyl, removed by concentrated acid (such as HBr or H2SO4) and strong reducing agents (sodium in liquid ammonia or sodium naphthalenide). troc (trichloroethyl chloroformate), removed by Zn insertion in the presence of acetic acid, and sulfonamides (Nosyl & Nps), removed by samarium iodide or tributyltin hydride.Formula II A

[0027] In one aspect, provided is a process for preparing a compound of Formula IA:ml( )m2nl( \ / )n2NR2IAor a salt thereof, comprising contacting a compound of Formula IB:or a salt thereof, with chlorosulfonyl isocyanate, in the presence of an alcohol of Formula R30H, wherein:R1is hydrogen, Ci-Ce alkyl, Cs-Ce cycloalkyl, -(Ci-Ce alkylene)C3-Ce cycloalkyl, 3- to 6-membered heterocyclyl, -(C1-C8 alkylene)3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)C6-aryl, 5- to 6-membered heteroaryl, -(Ci-Ce alkylene)5-to 6-membered heteroaryl. Ci-Ce haloalkyl, -(Ci-Ce alkylene)OR13, -(Ci-C6alkylene)SR13, -(Ci-C6alkylene)S(O)2R13, -(Ci-C6alkylene)S(O)2NR14R15, -(Ci-C6alkylene)NR13S(O)2R14, -(Ci-C6alkylene)NR14R15, -(Ci-C6alkylene)C(O)R13, -(Ci-C6alkylene)NR13C(O)R14, -(Ci-C6alkylene)NR13C(O)NR14R15, -(Ci-C6alkylene)C(O)OR13, -(C1-C6alkylene)C(O)ONR14R15, or -(C1-C6 alkylene)-C(O)NR14R15; wherein each may be optionally protected, and wherein each of which is optionally substituted with Rd;Rdis hydrogen, halo, -OH, oxo, -CN, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -COOH or Ci-Ce alkyl optionally substituted with -OH, halo, CN, or oxo; wherein each may be optionally protected;R2is a protecting group;R3is -C(O)OCi-C6alkyl;each R13, R14and R15is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of R13, R14and R15is independently optionally substituted by oxo, -OH, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH, or halo; wherein each may be optionally protected;or R14and R15are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH or halo; andeach ml, m2, nl, and n2 is independently 1. 2, 3, or 4.

[0028] In some embodiments, the compound of Formula IB, or salt thereof, is prepared by contacting a compound of Formula IC:OR2ICor a salt thereof, with a compound of Formula ID:H2N-R1IDor a salt thereof, in the presence of a reducing agent.

[0029] In some embodiments, ml is 1. In some embodiments, m2 is 1. In some embodiments, nl is 1. In some embodiments. n2 is 1. In some embodiments, ml. m2, nl, and n2 are each 1.

[0030] In some embodiments, the process is performed in the presence of a reducing agent under reductive amination reaction conditions. Reducing agents used are normally based on boranes, such as BHs-amine complexes or borohydride reagents, like NaBH4, NaHB(OAc)3, or NaH3BCN. Alternatively, traditional hydrogenation using supported metal catalysts and hydrogen gas. Occasionally with hydride reagents acids are added as catalysts, which protonate the imine and increase the rate of reduction. In some embodiments, the reducing agent is NaBH4.

[0031] In one aspect, provided is a process for preparing Formula I:or a salt thereof, comprising contacting a compound of Formula IIA:H2NX / P'. / SxMH IIAor a salt thereof, with Compound C:Cl Cor a salt thereof, under suitable coupling conditions: wherein the compound of Formula IIA, or a salt thereof, is prepared by contacting a compound of Formula IB:or a salt thereof, with chlorosulfonyl isocyanate, in the presence of an alcohol of Formula R3OH, to provide a compound of Formula IA:NR2IAor a salt thereof, and deprotecting the compound of Formula IA or a salt thereof, to provide the compound of Formula IIA, or a salt thereof, wherein:R1is hydrogen, Ci-Ce alkyl, C₃-C₆ cycloalkyl, -(C₁-C₆ alkylene)C₃-C₆ cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)C6-aryl, 5- to 6-membered heteroaryl, -(Ci-Ce alkylene)5- to 6-membered heteroaryl, Ci-Ce haloalkyl, -(Ci-Cg alkylene)OR13, -(Ci-C5alkylene)SR13. -(Ci-C6alkylene)S(O)2R13. -(Ci-C6alkylene)S(O)2NR14R15, -(C1-C8 alkylene)NR13S(O)2R14, -(Ci-C6alkylene)NR14R15, -(Ci-C6alkylene)C(O)R13, -(Ci-C6alkylene)NR13C(O)R14, -(Ci-C6alkylene)NR13C(O)NR14R15, -(Ci-C6alkylene)C(O)OR13, -(Ci-C6alkylene) C(O)ONR14R15, or -(Ci-Cg alkylene)-C(O)NR14R1’; wherein each may be optionally protected, and wherein each of which is optionally substituted with Rd;Rdis hydrogen, halo, -OH, oxo, -CN, Ci-Cg haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, -COOH, or Ci-Cg alkyl optionally substituted with -OH, halo, CN, or oxo; wherein each may be optionally protected;R2is a protecting group;R3is -C(O)OCi-C6alkyl;each R13, R14andR15is independently hydrogen, Ci-Cg alkyl, C2-Cg alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, C₃-C₆ cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of R13, R14, and R15is independently optionally substituted by oxo, -OH, C2-Cg alkenyl, C2-C6 alkynyl, -CN, halo, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halo; wherein each may be optionally protected;or R14and R15are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH. halo, or Ci-Ce alkyl optionally substituted by oxo, -OH or halo; andeach ml, m2, nl, and n2 is independently 1. 2, 3, or 4.

[0032] In some embodiments, R2is -C(O)OCi-Ce alkyl. In some embodiments, R2is -C(O)O--butyl. In some embodiments, R3is -C(O)O--butyl

[0033] In some embodiments, the compound of Formula IA, or salt thereof, is represented by Compoundor a salt thereof.

[0034] In one embodiment, provided is a process for preparing Compound A:or a salt thereof, comprising contacting Compound B:or a salt thereof, with chlorosulfonyl isocyanate, in the presence of 'BuOH

[0035] In one embodiment, provided is a process for preparing Compound I:Cl Ior a salt thereof, comprising contacting Compound 1 A:NHor a salt thereof, with Compound C:or a salt thereof, under suitable coupling conditions; wherein Compound 1 A, or a salt thereof, is prepared by contacting Compound B:HN’Xor a salt thereof, with chlorosulfonyl isocyanate in the presence of 'BuOH. to provide Compound IB:or a salt thereof, and deprotecting Compound IB, to provide Compound 1A, or a salt thereof.Compound C

[0036] In one aspect, provided is a process for preparing Compound C:Cl Cor a salt thereof, comprising chlorinating Compound D:or a salt thereof.

[0037] In some embodiments, the process comprises POCh and SO2CI2.

[0038] In some embodiments, the process further comprises A-chlorosuccinimide.

[0039] In some embodiments, the process comprises POCI3, SO2CI2, and JV-chlorosuccinimide.

[0040] In one aspect, provided is a process for preparing Formula I:Cl Ior a salt thereof, comprising contacting a compound of Formula IIA:dzNH 1IAor a salt thereof, with Compound C:or a salt thereof, under suitable coupling conditions: wherein Compound C. or a salt thereof, is prepared by chlorinating Compound D:or a salt thereof: whereinR1is hydrogen, Ci-Ce alkyl, Cs-Cg cycloalkyl. -(Ci-Cg alkylene)Cs-Cg cycloalkyl, 3- to 6-membered heterocyclyl. -(Ci-Cg alkylene)3- to 6-membered heterocyclyl, -(Ci-Cg alkylene)Cg-aryl, 5- to 6-membered heteroaryl, -(Ci-Cg alkylene)5-to 6-membered heteroaryl, Ci-Cg haloalkyl, -(Ci-Cg alkylene)OR13, -(Ci-Cg alkylene)SR13, -(C1-C6alkylene)S(O)2R13, -(C1-C6alkylene)S(O)2NR14R15, -(Ci-C6alkylene)NR13S(O)2R14, -(C1-C6alkylene)NR14R15, -(Ci-C6alkylene)C(O)R13, -(C1-C6alkylene)NR13C(O)R14, -(C1-C6alkylene)NR13C(O)NR14R15, -(C1-C6alkylene)C(O)OR13, -(Ci-C6alkylene) C(O)ONR14R15, or -(Ci-Cg alkylene)-C(O)NR14R15; wherein each may be optionally protected, and wherein each of which is optionally substituted with Rd:Rdis hydrogen, halo, -OH, oxo, -CN, Ci-Cg haloalkyl, Ci-Cg alkoxy, C1-C6haloalkoxy, -COOH. or Ci-Cg alkyl optionally substituted with -OH, halo. CN, or oxo; wherein each may be optionally protected;R2is a protecting group;R3is -C(O)OCi-C6alkyl;each R13, R14, and R15is independently hydrogen, C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, Cj-Ce cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of R13, R14, and R15is independently optionally substituted by oxo, -OH, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH, or halo; wherein each may be optionally protected;or R14and R15are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH or halo; andeach ml, m2, nl, and n2 is independently 1. 2, 3, or 4.

[0041] In some embodiments, the compound of Formula I prepared according to the procedures disclosed herein is selected from Table 1. It is understood that individual enantiomers and diastereomers are included in the generic compound structures shown in Table 1. Biological data for certain compounds of Table 1 are provided in US20220135598.Table 1No. Structure A Au9%. NH210y M1112No. Structure No. Structure %, NH2o VH2CX A '613 17N NZA^N rN-N^ WCl Cl°VNH2pr8', NH2F=CY^N'% F-TxX AFx14 180H^NN / A]A^N yA rN'N^ Cl Cl °AXNH2PPNH2,sJQC? 'b15,,cX 19N NZ / A^ANyA r'MCl Cl9' ^NHNH2F C °S'23'A A16 20 <*>'bN NA^ANA]NyA yACl ClNo. Structure No. StructureP%, NH2VAF / X21 24NCl, N~S «~NH222 25NX yN.y ClAA7A- °'S. NH NH2 2F3C^^> T I N>23 26NNyN-N^ yACl Cl1 %NH2f" M>27NAp ^N y'MClT No. Structure No. Structure T A A oA' A °'\XNH2Py^ z v z A / ° °VNH2FV ^x l VIo 1 'o IZ oo ox V l.oI28 32 AN LL AA^NyN'N^ yACl Cl29 M CT 33\z^ / (AAX Z\X \z z z$1 >_ o oH N zx °S"NH2AA A2Y^N'%30 34XN NZA=|AN> A wCl ClA °s'NH2" X '°31 35NyAClEXAMPLES

[0042] The following examples are included to demonstrate specific embodiments of tire disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.Synthesis of Compound D:NH2O'Ph-P-PhO1) t-BuOKDMF,0°C~RT2) HCONH2, 165°C

[0043] To a solution of ID (307 g, 1 eq) in DMF (6 L, 20 vol) at 0 °C was added t-BuOK (269.3 g, 1.2 eq) portion-wise over a period of 1 h. The resulting reaction mixture was allowed to stir at 0 °C for 1 h. Then (aminooxy)diphenylphosphine oxide (56 g, 1.2 eq) was added portion-wise over a period of 1 h. The mixture was allowed to warm to room temperature and stirred overnight. Tire reaction mixture was poured into ice-cold water (20 L) and extracted with ethyl acetate (3 x 4 L). The combined organic layers were washed with brine (4 x 3 L), dried over anhydrous sodium sulphate, filtered, and concentrated toafford ethyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate as a yellow oil (315 g, 93%). MS: m / z 169.1[M+H]+.

[0044] A solution of ethyl 1-amino-3-methyl-1H-pyrrole-2-carboxylate (315 g, 1 eq) in formamide (3.2 L, 10 vol) was heated at 180 °C for 16 h. After completion, tire reaction mixture was allowed to cool to room temperature and quenched with ice-water (5 L). The mixture was stirred for 30 min and filtered to get the filtrate (batch 1). The filtered cake was dissolved into THF (300 mL) and refluxed for 1 h and then filtered to get the filtrate (batch 2). The filtrates (batch 1 and batch 2) were combined and extracted with ethyl acetate (3 x 2 L). The combined organic layers were washed with brine (3 x 5 L), dried over anhydrous sodium sulphate, filtered and concentrated to afford Compound D as a brown solid (140 g, 50%). MS: m / z 150 [M+H]+.Synthesis of Compound C:OH 1) POCI3(1.26eq), DIPEA (0.8eq), AON, 85°CX 2) SO2CI2(1eq), 5°CN

[0045] To a suspension of Compound D (125 g, 1 eq) in ACN (1.2 L, 10 vol) at RT was added POCl3 (162 g, 1.26 eq). The mixture was cooled to <5 °C and DIPEA (87 g, 0.8 eq) was added portion wise over 20 min. The resultant mixture was heated at reflux for 6 h after which it was concentrated to dryness. The residue was dissolved in DCM (0.4 L) and washed with phosphate buffer (pH = 7.4, 4 L) followed by brine (0.3 L). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated to -125 mL. The solution was filtered through a silica pad (5:1 silica to compound) using DCM to remove color and the solution was concentrated to dryness to afford the step 1 product (110 g, 76% MS: m / z 168 [M+H]+; ’HNMR (400 MHz, CDC13) 5 ppm 8.08 (s, 1H), 7.76 (d, J= 4Hz, 1H), 6.77 (d, J= 4Hz, 1H), 2.61 (s, 3H).

[0046] To a solution of the step 1 product (220 g, 1 eq) in DCM (2.2 L. 10 vol) at 5 °C was added sulfuryl chloride (176 g, 1 eq) dropwise over 30 min. The mixture was stirred for an additional 30 min at 5 °C. The mixture was poured into NaHCOs (100 g / L, 2.2 L, 10 vol) and stirred until gas evolution ceased. The layers were separated and the aqueous layer was washed with DCM (0.5 L. 2 vol). The combined organic layers were washed with NaHCO3 (100 g / L, 0.9 L, 4 vol), dried over anhydrous sodium sulphate, filtered and concentrated to dryness. The residue was recrystallized from ethyl acetate (1.3 L) to afford Compound C (193 g, 73%). MS: m / z 202 [M+H]+;1H NMR (400 MHz, CDCl3) δ ppm 8.21 (s, 1H), 6.76 (s, 1H), 2.66 (s, 3H).Synthesis of Compound B:1) MeNH2(1.2eq), NaBH4(1.5eq), MeOH, 5-10°CO 2) Oxalic acid (1eq), EA3) NaOH (2eq), DCM NHBocN —BocN—1

[0047] To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (1 kg, 1 eq) in MeOH (13 L, 13 vol) at RT was added methylamine (40% in MeOH, 581 mL, 1.2 eq) and the resultant mixture was stirred for 16 h. The mixture was cooled to 0 °C and NaBH4 (pellets, 269 g, 1.5 eq) was added portion wise. The mixture was allowed to warm to RT and was stirred for 1 h. The mixture was concentrated to dryness and the residue was partitioned between aqueous KHCOs (5%, 1 L, 1 vol) and ethyl acetate (5 L, 5 vol). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 4 L, 2 x 4 vol), the combined organic layers were washed with aqueous KHCOs (5%, 5 L, 5 vol) and brine (5 L. 5 vol). The organic layers were dried over anhydrous sodium sulphate, filtered and concentrated to dryness to afford the crude amine (~1 kg, quant).

[0048] To a solution of oxalic acid (1069 g, 1 eq) in ethyl acetate (40 L, 15 vol) at 45 °C was added a solution of the crude amine (2.688 kg, 1 eq) in ethyl acetate (5.4 L, 2 vol) dropwise. The resultant slurry was stirred at 45 °C for 1 h then slowly cooled to RT overnight. After cooling to <10 °C, the slurry was filtered, the filter cake was washed with cold ethyl acetate (2 x 2.7 L, 2 x 1 vol) and then dried at 40 °C to afford the salt (2.8 kg, 75%). ’HNMR (400 MHz, DMSO-iC) 5 ppm 3.87 (br s, 2H), 3.78 (br s, 2H), 3.58-3.48 (m, 1H), 2.48-2.41 (m, 5H), 2.31-2.28 (m, 2H), 1.36 (s, 9H).

[0049] To a suspension of tire above material (2.815 kg, 1 eq) in DCM (11 L, 4 vol) and water (2.8 L, 1 vol) at <10 °C was added aqueous NaOH (30%. 2 eq) while maintaining tire temperature below 25 °C. The resultant slurry was filtered and tire filter cake washed with DCM (2 x 1.4 L, 2 x 0.5 vol). The combined mother liquors were separated and the organic layer washed with aqueous NaOH (0.5 M, 4.2 L, 1.5 vol), brine (4.2 L, 1.5 vol), dried over anhydrous sodium sulphate, filtered and concentrated to dryness to afford Compound B (1972 g, 98%).1H NMR (400 MHz, CDCl3) δ ppm 3.98-3.92 (m, 2H), 3.89-3.83 (m, 2H), 3.16-3.05 (m, 1H), 2.49-2.43 (m, 2H), 2.35 (s, 3H), 2.10-2.02 (br s, 2H), 1.95-1.89 (m, 2H), 1.45 (s, 9H).Synthesis of Compound A:Chlorosulfonyl isocyanate (1eq), t-BuOH (1.1eq), BocHN DCM, 0°C then Compound B (0.95eq),DI PEA (2eq), 0°CBocN— BocN

[0050] To a solution oftBuOH (410 g, 1.1 eq) in DCM (24 L, 22 vol) at -5 °C was added chlorosulfonyl isocyanate (710 g, 1 eq) dropwise to maintain the temperature below 0 °C and tire mixture was stirred for 10 min. To the mixture was added a solution of Compound B (1083 g, 0.95 eq) and DIPEA (1304 g, 2 eq) in DCM (1.5 L, 2.1 vol) dropwise over 100 min to ensure the temperature below 0 °C. The addition vessel was rinsed with DCM (350 mL) to ensure complete transferred. After 15 min below 0 °C, the temperature was increased to RT over 1 h. The mixture was washed with water (5 L, 7 vol), aqueous citric acid (10%, 2 x 5 L, 2 x 7 vol), water (5L, 7 vol), and brine (3 L, 4 vol). The organic layer dried over anhydrous sodium sulphate, filtered and concentrated to dryness to afford crude material. The crude material was combined with crude from a second batch of 1106 g scale and triturated from cyclohexane: ethyl acetate (2:1. 12 L. 8 vol). The solid was collected by filtration, rinsed with cyclohexane: ethyl acetate (5:1, 2 x 2 L, 2 x 1.5 vol) and dried at 40 °C to afford Compound A (2849 g, 73%).1H NMR (400 MHz, CDCl3) δ ppm 7.09 (s, 1H), 4.30-4.21 (m, 1H), 3.98 (br s, 2H), 3.87 (br s, 2H), 2.91 (s, 3H), 2.48-2.43 (m, 2H), 2.37-2.32 (m, 2H), 1.50 (s, 9H), 1.45 (s, 9H).Synthesis of Compound 1A:H2NXTFA (10eq), DCM, RT, 16h,then pTSA (1eq)tosylateHN

[0051] To a solution of Compound A (900 g, 1 eq) in DCM (3.6 L, 4 vol) at RT was added TFA (1788 g, 7 eq) dropwise over 30 min. The mixture was stirred at RT for 18 h and concentrated to dryness. The residue was diluted in ethyl acetate (9 L, 10 vol) and pTSA monohydrate (420 g, 1 eq) was added. The mixture was stirred at 40 °C for 15 min before cooling to RT. The resultant slurry was filtered and thefilter cake was washed with ethyl acetate (900 mL) and dried at 40 °C to afford Compound 1A as the tosylate salt (795 g, 93%).1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (br s, 2H), 7.49 (d, J= 8 Hz, 2H), 7.12 (d, J= 8 Hz, 2H), 6.71 (s, 2H), 4.06-3.98 (m, 2H), 3.89-3.86 (m, 2H), 3.73-3.65 (m, 1H), 2.43-2.24 (m, 7H).Synthesis of Compound I:Clc (1eq),DIPEA (2.1eq), ACN(10 vol), 50°C, 1h

[0052] To a solution of Compound 1A (11.7 g, 1 eq) and Compound C (6.3 g, 1 eq) in ACN (63 mL. 10 vol) was added DIPEA (8.5 g, 11.4 mL, 2.1 eq) at room temperature. Reaction mixture was heated at 50 °C for 1 h to achieve full conversion. The resultant suspension was cooled to 20 °C and poured onto water (50 mL). The crude product was collected by filtration, washed with ACN (10 mL), water (20 mL), MeOH (20 mL) and dried at 40 °C under reduced pressure (5 mbar) to afford crude Compound I (10 g, 87%, UPLC: -93% pure). A 4.8 g sample was dissolved in AcOH (45 mL, 9 vol) at 100 °C to afford a clear solution. The mixture was allowed to cool to room temperature and pure material was isolated by filtration. The filter cake was washed with MeOH (20 mL), water (20 mL), and MeOH (20 mL). The solid was dried at 60 °C under reduced pressure (3 mbar) for 24 h to afford Compound I (3.6 g, 75%). MS: m / z 371 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ ppm 7.91 (s, 1H), 6.70 (s, 2H), 6.63 (s, 1H), 4.42 (br s, 2H), 4.30 (br s, 2H), 3.79-3.73 (m, 1H), 2.54 (s, 3H), 2.45-2.31 (m, 7H).

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0054] The disclosure illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms ‘'comprising,” '‘including,” ‘'containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in tire use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure.

[0055] Thus, it should be understood that although the present disclosure has been specifically disclosed by certain embodiments and optional features, modification, improvement and variation may be resorted to by those skilled in the art. and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are exemplary', and are not intended as limitations on the scope of the disclosure.

[0056] Specific embodiments have been described broadly and generically herein. Each of tire narrower species and subgeneric groupings also form part of the disclosure. This includes the generic description with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0057] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

[0058] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

CLAIMSWhat is claimed is:

1. A process for preparing a compound of Formula IA:or a salt thereof, comprising contacting a compound of Formula IB:HN'R1ml( )m2nl ( A. )n2NR2IBor a salt thereof, with chlorosulfonyl isocyanate, in the presence of an alcohol of Formula R3OH, wherein:R1is hydrogen, Ci-Ce alkyl, Cs-Ce cycloalkyl, -(C1-C8 alkylene)C3-Ce cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)Ce-aryl, 5- to 6-membered heteroaryl, -(Ci-Ce alkylene)5-to 6-membered heteroaryl, Ci-Ce haloalkyl, -(Ci-Ce alkylene)OR13, -(Ci-C6alkylene)SR13, -(Ci-C6alkylene)S(O)2R13, -(Ci-C6alkylene)S(O)2NR14R15, -(Ci-C6alkylene)NR13S(O)2R14, -(Ci-C6alkylene)NR14R15, -(Ci-C6alkylene)C(O)R13. -(Ci-C6alkylene)NR13C(O)R14, -(Ci-C6alkylene )NR'3C(O)NR14R‘5, -(Ci-C6alkylene)C(O)OR13, -(Ci-C6alkylene) C(O)ONR14R, or -(Ci-Ce alkylene)-C(O)NR14R' wherein each may be optionally protected, and wherein each of which is optionally substituted with Rd;Rdis hydrogen, halo, -OH, oxo, -CN, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -COOH, or Ci-Ce alkyl optionally substituted with -OH, halo, CN or oxo; wherein each may be optionally protected;R2is a protecting group;R3is -C(O)OCi-C6alkyl;each R13, R14and R15is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3 - to 6-membered heterocyclyl, wherein each of R13, R14and R15is independently optionally substituted by oxo, -OH, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH, or halo; wherein each may be optionally protected;or R14and R15are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halo, or Ci-Ce alkyl optionally substituted by oxo, -OH or halo; andeach ml, m2, nl, and n2 is independently 1. 2, 3, or 4.

2. Tire process of claim 1, wherein the compound of Formula IB, or salt thereof, is prepared by contacting a compound of Formula IC:OR2ICor a salt thereof, with a compound of Formula ID:H2N-R1IDor a salt thereof, in the presence of a reducing agent.

3. The process of claim 1 or 2, wherein ml, m2, nl, and n2 are each 1.

4. The process of claim 2 or 3. wherein the reducing agent is NaBH4.

5. The process of claim 1, wherein the compound of Formula IA, or salt thereof, is represented by Compound A:or a salt thereof.

6. A process for preparing Compound C:Cl cor a salt thereof, comprising chlorinating Compound D:or a salt thereof.

7. Tire process of claim 6, wherein the process comprises POC13and SO2CI2.

8. The process of claim 6 or 7, wherein the process comprises N-chlorosuccinimide or SO2CI2.

9. A process for preparing a compound of Formula I:WCl Ior a salt thereof, comprising contacting a compound of Formula IIA:H IIAor a salt thereof, with Compound C:Cl Cor a salt thereof, under suitable coupling conditions; provided that the compound of Formula IIA, or a salt thereof, is prepared by deprotecting a compound of Formula IA as provided according to claim 1; or the Compound C is prepared according to claim 6;wherein:R1is hydrogen, Ci-Ce alkyl, Cs-Ce cycloalkyl, -(Ci-Ce alkylene)C3-Ce cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)Cfi-aryl, 5- to 6-membered heteroaryl, -(Ci-Ce alkylene)5- to 6-membered heteroaryl, Ci-Ce haloalkyl, -(Ci-Cg alkylene)OR13, -(Ci-C6alkylene)SR13, -(Ci-C6alkylene)S(O)2R13, -(Ci-C6alkylene)S(O)2NR14R15, -(C1-C8 alkylene)NR13S(O)2R14, -(Ci-C6alkylene)NR14R15, -(Ci-C6alkylene)C(O)R13. -(Ci-C6alkylene)NR13C(O)R14, -(Ci-C6alkylene)NR13C(O)NR14R15, -(Ci-C6alkylene)C(O)OR13, -(Ci-C6alkylene) C(O)ONR14R, or -(Ci-Ce alkylene)-C(O)NR14R13; wherein each may be optionally protected, and wherein each of which is optionally substituted with Rd;Rdis hydrogen, halo, -OH, oxo, -CN, Ci-Ce haloalkyl, Ci-Ce alkoxy, Ci-Ce haloalkoxy, -COOH, or Ci-Ce alkyl optionally substituted with -OH, halo, CN, or oxo;each R13, R14andR15is independently hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce haloalkyl, Cs-Ce cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of R13, R14and R15is independently optionally substituted by oxo, -OH, C2-Cg alkenyl, C2-Ce alkynyl, -CN, halo or Ci-Ce alkyl optionally substituted by oxo, -OH, or halo;or R14and R15are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH. halo, or Ci-Ce alkyl optionally substituted by oxo, -OH or halo; andeach ml, m2, nl, and n2 is independently 1. 2, 3, or 4.

10. A process for preparing Compound I:or a salt thereof, comprising contacting Compound 1A:or a salt thereof, with Compound C:Cl Cor a salt thereof, under suitable coupling conditions; wherein Compound 1 A, or a salt thereof, is prepared by contacting Compound B:HN^or a salt thereof, with chlorosulfonyl isocyanate in the presence of BuOH. to provide Compound IB:or a salt thereof, and deprotecting compound IB, to provide Compound 1A, or a salt thereof.

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