Methods for synthesizing EGFR inhibitors

Abstract

The present disclosure features methods for preparing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one-containing chemical entities (e.g., compounds or pharma- ceutically acceptable salts thereof) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2), as well as synthetic intermediates useful in the preparation of the chemical entities. The methods include, for example, improved methods for synthesizing compounds of formula (I), as described herein. TIFF2025509947000249.tif40128

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 323,249, filed March 24, 2022, No. 63 / 422,645, filed November 4, 2022, and No. 63 / 435,108, filed December 23, 2022, which are incorporated by reference in their entireties herein.

[0002] Technical Field The present disclosure features methods for preparing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one-containing chemical entities (e.g., compounds or pharma- ceutically acceptable salts thereof) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2), as well as synthetic intermediates useful in the preparation of the chemical entities. The methods include, for example, improved methods for synthesizing compounds of formula (I), as described herein. [Background technology]

[0003] background Epidermal growth factor receptor (EGFR, ERBB1) and human epidermal growth factor receptor 2 (HER2, ERBB2) are members of a protein family that regulates cellular processes involved in tumor growth, such as proliferation and differentiation. Several researchers have demonstrated the role of EGFR and HER2 in development and cancer (reviewed in Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232 (Non-Patent Document 1); Klapper, et al., Adv. Cancer Res. (2000) 77, 25-79 (Non-Patent Document 2); and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184 (Non-Patent Document 3)). Overexpression of EGFR is present in at least 70% of human cancers, such as non-small cell lung cancer (NSCLC), breast cancer, glioma, and prostate cancer. Overexpression of HER2 occurs in approximately 30% of all breast cancers. It is also involved in other human cancers, including colon, ovarian, bladder, stomach, esophageal, lung, uterine and prostate. Overexpression of HER2 also correlates with poor prognosis in human cancers, including metastasis and early recurrence.

[0004] Tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one-containing chemical entities that inhibit epidermal growth factor receptor and / or human epidermal growth factor receptor 2 are described, for example, in PCT / US2021 / 051504 (Patent Document 1), filed September 22, 2021; PCT / US2021 / 054191 (Patent Document 2), filed October 8, 2021; and PCT / US2021 / 057348 (Patent Document 3), filed October 8, 2021, each of which is incorporated by reference in its entirety. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] PCT / US2021 / 051504 [Patent Document 2] PCT / US2021 / 054191 [Patent Document 3] PCT / US2021 / 057348 [Non-patent literature]

[0006] [Non-Patent Document 1] Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232 [Non-Patent Document 2] Klapper, et al., Adv. Cancer Res. (2000) 77, 25-79 [Non-Patent Document 3] Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184 Summary of the Invention

[0007] overview The present disclosure features methods for preparing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one-containing chemical entities (e.g., compounds or pharma- ceutically acceptable salts thereof) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2), as well as synthetic intermediates useful in the preparation of the chemical entities. The methods include, for example, improved methods for synthesizing compounds of formula (I), as described herein.

[0008] In one aspect, the disclosure features a method of preparing a compound of formula (I), or a pharma- ceutically acceptable salt thereof, comprising contacting a compound of formula (II) with a compound of formula (III): TIFF2025509947000002.tif98128 where Y, Z, R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C can be as defined anywhere herein.

[0009] In one aspect, the disclosure features a compound of formula (I), or a pharma- ceutically acceptable salt thereof: TIFF2025509947000003.tif40128 formula, R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C can be as defined anywhere herein.

[0010] In another aspect, the disclosure features a compound of formula (I), or a pharma- ceutically acceptable salt thereof, prepared by a process as described anywhere herein: TIFF2025509947000004.tif40128 formula, R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C can be as defined anywhere herein.

[0011] Procedures previously used to prepare the compounds described herein have employed oxidizing agents (e.g., peroxyacids, e.g., m-CPBA) in certain bond-forming (e.g., cyclization) steps. Moreover, the oxidizing agents (e.g., peroxyacids, e.g., m-CPBA) have been used in at least stoichiometric amounts, typically in excess. Advantageously, the inventors have surprisingly discovered that these bond-forming (e.g., cyclization) steps can be carried out in the absence of oxidizing agents (e.g., peroxyacids, e.g., m-CPBA), thereby making the desired transformations safer and more amenable to more cost-effective scale-up.

[0012] The present disclosure may be more fully understood by reference to the following description, including the following glossary and final examples. It is understood that certain features of the compositions and methods of the present disclosure that are described herein in the context of separate aspects for clarity may also be provided in combination in a single aspect. Conversely, various features of the compositions and methods of the present disclosure that are described in the context of a single aspect for brevity may also be provided separately or in any subcombination.

[0013] The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

[0014] The term "oxo" refers to a divalent oxygen atom having a double bond (i.e., "=O"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl.

[0015] The term "alkyl" refers to an acyclic saturated hydrocarbon residue, which may be straight or branched, containing the indicated number of carbon atoms. For example, C 1-10 indicates that the group may have 1 to 10 (inclusive) carbon atoms. Alkyl groups can be either unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl. The term "saturated" as used in this context means that there are only single bonds between the constituent carbon atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0016] The term "alkoxy" refers to an -O-alkyl radical (eg, -OCH3).

[0017] The term "alkylene" refers to a divalent alkyl (eg, --CH.sub.2--).

[0018] The term "alkenyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group can have from 2 to 6 (inclusive) carbon atoms. Alkenyl groups can be either unsubstituted or substituted with one or more substituents.

[0019] The term "alkynyl" refers to an acyclic hydrocarbon chain, which may be straight or branched, having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C 2-6 indicates that the group can have from 2 to 6 (inclusive) carbon atoms. Alkynyl groups can be either unsubstituted or substituted with one or more substituents.

[0020] The term "aryl" refers to a monocyclic, bicyclic, tricyclic, or polycyclic group of 6 to 20 carbons in which at least one ring in the system is aromatic (e.g., a 6 carbon monocyclic, 10 carbon bicyclic, or 14 carbon tricyclic aromatic ring system); 0, 1, 2, 3, or 4 atoms of each ring may be substituted by substituents. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like.

[0021] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 3-20 ring carbons, preferably 3-16 ring carbons, more preferably 3-12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, where the cycloalkyl group may be substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may contain multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are connected by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, etc. The term "saturated" as used in this context means that there are only single bonds between the constituent carbon atoms.

[0022] The term "cycloalkenyl" as used herein means a cyclic partially unsaturated hydrocarbon group having 3-20 ring carbons, preferably 3-16 ring carbons, more preferably 3-12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, where the cycloalkenyl group may be substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As a cyclic partially unsaturated hydrocarbon group, the cycloalkenyl group may have any degree of unsaturation, provided that one or more double bonds are present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group as a whole is not fully saturated. The cycloalkenyl may contain multiple fused and / or bridged and / or spirocyclic rings.

[0023] The term "heteroaryl," as used herein, means a monocyclic, bicyclic, tricyclic, or polycyclic group having from 5 to 20 ring atoms, or alternatively 5, 6, 9, 10, or 14 ring atoms; at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S, and at least one ring in the system is aromatic (although it is not necessary that it be a ring that contains a heteroatom; e.g., tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can be either unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3 -d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiin, isoindoline, etc. In some embodiments, heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarity, heteroaryl refers to an aromatic lactam, an aromatic cyclic urea, or a vinyl analog thereof, such as a pyridone, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents). TIFF2025509947000005.tif20128, Pyrimidone TIFF2025509947000006.tif20128, Pyridazinone TIFF2025509947000007.tif20128, Pyrazinone TIFF2025509947000008.tif20128, and Imidazolone Also encompassed are one or more of TIFF2025509947000009.tif15128, where each ring nitrogen adjacent to the carbonyl is tertiary (i.e., where an oxo group (i.e., "=O") is part of the heteroaryl ring member).

[0024] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated ring system having 3 to 16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system), the heteroatoms being selected from O, N or S, with 1-3 heteroatoms in the monocyclic ring, 1-6 heteroatoms in the bicyclic ring or 1-9 heteroatoms in the tricyclic or polycyclic ring (e.g., carbon atoms and 1-3, 1-6 or 1-9 heteroatoms which are N, O or S in the monocyclic, bicyclic or tricyclic ring, respectively), where 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may contain multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclyls include: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 2-azabicyclo[2.2.3]octane, 2-azabicyclo[2.2.4]octane, 2-azabicyclo[2.2.5]octane, 2-azabicyclo[2.2.6]octane, 2-azabicyclo[2.2.7]octane, 2-azabicyclo[2.2.8]octane, 2-azabicyclo[2.2.9]octane, 2-azabicyclo[2.3.1]octane, 2-azabicyclo[2.3.2]octane, 2-azabicyclo[2.3.3]octane, 2-azabicyclo[2.3.4]octane, 2-azabicyclo[2.3.5]octane, 2-azabicyclo[2.3.6]octane, 2-azabicyclo[2.3.7]octane, 2-azabicyclo[2.3.8]octane, 2-azabicyclo[2.3.9]octane, 2-azabicyclo[2.3.1]octane, 2-azabicyclo[2.3. , 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like.Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycles in which the two rings are linked by only one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, and 7-azaspiro[4.5]decane. 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane, and the like. The term "saturated" as used in this context means that only single bonds exist between the constituent ring atoms and that other available valences are occupied by hydrogen and / or other substituents as defined herein.

[0025] The term "heterocycloalkenyl" as used herein means a partially unsaturated ring system having 3 to 16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) in which the heteroatoms are selected from O, N, or S, with 1-3 heteroatoms in the monocyclic ring, 1-6 heteroatoms in the bicyclic ring, or 1-9 heteroatoms in the tricyclic or polycyclic ring (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms that are N, O, or S in the monocyclic, bicyclic, or tricyclic ring, respectively), in which 0, 1, 2, or 3 atoms of each ring may be replaced by a substituent. Examples of heterocycloalkenyl groups include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, and dihydrothiophenyl. As a partially unsaturated ring group, a heterocycloalkenyl group can have any degree of unsaturation, provided that one or more double bonds are present within the ring, no ring in the ring system is aromatic, and the heterocycloalkenyl group as a whole is not fully saturated. A heterocycloalkenyl may contain multiple fused and / or bridged and / or spirocyclic rings.

[0026] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0027] As used herein, when a ring is described as being "partially unsaturated," this means that the ring has one or more additional degrees of unsaturation (in addition to those attributable to the ring itself; for example, one or more double or triple bonds between the constituent ring atoms), but the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0028] For the avoidance of doubt, unless otherwise indicated, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc. as described herein) that contain a sufficient number of ring atoms to form a bicyclic or higher ring system (e.g., tricyclic, polycyclic ring system), such rings and cyclic groups are not limited to those having fused rings, e.g., those in which the points of fusion are (i) on adjacent ring atoms (e.g., [xx0] ring systems, where 0 represents zero atom bridging). TIFF2025509947000010.tif13128); (ii) those present on a single ring atom (spiro-fused ring systems) TIFF2025509947000011.tif17128 or (iii) present on a series of contiguous ring atoms (bridged ring systems with a total bridge length >0). Please understand that this encompasses TIFF2025509947000012.tif13128.

[0029] The term "pharmaceutical acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not eliminate the biological activity and properties of the compound. In certain cases, pharmaceutical acceptable salts are obtained by reacting a compound described herein with an acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. In some cases, pharmaceutical acceptable salts are obtained by reacting a compound described herein having an acidic group with a base to form a salt, such as an ammonium salt, an alkali metal salt, such as a sodium salt or a potassium salt, an alkaline earth metal salt, such as a calcium salt or a magnesium salt, a salt of an organic base, such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and a salt of an amino acid, such as arginine, lysine, etc., or by other methods previously determined. There is no particular limit to the pharmacologically acceptable salt, as long as it can be used in medicine. Examples of the salts that the compounds described herein form with bases include: their salts with inorganic bases, such as sodium, potassium, magnesium, calcium and aluminum; their salts with organic bases, such as methylamine, ethylamine and ethanolamine; their salts with basic amino acids, such as lysine and ornithine; and ammonium salts.The salt may be an acid addition salt, and specifically includes the acid addition salts with mineral acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid and ethanesulfonic acid; and acidic amino acids, such as aspartic acid and glutamic acid.

[0030] In accordance with the present disclosure, the compounds prepared by the methods described herein may be obtained as a single stereoisomer or a mixture of stereoisomers.

[0031] The compounds prepared by the methods described herein may also contain unnatural proportions of one, two, three or more atomic isotopes at one or more of the atoms that constitute such compounds. Unnatural proportions of an isotope may be defined as ranging from the amount found in nature to the amount consisting of 100% of that atom. For example, the compounds may contain unnatural amounts of, for example, tritium ( 3 H), iodine-125( 125 I), Fluorine-18( 18 F), and / or radioisotopes such as carbon-14 (14C), or deuterium ( 2 H), Carbon-13( 13 C), and / or nitrogen-15 ( 15 Non-radioactive isotopes such as N) may be incorporated. Such isotopic variations may provide additional utility to those described elsewhere in this application. For example, isotopic variants of the compounds of the invention may find additional utility, including but not limited to, as diagnostic and / or imaging reagents, or cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the invention may have altered pharmacokinetic and pharmacodynamic properties that may contribute to improved safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.

[0032] The details of one or more aspects of the claimed subject matter are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0033] [Figure 1A] 1H NMR and LCMS spectra of a control experiment investigating the compatibility of 5a and 6a with NH4OAc. [Figure 1B-1] 1H NMR and LCMS spectra of a control experiment investigating the compatibility of 5a and 6a with NH4OAc. [Figure 1B-2] See description of Figure 1B-1. [Figure 1C] 1H NMR and LCMS spectra of a control experiment investigating the compatibility of 5a and 6a with NH4OAc. [Diagram 2] 1H NMR spectrum of compound 101 is shown. [Diagram 3] 1H NMR spectrum of compound 102 is shown. [Figure 4] Figure 4A shows the LC-MS spectrum of compound 102. Figure 4B shows the powder of compound 102. [Figure 5A] The 1H NMR, 13C NMR, 19F NMR, and NOESY NMR of the compounds synthesized in Examples 7 to 45 are shown below. [Figure 5B] See legend to Figure 5A. [Figure 5C] See legend to Figure 5A. [Figure 5D] See legend to Figure 5A. [Figure 5E] See legend to Figure 5A. [Figure 5F] See legend to Figure 5A. [Figure 5G] See legend to Figure 5A. [Figure 5H] See legend to Figure 5A. [Figure 5I] See legend to Figure 5A. [Figure 5J] See legend to Figure 5A. [Figure 5K] See legend to Figure 5A. [Figure 5L] See legend to Figure 5A. [Figure 5M] See legend to Figure 5A. [Figure 5N] See legend to Figure 5A. [Figure 5O] See legend to Figure 5A. [Figure 5P] See legend to Figure 5A. [Figure 5Q] See legend to Figure 5A. [Figure 5R] See legend to Figure 5A. [Figure 5S] See legend to Figure 5A. [Figure 5T] See legend to Figure 5A. [Figure 5U] See legend to Figure 5A. [Figure 5V] See legend to Figure 5A. [Figure 5W] See legend to Figure 5A. [Figure 5X] See legend to Figure 5A. [Figure 5Y] See legend to Figure 5A. [Figure 5Z] See legend to Figure 5A. [Figure 5AA] See legend to Figure 5A. [Figure 5AB] See legend to Figure 5A. [Figure 5AC] See legend to Figure 5A. [Figure 5AD] See legend to Figure 5A. [Figure 5AE] See legend to Figure 5A. [Figure 5AF] See legend to Figure 5A. [Figure 5A-G] See legend to Figure 5A. [Figure 5AH] See legend to Figure 5A. [Figure 5AI] See legend to Figure 5A. [Figure 5AJ] See legend to Figure 5A. [Figure 5AK] See legend to Figure 5A. [Figure 5AL] See legend to Figure 5A. [Figure 5AM] See legend to Figure 5A. [Figure 5AN] See legend to Figure 5A. [Figure 5AO] See legend to Figure 5A. [Figure 5AP] See legend to Figure 5A. [Figure 5AQ] See legend to Figure 5A. [Figure 5AR] See legend to Figure 5A. [Figure 5AS] See legend to Figure 5A. [Figure 5AT] See legend to Figure 5A. [Figure 5AU]See legend to Figure 5A. [Figure 5AV] See legend to Figure 5A. [Figure 5AW] See legend to Figure 5A. [Figure 5AX] See legend to Figure 5A. [Figure 5AY] See legend to Figure 5A. [Figure 5AZ] See legend to Figure 5A. [Figure 5BA] See legend to Figure 5A. [Figure 5BB] See legend to Figure 5A. [Figure 5BC] See legend to Figure 5A. [Figure 5BD] See legend to Figure 5A. [Figure 5BE] See legend to Figure 5A. [Figure 5BF] See legend to Figure 5A. [Figure 5BG] See legend to Figure 5A. [Figure 5BH] See legend to Figure 5A. [Figure 5BI] See legend to Figure 5A. [Figure 5BJ] See legend to Figure 5A. [Figure 5BK] See legend to Figure 5A. [Figure 5BL] See legend to Figure 5A. [Figure 5BM] See legend to Figure 5A. [Figure 5BN] See legend to Figure 5A. [Figure 5BO] See legend to Figure 5A. [Figure 5BP] See legend to Figure 5A. [Figure 5BQ] See legend to Figure 5A. [Figure 5BR] See legend to Figure 5A. [Figure 5BS] See legend to Figure 5A. [Figure 5BT] See legend to Figure 5A. [Figure 5BU] See legend to Figure 5A. [Figure 5BV] See legend to Figure 5A. [Figure 5BW] See legend to Figure 5A. [Figure 5BX] See legend to Figure 5A. [Figure 5BY] See legend to Figure 5A. [Figure 5BZ] See legend to Figure 5A. [Figure 5CA] See legend to Figure 5A. [Figure 5CB] See legend to Figure 5A. [Figure 5CC] See legend to Figure 5A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Detailed Description The present disclosure features methods for preparing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one-containing chemical entities (e.g., compounds or pharma- ceutically acceptable salts thereof) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2), as well as synthetic intermediates useful in the preparation of the chemical entities. The methods include, for example, improved methods for synthesizing compounds of formula (I), as described herein.

[0035] Preparation of Compounds of Formula (I) In one aspect, the disclosure features a method of preparing a compound of formula (I), or a pharma- ceutically acceptable salt thereof, comprising contacting a compound of formula (II) with a compound of formula (III): TIFF2025509947000013.tif102128 where Y, Z, R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C can be as defined anywhere herein. For example: Y is selected from -OH or -NH2; Z is -C(=O)H; or -CH(R)2 (where each R is halo, alkoxy, OH or SO3M (M = Li, Na, K or NH4 + provided that when one R is OH, the other R cannot be halo, alkoxy, or OH. Selected from R 1c H, and R d More selected; R 2a , R 2b , R 3a , and R 3b each of which is H; halo; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g independently selected from the group consisting of: Variable symbol R 2a , R 2b , R 3a , and R 3b two of, together with the ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms; Wherein 0 to 2 of the ring atoms are each independently selected heteroatoms (-N(R 1c When -N(R )- forms part of a fused saturated or unsaturated ring, 1c )-), where each independently selected heteroatom is selected from N, NH, N(R d ), O, and S(O) 0-2 and Here, the fused saturated or unsaturated ring of 3 to 12 ring atoms is oxo, R c , and R Wand optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 is H and R d selected from the group consisting of; Ring C is: TIFF2025509947000014.tif15128; TIFF2025509947000015.tif21128 where: ○Each X b are X and R independently c or H; and ○Each X a is H, halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 2-6 Alkenyl; -S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; Each may be substituted with X and may have 1 to 4 R c 2-pyridyl or 3-pyridyl, optionally further substituted by Each may be substituted with X and may have 1 to 4 R c 2-pyridonyl or 4-pyridonyl, optionally further substituted by, wherein the ring nitrogen atom is R d 2-pyridonyl or 4-pyridonyl, optionally substituted by Heteroaryls containing 6 ring atoms, where 2-4 of the ring atoms are N, N(H), and N(Rd ), wherein the heteroaryl is optionally substituted with X and is selected from the group consisting of 1 to 4 R c a heteroaryl containing 6 ring atoms, optionally further substituted with Heteroaryl containing 5 ring atoms, where 1-4 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is optionally substituted with X and has 1 to 4 R c heteroaryl containing 5 ring atoms, optionally further substituted with Bicyclic heteroaryl containing 7-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is substituted with X and is selected from the group consisting of oxo and R 7 a bicyclic heteroaryl containing 7 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ●Bicyclic C 5-10 Cycloalkyl or C 5-10 Cycloalkenyl, each of which is substituted with X and is selected from the group consisting of oxo and R 7 A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 5-10 Cycloalkyl or C 5-10 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heterocyclyl or heterocycloalkenyl is substituted with X and is selected from the group consisting of oxo and R 7a heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ● Substituted with X and 1 to 4 R 7 C which may be substituted with 10 or C 14 Aryl selected from the group consisting of; X is X*, where X* is selected from halo, triflate, tosylate, or mesylate; or X is X 1 and; Each R 7 is an independently selected R c and n is 0, 1, 2, or 3; X 1 (a) -OL 1 -R 5 and (b) TIFF2025509947000016.tif11128; L 1 and L 2 is a bond and 1 to 6 R a C which may be substituted with 1-10 independently selected from the group consisting of alkylene; R 5 is the following: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with 6-10 Aryl; Oxo and R c C3-10 Cycloalkyl or C 3-10 Cycloalkenyl; TIFF2025509947000017.tif16128 wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, wherein 0 to 2 ring atoms (R X (in addition to the ring nitrogen atom bonded to N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and -R c each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ●1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl); -R W -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y is selected from the group consisting of However, L 1 If is a bond, R 5 is 1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -RY Other than; R 6 teeth, ●H; ●Halo; ●-OH; ●-NR e R f ; -R g ; -R w -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and ●1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl); is selected from the group consisting of L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-and R W -L W -W, Here, L W is C(=O), S(O) 1-2 , OC(=O)*, NHC(=O)*, NR d C(=O)*, NHS(O) 1-2 *, or NR d S(O) 1-2 * where the asterisk indicates the point of attachment to W, and W is for C 2-6 Alkenyl; C 2-6Alkynyl; or C 3-10 arenyl, each of which is selected from 1 to 3 R a and R g where W is optionally further substituted with sp 2 or L through sp hybridized carbon atom W to provide an α,β-unsaturated system; and R X Each of them has 1 to 6 R a C(=O)(C 1-6 alkyl) or S(O)2(C 1-6 alkyl); and R Y -R g and -(L g ) g -R g is selected from the group consisting of R a Each occurrence of is -OH; -halo; -NR e R f ;C 1-4 Alkoxy;C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl); and cyano; R b Each occurrence of is independently 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, each of which is 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1-2 ;C(=O)NH*;C(=O)NR d *;S(O) 1-2 NH*; or S(O)1-2 N(R d )*, where the asterisk stands for R b Indicates the attachment point to; R c each occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 3-5 Cycloalkyl;C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy or C 1-4 C optionally substituted with haloalkoxy 1-4 Alkoxy;C 1-4 Haloalkoxy;-S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of is selected from 1 to 3 independently selected R a Or R g C which may be substituted with 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R e and R f Each occurrence of is H; 1-3 C 1-3 C optionally substituted with an alkyl group 3-5cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 are heteroatoms independently selected from the group consisting of oxo and R c Heterocyclyl containing 3 to 6 ring atoms, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: NR′R″, —OH, C 1-6 Alkoxy, C 1-6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy and halo; 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R g Each occurrence of is independently selected from the group consisting of: ●C 3-10 Cycloalkyl or C 3-10 cycloalkenyl, each of which is selected from oxo and R c C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with 6-10 Aryl; L g Each occurrence of is -O-, -NH-, -NR d , -S(O) 0-2 , C(O), and 1 to 3 R a C which may be substituted with 1-3 independently selected from the group consisting of alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g is a group; and Each occurrence of R' and R'' is H; -OH; and C 1-4 alkyl.

[0036] In another aspect, the disclosure features a method of preparing a compound of formula (I), or a pharma- ceutically acceptable salt thereof, comprising contacting a compound of formula (II) with a compound of formula (III); TIFF2025509947000018.tif97128 formula, Y is selected from -OH or -NH2; Z is -C(=O)H; or -CH(R)2 (where each R is halo, alkoxy, OH or SO3M (M = Li, Na, K or NH4 + provided that when one R is OH, the other R cannot be halo, alkoxy, or OH. Selected from R1c H, and R d More selected; R 2a , R 2b , R 3a , and R 3b each of which is H; halo; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g independently selected from the group consisting of: Variable symbol R 2a , R 2b , R 3a , and R 3b two of, together with the ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms; Wherein 0 to 2 of the ring atoms are each independently selected heteroatoms (-N(R 1c When -N(R )- forms part of a fused saturated or unsaturated ring, 1c )-), where each independently selected heteroatom is selected from N, NH, N(R d ), O, and S(O) 0-2 and Here, the fused saturated or unsaturated ring of 3 to 12 ring atoms is oxo, R c , and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 is H and R d selected from the group consisting of; Ring C is: TIFF2025509947000019.tif15128; TIFF2025509947000020.tif21128 where: ○Each X b are X and R independently c or H; and ○Each X a is H, halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 2-6 Alkenyl; -S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; Each may be substituted with X and may have 1 to 4 R c 2-pyridyl or 3-pyridyl, optionally further substituted by Each may be substituted with X and may have 1 to 4 R c 2-pyridonyl or 4-pyridonyl, optionally further substituted by, wherein the ring nitrogen atom is R d 2-pyridonyl or 4-pyridonyl, optionally substituted by Heteroaryls containing 6 ring atoms, where 2-4 of the ring atoms are N, N(H), and N(R d ), wherein the heteroaryl is optionally substituted with X and is selected from the group consisting of 1 to 4 R c a heteroaryl containing 6 ring atoms, optionally further substituted with Heteroaryl containing 5 ring atoms, where 1-4 of the ring atoms are N, N(H), N(Rd ), O, and S(O) 0-2 and wherein the heteroaryl is optionally substituted with X and has 1 to 4 R c heteroaryl containing 5 ring atoms, optionally further substituted with Bicyclic heteroaryl containing 7-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is optionally substituted with X and is selected from the group consisting of oxo and R 7 a bicyclic heteroaryl containing 7 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ●Bicyclic C 5-10 Cycloalkyl or C 5-10 Cycloalkenyl, each of which is optionally substituted with X, and oxo and R 7 A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 5-10 Cycloalkyl or C 5-10 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X, and is selected from the group consisting of oxo and R 7 a heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: X may be substituted and 1 to 4 R 7 C which may be substituted with 10 or C 14 Aryl; TIFF2025509947000021.tif15128, where ma is 0, 1, 2, or 3; ○R 8A is halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, R 9A R 10A N-, R 11A -C(O)-NH-, R 11A OC(O)-NH- or R 9A R 10A NC(O)-NH-, wherein the C 1-6 Alkoxy may be substituted 1, 2 or 3 times, independently of one another, with halogen and may be substituted with hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, or one or more R 5A phenyl, optionally substituted once with; ○R 5A is hydroxy, halogen, cyano, C 1-4 -Alkyl, C 1-4 -Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy; ○R 9A and R 10A is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, where the phenyl group is R 5A may be substituted one or more times, independently of each other; or R 9A and R 10Atogether with the nitrogen atom to which they are attached form a 3- to 6-membered nitrogen-containing heterocycle, which may contain one additional heteroatom or heteroatom-containing group selected from O, NH or S, and R 5A may be substituted, independently of each other, one or more times; ○R 11A is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 independently selected from halocycloalkyl; TIFF2025509947000022.tif19128, where ○R 5B is hydroxy, C 1-4 Alkoxy, R 7B R 8B N- or C optionally substituted with phenyl 2-5 alkyl, where the phenyl group is R 5A may be substituted one or more times with; or ○R 5B is R 6B -CH2-; ○R 6B teeth, Selected from TIFF2025509947000023.tif29128; ○R 7B and R 8B is C 1-3 Alkyl, C 1-3 haloalkyl; or ○R 7B and R 8B form, together with the nitrogen atom to which they are attached, a 5-6 membered nitrogen-containing heterocycle, the nitrogen-containing heterocycle being selected from the group consisting of O and -NH-, NH(C 1-3 alkyl); ○R 9B is hydrogen, C 1-4 Alkyl, or C 1-3 haloalkyl; ○R5A is hydroxy, halogen, cyano, C 1-4 -Alkyl, C 1-4 -Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy; TIFF2025509947000024.tif37128, where ○R 4C is selected from hydrogen or methyl; ○R 6C is hydrogen, C 1-3 Alkyl, C 1-3 haloalkyl; nc is 0 or 1; ○X C is NR 7C or O; ○Y C is NR 8C or O; ○R 7C is methyl; ○R 8C is selected from methyl, 2,2,2-trifloethyl, or 2,2-difluoroethyl; ○R 5C is selected from hydrogen or methyl, where R 5C X C and Y C is attached to any carbon atom of the ring including; mc is 0, 1, 2, or 3; TIFF2025509947000025.tif23128, where ○R 4D is selected from hydrogen or methyl; ○R 5D is selected from the group consisting of (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, and 3-azetidinyl, each of which is R 6D and wherein each azetidinyl is optionally substituted one, two or three times with R8D is replaced by; or ○R 5D teeth, TIFF2025509947000026.tif16128; ○R 6D Fluoro or C 1-3 selected from alkyl; md is selected from 0, 1, 2, or 3; ○R 7D is hydrogen, C 1-3 Alkyl, or C 1-3 haloalkyl; ○X D is ONR 8D and; ○R 8D is C 1-3 Alkyl or C 2-3 Selected from haloalkyl selected from the group consisting of; X is X*, where X* is selected from halo, triflate, tosylate, or mesylate; or X is X 1 and; Each R 7 is an independently selected R c and n is 0, 1, 2, or 3; X 1 (a) -OL 1 -R 5 and (b) TIFF2025509947000027.tif11128; L 1 and L 2 is a bond and 1 to 6 R a C which may be substituted with 1-10 independently selected from the group consisting of alkylene; R 5 is the following: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O)0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with 6-10 Aryl; Oxo and R c C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; TIFF2025509947000028.tif16128 wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, wherein 0 to 2 ring atoms (R X (in addition to the ring nitrogen atom bonded to N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and -R c each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ●1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl); -R W -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y is selected from the group consisting of However, L 1 If is a bond, R 5 is 1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Other than; R 6 teeth, ●H; ●Halo; ●-OH; ●-NR e R f ; -R g ; -R w -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and ●1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl); is selected from the group consisting of L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-and R W -LW -W, Here, L W is C(=O), S(O) 1-2 , OC(=O)*, NHC(=O)*, NR d C(=O)*, NHS(O) 1-2 *, or NR d S(O) 1-2 * where the asterisk indicates the point of attachment to W, and W is for C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10 arenyl, each of which is selected from 1 to 3 R a and R g where W is optionally further substituted with sp 2 or L through sp hybridized carbon atom W to provide an α,β-unsaturated system; and R X Each of them has 1 to 6 R a C(=O)(C 1-6 alkyl) or S(O)2(C 1-6 alkyl); and R Y -R g and -(L g ) g -R g is selected from the group consisting of R a Each occurrence of is -OH; -halo; -NR e R f ;C 1-4 Alkoxy;C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl); and cyano; R bEach occurrence of is independently 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, each of which is 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1-2 ;C(=O)NH*;C(=O)NR d *;S(O) 1-2 NH*; or S(O) 1-2 N(R d )*, where the asterisk stands for R b Indicates the attachment point to; R c each occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 3-5 Cycloalkyl;C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy or C 1-4 C optionally substituted with haloalkoxy 1-4 Alkoxy;C 1-4 Haloalkoxy;-S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of is selected from 1 to 3 independently selected R a Or R g C which may be substituted with 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R e and R f Each occurrence of is H; 1-3 C 1-3 C optionally substituted with an alkyl group 3-5 cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 are heteroatoms independently selected from the group consisting of oxo and R c Heterocyclyl containing 3 to 6 ring atoms, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: NR′R″, —OH, C 1-6 Alkoxy, C 1-6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy and halo; 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R g Each occurrence of is independently selected from the group consisting of: ●C 3-10 Cycloalkyl or C 3-10 cycloalkenyl, each of which is selected from oxo and R c C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with 6-10 Aryl; L g Each occurrence of is -O-, -NH-, -NR d , -S(O) 0-2 , C(O), and 1 to 3 R a C which may be substituted with 1-3 independently selected from the group consisting of alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g is a group; and Each occurrence of R' and R'' is H; -OH; and C 1-4 alkyl.

[0037] In another aspect, the disclosure features a method of preparing a compound of formula (I), or a pharma- ceutically acceptable salt thereof, comprising contacting a compound of formula (II) with a compound of formula (III); TIFF2025509947000029.tif97128 formula, Y is selected from -OH or -NH2; Z is -C(=O)H; or -CH(R)2 (where each R is halo, alkoxy, OH or SO3M (M = Li, Na, K or NH4 + provided that when one R is OH, the other R cannot be halo, alkoxy, or OH. Selected from R 1c H, and R d More selected; R 2a , R 2b , R 3a , and R 3b each of which is H; halo; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g independently selected from the group consisting of: Variable symbol R 2a , R 2b , R 3a , and R 3b two of, together with the ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms; Wherein 0 to 2 of the ring atoms are each independently selected heteroatoms (-N(R 1c When -N(R )- forms part of a fused saturated or unsaturated ring, 1c )-), where each independently selected heteroatom is selected from N, NH, N(R d ), O, and S(O) 0-2and Here, the fused saturated or unsaturated ring of 3 to 12 ring atoms is oxo, R c , and R W and optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 is H and R d selected from the group consisting of; Ring C is: TIFF2025509947000030.tif15128; TIFF2025509947000031.tif21128 where: ○Each X b are X and R independently c or H; and ○Each X a is H, halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 2-6 Alkenyl; -S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; Each may be substituted with X and may have 1 to 4 R c 2-pyridyl or 3-pyridyl, optionally further substituted by Each may be substituted with X and may have 1 to 4 R c 2-pyridonyl or 4-pyridonyl, optionally further substituted by, wherein the ring nitrogen atom is R d2-pyridonyl or 4-pyridonyl, optionally substituted by Heteroaryls containing 6 ring atoms, where 2-4 of the ring atoms are N, N(H), and N(R d ), wherein the heteroaryl is optionally substituted with X and is selected from the group consisting of 1 to 4 R c a heteroaryl containing 6 ring atoms, optionally further substituted with Heteroaryl containing 5 ring atoms, where 1-4 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is optionally substituted with X and has 1 to 4 R c heteroaryl containing 5 ring atoms, optionally further substituted with Bicyclic heteroaryl containing 7-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is optionally substituted with X and is selected from the group consisting of oxo and R 7 a bicyclic heteroaryl containing 7 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ●Bicyclic C 5-10 Cycloalkyl or C 5-10 Cycloalkenyl, each of which is optionally substituted with X, and oxo and R 7 A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 5-10 Cycloalkyl or C 5-10 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X, and is selected from the group consisting of oxo and R 7 a heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: X may be substituted and 1 to 4 R 7 C which may be substituted with 10 or C 14 Aryl selected from the group consisting of; X is X*, where X* is selected from halo, triflate, tosylate, or mesylate; or X is X 1 and; Each R 7 is an independently selected R c and n is 0, 1, 2, or 3; X 1 (a) -OL 1 -R 5 and (b) TIFF2025509947000032.tif11128; L 1 and L 2 is a bond and 1 to 6 R a C which may be substituted with 1-10 independently selected from the group consisting of alkylene; R 5 is the following: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with6-10 Aryl; Oxo and R c C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; TIFF2025509947000033.tif16128 wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, wherein 0 to 2 ring atoms (R X (in addition to the ring nitrogen atom bonded to N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and -R c each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ●1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl); -R W -R g2 -R W or -R g2 -R Y ; -L 5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y is selected from the group consisting of However, L 1 If is a bond, R 5 is 1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl);-L 5 -Rg ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Other than; R 6 teeth, ●H; ●Halo; ●-OH; ●-NR e R f ; -R g ; -R w -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and ●1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl); is selected from the group consisting of L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-and R W -L W -W, Here, L W is C(=O), S(O) 1-2 , OC(=O)*, NHC(=O)*, NR d C(=O)*, NHS(O) 1-2 *, or NR d S(O)1-2 * where the asterisk indicates the point of attachment to W, and W is for C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10 arenyl, each of which is selected from 1 to 3 R a and R g where W is optionally further substituted with sp 2 or L through sp hybridized carbon atom W to provide an α,β-unsaturated system; and R X Each of them has 1 to 6 R a C(=O)(C 1-6 alkyl) or S(O)2(C 1-6 alkyl); and R Y -R g and -(L g ) g -R g is selected from the group consisting of R a Each occurrence of is -OH; -halo; -NR e R f ;C 1-4 Alkoxy;C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4 alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl); and cyano; R b Each occurrence of is independently 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, each of which is 1 to 6 R a may be substituted with; L bEach occurrence of is independently C(=O);C(=O)O;S(O) 1-2 ;C(=O)NH*;C(=O)NR d *;S(O) 1-2 NH*; or S(O) 1-2 N(R d )*, where the asterisk stands for R b Indicates the attachment point to; R c each occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 3-5 Cycloalkyl;C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy or C 1-4 C optionally substituted with haloalkoxy 1-4 Alkoxy;C 1-4 Haloalkoxy;-S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of is selected from 1 to 3 independently selected R a Or R g C which may be substituted with 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R e and R f Each occurrence of is H; 1-3 C 1-3 C optionally substituted with an alkyl group 3-5 cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 are heteroatoms independently selected from the group consisting of oxo and R c Heterocyclyl containing 3 to 6 ring atoms, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: NR′R″, —OH, C 1-6 Alkoxy, C 1-6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy and halo; 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R g Each occurrence of is independently selected from the group consisting of: ●C 3-10 Cycloalkyl or C 3-10 cycloalkenyl, each of which is selected from oxo and R c C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2and wherein heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with 6-10 Aryl; L g Each occurrence of is -O-, -NH-, -NR d , -S(O) 0-2 , C(O), and 1 to 3 R a C which may be substituted with 1-3 independently selected from the group consisting of alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g is a group; and Each occurrence of R' and R'' is H; -OH; and C 1-4 alkyl.

[0038] In another aspect, the disclosure features a method of preparing a compound of formula (I), or a pharma- ceutically acceptable salt thereof, comprising contacting a compound of formula (II) with a compound of formula (III); TIFF2025509947000034.tif97128 formula, Y is selected from -OH or -NH2; Z is -C(=O)H; or -CH(R)2 (where each R is halo, alkoxy, OH or SO3M (M = Li, Na, K or NH4 + provided that when one R is OH, the other R cannot be halo, alkoxy, or OH. Selected from R 1c H, and R d More selected; R 2a , R 2b , R 3a , and R 3b each of which is H; halo; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g independently selected from the group consisting of: Variable symbol R 2a , R 2b , R 3a , and R 3b two of, together with the ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms; Wherein 0 to 2 of the ring atoms are each independently selected heteroatoms (-N(R 1c When -N(R )- forms part of a fused saturated or unsaturated ring, 1c )-), where each independently selected heteroatom is selected from N, NH, N(R d ), O, and S(O) 0-2 and Here, the fused saturated or unsaturated ring of 3 to 12 ring atoms is oxo, R c , and R Wand optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Ring A is R g and; R 4 is H and R d selected from the group consisting of; Ring C is: TIFF2025509947000035.tif16128, where ma is 0, 1, 2, or 3; ○R 8A is halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, R 9A R 10A N-, R 11A -C(O)-NH-, R 11A OC(O)-NH- or R 9A R 10A NC(O)-NH-, wherein the C 1-6 Alkoxy may be substituted 1, 2 or 3 times, independently of one another, with halogen and may be substituted with hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, or one or more R 5A phenyl, optionally substituted once with; ○R 5A is hydroxy, halogen, cyano, C 1-4 -Alkyl, C 1-4 -Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy; ○R 9A and R 10A is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, where the phenyl group is R 5A may be substituted one or more times, independently of each other; or R 9A and R 10A together with the nitrogen atom to which they are attached form a 3- to 6-membered nitrogen-containing heterocycle, which may contain one additional heteroatom or heteroatom-containing group selected from O, NH or S, and R 5A may be substituted, independently of each other, one or more times; ○R 11A is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 independently selected from halocycloalkyl; TIFF2025509947000036.tif19128, where ○R 5B is hydroxy, C 1-4 Alkoxy, R 7B R 8B N- or C optionally substituted with phenyl 2-5 alkyl, where the phenyl group is R 5A may be substituted one or more times with; or ○R 5B is R 6B -CH2-; ○R 6B teeth, Selected from TIFF2025509947000037.tif17130; ○R 7B and R 8B is C 1-3 Alkyl, C 1-3 haloalkyl; or ○R 7B and R 8B form, together with the nitrogen atom to which they are attached, a 5-6 membered nitrogen-containing heterocycle, the nitrogen-containing heterocycle being selected from the group consisting of O and -NH-, NH(C1-3 alkyl); ○R 9B is hydrogen, C 1-4 Alkyl, or C 1-3 haloalkyl; ○R 5A is hydroxy, halogen, cyano, C 1-4 -Alkyl, C 1-4 -Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy; TIFF2025509947000038.tif37128, where ○R 4C is selected from hydrogen or methyl; ○R 6C is hydrogen, C 1-3 Alkyl, C 1-3 haloalkyl; nc is 0 or 1; ○X C is NR 7C or O; ○Y C is NR 8C or O; ○R 7C is methyl; ○R 8C is selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; ○R 5C is selected from hydrogen or methyl, where R 5C X C and Y C is attached to any carbon atom of the ring including; mc is 0, 1, 2, or 3; TIFF2025509947000039.tif23128, where ○R 4D is selected from hydrogen or methyl; ○R 5Dis selected from the group consisting of (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, and 3-azetidinyl, each of which is R 6D and wherein each azetidinyl is optionally substituted one, two or three times with R 8D is replaced by; or ○R 5D teeth, TIFF2025509947000040.tif16128; ○R 6D Fluoro or C 1-3 selected from alkyl; md is selected from 0, 1, 2, or 3; ○R 7D is hydrogen, C 1-3 Alkyl, or C 1-3 haloalkyl; ○X D is ONR 8D and; ○R 8D is C 1-3 Alkyl or C 2-3 Selected from haloalkyl selected from the group consisting of; X is X*, where X* is selected from halo, triflate, tosylate, or mesylate; or X is X 1 and; Each R 7 is an independently selected R c and n is 0, 1, 2, or 3; X 1 (a) -OL 1 -R 5 and (b) TIFF2025509947000041.tif11128; L 1 and L 2 is a bond and 1 to 6 R a C which may be substituted with 1-10independently selected from the group consisting of alkylene; R 5 is the following: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with 6-10 Aryl; Oxo and R c C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; TIFF2025509947000042.tif16128 wherein ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, wherein 0 to 2 ring atoms (R X (in addition to the ring nitrogen atom bonded to N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclylene or heterocycloalkenylene is selected from the group consisting of oxo and -R c each of which is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: ●1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl); -R W -R g2 -R W or -R g2 -R Y ; -L5 -R g ; and -L 5 -R g2 -R W or -L 5 -R g2 -R Y is selected from the group consisting of However, L 1 If is a bond, R 5 is 1 to 6 R a -S(O) optionally substituted with 0-2 (C 1-6 alkyl);-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Other than; R 6 teeth, ●H; ●Halo; ●-OH; ●-NR e R f ; -R g ; -R w -L 6 -R g ; -R g2 -R W or -R g2 -R Y ; -L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and ●1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl); is selected from the group consisting of L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-and R W -L W -W, Here, L W is C(=O), S(O) 1-2 , OC(=O)*, NHC(=O)*, NR d C(=O)*, NHS(O) 1-2 *, or NR d S(O) 1-2 * where the asterisk indicates the point of attachment to W, and W is for C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10 arenyl, each of which is selected from 1 to 3 R a and R g where W is optionally further substituted with sp 2 or L through sp hybridized carbon atom W to provide an α,β-unsaturated system; and R X Each of them has 1 to 6 R a C(=O)(C 1-6 alkyl) or S(O)2(C 1-6 alkyl); and R Y -R g and -(L g ) g -R g is selected from the group consisting of R a Each occurrence of is -OH; -halo; -NR e R f ;C 1-4 Alkoxy;C 1-4 Haloalkoxy; -C(=O)O(C 1-4 alkyl);-C(=O)(C 1-4alkyl);-C(=O)OH;-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl); and cyano; R b Each occurrence of is independently 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 alkynyl, each of which is 1 to 6 R a may be substituted with; L b Each occurrence of is independently C(=O);C(=O)O;S(O) 1-2 ;C(=O)NH*;C(=O)NR d *;S(O) 1-2 NH*; or S(O) 1-2 N(R d )*, where the asterisk stands for R b Indicates the attachment point to; R c each occurrence of is selected from halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 3-5 Cycloalkyl;C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy or C 1-4 C optionally substituted with haloalkoxy 1-4 Alkoxy;C 1-4 Haloalkoxy;-S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 independently selected from the group consisting of: -alkyl; -C(=O)OH; -C(=O)NR'R''; and -SF5; R d Each occurrence of is selected from 1 to 3 independently selected R a Or R g C which may be substituted with 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R e and R f Each occurrence of is H; 1-3 C 1-3 C optionally substituted with an alkyl group 3-5 cycloalkyl; heterocyclyl containing 3 to 6 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 are heteroatoms independently selected from the group consisting of oxo and R c Heterocyclyl containing 3 to 6 ring atoms, optionally substituted by 1 to 4 substituents independently selected from the group consisting of: NR′R″, —OH, C 1-6 Alkoxy, C 1-6 C optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxy and halo; 1-6 Alkyl; -C(O)(C 1-4 alkyl);-C(O)O(C 1-4 alkyl);-CONR'R'';-S(O) 1-2 NR'R'';-S(O) 1-2 (C 1-4 alkyl);-OH; and C 1-4 independently selected from the group consisting of alkoxy; R g Each occurrence of is independently selected from the group consisting of: ●C 3-10 Cycloalkyl or C 3-10cycloalkenyl, each of which is selected from oxo and R c C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; Heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, where 1 to 3 of the ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclyl or heterocycloalkenyl is selected from the group consisting of oxo and R c a heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, optionally substituted with 1 to 4 substituents independently selected from the group consisting of: Heteroaryl containing 5-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein heteroaryl is selected from 1 to 4 R c heteroaryl containing 5 to 10 ring atoms, optionally substituted with ●1 to 4 R c C which may be substituted with 6-10 Aryl; L g Each occurrence of is -O-, -NH-, -NR d , -S(O) 0-2 , C(O), and 1 to 3 R a C which may be substituted with 1-3 independently selected from the group consisting of alkylene; each g is independently 1, 2, or 3; Each R g2 is a divalent R g is a group; and Each occurrence of R' and R'' is H; -OH; and C 1-4 alkyl.

[0039] Ring A in formula (I) can be as defined anywhere herein.

[0040] The variable R in formula (I) 1c , R 2a , R 2b , R 3a , and R 3b may be as defined anywhere herein.

[0041] Ring C in formula (I) can be as defined anywhere herein.

[0042] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a nitrogen source.

[0043] In some embodiments, the nitrogen source is ammonia or a derivative thereof.

[0044] In some embodiments, the nitrogen source is in the form of a salt.

[0045] In some embodiments, the nitrogen source is an ammonium salt.

[0046] Non-limiting examples of nitrogen sources include NHOAc, NHH0, NHCOH, NHOBz, NHCl, (NH)SO, (NHH)HPO, NHHPO, NHOTf, NHHCO, (NHCO, NHCOCF, NHBF, ammonium citrate dibasic, NHBr, ammonium carbamate, or any combination thereof. Other examples include primary alkyl and cycloalkyl amines, such as (C-C alkyl)-NH and (C-C cycloalkyl)-NH.

[0047] For example, the nitrogen source can be NH4OAc.

[0048] In some embodiments, the molar ratio of the nitrogen source to the compound of Formula (III) is from about 2:1 to about 8:1.

[0049] In certain embodiments, the molar ratio of the nitrogen source to the compound of Formula (III) is from about 4:1 to about 6:1.

[0050] In certain embodiments, the molar ratio of the nitrogen source to the compound of Formula (III) is about 4.5:1; 4.6:1; 4.7:1; 4.8:1; 4.9:1; 5:1; 5.1:1; 5.2:1; 5.3:1; 5.4:1; or 5.5:1.

[0051] For example, the molar ratio of the nitrogen source to the compound of formula (III) may be about 5:1.

[0052] In some embodiments, the compound of formula (III) is used in an equal amount or in excess with respect to the compound of formula (II).In some embodiments, the molar ratio of the compound of formula (III) to the compound of formula (II) is about 1:1 to about 3:1, for example, about 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, or about 3:1.In some embodiments, the molar ratio of the compound of formula (III) to the compound of formula (II) is about 1.3:1 or about 1.5:1 or about 2:1. In certain embodiments, the compound of formula (III) is added in portions, for example, over a period of about 2 hours to about 4 hours.

[0053] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a suitable solvent (e.g., a suitable organic solvent). A mixture of solvents (e.g., organic solvents) can also be used.

[0054] In some embodiments, the solvent is an aprotic solvent.

[0055] In some embodiments, the aprotic solvent is a non-polar aprotic solvent.

[0056] In some embodiments, the non-polar aprotic solvent is an aromatic hydrocarbon solvent.Aromatic hydrocarbon solvents include, but are not limited to, toluene, anisole, xylene (e.g., mixed xylenes (BTEX)), trifluorotoluene, benzene, chlorobenzene, 1,2-dichlorobenzene, 1,2-difluorobenzene, hexafluorobenzene, ethylbenzene, and high flash aromatic naphtha.For example, the aromatic hydrocarbon solvent can be toluene.

[0057] In some embodiments, the non-polar aprotic solvent is a non-aromatic hydrocarbon solvent, including, but not limited to, heptane, hexane, cyclohexane, methylcyclohexane, heptane, and isooctane.

[0058] In some embodiments, aprotic solvent is polar aprotic solvent.Polar aprotic solvent includes but is not limited to acetone, dichloromethane, cyclopentanone, methyl isobutyl ketone, methyl ethyl ketone, EtOAc, isopropyl acetate, isobutyl acetate, glycerol diacetate, isoamyl acetate, tetrahydrofuran, dimethoxyethane, dioxane, N-methyl-2-pyrrolidone, CPME, 1,4-dioxane, THF, acetonitrile, DMSO, 2-MeTHF, methyl tert-butyl ether (MTBE), 2,5-dimethylisosorbide and chloroform.

[0059] In certain embodiments, the aprotic solvent is an ether solvent, such as tetrahydrofuran, dimethoxyethane, dioxane, CPME, 1,4-dioxane, or THF.

[0060] In certain embodiments, the aprotic solvent is acetonitrile or DMSO.

[0061] In some embodiments, the solvent is a protic solvent, eg, a polar protic solvent, eg, acetic acid.

[0062] Other suitable protic (polar) solvents include t-amyl alcohol, t-butanol, n-propanol, ethanol, methanol, water, i-propanol, n-BuOH, t-butanol, ethylene glycol, 1-butanol, i-amyl alcohol, 1-heptanol, 1-octanol, and 1-propanol.

[0063] In some embodiments, the contacting step between the compound of formula (II) and the compound of formula (III) is carried out in the presence of a suitable mixture of two or more solvents, for example, a mixture of two solvents, for example, a mixture of one or more (for example, one) aromatic hydrocarbon solvents and one or more (for example, one) ether solvents, such as a mixture of toluene and dioxane (for example, a 1:1 mixture of toluene and dioxane).

[0064] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature sufficient to produce the compound of formula (I). Those skilled in the art will be able to easily ascertain the appropriate temperature using the methods described herein in combination with their knowledge in the art. Preferably, the reaction temperature is above ambient temperature, i.e., above 25°C, or above 35°C, or higher. For example, a suitable temperature for conversion to the compound of formula (I) is a temperature that is equal to or lower than the reflux temperature of the reaction solvent. In other embodiments, a suitable temperature for preparing the compound of formula (I) is a temperature that is lower than the reflux temperature of the reaction solvent.

[0065] In certain embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 80° C. to 110° C.; or about 80° C. to 100° C. (e.g., 90° C. or 95° C.); or about 90° C. to 110° C. (e.g., 100° C.).

[0066] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 90° C. to 100° C. (eg, 95° C.).

[0067] In certain embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 80° C. to 100° C. (eg, 85° C. to 95° C.; for example, 90° C.).

[0068] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 90° C. to 110° C. (eg, 85° C. to 95° C.; eg, 100° C.).

[0069] In one embodiment, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 20° C. to about 80° C. (eg, 20° C.).

[0070] Those skilled in the art can easily use the methods described herein in combination with knowledge in the art to ascertain the appropriate amount of time for the compounds of formula (II) and formula (III) to be converted to the compound of formula (I).For example, the conversion can be carried out until the conversion is substantially complete, as determined by HPLC.In some embodiments, the amount of time for substantial conversion to the compound of formula III is about 24 hours or less.In some embodiments, the amount of time for substantial conversion is less than 24 hours, for example, about 20, 18, 16, 14, 12, 10, or about 8 hours.

[0071] In some embodiments, the contacting of the compound of formula (II) with the compound of formula (III) is carried out in the presence of one or more additives, including but not limited to Na2SO4, HO, H2SO4, acetic acid, formic acid, Bi(OTf)3, PPh3, NH4OH, NHOAc, PPTS, PTSA, pyridine, or any combination thereof.

[0072] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out in an air-filled sealed container.

[0073] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out in a sealed vessel filled with an inert gas (eg, nitrogen).

[0074] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out in an open vessel.

[0075] In some embodiments, the step of contacting the compound of formula (II) with the compound of formula (III) is carried out in an open vessel connected to an inert gas (e.g., nitrogen) manifold.

[0076] 49. The method of any one of claims 1 to 48, wherein the step of contacting the compound of formula (II) with the compound of formula (III) is carried out in the absence of an oxidizing agent; for example, a peroxyacid, for example, m-CPBA.

[0077] Examples of compounds of formula (I) that can be prepared by the methods described herein include, but are not limited to, those generally and specifically described in PCT / US2021 / 051504, filed September 22, 2021; PCT / US2021 / 054191, filed October 8, 2021; and PCT / US2021 / 057348, filed October 8, 2021.

[0078] Compound of formula (II) and its preparation In some embodiments, the method further comprises contacting a compound of Formula (IIa) with a compound of Formula (IIb) to provide a compound of Formula (II): TIFF2025509947000043.tif48128.

[0079] In some embodiments, the compound of formula (IIb) is prepared by contacting a chlorinating agent with a compound of formula (IId): TIFF2025509947000044.tif14128.

[0080] Chlorinating agents include, but are not limited to, thionyl chloride, methanesulfonyl chloride, trichloromethanesulfonyl chloride, tert-butyl hypochlorite, dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl chloride, cyanuric chloride, N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate, trichloroisocyanuric acid, chloramine T trihydrate, PCl5, and POCl3.

[0081] As an example, a compound of formula (IIb) can be prepared by contacting a compound of formula (IIc) with a compound of formula (IId): TIFF2025509947000045.tif36128.

[0082] In some embodiments, Y in formula (II) is OH.

[0083] In some embodiments, Y in formula (II) is NH2.

[0084] Ring A can be as defined anywhere herein.

[0085] Variable symbol R 1c , R 2a , R 2b , R 3a , and R 3b may be as defined anywhere herein.

[0086] Exemplary compounds of formula (II) are The file is TIFF2025509947000046.tif23128.

[0087] Compounds of formula (III) and their preparation In some embodiments, Z in formula (III) is -C(=O)H.

[0088] In some embodiments, Z in formula (III) is -CH(R)-. In some embodiments, each R is halo (e.g., bromo). For example, Z can be -CH(Br). In other embodiments, each R is alkoxy (e.g., OCH). For example, Z can be -CH(OCH). In still other embodiments, one of R is OH and the other R is SO. - M + (M+ = Li, Na, K or NH4 + ). For example, Z is -CH(OCH3)(SO3 - Na + ).

[0089] In some embodiments of formula (III), X is X*. In some embodiments, formula (III) is further substituted with a substituent reactive in a Sonogashira coupling reaction, such as I, Br, Cl, F, triflate, tosylate, -C(O)Cl, and arylsulfonium triflate salts, such as triarylsulfonium triflate salts, alkyl(diaryl)sulfonium triflate salts, and aryl(dialkyl)sulfonium triflate salts. In some embodiments, X* is halo, such as bromo.

[0090] In some embodiments of formula (III), X is X 1 It is.

[0091] In one embodiment, X 1 teeth, The file is TIFF2025509947000047.tif11128.

[0092] In one embodiment, formula (III) If it is replaced with TIFF2025509947000048.tif11128, L 2 is a bond.

[0093] In one embodiment, formula (III) If replaced with TIFF2025509947000049.tif11128, R 6 -Rg2 -R W It is.

[0094] In some of the above embodiments, -R 6 teeth, TIFF2025509947000050.tif16128, where Ring D is a heterocyclylene containing 3 to 10 ring atoms, where R W (in addition to the ring nitrogen atom bonded to N, N(H), N(R d ), O, and S(O) 0-2 and wherein heterocyclylene is oxo and -R c and optionally, -R 6 is R W a monocyclic heterocyclylene ring containing 3 to 10 ring atoms as defined above having a nitrogen atom bonded to TIFF2025509947000051.tif40132; optionally, where -R 6 is R W A bicyclic heterocyclylene ring containing 3 to 10 ring atoms as defined above having a nitrogen atom bonded to The file is TIFF2025509947000052.tif68170.

[0095] In some of these embodiments, -R 6 1 to 2 R c may be substituted with TIFF2025509947000053.tif20128, where x1 and x2 are each independently 0, 1, or 2.

[0096] In some embodiments, x1=0, and x2=0; or x1=0, and x2=1; or x1=0, and x2=2.

[0097] As a non-limiting example, R 6 but, If it is TIFF2025509947000054.tif22128, R 6 teeth, TIFF2025509947000055.tif57157.

[0098] Ring C in formula (III) can be as defined anywhere herein.

[0099] Compounds of formula (III) can be prepared by conventional methods known to those skilled in the art and / or can be obtained commercially. Exemplary compounds of formula (III) are: The file is TIFF2025509947000056.tif16128.

[0100] As one of skill in the art will appreciate, performing the methods described herein with a compound of formula (III) where X is X* is expected to also produce a compound of formula (I) where X is X*. Thus, the methods described herein can be used to convert the resulting compound of formula (I) where X is X* into a compound of formula (I) where X is X*. 1 The resulting compound of formula (I) where X is X* may be converted to a compound of formula (I) where X is X. 1 The reagents and conditions for converting the compounds of formula (I) into compounds of formula (I), which are apparent to one of skill in the art, and representative syntheses are provided in the Examples section.

[0101] Variable symbol R 1c , R 2a , R 2b , R 3a , and R 3b In some embodiments, Y is -OH.

[0102] In some embodiments, R 1c is a protecting group.

[0103] Protecting groups include, but are not limited to, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trityl (Trt), acetyl, benzyl, and p-nitrobenzyloxycarbonyl (pNZ).

[0104] In one embodiment, R 1c forms a carbamate together with the nitrogen atom to which it is attached. For example, R 1c can be a Boc group.

[0105] In some of these embodiments, the method further comprises removing the protecting group from the compound of formula (I), for example, by using conventional deprotection conditions known to those of skill in the art or by carrying out the reaction at elevated temperature (e.g., 120° C.) to form the compound of formula (I).

[0106] In some embodiments, R 1c is H.

[0107] In some embodiments, R 2a , R 2b , R 3a , and R 3b each of which is H; halo; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g are independently selected from the group consisting of:

[0108] In some of these embodiments, R 2a , R 2b , R 3a , and R 3bOne of the is halo; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;1 to 6 R a each of which may be substituted with -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g R 2a , R 2b , R 3a , and R 3b The others are H.

[0109] In some embodiments, the variable R 2a , R 2b , R 3a , and R 3b Two of the are taken together with the Ring B ring atom to which they are each attached to form a fused saturated or unsaturated ring of 3 to 12 ring atoms.

[0110] In some embodiments, R 2a , R 2b , R 3a , and R 3b Each of is H.

[0111] In some embodiments, R 1c , R 2a , R 2b , R 3a , and R 3b Each of the above definitions applies to compounds of formula (II).

[0112] In some embodiments, R 1c , R 2a , R 2b , R 3a , and R 3b Each of the above definitions applies to compounds of formula (I).

[0113] Ring A In some embodiments, ring A is selected from 1 to 4 R c C which may be substituted with 6-10 It is aryl.

[0114] In some embodiments, ring A is selected from 1 to 4 R c and n is an optionally substituted phenyl.

[0115] For example, ring A may contain 1 to 2 R c It may be phenyl substituted with

[0116] In some embodiments, ring A is TIFF2025509947000057.tif23128, where each R cB is an independently selected R c It is.

[0117] In some embodiments, each R cB -halo, e.g., -Cl and -F; -CN; 1-4 Alkoxy;C 1-4 Haloalkoxy;C 1-3 alkyl; and C substituted with 1 to 6 independently selected halo 1-3 alkyl.

[0118] In some embodiments, ring A is TIFF2025509947000058.tif15128, where R cB1 is R c and R cB2 is H or R c It is.

[0119] In some of these embodiments, R cB1 is halo (e.g., -F or -Cl (e.g., -F)).

[0120] In one embodiment, R cB2 is C 1-4 Alkoxy or C 1-4 Haloalkoxy (e.g., C1-4 alkoxy (e.g., methoxy).

[0121] As a non-limiting example of the foregoing embodiment, ring A is It could be TIFF2025509947000059.tif19128.

[0122] In some embodiments, each of the above definitions of Ring A applies to compounds of Formula (II).

[0123] In some embodiments, each of the above definitions of Ring A applies to compounds of Formula (I).

[0124] Ring C In some embodiments, ring C is The file is TIFF2025509947000060.tif15128.

[0125] In some embodiments, ring C is TIFF2025509947000061.tif20128, where: ○Each X b are X and R independently c or H; and ○Each X a is H, halo; cyano; 1 to 6 independently selected R a C which may be substituted with 1-10 Alkyl;C 2-6 Alkenyl; -S(O) 1-2 (C 1-4 alkyl);-S(O)(=NH)(C 1-4 alkyl);-NR e R f ;-OH;-S(O) 1-2 NR'R'';-C 1-4 Thioalkoxy; -NO2; -C(=O)(C 1-10 alkyl);-C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF5.

[0126] In some embodiments, ring C is optionally substituted with each X and has 1 to 4 R c and n is 0, 1 or 2, optionally further substituted by

[0127] In some embodiments, ring C is optionally substituted with each X and has 1 to 4 R c 2-pyridonyl or 4-pyridonyl, optionally further substituted by, wherein the ring nitrogen atom is R d and 2-pyridonyl or 4-pyridonyl, optionally substituted by

[0128] In some embodiments, Ring C is a heteroaryl containing 6 ring atoms, where 2-4 of the ring atoms are selected from N, N(H), and N(R d ), wherein the heteroaryl is optionally substituted with X and is selected from the group consisting of 1 to 4 R c is a heteroaryl containing 6 ring atoms, optionally further substituted with

[0129] In certain embodiments, ring C is optionally further substituted with X. TIFF2025509947000062.tif21128, where each R cA are independently selected R c and n is 0, 1, or 2.

[0130] As a non-limiting example of the foregoing embodiment, ring C is It could be TIFF2025509947000063.tif16128.

[0131] In some of the foregoing embodiments, n is 0 and R cA is 1 to 6 independently selected R a C which may be substituted with 1-10 C optionally substituted with 1 to 3 independently selected halo, e.g., 1-3 It is an alkyl.

[0132] As a non-limiting example, ring C is It could be TIFF2025509947000064.tif13128.

[0133] In some embodiments, Ring C is a heteroaryl containing 5 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is optionally substituted with X and has 1 to 4 R c is a heteroaryl containing 5 ring atoms, optionally further substituted with

[0134] In some embodiments, Ring C is a bicyclic heteroaryl containing 7-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is substituted with X and is selected from the group consisting of oxo and R 7 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0135] In some embodiments, Ring C is a bicyclic heteroaryl containing 7-10 ring atoms, where 1-4 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heteroaryl is optionally substituted with X and is selected from the group consisting of oxo and R 7 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0136] In some embodiments, ring C is a bicyclic C 5-10 Cycloalkyl or C 5-10Cycloalkenyl, each of which is substituted with X and is selected from the group consisting of oxo and R 7 A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 5-10 Cycloalkyl or C 5-10 It is a cycloalkenyl.

[0137] In some embodiments, ring C is a bicyclic C 5-10 Cycloalkyl or C 5-10 Cycloalkenyl, each of which is optionally substituted with X, and oxo and R 7 A bicyclic C ring optionally substituted with 1 to 4 substituents independently selected from the group consisting of 5-10 Cycloalkyl or C 5-10 It is a cycloalkenyl.

[0138] In some embodiments, Ring C is a heterocyclyl or heterocycloalkenyl containing 5-10 ring atoms, where 1-3 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heterocyclyl or heterocycloalkenyl is substituted with X and is selected from the group consisting of oxo and R 7 and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0139] In some embodiments, Ring C is a heterocyclyl or heterocycloalkenyl containing 5-10 ring atoms, where 1-3 ring atoms are N, N(H), N(R d ), O, and S(O) 0-2 and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X, and is selected from the group consisting of oxo and R 7and optionally substituted with 1 to 4 substituents independently selected from the group consisting of:

[0140] In some embodiments, ring C is: TIFF2025509947000065.tif16128, where ma is 0, 1, 2, or 3; ○R 8A is halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, R 9A R 10A N-, R 11A -C(O)-NH-, R 11A OC(O)-NH- or R 9A R 10A NC(O)-NH-, wherein the C 1-6 Alkoxy may be substituted 1, 2 or 3 times, independently of one another, with halogen and may be substituted with hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, or one or more R 5A phenyl, optionally substituted once with; ○R 5A is hydroxy, halogen, cyano, C 1-4 -Alkyl, C 1-4 -Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy; ○R 9A and R 10A is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6halocycloalkyl or phenyl, where the phenyl group is R 5A may be substituted one or more times, independently of each other; or R 9A and R 10A together with the nitrogen atom to which they are attached form a 3- to 6-membered nitrogen-containing heterocycle, which may contain one additional heteroatom or heteroatom-containing group selected from O, NH or S, and R 5A may be substituted, independently of each other, one or more times; ○R 11A is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 independently selected from halocycloalkyl; TIFF2025509947000066.tif19128, where ○R 5B is hydroxy, C 1-4 Alkoxy, R 7B R 8B N- or C optionally substituted with phenyl 2-5 alkyl, where the phenyl group is R 5A may be substituted one or more times with; or ○R 5B is R 6B -CH2-; ○R 6B teeth, Selected from TIFF2025509947000067.tif17128; ○R 7B and R 8B is C 1-3 Alkyl, C 1-3 haloalkyl; or ○R 7B and R 8B form, together with the nitrogen atom to which they are attached, a 5-6 membered nitrogen-containing heterocycle, the nitrogen-containing heterocycle being selected from the group consisting of O and -NH-, NH(C 1-3alkyl); ○R 9B is hydrogen, C 1-4 Alkyl, or C 1-3 haloalkyl; ○R 5A is hydroxy, halogen, cyano, C 1-4 -Alkyl, C 1-4 -Alkoxy, C 1-4 Haloalkyl or C 1-4 haloalkoxy; TIFF2025509947000068.tif37128, where ○R 4C is selected from hydrogen or methyl; ○R 6C is hydrogen, C 1-3 Alkyl, C 1-3 haloalkyl; nc is 0 or 1; ○X C is NR 7C or O; ○Y C is NR 8C or O; ○R 7C is methyl; ○R 8C is selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; ○R 5C is selected from hydrogen or methyl, where R 5C X C and Y C is attached to any carbon atom of the ring including; mc is 0, 1, 2, or 3; TIFF2025509947000069.tif23128, where ○R 4D is selected from hydrogen or methyl; ○R 5Dis selected from the group consisting of (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, and 3-azetidinyl, each of which is R 6D and wherein each azetidinyl is optionally substituted one, two or three times with R 8D is replaced by; or ○R 5D teeth, TIFF2025509947000070.tif16128; ○R 6D Fluoro or C 1-3 selected from alkyl; md is selected from 0, 1, 2, or 3; ○R 7D is hydrogen, C 1-3 Alkyl, or C 1-3 haloalkyl; ○X D is ONR 8D and; ○R 8D is C 1-3 Alkyl or C 2-3 Selected from haloalkyl is selected from the group consisting of:

[0141] In some embodiments, ring C is substituted with X and 1 to 4 R 7 C which may be substituted with 10 or C 14 It is aryl.

[0142] In some embodiments, each of the above definitions of Ring A applies to compounds of Formula (III).

[0143] In some embodiments, each of the above definitions of Ring A applies to compounds of Formula (II).

[0144] In some embodiments, each of the above definitions of Ring A applies to compounds of Formula (I).

[0145] The compounds, intermediates, and reagents disclosed herein, in addition to those described herein, can be prepared in a variety of ways, for example, using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by using standard synthetic methods and procedures either known to those skilled in the art or in light of the teachings herein. The synthesis of the compounds disclosed herein can generally be accomplished by following the schemes and examples provided below, with modifications for the specific substituents desired.

[0146] Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from relevant scientific literature or standard textbooks in the field. Classical textbooks such as, but not limited to any one or several sources, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 are useful and recognized reference textbooks of organic synthesis known to those skilled in the art. The following descriptions of synthetic methods are designed to illustrate, but not limit, general procedures for the preparation of compounds of the present disclosure.

[0147] The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, variously substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although in certain cases it may be desirable to further convert the compound to its pharma-ceutically acceptable salt.

[0148] The compounds described herein can be isolated / purified using conventional methods known to those of skill in the art, for example, column chromatography, crystallization, HPLC (eg, chiral HPLC). EXAMPLES

[0149] A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

[0150] Example 1. Synthesis of tert-butyl 2-(3-bromopyridin-4-yl)-3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate TIFF2025509947000071.tif30128

[0151] A suspension of 3-bromopyridine-4-carbaldehyde (3.38 g, 18.2 mmol, 1.5 equiv) in dioxane (37.5 mL) / dioxane (37.5 mL) was stirred under heating (in an 80° C. mantle) until the aldehyde was dissolved. The resulting solution was then added dropwise via syringe pump over 3.0 hours to a 250 mL round bottom flask containing a 95° C. mixture of tert-butyl 3-[(3-chloro-2-methoxyphenyl)carbamothioyl]-2,4-dioxopiperidine-1-carboxylate (5.00 mg, 12.1 mmol, 1.0 equiv) and NHOAc (4.67 g, 60.6 mmol, 5.0 equiv) in toluene (50.0 mL) under an atmosphere of nitrogen. The mixture was then stirred at that temperature for 21 hours (total reaction time 24 hours). The reaction mixture was quenched with saturated aqueous NaHCO3 (100 mL) and diluted with MTBE (50 mL). The phases were separated and the aqueous layer was extracted with MTBE (50 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with n-heptane / EtOAc (3:1 to 0:1) to give tert-butyl 2-(3-bromopyridin-4-yl)-3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (3.03 g, 45.6% yield) as a yellow solid. TIFF2025509947000072.tif35148

[0152] Example 2. Synthesis of tert-butyl 5-((3-chloro-2-methoxyphenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate TIFF2025509947000073.tif27128

[0153] Thiophosgene (6.08 mL, 79.3 mmol, 1.0 equiv) was added dropwise to a mixture of 3-chloro-2-methoxyaniline (12.5 g, 79.3 mmol, 1.0 equiv) in DCM (125 mL) / saturated aqueous NaHCO3 (125 mL) at 0° C., and the mixture was stirred at that temperature for 3 h. The layers were separated, and the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-chloro-3-isothiocyanato-2-methoxybenzene (16.2 g, quantitative yield) as a brown oil.

[0154] TIFF2025509947000074.tif31128

[0155] DBU (17.2 mL, 115 mmol, 1.5 equiv) was added dropwise to a stirred suspension of tert-butyl 2,4-dioxopiperidine-1-carboxylate (16.4 g, 76.9 mmol, 1.0 equiv) and 1-chloro-3-isothiocyanato-2-methoxybenzene (16.2 g, 76.9 mmol, 1.0 equiv) in MeCN (375 mL) at room temperature and the reaction mixture was stirred for 20 h. The reaction mixture was diluted with ice water (100 mL) and HCl (1 M, 115 mL, 115 mmol, 1.5 equiv) was added to reach pH 6. The mixture was stirred for 15 min and then filtered to give 24 g of filter cake (86% purity). 1 g (x 2) of the filter cake was taken and slurried in MeCN (4 mL) or EtOAc (2 mL) overnight at room temperature and then filtered to give material with >99% purity, with more material recovered from the MeCN slurry than from the EtOAc (0.70 g versus 0.45 g). The remaining cake (22 g) was slurried in 4 volumes (88 mL) of MeCN for 4 hours, filtered, and dried overnight in a vacuum oven at 50° C. to give tert-butyl 3-[(3-chloro-2-methoxyphenyl)carbamothioyl]-2,4-dioxopiperidine-1-carboxylate (19.0 g, 59.8%) as a white solid. All the filtrates were combined and purified by silica gel column chromatography eluting with n-heptane / EtOAc (4:1 to 0:1) to give tert-butyl 3-[(3-chloro-2-methoxyphenyl)carbamothioyl]-2,4-dioxopiperidine-1-carboxylate (4.54 g, 14.0%) as an off-white solid. TIFF2025509947000075.tif21148

[0156] Example 3. Synthesis of sodium (3-bromopyridin-4-yl)(hydroxy)methanesulfonate TIFF2025509947000076.tif15128

[0157] A solution of NaHSO3 (565 mg, 5.43 mmol, 1.01 equiv) in water (1.8 mL) was added dropwise to a mixture of 3-bromopyridine-4-carbaldehyde (1.00 g, 5.38 mmol, 1 equiv) in EtOH (10 mL). The reaction mixture was stirred at room temperature for 2 h and a solid formed. EtOH (5 mL) was added and the mixture was stirred for an additional 5 min and then filtered. The filter cake was washed with EtOH (2 × 2.5 mL) and dried in a vacuum oven overnight to give sodium (3-bromopyridin-4-yl)(hydroxy)methanesulfonate (1.43 g, 91.7% yield) as a white solid. TIFF2025509947000077.tif19149

[0158] Example 4. Synthesis of tert-butyl 2-(3-bromopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-1H,6H,7H-pyrrolo[3,2-c]pyridine-5-carboxylate TIFF2025509947000078.tif35130

[0159] To an oven-dried vial was added tert-butyl 3-[(3-chloro-2-methoxyphenyl)carbamothioyl]-4-hydroxy-2-oxo-5,6-dihydropyridine-1-carboxylate Boc-3 (50 mg, 0.121 mmol, 1 equiv.) and ammonium acetate (46.7 mg, 0.61 mmol, 5 equiv.). Toluene (1 mL) was added and the formed suspension was heated at 95°C. Sodium (3-bromopyridin-4-yl)(hydroxy)methanesulfonate 18 (52.7 mg, 0.18 mmol, 1.5 equiv.) was added in five portions over 2.5 h (0.3 equiv. every 30 min) and the reaction mixture was then stirred at 95°C overnight (16-18 h). Aliquots were then taken and analyzed by LCMS and HPLC, giving the following results: LCMS: 44% Boc-8, 22% Boc-3 HPLC (toluene peak removed): 60% Boc-8, 31% Boc-3

[0160] Example 5. Representative Procedure 1 (GP1) for the Synthesis of Compounds of Formula (II) TIFF2025509947000079.tif37128

[0161] DBU (1.50 eq) was added to a stirred suspension of β-ketoamide (Formula (IIa)) (1.00 eq) and isothiocyanate (Formula (IIb)) (1.00 eq) in anhydrous acetonitirile (0.470 m) under a N2 atmosphere, and the resulting mixture was stirred at ambient temperature for 20 h. The reaction was quenched with HCl (1.00 m) to pH 6, diluted with water, and then extracted with EtOAc or DCM (3 × 50 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give compound (Formula (II)).

[0162] Example 6. Representative Procedure 2 (GP2) for the Synthesis of Compounds of Formula (I) TIFF2025509947000080.tif28128

[0163] To an oven-dried vial was added the compound of formula (II) (1.00 eq) and NHOAc (5.00 eq) and evacuated and backfilled with N three times. Anhydrous toluene (10.0 vol) was added and the reaction was heated to 90° C. A pre-made solution of the compound of formula (III) (1.50 eq) in anhydrous 1,4-dioxane (10.0 vol) was then added dropwise via syringe pump over 2.5 hours and the resulting mixture was stirred at 90° C. for 18 hours. The reaction was cooled to ambient temperature and directly concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give the compound of formula (I).

[0164] Example 7. GP2 reaction conditions TIFF2025509947000081.tif26150

[0165] A. Starting material: Enamine 8 a TIFF2025509947000082.tif30137 a Reaction conditions: 8 (0.144 mmol), 6a (0.144 mmol), NHOAc (0.720 mmol), solvent (1.0 mL), temperature, 20 h.

[0166] B. Starting Material: Enol 5a b TIFF2025509947000083.tif109151 b Reaction conditions: 5a (0.144 mmol), 6a (0.144 mmol), NHOAc (0.720 mmol), solvent (1.0 mL), temperature, 20 h.

[0167] C. Variation of aldehyde equivalents c TIFF2025509947000084.tif37128 c Reaction conditions: 5a (0.144 mmol), 6a, NHOAc (0.720 mmol), 1,4-dioxane (1.0 mL), 70 °C, 20 h. b The numbers in parentheses are the isolated yields.

[0168] D. Variations in concentration, temperature, ammonium source, and additives d TIFF2025509947000085.tif127165 d Reaction conditions: 5a (0.144 mmol), 6a (0.216 mmol), NH3 source, solvent, temperature, 20 h. b The numbers in parentheses are the isolated yields.

[0169] E. Variations in Aldehyde Addition and Solvent Mixtures e TIFF2025509947000086.tif146167 e Reaction conditions: 5a (0.144 mmol), 6a, NHOAc (0.720 mmol), solvent, temperature, 20 h. b Isolated yield.

[0170] Example 8. Optimization of reaction conditions The reaction of the enol 5a, NHOAc, and 4-pyridinecarboxaldehyde (6a) under a variety of conditions was examined (Table 1). When heated together in EtOH at 70 °C overnight, the starting material was consumed and 37% of the desired product 7a was detected by HPLC analysis (entry 1). The enamine 8 was identified as the major by-product (27%). To determine whether this enamine was productive, 8 was synthesized independently and subjected to the reaction conditions, and no conversion to 7a was observed. 11 Without wishing to be bound by theory, the reaction mechanism is believed to proceed via precondensation of ammonia with an aldehyde. Utilization of 1,4-dioxane increased the conversion to the desired product 7a (60%) and decreased the enamine 8 (4%); however, when the reaction was carried out in toluene, 74% of the starting material remained unconsumed (entries 2 and 3). Other ether solvents, such as THF, CPME, and TBME, were also productive. 11 Increasing the equivalents of aldehyde from 1.0 to 1.5 was beneficial (entry 4), affording 70% of pyrrole 7a (isolated in 58% yield); however, further increasing the equivalents offered no clear advantage (entry 5). Use of (NH4)2CO3 resulted in a significant decrease in conversion, while NH4Cl provided no detectable levels of product (entries 6 and 7). 1 The reaction was relatively insensitive to the equivalents of NHOAc, but adding >5 equivalents did not appear to be beneficial (entries 8 and 9). Running the reaction at 90 °C resulted in complete conversion of the starting material with 64% of pyrrole 7a detected (entry 11), while lowering the temperature to 50 °C resulted in a significant reduction in product formation (entry 11). When the reaction was run in toluene (entry 3), it was still observed that the formation of enamine 8 was also suppressed. In the mixed solvent system, 69% of product 7a was observed (entry 12), consistent with the conversion observed in 1,4-dioxane. Furthermore, complete consumption of the starting material was observed and the formation of enamine 8 was minimized.

[0171] (Table 1 a ) TIFF2025509947000087.tif158128 a 5a (0.144 mmol), 6a, NH source, solvent (20 vol), T °C, 20 h. b The numbers in parentheses are the isolated yields. c 6a was added as a solution in 1,4-dioxane (10 vol) to 5a and NH4OAc in solvent (10 vol) over 2.5 h.

[0172] Example 9. Synthesis of Compounds 9 and 10 5-Oxo-2-phenyl-4-(phenylamino)-7,8-dihydro-2H-pyrido[4,3-d][1,3]thiazine-6(5H)-carboxylate tert-butyl ester, 9 TIFF2025509947000088.tif26128

[0173] A stirred solution of 5a (500 mg, 1.44 mmol, 1.00 equiv), benzaldehyde (220 μL, 2.15 mmol, 1.50 eq), and NHOAc (553 mg, 7.18 mmol, 5.00 eq) in 1,4-dioxane (10.0 mL) was heated at 70 °C overnight. The reaction mixture was diluted with water (50 mL) and filtered. The precipitate was purified by silica gel chromatography using a 40 g SiO cartridge and a linear gradient of 0-50% EtOAc in heptane over 18 CV to give 9 (140 mg, 19%, 85% purity) as a yellow solid. TIFF2025509947000089.tif47151

[0174] Example 10. Conversion of 9 to pyrrole 7ac TIFF2025509947000090.tif69149TIFF2025509947000091.tif213149TIFF2025509947000092.tif47149

[0175] Example 11. tert-Butyl 4-hydroxy-6-oxo-5-(phenylcarbamothioyl)-3,6-dihydropyridine-1(2H)-carboxylate, 5a1 Synthesis of TIFF2025509947000093.tif17128

[0176] Synthesized according to GP1 using tert-butyl 2,4-dioxopiperidine-1-carboxylate (2.00 g, 9.38 mmol) and isothiocyanatobenzene (1.12 mL, 9.38 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-50% EtOAc in heptane over 15 CV gave 5a (3.13 g, 96%) as a white solid. TIFF2025509947000094.tif42149 1 H NMR data were consistent with those in the literature. 1 .

[0177] Example 12. Synthesis of tert-butyl 4-amino-6-oxo-5-(phenylcarbamothioyl)-3,6-dihydropyridine-1(2H)-carboxylate, 8 TIFF2025509947000095.tif17128

[0178] A mixture of 5a (1.00 g, 2.87 mmol, 1.00 eq) and NHOAc (2.21 g, 28.7 mmol, 10.0 eq) in EtOH (12 mL) was heated at 70° C. overnight. The reaction mixture was concentrated to approximately 4 mL and then quenched with saturated aqueous NaHCO. The mixture was extracted with DCM (3 × 20 mL) and the combined organic extracts were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 40 g SiO cartridge and a linear gradient of 5-100% EtOAc in heptane over 15 CV to give 8 (576 mg, 58%) as a pale yellow solid. TIFF2025509947000096.tif40149

[0179] Example 13. Synthesis of tert-butyl 5-((2-chlorophenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5r TIFF2025509947000097.tif23128

[0180] Synthesized according to GP1 using tert-butyl 2,4-dioxopiperidine-1-carboxylate (300 mg, 1.41 mmol) and 1-chloro-2-isothiocyanatobenzene (239 mg, 1.41 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-25% EtOAc in heptane over 15 CV afforded 5r (379 mg, 70%) as a white solid. TIFF2025509947000098.tif40151

[0181] Example 14. Synthesis of tert-butyl 5-((3-chlorophenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5s TIFF2025509947000099.tif23128

[0182] Synthesized according to GP1 using tert-butyl 2,4-dioxopiperidine-1-carboxylate (300 mg, 1.41 mmol) and 1-chloro-3-isothiocyanatobenzene (239 mg, 1.41 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-30% EtOAc in heptane over 15 CV afforded 5s (360 mg, 67%) as an off-white solid. TIFF2025509947000100.tif33151

[0183] Example 15. Synthesis of tert-butyl 5-((4-chlorophenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5t TIFF2025509947000101.tif20128

[0184] Synthesized according to GP1 using tert-butyl 2,4-dioxopiperidine-1-carboxylate (300 mg, 1.41 mmol) and 1-chloro-4-isothiocyanatobenzene (239 mg, 1.41 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-35% EtOAc in heptane over 15 CV afforded 5t (343 mg, 64%) as a white solid. TIFF2025509947000102.tif34150

[0185] Example 16. tert-Butyl 4-hydroxy-5-((2-methoxyphenyl)carbamothioyl)-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5u 2 Synthesis of TIFF2025509947000103.tif24128

[0186] Synthesized according to GP1 using tert-butyl 2,4-dioxopiperidine-1-carboxylate (300 mg, 1.41 mmol) and 1-isothiocyanato-2-methoxybenzene (190 μL, 1.41 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-35% EtOAc in heptane over 15 CV afforded 5u (396 mg, 74%) as a white solid. TIFF2025509947000104.tif33151

[0187] Example 17. Synthesis of tert-butyl 5-((4-(ethoxycarbonyl)phenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5v TIFF2025509947000105.tif25128

[0188] Synthesized according to GP1 using tert-butyl 2,4-dioxopiperidine-1-carboxylate (300 mg, 1.41 mmol) and ethyl 4-isothiocyanatobenzoate (292 mg, 1.41 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-45% EtOAc in heptane over 14 CV afforded 5v (319 mg, 54%) as a white solid. TIFF2025509947000106.tif40151

[0189] Example 18. Synthesis of tert-butyl 4-hydroxy-3-methyl-6-oxo-5-(phenylcarbamothioyl)-3,6-dihydropyridine-1(2H)-carboxylate, 5y TIFF2025509947000107.tif21128

[0190] Synthesized according to GP1 using tert-butyl 5-methyl-2,4-dioxopiperidine-1-carboxylate (500 mg, 2.20 mmol) and isothiocyanatobenzene (263 μL, 2.20 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-40% EtOAc in heptane over 15 CV afforded 5y (585 mg, 73%) as an off-white solid. TIFF2025509947000108.tif40148

[0191] Example 19. Synthesis of sodium hydroxy(pyridin-4-yl)methanesulfonate, 11 TIFF2025509947000109.tif18128

[0192] To a solution of 4-formylpyridine (600 uL, 6.37 mmol, 1.00 eq) in EtOH (12.7 mL) was added 3 m aqueous NaHSO3 (2.14 mL, 6.43 mmol, 1.01 eq) and the mixture was stirred at room temperature for 3 h. Toluene (10 mL) was added to the reaction mixture for azeotropic removal of water and the solvent was evaporated to dryness. Additional toluene (10 mL) was added and the solvent was evaporated to dryness again to give sodium hydroxy(pyridin-4-yl)methanesulfonate 11 (1.10 g, 82%) as a white solid, which was used without further purification. TIFF2025509947000110.tif12148

[0193] Example 20. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7a TIFF2025509947000111.tif20128

[0194] Small scale: Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and isonicotinaldehyde (40.6 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7a (81 mg, 70%) as an off-white solid.

[0195] 1 g scale: The reaction was carried out according to GP2 using 5a (1.00 g, 2.87 mmol) and isonicotinaldehyde (406 μL, 4.31 mmol) to give 7a (739 mg, 64%) as an off-white solid. TIFF2025509947000112.tif41150

[0196] Example 21. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(pyridin-2-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7b TIFF2025509947000113.tif22128

[0197] Synthesized according to GP2 using tert-butyl 5a (100 mg, 0.287 mmol) and 3-bromoisonicotinaldehyde (80.1 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV, followed by a linear gradient of 0-10% MeOH in DCM over 20 CV, afforded 7b (75 mg, 54%) as a yellow solid. TIFF2025509947000114.tif40151

[0198] Example 22. Synthesis of tert-butyl 2-(3-methylpyridin-4-yl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7c TIFF2025509947000115.tif20128

[0199] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 3-methylisonicotinaldehyde (52.2 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7c (50 mg, 42%) as a yellow solid. TIFF2025509947000116.tif40151

[0200] Example 23. Synthesis of tert-butyl 2-(2-bromopyridin-4-yl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7d TIFF2025509947000117.tif21128

[0201] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 2-bromoisonicotinaldehyde (80.1 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7d (56 mg, 40%) as a yellow solid. TIFF2025509947000118.tif40151

[0202] Example 24. Synthesis of tert-butyl 2-(2-methoxypyridin-4-yl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7e TIFF2025509947000119.tif21128

[0203] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 2-methoxyisonicotinaldehyde (40.9 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7e (100 mg, 80%) as an off-white solid. TIFF2025509947000120.tif40151

[0204] Example 25. Synthesis of tert-butyl 2-(2-fluoropyridin-4-yl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7f TIFF2025509947000121.tif20128

[0205] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 2-fluoroisonicotinaldehyde (53.9 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV, followed by a linear gradient of 0-10% MeOH in DCM over 20 CV, afforded 7f (72 mg, 59%) as a yellow solid. TIFF2025509947000122.tif55152

[0206] Example 26. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(pyridin-2-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7g TIFF2025509947000123.tif19128

[0207] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and picolinaldehyde (40.9 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV afforded 7g (57 mg, 49%) as an off-white solid. TIFF2025509947000124.tif47151

[0208] Example 27. Synthesis of tert-butyl 2-(5-bromopyridin-2-yl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7h TIFF2025509947000125.tif19128

[0209] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 5-bromopicolinaldehyde (40.9 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV, followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7h (72 mg, 52%) as a yellow solid. TIFF2025509947000126.tif40151

[0210] Example 28. Synthesis of tert-butyl 2-(5-methylpyridin-2-yl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7i TIFF2025509947000127.tif19128

[0211] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 5-methylpicolinaldehyde (52.2 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7i (76 mg, 63%) as an off-white solid. TIFF2025509947000128.tif40151

[0212] Example 29. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(quinolin-2-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7j TIFF2025509947000129.tif20128

[0213] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and quinoline-2-carbaldehyde (67.6 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7j (70 mg, 53%) as an orange solid. TIFF2025509947000130.tif47151

[0214] Example 30. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(pyridin-3-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7k TIFF2025509947000131.tif19128

[0215] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 3-formylpyridine (40.4 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7k (22 mg, 19% yield) as a yellow solid. TIFF2025509947000132.tif40151

[0216] Example 31. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(thiazol-2-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7l TIFF2025509947000133.tif19128

[0217] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and thiazole-2-carbaldehyde (37.8 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7l (40 mg, 34%) as a yellow solid. TIFF2025509947000134.tif41151

[0218] Example 32. Synthesis of tert-butyl 2-(1-methyl-1H-imidazol-2-yl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7m TIFF2025509947000135.tif21128

[0219] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (47.4 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7m (40 mg, 34%) as a yellow solid. TIFF2025509947000136.tif40151

[0220] Example 33. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(4-(trifluoromethyl)phenyl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7n TIFF2025509947000137.tif19129

[0221] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 4-(trifluoromethyl)benzaldehyde (60.0 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 0-55% EtOAc in heptane over 13 CV afforded 7n (93 mg, 69%) as a yellow solid. TIFF2025509947000138.tif47148

[0222] Example 34. Synthesis of tert-butyl 2-(4-nitrophenyl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7o TIFF2025509947000139.tif19129

[0223] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 4-nitrobenzaldehyde (65.1 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 0-90% EtOAc in heptane over 10 CV gave 7o (95 mg, 74%) as a red solid. TIFF2025509947000140.tif40149

[0224] Example 35. Synthesis of tert-butyl 2-(4-cyanophenyl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7p TIFF2025509947000141.tif19128

[0225] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 4-formylbenzonitrile (56.5 mg, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 10-100% EtOAc in heptane over 20 CV gave 7p (76 mg, 62%) as a yellow solid. TIFF2025509947000142.tif40151

[0226] Example 36. Synthesis of tert-butyl 2-(3,5-difluorophenyl)-4-oxo-3-(phenylamino)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7q TIFF2025509947000143.tif21128

[0227] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 3,5-difluorobenzaldehyde (40.0 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 0-55% EtOAc in heptane over 10 CV gave 7q (82 mg, 65%) as a yellow solid. TIFF2025509947000144.tif48149

[0228] Example 37. Synthesis of tert-butyl 4-oxo-3-(phenylamino)-2-(pyridin-3-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7a TIFF2025509947000145.tif19128

[0229] Due to solubility issues with the bisulfite adduct 11, the reaction was carried out in a one-pot fashion using 1,4-dioxane as the solvent rather than following GP2.

[0230] A mixture of 5a (100 mg, 0.287 mmol), 11 (90.9 mg, 0.431 mmol), and NHOAc (111 mg, 1.44 mmol) in 1,4-dioxane (2.00 mL) was heated at 70 °C for 18 h. Additional 11 (90.9 mg, 0.431 mmol) was added and the mixture was stirred at 70 °C for an additional 24 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification was carried out by silica gel chromatography eluting with n-heptane / EtOAc (80:20-0:100) and then DCM / MeOH (100:0-90:10) to give 7a (35 mg, 30% yield) as a white solid. TIFF2025509947000146.tif26151The NMR / MS spectrum was consistent with that obtained previously.

[0231] Example 38. Synthesis of tert-butyl 3-((2-chlorophenyl)amino)-4-oxo-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7r TIFF2025509947000147.tif22128

[0232] Synthesized according to GP2 using 5b (50.0 mg, 0.131 mmol) and 6a (18.5 μL, 0.197 mmol). Purification by silica gel chromatography using a 12 g SiO2 cartridge and a linear gradient of 0-100% EtOAc in heptane over 45 CV gave 7r (39.0 mg, 68%) as a yellow solid. TIFF2025509947000148.tif40151

[0233] Example 39. Synthesis of tert-butyl 3-((3-chlorophenyl)amino)-4-oxo-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7s TIFF2025509947000149.tif24128

[0234] Synthesized according to GP2 using 5s (50.0 mg, 0.131 mmol) and 6a (18.5 μL, 0.197 mmol). Purification by silica gel chromatography using a 12 g SiO2 cartridge and a linear gradient of 0-100% EtOAc in heptane over 45 CV gave 7s (35 mg, 61%) as a yellow solid. TIFF2025509947000150.tif41151

[0235] Example 40. Synthesis of tert-butyl 3-((4-chlorophenyl)amino)-4-oxo-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7t TIFF2025509947000151.tif20128

[0236] Synthesized according to GP2 using 5t (50.0 mg, 0.131 mmol) and 6a (18.5 μL, 0.197 mmol). Purification by silica gel chromatography using a 12 g SiO2 cartridge and a linear gradient of 0-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7t (35 mg, 61%) as a yellow solid. TIFF2025509947000152.tif40151

[0237] Example 41. Synthesis of tert-butyl 3-((2-methoxyphenyl)amino)-4-oxo-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7u TIFF2025509947000153.tif23128

[0238] Synthesized according to GP2 using 5u (50.0 mg, 0.132 mmol) and 6a (18.7 μL, 0.198 mmol). Purification by silica gel chromatography using a 12 g SiO2 cartridge and a linear gradient of 0-100% EtOAc in heptane over 40 CV afforded 7u (37 mg, 64%) as a yellow solid. TIFF2025509947000154.tif47151

[0239] Example 42. Synthesis of tert-butyl 3-((4-(ethoxycarbonyl)phenyl)amino)-4-oxo-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7v TIFF2025509947000155.tif20131

[0240] Synthesized according to GP2 using 5v (50.0 mg, 0.119 mmol) and 6a (16.8 μL, 0.178 mmol). Purification by silica gel chromatography using a 12 g SiO2 cartridge and a linear gradient of 0-100% EtOAc in heptane over 10 CV followed by a linear gradient of 0-10% MeOH in DCM over 20 CV gave 7v (35 mg, 61%) as a yellow solid. TIFF2025509947000156.tif47151

[0241] Example 43. Synthesis of tert-butyl 7-methyl-4-oxo-3-(phenylamino)-2-(pyridin-2-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate, 7y TIFF2025509947000157.tif21128

[0242] Synthesized according to GP2 using 5y (100 mg, 0.287 mmol) and 6a (39.0 μL, 0.431 mmol). Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 13 CV followed by a linear gradient of 0-10% MeOH in DCM over 13 CV gave 7y (75 mg, 65%) as a yellow solid. TIFF2025509947000158.tif47151

[0243] Example 45. Synthesis of 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-(2-methoxy-2-methylpropoxy)pyridin-4-yl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (18) 3-(2-Methoxy-2-methylpropoxy)isonicotinonitrile, 13 4 TIFF2025509947000159.tif14128

[0244] Following the modified literature procedure 42-Methoxy-2-methylpropan-1-ol (285 μL, 2.60 mmol, 1.20 eq) was added to a suspension of NaH (60% dispersion in mineral oil, 99.6 mg, 2.49 mmol, 1.15 eq) in DMF (6.00 mL) at 0° C. and the mixture was stirred at that temperature for 15 min. 3-Chloropyridine-4-carbonitrile (300 mg, 2.17 mmol, 1.00 eq) was added and the mixture was stirred for 2 h and allowed to warm to room temperature. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 5-70% EtOAc in heptane to afford 13 (392 mg, 88%) as a white solid. TIFF2025509947000160.tif33152 Data matched those in the literature 4 .

[0245] 3-(2-Methoxy-2-methylpropoxy)isonicotinaldehyde, 14 TIFF2025509947000161.tif18128

[0246] DIBAL-H (1.0 M in toluene, 2.18 mL, 0.728 mmol, 1.50 eq) was added dropwise to a solution of 13 (300 mg, 1.46 mmol, 1.00 eq) in toluene (15.0 mL) at 0 °C, and the mixture was stirred at that temperature for 4 h. DIBAL-H (1.0 M in toluene, 727 μL, 0.728 mmol, 0.500 eq) was added, and the mixture was stirred for an additional 2 h. The mixture was quenched with MeOH and then diluted with 0.1 m HCl (50 mL). The mixture was extracted with DCM (3 × 40 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 0–6% MeOH in DCM to give 14 (185 mg, 61%) as an orange solid. TIFF2025509947000162.tif33151

[0247] 1-Fluoro-3-isothiocyanato-2-methoxybenzene, 16 5 TIFF2025509947000163.tif16128

[0248] Following literature procedures 5 Thiophosgene (272 μL, 3.54 mmol, 1.00 eq) was added to a stirred mixture of 3-fluoro-2-methoxyaniline (500 mg, 3.54 mmol, 1.00 eq) in DCM (5.00 mL) and saturated aqueous NaHCO3 (5.00 mL) and the mixture was stirred at 0 °C for 2 h. The layers were separated and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give 16 (616 mg, 95%) as a brown oil which was used without further purification. TIFF2025509947000164.tif12141 Data were consistent with those in the literature 5 .

[0249] tert-Butyl 5-((3-fluoro-2-methoxyphenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 17 5 TIFF2025509947000165.tif22128

[0250] Synthesized according to GP1 using tert-butyl 2,4-dioxopiperidine-1-carboxylate (710 mg, 3.33 mmol) and 16 (610 mg, 3.33 mmol). Purification by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-50% EtOAc in heptane over 15 CV gave 17 (960 mg, 73%) as an off-white solid. TIFF2025509947000166.tif56149 Data were consistent with those in the literature 5 .

[0251] 184 TIFF2025509947000167.tif35138

[0252] A solution of 14 (79.2 mg, 0.378 mmol, 1.50 eq) in 1,4-dioxane (1.00 mL) was added dropwise over 2.5 h using a syringe pump to a mixture of 17 (100 mg, 0.252 mmol, 1.00 eq) and NHOAc (97.2 mg, 1.26 mmol, 5.00 eq) in toluene (1 mL) at 90 °C, the mixture was stirred at 90 °C for 18 h, then cooled to room temperature. The reaction mixture was concentrated to approximately 0.5 mL and EtOAc (1 mL) was added. HCl in 1,4-dioxane (4.0 m, 0.63 mL, 2.52 mmol, 10.0 eq) was added with vigorous stirring and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO3 (25 mL) and diluted with DCM (25 mL). The layers were separated and the aqueous layer was extracted with DCM (2 × 10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 13 CV, followed by a linear gradient of 0-10% MeOH in DCM over 20 CV to give 18 (64 mg, 56%) as an off-white solid. TIFF2025509947000168.tif69149 Data were consistent with those in the literature 4 .

[0253] Example 46. Scale-up synthesis of 2-(3-bromopyridin-4-yl)-3-((3-chloro-2-methoxyphenyl)amino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (compound 102) Step 1: TIFF2025509947000169.tif100147TIFF2025509947000170.tif207149TIFF2025509947000171.tif202149TIFF2025509947000172.tif121149

[0254] TIFF2025509947000173.tif52149TIFF2025509947000174.tif189149TIFF2025509947000175.tif226155TIFF2025509947000176.tif185149TIFF2025509947000177.tif20145

[0255] TIFF2025509947000178.tif102145

[0256] TIFF2025509947000179.tif47145TIFF2025509947000180.tif201170TIFF2025509947000181.tif100141

[0257] TIFF2025509947000182.tif65141

[0258] TIFF2025509947000183.tif198160

[0259] TIFF2025509947000184.tif104149

[0260] TIFF2025509947000185.tif88149

[0261] TIFF2025509947000186.tif51142TIFF2025509947000187.tif189154TIFF2025509947000188.tif105162

[0262] TIFF2025509947000189.tif39162

[0263] TIFF2025509947000190.tif223152

[0264] TIFF2025509947000191.tif108146

[0265] TIFF2025509947000192.tif125146

[0266] TIFF2025509947000193.tif31170

[0267] TIFF2025509947000194.tif160170

[0268] TIFF2025509947000195.tif30170

[0269] TIFF2025509947000196.tif120170TIFF2025509947000197.tif190170

[0270] TIFF2025509947000198.tif175149TIFF2025509947000199.tif78149

[0271] TIFF2025509947000200.tif103149TIFF2025509947000201.tif236149TIFF2025509947000202.tif200149TIFF2025509947000203.tif181149TIFF2025509947000204.tif105170

[0272] TIFF2025509947000205.tif104170TIFF2025509947000206.tif146152TIFF2025509947000207.tif157149

[0273] Example 47. Kilogram-scale synthesis of 2-(3-bromopyridin-4-yl)-3-((3-chloro-2-methoxyphenyl)amino)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (Compound 102)

[0274] Manufacturing overview TIFF2025509947000208.tif56155

[0275] Manufacturing of steps 1 and 2 1) Process Path TIFF2025509947000209.tif41128

[0276] 2) Process Description Preparation of 1-chloro-3-isothiocyanato-2-methoxybenzene, 1 Under nitrogen atmosphere, spray isopropyl acetate (IPAC) into the reactor, heat to reflux for at least 30 minutes, cool to 20±10°C, transfer through the feed line, filter tank, pneumatic pump, liquid transfer line to another reactor, heat to reflux for at least 30 minutes, cool to 20±10°C, place bucket, dry the reactor, and blow dry the discharge pipeline, pressure filter tank, pneumatic pump, liquid transfer pipeline.

[0277] 1st separation Place under nitrogen for at least 30 minutes, separate and collect the aqueous and organic phases.

[0278] 1st extraction Add the aqueous phase to the reactor under N2 and adjust the temperature to 20±5 C. Add IPAc (3.00 V) to the reactor at 20±5 C, stir for at least 20 min, allow to stand for at least 30 min, separate and collect the aqueous and organic phases. Take a sample of the aqueous phase for product loss testing (IPM) and the organic phase awaits combination and washing.

[0279] Washing Under N2, add 10% aqueous sodium chloride solution (3.33 w / w) to the reactor with the organic phase, adjust the temperature to 20±5 C, stir for at least 20 minutes, let stand for at least 30 minutes, separate and collect the organic phase and wait for the first concentration.

[0280] 1st concentration The organic phase is added to the reactor through a fluid filter. The reactor internal temperature is controlled to be less than 45 C or the jacket temperature is controlled to be less than 55 C, and the mixture is concentrated until the volume becomes 1.0-1.5 V.

[0281] 2nd concentration Add MeOH (3.00 V) to the reactor under N2. Control the reactor internal temperature below 45 °C or the jacket temperature below 55 °C, and concentrate until the volume is 1.0-1.5 V.

[0282] 3rd concentration Add MeOH (3.00 V) to the reactor under N2. Control the reactor internal temperature below 45 C or the jacket temperature below 55 C and concentrate until the volume is 1.0-1.5 V. Keep the temperature at 25±5 Adjust to C. Add MeOH (3.00 V) to the reactor. Sample for GC analysis. Criteria are area % IPAc≦5% and KF≦0.5%, if area % IPAc>5% or KF>0.5%, repeat solvent exchange procedure with MeOH until area % IPAc≦5% and KF≦0.5%. Sample for Q-NMR and report results. Drain concentrated system in reactor into drum.

[0283] Preparation of 1-chloro-3-isothiocyanato-2-methoxybenzene, 1 Addition and reaction Add IPAC (20.00 V) to the reactor and begin stirring under nitrogen. Adjust temperature to 20±5°C. After stirring for at least 5 minutes, take a sample for KF, criteria: KF should be 0.08% or less, if not, drain and add fresh solvent. Then add 3-chloro-2-methoxyaniline (SM1 1.00 eq) and DIPEA (2.50 eq) to the reactor in sequence. Cool to 0-5°C and add thiophosgene (0.98 eq) dropwise to the reactor at 5±5°C (at least 2 hours addition is recommended). Once addition is complete, continue to control temperature at 5±5°C and stir for at least 2 hours. Sample for HPLC analysis, criteria: area % of SM1 ≤ 3.0%, and total sample times should be ≤ 2. Sample for IPM analysis and report thiophosgene content.

[0284] Quench Under nitrogen, adjust the temperature of the hydrochloric acid solution to 5-10 C and exchange with nitrogen three times. Add reaction to 3 M aqueous hydrochloric acid (3.00 V) at 10±5 C. Take a sample for pH=1-4. Stir for at least 30 min and recheck pH, the standard being pH=1-4; if pH>4, add 3 M aqueous hydrochloric acid to ensure pH=1-4. Stir at 20±5 C for at least 3 h (pump in nitrogen while stirring to remove hydrogen in the system).

[0285] 4th concentration Control the reactor internal temperature below 45 C or the jacket temperature below 55 C, and concentrate until the volume is 3-4 V. Adjust the temperature to 20±5 C.

[0286] 2nd separation Add soften water (3.00 V) to the reactor under nitrogen at 20±5 C and begin stirring. When temperature is 20±5 C, add 10% aqueous sodium carbonate (6.67 w / w) dropwise to the reaction. Take a sample for pH=8-9, stir for at least 30 minutes, and recheck pH=8-9. If not, add sodium carbonate to the reactor at 20±5 C until pH=8-9, stir for at least 30 minutes, and recheck pH=8-9. Add IPAc (5.00 V), stir for at least 20 minutes, let stand for at least 30 minutes, separate, and collect the aqueous and organic phases.

[0287] 2nd extraction Add the aqueous phase to the reactor under N2 and adjust the temperature to 20±5 C. Add IPAc (5.00 V) to the reactor at 20±5 C, stir for at least 20 min, allow to stand for at least 30 min, separate and collect the aqueous and organic phases.

[0288] 3rd extraction Add the aqueous phase to the reactor under N2 and adjust the temperature to 20±5 C. Add IPAc (5.00 V) to the reactor at 20±5 C, stir for at least 20 min, allow to stand for at least 30 min, separate and collect the aqueous and organic phases. Combine the organic phase. Take a sample of the aqueous phase for product loss testing (IPM) and allow the organic phase to concentrate.

[0289] 5th concentration The organic phase is added to the reactor through a fluid filter. The reactor internal temperature is controlled to be less than 45 C or the jacket temperature is controlled to be less than 55 C, and the mixture is concentrated until the volume is 1.0-1.5 V.

[0290] 6th concentration Add DCM (5.00 V) to the reactor. Control the reactor internal temperature below 45 C or the jacket temperature below 55 C and concentrate until the volume is 1.0-1.5 V.

[0291] 7th concentration Add DCM (5.00 V) to the reactor. Control the reactor internal temperature below 45 C or the jacket temperature below 55 C and concentrate until the volume is 1.0-1.5 V. Keep the temperature at 25±5 Adjust to C. Add DCM (4.00 V) to the reactor. Sample for GC analysis. Criteria are Area % MeOH≦5% and Area % IPAc≦20% and KF≦0.2%, if Area % MeOH>5% or IPAc>20% or KF>0.2%, repeat solvent exchange procedure with DCM until Area % MeOH≦5% and Area % IPAc≦20% and KF≦0.2%.

[0292] Feed (liquid product) Sample for HPLC and Q-NMR testing. Report results. Transfer reactor product to drums, weigh, and label. Store at room temperature.

[0293] 3) Steps 1 and 2 of the process 1. Add IPAC (20 V) to the reactor under nitrogen. 2. Add SM1 (1.0 eq.) and TEA (2.5 eq.) to the reactor and begin stirring at 20±5° C. Cool to 3.5±5 C. 4. Add SCCl2 (1.0 eq.) dropwise to the reactor at 5±5 C. Stir at 5.5±5 C for 2 hours. 6. Sample for HPLC analysis. 7. Filter. 8. Add the IPAC solution and SM2 (1.0 eq.) to the reactor under nitrogen. Cool to 9.5±5 C. 10. Add a drop of DBU (1.1 eq.) to the reactor. 11. Stir at 20±5°C for 12 hours. 12. Sample for HPLC analysis. Adjust the pH of the reaction to 5-6 using aqueous citric acid (0.2 M) at 13.20 ± 5 °C. 14. Separate and wash the organic phase with 5% NaHCO3 aqueous solution (5 V) at 20±5 C. 15. Wash the organic phase with 15% NaCl aqueous solution (5 V) at 20±5°C. 16. Concentrate the organic phase to 3-4 V at 45 ± 5 C. 17. Add MeOH (10 V) and concentrate to 4-5 V at 45 ± 5 C. 18. Add MeOH (10 V) and concentrate to 4-5 V at 45 ± 5 C. 19. Stir at 20±5°C for 1 hour. 20. Filter and wash the cake with MeOH (2 V). 21. Collect the cake and dry at 40±5 C.

[0294] 4) Manufacturing data overview TIFF2025509947000210.tif107157

[0295] 5) Results • The 20 g scale test performed well with 97.9 A% IPC purity in step 1 and 88.8 A% IPC purity in step 2. ●A 29 ​​kg production batch performed well with 97.7 A% IPC purity in step 1 and 85.0 A% IPC purity in step 2, and after workup, 60 kg of compound 2 was obtained with 99.5 A% IPC purity and 78.9% yield (uncorrected by QNMR).

[0296] Manufacturing of steps 3 and 4 1) Process Path TIFF2025509947000211.tif49132

[0297] 2) Process Description Preparation of a 6% solution of citric acid Under nitrogen, add soft water (24.00V) to the reactor and start stirring. Add citric acid (1.51 w / w) to the reactor, adjust temperature to 20±10° C., stir to dissolve, and discharge into drum for temporary storage.

[0298] Addition and reaction Add IPAC (8.00 V) to the reactor containing the solution of 1-chloro-3-isothiocyanato-2-methoxybenzene and begin stirring under nitrogen. Adjust temperature to 20±5°C. After at least 5 minutes, take a sample for KF and report the result. Then add 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 20±5°C. Cool to 0-5°C and add diazabicyclo (1.10 eq) dropwise to the reactor at 5±5°C (recommended to add for at least 1 hour). Once addition is complete, adjust temperature to 20±5°C (recommended to let temperature rise for at least 1 hour) and stir for at least 12 hours. Sample for HPLC analysis, criteria: area % of 1-chloro-3-isothiocyanato-2-methoxybenzene (1) is ≦5.0%. If not, stir for at least 8 hours and sample for HPLC until the area % of 1-chloro-3-isothiocyanato-2-methoxybenzene (1) is ≦5.0%. Sample for IPM analysis and report the thiophosgene content.

[0299] Quenching and Isolation Add 6% citric acid solution to reaction to adjust pH to 5-6 at 20±5°C. Stir for at least 20 minutes and check pH=5-6. Stir for at least 2 hours at 20±5°C (system drum nitrogen). Sample for detected hydrogen sulfide. Hydrogen sulfide concentration in headspace should be less than 1 ppm. If fail, continue to blow with nitrogen until criteria are met. Hold for at least 30 minutes, separate and collect organic phase.

[0300] Washing Soft water (5.00V) is added to the organic phase, the temperature is adjusted to 20±5° C., stirred for at least 30 minutes, held for at least 30 minutes, separated, the organics are collected, treated and concentrated.

[0301] 1st concentration Control the jacket temperature below 45° C. and the internal temperature below 35° C. Concentrate to 5-6 V.

[0302] 2nd concentration Adjust the temperature to 20±10° C. and add methanol (10.00 V) to the reactor. Control the jacket temperature to be less than 45° C. and the internal temperature to be less than 35° C. Concentrate to 5-6 V.

[0303] 3rd concentration Adjust the temperature to 20±10° C. and add methanol (10.00 V) to the reactor. Control the jacket temperature to be less than 45° C. and the internal temperature to be less than 35° C. Concentrate to 5-6 V. Adjust the temperature to 20±5° C., sample for HPLC and GC (IPM), and report the content of 2 and area % of IPAC in the mother liquor.

[0304] Feed (liquid product) Sample for HPLC and Q-NMR testing. Report results. Transfer reactor concentrate to drums, weigh, and label. Store at room temperature.

[0305] 3) Steps 3 and 4 of the process 1. tert-Butyl 5-((3-chloro-2-methoxyphenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (2) (1.0 eq.) and NHOAc (5.0 eq.) are added to toluene (7.5 V). 2. Heat to 95±5° C. and add a previously prepared solution of SM3 (1.5 eq. in toluene / 1,4-dioxane 15 V, 1 / 1) dropwise at 95±5° C. to the reactor. Stir at 3.95±5° C. for 16 hours and sample for HPLC analysis with the criteria: tert-butyl 5-((3-chloro-2-methoxyphenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (2)≦5.0%. Concentrate to 3-4 V at 4.50 ± 5 C and add EA (6 V) to the reactor. Add 5.4 M HCl / EtOH (3 V) dropwise to the reactor at 25±5° C. and stir for at least 3 h. 6. Sample for HPLC analysis, with the criteria: 2-(3-bromopyridin-4-yl)-3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate tert-butyl (Compound 101) ≦2.0%. 7. Filter and wash the cake with EA (1 V). 8. Add the filter cake to EA / MeOH=10:1 (10 V). 9. Add 10% K2CO3 aqueous solution (10 V) to the reactor at 25±5 C and stir for at least 5 h. (Note: pH: 8~9) 10. Filter, wash the cake with MTBE (1 V) and dry under N2 at 50 C for 16 h. 11.1 V of DMAc and 3 V of toluene are added to the reactor and the crude (compound 102) is added to the reactor. Heat to 12.75±5 C and stir for at least 4 hours. Cool to 13.45±5° C. and add 5 V drops of toluene to the reactor. Stir at 14.45±5C for at least 2 hours. 15. Cool to 10±5 C and stir at 10±5 C for at least 3 hours. 16. Filter and wash with toluene (1 V). 17.10 V of water and the wet cake are added to the reactor. 18. Heat to 50±5 C and stir at 50±5 C for at least 3 hours. 19. Cool to 10±5C and stir at 10±5C for at least 3 hours. 20. Filter and wash with water (1-2 V). 21. Dry under N2 at 50±5 C for 16 hours.

[0306] Manufacturing Data Overview TIFF2025509947000212.tif176153

[0307] 4) Results The first 30.3 kg scale manufacturing batch performed well in step 3 with 57.9 A% IPC purity and 61.5% assay yield of compound 101 at the end of the reaction. A second 30.3 kg scale manufacturing batch performed well in step 3 with 60.1 A% IPC purity and 62.5% assay yield of compound 101 at the end of the reaction. After separate concentration, the two batches were directly combined for reaction in step 4, which worked well with 63.1 A% IPC purity. After workup and purification, 36 kg of compound 102 was obtained with 99.0 A% purity (toluene was not integrated) and 54.8% yield (uncorrected by QNMR).

[0308] Example 48. Synthesis of tert-butyl 3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate TIFF2025509947000213.tif27139A solution of isonicotinaldehyde (1.71 mL, 18.2 mmol, 1.5 eq) in 1,4-dioxane (50 mL) was added dropwise via syringe pump over 2.5 h to a preheated and stirred solution of tert-butyl 5-((3-chloro-2-methoxyphenyl)carbamothioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 12.1 mmol, 1.0 eq) and NHOAc (4.67 g, 60.6 mmol, 5.0 eq) in toluene (50 mL) at 90° C. The reaction mixture was stirred at 90° C. for 20 h and then concentrated under reduced pressure. The crude residue was adsorbed onto silica and then purified by silica gel chromatography (25-100% heptane / EtOAc and then 0-10% MeOH in DCM) to afford tert-butyl 3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-2-(pyridin-4-yl)-1,4,6,7-tetrahydro-5H-pyrrolo[3,2-c]pyridine-5-carboxylate (3.36 g, 59% yield) as an orange solid. TIFF2025509947000214.tif45149

[0309] References TIFF2025509947000215.tif81145

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising the step of contacting a compound of formula (II) with a compound of formula (III), During the ceremony, Y is either -OH or -NH 2 More selected; Z is ●-C(=O)H; or ●-CH(R) 2 (Here, each R is a halo, alkoxy, OH, or SO 3 M (M = Li, Na, K, or NH) 4 + (Selected independently from R, however, if one R is OH, the other R cannot be a halo, alkoxy, or OH.) More selected, R 1c H and R d More selected; R 2a 、R 2b 、R 3a 、and R 3b each of which is H; halo; -OH; -C(O)OH or -C(O)NH 2 ; -CN; -R b ; -L b -R b ; 1 to 6 R a Even if they are replaced by -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g Selected independently from the group consisting of; Variable symbol R 2a , R 2b , R 3a , and R 3b Two of these, together with the ring B ring atom to which they are bonded, form a condensed saturated or unsaturated ring of 3 to 12 ring atoms; ●Here, 0 to 2 ring atoms are heteroatoms that are independently selected (-N(R 1c If )- forms part of a condensed saturated or unsaturated ring, then -N(R 1c )-In addition), where each of the independently selected heteroatoms is N, NH, N(R d ), O, and S(O) 0-2 Selected from the group consisting of; and ●Here, condensed saturated or unsaturated rings of 3 to 12 ring atoms are oxo, R c , and R W They may be substituted with 1 to 4 substituents independently selected from the group consisting of; Ring A is R g And; R 4 H and R d Selected from the group consisting of; Ring C is as follows: ； Here: ○Each X b X and R are independent of each other. c , or H; and ○Each X a H, halo; cyano; 1 to 6 independently selected R a Even if replaced by C 1-10 Alkyl; C 2-6 Alkenyl; -S(O) 1-2 (C 1-4 Alkyl); -S(O)(=NH)(C 1-4 Alkyl); -NR e R f ;-OH;-S(O) 1-2 NR'R''; -C 1-4 Thioalkoxy; -NO 2 -C(=O)(C 1-10 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF 5 Selected independently from the group consisting of; ●Each can be substituted with X, and there are 1 to 4 R c 2-pyridyl or 3-pyridyl may be further substituted; ●Each can be substituted with X, and there are 1 to 4 R c A 2-pyridonyl or 4-pyridonyl which may be further substituted with R, where the ring nitrogen atom is R d 2-pyridonyl or 4-pyridonyl, which may be substituted with; ●A heteroaryl compound containing 6 ring atoms, where 2 to 4 ring atoms are N, N(H), and N(R) d A heteroatom independently selected from the group consisting of ), where the heteroaryl may be substituted with X and has 1 to 4 R c A heteroaryl compound containing six ring atoms, which may be further substituted; ●A heteroaryl compound containing 5 ring atoms, where 1 to 4 of the ring atoms are N, N(H), and N(R). d ), O, and S(O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and here, the heteroaryl may be substituted with X and has 1 to 4 R c A heteroaryl compound containing five ring atoms, which may be further substituted; ●A bicyclic heteroaryl compound containing 7 to 10 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R) d ), O, and S(O) 0-2 A heteroatom independently selected from the group consisting of, where the heteroaryl may be substituted with X, and oxo and R 7 A bicyclic heteroaryl comprising 7 to 10 ring atoms, which may be substituted with 1 to 4 substituents independently selected from the group consisting of; ●Bicyclic C 5-10 Cycloalkyl or C 5-10 A cycloalkenyl, each of which may be substituted with X, and which contains oxo and R 7 A bicyclic C may be substituted with 1 to 4 substituents independently selected from the group consisting of the above. 5-10 Cycloalkyl or C 5-10 Cycloalkenyl; ●A heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R) d ), O, and S(O) 0-2 A heteroatom independently selected from the group consisting of, where the heterocyclyl or heterocycloalkenyl may be substituted with X, and oxo and R 7 A heterocyclyl or heterocycloalkenyl containing 5 to 10 ring atoms, which may be substituted with 1 to 4 substituents independently selected from the group consisting of; and ●X may be substituted and there are 1 to 4 R 7 Even if replaced by C 10 or C 14 Ariel; Here, ○ma is 0, 1, 2, or 3; ○R 8A is selected independently of halogen, hydroxy, nitro, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 halocycloalkyl, R 9A R 10A N-, R 11A -C(O)-NH-, R 11A O-C(O)-NH- or R 9A R 10A is selected independently of N-C(O)-NH-, where the C 1-6 alkoxy may be substituted 1, 2 or 3 times independently of one another with halogen and may also be substituted once with hydroxy, C 1-4 alkoxy, R 9A R 10A N-, C 3-6 cycloalkyl, 4- to 7-membered heterocycloalkyl, or phenyl which may be substituted with one or more R 5A and may be substituted once; ○R 5A is selected from hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy; ○R 9A and R 10A is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 A halocycloalkyl group or a phenyl group is independently selected, where the phenyl group is R 5A And they may be substituted one or more times, independently of each other; or, R 9A and R 10A Together with the nitrogen atom to which they are bonded, they form a 3-6 membered nitrogen-containing heterocycle, and the nitrogen-containing heterocycle may contain one additional heteroatom or heteroatom-containing group selected from O, NH, or S, and R 5A And they may be substituted one or more times, independently of each other; ○R 11A C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 Independently selected from halocycloalkyl groups; Here, ○R 5B is hydroxy, C 1-4 Alkoxy, R 7B R 8B C may be substituted with N- or phenyl. 2-5 It is an alkyl group, where the phenyl group is R 5A It may be replaced once or more times; or ○R 5B is R 6B -CH 2 -and; ○R 6B teeth, More selected; ○R 7B and R 8B C 1-3 Alkyl, C 1-3 Independently selected from haloalkyl groups; or ○R 7B and R 8B Together with the nitrogen atoms to which they are bonded, they form a 5-6 member nitrogen-containing heterocycle, and this nitrogen-containing heterocycle consists of O and -NH-,NH(C 1-3 It may contain one additional heteroatom or heteroatom-containing group selected from alkyl groups; ○R 9B is hydrogen, C 1-4 Alkyl, or C 1-3 Selected from haloalkyls; ○R 5A These are hydroxy, halogen, cyano, and C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl or C 1-4 Selected from haloalkoxys; Here, ○R 4C is selected from hydrogen or methyl; ○R 6C is hydrogen, C 1-3 Alkyl, C 1-3 Selected from haloalkyls; ○nc is either 0 or 1; ○X C , NR 7C or O; ○Y C , NR 8C or O; ○R 7C It is methyl; ○R 8C This is selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; ○R 5C R is selected from hydrogen or methyl, where R 5C X C and Y C It is bonded to any carbon atom of the ring containing; ○mc is 0, 1, 2, or 3; Here, ○R 4D is selected from hydrogen or methyl; ○R 5D The group is selected from the group consisting of (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, and 3-azetidinyl, and each of them is R 6D The azetidinyl may be substituted once, twice, or three times, and each azetidinyl is R at nitrogen. 8D It is replaced by; or ○R 5D teeth, Selected from the group consisting of; ○R 6D is fluoro or C 1-3 Selected from alkyl groups; ○md is selected from 0, 1, 2, or 3; ○R 7D is hydrogen, C 1-3 Alkyl, or C 1-3 Selected from haloalkyls; ○X D , NR 8D or O; ○R 8D C 1-3 Alkyl or C 2-3 More applications than haloalkyl Selected from the group consisting of; X is X 1; or, X is X*, where X* is selected from halo, triflate, tosylate, or mesylate; Each R 7 R is selected independently c n is 0, 1, 2, or 3; X 1 teeth, (a) ; and (b)-O-L 1 -R 5 Selected from the group consisting of; L 1 and L 2 This involves a bond, and 1 to 6 R a Even if replaced by C 1-10 Independently selected from the group consisting of alkylenes; R 5 The following: ●A heteroaryl compound containing 5 to 10 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R) d ), O, and S(O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and here, the heteroaryl is composed of 1 to 4 R c A heteroaryl compound containing 5 to 10 ring atoms, which may be substituted with; ● 1 to 4 R c Even if replaced by C 6-10 Ariel; ●Oxo and R c Each of the following may be substituted with 1 to 4 substituents independently selected from the group consisting of C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; Here, ring D is a heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, where 0 to 2 ring atoms (R X In addition to the ring nitrogen atom bonded to it, N, N(H), N(R) d ), O, and S(O) 0-2 A heteroatom independently selected from the group consisting of, where the heterocyclylene or heterocycloalkenylene is oxo and -R c A heterocyclylene or heterocycloalkenylene containing 3 to 10 ring atoms, which may be substituted with 1 to 4 substituents independently selected from the group consisting of; ● 1 to 6 R a -S(O) may be substituted. 0-2 (C 1-6 Alkyl); ●-R W ●-R g2 -R W or -R g2 -R Y ; ●-L 5 -R g ; and ●-L 5 -R g2 -R W or -L 5 -R g2 -R Y Selected from the group consisting of, However, L 1 If R is a bond, 5 This is 1 to 6 R a -S(O) may be substituted. 0-2 (C 1-6 Alkyl); -L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y It is unexpected; R 6 teeth, ●H； ●Hello; ●-OH; ●-NR e R f ; ●-R g ； ●-R w ●-L 6 -R g ; ●-R g2 -R W or -R g2 -R Y ; ●-L 6 -R g2 -R W or -L 6 -R g2 -R Y ; and ● 1 to 6 R a Even if they are replaced by -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 Alkyl); Selected from the group consisting of, L 5 and L 6 These are independently -O- and -S(O) 0-2 -NH, or -N(R d )-and; and R W ha-L W -W is, Here, L W C(=O), S(O) 1-2 OC(=O)*, NHC(=O)*, NR d C(=O)*, NHS(O) 1-2 *, or NR d S(O) 1-2 * is where the asterisk indicates a connection point to W, and W is C 2-6 Alkenil; C 2-6 Alkinyl; or C 3-10 It is an allenyl, each containing 1 to 3 R a It is also fine if it is replaced with R g It may be further substituted, where W is sp 2 or via sp hybridized carbon atoms L W It is bonded to, thereby providing an α,β-unsaturated system; and R X Each of them has 1 to 6 R a It may be substituted with C(=O)(C 1-6 Alkyl) or S(O) 2 (C 1-6 Alkyl) and R Y is, -R g and -(L g ) g -R g Selected from the group consisting of, R a Each occurrence is -OH; -HALO; -NR e R f ;C 1-4 Alkoxy; C 1-4 Haloalkoxy; -C(=O)O(C 1-4 Alkyl); -C(=O)(C 1-4 Alkyl); -C(=O)OH; -CONR'R''; -S(O) 1-2 NR'R''; -S(O) 1-2 (C 1-4 Independently selected from the group consisting of alkyl and cyano; R b Each occurrence of C is independent. 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 It is an alkinyl, each containing 1 to 6 R a It is also fine if it is replaced with; L b Each occurrence of C(=O); C(=O)O; S(O) 1-2 ;C(=O)NH*;C(=O)NR d *; S(O) 1-2 NH*; or S(O) 1-2 N(R d )*, where the asterisk is R b It shows the connection point to; R c Each occurrence is a halo; cyano; 1 to 6 independently selected R a Even if replaced by C 1-10 Alkyl; C 3-5 Cycloalkyl; C 2-6 Alkenil; C 2-6 Alkinyl; C 1-4 Alkoxy or C 1-4 C may be substituted with haloalkoxy. 1-4 Alkoxy; C 1-4 Haloalkoxy; -S(O) 1-2 (C 1-4 Alkyl); -S(O)(=NH)(C 1-4 Alkyl); -NR e R f ;-OH;-S(O) 1-2 NR'R''; -C 1-4 Thioalkoxy; -NO 2 -C(=O)(C 1-10 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF 5 Selected independently from the group consisting of; R d Each occurrence of R is one to three independently selected R a Or R g Even if replaced by C 1-6 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R''; -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Independently selected from the group consisting of alkoxys; R e and R f Each occurrence is H; 1 to 3 C 1-3 C may be substituted with an alkyl group. 3-5 Cycloalkyl; a heterocycline containing 3 to 6 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R) d ), O, and S(O) 0-2 A heteroatom independently selected from the group consisting of , and oxo and R c A heterocyclyl containing 3 to 6 ring atoms, which may be substituted with 1 to 4 substituents independently selected from the group consisting of NR'R'', -OH, C 1-6 Alkoxy, C 1-6 C may be substituted with 1 to 3 substituents independently selected from the group consisting of haloalkoxys and halos. 1-6 Alkyl; -C(O)(C 1-4 Alkyl); -C(O)O(C 1-4 Alkyl); -CONR'R''; -S(O) 1-2 NR'R''; -S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Independently selected from the group consisting of alkoxys; R g Each occurrence is independently selected from the following group: ●C 3-10 Cycloalkyl or C 3-10 Cycloalkenyls, each of which is oxo and R c It may be substituted with 1 to 4 substituents independently selected from the group consisting of C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl; ●A heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, where 1 to 3 ring atoms are N, N(H), N(R) d ), O, and S(O) 0-2 A heteroatom independently selected from the group consisting of, where the heterocyclyl or heterocycloalkenyl is oxo and R c A heterocyclyl or heterocycloalkenyl containing 3 to 10 ring atoms, which may be substituted with 1 to 4 substituents independently selected from the group consisting of the following: ●A heteroaryl compound containing 5 to 10 ring atoms, where 1 to 4 ring atoms are N, N(H), N(R) d ), O, and S(O) 0-2 Each heteroatom is independently selected from the group consisting of the following, and here, the heteroaryl is composed of 1 to 4 R c A heteroaryl compound containing 5 to 10 ring atoms, which may be substituted with; and ● 1 to 4 R c Even if replaced by C 6-10 Ariel; L g Each occurrence of -O-, -NH-, -NR d , -S(O) 0-2 , C(O), and 1 to 3 R a Even if replaced by C 1-3 Independently selected from the group consisting of alkylenes; Each g is independently 1, 2, or 3; Each R g2 is a divalent R g It is the basis; and Each occurrence of R' and R'' is H; -OH; and C 1-4 A method independently selected from the group consisting of alkyl groups.

2. The step of contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a nitrogen source such as ammonia or a derivative thereof. In particular, the ammonia or its derivative is in the form of a salt, For example, if the nitrogen source is NH 4 OAc, NH 3 ・H 2 O, NH 4 CO 2 H, NH 4 OBz, NH 4 Cl, (NH 4 ) 2 SO 4 , (NH 4 ) 2 Hpo 4 NH 4 H 2 PO 4 NH 4 OTf, NH 4 HCO 3 , (NH 4 ) 2 CO 3 NH 4 CO 2 CF 3 NH 4 BF 4 , ammonium citrate dibasic, (C 1 -C 6 Alkyl)-NH 2 , and (C 3 -C 6 Cycloalkyl)-NH 2 The method according to claim 1, wherein a selection is made from, or any combination thereof, and is in particular NH4OAc.

3. The molar ratio of the nitrogen source to the compound of formula (III) is approximately 2:1 to approximately 8:

1. In particular, the method according to claim 2, wherein the molar ratio of the nitrogen source to the compound of formula (III) is about 4:1 to about 6:1, for example, about 5:

1.

4. The step of contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a solvent. for example, (i) The solvent is an aprotic solvent, in particular: - The aprotic solvent is a nonpolar aprotic solvent, for example, (a) The nonpolar aprotic solvent is an aromatic hydrocarbon solvent such as toluene, or (b) The nonpolar aprotic solvent is a non-aromatic hydrocarbon such as heptane or hexane, - The aprotic solvent is a polar aprotic solvent, for example, (a) The polar aprotic solvent is an ether solvent such as CPME, 1,4-dioxane, or THF, - The aprotic solvent is acetonitrile or DMSO, or (ii) The method according to any one of claims 1 to 3, wherein the solvent is a protic solvent, and in particular a polar protic solvent such as acetic acid.

5. The method according to any one of claims 1 to 3, wherein the step of contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 80°C to 110°C; about 80°C to 100°C (e.g., 90°C); or about 90°C to 110°C (e.g., 100°C); or at a temperature of about 20°C to about 80°C (e.g., 20°C).

6. The method according to any one of claims 1 to 3, wherein the step of contacting a compound of formula (II) with a compound of formula (III) is carried out in the presence of an additive, the additive being selected from, for example, Na₂SO₄, H₂O, H₂SO₄, acetic acid, formic acid, Bi(OTf)₃, PPh₃, NH₄OH, NH₄OAc, PPTS, PTSA, pyridine, or any combination thereof.

7. The step of bringing the compound of formula (II) into contact with the compound of formula (III) is, (i) In a sealed container filled with air or an inert gas (e.g., nitrogen), (ii) Perform the procedure in an open container, or (iii) The method according to any one of claims 1 to 3, carried out in an open container connected to an inert gas (e.g., nitrogen) manifold.

8. The molar ratio of compound (II) to compound (III) is, (i) The ratio is approximately 1:1 to approximately 1:

3. (ii) The ratio is approximately 1:1 to approximately 1:

2. (iii) It is approximately 1:1.

3. (iv) It is approximately 1:1.5, or (v) The method according to any one of claims 1 to 3, wherein the ratio is approximately 1:

2.

9. The method according to any one of claims 1 to 3, wherein the compound of formula (III) is added to the reaction little by little.

10. To provide the compound of formula (II), the following: The method according to any one of claims 1 to 3, further comprising the step of contacting a compound of formula (IIa) with a compound of formula (IIb).

11. Compound (IIb) with a chlorinating agent and compound (IId): The method according to claim 10, wherein preparation is carried out by bringing into contact with the other.

12. The compound of formula (IIb) is as follows: The method according to claim 10, wherein the compound is prepared by contacting the compound of formula (IIc) with the compound of formula (IId).

13. The method according to any one of claims 1 to 3, wherein the step of contacting a compound of formula (II) with a compound of formula (III) is carried out in the absence of an oxidizing agent, in particular, the oxidizing agent is m-CPBA.

14. A method according to any one of claims 1 to 3, comprising isolating / purifying a compound of formula (I) by column chromatography.

15. R 1c but, (i) It is a protecting group such as a Boc group, or (ii) R 1c, together with the nitrogen atom to which it is bonded, forms a carbamate. The method according to any one of claims 1 to 3, further comprising optionally a step of removing a protecting group from a compound of formula (I).

16. R 1c The method according to any one of claims 1 to 3, wherein H.

17. -R 2a , R 2b , R 3a , and R 3b Each of these is H; Hal; -OH; -C(O)OH or -C(O)NH 2 -CN;-R b ;-L b -R b ; 1 to 6 R a Even if they are replaced by -C 1-6 Alkoxy or -C 1-6 Thioalkoxy; -NR e R f ;-R g ; and -(L g ) g -R g Independently selected from the group consisting of, in particular, halo; -OH; -C(O)OH or -C(O)NH2; -CN; -Rb; -Lb -Rb; -C1-6 alkoxy or -C1-6 thioalkoxy; -NRe Rf; -Rg; and -(Lg)g -Rg, wherein the other of R2a, R2b, R3a, and R3b is H, or, - Two of the variable symbols R2a, R2b, R3a, and R3b, together with the ring B ring atom to which they are bonded, form a condensed saturated or unsaturated ring of 3 to 12 ring atoms, or - Each of R2a, R2b, R3a, and R3b is H, and / or - Ring A is a C6-10 aryl which may be substituted with 1 to 4 Rc groups, and in particular, ring A is a phenyl which may be substituted with 1 to 4 Rc groups, for example, ring A is a phenyl which is substituted with 1 to 2 Rc groups. For example, ring C is The method according to any one of claims 1 to 3.

18. Ring C is And here: ○Each X b X and R are independent of each other. c , or H; and ○Each X a H, halo; cyano; 1 to 6 independently selected R a Even if replaced by C 1-10 Alkyl; C 2-6 Alkenyl; -S(O) 1-2 (C 1-4 Alkyl); -S(O)(=NH)(C 1-4 Alkyl); -NR e R f ;-OH;-S(O) 1-2 NR'R''; -C 1-4 Thioalkoxy; -NO 2 -C(=O)(C 1-10 Alkyl); -C(=O)O(C 1-4 Alkyl); -C(=O)OH; -C(=O)NR'R''; and -SF 5 A method according to any one of claims 1 to 3, independently selected from the group consisting of the following.

19. Ring C is ●Each can be substituted with X, and there are 1 to 4 R c 2-pyridyl or 3-pyridyl may be further substituted with; or ●Each can be substituted with X, and there are 1 to 4 R c A 2-pyridonyl or 4-pyridonyl which may be further substituted with R, where the ring nitrogen atom is R d 2-pyridonyl or 4-pyridonyl may be substituted with A method according to any one of claims 1 to 3, which is selected from the above.

20. The ring C is a heteroaryl compound containing 6 ring atoms, where 2 to 4 ring atoms are N, N(H), and N(R). d A heteroatom independently selected from the group consisting of ), where the heteroaryl may be substituted with X and has 1 to 4 R c The method according to any one of claims 1 to 3, wherein the heteroaryl compound comprises six ring atoms, which may be further substituted. 。

21. Ring C is as follows: Here, ○ma is 0, 1, 2, or 3; ○R 8A These are halogens, hydroxyl, nitro, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, R 9A R 10A N-, R 11A -C(O)-NH-, R 11A OC(O)-NH- or R 9A R 10A Selected independently from NC(O)-NH-, where C 1-6 The alkoxys are halogens, which may be independently substituted with each other once, twice, or three times, and may also contain hydroxyl and C atoms. 1-4 Alkoxy, R 9A R 10A N-, C 3-6 Cycloalkyl groups, 4- to 7-membered heterocycloalkyl groups, or one or more R groups. 5A It may be substituted with phenyl once; ○R 5A These are hydroxy, halogen, cyano, and C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl or C 1-4 Selected from haloalkoxys; ○R 9A and R 10A is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 A halocycloalkyl group or a phenyl group is independently selected, where the phenyl group is R 5A And they may be substituted one or more times, independently of each other; or, R 9A and R 10A Together with the nitrogen atom to which they are bonded, they form a 3-6 membered nitrogen-containing heterocycle, and the nitrogen-containing heterocycle may contain one additional heteroatom or heteroatom-containing group selected from O, NH, or S, and R 5A And they may be substituted one or more times, independently of each other; ○R 11A C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 Independently selected from halocycloalkyl groups; Here, ○R 5B is hydroxy, C 1-4 Alkoxy, R 7B R 8B C may be substituted with N- or phenyl. 2-5 It is an alkyl group, where the phenyl group is R 5A It may be replaced once or more times; or ○R 5B is R 6B -CH 2 -and; ○R 6B teeth, More selected; ○R 7B and R 8B C 1-3 Alkyl, C 1-3 Independently selected from haloalkyl groups; or ○R 7B and R 8B Together with the nitrogen atoms to which they are bonded, they form a 5-6 member nitrogen-containing heterocycle, and this nitrogen-containing heterocycle consists of O and -NH-,NH(C 1-3 It may contain one additional heteroatom or heteroatom-containing group selected from alkyl groups; ○R 9B is hydrogen, C 1-4 Alkyl, or C 1-3 Selected from haloalkyls; ○R 5A These are hydroxy, halogen, cyano, and C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl or C 1-4 Selected from haloalkoxys; Here, ○R 4C is selected from hydrogen or methyl; ○R 6C is hydrogen, C 1-3 Alkyl, C 1-3 Selected from haloalkyls; ○nc is either 0 or 1; ○X C , NR 7C or O; ○Y C , NR 8C or O; ○R 7C It is methyl; ○R 8C This is selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; ○R 5C R is selected from hydrogen or methyl, where R 5C X C and Y C It is bonded to any carbon atom of the ring containing; ○mc is 0, 1, 2, or 3; Here, ○R 4D is selected from hydrogen or methyl; ○R 5D The group is selected from the group consisting of (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, and 3-azetidinyl, and each of them is R 6D The azetidinyl may be substituted once, twice, or three times, and each azetidinyl is R at nitrogen. 8D It is replaced by; or ○R 5D teeth, Selected from the group consisting of; ○R 6D is fluoro or C 1-3 Selected from alkyl groups; ○md is selected from 0, 1, 2, or 3; ○R 7D is hydrogen, C 1-3 Alkyl, or C 1-3 Selected from haloalkyls; ○X D , NR 8D or O; ○R 8D C 1-3 Alkyl or C 2-3 More applications than haloalkyl A method according to any one of claims 1 to 3, selected from the group consisting of the following.

22. X The method according to any one of claims 1 to 3.

23. R 7 The method according to any one of claims 1 to 3, wherein each occurrence of is H.

24. R 4 The method according to any one of claims 1 to 3, wherein H.

25. Compounds of formula (I) where X is X* 1 The method according to any one of claims 1 to 3, further comprising the step of converting to a compound of formula (I).

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