Method for synthesizing EGFR inhibitor

Abstract

The present disclosure features processes for the preparation of tetrahydro-4H-pyrrolo [3, 2-c] pyridin-4-one-containing chemical entities (e.g., compounds or pharmaceutically acceptable salts thereof) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2), which are also useful for the preparation of synthetic intermediates for the chemical entities. The methods include, for example, improved methods for synthesizing compounds of formula (I) as described herein. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 323,249 filed on March 24, 2022, U.S. Provisional Application No. 63 / 422,645 filed on November 4, 2022, and U.S. Provisional Application No. 63 / 435,108 filed on December 23, 2022, which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure features methods for preparing a chemical entity (e.g., a compound or a pharmaceutically acceptable salt thereof) containing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, wherein the chemical entity inhibits epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2), and the method can also be used to prepare a synthetic intermediate of the chemical entity. The method includes, for example, an improved method for synthesizing a compound of formula (I) as described herein. Background Art

[0004] 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 associated with tumor growth, including proliferation and differentiation. Some researchers have demonstrated the role of EGFR and HER2 in development and cancer (described in Salomon et al. Crit. Rev. Oncol. Hematol. (1995) 19: 183-232, Klapper et al. Adv. Cancer Res. (2000) 77, 25-79 and Hynes and Stern's Biochim. Biophys. Acta (1994) 1198: 165-184). EGFR overexpression is present in at least 70% of human cancers, such as non-small cell lung cancer (NSCLC), breast cancer, gliomas and prostate cancer. HER2 overexpression occurs in about 30% of all breast cancers. It is also associated with other human cancers, including colon, ovarian, bladder, stomach, esophageal, lung, uterine, and prostate cancers. HER2 overexpression is also associated with poor prognosis in human cancers, including metastasis and early recurrence.

[0005] Chemical entities containing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one that inhibit epidermal growth factor receptor and / or human epidermal growth factor receptor 2 are described, for example, in PCT / US2021 / 051504, filed on September 22, 2021; PCT / US2021 / 054191, filed on October 8, 2021; and PCT / US2021 / 057348, filed on October 8, 2021, each of which is incorporated herein by reference in its entirety. Summary of the invention

[0006] The present disclosure features methods for preparing a chemical entity (e.g., a compound or a pharmaceutically acceptable salt thereof) containing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one, wherein the chemical entity inhibits epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2), and the method can also be used to prepare a synthetic intermediate of the chemical entity. The method includes, for example, an improved synthesis method of a compound of formula (I) as described herein.

[0007] In one aspect, the disclosure features a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising contacting a compound of formula (II) with a compound of formula (III),

[0008]

[0009] Among them, Y, Z, R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C may be as defined anywhere herein.

[0010] In one aspect, the disclosure features a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0011]

[0012] Where R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C may be as defined anywhere herein.

[0013] In another aspect, the disclosure features a compound of formula (I) or a pharmaceutically acceptable salt thereof,

[0014]

[0015] It is prepared by a method as described anywhere herein, and wherein R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C may be as defined anywhere herein.

[0016] Heretofore, processes for preparing the compounds described herein have used oxidants (e.g., peroxyacids such as m-CPBA) in certain bonding (e.g., cyclization) steps. Furthermore, the oxidants (e.g., peroxyacids such as m-CPBA) are used at least in stoichiometric amounts, and are often used in excess. Advantageously, the inventors have surprisingly discovered that these bonding (e.g., cyclization) steps can be accomplished in the absence of oxidants (e.g., peroxyacids such as m-CPBA), thereby making the desired transformations more amenable to safer and more cost-effective scale-up.

[0017] The present disclosure may be more fully understood by reference to the following description (including the following list of terms and general examples). It should be understood that, for the purpose of clarity, certain features of the disclosed compositions and methods described herein in the context of independent aspects may also be combined and provided in a single aspect. On the contrary, for the purpose of brevity, each feature of the disclosed compositions and methods described in the context of a single aspect may also be provided separately, or in any sub-item combination.

[0018] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0019] The term "oxo" refers to a divalent double-bonded oxygen atom (ie, "=0"). As used herein, an oxo group is attached to a carbon atom to form a carbonyl group.

[0020] The term "alkyl" refers to a non-cyclic saturated hydrocarbon group which may be straight or branched and contains the indicated number of carbon atoms. 1-10 Meaning that there may be 1 to 10 (inclusive) carbon atoms in the group. The alkyl group may be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, isopropyl, tert-butyl, n-hexyl. The term "saturated" as used herein refers to the presence of only single bonds between the carbon atoms that constitute and other available valences occupied by hydrogen and / or other substituents defined herein.

[0021] The term "alkoxy" refers to an -O-alkyl group (eg, -OCH3).

[0022] The term "alkylene" refers to a divalent alkyl group (eg, -CH2-).

[0023] The term "alkenyl" refers to a non-cyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon double bonds. The alkenyl moiety contains the specified number of carbon atoms. For example, C 2-6 It means that the group may have 2 to 6 (inclusive) carbon atoms. The alkenyl group may be unsubstituted or substituted with one or more substituents.

[0024] The term "alkynyl" refers to a non-cyclic hydrocarbon chain that may be straight or branched and has one or more carbon-carbon triple bonds. The alkynyl moiety contains the specified number of carbon atoms. For example, C 2-6 It means that the group may have 2 to 6 (inclusive) carbon atoms. The alkynyl group may be unsubstituted or substituted with one or more substituents.

[0025] The term "aryl" refers to a monocyclic, bicyclic, tricyclic or polycyclic group of 6-20 carbons, wherein 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); and wherein 0, 1, 2, 3 or 4 atoms of each ring may be substituted with a substituent. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, etc.

[0026] The term "cycloalkyl" as used herein refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons, or 3-10 ring carbons, or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Cycloalkyl groups may include 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 spirocycles (e.g., spirobicycles 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.

[0027] The term "cycloalkenyl" as used herein means a partially unsaturated cyclic hydrocarbon group having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. As a partially unsaturated cyclic hydrocarbon group, the cycloalkenyl group may have any degree of unsaturation, provided that one or more double bonds are present in the ring, the rings in the ring system are not aromatic, and the cycloalkenyl group is generally not fully saturated. The cycloalkenyl group may include multiple condensed rings and / or bridged rings and / or spiro rings.

[0028] The term "heteroaryl" as used herein means a monocyclic, bicyclic, tricyclic or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from N, O and S, and at least one ring in the system is aromatic (but not necessarily a heteroatom-containing ring, such as tetrahydroisoquinolyl, such as tetrahydroquinolyl). Heteroaryl groups may be unsubstituted or substituted with one or more substituents. Examples of heteroaryl groups include thienyl, pyridyl, furanyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiadiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolylbenzothiophenyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazoline , 1,2-dihydrobenzo[b][1,4]oxathiine, dihydroisoindole, etc. In some embodiments, the heteroaryl group is selected from thienyl, pyridyl, furanyl, pyrazolyl, imidazolyl, dihydroisoindolyl, pyranyl, pyrazolyl, imidazolyl, dihydroisoindolyl, pyranyl, pyrazolyl, and pyrimidinyl. For the purpose of clarity, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to the carbonyl group is tertiary nitrogen (i.e., all three valence states are occupied by non-hydrogen substituents), such as one or more of the following: pyridones (e.g. or ), pyrimidone (e.g. ), pyridazinones (e.g. ), pyrazinones (e.g. ), and imidazolones (e.g. ), wherein each ring nitrogen adjacent to the carbonyl group is a tertiary nitrogen (ie, an oxo group (ie, "=O") is part of a heteroaryl ring).

[0029] The term "heterocyclyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic or 11-14 membered tricyclic ring system), 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, the heteroatoms being selected from O, N or S (e.g., 1-3, 1-6 or 1-9 heteroatoms selected from N, O or S and carbon atoms if monocyclic, bicyclic or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted with substituents. Examples of heterocyclyls include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyls may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heterocyclic groups 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]oct ... 1 .0]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, etc. Heterocyclyl also includes spirocycles (e.g., spirobicycles in which the two rings are connected 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, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undec ...2-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4 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, etc. The term "saturated" as used in this context means that there are only single bonds between the constituent ring atoms and the other available valencies occupied by hydrogen and / or other substituents as defined herein.

[0030] The term "heterocycloalkenyl" as used herein refers to a partially unsaturated ring system having 3-16 ring atoms (e.g., a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic system), 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, the heteroatoms being selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S corresponding to the monocyclic, bicyclic, or tricyclic ring, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl include, but are not limited to, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothienyl. As a partially unsaturated cyclic group, the heterocycloalkenyl group may have any degree of unsaturation, provided that there are one or more double bonds in the ring, none of the rings in the ring system is aromatic, and the heterocycloalkenyl group is not fully saturated overall. The heterocycloalkenyl group may include multiple fused rings and / or bridged rings and / or spiro rings.

[0031] As used herein, examples of aromatic rings include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, and the like.

[0032] As used herein, when a ring is described as "partially unsaturated", it is meant that the ring has one or more additional unsaturations (beyond the unsaturation attributed to the ring itself; for example, one or more double or triple bonds between atoms constituting the ring), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, etc.

[0033] For the avoidance of doubt, unless otherwise specified, rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, etc., as described herein) containing a sufficient number of ring atoms to form a bicyclic or higher order ring system (e.g., tricyclic, polycyclic ring system), it is understood that such rings and cyclic groups include those having fused rings, including: (i) the sites of fusion being on adjacent ring atoms (e.g., a [xx0] ring system, where 0 represents a zero atom bridge (e.g., ); (ii) the fusion site is located on a single ring atom (spiro-fused ring system) (e.g. ), or (iii) the fusion site is located on a contiguous array of ring atoms (all bridged ring systems with bridge length > 0) (e.g. ).

[0034] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to an organism to which it is administered and does not eliminate the biological activity and properties of the compound. In some cases, a pharmaceutically acceptable salt is 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, and the like. In some cases, a pharmaceutically acceptable salt is 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 or 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 by reacting with an amino acid to form a salt, such as arginine, lysine, and the like, or by other methods previously determined. There is no particular limitation on the pharmacologically acceptable salt, as long as it can be used in medicine. Examples of salts formed with bases of the compounds described herein include the following: salts formed with inorganic bases, such as sodium, potassium, magnesium, calcium and aluminum bases; salts formed with organic bases (such as methylamine, ethylamine and ethanolamine); salts formed with basic amino acids such as lysine and ornithine; and ammonium salts. The salts may be acid addition salts, specific examples of which are acid addition salts formed with: inorganic 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; acidic amino acids such as aspartic acid and glutamic acid.

[0035] In accordance with the present disclosure, compounds prepared by the methods described herein may be obtained as a single stereoisomer or a mixture of stereoisomers.

[0036] The compounds prepared by the methods described herein may also contain unnatural ratios of one, two, three or more atomic isotopes at one or more atoms that make up the compound. Unnatural ratios of isotopes may be defined as ranging from the amount that occurs naturally to the amount that makes up 100% of the target atom. For example, the compound may contain a radioactive isotope, such as tritium ( 3 H), iodine-125 ( 125 I), fluorine-18( 18 F), and / or carbon-14 (14C), or non-radioactive isotopes such as deuterium ( 2 H), carbon-13 ( 13 C), and / or nitrogen-15( 15 N). Such isotopic variants may provide uses beyond those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may have additional uses, including but not limited to as diagnostic and / or imaging agents, or as cytotoxic / radiotoxic therapeutic agents. In addition, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic properties, which may help enhance safety, tolerability, or effectiveness during treatment. All isotopic variants of the compounds described herein, whether or not radioactive, are intended to be included within the scope of the present invention.

[0037] The details of one or more implementations of the claimed subject matter are set forth in the accompanying drawings and the detailed description that follows.Other features and advantages of the invention will be apparent from the description, drawings, and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figures 1A-1C The comparative experiments investigating the compatibility of 5a and 6a with NH4OAc are shown. 1 HNMR and LCMS spectra.

[0039] Figure 2 The compound 101 is shown 1 H NMR spectrum.

[0040] Figure 3 The compound 102 1 H NMR spectrum.

[0041] Figure 4A The LC-MS spectrum of compound 102 is shown. Figure 4B A powder of Compound 102 is shown.

[0042] Figure 5A-5CC The compounds synthesized in Examples 7-45 are shown 1 H NMR, 13 C NMR, 19F NMR, and NOESY NMR. DETAILED DESCRIPTION

[0043] The present disclosure features methods for preparing chemical entities (e.g., compounds or pharmaceutically acceptable salts thereof) containing tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one that inhibit epidermal growth factor receptor (EGFR, ERBB1) and / or human epidermal growth factor receptor 2 (HER2, ERBB2) and synthetic intermediates that can be used to prepare the chemical entities. The methods include, for example, improved synthetic methods for compounds of formula (I) described herein.

[0044] Preparation of compounds of formula (I):

[0045] In one aspect, the disclosure features a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising contacting a compound of formula (II) with a compound of formula (III),

[0046]

[0047]

[0048] Among them, Y, Z, R 1c , R 2a , R 2b , R 3a , R 3b , R 4 , Ring A and Ring C may be defined as anywhere in this document. For example:

[0049] Y is selected from -OH or -NH2;

[0050] Z is selected from

[0051] –C(=O)H; or

[0052] -CH(R)2, wherein each R is independently selected from: halogen, alkoxy, OH, or SO3M (M = Li, Na, K or NH4 + ), provided that, when one R is OH, the other R cannot be halogen, alkoxy, or OH;

[0053] R 1c Selected from H and R d ;

[0054] R 2a , R 2b , R 3a and R 3b Each of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by 1 to 6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g replace;

[0055] Variable R 2a , R 2b , R 3a and R 3b Two of them, together with the ring B atoms to which they are attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

[0056] · wherein 0-2 of the ring atoms are independently selected heteroatoms (when -N(R 1c )- forms part of a fused saturated or unsaturated ring, then in -N(R 1c )-, wherein each of the independently selected heteroatoms is selected from: N, NH, N(R d ), O, and S(O) 0-2 ;as well as

[0057] wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally independently selected from oxo, R c , and R W substituted with 1 to 4 substituents;

[0058] Ring A is R g ;

[0059] R 4 Selected from: H and R d ;

[0060] Ring C is selected from:

[0061] ·

[0062] · in:

[0063] οEach X b Independently for X, R c , or H; and

[0064] οEach X a independently selected from: H, halogen; cyano; optionally 1-6 independently selected R a Substituted 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; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5;

[0065] · 2-pyridyl or 3-pyridyl, each of which is optionally substituted by X, and further optionally substituted by 1-4 R c replace;

[0066] 2-pyridonyl or 4-pyridonyl, each of which is optionally substituted by X, and further optionally substituted by 1 to 4 R c substituted, wherein the ring nitrogen atom is optionally replaced by R d replace;

[0067] A heteroaryl group comprising 6 ring atoms, wherein 2 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4R c replace;

[0068] A heteroaryl group comprising 5 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4 R c replace;

[0069] A bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents;

[0070] Bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is substituted by X and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents;

[0071] A heterocyclic or heterocyclic alkenyl group comprising 5 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is substituted by X, and is optionally independently selected from oxo, each R 7 substituted with 1 to 4 substituents of; and

[0072] ·C 10 or C 14 Aryl, which is substituted by X and optionally by 1-4 R 7 replace;

[0073] X is X*, wherein X* is selected from halogen, triflate, tosylate, or mesylate; or

[0074] X is X 1 ;

[0075] Each R 7 R are independently selected c ; n is 0, 1, 2, or 3;

[0076] X 1 Selected from: (a) – OL 1 -R 5 ; and (b)

[0077] L 1 and L 2 independently selected from: a bond, and optionally 1-6 R a Substituted C 1-10 Alkylene;

[0078] R 5 Selected from:

[0079] A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace;

[0080] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0081] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R csubstituted with 1 to 4 substituents;

[0082] · Wherein ring D is a heterocyclylene or heterocycloalkenylene group including 3-10 ring atoms, wherein 0-2 ring atoms (excluding those with R X 0-2 ring atoms other than the ring nitrogen atom to which the bond is attached) are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally each independently selected from oxo and -R c substituted with 1 to 4 substituents;

[0083] -S(O) 0-2 (C 1-6 alkyl), which is optionally substituted by 1 to 6 R a replace;

[0084] -R W

[0085] -R g2 -R W or -R g2 -R Y ;

[0086] -L 5 -R g ;as well as

[0087] -L 5 -R g2 -R W or –L 5 -R g2 -R Y ;

[0088] The condition is that when L 1 When is a key, then R 5 Not optionally 1-6 R a ;-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Substituted -S(O) 0-2 (C 1-6 alkyl);

[0089] R 6 Selected from:

[0090] H;

[0091] ·halogen;

[0092] -OH;

[0093] -NR e R f ;

[0094] -R g ;

[0095] -R w

[0096] -L 6 -R g ;

[0097] -R g2 -R W or -R g2 -R Y ;

[0098] -L 6 -R g2 -R W or -L 6 -R g2 -R Y ;as well as

[0099] -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a replace;

[0100] L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-;as well as

[0101] R W For –L W -W,

[0102] Where 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 *, where the asterisk (*) indicates the point of attachment to W, and

[0103] W is C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10Allenyl, each of which is optionally substituted by 1 to 3 R a and further optionally substituted by R g Substitution, where W is via sp 2 or sp hybridized carbon atoms connected to L W , thereby obtaining an α,β-unsaturated system; and

[0104] R X is C(=O)(C 1-6 Alkyl) or S(O)2(C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a Replacement; and

[0105] R Y Selected from: -R g and-(L g ) g -R g ;

[0106] R a Each occurrence is independently selected from: -OH; -halogen; -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;

[0107] R b Each occurrence is independently: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R a replace;

[0108] L b Each occurrence is independently: C(=O); C(=O)O; S(O) 1-2 ; C(=O)NH*; C(=O)NR d *;S(O) 1- 2NH*; or S(O) 1-2 N(R d )*, where the asterisk (*) indicates b The connection point;

[0109] R cEach occurrence is independently selected from: halogen; cyano; optionally 1-6 independently selected R a Substituted C 1-10 Alkyl; C 3-5 Cycloalkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy, which is optionally substituted by C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution; 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 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5;

[0110] R d Each occurrence is independently selected from: optionally 1-3 independently selected R a or R g Substituted 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 Alkoxy;

[0111] R e and R f Each occurrence is independently selected from: H; C 3-5 Cycloalkyl, which is optionally substituted by 1-3 C 1-3 Alkyl group substituted; heterocyclic group including 3-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , the heterocyclic group is optionally independently selected from oxo and R c substituted with 1 to 4 substituents; C 1-6 Alkyl, which is optionally substituted by 1-3 substituents, each of which is independently selected from NR'R", -OH, C 1-6 Alkoxy, C1-6 Haloalkoxy, and halogen; -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 Alkoxy;

[0112] R g Each occurrence is independently selected from:

[0113] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0114] A heterocyclic or heterocyclic alkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0115] A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c Replacement; and

[0116] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0117] L g Each occurrence is independently selected from: -O-, -NH-, -NR d 、-S(O) 0-2 , C(O) and optionally 1-3 R a Substituted C 1-3 Alkylene;

[0118] Each g is independently 1, 2, or 3;

[0119] Each R g2 R g group; and

[0120] R' and R" are independently selected at each occurrence from: H; -OH; and C1-4 alkyl.

[0121] In another aspect, the disclosure features a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising contacting a compound of formula (II) with a compound of formula (III),

[0122]

[0123] in

[0124] Y is selected from -OH or -NH2;

[0125] Z is selected from

[0126] –C(=O)H; or

[0127] -CH(R)2, wherein each R is independently selected from: halogen, alkoxy, OH, or SO3M (M = Li, Na, K, or NH4 + ), provided that, when one R is OH, the other R cannot be halogen, alkoxy, or OH;

[0128] R 1c Selected from H, and R d ;

[0129] R 2a , R 2b , R 3a , and R 3b Each of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by 1 to 6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g replace;

[0130] Variable R 2a , R 2b , R 3a , and R 3b Two of them, together with the ring B atoms to which they are attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

[0131] · wherein 0-2 ring atoms in the ring atoms are each independently selected heteroatoms (when -N(R 1c)- forms part of the fused saturated or unsaturated ring, except for -N(R 1c )-), wherein each of the independently selected heteroatoms is selected from: N, NH, N(R d ), O, and S(O) 0-2 ;as well as

[0132] wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally independently selected from oxo, R c , and R W substituted with 1 to 4 substituents;

[0133] Ring A is R g ;

[0134] R 4 Selected from: H and R d ;

[0135] Ring C is selected from:

[0136] ·

[0137] · in:

[0138] οEach X b Independently for X, R c , or H; and

[0139] οEach X a independently selected from: H, halogen; cyano; optionally 1-6 independently selected R a Substituted 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; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5;

[0140] · 2-pyridyl or 3-pyridyl, each of which is optionally substituted by X, and further optionally substituted by 1-4 R c replace;

[0141] 2-pyridonyl or 4-pyridonyl, each of which is optionally substituted by X, and further optionally substituted by 1 to 4 R c substituted, wherein the ring nitrogen atom is optionally replaced by R d replace;

[0142] A heteroaryl group comprising 6 ring atoms, wherein 2 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4R c replace;

[0143] A heteroaryl group comprising 5 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4 R c replace;

[0144] A bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents;

[0145] Bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is optionally substituted by X and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents;

[0146] A heterocyclic or heterocyclic alkenyl group comprising 5 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents of; and

[0147] ·C 10 or C 14 Aryl, which is optionally substituted by X, and optionally substituted by 1-4 R 7 replace;

[0148] · in

[0149] οma is 0, 1, 2 or 3;

[0150] οR 8A Independently selected from: halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, 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 The alkoxy group is optionally substituted, independently of one another, 1, 2, or 3 times by halogen and optionally substituted once by: hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl or phenyl, which is optionally substituted by one or more R 5A replace;

[0151] οR 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0152] οR 9A and R 10A Each independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, wherein the phenyl groups are independently optionally replaced by R 5A Replace one or more times; or R 9A and R 10A Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic ring, which optionally contains one additional heteroatom or heteroatom-containing group selected from O, NH or S, and which may be independently optionally replaced by R 5A Replace one or more times;

[0153] οR 11A Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C1-4 Haloalkyl or C 3-6 Halogenated cycloalkyl;

[0154] · in

[0155] οR 5B C 2-5 Alkyl, which is optionally substituted by: hydroxy, C 1-4 Alkoxy, R 7B R 8B N-, or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times; or

[0156] οR 5B For R 6B -CH2-;

[0157] οR 6B Selected from or

[0158] οR 7B and R 8B Independently selected from C 1-3 Alkyl, C 1-3 haloalkyl; or

[0159] οR 7B and R 8B Together with the nitrogen atom to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring optionally contains an additional heteroatom or a heteroatom-containing group selected from O and -NH-, NH(C 1-3 alkyl);

[0160] οR 9B Selected from hydrogen, C 1-4 Alkyl, or C 1-3 Haloalkyl;

[0161] οR 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0162] · in

[0163] οR 4C is selected from hydrogen or methyl;

[0164] οR 6C Selected from hydrogen, C 1-3 Alkyl, C 1-3Haloalkyl;

[0165] οnc is 0 or 1;

[0166] οX C NR 7C or O;

[0167] οY C NR 8C or O;

[0168] οR 7C is methyl;

[0169] οR 8C Selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl;

[0170] οR 5C is selected from hydrogen or methyl, wherein R 5C Connect to the containing X C and Y C Any carbon atom of a ring;

[0171] οmc is 0, 1, 2 or 3;

[0172] · in

[0173] οR 4D is selected from hydrogen or methyl;

[0174] οR 5D Selected from: (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, 3-azetidinyl, each of which is optionally replaced by R 6D substituted 1, 2, or 3 times, and wherein each azetidinyl group is replaced on the nitrogen by R 8D replace; or

[0175] οR 5D Selected from

[0176] οR 6D Selected from Fluorine or C 1-3 alkyl;

[0177] omd is selected from 0, 1, 2, or 3;

[0178] οR 7D Selected from hydrogen, C 1-3 Alkyl, or C 1-3 Haloalkyl;

[0179] οX D NR 8D or O;

[0180] οR 8D Selected from C 1-3 Alkyl or C 2-3 Haloalkyl;

[0181] X is X*, wherein X* is selected from halogen, triflate, tosylate, or mesylate; or

[0182] X is X 1 ;

[0183] Each R 7 R are independently selected c ; n is 0, 1, 2, or 3;

[0184] X 1 Selected from: (a) – OL 1 -R 5 ; and (b)

[0185] L 1 and L 2 independently selected from: a bond, and optionally 1-6 R a Substituted C 1-10 Alkylene;

[0186] R5 is selected from:

[0187] A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace;

[0188] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0189] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0190] · Wherein ring D is a heterocyclylene or heterocycloalkenylene group including 3-10 ring atoms, wherein 0-2 ring atoms (excluding those with R X 0-2 ring atoms other than the ring nitrogen atom to which the bond is attached) are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2, and wherein the heterocyclylene or heterocycloalkenylene is optionally each independently selected from oxo and -R c substituted with 1 to 4 substituents;

[0191] -S(O) 0-2 (C 1-6 alkyl), which is optionally substituted by 1 to 6 R a replace;

[0192] -R W

[0193] -R g2 -R W or -R g2 -R Y ;

[0194] -L 5 -R g ;as well as

[0195] -L 5 -R g2 -R W or –L 5 -R g2 -R Y ;

[0196] The condition is that when L 1 When is a key, then R 5 Not optionally 1-6 R a ;-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Substituted -S(O) 0-2 (C 1-6 alkyl);

[0197] R 6 Selected from:

[0198] H;

[0199] ·halogen;

[0200] -OH;

[0201] -NR e R f ;

[0202] -R g ;

[0203] -R w

[0204] -L 6 -R g ;

[0205] -R g2 -R W or -R g2 -R Y ;

[0206] -L 6 -R g2 -R W or -L 6 -R g2 -R Y ;as well as

[0207] -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a replace;

[0208] L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-;as well as

[0209] R W For –L W -W,

[0210] Where 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 *, where the asterisk (*) indicates the point of attachment to W, and

[0211] W is C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10 Allenyl, each of which is optionally substituted by 1 to 3 R a and further optionally substituted by R g Substitution, where W is via sp 2 or sp hybridized carbon atoms connected to L W , thereby obtaining an α,β-unsaturated system; and

[0212] R X is C(=O)(C 1-6 Alkyl) or S(O)2(C1-6 alkyl), each of which is optionally substituted by 1 to 6 R a Replacement; and

[0213] R Y Selected from: -R g and-(L g ) g -R g ;

[0214] R a Each occurrence is independently selected from: -OH; -halogen; -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;

[0215] R b Each occurrence is independently: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R a replace;

[0216] L b Each occurrence is independently: C(=O); C(=O)O; S(O) 1-2 ; C(=O)NH*; C(=O)NR d *;S(O) 1- 2NH*; or S(O) 1-2 N(R d )*, where the asterisk (*) indicates b The connection point;

[0217] R c Each occurrence is independently selected from: halogen; cyano; optionally 1-6 independently selected R a Substituted C 1-10 Alkyl; C 3-5 Cycloalkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy, which is optionally substituted by C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution; C 1-4 Haloalkoxy; -S(O) 1-2 (C1-4 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;

[0218] R d Each occurrence is independently selected from: optionally 1-3 independently selected R a or R g Substituted 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 Alkoxy;

[0219] R e and R f Each occurrence is independently selected from: H; C 3-5 Cycloalkyl, which is optionally substituted by 1-3 C 1-3 Alkyl group substituted; heterocyclic group including 3-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , which are optionally independently selected from oxo and R c substituted with 1 to 4 substituents; C 1-6 Alkyl, which is optionally substituted by 1-3 substituents, each of which is independently selected from NR'R", -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and halogen; -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 Alkoxy;

[0220] R g Each occurrence is independently selected from:

[0221] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0222] A heterocyclic or heterocyclic alkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0223] A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace;

[0224] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0225] L g Each occurrence is independently selected from: -O-, -NH-, -NR d 、-S(O) 0-2 , C(O) and optionally 1-3 R a Substituted C 1-3 Alkylene;

[0226] Each g is independently 1, 2, or 3;

[0227] Each R g2 R g group; and

[0228] R' and R" are independently selected at each occurrence from: H; -OH; and C 1-4 alkyl.

[0229] In another aspect, the disclosure features a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising contacting a compound of formula (II) with a compound of formula (III),

[0230]

[0231] in

[0232] Y is selected from -OH or -NH2;

[0233] Z is selected from

[0234] –C(=O)H; or

[0235] -CH(R)2, wherein each R is independently selected from: halogen, alkoxy, OH, or SO3M (M = Li, Na, K, or NH4 + ), provided that, when one R is OH, the other R cannot be halogen, alkoxy, or OH;

[0236] R 1c Selected from H, and R d ;

[0237] R 2a , R 2b , R 3a , and R 3b Each of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by 1 to 6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g replace;

[0238] Variable R 2a , R 2b , R 3a , and R 3b Two of them, together with the ring B atoms to which they are attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

[0239] · wherein 0-2 of the ring atoms are independently selected heteroatoms (when -N(R 1c )- forms part of the fused saturated or unsaturated ring, except for -N(R 1c )-), wherein each of the independently selected heteroatoms is selected from: N, NH, N(R d ), O, and S(O) 0-2 ;as well as

[0240] wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally independently selected from oxo, R c , and R Wsubstituted with 1 to 4 substituents;

[0241] Ring A is R g ;

[0242] R 4 Selected from: H and R d ;

[0243] Ring C is selected from:

[0244] ·

[0245] · in:

[0246] οEach X b Independently for X, R c , or H; and

[0247] οEach X a independently selected from: H, halogen; cyano; optionally 1-6 independently selected R a Substituted 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; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5;

[0248] · 2-pyridyl or 3-pyridyl, each of which is optionally substituted by X, and further optionally substituted by 1-4 R c replace;

[0249] 2-pyridonyl or 4-pyridonyl, each of which is optionally substituted by X, and further optionally substituted by 1 to 4 R c substituted, wherein the ring nitrogen atom is optionally replaced by R d replace;

[0250] A heteroaryl group comprising 6 ring atoms, wherein 2 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4 R c replace;

[0251] A heteroaryl group comprising 5 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4 R c replace;

[0252] A bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents;

[0253] Bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is optionally substituted by X and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents;

[0254] A heterocyclic or heterocyclic alkenyl group comprising 5 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents of; and

[0255] ·C 10 or C 14 Aryl, which is optionally substituted by X, and optionally substituted by 1-4 R 7 replace;

[0256] X is X*, wherein X* is selected from halogen, triflate, tosylate, or mesylate; or

[0257] X is X 1 ;

[0258] Each R 7 R are independently selected c ; n is 0, 1, 2, or 3;

[0259] X 1 Selected from: (a) – OL 1 -R 5 ; and (b)

[0260] L1 and L 2 independently selected from: a bond, and optionally 1-6 R a Substituted C 1-10 Alkylene;

[0261] R 5 Selected from:

[0262] A heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace;

[0263] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0264] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0265] · Wherein ring D is a heterocyclylene or heterocycloalkenylene group comprising 3-10 ring atoms, wherein 0-2 ring atoms (excluding those with R X 0-2 ring atoms other than the ring nitrogen atom to which the bond is attached) are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally each independently selected from oxo and -R c substituted with 1 to 4 substituents;

[0266] -S(O) 0-2 (C 1-6 alkyl), which is optionally substituted by 1 to 6 R a replace;

[0267] -R W

[0268] -R g2 -R W or -R g2 -R Y ;

[0269] -L 5 -R g ;as well as

[0270] -L 5 -Rg2 -R W or –L 5 -R g2 -R Y ;

[0271] The condition is that when L 1 When is a key, then R 5 Not optionally 1-6 R a ;-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Substituted -S(O) 0-2 (C 1-6 alkyl);

[0272] R 6 Selected from:

[0273] H;

[0274] ·halogen;

[0275] -OH;

[0276] -NR e R f ;

[0277] -R g ;

[0278] -R w

[0279] -L 6 -R g ;

[0280] -R g2 -R W or -R g2 -R Y ;

[0281] -L 6 -R g2 -R W or -L 6 -R g2 -R Y ;as well as

[0282] -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a replace;

[0283] L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-;as well as

[0284] R W For –L W -W,

[0285] Where 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 *, where the asterisk (*) indicates the point of attachment to W, and

[0286] W is C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10 Allenyl, each of which is optionally substituted by 1 to 3 R a and further optionally substituted by R g Substitution, where W is via sp 2 or sp hybridized carbon atoms connected to L W , thereby obtaining an α,β-unsaturated system; and

[0287] R X is C(=O)(C 1-6 Alkyl) or S(O)2(C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a Replacement; and

[0288] R Y Selected from: -R g and-(L g ) g -R g ;

[0289] R a Each occurrence is independently selected from: -OH; -halogen; -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;

[0290] R b Each occurrence is independently: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R a replace;

[0291] L b Each occurrence is independently: C(=O); C(=O)O; S(O) 1-2 ; C(=O)NH*; C(=O)NR d *;S(O) 1- 2NH*; or S(O) 1-2 N(R d )*, where the asterisk (*) indicates b The connection point;

[0292] R c Each occurrence is independently selected from: halogen; cyano; optionally 1-6 independently selected R a Substituted C 1-10 Alkyl; C 3-5 Cycloalkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy, which is optionally substituted by C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution; 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 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5;

[0293] R d Each occurrence is independently selected from: optionally 1-3 independently selected R a or R g Substituted C 1-6 Alkyl; -C(O)(C 1-4 alkyl); -C(O)O(C 1-4alkyl); -CONR'R"; -S(O) 1-2 NR'R";-S(O) 1-2 (C 1-4 alkyl); -OH; and C 1-4 Alkoxy;

[0294] R e and R f Each occurrence is independently selected from: H; C 3-5 Cycloalkyl, which is optionally substituted by 1-3 C 1-3 Alkyl group substituted; heterocyclic group including 3-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , which are optionally independently selected from oxo and R c substituted with 1 to 4 substituents; C 1-6 Alkyl, which is optionally substituted by 1-3 substituents, each of which is independently selected from NR'R", -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and halogen; -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 Alkoxy;

[0295] R g Each occurrence is independently selected from:

[0296] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0297] A heterocyclic or heterocyclic alkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0298] A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O)0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace;

[0299] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0300] L g Each occurrence is independently selected from: -O-, -NH-, -NR d 、-S(O) 0-2 , C(O) and optionally 1-3 R a Substituted C 1-3 Alkylene;

[0301] Each g is independently 1, 2, or 3;

[0302] Each R g2 R g group; and

[0303] R' and R" are independently selected at each occurrence from: H; -OH; and C 1-4 alkyl.

[0304] In another aspect, the disclosure features a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising contacting a compound of formula (II) with a compound of formula (III),

[0305]

[0306]

[0307] in

[0308] Y is selected from -OH or -NH2;

[0309] Z is selected from

[0310] –C(=O)H; or

[0311] -CH(R)2, wherein each R is independently selected from: halogen, alkoxy, OH, or SO3M (M = Li, Na, K, or NH4 + ), provided that, when one R is OH, the other R cannot be halogen, alkoxy, or OH;

[0312] R 1c Selected from H, and R d ;

[0313] R 2a , R 2b , R 3a , and R 3bEach of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by: 1-6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g ;

[0314] Variable R 2a , R 2b , R 3a , and R 3b Two of them, together with the ring B atoms to which they are attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

[0315] · wherein 0-2 of the ring atoms are independently selected heteroatoms (when -N(R 1c )- forms part of the fused saturated or unsaturated ring, except -N(R 1c )-), wherein each of the independently selected heteroatoms is selected from: N, NH, N(R d ), O, and S(O) 0-2 ;as well as

[0316] wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally independently selected from oxo, R c , and R W substituted with 1 to 4 substituents;

[0317] Ring A is R g ;

[0318] R 4 Selected from: H and R d ;

[0319] Ring C is selected from:

[0320] · in

[0321] οma is 0, 1, 2 or 3;

[0322] οR 8A Independently selected from: halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, 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 The alkoxy group is optionally substituted, independently of one another, 1, 2, or 3 times by halogen and optionally substituted once by: hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl or phenyl, which is optionally substituted by one or more R 5A replace;

[0323] οR 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0324] οR 9A and R 10A Each independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, wherein the phenyl groups are independently optionally replaced by R 5A Replace one or more times; or R 9A and R 10A Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic ring, which optionally contains one additional heteroatom or heteroatom-containing group selected from O, NH or S, and which may be independently optionally replaced by R 5A Replace one or more times;

[0325] οR 11A Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 Halogenated cycloalkyl;

[0326] · in

[0327] οR 5B C 2-5Alkyl, which is optionally substituted by: hydroxy, C 1-4 Alkoxy, R 7B R 8B N-, or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times; or

[0328] οR 5B For R 6B -CH2-;

[0329] οR 6B Selected from or

[0330] οR 7B and R 8B Independently selected from C 1-3 Alkyl, C 1-3 haloalkyl; or

[0331] οR 7B and R 8B Together with the nitrogen atom to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring optionally contains an additional heteroatom or a heteroatom-containing group selected from O and -NH-, NH(C 1-3 alkyl);

[0332] οR 9B Selected from hydrogen, C 1-4 Alkyl, or C 1-3 Haloalkyl;

[0333] οR 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0334] · in

[0335] οR 4C is selected from hydrogen or methyl;

[0336] οR 6C Selected from hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl;

[0337] οnc is 0 or 1;

[0338] οX C NR 7C or O;

[0339] οYC NR 8C or O;

[0340] οR 7C is methyl;

[0341] οR 8C Selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl;

[0342] οR 5C is selected from hydrogen or methyl, wherein R 5C Connect to the containing X C and Y C Any carbon atom of a ring;

[0343] οmc is 0, 1, 2 or 3;

[0344] · in

[0345] οR 4D is selected from hydrogen or methyl;

[0346] οR 5D Selected from: (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, 3-azetidinyl, each of which is optionally replaced by R 6D substituted 1, 2, or 3 times, and wherein each azetidinyl group is replaced on the nitrogen by R 8D replace; or

[0347] οR 5D Selected from

[0348] οR 6D Selected from Fluorine or C 1-3 alkyl;

[0349] omd is selected from 0, 1, 2, or 3;

[0350] οR 7D Selected from hydrogen, C 1-3 Alkyl, or C 1-3 Haloalkyl;

[0351] οX D NR 8D or O;

[0352] οR 8D Selected from C 1-3 Alkyl or C 2-3 Haloalkyl;

[0353] X is X*, wherein X* is selected from halogen, triflate, tosylate, or mesylate; or

[0354] X is X 1 ;

[0355] Each R 7 R are independently selected c ; n is 0, 1, 2, or 3;

[0356] X 1 Selected from: (a) – OL 1 -R 5 ; and (b)

[0357] L 1 and L 2 independently selected from: a bond, and optionally 1-6 R a Substituted C 1-10 Alkylene;

[0358] R 5 Selected from:

[0359] A heteroaryl group comprising 5-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace;

[0360] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0361] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0362] · Wherein ring D is a heterocyclylene or heterocycloalkenylene group including 3-10 ring atoms, wherein 0-2 ring atoms (excluding those with R X 0-2 ring atoms other than the ring nitrogen atom to which the bond is attached) are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally each independently selected from oxo and -R c substituted with 1 to 4 substituents;

[0363] -S(O) 0-2 (C 1-6 alkyl), which is optionally substituted by 1 to 6 R areplace;

[0364] -R W

[0365] -R g2 -R W or -R g2 -R Y ;

[0366] -L 5 -R g ;as well as

[0367] -L 5 -R g2 -R W or –L 5 -R g2 -R Y ;

[0368] The condition is that when L 1 When is a key, then R 5 Not optionally 1-6 R a ;-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Substituted -S(O) 0-2 (C 1-6 alkyl);

[0369] R 6 Selected from:

[0370] H;

[0371] ·halogen;

[0372] -OH;

[0373] -NR e R f ;

[0374] -R g ;

[0375] -R w

[0376] -L 6 -R g ;

[0377] -R g2 -R W or -R g2 -R Y ;

[0378] -L 6 -R g2 -R W or -L 6 -R g2 -R Y ;as well as

[0379] -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a replace;

[0380] L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-;as well as

[0381] R W For –L W -W,

[0382] Where 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 *, where the asterisk (*) indicates the point of attachment to W, and

[0383] W is C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10 Allenyl, each of which is optionally substituted by 1 to 3 R a and further optionally substituted by R g Substitution, where W is via sp 2 or sp hybridized carbon atoms connected to L W , thereby providing an α,β-unsaturated system; and

[0384] R X is C(=O)(C 1-6 Alkyl) or S(O)2(C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a Replacement; and

[0385] R Y Selected from: -R g and-(L g ) g -R g ;

[0386] R a Each occurrence is independently selected from: -OH; -halogen; -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;

[0387] R b Each occurrence is independently: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R a replace;

[0388] L b Each occurrence is independently: C(=O); C(=O)O; S(O) 1-2 ; C(=O)NH*; C(=O)NR d *;S(O) 1- 2NH*; or S(O) 1-2 N(R d )*, where the asterisk (*) indicates b The connection point;

[0389] R c Each occurrence is independently selected from: halogen; cyano; optionally 1-6 independently selected R a Substituted C 1-10 Alkyl; C 3-5 Cycloalkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy, which is optionally substituted by C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution; 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 1-10alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5;

[0390] R d Each occurrence is independently selected from: optionally 1-3 independently selected R a or R g Substituted 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 Alkoxy;

[0391] R e and R f Each occurrence is independently selected from: H; C 3-5 Cycloalkyl, which is optionally substituted by 1-3 C 1-3 Alkyl group substituted; heterocyclic group including 3-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , the heterocyclic group is optionally independently selected from oxo and R c substituted with 1 to 4 substituents; C 1-6 Alkyl, which is optionally substituted by 1-3 substituents, each of which is independently selected from NR'R", -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and halogen; -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 Alkoxy;

[0392] R g Each occurrence is independently selected from:

[0393] ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0394] A heterocyclic or heterocyclic alkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally independently selected from oxo and R c substituted with 1 to 4 substituents;

[0395] A heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c Replacement; and

[0396] ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace;

[0397] L g Each occurrence is independently selected from: -O-, -NH-, -NR d 、-S(O) 0-2 , C(O) and optionally 1-3 R a Substituted C 1-3 Alkylene;

[0398] Each g is independently 1, 2, or 3;

[0399] Each R g2 R g group; and

[0400] R' and R" are independently selected at each occurrence from: H; -OH; and C 1-4 alkyl.

[0401] Ring A in formula (I) may be as defined anywhere herein.

[0402] The variable R in formula (I) 1c , R 2a , R 2b , R 3a , and R 3b May be as defined anywhere herein.

[0403] Ring C in formula (I) may be as defined anywhere herein.

[0404] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is performed in the presence of a nitrogen source.

[0405] In certain embodiments, the nitrogen source is ammonia or a derivative thereof.

[0406] In certain embodiments, the nitrogen source is in the form of a salt.

[0407] In certain embodiments, the nitrogen source is an ammonium salt.

[0408] Non-limiting examples of the nitrogen source include: NH4OAc, NH3·H2O, NH4CO2H, NH4OBz, NH4Cl, (NH4)2SO4, (NH4)2HPO4, NH4H2PO4, NH4OTf, NH4HCO3, (NH4)2CO3, NH4CO2CF3, NH4BF4, diammonium hydrogen citrate, NH4Br, ammonium carbamate, or any combination thereof. Other examples include primary alkyl and cycloalkylamines, such as (C1-C6 alkyl)-NH2 and (C3-C6 cycloalkyl)-NH2.

[0409] For example, the nitrogen source may be NH4OAc.

[0410] 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.

[0411] 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.

[0412] 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.

[0413] For example, the molar ratio of the nitrogen source to the compound of formula (III) may be about 5:1.

[0414] In some embodiments, an equal amount or excess of a compound of formula (III) relative to a compound of formula (II) may be used. In certain embodiments, the molar ratio of the compound of formula (III) relative 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 certain embodiments, the molar ratio of the compound of formula (III) relative 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.

[0415] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a suitable solvent (eg, a suitable organic solvent). A mixture of solvents (eg, organic solvents) may also be used.

[0416] In some embodiments, the solvent is an aprotic solvent.

[0417] In some embodiments, the aprotic solvent is a non-polar aprotic solvent.

[0418] In certain 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 point aromatic naphtha. For example, the aromatic hydrocarbon solvent may be toluene.

[0419] In certain embodiments, the non-polar aprotic solvent is a non-aromatic hydrocarbon solvent. Non-aromatic hydrocarbon solvents include, but are not limited to, heptane, hexane, cyclohexane, methylcyclohexane, heptane, and isooctane.

[0420] In some embodiments, the aprotic solvent is a polar aprotic solvent. Polar aprotic solvents include, but are not limited to, acetone, dichloromethane, cyclopentanone, methyl isobutyl ketone, methyl ethyl ketone, EtOAc, isopropyl acetate, isobutyl acetate, diacetin, 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-dimethyl isosorbide, and chloroform.

[0421] In certain embodiments, the aprotic solvent is an ether solvent, such as tetrahydrofuran, dimethoxyethane, dioxane, CPME, 1,4-dioxane, or THF.

[0422] In certain embodiments, the aprotic solvent is acetonitrile or DMSO.

[0423] In some embodiments, the solvent is a protic solvent, such as a polar protic solvent, such as acetic acid.

[0424] Other suitable protic (polar) solvents include: t-pentanol, t-butanol, n-propanol, ethanol, methanol, water, i-propanol, n-BuOH, t-butanol, ethylene glycol, 1-butanol, i-pentanol, 1-heptanol, 1-octanol, and 1-propanol.

[0425] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a suitable mixture of two or more solvents, such as a mixture of two solvents, such as a mixture of one or more (e.g., one) aromatic hydrocarbon solvents and one or more (e.g., one) ether solvents, such as a mixture of toluene and dioxane (e.g., a 1:1 mixture of toluene and dioxane).

[0426] In some embodiments, 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 can easily determine suitable temperature using the methods described herein and knowledge in the art. Preferably, the reaction temperature is higher than ambient temperature, i.e., higher than 25 ° C, or higher than 35 ° C, or higher. For example, the suitable temperature for converting into the compound of formula (I) is a temperature equal to or less than the reflux temperature of the reaction solvent. In other embodiments, the suitable temperature for preparing the compound of formula (I) is a temperature lower than the reflux temperature of the reaction solvent.

[0427] In certain embodiments, 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).

[0428] In certain embodiments, contacting the compound of formula (II) with the compound of formula (III) is conducted at a temperature of about 90°C to 100°C (eg, 95°C).

[0429] In certain embodiments, 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; eg, 90°C).

[0430] In certain embodiments, 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).

[0431] In certain embodiments, contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 20°C to 80°C (eg, 20°C).

[0432] Using the methods described herein in conjunction with knowledge in the art, those skilled in the art can easily determine the appropriate time for converting a compound of formula (II) and a compound of formula (III) into a compound of formula (I). For example, the conversion can be performed until the conversion is substantially complete, as determined by HPLC. In some embodiments, for a compound of formula III, the time of substantial conversion is about 24 hours or less. In certain embodiments, the time of substantial conversion is less than 24 hours, for example, about 20, 18, 16, 14, 12, 10 or about 8 hours.

[0433] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of one or more additives. The additives include, but are not limited to, Na2SO4, H2O, H2SO4, acetic acid, formic acid, Bi(OTf)3, PPh3, NH4OH, NH4OAc, PPTS, PTSA, pyridine, or any combination thereof.

[0434] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is performed in a sealed container filled with air.

[0435] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is performed in a sealed container filled with an inert gas (eg, nitrogen).

[0436] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is performed in an open container.

[0437] In some embodiments, contacting the compound of formula (II) with the compound of formula (III) is performed in an open container connected to an inert gas (eg, nitrogen) manifold.

[0438] The method of any one of claims 1 to 48, wherein contacting the compound of formula (II) with the compound of formula (III) is carried out in the absence of an oxidizing agent; the oxidizing agent is, for example, a peroxyacid, such as m-CPBA.

[0439] Examples of compounds of Formula (I) that can be prepared by the methods described herein include, but are not limited to, compounds described generally or specifically in the following documents: PCT / US2021 / 051504, filed on September 22, 2021; PCT / US2021 / 054191, filed on October 8, 2021; and PCT / US2021 / 057348, filed on October 8, 2021.

[0440] Compounds of formula (II) and their preparation

[0441] In some embodiments, the method further comprises contacting a compound of formula (IIa) with a compound of formula (IIb) to obtain the compound of formula (II):

[0442]

[0443] In some embodiments, the compound of formula (IIb) is prepared by contacting a chlorinating agent with a compound of formula (IId):

[0444]

[0445] 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.

[0446] For example, the compound of formula (IIb) can be prepared by contacting a compound of formula (IIc) with a compound of formula (IId):

[0447]

[0448] In some embodiments, Y in formula (II) is OH.

[0449] In some embodiments, Y in formula (II) is NH2.

[0450] Ring A may be as defined anywhere herein.

[0451] Variable R 1c , R 2a , R 2b , R3a , and R 3b May be as defined anywhere herein.

[0452] Exemplary compounds of formula (II) are:

[0453] Compounds of formula (III) and their preparation

[0454] In some embodiments, Z in formula (III) is -C(=O)H.

[0455] In some embodiments, Z in formula (III) is -CH(R)2-. In some embodiments, each R is a halogen (e.g., bromine). For example, Z can be -CH(Br)2. In other embodiments, each R is an alkoxy group (e.g., OCH3). For example, Z can be -CH(OCH3)2. In other embodiments, one R is OH and the other R is SO3 - M + (M+=Li, Na, K, or NH4 + ). For example, Z may be –CH(OCH3)(SO3 - Na + ).

[0456] In some embodiments of formula (III), X is X*. In certain embodiments, formula (III) is further substituted by a substituent reactive in a Sonogashira coupling reaction, such as I, Br, Cl, F, triflate, toluenesulfonate, -C(O)Cl, and arylsulfonium triflate, such as triarylsulfonium triflate, alkyl (diaryl) sulfonium triflate, and aryl (dialkyl) sulfonium triflate. In some embodiments, X* is halogen, such as bromine.

[0457] In some embodiments of formula (III), X is X 1 .

[0458] In certain embodiments, X 1 for

[0459] In certain embodiments, when formula (III) is When replaced, L 2 is the key.

[0460] In certain embodiments, when formula (III) is When replaced, R 6 For-R g2 -R W .

[0461] In certain of the foregoing embodiments, –R 6 for wherein ring D is a heterocyclylene group comprising 3-10 ring atoms, wherein 0-2 ring atoms (excluding those with R W 0-2 ring atoms other than the ring nitrogen atom to which the bond is attached) are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene radicals are optionally each independently selected from oxo and -R c substituted with 1 to 3 substituents; optionally wherein -R 6 is a monocyclic heterocyclylene group comprising 3 to 10 ring atoms, as defined above, wherein the nitrogen atom is bonded to R W (For example Such as Such as ); optionally wherein -R 6 is a bicyclic heterocyclylene ring comprising 3 to 10 ring atoms, as defined above, wherein the nitrogen atom is bonded to R W (For example Such as Such as Such as ).

[0462] In certain of these embodiments, -R 6 for It is optionally replaced by 1-2 R c Substitution, wherein x1 and x2 are each independently 0, 1, or 2.

[0463] In certain embodiments, x1=0, and x2=0; or x1=0 and x2=1; or x1=0 and x2=2.

[0464] As a non-limiting example, when R 6 for (For example ), R 6 You can choose from: Such as Such as Such as Such as as well as Such as

[0465] Ring C in formula (III) may be as defined anywhere herein.

[0466] 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 (II) are:

[0467]

[0468] As will be appreciated by those skilled in the art, it is contemplated that the methods described herein using compounds of formula (III) wherein X is X* also produce compounds of formula (I) wherein X is X*. Thus, the methods described herein further comprise converting the resulting compounds of formula (I) wherein X is X* into compounds wherein X is X*. 1 For converting the obtained compound of formula (I) wherein X is X* into a compound of formula (I) wherein X is X 1 The reagents and conditions for preparing compounds of formula (I) will be apparent to those skilled in the art and representative syntheses are provided in the Examples section.

[0469] Variable R 1c , R 2a , R 2b , R 3a , and R 3b

[0470] In some embodiments, Y is -OH.

[0471] In some embodiments, R 1c For the protecting group.

[0472] Protecting groups include, but are not limited to, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z), 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trityl (trityl) (Trt), acetyl, benzyl, and p-nitrobenzyloxycarbonyl (pNZ).

[0473] In certain embodiments, R 1c Together with the nitrogen atom to which it is attached, it forms a carbamate. For example, R 1c It may be a Boc group.

[0474] In certain of these embodiments, the method further comprises: removing the protecting group from the compound of formula (I), for example using conventional deprotection conditions known to those skilled in the art, or by conducting the reaction to form the compound of formula (I) at an elevated temperature (e.g., 120°C).

[0475] In some embodiments, R 1c It's H.

[0476] In some embodiments, R 2a , R 2b , R3a , and R 3b Each of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by 1 to 6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g replace;

[0477] In certain of these embodiments, R 2a , R 2b , R 3a , and R 3b one of which is independently selected from: halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by 1 to 6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g Replace; and R 2a ,R 2b ,R 3a and R 3b The other one is H.

[0478] In some embodiments, the variable R 2a , R 2b , R 3a , and R 3b Two of them, together with the ring B atoms to which they are attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms;

[0479] In some embodiments, R 2a , R 2b , R 3a , and R 3b Each is H.

[0480] In some embodiments, R 1c , R 2a , R2b , R 3a and R 3b The above definitions of apply to the compounds of formula (II).

[0481] In some embodiments, R 1c , R 2a , R 2b , R 3a and R 3b The above definitions of apply to the compounds of formula (I).

[0482] Ring A

[0483] In some embodiments, Ring A is optionally substituted with 1-4 R c Substituted C 6-10 Aryl.

[0484] In certain embodiments, Ring A is optionally substituted with 1-4 R c Substituted phenyl.

[0485] For example, ring A may be surrounded by 1-2 R c Substituted phenyl.

[0486] In certain embodiments, Ring A is (For example ), where each R cB R is independently selected c .

[0487] In certain embodiments, each R cB Independently selected from: -halogen, such as -Cl and -F; -CN; C 1-4 Alkoxy; C 1-4 Haloalkoxy; C 1-3 and C optionally substituted by 1-6 independently selected halogens 1-3 alkyl.

[0488] In certain embodiments, Ring A is Where R cB1 For R c ; and R cB2 H or R c .

[0489] In certain of these embodiments, R cB1 is a halogen (eg, –F or –Cl (eg, –F)).

[0490] In certain embodiments, R cB2 C 1-4 Alkoxy or C 1-4 Haloalkoxy (e.g. C 1-4 Alkoxy (eg methoxy)).

[0491] As a non-limiting example of the foregoing embodiment, Ring A may be

[0492] In some embodiments, each of the above definitions of Ring A applies to the compound of Formula (II).

[0493] In some embodiments, each of the above definitions of Ring A applies to the compounds of Formula (I).

[0494] Ring C

[0495] In some embodiments, Ring C is

[0496] In some embodiments, Ring C is in:

[0497] οEach X b Independently for X, R c , or H; and

[0498] οEach X a independently selected from: H, halogen; cyano; optionally 1-6 independently selected R a Substituted 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; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5.

[0499] In some embodiments, Ring C is 2-pyridyl or 3-pyridyl, each of which is optionally substituted with X, which is further optionally substituted with 1-4 R c replace.

[0500] In some embodiments, ring C is 2-pyridonyl or 4-pyridonyl, and each of ADW is optionally substituted with X, and further optionally substituted with 1-4 R c substituted, wherein the ring nitrogen atom is optionally replaced by R d replace.

[0501] In some embodiments, Ring C is a heteroaryl group comprising 6 ring atoms, wherein 2-4 of the ring atoms are heteroatoms, each of which is independently selected from the group consisting of N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4 R c replace.

[0502] In certain embodiments, Ring C is It is further optionally substituted with X, wherein each R cA R for independent selection c ; and n is 0, 1, or 2.

[0503] As a non-limiting example of the foregoing embodiment, Ring C may be Such as (For example ).

[0504] In certain of the foregoing embodiments, n is 0, and R cA is optionally 1-6 independently selected R a Substituted C 1-10 Alkyl, for example, optionally substituted with 1-3 independently selected halogens C 1-3 alkyl.

[0505] As a non-limiting example, Ring C may be

[0506] In some embodiments, Ring C is a heteroaryl group comprising 5 ring atoms, wherein 1-4 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4 R c replace.

[0507] In some embodiments, Ring C is a bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is substituted by X, and is optionally independently selected from oxo and R 7 The compound is substituted with 1 to 4 substituents.

[0508] In some embodiments, Ring C is a bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2, and wherein the heteroaryl is optionally substituted by X, and is optionally independently selected from oxo and R 7 The compound is substituted with 1 to 4 substituents.

[0509] In some embodiments, Ring C is a bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is substituted by X and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents;

[0510] In some embodiments, Ring C is a bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is substituted by X and is optionally independently selected from oxo and R 7 The compound is substituted with 1 to 4 substituents.

[0511] In some embodiments, ring C is a heterocyclyl or heterocycloalkenyl group containing 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is independently selected from oxo and R c The compound is substituted with 1 to 4 substituents.

[0512] In some embodiments, ring C is a heterocyclyl or heterocycloalkenyl group comprising 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by X, and is optionally independently selected from oxo and R 7 The compound is substituted with 1 to 4 substituents.

[0513] In some embodiments, Ring C is selected from:

[0514] · in

[0515] οma is 0, 1, 2 or 3;

[0516] οR 8A Independently selected from: halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, R 9A R 10A N-, R 11A -C(O)-NH-,R11A OC(O)-NH-, or R 9A R 10A NC(O)-NH-, wherein the C 1-6 The alkoxy group is optionally substituted, independently of one another, 1, 2, or 3 times by halogen and optionally substituted once by: hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl or phenyl, which is optionally substituted by one or more R 5A replace;

[0517] οR 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0518] οR 9A and R 10A Each independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times independently of each other; or R 9A and R 10A Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic ring, which optionally contains an additional heteroatom or heteroatom-containing group selected from O, NH or S, and which may be optionally replaced by R 5A replace one or more times independently of each other;

[0519] οR 11A Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 Halogenated cycloalkyl;

[0520] · in

[0521] οR 5B C 2-5 Alkyl, which is optionally substituted by: hydroxy, C 1-4 Alkoxy, R 7B R 8B N-, or phenyl, wherein the phenyl group is optionally replaced by R 5Areplace one or more times; or

[0522] οR 5B For R 6B -CH2-;

[0523] οR 6B Selected from or

[0524] οR 7B and R 8B Independently selected from C 1-3 Alkyl, C 1-3 haloalkyl; or

[0525] οR 7B and R 8B Together with the nitrogen atom to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring optionally contains an additional heteroatom or a heteroatom-containing group selected from O and -NH-, NH(C 1-3 alkyl);

[0526] οR 9B Selected from hydrogen, C 1-4 Alkyl, or C 1-3 Haloalkyl;

[0527] οR 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy;

[0528] · in

[0529] οR 4C is selected from hydrogen or methyl;

[0530] οR 6C Selected from hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl;

[0531] οnc is 0 or 1;

[0532] οX C NR 7C or O;

[0533] οY C NR 8C or O;

[0534] οR 7C is methyl;

[0535] οR 8C Selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl;

[0536] οR 5C is selected from hydrogen or methyl, wherein R 5C Connect to the containing X C and Y C Any carbon atom of a ring;

[0537] οmc is 0, 1, 2 or 3;

[0538] · in

[0539] οR 4D is selected from hydrogen or methyl;

[0540] οR 5D Selected from: (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, 3-azetidinyl, each of which is optionally replaced by R 6D substituted 1, 2, or 3 times, and wherein each azetidinyl group is replaced on the nitrogen by R 8D replace; or

[0541] οR 5D Selected from

[0542] οR 6D Selected from Fluorine or C 1-3 alkyl;

[0543] omd is selected from 0, 1, 2, or 3;

[0544] οR 7D Selected from hydrogen, C 1-3 Alkyl, or C 1-3 Haloalkyl;

[0545] οX D NR 8D or O;

[0546] οR 8D Selected from C 1-3 Alkyl or C 2-3 Haloalkyl;

[0547] In some embodiments, ring C is C 10 or C 14 Aryl, which is substituted by X and optionally by 1-4 R 7 replace.

[0548] In some embodiments, each of the above definitions of Ring A applies to the compound of formula (III).

[0549] In some embodiments, each of the above definitions of Ring A applies to the compound of Formula (II).

[0550] In some embodiments, each of the above definitions of Ring A applies to the compounds of Formula (I).

[0551] The compounds, intermediates and reagents disclosed herein can be prepared in a variety of ways other than the methods described herein, for example, using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art or as taught herein. The synthesis of the compounds disclosed herein can generally be achieved by following the schemes and examples provided below, and by varying for specific desired substituents.

[0552] Standard synthetic methods and procedures for preparing organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or standard textbooks in the field. Although not limited to any one or more sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Press (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 and Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley and Sons: New York, 1999, are useful and recognized reference textbooks for organic synthesis well known to those skilled in the art. The following description of synthetic methods is intended to illustrate but not limit the general procedures for preparing the disclosed compounds.

[0553] The synthetic process disclosed herein can tolerate a variety of functional groups; therefore, various substituted starting materials can be used. The process generally provides the desired final compound at or near the end of the entire process, although in some cases it may be desirable to further convert the compound into a pharmaceutically acceptable salt.

[0554] The compounds described herein can be isolated / purified using conventional methods known to those skilled in the art, such as, for example, column chromatography, crystallization, HPLC (eg, chiral HPLC).

[0555] Example

[0556] Many embodiments of the present invention have been described. However, it should be understood that various modifications can be made without departing from the spirit and scope of the present invention. Therefore, other embodiments are also within the scope of the appended claims.

[0557] 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

[0558]

[0559] A suspension of 3-bromopyridine-4-carboxaldehyde (3.38 g, 18.2 mmol, 1.5 equivalents (eq)) in dioxane (37.5 mL) / dioxane (37.5 mL) was stirred under heating (in a heating mantle at 80°C) until the aldehyde dissolved. The resulting solution was then added dropwise to a 250 mL round-bottom flask containing a 95°C mixture of tert-butyl 3-[(3-chloro-2-methoxyphenyl)aminomethylthioyl]-2,4-dioxopiperidine-1-carboxylate (5.00 mg, 12.1 mmol, 1.0 eq) and a mixture of NH4OAc (4.67 g, 60.6 mmol, 5.0 eq) in toluene (50.0 mL) under a nitrogen atmosphere via a syringe pump over 3.0 hours. The mixture was then stirred at this temperature for 21 hours (total reaction time 24 h). The reaction mixture is quenched with saturated NaHCOaqueous solution (100mL), and diluted with MTBE (50mL). Separate all phases, and extract aqueous layer with MTBE (50mL). Combined organic extracts are washed with NaHCOsaturated aqueous solution (50mL) and brine (50mL), washed with NaSO, dried on, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with n-heptane / EtOAc (3: 1 to 0: 1), and 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- carboxylic acid tert-butyl ester (3.03g, 45.6% yield) is obtained as a yellow solid.

[0560] LCMS (ES, m / z): [M+H] + :547 / 549;

[0561] 1H NMR (400MHz, CDCl3) δ9.39 (s, 1H), 8.64 (s, 1H), 8.17 (d, J = 5.4Hz, 1H), 7.84 (s, 1H), 7.28 (d, J = 5.3Hz, 1H), 6.70 (dd, J = 8.1, 1.4Hz ,1H),6.54(t,J=8.1Hz,1H),6.15(dd,J=8.2,1.5Hz,1H),4.14(t,J=6.3Hz,2H),4.00(s,3H),3.01(t,J=6.4Hz,2H),1.56(s,9H).

[0562] Example 2. Synthesis of tert-butyl 5-((3-chloro-2-methoxyphenyl)aminomethylthioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate

[0563]

[0564] 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) was added thiophosgene (6.08 mL, 79.3 mmol, 1.0 equiv) dropwise at 0° C., and the mixture was stirred at this temperature for 3 hours. 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.

[0565]

[0566] To a stirred suspension of tert-butyl 2,4-dioxopiperidin-1-carboxylate (16.4 g, 76.9 mmol, 1.0 eq) and 1-chloro-3-isothiocyanato-2-methoxybenzene (16.2 g, 76.9 mmol, 1.0 eq) in MeCN (375 mL) was added DBU (17.2 mL, 115 mmol, 1.5 eq) dropwise at room temperature, and the reaction mixture was stirred for 20 hours. The reaction mixture was diluted with ice water (100 mL), and HCl (1 M, 115 mL, 115 mmol, 1.5 eq) was added to pH 6. The mixture was stirred for 15 minutes and then filtered to give 24 g of filter cake (86% purity). Take 1g (x 2) filter cake, and slurry overnight in MeCN (4mL) or EtOAc (2mL) at room temperature, then filter to obtain> 99% purity material, the material recovered from MeCN slurry is more than the material recovered from EtOAc slurry (0.70g vs 0.45g). The remaining filter cake (22g) was slurried in 4 volumes (88mL) of MeCN for 4 hours, filtered, and dried overnight at 50°C in a vacuum oven to obtain 3-[(3-chloro-2-methoxyphenyl) aminomethylsulfonyl]-2,4-dioxopiperidine-1-carboxylic acid tert-butyl ester (19.0g, 59.8%) as a white solid. All filtrates were combined and purified by silica gel column chromatography using n-heptane / EtOAc (4:1 to 0:1) to give tert-butyl 3-[(3-chloro-2-methoxyphenyl)carbamethanesulfonyl]-2,4-dioxopiperidine-1-carboxylate as an off-white solid (4.54 g, 14.0%)

[0567] LCMS(ES,m / z):[MH] - :411,[M+H] + :313 (des-Boc);

[0568] 1 H NMR (400MHz, CDCl3) δ13.67 (s, 1H), 7.78 (d, J = 8.2Hz, 1H), 7.32 (d, J = 8.2Hz, 1H), 7.09 (td, J = 8.0, 2.5Hz, 1H), 3.86 (m, 5H), 2.82 (t, J = 6.9Hz, 2H).

[0569] Example 3. Synthesis of Sodium (3-bromopyridin-4-yl)(hydroxy)methanesulfonate

[0570]

[0571] To a mixture of 3-bromopyridine-4-carboxaldehyde (1.00 g, 5.38 mmol, 1 equivalent) in EtOH (10 mL) was added dropwise NaHSO3 (565 mg, 5.43 mmol, 1.01 equivalent) in water (1.8 mL). The reaction mixture was stirred at room temperature for 2 hours to form a solid. EtOH (5 mL) was added, and the mixture was stirred for another 5 minutes and then filtered. The filter cake was washed with EtOH (2 × 2.5 mL) and dried overnight in a vacuum oven to give (3-bromopyridin-4-yl) (hydroxy) sodium methanesulfonate (1.43 g, 91.7% yield) as a white solid.

[0572] LCMS (ESI, m / z): [M-Na] – 266 / 268;

[0573] 1 H NMR (400MHz, DMSO-d6) δ 8.59 (s, 1H), 8.44 (d, J = 5.0Hz, 1H), 7.64 (d, J = 5.0Hz, 1H), 6.38 (d, J = 6.0Hz, 1H), 5.29 (d, J = 6.0Hz, 1H).

[0574] 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

[0575]

[0576] An oven dried vial was charged with tert-butyl 3-[(3-chloro-2-methoxyphenyl)aminomethylthioyl]-4-hydroxy-2-oxo-5,6-dihydropyridine-1-carboxylate Boc-3 (50 mg, 0.121 mmol, 1 eq) and ammonium acetate (46.7 mg, 0.61 mmol, 5 eq). Toluene (1 mL) was added and the resulting suspension was heated at 95 °C. Sodium (3-bromopyridin-4-yl)(hydroxy)methanesulfonate 18 (52.7 mg, 0.18 mmol, 1.5 eq) was added in 5 portions over a 2.5 h period (0.3 eq / 30 min) and the reaction mixture was then stirred at 95 °C overnight (16-18 h). A sample was then taken and analyzed by LCMS and HPLC to give the following results:

[0577] LCMS: 44% Boc-8, 22% Boc-3

[0578] HPLC (removing toluene peak): 60% Boc-8, 31% Boc-3

[0579] Example 5. Representative Procedure for the Synthesis of Compounds of Formula (II) (GP1)

[0580]

[0581] Under N2 atmosphere, DBU (1.50 equivalents) was added to a stirred suspension of β-ketoamide (Formula (IIa)) (1.00 equivalents) and isothiocyanate (Formula (IIb)) (1.00 equivalents) in anhydrous acetonitrile (0.470m), and the resulting mixture was stirred for 20h at ambient temperature. The reaction was quenched with HCl (1.00m) to pH 6, diluted with water, and then extracted with EtOAc or DCM (3×50mL). The combined organic extracts were washed with a saturated aqueous solution of NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to obtain compound (Formula (II)).

[0582] Example 6. Representative Procedure 2 (GP2) for the Synthesis of Compounds of Formula (I)

[0583]

[0584] The oven-dried vial is filled with the compound of formula (II) (1.00 equivalent) and NH4OAc (5.00 equivalent), and the vial is emptied and backfilled three times with N2. Anhydrous toluene (10.0 volumes) is added, and the reaction is heated to 90 ° C. Subsequently, a syringe pump is used to add a solution of the prefabricated compound of formula (III) (1.50 equivalents) in anhydrous 1,4-dioxane (10.0 volumes) dropwise during 2.5 hours, and the resulting mixture is stirred at 90 ° C for 18 hours. The reaction is cooled to ambient temperature and directly concentrated under reduced pressure. The crude residue is purified by silica gel chromatography to obtain a compound of formula (I).

[0585] Example 7. GP2 reaction conditions

[0586]

[0587] A. Starting material: Enamine 8 a

[0588] entry Solvents T / ℃ HPLC area % (254 nm) 1 EtOH 70 85％8 2 Toluene 70 91% 8 / Toluene 3 Toluene 100 4%des(Boc)8,81%8 / Toluene

[0589] a Reaction conditions: 8 (0.144 mmol), 6a (0.144 mmol), NH4OAc (0.720 mmol), solvent (1.0 mL), temperature, 20 h.

[0590] B. Starting materials: Enol 5a b

[0591] entry Solvents T / ℃ <![CDATA[HPLC area % (254 nm) b > 1 EtOH 70 37% 7a, 27% 8, 0% 5a 2 1,4-Dioxane 70 60% 7a, 4% 8, 10% 5a 3 Toluene 70 17%7a,74%5a 4 1,4-Dioxane 100 59％7a,4％8 5 Toluene 100 35%7a,5%8,23%5a 6 1:1 Toluene / 1,4-Dioxane 70 56%7a,2%8,23%5a 7 1:1 Toluene / 1,4-Dioxane 100 66％7a,5％8 8 2-MeTHF 80(Reflux) 42%7a,4%8,34%5a 9 CPME 100 41％3,9％8 10 1:1 Toluene / 2-MeTHF 100 59%7a,5%8,0%5a 11 1:1 Toluene / CPME 100 44%7a,7%8,0%5a

[0592] b Reaction conditions: 5a (0.144 mmol), 6a (0.144 mmol), NH4OAc (0.720 mmol), solvent (1.0 mL), temperature, 20 h.

[0593] C. Change the aldehyde equivalent c

[0594] entry 6a equivalent <![CDATA[HPLC area % (254 nm) b > 1 1.0 60% 7a, 4% 8, 10% 5a 2 1.3 67%7A,5%8,8%5a 3 1.5 70% 7A, 5% 8, 6% 5a (58%) 4 2.0 65%7A,3%8,4%5a

[0595] c Reaction conditions: 5a (0.144 mmol), 6a, NH4OAc (0.720 mmol), 1,4-dioxane (1.0 mL), 70°C, 20 h. b Isolated yields are given in parentheses.

[0596] D. Change concentration, temperature, ammonium source and additives d

[0597]

[0598] d Reaction conditions: 5a (0.144 mmol), 6a (0.216 mmol), NH3 source, solvent, temperature, 20 h. b Isolated yields are given in parentheses.

[0599] E. Variation of aldehyde addition and solvent mixture e

[0600]

[0601]

[0602] e Reaction conditions: 5a (0.144 mmol), 6a, NH4OAc (0.720 mmol), solvent, temperature, 20 h. b Isolated yield

[0603] Example 8. Optimization of reaction conditions

[0604] The reaction of enol 5a, NH4OAc, and 4-pyridinepyrrolecarboxaldehyde (6a) under different conditions was studied (Table 1). When heated at 70°C overnight in EtOH, the starting material was consumed and 37% of the desired product 7a was detected by HPLC analysis (entry 1). Enamine 8 was identified as the major byproduct (27%). To investigate whether this enamine was of production significance, 8 was synthesized independently and subjected to reaction conditions in which no conversion to 7a was observed. 11Without wishing to be bound by theory, the reaction mechanism is believed to proceed via condensation of an initial ammonia with an aldehyde. Use of 1,4-dioxane resulted in increased conversion of the desired product 7a (60%) and decreased enamine 8 (4%); however, when the reaction was carried out in toluene, 74% of the starting material was not consumed (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) and afforded 70% of pyrrole 7a (isolated in 58% yield); however, further increases in equivalents did not provide significant benefit (entry 5). Use of (NH4)2CO3 resulted in a significant decrease in conversion, while NH4Cl did not afford detectable levels of product (entries 6 and 7). 1 The reaction was relatively insensitive to the equivalents of NH4OAc, but the addition of >5 equivalents did not appear to be beneficial (entries 8 and 9). Conducting the reaction at 90 °C resulted in complete conversion of the gaseous material, and 64% of pyrrole 7a was detected (entry 11), while lowering the temperature to 50 °C resulted in a significant reduction in product formation (entry 11). It was also observed that the formation of enamine 8 was also suppressed when the reaction was carried out in toluene (entry 3). In a mixed solvent system, 69% of product 7a was observed (entry 12), matching the conversion observed in 1,4-dioxane. In addition, complete consumption of the starting material was observed, and the formation of enamine 8 was minimized.

[0605] Table 1. a

[0606]

[0607]

[0608]

[0609] a 5a (0.144 mmol), 6a, NH3 source, solvent (20 vol), T°C, 20 h. b Isolated yields are given in parentheses. 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.

[0610] Example 9. Synthesis of Compounds 9 and 10

[0611] 5-Oxo-2-phenyl-4-(phenylamino)-7,8-dihydro-2H-pyrido[4,3-d][1,3]thiazine-6(5H)- Tert-butyl carboxylate, 9

[0612]

[0613] A stirred solution of 5a (500 mg, 1.44 mmol, 1.00 equiv), benzaldehyde (220 μL, 2.15 mmol, 1.50 equiv), and NH4OAc (553 mg, 7.18 mmol, 5.00 equiv) in 1,4-dioxane (10.0 mL) was heated to 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 SiO2 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.

[0614] 1 H NMR (400MHz, chloroform-d) δ13.33(s,1H),7.49–7.42(m,2H),7.28(dd,J=8.2,6.5H z,4H),7.25–7.16(m,2H),7.15–7.05(m,2H),5.55(d,J=1.8Hz,1H),3.97(d t,J=12.9,5.3Hz,1H),3.62(ddd,J=12.9,10.9,3.8Hz,1H),2.85(dddd,J=1 5.9,11.0,4.9,1.9Hz,1H),2.73(ddd,J=15.0,5.7,3.8Hz,1H),1.50(s,9H);

[0615] 13 C NMR (101 MHz, chloroform- d ) δ 167.8, 166.8, 165.4, 152.0, 138.9, 136.8, 129.0, 128.8, 128.8, 127.9, 127.5, 125.4, 94.8, 83.1, 64.1, 42.8, 33.7, 28.1;

[0616] HRMS (ESI) for C 21 H 25 N3O3S + Calculation, [M+H] + 436.1695; found m / z 436.1697.

[0617] Example 10.9 Conversion into 7ac

[0618]

[0619]

[0620]

[0621] Example 11. Synthesis of tert-butyl 4-hydroxy-6-oxo-5-(phenylaminomethylthioyl)-3,6-dihydropyridine-1(2H)-carboxylate, 5a 1

[0622]

[0623] 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 linear gradient of 0-50% EtOAc in heptane over 15 CV gave 5a (3.13 g, 96%) as a white solid.

[0624] 1 H NMR (400MHz, DMSO-d6) δ15.31(s,1H),12.84(s,1H),7.57(d,J=7.9Hz,2H),7.44(t,J=7.7 Hz,2H),7.31(t,J=7.4Hz,1H),3.77(t,J=6.5Hz,2H),2.81(t,J=6.4Hz,2H),1.47(s,9H);

[0625] 13 C NMR (400MHz, DMSO-d6) δ189.5,181.7,166.1,152.4,138.4,129.3,127.4,125.2,105.7,82.8,41.0,30.8,28.1;

[0626] HRMS (ESI) for C 17 H 21 N2O4S + Calculate [M+H] + 349.1222; found m / z 349.1223.

[0627] 1 H NMR data are consistent with literature 1 match.

[0628] Example 12. Synthesis of tert-butyl 4-amino-6-oxo-5-(phenylaminomethylthioyl)-3,6-dihydropyridine-1(2H)-carboxylate, 8

[0629]

[0630] A mixture of 5a (1.00 g, 2.87 mmol, 1.00 equiv) and NH4OAc (2.21 g, 28.7 mmol, 10.0 equiv) in EtOH (12 mL) was heated to 70 ° C overnight. The reaction mixture was concentrated to ~4 mL and then quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (3×20 mL), and the combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 5-100% EtOAc in heptane over 15 CV to give 8 (576 mg, 58%) as a light yellow solid.

[0631] 1 H NMR (400MHz, DMSO-d6) δ13.18(s,1H),11.30(s,1H),8.74(s,1H),7.51(d,J=7.9Hz,2H),7.38(t ,J=7.8Hz,2H),7.22(t,J=7.4Hz,1H),3.67(t,J=6.3Hz,2H),2.76(t,J=6.2Hz,2H),1.46(s,9H);

[0632] 13 C NMR (101MHz, DMSO-d6) δ190.8,168.0,166.8,152.8,139.7,128.9,126.,125.6,98.7,82.1,41.0,31.3,28.2;

[0633] HRMS (ESI) for C 17 H 20 N3O3S – Calculation, [MH] – 346.1225; found m / z 346.1227.

[0634] Example 13. Synthesis of tert-butyl 5-((2-chlorophenyl)aminomethylthioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5r

[0635]

[0636] 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 15CV gave 5r (379 mg, 70%) as a white solid.

[0637] 1 H NMR (400 MHz, chloroform-d) δ 13.50 (s, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.35–7.27 (m, 2H), 3.87 (t, J = 6.6 Hz, 2H), 2.83 (t, J = 6.6 Hz, 2H), 1.56 (s, 9H);

[0638] 13 C NMR (101 MHz, chloroform-d) δ 191.1, 186.7, 167.9, 152.4, 135.6, 131.3, 130.6, 129.3, 129.3, 127.5, 102.5, 84.3, 40.8, 32.2, 28.5;

[0639] HRMS (ESI) for C 17 H 19 ClN2O3SNa + Calculation, [M+Na] + 405.0652; found m / z 405.0651.

[0640] Example 14. Synthesis of tert-butyl 5-((3-chlorophenyl)aminomethylthioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5s

[0641]

[0642] 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). Purified by silica gel chromatography using a 40 g SiO2 cartridge and a linear gradient of 0-30% EtOAc in heptane over 15CV to give 5s (360 mg, 67%) as an off-white solid.

[0643] 1 H NMR (400 MHz, chloroform-d) δ 13.57 (s, 1H), 7.43 (s, 1H), 7.32–7.24 (m, 1H), 7.22–7.19 (m, 2H), 3.78 (t, J = 6.6 Hz, 2H), 2.75 (t, J = 6.6 Hz, 2H), 1.49 (s, 9H);

[0644] 13C NMR (101 MHz, chloroform-d) δ 189.7, 186.4, 167.8, 152.0, 138.8, 134.6, 130.0, 127.6, 126.1, 124.1, 102.1, 84.1, 40.5, 31.9, 28.2.

[0645] HRMS (ESI) for C 17 H 20 ClN2O3S + Calculation, [M+H] + 383.0832; found m / z 383.0829.

[0646] Example 15. Synthesis of tert-butyl 5-((4-chlorophenyl)aminomethylthioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5t

[0647]

[0648] 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 15CV afforded 5t (343 mg, 64%) as a white solid.

[0649] 1 H NMR (400 MHz, chloroform-d) δ 13.60 (s, 1H), 7.38 (s, 4H), 3.85 (t, J = 6.6 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H), 1.56 (s, 9H);

[0650] 13 C NMR (101 MHz, chloroform-d) δ 189.9, 186.6, 168.1, 152.2, 136.5, 133.3, 129.6, 127.6, 102.4, 84.4, 40.8, 32.2, 28.5;

[0651] HRMS (ESI) for C 17 H 20 ClN2O3S + Calculation, [M+H] + 383.0832; found m / z 383.0826.

[0652] Example 16. Synthesis of tert-butyl 4-hydroxy-5-((2-methoxyphenyl)aminomethylsulfonyl)-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5u 2

[0653]

[0654] 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 15CV afforded 5u (396 mg, 74%) as a white solid.

[0655] 1 H NMR (400 MHz, chloroform-d) δ 13.33 (s, 1H), 7.66 (d, 1H), 7.18 (t, J = 7.8, 1.6 Hz, 1H), 6.91–6.86 (m, 2H), 3.78–3.71 (m, 5H), 2.69 (t, J = 6.6 Hz, 2H), 1.47 (s, 9H);

[0656] 13 C NMR (101 MHz, chloroform-d) δ 188.9, 185.7, 167.5, 153.4, 152.2, 128.5, 127.0, 126.6, 120.2, 111.6, 102.4, 83.7, 56.1, 40.5, 31.9, 28.3;

[0657] HRMS (ESI) for C 18 H 21 N2O5S – Calculation, [MH] – 377.1171; found m / z 377.1169.

[0658] Example 17. Synthesis of tert-butyl 5-((4-(ethoxycarbonyl)phenyl)aminomethylthioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate, 5v

[0659]

[0660] 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 14CV gave 5v (319 mg, 54%) as a white solid.

[0661] 1 H NMR (400 MHz, chloroform-d) δ 13.81 (s, 1H), 8.09 (d, 2H), 7.59 (d, 2H), 4.38 (q, J = 7.1 Hz, 2H), 3.85 (t, J = 6.6 Hz, 2H), 2.83 (t, J = 6.6 Hz, 2H), 1.56 (s, 9H), 1.39 (t, J = 7.1 Hz, 3H);

[0662] 13 C NMR (101 MHz, chloroform-d) δ 189.8, 186.8, 168.1, 166.3, 152.2, 142.0, 130.8, 129.4, 125.7, 102.6, 84.5, 61.5, 40.8, 32.2, 28.5, 14.8;

[0663] HRMS (ESI) for C 20 H 25 N2O6S + Calculation, [M+H] + 421.1433; found m / z 421.1429.

[0664] Example 18. Synthesis of tert-butyl 4-hydroxy-3-methyl-6-oxo-5-(phenylaminomethylthioyl)-3,6-dihydropyridine-1(2H)-carboxylate, 5y

[0665]

[0666] 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.

[0667] 1H NMR (400MHz, CDCl3) δ13.61(s,1H),7.42(d,J=4.3Hz,4H),7.35–7.27(m,1H),3.86(dd,J=13.0,4.6H z,1H),3.63(dd,J=13.0,7.1Hz,1H),2.86(td,J=7.1,4.8Hz,1H),1.56(s,9H),1.34(d,J=7.0Hz,3H);

[0668] 13 C NMR (101MHz, CDCl3) δ189.7,189.3,167.5,152.1,137.6,129.0,127.4,125.9,100.9,83.8,46.6,35.9,28.1,14.4;

[0669] HRMS (ESI) for C 18 H 23 N2O4S + Calculation, [M+H] + 363.1378; found m / z 363.1379.

[0670] Example 19. Synthesis of Sodium Hydroxy(4-pyridinyl)methanesulfonate, 11

[0671]

[0672] To a solution of 4-formylpyridine (600 uL, 6.37 mmol, 1.00 equiv) in EtOH (12.7 mL) was added 3 m NaHSO3 aqueous solution (2.14 mL, 6.43 mmol, 1.01 equiv) and the mixture was stirred at room temperature for 3 hours. Toluene (10 mL) was added to the reaction mixture to remove water azeotropically 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.

[0673] 1 H NMR (400MHz, DMSO-d6) δ8.55–8.34(m,2H),7.52–7.25(m,2H),6.25(s,1H),5.01(s,1H).

[0674] 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

[0675]

[0676] Small scale: Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and isonicotinaldehyde (40.6 μL, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV afforded 7a (81 mg, 70%) as an off-white solid.

[0677] 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 afford 7a (739 mg, 64%) as an off-white solid.

[0678] 1 H NMR (400 MHz, CHLOROFORM-d) 11.25 (s, 1H), 8.34–8.24 (m, 2H), 7.39–7.28 (m, 2H), 7.23 (s, 1H), 7.12–6.99 (m, 2H), 6.75 (tt, J=7.4, 1.1 Hz, 1H), 6.70–6.58 (m, 2H), 4.04 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.3 Hz, 2H), 1.52 (s, 9H).

[0679] 13 C NMR (101 MHz, chloroform-d) δ 164.0, 152.8, 148.9, 143.3, 139.3, 138.8, 129.2, 128.8, 120.1, 119.0, 118.6, 116.1, 108.8, 83.0, 45.3, 28.2, 22.8.

[0680] HRMS (ESI) for C 23 H 25 N4O3 + Calculation, [M+H] + 405.1927; found m / z 405.1929.

[0681] 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

[0682]

[0683] Synthesized according to GP2 using tert-butyl ester 5a (100 mg, 0.287 mmol) and 3-bromoisonicotinaldehyde (80.1 mg, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV afforded 7b (75 mg, 54%) as a yellow solid.

[0684] 1 H NMR (400MHz, chloroform-d) δ9.29(s,1H),8.60(s,1H),8.08(d,J=5.1Hz,1H),7.18(d,J=5.1Hz,1H),6.98(t,J=7.7Hz ,2H),6.69(t,J=7.3Hz,1H),6.61(d,J=8.0Hz,2H),4.12(t,J=6.2Hz,2H),2.96(t,J=6.3Hz,2H),1.55(s,9H);

[0685] 13 C NMR (101 MHz, chloroform- d ) δ 164.0, 152.9, 152.2, 147.5, 138.9, 136.8, 137.3, 128.6, 130.4, 124.1, 120.5, 116.7, 112.9, 83.1, 83.0, 45.1, 28.2, 23.1;

[0686] HRMS (ESI) for C 23 H 24 BrN4O3 + Calculation, [M+H] + 485.1014; found m / z 485.1012.

[0687] 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

[0688]

[0689] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 3-methylisonicotinaldehyde (52.2 mg, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV afforded 7c (50 mg, 42%) as a yellow solid.

[0690] 1 H NMR (400MHz, chloroform-d) δ9.31(s,1H),8.11(s,2H),7.40(s,1H),7.10(d,J=5.2Hz,1H),6.83(t,J=7.7Hz,2H),6.56( t,J=7.3Hz,1H),6.45(d,J=8.0Hz,2H),4.04(t,J=6.3Hz,2H),2.86(t,J=6.3Hz,2H),2.10(s,3H),1.49(s,9H);

[0691] 13 C NMR (101 MHz, chloroform-d) δ 164.2, 153.1, 150.5, 145.9, 142.9, 141.2, 137.3, 131.5, 128.4, 128.4, 122.0, 119.8, 116.0, 115.1, 107.6, 82.69, 45.2, 28.2, 23.0, 17.4.

[0692] HRMS (ESI) for C 24 H 27 rN4O3 + Calculation, [M+H] + 419.2083; found m / z 419.2083.

[0693] 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

[0694]

[0695] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 2-methylisonicotinaldehyde (80.1 mg, 0.431 mmol). 7d (56 mg, 40%) was obtained as a yellow solid by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV.

[0696] 1H NMR (400 MHz, chloroform-d) δ9.52 (s, 1H), 8.01 (d, J = 5.4 Hz, 1H), 7.36 (s, 1H), 7.15–7.03 (m, 3H), 6.79 (t, J = 7.2 Hz, 1H), 6.62 (d, J = 7.9 Hz, 2H), 4.11 (t, J = 6.4 Hz, 2H), 2.95 (d, J = 6.4 Hz, 2H), 1.53 (s, 9H);

[0697] 13 C NMR (101 MHz, chloroform-d) δ 164.0, 152.7, 150.3, 149.5, 142.5, 142.1, 140.9, 139.0, 130.2, 129.0, 121.8, 120.7, 118.1, 116.6, 116.4, 108.9, 83.4, 45.2, 28.1, 22.9;

[0698] HRMS (ESI) for C 23 H 24 BrN4O3 + Calculation, [M+H] + 483.1032; found m / z 483.1028.

[0699] 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

[0700]

[0701] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 2-methoxyisonicotinaldehyde (40.9 μL, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV gave 7e (100 mg, 80%) as an off-white solid.

[0702] 1 H NMR (400MHz, chloroform-d) δ10.00(s,1H),7.90(d,J=5.6Hz,1H),7.10–7.01(m,3H),6.95(d,J=5.6Hz,1H), 6.77–6.69(m,2H),6.62(d,J=8.0Hz,2H),4.03(t,J=6.3Hz,2H),2.85(t,J=6.3Hz,2H),1.51(s,9H);

[0703] 13 C NMR (101 MHz, chloroform-d) δ 164.6, 164.1, 152.8, 146.7, 143.5, 141.3, 138.2, 128.8, 128.4, 119.9, 119.0, 115.9, 112.87, 108.9, 104.2, 83.0, 53.6, 45.3, 28.1, 22.8;

[0704] HRMS (ESI) for C 24 H 27 N4O4 + Calculation, [M+H] + 435.2032; found m / z 435.2035.

[0705] 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

[0706]

[0707] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 2-fluoroisonicotinaldehyde (53.9 mg, 0.431 mmol). 7f (72 mg, 59%) was obtained as a yellow solid by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV.

[0708] 1 H NMR (400MHz, chloroform-d) δ10.02(s,1H),7.89(d,J=5.5Hz,1H),7.21–7.11(m,2H),7.07(t,J=7.7Hz,2H),6.88(d,J=1. 4Hz,1H),6.77(t,J=7.3Hz,1H),6.63(d,J=7.9Hz,2H),4.06(t,J=6.3Hz,2H),2.90(t,J=6.3Hz,2H),1.52(s,9H);

[0709] 13C NMR (101 MHz, chloroform-d) δ 164.2, 152.8, 147.1 (d, J = 15.1 Hz), 143.8 (d, J = 9.2 Hz), 143.0, 139.15, 130.0, 129.1, 120.6, 117.9, 116.9, 116.3, 109.0, 103.5 (d, J = 39.2 Hz), 83.4, 45.4, 28.2, 22.8;

[0710] 19 F NMR (376 MHz, chloroform-d) δ –69.1;

[0711] HRMS (ESI) for C 23 H 24 FN4O3 + Calculation, [M+H] + 423.1833; found m / z 428.1830.

[0712] 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, 7 g

[0713]

[0714] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and picolinaldehyde (40.9 μL, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV afforded 7g (57 mg, 49%) as an off-white solid.

[0715] 1 H NMR(400MHz,chloroform-d)δ10.01(br s,1H),8.43(d,J=5.0Hz,1H),7.46(td,J=7.7,1.8Hz,1H),7.23(s,1H),7.18(d,J=8.2Hz,1H),7.11(t,J=8.5,7.2Hz,2H),6.99(dd d,J=7.6,4.9,1.1Hz,1H),6.78(t,J=7.3Hz,1H),6.73(d,J=7.6Hz,2H),4.10(t,J=6.3Hz,2H),2.91(t,J=6.3Hz,2H),1.55(s,9H);

[0716] 13C NMR (101 MHz, chloroform-d3) δ 163.8, 153.0, 148.6, 148.0, 143.9, 136.1, 136.7, 128.9, 127.3, 121.8, 121.0, 120.4, 119.8, 116.0, 109.3, 82.7, 45.2, 28.2, 22.9;

[0717] HRMS (ESI) for C 23 H 25 N4O3 + Calculation, [M+H] + 405.1927; found m / z 405.1928.

[0718] 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

[0719]

[0720] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 5-bromopicolinaldehyde (40.9 μL, 0.431 mmol). 7h (72 mg, 52%) was obtained as a yellow solid by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV.

[0721] 1 H NMR (400MHz, chloroform-d) δ9.59(s,1H),8.48(d,J=2.3Hz,1H),7.54(dd,J=8.6,2.4Hz,1H),7.18–7.08(m,2H),7.00(d ,J=8.6Hz,1H),6.85–6.76(m,1H),6.75–6.68(m,2H),4.11(t,J=6.3Hz,2H),2.94(t,J=6.3Hz,2H),1.56(s,9H);

[0722] 13 C NMR (101 MHz, chloroform-d) δ 163.7, 153.0, 149.0, 146.8, 143.5, 139.0, 137.0, 129.0, 127.9, 121.9, 120.9, 120.1, 116.4, 116.0, 109.4, 82.9, 45.1, 28.2, 22.9;

[0723] HRMS (ESI) for C 23 H 24 BrN4O3 + Calculation, [M+H] + 483.1032; found m / z 483.1026.

[0724] 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

[0725]

[0726] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 5-methylpicolinaldehyde (52.2 μL, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV afforded 7i (76 mg, 63%) as an off-white solid.

[0727] 1 H NMR (400 MHz, chloroform-d) δ 10.60 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 7.42–7.35 (m, 1H), 7.30–7.15 (m, 3H), 6.85 (dd, J = 20.3, 7.6 Hz, 3H), 4.17 (t, J = 6.3 Hz, 2H), 2.92 (t, J = 6.3 Hz, 2H), 2.35 (s, 3H), 1.64 (s, 9H);

[0728] 13 C NMR (101 MHz, chloroform-d) δ 163.9, 153.1, 148.1, 146.3, 144.2, 137.4, 136.6, 130.0, 128.8, 126.6, 122.2, 120.6, 119.62, 115.9, 109.3, 82.7, 45.2, 28.2, 22.8, 18.2;

[0729] HRMS (ESI) for C 24 H 27 N4O3 + Calculation, [M+H] + 419.2083; found m / z 419.2086.

[0730] 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

[0731]

[0732] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and quinoline-2-carbaldehyde (67.6 mg, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV gave 7j (70 mg, 53%) as an orange solid.

[0733] 1 H NMR (400MHz, chloroform-d3) δ7.96(d,J=8.5Hz,1H),7.90(d,J=8.8Hz,1H),7.73–7.61(m,2H),7.48(d,J=8.7Hz,1H),7.43(t,J=7 .5Hz,1H),7.34(s,1H),7.13–7.05(m,2H),6.85–6.74(m,3H),4.09(t,J=6.3Hz,2H),2.84(t,J=6.3Hz,2H),1.55(s,9H);

[0734] 13 C NMR (101 MHz, chloroform-d) δ 163.2, 152.4, 143.9, 137.5, 135.8, 129.2, 128.3, 127.4, 127.1, 126.0, 124.9, 120.1, 115.4, 119.0, 108.8, 82.1, 44.5, 27.6, 22.2;

[0735] HRMS (ESI) for C 27 H 27 N4O3 + Calculation, [M+H] + 455.2083; found m / z 455.2086.

[0736] 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

[0737]

[0738] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 3-formylpyridine (40.4 μL, 0.431 mmol). 7k (22 mg, 19% yield) was obtained as a yellow solid by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV.

[0739] 1 H NMR (400MHz, chloroform-d) δ11.23(s,1H),9.00(s,1H),8.20(d,J=4.9Hz,1H),7.79(dd,J=8.1,2.0Hz,1H),7.19–6.97( m, 4H), 6.71 (t, J = 7.3Hz, 1H), 6.62 (d, J = 7.9Hz, 2H), 4.03 (t, J = 6.3Hz, 2H), 2.88 (t, J = 6.3Hz, 2H), 1.53 (s, 9H).

[0740] 13 C NMR (101 MHz, chloroform-d) δ 164.0, 152.92, 143.7, 143.4, 138.4, 134.1, 129.2, 128.9, 127.5, 124.1, 119.8, 117.5, 115.9, 108.6, 82.8, 45.4, 28.2, 22.7.

[0741] HRMS (ESI) for C 23 H 25 N4O3 + Calculation, [M+H] + 405.1927; found m / z 405.1927.

[0742] 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, 71

[0743]

[0744] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and thiazole-2-carbaldehyde (37.8 μL, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV gave 71 (40 mg, 34%) as a yellow solid.

[0745] 1 H NMR (400MHz, chloroform-d) δ10.57 (s, 1H), 7.64 (d, J = 3.3Hz, 1H), 7.21–7.12 (m, 3H), 7.10 (s, 1H), 6.86 (t ,J=7.3Hz,1H),6.79(d,J=8.0Hz,2H),4.10(t,J=6.3Hz,2H),2.91(t,J=6.3Hz,2H),1.55(s,9H);

[0746] 13 C NMR (101 MHz, chloroform-d3) δ 163.2, 157.0, 153.0, 143.0, 139.1, 138.7, 129.0, 120.8, 118.4, 118.2, 116.9, 109.2, 83.0, 45.0, 28.2, 22.9;

[0747] HRMS (ESI) for C 21 H 22 N4O3SNa + Calculation, [M+Na] + 433.1310; found m / z 433.1308.

[0748] 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

[0749]

[0750] Synthesized according to GP2 using 5a (100 mg, 0.287 mmol) and 1-methyl-1H-imidazole-2-carbaldehyde (47.4 mg, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV afforded 7m (40 mg, 34%) as a yellow solid.

[0751] 1 H NMR (400 MHz, chloroform-d) δ 12.75 (br s, 1H), 7.04–6.94 (m, 3H), 6.73 (t, J = 7.3 Hz, 1H), 6.69–6.63 (m, 3H), 4.10 (t, J = 6.3 Hz, 2H), 3.34 (s, 3H), 2.94 (t, J = 6.3 Hz, 2H), 1.56 (s, 9H);

[0752] 13 C NMR (101 MHz, chloroform-d) δ 164.5, 153.1, 143.3, 141.8, 138.1, 128.8, 128.6, 126.4, 121.0, 120.0, 115.2, 106.8, 106.5, 82.7, 45.4, 33.6, 28.2, 22.6;

[0753] HRMS (ESI) for C 22 H 26 N5O3 + Calculation, [M+H] + 408.2036; found m / z 408.2035.

[0754] 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

[0755]

[0756] 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 gave 7n (93 mg, 69%) as a yellow solid.

[0757] 1 H NMR (400MHz, DMSO-d6) δ11.96(s,1H),7.77(d,J=8.1Hz,2H),7.64(d,J=8.1Hz,2H),7.35(s,1H),7 .02(t,J=7.6Hz,1H),6.63–6.55(m,3H),3.96(t,J=6.0Hz,2H),2.95(t,J=6.0Hz,2H),1.44(s,9H);

[0758] 13 C NMR (101MHz, DMSO-d6) δ161.7,153.1,146.1,139.0,135.3,128.7,125.4,124.7,124.6,122.6,117.6,114.0,109.4,81.3,45.1,27.8,22.3;

[0759] 19F NMR(376MHz,DMSO-d6)δ-60.7;

[0760] HRMS (ESI) for C 25 H 25 F3N3O3 + Calculation, [M+H] + 472.1848; found m / z 472.1845.

[0761] 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

[0762]

[0763] 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 linear gradient of 0-90% EtOAc in heptane over 10CV gave 7o (95 mg, 74%) as a red solid.

[0764] 1 H NMR (400MHz, DMSO-d6) δ12.10(s,1H),8.14(d,J=8.6Hz,2H),7.77(d,J=8.6Hz,2H),7.51(s,1H),7 .04(t,J=7.6Hz,2H),6.71–6.54(m,3H),3.97(t,J=6.2Hz,2H),2.98(t,J=6.3Hz,2H),1.45(s,9H);

[0765] 13 C NMR(101MHz,DMSO-d6)δ162.2,153.5,145.8,144.6,140.7,138.2,129.2, 127.2,124.9,124.,122.2,118.6,114.8,109.84,81.9,45.5,28.3,22.8;

[0766] HRMS (ESI) for C 24 H 25 N4O5 + Calculation, [M+H] + 449.1823; found m / z 449.1823.

[0767] 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

[0768]

[0769] 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 20CV gave 7p (76 mg, 62%) as a yellow solid.

[0770] 1 H NMR (400 MHz, chloroform-d) δ9.83 (s, 1H), 7.49 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.06–6.95 (m, 3H), 6.78–6.67 (m, 1H), 6.67–6.50 (m, 2H), 4.03 (t, J = 6.3 Hz, 2H), 2.89 (t, J = 6.3 Hz, 2H), 1.50 (s, 9H);

[0771] 13 C NMR (101 MHz, chloroform-d) δ 164.3, 152.6, 143.4, 138.3, 135.8, 132.2, 128.8, 127.6, 124.8, 120.0, 119.8, 119.3, 115.8, 108.8, 108.0, 83.1, 45.4, 28.1, 22.8;

[0772] HRMS (ESI) for C 25 H 23 N4O3 – Calculation, [MH] – 427.1770; found m / z 427.1773.

[0773] 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

[0774]

[0775] 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 10CV gave 7q (82 mg, 65%) as a yellow solid.

[0776] 1 H NMR(400MHz,DMSO-d6)δ11.90(br s,1H),7.34(s,1H),7.30–7.23(m,2H),7.10–7.00(m,2H),6.97(t,J=9.0Hz,1H ),6.65–6.56(m,3H),3.95(t,J=6.2Hz,2H),2.94(t,J=6.2Hz,2H),1.44(s,9H);

[0777] 13 C NMR (101MHz, DMSO-d6) δ164.3,162.0,146.4,139.4,134.8,129.2,125.2,122.5,118.2,114.4,110.0,107.7,107.4,81.8,45.5,28.3,22.7;

[0778] 19 F NMR(376MHz,DMSO-d6)δ-110.0;

[0779] HRMS (ESI) for C 24 H 24 F2N3O3 + Calculation, [M+H] + 440.1786; found m / z 440.1786.

[0780] 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

[0781]

[0782] Due to the solubility problem of the bisulfite adduct 11, the reaction was performed in a one-pot procedure with 1,4-dioxane as solvent instead of following GP2.

[0783] A mixture of 5a (100 mg, 0.287 mmol), 11 (90.9 mg, 0.431 mmol), and NH4OAc (111 mg, 1.44 mmol) in 1,4-dioxane (2.00 mL) was heated to 70 ° C for 18 hours. Additional 11 (90.9 mg, 0.431 mmol) was added, and the mixture was stirred at 70 ° C for another 24 hours. The reaction mixture was quenched with a saturated aqueous solution of 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 performed by silica gel chromatography, eluting with n-heptane / EtOAc (80:20 to 0:100) and then DCM / MeOH (100:0 to 90:10) to give 7a (35 mg, 30% yield) as a white solid.

[0784] 1 H NMR (400 MHz, chloroform-d) δ 10.20 (s, 1H), 8.37–8.27 (m, 2H), 7.32–7.22 (m, 3H), 7.11–7.00 (m, 2H), 6.76 (tt, J = 7.3, 1.1 Hz, 1H), 6.70–6.61 (m, 2H), 4.08 (t, J = 6.3 Hz, 2H), 2.91 (t, J = 6.3 Hz, 2H), 1.54 (s, 9H);

[0785] LCMS (ESI) for C 23 H 25 N4O3 + Calculation, [M+H] + 405.2; found m / z 405.3.

[0786] The NMR / MS spectrum matched that obtained previously.

[0787] 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

[0788]

[0789] 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 45CV gave 7r (39.0 mg, 68%) as a yellow solid.

[0790] 1 H NMR (400MHz, chromatogram-d) δ11.27(s,1H),8.31(d,J=5.4Hz,2H),7.33(d,J=5.4Hz,2H),7.27(d,J=4.7Hz,3H),6.84(t,J=7 .7Hz,1H),6.66(t,J=7.6Hz,1H),6.41(d,J=8.1Hz,1H),4.06(t,J=6.4Hz,2H),2.90(t,J=6.3Hz,2H),1.51(s,9H);

[0791] 13 C NMR (101 MHz, chloroform-d) δ 163.8, 152.2, 144.0, 141.9, 141.7, 139.4, 129.5, 127.2, 121.6, 120.6, 119.7, 119.2, 114.4, 109.0, 83.5, 45.3, 28.2, 27.9, 22.5;

[0792] HRMS (ESI) for C 23 H 24 ClN4O3 + Calculation, [M+H] + 439.1541; found m / z 439.1541.

[0793] 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

[0794]

[0795] 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 45CV gave 7s (35 mg, 61%) as a yellow solid.

[0796] 1H NMR (400MHz, chloroform-d) δ11.10(s,1H),8.32(d,J=6.3Hz,2H),7.34(d,J=6.3Hz,2H),7.19(s,1H),6.98(t,J=8.0 Hz,1H),6.71(d,J=7.9Hz,1H),6.59–6.53(m,2H),4.07(t,J=6.3Hz,2H),2.91(t,J=6.3Hz,2H),1.54(s,9H);

[0797] 13 C NMR (101 MHz, chloroform-d) δ 164.3, 153.2, 148.1, 145.2, 140.3, 140.2, 135.1, 129.3, 130.4, 120.5, 119.5, 116.2, 114.7, 109.6, 83.7, 45.7, 28.8, 28.6, 23.2;

[0798] HRMS (ESI) for C 23 H 24 ClN4O3 + Calculation, [M+H] + 439.1541; found m / z 439.1533.

[0799] 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

[0800]

[0801] Synthesized according to GP2 using 5t (50.0 mg, 0.131 mmol) and 6a (18.5 μL, 0.197 mmol). Silica gel chromatography using a 12 g SiO2 cartridge and a linear gradient of 0-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV gave 7t (35 mg, 61%) as a yellow solid.

[0802] 1 H NMR (400MHz, chloroform-d) δ10.94(s,1H),8.31(d,J=6.1Hz,2H),7.28(d,J=6.1Hz,2H),7.25(s,1H),7.00 (d,J=8.8Hz,2H),6.57(d,J=8.8Hz,2H),4.08(t,J=6.3Hz,2H),2.91(t,J=6.3Hz,2H),1.54(s,9H);

[0803] 13 C NMR (101 MHz, chloroform-d) δ 163.9, 152.4, 143.9, 141.7, 141.6, 141.4, 131.5, 128.8, 125.1, 119.0, 118.1, 117.1, 108.6, 83.3, 45.1, 28.2, 27.9;

[0804] HRMS (ESI) for C 23 H 24 ClN4O3 + Calculation, [M+H] + 439.1541; found m / z 439.1539.

[0805] 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

[0806]

[0807] 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 40CV gave 7u (37 mg, 64%) as a yellow solid.

[0808] 1 H NMR (400MHz, chloroform-d) δ10.56(s,1H),8.31(d,J=5.4Hz,2H),7.47(s,1H),7.32(d,J=5.5Hz,2H),6.81(d,J=8.0Hz,1H),6.70(t,J=7 .7Hz,1H),6.54(t,J=7.6Hz,1H),6.26(d,J=7.8Hz,1H),4.05(t,J=6.3Hz,2H),3.86(s,3H),2.89(t,J=6.3Hz,2H),1.51(s,9H);

[0809] 13 C NMR (101 MHz, methanol-d4) δ 174.6, 163.0, 158.8, 158.5, 150.3, 150.1, 143.0, 139.0, 130.2, 129.5, 129.4, 129.1, 123.1, 120.4, 118.6, 93.0, 65.2, 55.8, 42.0, 37.3;

[0810] HRMS (ESI) for C 24 H 26 N4O4 + Calculate [M+H] + 435.2032; found m / z 435.2032.

[0811] 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

[0812]

[0813] Synthesized according to GP2 using 5v (50.0 mg, 0.119 mmol) and 6a (16.8 μL, 0.178 mmol). Silica gel chromatography using a 12 g SiO2 cartridge and a linear gradient of 0-100% EtOAc in heptane over 10CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV gave 7v (35 mg, 61%) as a yellow solid.

[0814] 1 H NMR (400MHz, chloroform-d) δ11.42(s,1H),8.29(d,J=6.0Hz,2H),7.74(d,J=8.5Hz,2H),7.39(s,1H),7.31(d,J=6.0Hz,2H),6.60 (d,J=8.5Hz,2H),4.27(q,J=7.1Hz,2H),4.06(t,J=6.3Hz,2H),2.90(t,J=6.3Hz,2H),1.52(s,9H),1.32(t,J=7.1Hz,3H);

[0815] 13 C NMR (101 MHz, chloroform-d) δ 167.2, 164.2, 153.1, 148.0, 139.6, 139.4, 131.4, 127.5, 121.7, 120.1, 119.5, 115.2, 109.6, 83.5, 61.0, 45.7, 28.8, 28.5, 23.2, 14.8;

[0816] HRMS (ESI) for C 26 H 29 N4O5 + Calculate [M+H] + 477.2138; found m / z 477.2138.

[0817] 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

[0818]

[0819] Synthesized according to GP2 using 5y (100 mg, 0.287 mmol) and 6a (39.0 μL, 0.431 mmol). Silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 13CV followed by a linear gradient of 0-10% MeOH in DCM over 13CV afforded 7y (75 mg, 65%) as a yellow solid.

[0820] 1 H NMR (400MHz, chloroform-d) δ9.94 (br s,1H),8.30–8.24(m,2H),7.37(s,1H),7.28(d,J=5.7Hz,2H),7.06(t,J=7.6Hz,2H),6.76(t,J=7.3Hz,1H),6.65(d,J=7.9 Hz,2H),4.15(dd,J=13.1,4.6Hz,1H),3.70(dd,J=13.0,8.3Hz,1H),3.26–3.13(m,1H),1.55(s,9H),1.37(d,J=7.3Hz,3H);

[0821] 13 C NMR (101 MHz, chloroform-d) δ 163.8, 153.0, 148.5, 143.2, 138.9, 139.1, 129.0, 129.6, 120.2, 118.9, 117.8, 116.3, 108.0, 83.0, 51.9, 28.5, 28.2, 15.9;

[0822] HRMS (ESI) for C 24 H 27 N4O3 + Calculation, [M+H] + 419.2083; found m / z 419.2082.

[0823] 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)

[0824] 3-(2-methoxy-2-methylpropoxy)isonicotinonitrile, 13 4

[0825]

[0826] According to the changed literature procedure, 4 To a suspension of NaH (60% dispersion in mineral oil, 99.6 mg, 2.49 mmol, 1.15 equiv) in DMF (6.00 mL) at 0 ° C was added 2-methoxy-2-methylpropane-1-ol (285 μL, 2.60 mmol, 1.20 equiv) and the mixture was stirred at this temperature for 15 minutes. 3-Chloropyridine-4-carbonitrile (300 mg, 2.17 mmol, 1.00 equiv) was added and the mixture was stirred for 2 hours, allowing it to warm to room temperature. Subsequently, 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 give 13 (392 mg, 88%) as a white solid,

[0827] 1 H NMR (400 MHz, chloroform-d) δ 8.72 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 7.77 (dd, J = 4.8, 0.7 Hz, 1H), 4.19 (s, 2H), 3.17 (s, 3H), 1.24 (s, 6H);

[0828] 13 C NMR (101MHz, DMSO-d6) δ155.2,142.7,137.3,126.5,114.8,108.3,75.2,74.3,49.8,22.3;

[0829] HRMS (ESI) for C 11 H 15 N2O2 + Calculate [M+H] + 207.1134; found m / z 207.1138.

[0830] Data and Literature 4 The match in .

[0831] 3-(2-methoxy-2-methylpropoxy)isonicotinaldehyde,14

[0832]

[0833] To a solution of 13 (300 mg, 1.46 mmol, 1.00 equiv) in toluene (15.0 mL) was added DIBAL-H (1.0 M in toluene, 2.18 mL, 0.728 mmol, 1.50 equiv) dropwise at 0 °C, and the mixture was stirred at this temperature for 4 hours. DIBAL-H (1.0 M in toluene, 727 μL, 0.728 mmol, 0.500 equiv) was added, and the mixture was stirred for another 2 hours. 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.

[0834] 1 H NMR (400 MHz, chloroform-d) δ 10.58 (s, 1H), 8.55 (s, 1H), 8.40 (d, J = 4.8 Hz, 1H), 7.59 (d, J = 4.8 Hz, 1H), 4.06 (s, 2H), 3.29 (s, 3H), 1.34 (s, 6H);

[0835] 13 C NMR (101 MHz, chloroform-d) δ 188.9, 155.3, 143.1, 137.2, 129.4, 119.9, 75.3, 74.2, 49.9, 22.1;

[0836] HRMS (ESI) for C 11 H 15 NO3 + Calculate [M+H] + 210.1130; found m / z 210.1134.

[0837] 1-Fluoro-3-isothiocyanato-2-methoxybenzene,16 5

[0838]

[0839] According to the literature procedure 5, thiophosgene (272 μL, 3.54 mmol, 1.00 equiv) was added to a stirred mixture of 3-fluoro-2-methoxyaniline (500 mg, 3.54 mmol, 1.00 equiv) in DCM (5.00 mL) and saturated NaHCO3 aqueous solution (5.00 mL), and the mixture was stirred at 0°C for 2 hours. 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.

[0840] 1 H NMR (400 MHz, chloroform-d) δ 7.09–6.79 (m, 3H), 4.03 (d, J = 1.9 Hz, 3H);

[0841] 19 F NMR (376 MHz, chloroform-d) δ–129.1.

[0842] Data and Literature 5 The match in .

[0843] 5-((3-Fluoro-2-methoxyphenyl)aminomethylsulfonyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)- Tert-butyl carboxylate, 17 5

[0844]

[0845] 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 afforded 17 (960 mg, 73%) as an off-white solid.

[0846] 1 H NMR (400MHz, DMSO-d6) δ13.38(s,1H),7.57(dt,J=8.1,1.5Hz,1H),7.26(ddd,J=11.3,8.4,1.6Hz,1H),7.1 6(td,J=8.3,5.8Hz,1H),3.86(d,J=1.5Hz,3H),3.79(t,J=6.5Hz,2H),2.89(t,J=6.5Hz,2H),1.49(s,9H);

[0847] 13C NMR (101MHz, DMSO-d6) δ189.9, 186.2, 155.6 (d, J = 245.0Hz), 152.3, 132.4 (d, J = 4.3Hz), 123.8 (d ,J=8.7Hz),123.1(d,J=3.1Hz),116.1(d,J=18.9Hz),103.1,83.1,62.0(d,J=4.9Hz),31.4,28.1;

[0848] 19 F NMR(376MHz,DMSO-d6)δ-130.0;

[0849] HRMS (ESI) for C 18 H 20 FN2O5S – Calculation, [MH] – 395.1077; found m / z 395.1077.

[0850] Data and Literature 5 The match in .

[0851] 18 4

[0852]

[0853] To a mixture of 17 (100 mg, 0.252 mmol, 1.00 equiv) and NH4OAc (97.2 mg, 1.26 mmol, 5.00 equiv) in toluene (1 mL) was added dropwise over 2.5 hours using a syringe pump at 90 ° C. A solution of 14 (79.2 mg, 0.378 mmol, 1.50 equiv) in 1,4-dioxane (1.00 mL) was added, and the mixture was stirred at 90 ° C. for 18 hours and then cooled to room temperature. The reaction mixture was concentrated to about 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 equiv) was added under vigorous stirring, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (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. Purification by silica gel chromatography using a 24 g SiO2 cartridge and a linear gradient of 20-100% EtOAc in heptane over 13CV followed by a linear gradient of 0-10% MeOH in DCM over 20CV afforded 18 (64 mg, 56%) as an off-white solid.

[0854] 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 8.42 (s, 1H), 8.02 (d, J = 5.1Hz, 1H), 7.51 (s, 1H) ),7.29(d,J=5.1Hz,1H),7.16(t,J=2.6Hz,1H),6.67(td,J=8.3,6.1Hz,1H),6.51(dd d,J=11.0,8.4,1.5Hz,1H),6.04(dt,J=8.3,1.3Hz,1H),4.19(s,2H),3.92(d,J=0.8H z,3H),3.43(td,J=6.9,2.5Hz,2H),3.26(s,3H),2.84(t,J=6.8Hz,2H),1.28(s,6H);

[0855] 13 C NMR (101MHz, DMSO-d6) δ165.8,155.8(d,J=242.0Hz),150.2,143.3,140.0(d,J=4.7Hz),137.4,136.1,135.5(d,J=13.4Hz ),127.8,125.9,124.0(d,J=9.8Hz),120.4,117.1,109.2,108.1,106.2(d,J=19.0Hz),75.5,75.1,49.7,40.5,22.5,22.1;

[0856] 19 F NMR(376MHz,DMSO-d6)δ–132.7;

[0857] HRMS (ESI) for C 24 H 28 Calculated for FN4O4, [M+H] + 455.2095; found m / z 455.2098.

[0858] Data and Literature 4 The match in .

[0859] 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)

[0860] Step 1:

[0861]

[0862]

[0863] √

[0864]

[0865]

[0866]

[0867]

[0868] IPAc at 10 V gave the highest IPC purity (97.9 A%).

[0869]

[0870] Comparing different bases (TEA, DIIEA and DBU) on a 5 g scale reaction, DIEA provided 98.2A% IPC purity.

[0871]

[0872] Step 2:

[0873]

[0874]

[0875]

[0876] √

[0877]

[0878] Screening different bases (DBU, DIEA and TEA), base equivalents, and temperatures, using 20 V of IPAc as solvent, 1.1 equivalents of DBU gave 90.4% IPC purity.

[0879]

[0880]

[0881]

[0882] Screening different bases (DBU, DIEA and TEA), base equivalents, and temperatures, using 20 V of IPAc as solvent, 1.1 equivalents of DBU gave 90.4% IPC purity. This condition was used for scale-up.

[0883] Solubility data of compound 2 and compound 2 containing DBU

[0884]

[0885] Steps 1 and 2 (Folding Procedure)

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892] Step 3:

[0893]

[0894] Step 3:

[0895]

[0896]

[0897] Figure 2 The H NMR data of compound 101 are included.

[0898] Solubility data of compound 101

[0899] Solvents Solubility n-Heptane <5mg / ml EtOAc 6.25mg / ml DCM >125mg / ml MeOH 7.1mg / ml EtOH 6.25mg / ml MTBE 6.25mg / ml ACN 33mg / ml Toluene <5mg / ml

[0900]

[0901]

[0902] Steps 3 and 4

[0903]

[0904]

[0905]

[0906]

[0907] Crystallization of compound 102 using 5V of different solvents (DCM, MeCN, MTBE, THF, MeOH, EtOAc and toluene) was attempted for purification, however, compound 102 was insoluble in all these solvents except THF under reflux.

[0908] √THF was used as the solvent for purification, and the purity of compound 102 increased from 95.3A% to 98.6A% with a yield of about 40%.

[0909] √ In the case of toluene as the solvent for purification, the residual S by IC decreased from 1.0% w / w to 0.056% w / w, while QNMR increased from 87.1% to 95.7%, HPLC purity 97.1A).

[0910] Solubility data of compound 102

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919] In order to improve the purity of compound 102 and reduce the sulfur content in compound 102, different solvents were tried for crystallization / slurry. DMAc / toluene conditions obtained the best purity improvement results (from 95.2A% to 99.2A%), and NMP / water and DMAc / water conditions obtained the best S removal ability (2.24% to 0.10%).

[0920] 5 g of crude compound 102 was purified using DMAc / toluene conditions. 3.6 g of compound 102 was obtained with a purity of 99.1A% (without integration of DMAC) and a yield of 72% (without QNMR correction). The residual S was 0.35% and the potency obtained by QNMR was 88%.

[0921] Figure 3 Compound 102 1H NMR. About 12% of DMAC was retained in compound 102.

[0922]

[0923] To remove DMAc, 3.5 g of compound 102 (QNMR: 88%) was reslurried with 10 V of water to give 2.7 g of compound 102 with a purity of 99.2A% and a yield of 77% (not corrected by QNMR).

[0924] To increase the crystallization yield (DMAc / toluene system), 2 V of DMAC and 7 V of toluene were tried, yielding compound 102 in 99.2 A% purity (DMAC not integrated).

[0925] Compound 102

[0926] 10 g of crude compound 102 was purified using 2V DMAC / 7V toluene to obtain 8.5 g of compound 102 with a purity of 99.2A% (without integration of DMAC) and a yield of 85% (without QNMR correction). The 8.5 g of compound 102 was reslurried with water to remove DMAc. Figure 4A-4B The LC-MS spectrum and powder pattern of compound 102 are included.

[0927]

[0928]

[0929]

[0930] 10 g of compound 102 (88% assay) were purified via stage 1 (crystallization from DMAc / toluene) and stage 2 (slurrying with water).

[0931] In stage 1, 8.5 g (containing -12% w / w DMAc by QNMR) of compound 102 was obtained with a purity of 99.0A% (without integration of DMAc) and a yield of 85% (without QNMR correction).

[0932] Stage 2, 6.5 g of compound 102 was obtained with a purity of 99.7A% and a potency of 99.5% as determined by QNMR. The yield was 65% yield (for 10 g of crude compound 102) and the residual S was 119 ppm.

[0933]

[0934] To reduce losses during purification, different ratios of DMAC / toluene (1 V / 3 V, 0.5 V / 3.5 V) were tried on a 5 g scale.

[0935] DMAC / toluene=1V / 3V, 3.5g of compound 102 was obtained with a purity of 99.6A%, a potency of 99.5%, and a recovery yield of 70% as determined by QNMR, and a residual S of 119ppm.

[0936] DMAC / toluene=0.5V / 3.5V, 3.6g of compound 102 was obtained with a purity of 96.9A%, a potency of 98.5%, and a recovery yield of 72% as determined by QNMR, with a residual S of 423ppm.

[0937]

[0938] Mass balance data for steps 3 and 4 were collected, based on which approximately 20% of the product was lost during workup and purification.

[0939]

[0940]

[0941] A pilot batch on a 300 g scale gave 57.5 A% IPC purity in step 3 (assay yield at the end of the reaction: 61.9 A%) and 58.0 A% IPC purity in step 4. After work-up, 143 g of compound 102 were obtained with a purity of 99.4 A% and a yield of 44% (corrected by QNMR).

[0942] 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)

[0943] Production Overview

[0944]

[0945] Production of steps 1 and 2

[0946] 1) Production path

[0947]

[0948] 2) Process Description

[0949] Preparation of 1-chloro-3-isothiocyanato-2-methoxybenzene, 1

[0950] Under nitrogen atmosphere, isopropyl acetate (IPAC) was sprayed into the reactor, heated to reflux for at least 30 minutes, and cooled to 20±10°C, and transferred to another reactor through the feed line, filter tank, pneumatic pump, and liquid transfer line, heated to reflux for at least 30 minutes, and cooled to 20±10°C, and placed in a bucket. The reactor was dried, and the discharge pipe, pressure filter tank, pneumatic pump, and liquid transfer line were blown dry.

[0951] First separation

[0952] Allow to stand under nitrogen for at least 30 minutes, separate, and collect the aqueous and organic phases.

[0953] First extraction

[0954] Under N2, add the aqueous phase to the reactor and adjust the temperature to 20±5°C. Add IPAc (3.00V) to the reactor at 20±5°C, stir for at least 20 minutes, let stand for at least 30 minutes, separate, and collect the aqueous phase and organic phase. Take a sample of the aqueous phase for product loss test (IPM), and the organic phase is to be combined and washed.

[0955] washing

[0956] Under N2, 10% sodium chloride aqueous solution (3.33w / w) and the organic phase were added to the reactor, the temperature was adjusted to 20±5°C, stirred for at least 20 minutes, allowed to stand for at least 30 minutes, separated, the organic phase was collected, and waited for the first concentration.

[0957] First Concentration

[0958] Add the organic phase to the reactor through a fluid filter. Control the internal temperature of the reactor not to exceed 45°C, or the jacket temperature not to exceed 55°C, and concentrate until the volume is 1.0-1.5V.

[0959] Second Concentration

[0960] Under N2, MeOH (3.00 V) was added to the reactor. The internal temperature of the reactor was controlled not to exceed 45°C or the jacket temperature was controlled not to exceed 55°C, and the reaction mixture was concentrated to a volume of 1.0-1.5 V.

[0961] The third concentration

[0962] Under N2, feed MeOH (3.00V) into the reactor. Control the internal temperature of the reactor not to exceed 45C, or the jacket temperature not to exceed 55C, and concentrate until the volume is 1.0-1.5V. Adjust the temperature to 25±5C. Feed MeOH (3.00V) into the reactor. Take a sample for GC analysis. The standard is: area % of IPAc ≤5% and KF ≤0.5%. If the area % of IPAc is >5% or KF>0.5%, repeat the solvent exchange procedure with MeOH until the area % of IPAc is ≤5% and KF ≤0.5%. Take a sample for Q-NMR and report the results. Discharge the concentrated system in the reactor to the cylinder.

[0963] Preparation of 1-chloro-3-isothiocyanato-2-methoxybenzene, 1

[0964] Feeding and reaction

[0965] Under nitrogen, add IPAC to the reactor and start stirring. Adjust the temperature to 20±5°C. After stirring for at least 5 minutes, take a sample for KF, standard: KF does not exceed 0.08%. If not, discharge and add new solvent. Subsequently, add 3-chloro-2-methoxyaniline (SM1 1.00 equivalents) and DIPEA (2.50 equivalents) to the reactor. Cool to 0-5°C and add thiophosgene (0.98 equivalents) dropwise to the reactor at 5±5°C (it is recommended to add for at least 2 hours). After the addition is complete, continue to control the temperature at 5±5°C and stir for at least 2 hours. Take a sample for HPLC analysis, standard: the area % of SM1 ≤3.0%, and the total number of samplings should not exceed two times. Take a sample for IPM analysis and report the content of thiophosgene.

[0966] Quenching

[0967] Under nitrogen, adjust the temperature of the hydrochloric acid solution to 5-10°C and replace with nitrogen three times. At 10±5°C, add 3M hydrochloric acid aqueous solution (3.00V) to the reaction system. Take a sample, pH = 1-4. Stir for at least 30 minutes, and then test the pH, the standard is pH = 1-4; if pH>4, add 3M hydrochloric acid aqueous solution to ensure pH = 1-4. Stir at 20±5°C for at least 3 hours (during stirring, pump nitrogen to remove hydrogen in the system).

[0968] Fourth Concentration

[0969] Control the internal temperature of the reactor not to exceed 45°C or the jacket temperature not to exceed 55°C, and concentrate until the volume is 3-4 V. Adjust the temperature to 20±5°C.

[0970] Second separation

[0971] Add demineralized water (3.00V) to the reactor at 20±5°C under nitrogen. When the temperature is 20±5°C, add 10% sodium carbonate aqueous solution (6.67w / w) to the reaction dropwise. Take a sample, check pH=8-9, stir for at least 30 minutes, and then test 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 then test pH=8-9. Add IPAc (5.00V), stir for at least 20 minutes, let stand for at least 30 minutes, separate, and collect the aqueous and organic phases.

[0972] Second extraction

[0973] Under N2, the aqueous phase was introduced into the reactor and the temperature was adjusted to 20±5° C. IPAc (5.00 V) was introduced into the reactor at 20±5° C., stirred for at least 20 minutes, allowed to stand for at least 30 minutes, separated, and the aqueous phase and the organic phase were collected.

[0974] The third extraction

[0975] Under N2, add the aqueous phase to the reactor and adjust the temperature to 20±5°C. Add IPAc (5.00V) to the reactor at 20±5°C, stir for at least 20 minutes, let stand for at least 30 minutes, separate, and collect the aqueous phase and organic phase. Combine the organic phase. Take a sample of the aqueous phase for product loss test (IPM), and the organic phase is to be concentrated. Fifth concentration.

[0976] The organic phase was added to the reactor through a fluid filter. The internal temperature of the reactor was controlled not to exceed 45°C or the jacket temperature not to exceed 55°C, and concentrated to a volume of 1.0-1.5V.

[0977] Sixth Concentration

[0978] DCM (5.00 V) was added to the reactor. The internal temperature of the reactor was controlled not to exceed 45°C or the jacket temperature was controlled not to exceed 55°C, and the reaction mixture was concentrated until the volume was 1.0-1.5 V.

[0979] Seventh Concentration

[0980] DCM (5.00 V) is added to the reactor. The internal temperature of the reactor is controlled not to exceed 45°C or the jacket temperature is controlled not to exceed 55°C, and the volume is concentrated until the volume is 1.0-1.5 V. The temperature is adjusted to 25±5°C. DCM (4.00 V) is added to the reactor. Samples are taken for GC analysis. The standards are: the area % of MeOH ≤ 5% and the area % of IPAc ≤ 20% and KF ≤ 0.2%. If the area % of MeOH> 5% or IPAc> 20% or KF> 0.2%, the solvent exchange procedure with DCM is repeated until the area % of MeOH ≤ 5% and the area % of IPAc ≤ 20% and KF ≤ 0.2%.

[0981] Feed (liquid product)

[0982] Take samples for HPLC and Q-NMR testing. Report results. Transfer product from reactor to cartridges, weigh and label. Store at room temperature.

[0983] 3) Process of steps 1 and 2

[0984] 1. Charge IPAC (20 V) into the reactor under nitrogen.

[0985] 2. Charge SM1 (1.0 eq.) and TEA (2.5 eq.) into the reactor and start stirring at 20±5°C.

[0986] 3. Cool to 5±5C.

[0987] 4. Add SCCl2 (1.0 equivalent) dropwise into the reactor at 5±5°C

[0988] 5. Stir at 5±5°C for 2h.

[0989] 6. Take samples for HPLC analysis.

[0990] 7. Filter.

[0991] 8. Charge IPAC solution and SM2 (1.0 eq.) to the reactor under nitrogen.

[0992] 9. Cool to 5±5C.

[0993] 10. DBU (1.1 eq.) was added dropwise into the reactor.

[0994] 11. Stir at 20±5°C for 12h.

[0995] 12. Take samples for HPLC analysis.

[0996] 13. Adjust the pH of the reaction to 5-6 using aqueous citric acid solution (0.2 M) at 20±5°C.

[0997] 14. Separate and wash the organic phase with 5% aqueous NaHCO3 solution (5V) at 20±5°C.

[0998] 15. Wash the organic phase with 15% NaCl aqueous solution (5V) at 20±5°C.

[0999] 16. Concentrate the organic phase to 3-4V at 45±5C.

[1000] 17. Add MeOH (10 V) at 45 ± 5 C and concentrate to 4-5 V.

[1001] 18. Add MeOH (10 V) at 45 ± 5 C and concentrate to 4-5 V.

[1002] 19. Stir at 20±5°C for 1 hour.

[1003] 20. Filter and wash the filter cake with MeOH (2V).

[1004] 21. Collect and dry the filter cake at 40±5C.

[1005] 4) Production data summary

[1006]

[1007] 5) Results

[1008] The 20 g scale test ran well with an IPC purity of 97.9 A% in step 1 and 88.8 A% in step 2.

[1009] The 29 kg production batch ran well with an IPC purity of 97.7 A% in step 1 and 85.0 A% in step 2. After work-up, 60 kg of compound 2 was obtained with an IPC purity of 99.5 A% in 78.9% yield (not corrected by QNMR).

[1010] Production of steps 3 and 4

[1011] 1) Process path

[1012]

[1013] 2) Process Description

[1014] Prepare 6% citric acid solution

[1015] Under nitrogen, demineralized water (24.00 V) was added to the reactor and agitation was started. Citric acid (1.51 w / w) was added to the reactor, the temperature was adjusted to 20±10° C., stirred for dissolution, and discharged into a cylinder for temporary storage.

[1016] Feeding and reaction

[1017] Add IPAC (8.00 V) to the reactor storing 1-chloro-3-isothiocyanato-2-methoxybenzene and start stirring under nitrogen. Adjust the temperature to 20±5°C. After stirring for 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 equivalents) dropwise to the reactor at 5±5°C (it is recommended to add for at least 1 hour). After the addition is complete, adjust the temperature to 20±5°C (it is recommended that the temperature increase continue for at least 1 hour), and stir for at least 12 hours. Take a sample for HPLC analysis, standard: area % of 1-chloro-3-isothiocyanato-2-methoxybenzene (1) ≤5.0%. If not, stir for at least 8 hours and take a sample for HPLC until the area % of 1-chloro-3-isothiocyanato-2-methoxybenzene (1) is ≤ 5.0%. Take a sample for IPM analysis and report the thiophosgene content.

[1018] Quenching and separation

[1019] Add 6% citric acid solution to the reaction system at 20±5°C to adjust the pH to 5-6. Stir for at least 20 minutes and test pH=5-6. Stir for at least 2 hours at 20±5°C (nitrogen is blown into the system). Take a sample to detect hydrogen sulfide. The hydrogen sulfide concentration in the head space is less than 1ppm. If it does not meet the standard, continue to blow nitrogen until it meets the standard. Keep for at least 30 minutes, separate, and collect the organic phase.

[1020] washing

[1021] Add demineralized water (5.00 V) to the organic phase, adjust the temperature to 20 ± 5 ° C, incubate for at least 30 minutes, maintain for at least 30 minutes, separate, and collect the organic treatment concentrate.

[1022] First Concentration

[1023] Control the jacket temperature not to exceed 45° C. and the internal temperature not to exceed 35° C. Concentrate to 5-6V.

[1024] Second Concentration

[1025] Adjust the temperature to 20±10°C, add methanol (10.00V) into the reactor, control the jacket temperature not to exceed 45°C, and the internal temperature not to exceed 35°C, and concentrate to 5-6V.

[1026] The third concentration

[1027] Adjust the temperature to 20±10°C and add methanol (10.00V) to the reactor. Control the jacket temperature not to exceed 45°C and the internal temperature not to exceed 35°C. Concentrate to 5-6V. Adjust the temperature to 20±5°C, take samples for HPLC and GC (IPM), and report the content of 2 and the area % of IPAC in the mother liquor.

[1028] Feed (liquid product)

[1029] Take samples for HPLC and Q-NMR testing. Report results. Transfer the concentrate from the reactor to a cartridge, weigh and label. Store at room temperature.

[1030] 3) Process of steps 3 and 4

[1031] 1. Add 5-((3-chloro-2-methoxyphenyl)aminomethylthioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2) (1.0 equivalent) and NH4OAc (5.0 equivalent) to toluene (7.5 V)

[1032] 2. Heat to 95±5°C and add the previously prepared solution of SM3 (1.5 equivalents, in toluene / 1,4-dioxane, 15V, 1 / 1) dropwise into the reactor at 95±5°C.

[1033] 3. Stir at 95±5°C for 16 h and take a sample for HPLC analysis. Standard: tert-butyl 5-((3-chloro-2-methoxyphenyl)aminomethylthioyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (2) ≤ 5.0%

[1034] 4. Concentrate to 3-4V at 50±5C and add EA (6V) to the reactor.

[1035] 5. Add 4M HCl / EtOH (3V) dropwise into the reactor at 25±5°C and stir for at least 3 h.

[1036] 6. Samples were taken for HPLC analysis, standard: 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-carboxylic acid tert-butyl ester (Compound 101) ≤ 2.0%

[1037] 7. Filter and wash the filter cake with EA (1V).

[1038] 8. The filter cake was placed into EA / MeOH=10:1 (10 V).

[1039] 9. Add 10% K2CO3 aqueous solution (10V) to the reactor at 25±5°C and stir for at least 5 hours. (Note: pH: 8-9)

[1040] 10. Filter and wash the filter cake with MTBE (1V) and dry at 50°C under N2 for 16 h.

[1041] 11. Charge 1V of DMAc and 3V of toluene to the reactor, and charge crude (Compound 102) to the reactor.

[1042] 12. Heat to 75±5°C and stir for at least 4h.

[1043] 13. Cool to 45±5°C and add 5V of toluene dropwise into the reactor.

[1044] 14. Stir at 45±5°C for at least 2h.

[1045] 15. Cool to 10±5°C and stir at 10±5°C for at least 3h.

[1046] 16. Filter and wash with toluene (1V).

[1047] 17. Add 10V of water and wet cake to the reactor.

[1048] 18. Heat to 50±5°C and stir at 50±5°C for at least 3h.

[1049] 19. Cool to 10±5°C and stir at 10±5°C for at least 3h.

[1050] 20. Filter and wash with water (1-2V).

[1051] 21. Dry at 50±5C under N2 for 16h.

[1052] Production data summary

[1053]

[1054]

[1055] 4) Results

[1056] The first 30.3 kg production scale batch ran well with an IPC purity of 57.9A% in step 3 and an assay yield of 61.5% for compound 101 at the end of the reaction.

[1057] The second 30.3 kg production scale batch ran well with an IPC purity of 60.1A% in step 3 and an assay yield of 62.5% for compound 101 at the end of the reaction.

[1058] After separate concentrations, the two batches were combined and used directly in step 4. Step 4 reaction ran well with an IPC purity of 63.1A%.

[1059] After work-up and purification, 36 kg of compound 102 were obtained with a purity of 99.0A% (toluene was not integrated) and a yield of 54.8% (not corrected by QNMR).

[1060] 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

[1061]

[1062] To a preheated, stirred solution of tert-butyl 5-((3-chloro-2-methoxyphenyl)carbamethanethionyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H)-carboxylate (5.00 g, 12.1 mmol, 1.0 equiv) and NHOAc (4.67 g, 60.6 mmol, 5.0 equiv) in toluene (50 mL) was added a solution of isonicotinoaldehyde (1.71 mL, 18.2 mmol, 1.5 equiv) in 1,4-dioxane (50 mL) dropwise over 2.5 hours at 90° C. using a syringe pump. The reaction mixture was stirred at 90° C. for 20 hours and then concentrated under reduced pressure. The crude residue was adsorbed onto silica then purified by silica gel chromatography (25-100% heptane / EtOAc 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.

[1063] LCMS (ES, m / z): [M+H] + :469.2;

[1064] 11H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.45 (d, J = 5.0 Hz, 2H), 7.47 (d, J = 4.9 Hz, 2H), 7.36 (s, 1H), 6.73 (d, J = 7.5 Hz, 2H), 6.16 (dt, J = 7.1, 2.1 Hz, 1H), 3.97 (t, J = 6.3 Hz, 2H), 3.91 (s, 3H), 2.98 (t, J = 6.3 Hz, 2H), 1.44 (s, 9H);

[1065] 13 13C NMR (101 MHz, DMSO-d6) δ 162.3, 153.2, 150.3, 143.7, 140.7, 140.1, 138.3, 127.0, 125.6, 125.4, 122.3, 118.9, 118.8, 112.2, 109.8, 81.9, 60.2, 45.6, 28.2, 22.8.

[1066] References

[1067] 1. Graham, K.; Klar, U.; Briem, H.; Schulze, V.; Siemeister, G.; Lienau, P.; Tempel, R.; Balint, J. 4H-Pyrrolo[3,2-c]pyridin-4-one Derivatives. WO2016 / 120196A1, 2016.

[1068] 2. Siegel, F.; Korr, D.; J.; Siegel, S.; Greulich, H.; Kaplan, B.; Meyerson, M. 4H-Pyrrolo[3,2-c]pyridin-4-one Derivatives. WO2020 / 216774A1, 2020.

[1069] 3. Jagodziński, T. S.; J. G.; Struk, L. ARKIVOC 2017, 5, 43–57.

[1070] 4. Siegel, S.; Siegel, F.; Schulze, V.; Berger, M.; Graham, K.; Klar, U.; Eis, K.; Sülzle, D.; U.; Korr, D.; Peterson, K.; U.; U.;Moosmayer,D.;Meyerson,M.;Greulich,H.;Kaplan,B.;Harb,H.Y.;Dinh,P.M.4H-Pyrrolo[3,2-c]pyridin-4-one Derivatives.WO2019 / 081486A1,2019。

[1071] 5.Milgram,B.C.;White,R.D.;St.Jean Jr.,D.;Guzman-Perez,A.Pyrrolo[3,2-c]pyridin-4-one Derivatives Useful in the Treatment of Cancer.WO2022 / 066734A1,2022。

Claims

1. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising contacting a compound of formula (II) with a compound of formula (III), in Y is selected from -OH or -NH2; Z is selected from –C(=O)H; or -CH(R)2, wherein each R is independently selected from: halogen, alkoxy, OH, or SO3M (M = Li, Na, K, or NH4 + ), provided that, when one R is OH, the other R cannot be halogen, alkoxy, or OH; R 1c Selected from H, and R d ; R 2a , R 2b , R 3a , and R 3b Each of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each optionally substituted by: 1-6R a ;-NR e R f ;-R g ; and -(L g ) g -R g ; Variable R 2a , R 2b , R 3a , and R 3b The two of them, together with the ring B atoms to which they are attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms; · wherein 0-2 of the ring atoms are independently selected heteroatoms (when -N(R 1c )- forms part of the fused saturated or unsaturated ring, except for -N(R 1c )-), wherein each of the independently selected heteroatoms is selected from: N, NH, N(R d ), O, and S(O) 0-2 ;as well as wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally independently selected from oxo, R c , and R W substituted with 1 to 4 substituents; Ring A is R g ; R 4 Selected from: H and R d ; Ring C is selected from: · · in: ○ Each X b Independently for X, R c , or H; and ○ Each X a independently selected from: H, halogen; cyano; optionally 1-6 independently selected R a Substituted 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; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; 2-pyridyl or 3-pyridyl, each of which is optionally substituted by X, and further optionally substituted by 1-4 R c replace; 2-pyridonyl or 4-pyridonyl, each optionally substituted by X, and further optionally substituted by 1 to 4 R c substituted, wherein the ring nitrogen atom is optionally replaced by R d replace; A heteroaryl group comprising 6 ring atoms, wherein 2 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted by X, and is also optionally substituted by 1-4 R c replace; A heteroaryl group comprising 5 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and is further optionally substituted by 1-4 R c replace; A bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents; Bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is optionally substituted by X and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents; A heterocyclic or heterocyclic alkenyl group comprising 5 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents of; and ·C 10 or C 14 Aryl, which is optionally substituted by X, and optionally substituted by 1-4 R 7 replace; · in ○ma is 0, 1, 2 or 3; ○R 8A Independently selected from: halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, 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 The alkoxy group is optionally substituted, independently of one another, 1, 2, or 3 times by halogen and optionally substituted once by: hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl or phenyl, which is optionally substituted by one or more R 5A replace; ○R 5A 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 are each independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, wherein the phenyl groups are independently optionally replaced by R 5A Replace one or more times; or R 9A and R 10A Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic ring, which optionally contains one additional heteroatom or heteroatom-containing group selected from O, NH or S, and which may be independently optionally replaced by R 5A Replace one or more times; ○R 11A Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 Halogenated cycloalkyl; · in ○R 5B C 2-5 Alkyl, which is optionally substituted by: hydroxy, C 1-4 Alkoxy, R 7B R 8B N-, or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times; or ○R 5B For R 6B -CH2-; ○R 6B Selected from or ○R 7B and R 8B Independently selected from C 1-3 Alkyl, C 1-3 haloalkyl; or ○R 7B and R 8B Together with the nitrogen atom to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring optionally contains an additional heteroatom or a heteroatom-containing group selected from O and -NH-, NH(C 1-3 alkyl); ○R 9B Selected from hydrogen, C 1-4 Alkyl, or C 1-3 Haloalkyl; ○R 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy; · in ○R 4C is selected from hydrogen or methyl; ○R 6C Selected from hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl; ○nc is 0 or 1; ○X C NR 7C or O; ○Y C NR 8C or O; ○R 7C is methyl; ○R 8C Selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; ○R 5C is selected from hydrogen or methyl, wherein R 5C Connect to the containing X C and Y C Any carbon atom of a ring; ○mc is 0, 1, 2 or 3; · in ○R 4D is selected from hydrogen or methyl; ○R 5D Selected from: (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, 3-azetidinyl, each of which is optionally replaced by R 6D substituted 1, 2, or 3 times, and wherein each azetidinyl group is replaced on the nitrogen by R 8D replace; or ○R 5D Freedom to choose The group composed of; ○R 6D Selected from Fluorine or C 1-3 alkyl; ○md is selected from 0, 1, 2, or 3; ○R 7D Selected from hydrogen, C 1-3 Alkyl, or C 1-3 Haloalkyl; ○X D NR 8D or O; ○R 8D Selected from C 1-3 Alkyl or C 2-3 Haloalkyl; X is X*, wherein X* is selected from halogen, triflate, tosylate, or mesylate; or X is X 1 ; Each R 7 R are independently selected c ; n is 0, 1, 2, or 3; X 1 Selected from: (a) – OL 1 -R 5 ; and (b) L 1 and L 2 independently selected from: a bond, and optionally 1-6 R a Substituted C 1-10 Alkylene; R 5 Selected from: A heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace; ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents; · Wherein ring D is a heterocyclylene or heterocycloalkenylene group including 3-10 ring atoms, wherein 0-2 ring atoms (excluding those with R X The ring atoms other than the ring nitrogen atoms to which the ring is bonded) are heteroatoms independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclylene or heterocycloalkenylene is optionally each independently selected from oxo and -R c substituted with 1 to 4 substituents; -S(O) 0-2 (C 1-6 alkyl), which is optionally substituted by 1 to 6 R a replace; ·-R W -R g2 -R W or -R g2 -R Y ; -L 5 -R g ;as well as -L 5 -R g2 -R W or –L 5 -R g2 -R Y ; The condition is that when L 1 When is a key, then R 5 Not optionally 1-6 R a ;-L 5 -R g ;-L 5 -R g2 -R W ; or -L 5 -R g2 -R Y Substituted -S(O) 0-2 (C 1-6 alkyl); R 6 Selected from: ·H； ·halogen; -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 ;as well as -C 1-6 Alkoxy or -S(O) 0-2 (C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a replace; L 5 and L 6 are independently -O-, -S(O) 0-2 , -NH, or -N(R d )-;as well as R W For –L W -W, Where 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 *, where the asterisk (*) indicates the point of attachment to W, and W is C 2-6 Alkenyl; C 2-6 Alkynyl; or C 3-10 Allenyl, each of which is optionally substituted by 1 to 3 R a and optionally further substituted by R g Substitution, wherein W is via sp 2 or sp hybridized carbon atoms connected to L W , thereby providing an α,β-unsaturated system; and R X is C(=O)(C 1-6 Alkyl) or S(O)2(C 1-6 alkyl), each of which is optionally substituted by 1 to 6 R a Replacement; and R Y Selected from: -R g and-(L g ) g -R g ; R a Each occurrence is independently selected from: -OH; -halogen; -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 is independently: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R a replace; L b Each occurrence 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 indicates the same b The connection point; R c Each occurrence is independently selected from: halogen; cyano; optionally 1-6 independently selected R a Substituted C 1-10 Alkyl; C 3-5 Cycloalkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy, which is optionally substituted by C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution; 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 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; R d Each occurrence is independently selected from: optionally 1-3 independently selected R a or R g Substituted 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 Alkoxy; R e and R f Each occurrence is independently selected from: H; C 3-5 Cycloalkyl, which is optionally substituted by 1-3 C 1-3 Alkyl group substituted; heterocyclic group including 3-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , which are optionally independently selected from oxo and R c substituted with 1 to 4 substituents; C 1-6 Alkyl, which is optionally substituted by 1-3 substituents, each of which is independently selected from NR'R", -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and halogen; -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 Alkoxy; R g Each occurrence is independently selected from: ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents; A heterocyclic or heterocyclic alkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally independently selected from oxo and R c substituted with 1 to 4 substituents; A heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace; ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; L g Each occurrence is independently selected from: -O-, -NH-, -NR d 、-S(O) 0-2 , C(O) and optionally 1-3 R a Substituted C 1-3 Alkylene; Each g is independently 1, 2, or 3; Each R g2 R g group; and R' and R" are independently selected at each occurrence from: H; -OH; and C 1-4 alkyl.

2. The process of claim 1, wherein contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a nitrogen source.

3. The method of claim 2, wherein the nitrogen source is ammonia or a derivative thereof.

4. The method of claim 3, wherein the nitrogen source is in the form of a salt.

5. The method of any one of claims 2-4, wherein the nitrogen source is selected from the group consisting of NH4OAc, NH3·H2O, NH4CO2H, NH4OBz, NH4Cl, (NH4)2SO4, (NH4)2HPO4, NH4H2PO4, NH4OTf, NH4HCO3, (NH4)2CO3, NH4CO2CF3, NH4BF4, diammonium hydrogen citrate, (C1-C6 alkyl)-NH2, and (C3-C6 cycloalkyl)-NH2, or any combination thereof.

6. The method of any one of claims 2-5, wherein the nitrogen source is NH4OAc.

7. The method of any one of claims 2-6, wherein the molar ratio of the nitrogen source to the compound of formula (III) is from about 2:1 to about 8:

1.

8. The method of any one of claims 2-6, wherein the molar ratio of the nitrogen source to the compound of formula (III) is from about 4:1 to about 6:

1.

9. The method of any one of claims 2-6, wherein the molar ratio of the nitrogen source to the compound of formula (III) is about 5:

1.

10. The method of any one of claims 1 to 9, wherein contacting the compound of formula (II) with the compound of formula (III) is carried out in the presence of a solvent.

11. The method of claim 10, wherein the solvent is an aprotic solvent.

12. The method of claim 11, wherein the aprotic solvent is a non-polar aprotic solvent.

13. The method of claim 12, wherein the non-polar aprotic solvent is an aromatic hydrocarbon solvent.

14. The method of claim 13, wherein the aromatic hydrocarbon solvent is toluene.

15. The method of claim 12, wherein the non-polar aprotic solvent is a non-aromatic hydrocarbon.

16. The method of claim 13, wherein the non-aromatic hydrocarbon is heptane or hexane.

17. The solvent of claim 11, wherein the aprotic solvent is a polar aprotic solvent.

18. The solvent according to claim 17, wherein the aprotic solvent is an ether solvent.

19. The solvent according to claim 18, wherein the ether solvent is CPME, 1,4-dioxane, or THF.

20. The solvent of claim 17, wherein the aprotic solvent is acetonitrile or DMSO.

21. The method of claim 10, wherein the solvent is a protic solvent.

22. The method of claim 21, wherein the solvent is a polar protic solvent.

23. The method of claim 21 or 22, wherein the solvent is acetic acid.

24. The method of any one of claims 1-23, wherein 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 about 90°C to 110°C (e.g., 100°C).

25. The method of any one of claims 1-24, wherein 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.

26. The method of any one of claims 1-24, wherein 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, 90°C).

27. The method of any one of claims 1-24, wherein 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, 100°C).

28. The method of any one of claims 1-23, wherein contacting the compound of formula (II) with the compound of formula (III) is carried out at a temperature of about 20°C to 80°C (eg, 20°C).

29. The method of any one of claims 1 to 28, wherein contacting the compound of formula (II) with the compound of formula (III) is performed in the presence of an additive.

30. The method of any one of claims 1-28 or 29, wherein the additive is selected from: Na2SO4, H2O, H2SO4, acetic acid, formic acid, Bi(OTf)3, PPh3, NH4OH, NH4OAc, PPTS, PTSA, pyridine, or any combination thereof.

31. The method of any one of claims 1 to 30, wherein contacting the compound of formula (II) with the compound of formula (III) is performed in a sealed container filled with air.

32. The method of any one of claims 1 to 30, wherein contacting the compound of formula (II) with the compound of formula (III) is performed in a sealed container filled with an inert gas (eg, nitrogen).

33. The method of any one of claims 1-30, wherein contacting the compound of formula (II) with the compound of formula (III) is performed in an open container.

34. The process of any one of claims 1-30, wherein contacting the compound of formula (II) with the compound of formula (III) is performed in an open container connected to an inert gas (eg, nitrogen) manifold.

35. The method of any one of claims 1-31, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is from about 1:1 to about 1:

3.

36. The method of any one of claims 1-35, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is from about 1:1 to about 1:

2.

37. The method of any one of claims 1-35, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is about 1:1.3, or about 1:1.5, or about 1:

2.

38. The method of any one of claims 1-37, wherein the compound of formula (III) is added to the reaction in batches.

39. The method of any one of claims 1 to 38, wherein the method further comprises: contacting a compound of formula (IIa) with a compound of formula (IIb) to obtain the compound of formula (II):

40. The method of claim 39, wherein the compound of formula (IIb) is prepared by contacting a chlorinating agent with a compound of formula (IId):

41. The method of any one of claims 38 or 39, wherein the compound of formula (IIb) is prepared by contacting a compound of formula (IIc) with a compound of formula (IId):

42. The method of any one of claims 1-41, wherein contacting the compound of formula (II) with the compound of formula (III) is performed in the absence of an oxidizing agent.

43. The method of claim 42, wherein the oxidizing agent is m-CPBA.

44. The method of any one of claims 1-43, wherein the compound of formula (I) is isolated / purified by column chromatography.

45. The method of any one of claims 1 to 44, wherein R 1c For the protecting group.

46. ​​The method of any one of claims 1 to 44, wherein R 1c Together with the nitrogen atom to which it is attached, it forms a carbamate.

47. The method of any one of claims 1 to 45, wherein R 1c It is a Boc group.

48. The method of any one of claims 45-47, wherein the method further comprises: removing the protecting group from the compound of formula (I).

49. The method of any one of claims 1 to 44, wherein R 1c It's H.

50. The method of any one of claims 1 to 49, wherein R 2a , R 2b , R 3a , and R 3b Each of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by: 1-6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g .

51. The method of any one of claims 1 to 50, wherein R 2a , R 2b , R 3a , and R 3b One is independently selected from: halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by: 1-6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g ; and R 2a ,R 2b ,R 3a and R 3b The other one is H.

52. The method of any one of claims 1 to 49, wherein the variable R 2a , R 2b , R 3a , and R 3b The two of them together with the Ring B ring atoms to which they are attached form a fused saturated or unsaturated ring of 3 to 12 ring atoms.

53. The method of any one of claims 1 to 50, wherein R 2a , R 2b , R 3a , and R 3b Each of them is H.

54. The method of any one of claims 1-53, wherein ring A is C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace.

55. The method of any one of claims 1-54, wherein Ring A is phenyl, which is optionally substituted with 1-4 R c replace.

56. The method of any one of claims 1-55, wherein ring A is phenyl, which is optionally substituted with 1-2 R c replace.

57. The method of any one of claims 1-56, wherein ring C is 58. The method of any one of claims 1-56, wherein ring C is in: ○ Each X b Independently for X, R c , or H; and ○ Each X a independently selected from: H, halogen; cyano; optionally 1-6 independently selected R a Substituted 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; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5.

59. The method of any one of claims 1-56, wherein Ring C is selected from: 2-pyridyl or 3-pyridyl, each of which is optionally substituted by X, and further optionally substituted by 1-4 R c replace; or 2-pyridonyl or 4-pyridonyl, each of which is optionally substituted by X, and further optionally substituted by 1 to 4 R c substituted, wherein the ring nitrogen atom is optionally replaced by R d replace.

60. The method of any one of claims 1-56, wherein Ring C is a heteroaryl group comprising 6 ring atoms, wherein 2-4 of the ring atoms are heteroatoms, each of which is independently selected from the group consisting of: N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted by X, and is also optionally substituted by 1-4 R c replace.

61. The method of any one of claims 1-56, wherein Ring C comprises a heteroaryl group of 5 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and further optionally substituted by 1-4 R c replace.

62. The method of any one of claims 1-56, wherein Ring C is a bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from the group consisting of: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and is optionally independently selected from oxo and R 7 The compound is substituted with 1 to 4 substituents.

63. The method of any one of claims 1-56, wherein ring C is a bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is optionally substituted by X and is optionally independently selected from oxo and R 7 The compound is substituted with 1 to 4 substituents.

64. The method of any one of claims 1-56, wherein Ring C is a heterocyclyl or heterocycloalkenyl group comprising 5-10 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by X, and is optionally independently selected from oxo and R 7 The compound is substituted with 1 to 4 substituents.

65. The method of any one of claims 1-56, wherein ring C is C 10 or C 14 Aryl, which is optionally substituted by X, and optionally substituted by 1-4 R 7 replace.

66. The method of any one of claims 1 to 56, wherein: Ring C is selected from: · in ○ma is 0, 1, 2 or 3; ○R 8A Independently selected from: halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, 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 The alkoxy group is optionally substituted, independently of one another, 1, 2, or 3 times by halogen and optionally substituted once by: hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl or phenyl, which is optionally substituted by one or more R 5A replace; ○R 5A 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 are each independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times independently of each other; or R 9A and R 10A Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic ring, which optionally contains one additional heteroatom or heteroatom-containing group selected from O, NH or S, and which may be independently optionally replaced by R 5A Replace one or more times; ○R 11A Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 Halogenated cycloalkyl; · in ○R 5B C 2-5 Alkyl, which is optionally substituted by: hydroxy, C 1-4 Alkoxy, R 7B R 8B N-, or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times; or ○R 5B For R 6B -CH2-; ○R 6B Selected from or ○R 7B and R 8B Independently selected from C 1-3 Alkyl, C 1-3 haloalkyl; or ○R 7B and R 8B Together with the nitrogen atom to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring optionally contains an additional heteroatom or a heteroatom-containing group selected from O and -NH-, NH(C 1-3 alkyl); ○R 9B Selected from hydrogen, C 1-4 Alkyl, or C 1-3 Haloalkyl; ○R 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy; · in ○R 4C is selected from hydrogen or methyl; ○R 6C Selected from hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl; ○nc is 0 or 1; ○X C NR 7C or O; ○Y C NR 8C or O; ○R 7C is methyl; ○R 8C Selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; ○R 5C is selected from hydrogen or methyl, wherein R 5C Connect to the containing X C and Y C Any carbon atom of a ring; ○mc is 0, 1, 2 or 3; · in ○R 4D is selected from hydrogen or methyl; ○R 5D Selected from: (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, 3-azetidinyl, each of which is optionally replaced by R 6D substituted 1, 2, or 3 times, and wherein each azetidinyl group is replaced on the nitrogen by R 8D replace; or ○R 5D Selected from ○R 6D Selected from Fluorine or C 1-3 alkyl; ○md is selected from 0, 1, 2, or 3; ○R 7D Selected from hydrogen, C 1-3 Alkyl, or C 1-3 Haloalkyl; ○X D NR 8D or O; ○R 8D Selected from C 1-3 Alkyl or C 2-3 Halogenated alkyl.

67. The method of any one of claims 1-66, wherein X is halogen.

68. The process of any one of claims 1-67, wherein X is bromine.

69. The method of any one of claims 1 to 66, wherein X is X 1 .

70. The method of any one of claims 1-66 or 69, wherein X is -OL 1 -R 5 .

71. The method of any one of claims 1-66 or 69, wherein X is 72. The method of any one of claims 1 to 71, wherein R 7 Each occurrence is H.

73. The method of any one of claims 1 to 72, wherein R 4 For H.

74. The method of any one of claims 1 to 72, wherein the method further comprises: converting a compound of formula (I) wherein X is X* to a compound of formula (I) wherein X is X 1 A compound of formula (I).

75. A compound of formula (I) or a pharmaceutically acceptable salt thereof, prepared by the method described in any one of 1-74:

76. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: R 1c H, -R d or a protecting group (e.g. a Boc group); R 2a , R 2b , R 3a , and R 3b Each of them is independently selected from: H; halogen; -OH; -C(O)OH or -C(O)NH2; -CN; -R b ;-L b -R b ;-C 1-6 Alkoxy or -C 1-6 Thioalkoxy, each of which is optionally substituted by: 1-6 R a ;-NR e R f ;-R g ; and -(L g ) g -R g ; Variable R 2a , R 2b , R 3a , and R 3b The two of them, together with the ring B atoms to which they are attached, form a fused saturated or unsaturated ring of 3 to 12 ring atoms; · wherein 0-2 of the ring atoms are independently selected heteroatoms (when -N(R 1c )- forms part of the fused saturated or unsaturated ring, except for -N(R 1c )-), wherein each of the independently selected heteroatoms is selected from: N, NH, N(R d ), O, and S(O) 0-2 ;as well as wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally independently selected from oxo, R c , and R W substituted with 1 to 4 substituents; Ring A is R g ; R 4 Selected from: H and R d ; Ring C is selected from: · · in: ○ Each X b Independently for X, R c , or H; and ○ Each X a independently selected from: H, halogen; cyano; optionally 1-6 independently selected R a Substituted 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; -NO2; -C(=O)(C 1-10 alkyl); -C(=O)O(C 1-4 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; · 2-pyridyl or 3-pyridyl, each of which is optionally substituted by X, and further optionally substituted by 1-4 R c replace; 2-pyridonyl or 4-pyridonyl, each of which is optionally substituted by X, and further optionally substituted by 1 to 4 R c substituted, wherein the ring nitrogen atom is optionally replaced by R d replace; A heteroaryl group comprising 6 ring atoms, wherein 2 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), and N(R d ), and wherein the heteroaryl is optionally substituted by X, and is also optionally substituted by 1-4R c replace; A heteroaryl group comprising 5 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and is further optionally substituted by 1-4 R c replace; A bicyclic heteroaryl group comprising 7-10 ring atoms, wherein 1-4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents; Bicyclic C 5-10 Cycloalkyl or C 5-10 cycloalkenyl, each of which is optionally substituted by X and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents; A heterocyclic or heterocyclic alkenyl group comprising 5 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted by X, and is optionally independently selected from oxo and R 7 substituted with 1 to 4 substituents of; and ·C 10 or C 14 Aryl, which is optionally substituted by X, and optionally substituted by 1-4 R 7 replace; X is X*, wherein X* is selected from halogen, triflate, tosylate, or mesylate; or Each R 7 R are independently selected c ; n is 0, 1, 2, or 3; R a Each occurrence is independently selected from: -OH; -halogen; -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 is independently: C 1-6 Alkyl, C 2-6 Alkenyl, or C 2-6 Alkynyl, each of which is optionally substituted by 1 to 6 R a replace; L b Each occurrence 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 indicates the same b The connection point; R c Each occurrence is independently selected from: halogen; cyano; optionally 1-6 independently selected R a Substituted C 1-10 Alkyl; C 3-5 Cycloalkyl; C 2-6 Alkenyl; C 2-6 Alkynyl; C 1-4 Alkoxy, which is optionally substituted by C 1-4 Alkoxy or C 1-4 Haloalkoxy substitution; 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 alkyl); -C(=O)OH; -C(=O)NR'R"; and -SF5; R d Each occurrence is independently selected from: optionally 1-3 independently selected R a or R g Substituted 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 Alkoxy; R e and R f Each occurrence is independently selected from: H; C 3-5 Cycloalkyl, which is optionally substituted by 1-3 C 1-3 Alkyl group substituted; heterocyclic group including 3-6 ring atoms, wherein 1-3 ring atoms are heteroatoms, each of which is independently selected from: N, N(H), N(R d ), O, and S(O) 0-2 , which are optionally independently selected from oxo and R c substituted with 1 to 4 substituents; C 1-6 Alkyl, which is optionally substituted by 1-3 substituents, each of which is independently selected from NR'R", -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, and halogen; -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 Alkoxy; R g Each occurrence is independently selected from: ·C 3-10 Cycloalkyl or C 3-10 Cycloalkenyl, each of which is optionally independently selected from oxo and R c substituted with 1 to 4 substituents; A heterocyclic or heterocyclic alkenyl group comprising 3 to 10 ring atoms, wherein 1 to 3 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heterocyclyl or heterocycloalkenyl is optionally independently selected from oxo and R c substituted with 1 to 4 substituents; A heteroaryl group comprising 5 to 10 ring atoms, wherein 1 to 4 of the ring atoms are heteroatoms, each of which is independently selected from N, N(H), N(R d ), O, and S(O) 0-2 , and wherein the heteroaryl is optionally substituted by 1-4 R c replace; ·C 6-10 Aryl, which is optionally substituted by 1 to 4 R c replace; · in ○ma is 0, 1, 2 or 3; ○R 8A Independently selected from: halogen, hydroxy, nitro, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, 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 is optionally substituted one, two or three times independently of one another by halogen and optionally substituted once by hydroxy, C 1-4 Alkoxy, R 9A R 10A N-, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl or phenyl, which is optionally substituted by one or more R 5A replace; ○R 5A 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 are each independently selected from: hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 3-6 halocycloalkyl or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times independently of each other; or R 9A and R 10A Together with the nitrogen atom to which they are attached, they form a 3- to 6-membered nitrogen-containing heterocyclic ring, which optionally contains one additional heteroatom or heteroatom-containing group selected from O, NH or S, and which may be independently optionally replaced by R 5A Replace one or more times; ○R 11A Independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or C 3-6 Halogenated cycloalkyl; · in ○R 5B C 2-5 Alkyl, which is optionally substituted by: hydroxy, C 1-4 Alkoxy, R 7B R 8B N-, or phenyl, wherein the phenyl group is optionally replaced by R 5A replace one or more times; or ○R 5B For R 6B -CH2-; ○R 6B Selected from or ○R 7B and R 8B Independently selected from C 1-3 Alkyl, C 1-3 haloalkyl; or ○R 7B and R 8B Together with the nitrogen atom to which they are attached, they form a 5- to 6-membered nitrogen-containing heterocyclic ring, wherein the nitrogen-containing heterocyclic ring optionally contains an additional heteroatom or a heteroatom-containing group selected from O and -NH-, NH(C 1-3 alkyl); ○R 9B Selected from hydrogen, C 1-4 Alkyl, or C 1-3 Haloalkyl; ○R 5A Selected from: hydroxy, halogen, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, C 1-4 Haloalkyl, or C 1-4 Haloalkoxy; · in ○R 4C is selected from hydrogen or methyl; ○R 6C Selected from hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl; ○nc is 0 or 1; ○X C NR 7C or O; ○Y C NR 8C or O; ○R 7C is methyl; ○R 8C Selected from methyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; ○R 5C is selected from hydrogen or methyl, wherein R 5C Connect to the containing X C and Y C Any carbon atom of a ring; ○mc is 0, 1, 2 or 3; · in ○R 4D is selected from hydrogen or methyl; ○R 5D Selected from: (R / S)-2-oxetanyl, (S)-2-oxetanyl, 3-oxetanyl, (R / S)-2-azetidinyl, (S)-2-azetidinyl, 3-azetidinyl, each of which is optionally replaced by R 6D substituted 1, 2, or 3 times, and wherein each azetidinyl group is replaced on the nitrogen by R 8D replace; or ○R 5D Selected from ○R 6D Selected from Fluorine or C 1-3 alkyl; ○md is selected from 0, 1, 2, or 3; ○R 7D Selected from hydrogen, C 1-3 Alkyl, or C 1-3 Haloalkyl; ○X D NR 8D or O; ○R 8D Selected from C 1-3 Alkyl or C 2-3 Haloalkyl; L g Each occurrence is independently selected from: -O-, -NH-, -NR d 、 -S(O) 0-2 , C(O) and optionally 1-3 R a Substituted C 1-3 Alkylene; Each g is independently 1, 2, or 3; Each R g2 R g group; and R' and R" are independently selected at each occurrence from: H; -OH; and C 1-4 alkyl.

77. The method of any one of claims 1-74, wherein Y is -OH.

78. The method of claim 75 or 76, wherein Y is -OH.

Images