Mcl-1 inhibitors

Abstract

The present invention relates generally to compounds and pharmaceutical compositions useful in methods of treating cancer. In particular, the present invention relates to MCL-1 inhibitors.

Description

[0001] This application is a divisional application of Chinese invention patent application (application date: May 13, 2019; application number: 201980032695.2 (international application number: PCT / US2019 / 032053); invention title: MCL-1 inhibitor).

[0002] Cross-references to related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 671,306, filed May 14, 2018, and U.S. Provisional Application No. 62 / 749,918, filed October 24, 2018, the entire contents of which are incorporated herein by reference.

[0004] Invention Field

[0005] This invention generally relates to certain compounds that inhibit MCL-1, pharmaceutical compositions comprising said compounds, the use of said compounds in the treatment of cancer, and methods for preparing said compounds. Background of the Invention

[0007] Apoptosis (programmed cell death) is the process by which harmful or potentially dangerous cells are eliminated from an organism. Preventing apoptosis is crucial for tumor development and sustained growth. Myeloid leukemia 1 protein (MCL-1, also abbreviated as Mcl-1 or MCL1) is an anti-apoptotic member of the Bcl-2 protein family. MCL-1 is overexpressed in many cancers. Overexpression of MCL-1 can prevent cancer cell apoptosis. Studies have shown that MCL-1 inhibitors may be used to treat cancer. Therefore, new compounds that inhibit MCL-1 are needed. Invention Overview

[0009] This disclosure addresses the aforementioned needs. In particular, this document provides inhibitors of MCL-1.

[0010] In one embodiment, this disclosure provides a compound according to formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0011]

[0012] in: It can be a single bond or a double bond;

[0013] X is O or NR 7 ;

[0014] R 12 For hydrogen or –C(O)R 1 ;

[0015] R 1 C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-12 heterocyclic, 5-10 heteroaryl, –OR 7 Or –NR 8 R 9 ,in

[0016] The C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl,

[0017] 3-12-membered heterocyclic groups and 5-10-membered heteroaryl groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups;

[0018] R 2 For hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl or 3-12 membered heterocyclic groups, wherein

[0019] The C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups;

[0020] R 3 and R 4 Independently hydrogen, C 1-6 Alkyl, –OR 7 C 1-6 Heteroalkyl, –NR 8 R 9 NR 8 C(O)R 9 –NR 8 C(O)OR 9 C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 3-12-membered heterocyclic, –C(O)R 7 –C(O)OR 7 –C(O)NR 8 R 9 –OC(O)NR 8 R 9 –CN or –SO2R 7 ,in

[0021] The C1-6 Alkyl, C 1-6 Heteroalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 3-12-membered heterocyclic groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups;

[0022] R 5 For hydrogen, C 1-6 Alkyl group, –(CH2CH2O) p R 7 C 1-6 Heteroalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl or 3-12-membered heterocyclic, wherein

[0023] The C 1-6 Alkyl, C 1-6 Heteroalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 3-12-membered heterocyclic groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups;

[0024] R 6 It is hydrogen or halogen;

[0025] Each R 7 Independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl, among which

[0026] The C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coated with 1-5 R groups. 10 Replaced;

[0027] Each R 8 and R 9 Independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, or R 8 and R 9 Together with the atoms they are attached to, they form 3-12 membered heterocycles, in which

[0028] The C 1-6 Alkyl, C3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coated with 1-5 R groups. 10 Replaced;

[0029] Each R 10 Independently for C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, halogen, oxo group, –OR a –C(O)R a –C(O)OR a –C(O)NR a R b –OC(O)NR a R b –NR a R b –NR a C(O)R b –NR a C(O)OR b –S(O) q R a –S(O)2NR a R b –NR a S(O)2R b –N3, –CN, or –NO2, or two Rs 10 Groups form fused, spirocyclic, or bridged C 3-10 Cycloalkyl or 3-12 membered heterocyclic groups, wherein

[0030] Each C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl, optionally with 1-5 Rs 20 Substituted by groups;

[0031] Each R a and R b Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 aryl, 5-10 quinone heteroaryl, or R a and R bTogether with the atoms they are attached to, they form 3-12 membered heterocyclic groups, in which

[0032] The C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl, 5-10 aryl groups, optionally coated with 1-5 R groups 20 Substituted by groups;

[0033] Each R 20 Independently for C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C6-C 10 Aryl, 5-10 heteroaryl, hydroxyl, C 1-6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl group 2, -COOH, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl or halogen;

[0034] n is 0, 1, or 2;

[0035] p is 0, 1, or 2; and

[0036] q can be 0, 1, or 2.

[0037] In some embodiments, this document provides pharmaceutical compositions comprising a compound according to formula (I), or a tautomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0038] In some implementations, this document provides a method for inhibiting MCL-1 in a patient, the method comprising administering to the patient a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0039] In some implementations, this document provides a method for treating a patient with cancer, the method comprising administering to the patient a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof. Invention Details

[0041] Unless the context otherwise requires, the word “comprising” and its variations (e.g., “containing” and “including”) shall be interpreted in an open, inclusive sense, meaning “including but not limited to”.

[0042] Prefixes such as "C"u-v "or (C u -C v ) represents the following groups having u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0043] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -CONH2 is connected by a carbon atom. The hyphen before or after a chemical group is for convenience; a chemical group may or may not be depicted with one or more hyphens without losing its usual meaning. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0044] For example, as shown below The wavy line on a chemical group indicates a connection point, that is, it shows a broken bond, through which the group is connected to another described group.

[0045] The term "substituted" means that one or more hydrogen atoms on a hydrocarbon are replaced by one or more atoms or groups other than hydrogen, as long as the replacement does not exceed the normal valence of the specified carbon atom or atom. A "substituent" is an atom or group that replaces a hydrogen atom on a hydrocarbon when it is "substituted". Unless otherwise stated, when a group is described as an optional substitution, any substituent in that group is itself unsubstituted.

[0046] The term “about” refers to a value or parameter indicated by ±10%.

[0047] As used herein, “alkyl” refers to a straight-chain or branched saturated monovalent hydrocarbon. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)2), and 2-butyl (s-Bu, sec-butyl, -CH(CH3)2). 3) CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl 2-Methyl-1-butyl (-CH2CH2CH(CH3)2), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-C H(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), and 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0048] "Alkenyl" refers to an aliphatic group containing at least one carbon-carbon double bond. Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0049] As used in this article, "alkoxy" refers to the formula –OR A The group, wherein R A It is an alkyl group as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy.

[0050] "Alkyne" refers to an aliphatic group containing at least one carbon-carbon triple bond.

[0051] “Aryl” refers to a monovalent or divalent aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused ring systems in which one or more fused rings are fully or partially unsaturated. Non-limiting examples of aryl groups used herein include phenyl, naphthyl, fluorenyl, indanyl, tetrahydroindanuyl, and anthraceneyl. However, aryl groups do not in any way include or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl group. The classification of monovalent or divalent indicates whether the aryl group terminates the chain (monovalent) or remains within the chain (divalent). The above definitions do not exclude other substituents on the aryl group. For example, as used herein, the aryl group in “A-aryl-B” is divalent, while the aryl group in “AB-aryl” is monovalent, although additional substituents may be present on each aryl group.

[0052] The term "aryloxy group" refers to the -O-aryl group.

[0053] "Cycloalkyl" refers to a saturated or partially saturated cyclic alkyl group that has a monocyclic or polycyclic structure (including fused, bridged, and spirocyclic systems). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0054] As used in this article, "halogenated" and "halogen" refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0055] As used herein, the term "haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by halogen substituents, which may be the same or different. For example, C 1-6 Haloalkyl is one of them. 1-6 One or more hydrogen atoms of an alkyl group have been replaced by halogen substituents. 1-6 Alkyl groups. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

[0056] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms selected from nitrogen, sulfur, phosphorus, and oxygen. The heteroatoms within a "heteroalkyl" can be oxidized, for example, to -N(O)-, -S(O)-, or -S(O)2-. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen or an alkyl group.

[0057] "Heteroaryl" refers to a monovalent or divalent aromatic group having a monocyclic, polycyclic, or fused ring structure, wherein one or more heteroatoms are independently selected from nitrogen, oxygen, and sulfur. The heteroatoms within a "heteroaryl" can be oxidized, for example, to -N(O)-, -S(O)-, or -S(O)2-. This term includes fused ring systems where one or more fused rings are fully or partially unsaturated. The classification of monovalent or divalent indicates whether the heteroaryl terminates the chain (monovalent) or remains within the chain (divalent). The above definition does not exclude other substituents on the heteroaryl. For example, the heteroaryl in "A-heteroaryl-B" is divalent, while the heteroaryl in "AB-heteroaryl" is monovalent, although additional substituents may be present on each heteroaryl. A heteroaryl does not contain or overlap with the aryl groups defined above. Non-limiting examples of heteroaryl groups include, but are not limited to, azaheptatrienyl, acridinel, benzimizolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxazolyl, 1,4-benzodioxyl, benzonaphthofuranyl, benzooxazolyl, benzodioxolyl, benzodioxolyl, benzodioxolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothienyl (or benzothiophenyl), benzotriazolyl, and benzo[4,6]imidazole. [1,2-a]pyridyl, carbazole, cenolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazoyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, inazinyl, isoxazolyl, naphridyl, oxadiazolyl, 2-oxoazonicycloheptatrienyl, oxazolyl, ethylene oxide, 1-oxopyridyl, 1-oxopyridyl Pyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenotoxazinyl, phthalazinyl, pteridinyl, purineyl, pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.

[0058] The term "heteroaryloxy" refers to the -O-heteroaryl group.

[0059] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to a monovalent or divalent saturated or unsaturated group having a monocyclic or multiple fused rings, wherein one or more heteroatoms are selected from nitrogen, sulfur, phosphorus, and / or oxygen. The heteroatoms in a "heterocyclic group" can be oxidized, for example, -N(O)-, -S(O)-, -S(O)2-. Heterocyclic groups can be monocyclic or polycyclic, wherein the polycyclic rings can be fused, bridged, or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group regardless of its bonding (i.e., it can be bonded by carbon atoms or heteroatoms). Exemplary heterocyclic groups include, but are not limited to, azirrocyclobutyl, dioxopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolyl, pyrazolyl, quininecyclo, thiazoalkyl, tetrahydrofuranyl, thietanyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0060] The term "cyano" refers to the -CN group.

[0061] The term "oxo" refers to a group that is equal to O.

[0062] The term "carboxyl group" refers to the group -C(O)-OH.

[0063] "Isomers" are different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers.

[0064] "Stereoisomers" are isomers that differ only in the spatial arrangement of their atoms.

[0065] An enantiomer is a pair of non-overlapping, mirror-image stereoisomers. A 1:1 mixture of a pair of enantiomers is a racemic mixture. Where appropriate, the symbol “(±)” is used to denote a racemic mixture.

[0066] A "diastereomer" is a stereoisomer that has at least two asymmetric atoms that are not mirror images of each other.

[0067] As used herein, “treatment” or “management” is a method for achieving a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, the reduction of symptoms and / or the reduction of the severity of symptoms associated with a disease or condition. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, the reduction of symptoms and / or the reduction of the severity of symptoms associated with a disease or condition. In one embodiment, “treatment” or “management” includes one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the severity of a disease or condition); b) slowing or halting the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and c) alleviating a disease or condition, such as resulting in the resolution of clinical symptoms, improvement of disease status, delaying disease progression, improving quality of life, and / or prolonging survival.

[0068] As used herein, “prevention” or “avoidance” refers to a program that prevents the onset of a disease or condition from developing its clinical symptoms. Therefore, “prevention” involves administering treatment to a subject before signs of disease are detectable in the subject. A subject may be an individual at risk of developing a disease or condition, such as an individual with one or more known risk factors associated with the development or onset of a disease or condition.

[0069] As used herein, the term "therapeutic effective amount" or "effective amount" refers to an amount that effectively elicits the desired biological or medical response, including an amount of compound sufficient to treat a disease when administered to a subject. Effective amounts will vary depending on the specific compound and the characteristics of the subject being treated, such as age, weight, etc. Effective amounts can include a range of amounts. As understood in the art, an effective amount can be one or more doses, meaning that a single or multiple doses may be required to achieve the desired therapeutic endpoint. Effective amounts can be considered when one or more therapeutic agents are administered, and a single agent (in combination with one or more other agents) can be considered to have achieved or obtained a desirable or beneficial result if such a single agent is administered at an effective amount. Due to the combined effects of compounds (e.g., additive or synergistic effects), the appropriate dose of any co-administered compounds may optionally be reduced.

[0070] As used herein, “co-dosing” includes administering a unit dose of the disclosed compound before or after administration of a unit dose of one or more other therapeutic agents, for example, within seconds, minutes, or hours of administration of one or more other therapeutic agents. For example, in some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the disclosed compound within seconds or minutes. In some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more other therapeutic agents several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the disclosed compound several hours (e.g., 1-12 hours).

[0071] This document also provides pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other substances suitable for veterinary or human pharmaceutical use.

[0072] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts of compounds in their free base form, possessing the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting them with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propionates, oxalates, malonates, succinates, octanoates, sebacic acid, fumarates, maleates, butyryne- 1,4-Diositates, hexyn-1,6-Diositates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methanesulfonates, propanesulfonates, benzoates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21.st Found in Edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0073] Non-limiting examples of pharmaceutically acceptable salts of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and NX4. + (Where X is a C1-C4 alkyl group). It also includes base addition salts, such as sodium or potassium salts.

[0074] "Stereoisomers" are compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures (which are not interchangeable). This invention covers various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are mirror images of each other that are not superimposed.

[0075] "Tautomerism" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This disclosure includes tautomerisms of any of the said compounds.

[0076] "Solvates" are formed through the interaction between the solvent and the compound. Solvates of salts of the compounds described herein are also provided.

[0077] As used in this article, the term "prodrug" is a biologically inactive derivative of a drug that, after being administered to the human body, is converted into a biologically active parent drug through some chemical or enzymatic pathway.

[0078] List of abbreviations and shorthands

[0079] Abbreviation meaning

[0080] ACN Acetonitrile

[0081] MeTHF 2-methyltetrahydrofuran

[0082] Boc tert-butyloxycarbonyl

[0083] BSA (Bovine Serum Albumin)

[0084] calcd or calc'd calculated value

[0085] DCM dichloromethane

[0086] DIPEA N,N-Diisopropylethylamine

[0087] DMAP 4-Dimethylaminopyridine

[0088] DMF (dimethylformamide)

[0089] DMSO (dimethyl sulfoxide)

[0090] Et Ethyl

[0091] EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0092] EDTA (ethylenediaminetetraacetic acid)

[0093] ESI Electrospray Ionization

[0094] EtOAc (ethyl acetate)

[0095] EtOH (ethanol)

[0096] H or hr(s) hours

[0097] i-Pr isopropyl

[0098] KHMDS bis(trimethylsilyl)aminopotassium

[0099] LCMS or LC / MS liquid chromatography-mass spectrometry

[0100] MeOH (methanol)

[0101] min minutes

[0102] MS mass spectrometry

[0103] m / z mass-to-charge ratio

[0104] NMR (Nuclear Magnetic Resonance) spectroscopy

[0105] n-BuLi n-Butyllithium

[0106] RT or rt room temperature

[0107] STAB sodium triacetoxyborohydride

[0108] SFC Supercritical Fluid Chromatography

[0109] TBAF Tetra-n-Butyl Ammonium Fluoride

[0110] TBDMS tert-butyldimethylsilyl

[0111] TBDMSCl tert-butyldimethylchlorosilane

[0112] TBSOTf tert-butyl dimethylsilyl trifluoromethanesulfonate

[0113] TEA Trimethylamine

[0114] TFA (trifluoroacetic acid)

[0115] THF Tetrahydrofuran

[0116] TLC (Thin Layer Chromatography)

[0117] compound

[0118] In some embodiments, this disclosure provides a compound according to formula (I), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0119]

[0120] in: It can be a single bond or a double bond;

[0121] X is O or NR 7 ;

[0122] R 12 For hydrogen or –C(O)R 1 ;

[0123] R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-12 heterocyclic, 5-10 heteroaryl, –OR 7 Or –NR 8 R 9 ,in

[0124] The C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Fang

[0125] 1-5 R groups are selected from 3-12-membered heterocyclic groups and 5-10-membered heteroaryl groups. 10 Substituted by groups;

[0126] R 2 For hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl or 3-12 membered heterocyclic groups, wherein

[0127] The C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups;

[0128] R 3and R 4 Independently hydrogen, C 1-6 Alkyl, –OR 7 C 1-6 Heteroalkyl, –NR 8 R 9 NR 8 C(O)R 9 –NR 8 C(O)OR 9 C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl, 3-12-membered heterocyclic, –C(O)R 7 –C(O)OR 7 –C(O)NR 8 R 9 –OC(O)NR 8 R 9 –CN or –SO2R 7 ,in

[0129] The C 1-6 Alkyl, C 1-6 Heteroalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 3-12-membered heterocyclic groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups;

[0130] R 5 For hydrogen, C 1-6 Alkyl group, –(CH2CH2O) p R 7 C 1-6 Heteroalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl or 3-12-membered heterocyclic, wherein

[0131] The C 1-6 Alkyl, C 1-6 Heteroalkyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10-membered heteroaryl and 3-12-membered heterocyclic groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups;

[0132] R 6 It is hydrogen or halogen;

[0133] Each R 7 Independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10Aryl or 5-10 heteroaryl, among which

[0134] The C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coated with 1-5 R groups. 10 Replaced;

[0135] Each R 8 and R 9 Independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, or R 8 and R 9 Together with the atoms they are attached to, they form 3-12 membered heterocycles, in which

[0136] The C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coated with 1-5 R groups. 10 Replaced;

[0137] Each R 10 Independently for C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, halogen, oxo group, –OR a –C(O)R a 、–

[0138] C(O)OR a –C(O)NR a R b –OC(O)NR a R b –NR a R b –NR a C(O)R b –NR a C(O)OR b –S(O) q R a –S(O)2NR a R b –NR a S(O)2R b–N3, –CN, or –NO2, or two Rs 10 Groups form fused, spirocyclic, or bridged C 3-10 Cycloalkyl or 3-12 membered heterocyclic groups, wherein

[0139] Each C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl, optionally with 1-5 Rs 20 Substituted by groups;

[0140] Each R a and R b Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 aryl, 5-10 quinone heteroaryl, or R a and R b Together with the atoms they are attached to, they form 3-12 membered heterocyclic groups, in which

[0141] The C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl, 5-10 aryl groups, optionally coated with 1-5 R groups 20 Substituted by groups;

[0142] Each R 20 Independently for C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C6-C 10 Aryl, 5-10 heteroaryl, hydroxyl, C 1-6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl group 2, -COOH, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl or halogen;

[0143] n is 0, 1, or 2;

[0144] p is 0, 1, or 2; and

[0145] q can be 0, 1, or 2.

[0146] In some embodiments, this disclosure provides compounds of formula (I) according to formula (Ia), or tautomers thereof, or pharmaceutically acceptable salts thereof:

[0147]

[0148] In some embodiments, this disclosure provides a compound according to formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0149]

[0150] in: It can be a single bond or a double bond;

[0151] R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, C 1-6 Hydroxyalkyl, –OC 1-6 Alkyl, –NHC 1-6 Alkyl, –NHC 1-6 Haloalkyl, 4-6 membered heterocyclic, C 3-6 cycloalkyl, –NHC 3-10 cycloalkyl or –N(C) 1-6 alkyl)2, wherein

[0152] The C 1-6 The alkyl group may be optionally replaced by the following groups: C 1-6 Alkoxy, –N(C) 1-6 Alkyl) 2, 5-10 heteroaryl, C 3-6 cycloalkyl, –SO2C 1-6 Alkyl, phenyl, 5-membered heteroaryloxy, phenoxy, or –O– (4-10-membered heterocyclic groups)

[0153] The 5-10 aryl group is optionally selected from halogens, C, or other compounds, with one or two selected from halogens. 1-6 Alkyl and C 1-6 Substituents of haloalkyl groups,

[0154] The 5-membered heteroaryloxy group is optionally surrounded by 1-3 carbon atoms. 1-6 Alkyl groups are substituted, and the phenyl group is optionally replaced by 1-3 halogens or C. 1-6 Substituted with haloalkyl groups;

[0155] The –NHC 3-6 cycloalkyl groups are optionally C 1-3Substituted with haloalkyl groups;

[0156] The –NHC 1-6 Alkyl groups may be replaced by phenyl, 5-6 heteroaryl, or C. 3-6 Cycloalkyl substituted, of which

[0157] The phenyl group may optionally be replaced by 1-5 halogens.

[0158] The 5-6 quinone heteroaryl group is optionally coated with 1-3 halogens or C. 1-6 Alkyl-substituted,

[0159] and

[0160] The C 1-6 The hydroxyalkyl group may be optionally replaced by a phenyl group;

[0161] The C 3-6 The cycloalkyl group is optionally replaced by a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally replaced by a C-membered heteroaryl group. 1-6 Alkyl groups are substituted;

[0162] The –OC 1-6 The alkyl group may optionally be replaced by a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group may optionally be C 1-6 Alkyl groups are substituted;

[0163] The 5-10 quinone heteroaryl group is optionally coated with C. 1-6 Alkyl groups are substituted;

[0164] R 2 It is hydrogen or C 1-6 alkyl;

[0165] R 3 It is hydrogen or C 1-6 alkyl;

[0166] R 4 For hydrogen; and

[0167] R 5 It is hydrogen or C 1-6 Alkyl, wherein

[0168] The C 1-6 Alkyl groups may be optionally replaced by 5-6 membered heterocyclic groups.

[0169] In some embodiments, this disclosure provides compounds of formula (II) according to formula (IIa), or tautomers thereof, or pharmaceutically acceptable salts thereof:

[0170]

[0171] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), or formula (IIa), or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0172] R 2 It is hydrogen or C 1-3 alkyl;

[0173] R 3 It is hydrogen or C 1-3 alkyl;

[0174] R 4 For hydrogen; and

[0175] R 5 C 1-3 Alkyl, wherein

[0176] The C 1-3 Alkyl groups may be optionally replaced by 5-6 membered heterocyclic groups.

[0177] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), or formula (IIa), or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0178] R 2 It can be hydrogen, methyl, or ethyl;

[0179] R 3 It can be hydrogen or methyl;

[0180] R 4 For hydrogen; and

[0181] R 5 For hydrogen, methyl,

[0182] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), or formula (IIa), or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0183] R 2 For hydrogen; and

[0184] R 3 C 1-3 alkyl.

[0185] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), or formula (IIa), or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0186] R 2 C 1-3 Alkyl; and

[0187] R3 It is hydrogen.

[0188] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), or formula (IIa), or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein:

[0189] R 2 For hydrogen; and

[0190] R 3 It is hydrogen.

[0191] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), or formula (IIa), or pharmaceutically acceptable salts thereof, wherein:

[0192] R 2 C 1-3 Alkyl; and

[0193] R 3 C 1-3 alkyl.

[0194] In some embodiments, this disclosure provides a compound according to formula (III), or a pharmaceutically acceptable salt thereof:

[0195]

[0196] in: It can be a single bond or a double bond;

[0197] R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-10 Aryl, 3-12 heterocyclic, 5-10 heteroaryl, –OR 7 Or –NR 8 R 9 ;

[0198] Where R 1 The C mentioned in 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 acetylene

[0199] base, C 3-10 cycloalkyl, C 6-10 Aryl, 3-12-membered heterocyclic and 5-10-membered heteroaryl groups are optionally and independently bound by 1-5 R groups. 10 Substituted by groups;

[0200] Each R 2 R 3 R 4 and R 5 Independently hydrogen or C 1-6 alkyl;

[0201] R 6 It is hydrogen or halogen;

[0202] Each R 7 Independently hydrogen or C 1-6 Alkyl, wherein

[0203] The C 1-6 Alkyl groups are optionally surrounded by 1-5 Rs. 10 Replaced;

[0204] Each R 8 and R 9 Independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, or R 8 and R 9 Together with the atoms they are attached to, they form 3-12 membered heterocycles, in which

[0205] R 8 and R 9 The C mentioned in 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl groups and 5-10 heteroaryl groups are optionally and independently bounded by 1-5 R groups. 10 Place

[0206] replace;

[0207] Each R 10 Independently for C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl, 5-10 heteroaryl, halogen, oxo group, –OR a –C(O)R a –C(O)OR a –C(O)NR a R b –OC(O)NR a R b –NR a R b –NR aC(O)R b –NR a C(O)OR b –S(O) q R a –S(O)2NR a R b –NR a S(O)2R b –N3, –CN, or –NO2, or two Rs 10 Groups form fused, spirocyclic, or bridged C 3-10 Cycloalkyl or 3-12 membered heterocyclic groups, wherein

[0208] R 10 Each C in 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkynyl group, C 3-10 cycloalkyl,

[0209] C 6-10 Aryl, 3-12-membered heterocyclic and 5-10-membered heteroaryl groups are optionally and independently bound by 1-5 R groups. 20 Substituted by groups;

[0210] Each R a and R b Independently hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10 aryl or 5-10 heteroaryl, or R a and R b Together with the atoms they are attached to, they form 3-12 membered heterocyclic groups, in which

[0211] R a and R b Each of the C in 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6

[0212] Heteroalkyl, 3-12 membered heterocyclic, C 6-10 Aryl groups and 5-10 heteroaryl groups are independently coated with 1-5 R groups. 20 Substituted by groups;

[0213] Each R 20 Independently for C 1-6 Alkyl, C 3-10 cycloalkyl, C 1-6 Heteroalkyl, 3-12 membered heterocyclic, C 6-10Aryl, 5-10 heteroaryl, hydroxyl, C 1-6 Alkoxy, amino, -CN, -C(O)H, -C(O)NH2, -C(O)NH(C 1-6 Alkyl), -C(O)N(C 1-6 Alkyl group 2, -COOH, -C(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl or halogen;

[0214] n is 0, 1, or 2; and

[0215] q can be 0, 1, or 2.

[0216] In some embodiments, this disclosure provides compounds of formula (III) according to formula (IIIa) or pharmaceutically acceptable salts thereof:

[0217]

[0218] In some embodiments, this disclosure provides compounds of formula (III) according to formula (IIIb) or pharmaceutically acceptable salts thereof:

[0219]

[0220] Where: R 1 C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 5-10 heteroaryl, –NHC 1-6 Alkyl, –NHC 1-6 Haloalkyl, 4-6 membered heterocyclic, C 3-6 cycloalkyl, –NHC 3-10 cycloalkyl or –

[0221] NH (4-6 membered heterocyclic group);

[0222] R 1 Each C in 1-6 Alkyl and –NHC 1-6 The alkyl group may be independently substituted by 1 to 3 substituents independently selected from the following: hydroxyl, C 1-6 Alkyl groups, 5-10 quinone aromatic compounds

[0223] base, C 3-6 Cycloalkyl, phenyl, or –O– (4-10 membered heterocyclic groups);

[0224] Each of the 5-10 quinone heteroaryl groups, C 3-6 Cycloalkyl, phenyl, and –O– (4-10 membered heterocyclic groups) are optionally and independently surrounded by 1-4 independently selected halogens, C 1-6 Alkyl and C 1-6Substituents of haloalkyl groups;

[0225] R 1 Each C in 6-10 The aryl group and the 5-10 heteroaryl group are optionally substituted by 1-3 independent substituents selected from the following: halogen, hydroxyl, –CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, 4-6 membered heterocyclic and C 3-6 cycloalkyl; and

[0226] R 1 Each 4-6 member heterocyclic group, C 3-6 cycloalkyl, –NHC 3-10 cycloalkyl and –

[0227] NH (4-6 membered heterocyclic group) is optionally taken by 1-3 independent substituents selected from the following

[0228] Substitutes: halogens, oxy groups, hydroxyl groups, –CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Heteroalkyl, -C(O)OR a C 6-10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic and C 3-6 cycloalkyl;

[0229] Each C 6-10 Aryl, 5-10 membered heteroaryl, 4-6 membered heterocyclic and C 3-6 The cycloalkyl group is optionally and independently selected by 1-3 independently selected halogens, C 1-4 Alkyl and C 1-4 Substituents of haloalkyl groups;

[0230] Each R 2 R 3 R 4 and R 5 Independently hydrogen or C 1-6 Alkyl; and

[0231] R 6 It is hydrogen or halogen.

[0232] In some embodiments, this disclosure provides compounds of formula (IIIc) or pharmaceutically acceptable salts thereof:

[0233]

[0234] Each R 1 R 2 R 3 R 4 R5 and R 6 As defined above or elsewhere in this disclosure.

[0235] In some embodiments, this disclosure provides a compound of formula (IIId) or a pharmaceutically acceptable salt thereof:

[0236]

[0237] Each R 1 R 2 R 3 R 4 R 5 and R 6 As defined above or elsewhere in this disclosure.

[0238] In some embodiments, this disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof:

[0239]

[0240] Where: R 1 C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups;

[0241] Where R 1 Optionally and independently controlled by 1-4 R 10 Replaced;

[0242] Each R 10 Independently selected from: halogen, hydroxyl, –CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl and 3-12 membered heterocyclic groups;

[0243] Where R 10 C in 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 The cycloalkyl group and the 3-12 membered heterocyclic group are optionally and independently substituted by 1-4 substituents independently selected from the following: halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl and C 1-4 Heteroalkyl;

[0244] R 2 For hydrogen, C 1-6 Alkyl or C 1-6 Heteroalkyl;

[0245] Where R 2 C in 1-6 Alkyl and C 1-6The heteroalkyl group may be optionally substituted by 1 to 3 substituents independently selected from halogens, oxo groups and hydroxyl groups;

[0246] R 3 and R 4 Independently hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OR 7 or -SO2R 7 ;

[0247] Where R 3 and R 4 C in 1-6 Alkyl and C 1-6 The heteroalkyl group may be independently substituted by 1 to 3 substituents independently selected from the following: halogen, oxo, C. 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 Aryl and 5-10 heteroaryl groups;

[0248] Where C 3-6 cycloalkyl, 4-6 membered heterocyclic, C 6-10 The aryl group and 5-10 heteroaryl group are optionally and independently selected by 1-3 independently selected halogens, C 1-4 Alkyl and C 1-4 Substituents of heteroalkyl groups;

[0249] R 5 For hydrogen, C 1-6 Alkyl or C 1-6 Heteroalkyl;

[0250] Where R 5 C in 1-6 Alkyl and C 1-6 The heteroalkyl group may be optionally substituted by 1 to 3 independent substituents selected from the following: halogen, oxo, C. 3-6 cycloalkyl and 4-6 membered heterocycles

[0251] base; and

[0252] R 7 Independently hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic rings

[0253] base, C 6-10 Aryl or 5-10 heteroaryl groups;

[0254] Where R 7 C in 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10The aryl group and the 5-10 heteroaryl group are optionally substituted by 1-4 independent substituents selected from the following: halogen, oxo group, C... 1-4 Alkyl, C 1-4 Halogenated alkyl and C 1-4 Heteroalkyl groups.

[0255] In some embodiments, this disclosure provides compounds of formula (IV) according to formula (IVa) or pharmaceutically acceptable salts thereof:

[0256]

[0257] Where: R 1 It is a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group;

[0258] Where R 1 Optionally and independently controlled by 1-4 R 10 Replaced;

[0259] Each R 10 Independently selected from: halogen, hydroxyl, –CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0260] Each R 2 R 3 and R 4 Independently hydrogen, C 1-4 Alkyl or C 1-4 Alkyl group.

[0261] In some embodiments, this disclosure provides compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), or (IIIb), or tautomers thereof, or pharmaceutically acceptable salts thereof, wherein the heterocyclic group is a partially unsaturated ring system containing one or more double bonds. In some embodiments, the heterocyclic group is a fused ring system having an aromatic ring and a non-aromatic ring, but not a fully aromatic ring system.

[0262] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 2 It is hydrogen.

[0263] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 2C 1-3 alkyl.

[0264] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 2 It is a methyl group.

[0265] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 3 C 1-3 alkyl.

[0266] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 3 It is a methyl group.

[0267] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 4 It is hydrogen.

[0268] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 5 C 1-3 alkyl.

[0269] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 5 It is a methyl group.

[0270] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 6 It is Cl.

[0271] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II) or formula (IIa) or their tautomers or pharmaceutically acceptable salts thereof, wherein –C(O)R 1 Selected from:

[0272]

[0273]

[0274] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 1 Selected from: Or its pharmaceutically acceptable salt.

[0275] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 1 Selected from: Or its pharmaceutically acceptable salt.

[0276] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa) or formula (IIIb), or tautomers thereof or pharmaceutically acceptable salts thereof, wherein R 1 Selected from:

[0277] In some embodiments, this disclosure provides compounds of formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or pharmaceutically acceptable salts thereof, wherein R 1 It is a 3-12 membered heterocyclic group or a 5-10 membered heteroaryl group, which is optionally surrounded by 1-2 R groups. 10 replace.

[0278] In some embodiments, this disclosure provides compounds of formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or pharmaceutically acceptable salts thereof, wherein R 1 Selected from: Each of them can be randomly selected by 1-2 Rs 10 Replaced. In some implementations, each R 10 Independently selected from: -CH3, -CHF2 and -OCH3.

[0279] In some implementation schemes, R 1 For any 1-2 Rs 10 Replacement In some implementation schemes, R 1 For any 1-2 Rs 10 Replacement In some implementation schemes, R 10 Selected independently from C 1-4 Alkyl and C 1-4 Alkyl group. In some embodiments, R 10 It is independently selected from -CH3 and -OCH3. In some embodiments, R 1 For those replaced by -CH3 and -OCH3

[0280] In some implementation schemes, R 1 for In some implementation schemes, R 1 for

[0281] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or pharmaceutically acceptable salts thereof, wherein R 2 It is hydrogen or C 1-3 Alkyl group. In some embodiments, R 2 Selected from hydrogen and methyl. In some embodiments, R 2 It is hydrogen. In some implementations, R 2 It is a methyl group.

[0282] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or pharmaceutically acceptable salts thereof, wherein R 3 It is hydrogen or C 1-3 Alkyl group. In some embodiments, R 3 Selected from hydrogen and methyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 It is hydrogen.

[0283] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or pharmaceutically acceptable salts thereof, wherein R 4 For hydrogen, C 1-3 Alkyl or C 1-3 Alkyl group. In some embodiments, R 4 Selected from hydrogen, methyl, and -OCH3. In some embodiments, R 4 It is hydrogen. In some implementations, R 4 For -OCH3. In some implementations, R 4 It is a methyl group.

[0284] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or pharmaceutically acceptable salts thereof, wherein R 2 and R 4 It is hydrogen, and R 3 It is methyl. In some embodiments, R 2 and R 3 It is methyl, and R 4 It is hydrogen. In some implementations, R 2 For hydrogen, R 3 It is methyl, and R 4 It is -OCH3.

[0285] In some embodiments, this disclosure provides compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId) or formula (IV), or pharmaceutically acceptable salts thereof, wherein R 5 It is hydrogen or C 1-3 Alkyl group. In some embodiments, R 5 It is methyl. In some embodiments, R 5 It is hydrogen.

[0286] In some embodiments, this disclosure provides compounds selected from Examples 1-464.

[0287] In some embodiments, this disclosure provides compounds selected from Examples 1-154.

[0288] In some embodiments, this disclosure provides compounds selected from Examples 155-464.

[0289] In some embodiments, this disclosure provides compounds selected from the following:

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301] Or its pharmaceutically acceptable salt.

[0302] In some embodiments, this disclosure provides compounds selected from the following:

[0303]

[0304]

[0305]

[0306]

[0307]

[0308] In some embodiments, this disclosure provides compounds selected from the following:

[0309]

[0310]

[0311] In some embodiments, isotopically labeled forms of compounds of formula (I), (Ia), (II), or (IIa) are provided herein. In some embodiments, isotopically labeled forms of compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa) are provided herein. The isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by isotopes having selected atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, but not limited to, those of other types. 2 H (deuterium, D) 3 H (tritium) 11 C 13 C 14 C 15 N、 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. This invention includes compounds of this invention labeled with various isotopes, such as those with radioactive isotopes such as 3 H, 13 C and 14 Compounds incorporating C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays or for patient treatment. Such isotopically labeled analogs of the compounds disclosed herein can also be used to treat the diseases disclosed herein because they provide improved pharmacokinetic and / or pharmacodynamic properties compared to the unlabeled form of the same compounds. Such isotopically labeled forms or analogs of the compounds herein are within the scope of this disclosure. Those skilled in the art can prepare and use such isotopically labeled forms according to processes used for isotopically labeled compounds or compounds to obtain isotopically or radiolabeled analogs of the compounds disclosed herein.

[0312] The compounds disclosed herein may contain one or more asymmetric centers, thus yielding enantiomers, diastereomers, and other stereoisomers that can be defined according to absolute stereochemistry as (R)- or (S)- or (D)- or (L)-amino acids. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). Similarly, all tautomeric forms should also be included.

[0313] In some embodiments, this disclosure provides pharmaceutical compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises one or more other therapeutic agents, as described in more detail below.

[0314] Pharmaceutical compositions comprising the compounds disclosed herein or their pharmaceutically acceptable salts may be prepared with one or more pharmaceutically acceptable excipients, which may be selected in accordance with conventional practice. “Pharmaceutically acceptable excipients” include, but are not limited to, any adjuvant, carrier, excipient, gliding agent, sweetener, diluent, preservative, dye / coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0315] In some embodiments, the pharmaceutical composition is provided in a solid dosage form, including a solid oral dosage form, such as a tablet. Tablets may contain excipients, including flow aids, fillers, binders, etc. Aqueous compositions may be prepared aseptically and are typically isotonic when intended for delivery by means other than oral administration. All compositions may optionally contain excipients, such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 6th Edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

[0316] The pharmaceutical compositions disclosed herein include those suitable for various routes of administration, including oral administration. The compositions may be present in unit dosage forms and can be prepared by any method known in the pharmaceutical field. Such methods involve the step of conjugating an active ingredient (e.g., a compound of this disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The composition can be prepared by uniformly and tightly binding the active ingredient with a liquid excipient or a finely divided solid excipient, or both, and then shaping the product if necessary. (Remington: The Science and Practice of Pharmacy, 21) st The techniques and formulations were discovered in Edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0317] The compositions suitable for oral administration described herein may be available in discrete units (unit dosage forms), including but not limited to capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0318] The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, along with pharmaceutically acceptable excipients and optional other therapeutic agents. Pharmaceutical compositions containing an active ingredient can be in any form suitable for the intended method of administration. When intended for oral administration, they can be prepared, for example, tablets, lozenges, sugar tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions for oral administration can be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for tablet preparation are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets can be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate, alone or in combination with waxes, can be used.

[0319] The amount of active ingredient that can be combined with an inactive ingredient to produce a dosage form can vary depending on the intended treatment subjects and the specific route of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 to 1000 mg of the active substance, formulated together with an appropriate and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient comprises about 5% to about 95% (by weight) of the total composition.

[0320] method

[0321] In some embodiments, this disclosure provides a method for inhibiting MCL-1. In some embodiments, this disclosure provides a method for inhibiting MCL-1 in an individual (e.g., a human), comprising administering to the individual a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0322] In some embodiments, this disclosure provides methods for treating or preventing cancer. In some embodiments, this disclosure provides methods for treating or preventing cancer in an individual, said methods comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is a hematologic malignancy. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is selected from: breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, and leukemia.

[0323] The compounds disclosed herein can be administered via any route suitable for the methods described herein. Suitable routes include oral, rectal, nasal, local (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural).

[0324] The compounds disclosed herein can be administered to an individual for the desired period of time or duration, according to an effective dosing regimen, such as at least one week, at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or longer. In one variant, the compound is administered daily or intermittently throughout the patient's lifetime.

[0325] The dosage or frequency of administration of the compounds disclosed herein can be adjusted during treatment based on the judgment of the treating physician.

[0326] The therapeutically effective dose of the compounds disclosed herein is from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, for example, from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day, or from about 0.3 μg per day to about 30 mg per day, or from about 0.3 μg per day to about 30 mg per day.

[0327] Compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, may be combined with one or more other therapeutic agents in any dose of the disclosed compound (e.g., from 1 mg to 1000 mg). The therapeutically effective amount of compounds of formula (I), (Ia), (II), or (IIa), or their tautomers or pharmaceutically acceptable salts, may be from about 0.01 mg to about 1000 mg per dose, for example from about 0.01 mg to about 100 mg per dose, or for example from about 0.1 mg to about 100 mg per dose, or for example from about 1 mg to about 100 mg per dose, or for example from about 1 mg to about 10 mg per dose. Other therapeutically effective doses of compounds of formula (I), (Ia), (II), or (IIa) are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective doses of compounds of formula (I), (Ia), (II), or (IIa) are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, or about 500 mg per dose.

[0328] The therapeutically effective amount of a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or its tautomer or pharmaceutically acceptable salt, may be from about 0.01 mg to about 1000 mg per dose, for example from about 0.01 mg to about 100 mg per dose, or for example from about 0.1 mg to about 100 mg per dose, or for example from about 1 mg to about 100 mg per dose, or for example from about 1 mg to about 10 mg per dose. Other therapeutically effective doses of compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa) are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 mg per dose. Other therapeutically effective doses of compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa) are about 100 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450 or about 500 mg per dose.

[0329] A single dose may be administered hourly, daily, or weekly. For example, a single dose may be administered every 1 hour, 2, 3, 4, 6, 8, 12, 16 hours, or every 24 hours. A single dose may also be administered every 1 day, 2, 3, 4, 5, 6 days, or every 7 days. A single dose may also be administered every 1 week, 2, 3 weeks, or 4 weeks. In some embodiments, a single dose may be administered weekly. A single dose may also be administered monthly. In some embodiments, the compound disclosed herein is administered once daily using the methods disclosed herein. In some embodiments, the compound disclosed herein is administered twice daily using the methods disclosed herein.

[0330] The dosage frequency of the compounds disclosed herein will be determined by the individual patient's needs and may be, for example, once daily, twice daily, or more. Administration of the compounds will continue for the duration required to treat the cancer. For example, the compounds disclosed herein may be administered to a person with cancer for a period of 20 to 180 days, or for, for, for, for, for, 20 to 90 days, or for, for, for, for, for, 30 to 60 days.

[0331] Dosing may be intermittent, with the patient receiving a daily dose of the compound disclosed herein for several days or more, followed by periods without the daily dose. For example, the patient may receive one dose of the compound every other day or three times a week. Again, as a non-limiting example, the patient may receive one dose of the compound daily for 1 to 14 days, then abstain from the compound for 7 to 21 days, and then resume receiving the daily dose of the compound for a subsequent period (e.g., 1 to 14 days). Alternating periods of repeated and discontinued administration of the compound may be permitted as needed to treat the patient's clinical needs.

[0332] Combination therapy

[0333] Treatment methods are also provided in which a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, is given to a patient in combination with one or more other active agents or therapies.

[0334] Therefore, in one embodiment, a method for treating cancer and / or diseases or symptoms coexisting with or exacerbating or caused by cancer (e.g., allergic diseases and / or autoimmune and / or inflammatory diseases, and / or acute inflammatory reactions) includes administering to a patient in need an effective amount of a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, optionally in combination with other agents (e.g., a second, third, fourth, or fifth active agent) that can be used to treat cancer, cancer-related or coexisting allergic diseases and / or autoimmune and / or inflammatory diseases and / or acute inflammatory reactions. Treatment with a second, third, fourth, or fifth active agent may be performed before, simultaneously with, or after treatment with a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is combined with another active agent in a single dosage form. Suitable antitumor or anticancer therapeutic agents that can be used in combination with compounds of formula (I), (Ia), (II), or (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, include, but are not limited to, chemotherapeutic agents such as mitomycin C, carboplatin, taxol, cisplatin, paclitaxel, etoposide, doxorubicin, or combinations comprising at least one of the aforementioned chemotherapeutic agents. Radiotherapy antitumor agents can also be used alone or in combination with chemotherapeutic agents.

[0335] Compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, can be used as chemosensitizers and therefore can be used in combination with other chemotherapeutic agents, particularly those that induce apoptosis. Therefore, in one embodiment, this disclosure provides a method for increasing the sensitivity of cancer cells to chemotherapy, the method comprising administering a chemotherapeutic agent and a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, to a patient who requires or is receiving chemotherapy, in an amount sufficient to increase the sensitivity of cancer cells to the chemotherapeutic agent.

[0336] Examples of other chemotherapeutic agents that may be used in combination with compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, include topoisomerase I inhibitors (camptothecin or topotecan), topoisomerase II inhibitors (e.g., donomycin and etoposide), alkylating agents (e.g., cyclophosphamide, melphalan, and BCNU), tubulin-directing agents (e.g., paclitaxel and vincristine), and biologics (e.g., antibodies such as anti-CD20 antibodies, IDEC 8, immunotoxins, and cytokines).

[0337] In some embodiments, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, is mixed with... (Rituximab) and / or other drugs that work by selectively depleting CD20+ B cells.

[0338] This article includes treatment methods in which compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, are administered in combination with anti-inflammatory drugs. Anti-inflammatory drugs include, but are not limited to, NSAIDs, nonspecific and COX-2 specific cyclooxygenase inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

[0339] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprazine, diflunisal, piroxicam, indomethacin, etodoxacin, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tometidine sodium, and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors (i.e., compounds that inhibit COX-2, whose IC50 value is less than 1000 mg / kg / dL). 50 IC for COX-1 50 (Up to 1 / 50) For example, celecoxib, vardicoxib, rumicoxib, etoricoxib and / or rofecoxib.

[0340] In another embodiment, the anti-inflammatory drug is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, choline, and magnesium salicylate.

[0341] The anti-inflammatory drug can also be a corticosteroid. For example, the corticosteroid can be selected from cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, and prednisone. In some embodiments, the anti-inflammatory therapeutic agent is a gold compound, such as sodium gold thiomalate or auronoxine. In some embodiments, the anti-inflammatory drug is a metabolic inhibitor, such as a dihydrofolate reductase inhibitor, such as methotrexate, or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

[0342] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, is used in combination with at least one anti-inflammatory compound, said anti-inflammatory compound being an anti-C5 monoclonal antibody (e.g., eculizumab or pecrolimus), a TNF antagonist such as entanercept, or infliximab (which is an anti-TNFα monoclonal antibody).

[0343] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, is used in combination with at least one active agent, said active agent being an immunosuppressant compound such as methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

[0344] In other embodiments, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, is used in combination with one or more phosphatidylinositol 3-kinase (PI3K) inhibitors, including, for example, compounds A, B and C (the structures of which are provided below) or pharmaceutically acceptable salts thereof.

[0345]

[0346] Compounds A, B, and C are disclosed in WO2015 / 017460 and WO2015 / 100217. Other examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-6946), duvelisib, GDC-0941, GDC-0980, GSK2636771, GSK2269557, and idelalisib (…). IPI-145, IPI-443, IPI-549, KAR4141, LY294002, LY3023414, MLN1117, OXY111A, PA799, PX-866, RG7604, rigosertib, RP5090, taselisib, TG100115, TGR-1202, TGX221, WX-037, X-339, X-414, XL147 (SAR245408), XL499, XL756, wortmannin, ZSTK474, and WO 2005 / 113556 (ICOS), WO 2013 / 052699 (Gilead Calistoga), WO The compounds described in WO 2013 / 116562 (Gilead Calistoga), WO 2014 / 100765 (Gilead Calistoga), WO 2014 / 100767 (Gilead Calistoga) and WO 2014 / 201409 (Gilead Sciences).

[0347] In another embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, may be used in combination with a spleen tyrosine kinase (SYK) inhibitor. Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entespletinib, flotatinib (R788), HMPL-523, NVP-QAB 205AA, R112, R343, tamatinib (R406), and those described in US8450321 (Gilead Connecticut) and US2015 / 0175616.

[0348] In another embodiment, compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, may be used in combination with tyrosine kinase inhibitors (TKIs). The TKIs may target receptors for epidermal growth factor receptor (EGFR), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF). Examples of TKIs include, but are not limited to, afatinib, ARQ-087, asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, sildenafil, crenolanib, dacomitinib, dasatinib, duvitinib, E-6201, erdafitinib, erlotinib, gefitinib, gilteritinib (ASP-2215), FP-1039, and HM617. 13. Icotinib, Imatinib, KX2-391 (Src), Lapatinib, Lettatinib, Midotutolin, Nintedanib, ODM-203, Osimertinib (AZD-9291), Ponatinib, Poziotinib, Quizartinib, Radotinib, Rociletinib, Sulfatinib (HMPL-012), Sunitinib, and TH-4000.

[0349] In other embodiments, compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, may be used in combination with one or more inhibitors of lysyl oxidase-like 2 (LOXL) or substances that bind to LOXL, including, for example, humanized monoclonal antibodies (mAbs) having an immunoglobulin IgG4 isotype against human LOXL2. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in WO 2009 / 017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, the antibodies described in WO 2009 / 017833 (Arresto Biosciences), WO 2009 / 035791 (Arresto Biosciences), and WO 2011 / 097513 (Gilead Biologics).

[0350] In another embodiment, compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, may be used in combination with a Toll-like receptor 8 (TLR8) inhibitor. Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, requimomod, VTX-1463, and VTX-763.

[0351] In another embodiment, compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, may be used in combination with a Toll-like receptor (TLR9) inhibitor. Examples of TLR9 inhibitors include, but are not limited to, IMO-2055, IMO-2125, lefitolimod, linimod, MGN-1601, and PUL-042.

[0352] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is combined with a BTK (Bruton's tyrosine protein kinase) inhibitor for the treatment of cancer. An example of such a BTK inhibitor is a compound disclosed in U.S. Patent 7,405,295. Other examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-ynyl)pyrrolidone-3-yl)-7-(4-phenoxyphenyl)-7H-purine-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, HM71224, ibrutinib, M-2951, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), and TAK-020.

[0353] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is combined with a BET inhibitor for the treatment of cancer. Examples of such BET inhibitors are compounds disclosed in WO2014 / 182929, the entire contents of which are incorporated herein by reference.

[0354] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is combined with a TBK (Tank-binding kinase) inhibitor for the treatment of cancer. An example of such a TBK inhibitor is a compound disclosed in WO2016 / 049211.

[0355] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is combined with an OX40 inhibitor for the treatment of cancer. Examples of such OX40 inhibitors are compounds disclosed in US 8,450,460, the entire contents of which are incorporated herein by reference.

[0356] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, may be combined with a JAK-1 inhibitor for the treatment of cancer. An example of such a JAK-1 inhibitor is a compound disclosed in WO2008 / 109943. Other examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110, letatinib, momelotinib (CYT0387), NS-018, pacritinib (SB1518), peficitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), and XL019.

[0357] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is combined with an indoleamine-pyrrole-2,3-dioxygenase (IDO) inhibitor for the treatment of cancer. An example of such an IDO inhibitor is a compound disclosed in WO2016 / 186967. In one embodiment, the compound of formula (I), formula (Ia), formula (II), or formula (IIa) is combined with an IDO1 inhibitor for the treatment of cancer, said IDO1 inhibitor including, but not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919-based vaccines, PF-06840003, pyranoquinone derivatives (SN-35837), resminostat, SBLK-200802, and shIDO-ST.

[0358] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is used in combination with a mitogen-activated protein kinase (MEK) inhibitor for the treatment of cancer. MEK inhibitors used in combination with compounds of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa) include antroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selmetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib, and trametinib.

[0359] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, is combined with an apoptosis signal-regulated kinase (ASK) inhibitor for the treatment of cancer: the ASK inhibitor includes, but is not limited to, those described in WO2011 / 008709 (Gilead Sciences) and WO 2013 / 112741 (Gilead Sciences), including, for example, selonsertib.

[0360] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, may be combined with a differentiation cluster 47 (CD47) inhibitor. Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAbs (Vx-1004), anti-human CD47 mAbs (CNTO-7108), CC-90002, CC-90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938, and TTI-621.

[0361] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, may be combined with a cyclin-dependent kinase (CDK) inhibitor. CDK inhibitors include CDK 1, 2, 3, 4, 6, and 9 inhibitors, such as abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, FLX-925, LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, and TG-02.

[0362] In one embodiment, compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, may be combined with a discoidal domain receptor (DDR) inhibitor for the treatment of cancer. DDR inhibitors include DDR1 and / or DDR2 inhibitors. Examples of DDR inhibitors include, but are not limited to, those disclosed in WO 2014 / 047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 2011-0287011 (Oncomed Pharmaceuticals), WO2013 / 027802 (Chugai Pharmaceutical), and WO 2013 / 034933 (Imperial Innovations).

[0363] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, may be combined with a histone deacetylase (HDAC) inhibitor, such as those disclosed in U.S. Patent 8,575,353 and its equivalents. Other examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinstat, CKD-581, CS-055 (HBI-8000), CUDC-907, entinostat, givinostat, mocetinostat, panobinostat, pracinostat, quisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), and vorinostat.

[0364] In one embodiment, a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is used in combination with standard care for the treatment of the corresponding cancer for the treatment of cancer. Those skilled in the art are familiar with the standards of care in a particular area of ​​cancer treatment at a given date or for a given cancer.

[0365] Some embodiments of this application include or use one or more additional therapeutic agents. These one or more additional therapeutic agents may be agents used to treat cancer, inflammation, autoimmune diseases, and / or related conditions. These one or more additional therapeutic agents may be chemotherapeutic agents, anti-angiogenic agents, anti-fibrotic agents, anti-inflammatory agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, radiotherapy agents, antitumor agents, anticancer agents, antiproliferative agents, or any combination thereof. In some embodiments, the compounds described herein may be used or combined with chemotherapeutic agents, anti-angiogenic agents, antifibrotic agents, anti-inflammatory agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, radiotherapy agents, antitumor agents or anticancer agents, antiproliferative agents, or any combination thereof.

[0366] In one embodiment, compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts thereof, optionally in combination with other anticancer agents described herein, may be used or in combination with antitumor agents or anticancer agents, antifibrotic agents, anti-inflammatory agents, or immunomodulators.

[0367] In one embodiment, a kit is provided comprising a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (II), or formula (IIa) or a tautomer thereof or a pharmaceutically acceptable salt thereof, and at least one additional anticancer agent or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In another embodiment, a kit is provided comprising a pharmaceutical composition comprising a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa) or a tautomer thereof or a pharmaceutically acceptable salt thereof, and at least one additional anticancer agent or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In one embodiment, the kit includes instructions for use in treating cancer. In one embodiment, the instructions for use in the kit pertain to the use of the pharmaceutical composition in treating hematologic malignancies, multiple myeloma, breast cancer, colorectal cancer, skin cancer, melanoma, ovarian cancer, kidney cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, and / or leukemia.

[0368] This application also provides a method for treating a subject receiving one or more standard therapies (e.g., chemotherapy, radiotherapy, immunotherapy, surgery, or combinations thereof), the method comprising administering to or co-administering to the subject a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof. Thus, one or more compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, can be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery, or combinations thereof.

[0369] In one implementation, the subject may be (i) a person substantially refractory to at least one chemotherapy therapy, or (ii) a person who has relapsed after chemotherapy treatment, or both (i) and (ii). In some implementations, the subject is refractory to at least two, at least three, or at least four chemotherapy therapies (including standard or experimental chemotherapy therapies).

[0370] In one implementation, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy therapies (including standard or experimental chemotherapy), said chemotherapy being selected from fludarabine, rituximab, obinutuzumab, alkylating agents, alenzusab, and other chemotherapy therapies such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; tamsurolimus and rituximab; tamsurolimus and Iodine-131 tosimomab ( ) and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (ifosfamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and DTPACE (dexamethasone, thalidomide, cisplatin, (Cyclophosphamide, etoposide).

[0371] Other examples of chemotherapy (including standard or experimental chemotherapy) are described below. Furthermore, treatments for certain lymphomas are reviewed in Cheson, BD, Leonard, JP, “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's lymphoma”, The New England Journal of Medicine, 2008, 359(6), pp. 613–626; and Wierda, WG, “Current and Investigational Therapies for Patients with CLL”, Hematology, 2006, pp. 285–294. Lymphoma incidence patterns in the United States are outlined in Morton, LM, et al., “Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992–2001”, Blood, 2006, 107(1), pp. 265–276.

[0372] Examples of immunotherapeutic agents for the treatment of lymphoma or leukemia include, but are not limited to, rituximab (e.g., rituximab), alenzumab (e.g., Camppath, MabCampath), anti-CD19 antibody, anti-CD20 antibody, anti-MN-14 antibody, anti-TRAIL, anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibody, apolizumab, bevacizumab, CHIR-12.12, epazolizumab (hLL2-anti-CD22 humanized antibody), rituximab, ha20, tiimozumab, ruximab, mirazolizumab, ofamumab, PRO131921, SGN-40, WT-1 peptide-like vaccine, WT1 126-134 peptide vaccine, tosimomumab, autologous human tumor-derived HSPPC-96, and vetuzumab. Other immunotherapeutic agents include cancer vaccines used based on the individual patient's tumor genetic composition, such as the lymphoma vaccine GTOP-99. ).

[0373] Examples of chemotherapy agents used to treat lymphoma or leukemia include adefovir, avodiidine, antitumor ketone AS2-1, antitumor ketone A10, antithymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, β-alethine, Bcl-2 family protein inhibitors ABT-263, BMS-345541, and bortezomib. ), bryozoxin 1, busulfan, carboplatin, campaszolium-1H, CC-5103, carmustine, caspofungin acetate, clofarabine, cisplatin, leustarin, chlorambucil, curcumin, cyclosporine, cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), cytarabine, diphenhydramine 2, dexamethasone, DT PACE, docetaxel, dolastatin 10, doxorubicin ( Doxorubicin, doxorubicin hydrochloride, enzartolin, eportine α, etoposide, everolimus (RAD001), fenvitamin A, filgrastim, melphalan, mesna, flavopiridol, fludarabine (Fudawa), geldromycin (17-AAG), ifosfamide, irinotecan hydrochloride, ixaprone, lenalidomide ( (CC-5013), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, motexafen gadolinium, mycophenolate mofetil, nerabine, Genasense octaclata (GX15-070), octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, PD0332991, PEGylated doxorubicin hydrochloride liposomes, pefexine, pentstatin (Nipent), perifolliculin, prednisolone, prednisone, R-r oscovitine (Selicilib, CYC202), recombinant interferon-α, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, rituximab, saxaglastine, sildenafil citrate, simvastatin, sirolimus, styrylsulphones, tacrolimus, spiramycin, tamsurolimus (CCl-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tepifenabil, (Bortezomib or PS-341), Vincristine (Oncovin), Vincristine Sulfate, Vinorelbine Bitartrate, Volindustat (SAHA), Volindustat and FR (Fludarabine, Rituximab), CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone), CVP (Cyclophosphamide, Vincristine, and Prednisone), FCM (Fludarabine, Cyclophosphamide, Mitoxantrone), FCR (Fludarabine, Cyclophosphamide, Rituximab), HyperC VAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (ifosfamide, carboplatin, and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (rituximab-MCP).

[0374] In some implementations, the cancer is melanoma. Suitable agents used in combination with the compounds described herein include, but are not limited to, dacarbazine (DTIC), optionally administered with other chemotherapy agents such as carmustine (BCNU) and cisplatin; the "Dartmouth therapy" consisting of DTIC, BCNU, cisplatin, and tamoxifen; and cisplatin, vincristine, and DTIC, temozolomide, or yervoy. TM In the treatment of melanoma, the compounds disclosed herein can also be combined with immunotherapy agents, including cytokines such as interferon-alpha, interleukin-2, and tumor necrosis factor (TNF).

[0375] The compounds described in this article can also be used in combination with vaccine therapy for the treatment of melanoma. Anti-melanoma vaccines are in some respects similar to antiviral vaccines used to prevent viral diseases such as polio, measles, and mumps. A portion of weakened melanoma cells, or melanoma cells called antigens, can be injected into the patient to stimulate the body's immune system to destroy the melanoma cells.

[0376] Melanoma limited to the arm or leg can also be treated with a combination of agents comprising one or more of the compounds described herein, for example using a hyperthermia-isolated limb perfusion technique. This treatment temporarily isolates the circulation of the affected limb from the rest of the body and injects a high dose of chemotherapy into the arteries supplying the limb, thereby delivering a high dose to the tumor area without exposing internal organs to these doses that could cause serious side effects. The fluid is typically heated to 102° to 104°F. Melphalan is the most commonly used drug in this chemotherapy. Treatment can also be given with another drug called tumor necrosis factor (TNF), optionally in combination with compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa).

[0377] The above treatments can be supplemented or combined with any of them through stem cell transplantation or therapy. An example of a modified approach is radioimmunotherapy, which combines monoclonal antibodies with radioactive isotope particles such as indium In111, yttrium Y90, and iodine I-131. Examples of combination therapies include, but are not limited to, iodine-131 tosimomumab (…). Yttrium-90 timatumab ( ), With CHOP.

[0378] Other treatments that combine with treatments using compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa) or their tautomers or pharmaceutically acceptable salts include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biotherapy, enzyme inhibitor therapy, whole-body radiation, stem cell infusion, bone marrow stem cell support ablation, peripheral blood stem cell transplantation with in vitro therapy, umbilical cord blood transplantation, immunoenzyme technology, pharmacological studies, low-LET cobalt-60 gamma radiation therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0379] In some embodiments, this disclosure provides pharmaceutical compositions comprising a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with an MMP9-binding protein and / or one or more additional therapeutic agents, and a pharmaceutically acceptable diluent, carrier, or excipient. In one embodiment, the pharmaceutical composition comprises an MMP9-binding protein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient, carrier, or diluent. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) and an anti-MMP9 antibody AB0045.

[0380] In one embodiment, the pharmaceutical composition comprises a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV), or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, an anti-MMP9 antibody AB0045, at least one additional therapeutic agent (which is an immunomodulator), and a pharmaceutically acceptable diluent, carrier, or excipient. In some other embodiments, the pharmaceutical composition comprises an anti-MMP9 antibody AB0045, at least one additional therapeutic agent (which is an anti-inflammatory agent), and a pharmaceutically acceptable diluent, carrier, or excipient. In some other embodiments, the pharmaceutical composition comprises a compound of formula (I), formula (Ia), formula (II), formula (IIa), formula (III), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IV) or formula (IVa), or a tautomer thereof or a pharmaceutically acceptable salt thereof, an anti-MMP9 antibody AB0045, at least one additional therapeutic agent (which is an antitumor or anticancer agent), and a pharmaceutically acceptable diluent, carrier or excipient. In one embodiment, the MMP9 compounds used for treatment with compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, include, but are not limited to, marimastastat (BB-2516), cipemastat (Ro 32-3555), and those described in WO 2012 / 027721 (Gilead Biologics).

[0381] In one embodiment, the one or more additional therapeutic agents are immunomodulators, such as immunostimulants or immunosuppressants. In some other embodiments, the immunomodulator is a drug capable of altering the function of immune checkpoints, including CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and / or the PD-1 pathway. In other embodiments, the immunomodulator is an immune checkpoint modulator. Exemplary immune checkpoint modulators include anti-CTLA-4 antibodies (e.g., ipilimumab), anti-LAG-3 antibodies, anti-B7-H3 antibodies, anti-B7-H4 antibodies, anti-Tim3 antibodies, anti-BTLA antibodies, anti-KIR antibodies, anti-A2aR antibodies, anti-CD200 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CD28 antibodies, anti-CD80 or anti-CD86 antibodies, anti-B7RP1 antibodies, anti-B7-H3 antibodies, anti-HVEM antibodies, anti-CD137 or -CD137L antibodies, anti-OX40 or anti-OX40L antibodies, anti-CD40 or anti-CD40L antibodies, anti-GAL9 antibodies, anti-IL-10 antibodies, and A2aR drugs. For certain gene products of such immune pathways, antagonists or agonists of such gene products, as well as small molecule modulators of such gene products, are considered. In one embodiment, the immunomodulator is an anti-PD-1 or anti-PD-L1 antibody. In some implementations, immunomodulators include those agents capable of altering the function of mediators in cytokine-mediated signaling pathways.

[0382] In some implementations, the one or more additional therapies or anticancer agents are cancer gene therapies or cell therapies. Cancer gene therapies and cell therapies include inserting normal genes into cancer cells to replace mutated or altered genes; gene modification to silence mutated genes; genetic methods that directly kill cancer cells; including the injection of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response against cancer cells, or to activate the patient's own immune system (T cells or natural killer cells) to kill cancer cells, or to detect and kill cancer cells; and genetic methods that alter cell activity to further modify the endogenous immune response against cancer. Non-limiting examples include Algenpantucel-L (two pancreatic cell lines), Sipuleucel-T, and SGT-53 liposome nanodelivery (scL) of the p53 gene; T-cell therapies such as CD19 CAR-T. tisagenlecleucel-T(CTL019)WO2012079000, WO2017049166, axicabtageneciloleucel(KTE-C19)US774 1465, US6319494, JCAR-015US7446190, JCAR-014, JCAR-020, JCAR-024, JCAR-023, JTCR-016, JCAR-018WO2 016090190, JCAR-017, (WO2016196388, WO2016033570, WO2015157386), BPX-501US9089520, WO2016100236, AU-105, UCART-22, ACTR-087, P-BCMA-101; activated allogeneic natural killer cells CNDO-109-AANK, FATE-NK100 and LFU-835 hematopoietic stem cells.

[0383] In one embodiment, the one or more additional therapeutic agents are immune checkpoint inhibitors. Tumors exploit a mechanism called T-cell exhaustion, which is caused by prolonged exposure to antigens and is characterized by the upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0384] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuators (BTLA; CD272), T-cell immunoglobulin and mucin domain 3 (Tim-3), lymphocyte activation gene 3 (Lag-3; CD223), and others commonly referred to as checkpoint regulators, act as molecular determinants influencing whether cell cycle progression and other intracellular signaling processes should proceed based on extracellular information.

[0385] In addition to specific antigen recognition via T cell receptors (TCRs), T cell activation is regulated by the balance between positive and negative signals provided by co-stimulatory receptors. These surface proteins are typically members of the TNF receptor or the B7 superfamily. Antagonistic antibodies against activating co-stimulatory molecules and blocking antibodies against negative co-stimulatory molecules can enhance T cell stimulation to promote tumor destruction.

[0386] Programmed cell death protein 1 (PD-1 or CD279) (a 55 kDa type 1 transmembrane protein) is a member of the CD28 family of T cell costimulatory receptors, which includes immunoglobulin superfamily members CD28, CTLA-4, inducible costimulatory agents (ICOS), and BTLA. PD-1 is highly expressed on activated T cells and B cells. PD-1 expression can also be detected on memory T cell subsets with variable expression levels. Two PD-1-specific ligands have been identified: programmed death ligand 1 (PD-L1, also known as B7-H1 or CD274) and PD-L2 (also known as B7-DC or CD273). In mouse and human systems, both PD-L1 and PD-L2 downregulate T cell activation upon binding to PD-1 (Okazaki et al., Int. Immunol., 2007; 19: 813-824). PD-1 interacts with its ligands PD-L1 and PD-L2 (expressed on antigen-presenting cells (APCs) and dendritic cells (DCs)) to deliver negative regulatory stimuli, thereby downregulating the activated T-cell immune response. Blockade of PD-1 inhibits this negative signaling and amplifies the T-cell response. Numerous studies have shown that the cancer microenvironment manipulates the PD-L1 / PD-1 signaling pathway, and that induction of PD-L1 expression is associated with the suppression of the immune response against cancer, thus allowing cancer progression and metastasis. This PD-L1 / PD-1 signaling pathway is a major mechanism for cancer immune escape for a variety of reasons. This pathway is involved in the negative regulation of the immune response of activated T effector cells found in the periphery. PD-L1 is upregulated in the cancer microenvironment, and PD-1 is also upregulated on activated tumor-infiltrating T cells, potentially enhancing the vicious cycle of suppression. This pathway also participates in the regulation of innate and adaptive immunity through bidirectional signaling. These factors make the PD-1 / PD-L1 complex a central point where cancer can manipulate immune responses and promote its own progression.

[0387] The first immune checkpoint inhibitor tested in clinical trials was Yervoy (Bristol-Myers Squibb), a CTLA-4 mAb. CTLA-4 belongs to the receptor immunoglobulin superfamily, which also includes PD-1, BTLA, TIM-3, and the V-domain immunoglobulin inhibitor of T cell activation (VISTA). Anti-CTLA-4 mAbs are potent checkpoint inhibitors that eliminate “breakdowns” from both native and antigen-experienced cells.

[0388] Treatment enhances the anti-tumor function of CD8+ T cells, increases the ratio of CD8+ T cells to Foxp3+ T regulatory cells, and inhibits the suppressive function of T regulatory cells. TIM-3 has been identified as another important inhibitory receptor expressed by exhausted CD8+ T cells. In mouse models of cancer, it has been shown that the most dysfunctional tumor-infiltrating CD8+ T cells actually co-express PD-1 and LAG-3. LAG-3 is another recently discovered inhibitory receptor that limits effector T cell function and enhances the suppressive activity of T regulatory cells. Recently, it was found that PD-1 and LAG-3 are widely co-expressed in tumor-infiltrating T cells in mice, and combined blockade of PD-1 and LAG-3 elicits a potent synergistic anti-tumor immune response in mouse models of cancer.

[0389] Therefore, in one embodiment, this disclosure provides the use of a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more additional immune checkpoint inhibitors. In one embodiment, this disclosure provides the use of a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, in combination with one or more immune checkpoint inhibitors and an anti-MMP9 antibody or an antigen-binding fragment thereof in the treatment or prevention of cancer. In some embodiments, the immune checkpoint inhibitor may be an anti-PD-1 and / or anti-PD-L1 antibody or an anti-PD-1 / PD-L1 interaction inhibitor. In some embodiments, the anti-PD-L1 antibody may be B7-H1 antibody, BMS 936559 antibody, MPDL3280A (atezolizumab) antibody, MEDI-4736 antibody, MSB0010718C antibody, or a combination thereof. According to another embodiment, the anti-PD-1 antibody may be nivolumab antibody, pembrolizumab antibody, pidilizumab antibody, or a combination thereof.

[0390] Additionally, PD-1 can also be targeted by AMP-224, a recombinant PD-L2-IgG fusion protein. Other antagonists of inhibitory pathways in the immune response include IMP321, soluble LAG-3Ig fusion proteins, and MHC class II agonists, which can be used to enhance the immune response against tumors. Lirilumab is an antagonist of the KIR receptor, and BMS 986016 is an antagonist of LAG3. The TIM-3-galactagogue-9 pathway is another inhibitory checkpoint pathway and a promising target for checkpoint inhibition. RX518 targets and activates the glucocorticoid-induced tumor necrosis factor receptor (GITR), a member of the TNF receptor superfamily, expressed on the surface of various types of immune cells, including regulatory T cells, effector T cells, B cells, natural killer (NK) cells, and activated dendritic cells. Therefore, in one embodiment, the compound of formula (I) or its tautomer or pharmaceutically acceptable salt is used in combination with IMP321, Lirilumab and / or BMS 986016.

[0391] Anti-PD-1 antibodies that can be used in the compositions and methods described herein include, but are not limited to: nivolumab / MDX-1106 / BMS-936558 / ONO1152, fully human IgG4 anti-PD-1 monoclonal antibody; pidilizumab (MDV9300 / CT-011), humanized IgG1 monoclonal antibody; pembrolizumab (MK-3475 / lambrolizumab), humanized monoclonal IgG4 antibody; durvalumab (MEDI-4736); and atezolizumab. Anti-PD-L1 antibodies that can be used in the compositions and methods described herein include, but are not limited to: avelumab; BMS-936559, a fully human IgG4 antibody; atezolizumab (MPDL3280A / RG-7446), a human monoclonal antibody; MEDI4736; MSB0010718C and MDX1105-01.

[0392] In one embodiment, a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is administered in combination with an anti-PD-1 antibody (nivolumab, pembrolizumab, and / or pidilizumab) to a patient requiring treatment. In one embodiment, the anti-PD-L1 antibody used for treatment in combination with a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is BMS-936559, atezolizumab, or avelumab. In one embodiment, the immunomodulator inhibits the immune checkpoint pathway. In another embodiment, the immune checkpoint pathway is selected from CTLA-4, LAG-3, B7-H3, B7-H4, Tim3, BTLA, KIR, A2aR, CD200, and PD-1. Additional antibodies that may be used in combination with compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa), or their tautomers or pharmaceutically acceptable salts, in the compositions and methods described herein include anti-PD-1 and anti-PD-L1 antibodies, respectively, disclosed in U.S. Patent Nos. 8,008,449 and 7,943,743.

[0393] In one embodiment, one or more additional therapeutic agents are anti-inflammatory agents. In some other embodiments, the anti-inflammatory agent is a tumor necrosis factor α (TNF-α) inhibitor. As used herein, the terms “TNFα,” “TNF-α,” and “TNFα” are interchangeable. TNF-α is a pro-inflammatory cytokine primarily secreted by macrophages, but also secreted by a variety of other cell types, including lymphoid cells, mast cells, endothelial cells, cardiomyocytes, adipose tissue, fibroblasts, and neurons. TNF-α is also known as endotoxin-inducing factor in serum, cachexia, and differentiation-inducing factors. The tumor necrosis factor (TNF) family includes TNFα, TNFβ, CD40 ligand (CD40L), Fas ligand (FasL), TNF-associated apoptosis-inducing ligand (TRAIL), and LIGHT (homogeneous with lymphotoxin, exhibiting inducible expression, and competing with HSV glycoprotein D for HVEM (the receptor expressed by T lymphocytes)). Among other physiological processes, some of the most important cytokines are involved in systemic inflammation, tumor lysis, apoptosis, and the initiation of acute phase responses.

[0394] When used in combination with the compounds disclosed herein, the aforementioned therapeutic agents may be used, for example, in amounts indicated in a reference manual (e.g., a Physicians' Desk Reference) or in amounts commonly known to a qualified caregiver (i.e., a person of ordinary skill in the art). In the methods of this disclosure, other such therapeutic agents may be administered before, concurrently with, or after administration of a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IIIb), (IIIc), (IIId), (IV), or (IVa) or its tautomers or pharmaceutically acceptable salts. Where appropriate, certain other therapeutic agents may be combined into a single formulation or kit. For example, tablets, capsules, or liquid formulations may be combined with other tablets, capsules, or liquid formulations to form a fixed or combined dose formulation or regimen. Other combinations may be given separately, simultaneously, or otherwise.

[0395] Compound preparation

[0396] Some embodiments of this disclosure relate to methods and intermediates for preparing the subject compound or a pharmaceutically acceptable salt thereof.

[0397] The compounds described herein can be purified by any means known in the art, including chromatography such as high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, rapid column chromatography, and ion-exchange chromatography. Any suitable stationary phase can be used, including normal and reversed-phase phases, as well as ion exchange resins. Most typically, the disclosed compounds are purified by silica gel and / or alumina chromatography.

[0398] In any method for preparing the subject compound, it may be necessary and / or desirable to protect any sensitive or reactive groups on the relevant molecule. This can be achieved through standard works such as TW Greene and PGM Uts, “Protective Groups in Organic Synthesis,” 4. th The conventional protecting base described in ed., Wiley, New York 2006 is used. The protecting base can be removed at a convenient subsequent stage using methods known in the art.

[0399] General synthesis scheme

[0400] Scheme 1: Preparation of optically pure compound of formula (I)

[0401] Option 1

[0402]

[0403] Intermediates A and E can be prepared using the process described in International Publication No. WO 2016 / 033486.

[0404] Step 1: Intermediate B can be prepared by treating a solution of A in a suitable solvent (e.g., THF) with a suitable base (e.g., sodium hydride) and then with a suitable alkylating agent (e.g., iodomethane).

[0405] Step 2: Intermediate C can be prepared by treating a solution of B in a suitable solvent (e.g., DMF) with a suitable base (e.g., sodium hydride) and then treating the mixture with a suitable alkylating agent (e.g., iodomethane).

[0406] Step 3: Intermediate D can be prepared by treating intermediate C overnight at an elevated temperature, preferably 60°C, with a suitable base (e.g., aqueous solution of NaOH, KOH, or LiOH) in a suitable solvent (e.g., MeOH, EtOH, or THF). After cooling the mixture, acidify it with a suitable acidic reagent (e.g., HCl), concentrate and filter, dissolving the resulting solid carboxylic acid in a suitable solvent (e.g., CH₂Cl₂ or 1,2-dichloroethane). A suitable acyl chloride forming agent (e.g., thionyl chloride or oxalyl chloride) can be added to provide intermediate D, which can be used immediately in the next step.

[0407] Step 4: Intermediate F can be prepared by dissolving intermediate E in a suitable solvent (e.g., THF, DMF or CH2Cl2) and treating it with a suitable organic base (e.g., trimethylamine, diisopropylethylamine or imidazole) and a suitable silylating agent (e.g., TBDMSCl or TBDMSOTf) at a suitable temperature (preferably 0°C).

[0408] Step 5: Intermediate G can be prepared by the following method: under N2 atmosphere, suspend Ph3PCl2 in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane), add a suitable organic base (e.g., trimethylamine or diisopropylethylamine), then add a solution of intermediate F in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane), and then bubble in ammonia gas.

[0409] Step 6: Intermediate H can be prepared by dissolving intermediate D in a suitable polar solvent (e.g., acetonitrile) and adding pyridazine, followed by adding a solution of intermediate G in a suitable polar solvent such as acetonitrile.

[0410] Step 7: Intermediates I-1 and I-2 can be prepared by adding triethylamine and acyl chloride to a solution of intermediate H in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane) under ice bath cooling. The two stereoisomers can be separated during purification.

[0411] Steps 8 and 9: J-1 and J-2 can be prepared by stirring intermediate I-1 or I-2 with Hoveyda Grubbs second-generation catalyst, respectively, in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane) at an elevated temperature (preferably 60°C). After concentration, the residue can be purified by preparative HPLC or by silica gel column chromatography.

[0412] Scheme 2: Preparation of optically pure compound of formula (I)

[0413] Option 2

[0414]

[0415] J-1 and J-2 can also be prepared from H as shown in Scheme 2. The intermediate H in a solution of di-tert-butyl dicarbonate in a suitable solvent (e.g., CH₂Cl₂ or 1,2-dichloroethane) can be treated with di-tert-butyl dicarbonate in the presence of a suitable base (e.g., DIPEA or TEA) under ice bath cooling and stirred overnight at room temperature. After concentration and purification by silica gel chromatography, the mixture of Boc-protected diastereomers can be treated with a Hoveyda Grubbs second-generation catalyst in a suitable solvent (e.g., CH₂Cl₂ or 1,2-dichloroethane) at an elevated temperature (preferably 60°C). After concentration, the mixture of diastereomers L can be acylated with a suitable acylation agent, such as an acyl chloride and an organic base, or a carboxylic acid with EDCI and an organic base.

[0416] Scheme 3: Preparation of optically pure compound of formula (I)

[0417] After intermediate H is acylated and intermediate I is macrocyclized with Hoveyda Grubbs second-generation catalyst, J-1 and J-2 can be separated by silica gel column chromatography or by chiral HPLC.

[0418] Option 3

[0419]

[0420] Scheme 4: Preparation of optically pure compound of formula (I)

[0421] Option 4

[0422]

[0423] Step 1: Intermediates K-1 and K-2 can be prepared by adding triethylamine and di-tert-butyl dicarbonate to a solution of intermediate H in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane) under ice bath cooling, and stirring the mixture overnight at room temperature. After concentrating the reaction mixture, the residue can be purified by preparative HPLC or silica gel column chromatography to separate the diastereomers.

[0424] Steps 2 and 3: J-1 and J-2 can be prepared by stirring intermediate K-1 or K-2 and Hoveyda Grubbs second-generation catalyst in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane) at an elevated temperature (preferably 60°C). After concentrating the reaction mixture and purifying the residue by preparative HPLC, a suitable acylation agent, such as an acyl chloride and an organic base, or a carboxylic acid with EDCI and an organic base, is added to acylate intermediate L-1 or L-2, which can be purified by preparative HPLC or silica gel column chromatography to obtain J-1 or J-2.

[0425] Scheme 5: Preparation of optically pure compound of formula (I)

[0426] After Boc protection and macrocyclization with Hoveyda Grubbs second-generation catalyst, intermediates L-1 and L-2 can be separated by silica gel column chromatography or chiral HPLC, and then acylated to provide J-1 and J-2, respectively.

[0427] Option 5

[0428]

[0429] Scheme 6: Preparation of optically pure compound of formula (I)

[0430] Option 66

[0431]

[0432] N-1 and N-2 can be prepared from L as shown in Scheme 6, separated by silica gel column chromatography or chiral HPLC after acylation, and then macrocyclized with Hoveyda Grubbs second-generation catalyst.

[0433] Schemes 7 and 8: where –C(O)R 1 –C(O)NHR 8 Preparation of compound of formula (I)

[0434] Option 7

[0435]

[0436] M-2 can be prepared from L-2 by adding triethylamine and a substituted isocyanate in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane) under ice bath cooling.

[0437] Alternatively, in the presence of a suitable base (e.g., triethylamine) and in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane), L-2 can be treated with a substituted isocyanate, and the two stereoisomers M-1 and M-2 can be separated by silica gel column chromatography or by chiral HPLC.

[0438] Option 8

[0439]

[0440] Option 9: Where –C(O)R 1 For –C(O)NR 8 R 9 Preparation of compound of formula (I)

[0441]

[0442] M-3 can be prepared by treating L-2 with diphenyl carbonate followed by a suitable amine (Scheme 9).

[0443] Schemes 10, 11, and 12: where –C(O)R 1 -C(O)OR 7 Preparation of compound of formula (I)

[0444] O-2 can be prepared by treating L-2 with a suitable chloroformate and a suitable base (e.g., triethylamine) in a suitable solvent (e.g., CH2Cl2 or 1,2-dichloroethane).

[0445]

[0446] Option 11

[0447]

[0448] Alternatively, O-2 can be prepared by treating L-2 with diphenyl carbonate followed by a suitable alcohol.

[0449] Alternatively, under ice bath cooling, the mixture of diastereomers L is treated with diphenyl carbonate, followed by a suitable alcohol as a nucleophile or with a substituted chloroformate, and the two stereoisomers are separated by silica gel column chromatography or by chiral HPLC to obtain O-2 (Scheme 12).

[0450] Option 12

[0451] Example

[0452] Exemplary chemical entities of this disclosure are provided in the following specific embodiments. Those skilled in the art will recognize that, in order to obtain the various compounds described herein, the starting materials can be suitably selected so that the ultimately desired substituent is carried by the reaction scheme with or without appropriate protection, yielding the desired product. Alternatively, it may be necessary or desirable to use a suitable group to replace the ultimately desired substituent, which can be carried by the reaction scheme and suitably replaced by the desired substituent. Furthermore, those skilled in the art will recognize that the transformations shown in the following schemes can be carried out in any order compatible with the function of the particular side groups.

[0453] The embodiments provided herein describe the synthesis of the disclosed compounds and intermediates for preparing said compounds. It should be understood that the various steps described herein can be combined. It should also be understood that different batches of the compounds can be combined and then carried out in the next synthetic step.

[0454] In the following description of embodiments, specific implementations are described. These implementations are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other implementations may be utilized, and logical and other changes may be made, without departing from the scope of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure.

[0455] Example 1.

[0456]

[0457] Step 1: Preparation of methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptanetriene-3,1'-naphthalene]-7-carboxylic acid (1-1): In an ice bath, under stirring, methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptanetriene-3,1'-naphthalene]-7-carboxylic acid (according to International Patent Application No. WO Sodium hydride (60% in mineral oil, 183.1 mg, 4.57 mmol) was added to a THF (10 mL) solution prepared according to the process described in 2016 / 033486, followed by iodomethane (618.7 mg, 4.359 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction mixture was then poured into ice-cold H2O and extracted with CH2Cl2. The organic layer was concentrated and purified by silica gel column chromatography (EtOAc / hexane = 2 / 3) to give methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptadiene-3,1'-naphthalene]-7-carboxylate. LCMS-ESI+: (m / z): [M+H]+ C 28 H 32 ClNO4: Calculated value: 482.0; Measured value: 482.2.

[0458] Step 2: Preparation of methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptanetriene-3,1'-naphthalene]-7-carboxylate (1-2): In an ice bath, under stirring, (S)-6'-chloro-5-(((1R,2R)-2-((S)-1- A solution of methyl hydroxyallyl(cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxylate (707.0 mg, 1.4 mmol) in DMF (8 mL) was mixed with sodium hydride (60% in mineral oil, 88.0 mg, 2.2 mmol), followed by methyl iodoform (312.3 mg, 2.2 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was then poured into ice-cold H2O and extracted with CH2Cl2. The organic layer was concentrated and purified by silica gel column chromatography (EtOAc / hexane = 1 / 4) to give methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptadiene-3,1'-naphthalene]-7-carboxylate. LCMS-ESI+: (m / z): [M+H]+ C 29 H 34 ClNO4: Calculated value: 496.0; Measured value: 496.2.

[0459] Step 3: Preparation of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatriene-3,1'-naphthalene]-7-carboxyl chloride (1-3): At 60 °C, (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatriene-3,1'-naphthalene]-7-carboxyl chloride (1-3) was prepared. Methyl benzo[b][1,4]oxazolidinyl-3,1'-naphthalene]-7-carboxylate (659.0 mg, 1.33 mmol) was stirred overnight in 2N NaOH aqueous solution (3 mL) and MeOH (8 mL). After cooling, the mixture was acidified with HCl and concentrated. The resulting solid was treated with CH2Cl2 and filtered. The filtrate was concentrated, and 174.5 mg (0.36 mmol) was dissolved in CH2Cl2 (6 mL). Thionyl chloride (1.5 mL) was added to the solution in an ice bath. The resulting mixture was stirred at room temperature for 2 hours and concentrated. The crude product (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-3,1'-naphthalene]-7-carboxyl chloride was used directly in the next step.

[0460] Step 4: Preparation of (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide (1-4): In an ice bath, triethylamine (3.15 mL, 22.57 mmol) was added to a THF (16 mL) solution of (2R,3S)-3-methylhex-5-ene-2-sulfonamide (2.00 g, 11.28 mmol) under stirring, followed by the slow addition of a THF (8 mL) solution of TBDMSCl (2.13 g, 14.10 mmol). The resulting mixture was stirred at room temperature for 2 days. The precipitate was filtered and washed with diethyl ether. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc / hexane = 1 / 4) to give (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide. 1¹H NMR (400MHz, chloroform-d) δ 5.76–5.67 (m, 1H), 5.08–5.02 (m, 2H), 3.95 (s, 1H), 3.95–2.97 (m, 1H), 2.44–2.41 (m, 1H), 2.14–2.08 (m, 1H), 2.02–1.96 (m, 1H), 1.27 (d, J = 8.0Hz, 3H), 1.02 (d, J = 8.0Hz, 3H), 0.94 (m, 9H), 0.27–0.26 (m, 6H).

[0461] Step 5: Preparation of (2R,3S)-N'-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-iminosulfonamide (1-5): Under a N2 atmosphere, trimethylamine (0.43 mL, 3.087 mmol) was added to a stirred suspension of Ph3PCl2 (754.33 mg, 2.264 mmol) in CH2Cl2 (4.0 mL). The mixture was stirred at room temperature for 10 minutes, then cooled to 0°C, and a solution of (2R,3S)-N-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-sulfonamide (600.00 mg, 2.058 mmol) in CH2Cl2 (4 mL) was added. The reaction mixture was stirred at 0°C for 1 hour. Ammonia was bubbled into the reaction mixture. The reaction vessel was sealed and stirred at 0°C for 2 hours. The resulting precipitate was filtered and washed with CH2Cl2. The filtrate was concentrated and purified by silica gel column chromatography (EtOAc / hexane = 1 / 4) to obtain (2R,3S)-N'-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-iminosulfonamide (1-5). 1 ¹H NMR (400MHz, chloroform-d) δ 5.80–5.69 (m, 1H), 5.08–5.02 (m, 2H), 4.17 (w, 2H), 3.06–2.98 (m, 1H), 2.54–2.46 (m, 1H), 2.11–1.95 (m, 2H), 1.29–1.26 (m, 3H), 1.01–0.98 (m, 3H), 0.92–0.88 (m, 9H), 0.13–0.11 (m, 6H).

[0462] Step 6: Preparation of (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxoyl)-16-thionyl(sulfanylidene))-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide (1-6): Add (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl to a mixture under stirring. A solution of propyl(cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatriene-3,1'-naphthalene]-7-carboxyl chloride (181.00 mg, 0.362 mmol) in acetonitrile (2.0 mL) was added, followed by a solution of (2R,3S)-N'-(tert-butyldimethylsilyl)-3-methylhex-5-ene-2-iminosulfonamide (126.00 mg, 0.434 mmol) in acetonitrile (2.0 mL). The resulting mixture was stirred at room temperature for 3 hours. After concentration, the residue was purified by silica gel column chromatography (EtOAc / hexane = 2 / 3) to obtain (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxoyl)-16-thionyl)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide. 1 ¹H NMR (400 MHz, chloroform-d) δ 7.70 (d, J = 11.6 Hz, 1H), 7.62–7.58 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.10–7.07 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.80–5.49 (m, 2H), 5.18–5.02 (m, 4H), 4.15 (dd, J = 12.0, 5.2 Hz, 1H), 4.05 (d d,J=12.0,4.4Hz,1H),3.71-3.61(m,2H),3.49-3.28(m,3H),3.25-3.24(m,3H),2.81-2.45(m,5H),2.1 5-1.52(m,10H),1.40(dd,J=12.8,6.8Hz,3H),1.09(dd,J=28.4,6.8Hz,3H).LCMS-ESI+: (m / z):[M+H]+ C 35 H 46ClN3O4S: Calculated value: 640.3; Measured value: 640.3.

[0463] Step 7: Preparation of 1-7 and 1-8: In an ice bath, triethylamine (0.01 mL, 0.07 mmol) was added to a stirred solution of (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxo)-16-thionyl)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide (30.00 mg, 0.047 mmol) in CH2Cl2 (4.0 mL), followed by propionyl chloride (5.20 mg, 0.056 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC (Phenomenex Luna 5μm C18(2), 150x 21.2mm, 50% to 90-95% acetonitrile / water (containing 0.1% trifluoroacetic acid), 15mL / min, used throughout the experimental section unless otherwise specified) to obtain fractions 1-7 (more polar fractions) and 1-8 (less polar fractions). LCMS-ESI+:(m / z):[M+H]+ C 38 H 50 ClN3O5S: Calculated value: 696.3; Measured value: 696.3.

[0464] Step 8: Preparation of Example 1: The single diastereomer 1-7 (11.0 mg, 0.016 mmol) obtained from Step 7 and the Hoveyda Grubbs second-generation catalyst (2.0 mg, 0.003 mmol) were stirred at 60 °C for 4 hours in 6.0 mL of 1,2-dichloroethane. After concentration, the residue was purified by preparative HPLC to obtain Example 1. 1¹H NMR (400MHz, chloroform-d) δ 7.72 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.2, 1.8 Hz, 1H), 7.19–7.16 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.86–5.80 (m, 1H), 5.69 (dd, J = 15.8, 7.4 Hz, 1H), 4.30–4.26 (m, 1H), 4.05 (dd, J = 22.8, 12.0 Hz) z,2H),3.80-3.72(m,3H),3.37(d,J=14.4Hz,1H),3.27(s,3H),3.06(dd,J=14.8,10.8Hz,1H),2.85-2.75(m,3H), 2.58-1.68(m,14H),1.42(d,J=6.8Hz,3H),1.15(t,J=7.6Hz,3H),1.11(d,J=6.8Hz,3H).LCMS-ESI+: (m / z):[M+H]+ C 36 H 46 ClN3O5S: Calculated value: 668.3; Measured value: 668.3.

[0465] Example 2.

[0466]

[0467] Example 2 was synthesized using diastereomers 1-8 instead of 1-7, following the same method as in Example 1 (step 8). 1H NMR (400MHz, chloroform-d) δ7.70(d,J=8.8Hz,1H),7.18(dd,J=8.4,2.4Hz,1H),7.13(d,J=8.4Hz,1H),7.08(d,J=2.4Hz,1H),7.02( s,1H),6.94(d,J=8.0Hz,1H),5.99-5.92(m,1H),5.50(dd,J=15.2,8.8Hz,1H),4.47(w,1H),4.13-4.04(m,2H),3.82(d,J=1 5.2Hz,1H),3.71-3.65(m,2H),3.31-3.24(m,1H),3.22(s,3H),2.99(dd,J=15.2,10.0Hz,1H),2.80-2.70(m,3H),2.49-1.6 4(m,13H),1.54(d,J=6.8Hz,3H),1.42-1.36(m,1H),1.17(t,J=7.6Hz,3H),1.02(d,J=6.4Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 36 H 46 ClN3O5S: Calculated value: 668.3; Measured value: 668.3.

[0468] Examples 3 and 4.

[0469]

[0470] Step 1: Preparation of N'-(tert-butyldimethylsilyl)pent-4-ene-1-iminosulfonamide: N'-(tert-butyldimethylsilyl)pent-4-ene-1-iminosulfonamide was prepared by replacing (2R,3S)-3-methylhex-5-ene-2-sulfonamide with pent-4-ene-1-sulfonamide in the same manner as in Example 1 (steps 4 and 5). 1 ¹H NMR (400MHz, chloroform-d) δ 5.78 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.09–5.01 (m, 2H), 3.13–3.05 (m, 2H), 2.22–2.16 (m, 2H), 1.98–1.90 (m, 2H), 0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H).

[0471] Step 2: Preparation of (3S)-N-(amino(oxo)(pent-4-en-1-yl)-16-thionyl)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide: according to the same procedure as in Example 1 (Step 6) In a similar manner, in the presence of pyridazine, N'-(tert-butyldimethylsilyl)pent-4-en-1-iminosulfonamide was treated with (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-formyl chloride to obtain the title compound.

[0472] Step 3: Preparation of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N-((R)-oxo(pent-4-en-1-yl)(propamidyl)-l6-thionyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide: In an ice bath, under stirring, (3S)-N-(amino(oxo)(pent-4-en-1-yl)-l6- Triethylamine (0.02 mL, 0.162 mmol) was added to a CH2Cl2 (5.0 mL) solution of thionyl)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptadiene-3,1'-naphthalene]-7-carboxamide (66 mg, 0.11 mmol), followed by propionyl chloride (11.97 mg, 0.129 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to obtain (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N-((R)-oxo(pent-4-en-1-yl)(propamido)-16-thionyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide.

[0473] Step 4: Preparation of Examples 3 and 4: (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-N-((R)-oxo(pent-4-en-1-yl)(propamido)-16-thionyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide (55.0 mg, 0.082 mmol) and Hoveyda Grubbs second-generation catalyst (5.14 mg, 0.008 mmol) were stirred at 60 °C for 4 hours in 1,2-dichloroethane (16.0 mL). After concentration, the residue was purified by preparative HPLC to obtain the fraction with higher polarity (LCMS-ESI+(m / z): [M+H]+ C). 34 H 42 ClN3O5S: Calculated value: 640.2; Measured value: 640.2) and Example 4 (fraction with lower polarity) ( 1 ¹H NMR (400MHz, chloroform-d) δ 7.68 (d, J = 9.2Hz, 1H), 7.37–7.35 (m, 1H), 7.23 (s, 1H), 7.08–7.06 (m, 2H), 6.92 (d, J = 8.4Hz, 1H), 5.86–5.82 (m, 1H), 5.74–5.70 (m, 1H), 4.06 (d, J = 12.0Hz, 1H), 3.99–3.95 (m, 2H), 3.81–3.71 (m ,4H),3.59-3.57(m,1H),3.34(d,J=14.8Hz,1H),3.29(s,3H),3.04-2.98(m,1H),2.78-2.73(m,4H),2.50 (q,J=7.4Hz,2H),2.38-1.66(m,10H),1.39-1.34(m,1H),1.22(t,J=7.4Hz,3H).LCMS-ESI+(m / z):[M+H]+C 34 H 42 ClN3O5S: Calculated value: 640.2; Measured value: 640.2).

[0474] Examples 5 and 6.

[0475]

[0476] Method 1:

[0477] Step 1: ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonimidoyl) tert-butyl carbamate and (N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-3,1'-naphthalene]-7-carbonyl)pent-4-en-1- Preparation of tert-butyl carbamate (3S)-N-(amino(oxo)(pent-4-en-1-yl)-16-thionyl)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide (Example 3 / 4, step 2, 32.00 mg, 0.052 mmol)) in CH2Cl2 (5.0 mL) was added, followed by the addition of ditert-butyl dicarbonate (17.11 mg, 0.078 mmol). The resulting mixture was stirred overnight at room temperature. After concentration, the residue was purified by preparative HPLC, yielding ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetanetrien-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonamide from the more polar fraction. (Acyl) tert-butyl carbamate, and from the fraction with lower polarity, (N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetanetrien-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonyl) tert-butyl carbamate.

[0478] Step 2: Preparation of Example 5: (N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonyl)carbamate tert-butyl ester (14 mg, 0.02 mmol) and Hoveyda Grubbs second-generation catalyst (1.25 mg, 0.002 mmol) were stirred in 1,2-dichloroethane (6.0 mL) at 60 °C for 4 hours. After concentration, the residue was purified by preparative HPLC to obtain Example 5. LCMS-ESI+(m / z): [M+H]+ C 31 H 38 ClN3O4S: Calculated value: 584.2; Measured value: 584.2.

[0479] Step 3: Preparation of Example 6: Example 6 was synthesized using ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetanetrien-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonyl)carbamate tert-butyl ester, following the same method as in Example 5. LCMS-ESI+(m / z): [M+H]+C 31 H 38 ClN3O4S: Calculated value: 584.2; Measured value: 584.2.

[0480] Method 2:

[0481]

[0482] Step 1: Preparation of ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonyl)tert-butyl carbamate: In an ice bath, under stirring, (3S)-N-(amino(oxo)(pent-4-en-1-yl)-16-thionyl)-6' A solution of chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide (140.00 mg, 0.229 mmol) in CH2Cl2 (5.0 mL) was treated with triethylamine (0.06 mL, 0.458 mmol), followed by di-tert-butyl dicarbonate (74.97 mg, 0.343 mmol). The resulting mixture was stirred overnight at room temperature. After concentration, the residue was purified by preparative HPLC to obtain ((R)-N-((S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetanetrien-3,1'-naphthalene]-7-carbonyl)pent-4-en-1-ylsulfonyl)carbamate tert-butyl ester, which is a mixture of diastereomers.

[0483] Steps 2 and 3: The mixture of Boc-protected diastereomers obtained from Step 1 of Method 2 (112.0 mg, 0.157 mmol) and Hoveyda Grubbs second-generation catalyst (9.83 mg, 0.016 mmol) were stirred at 60 °C for 4 hours in 6.0 mL of 1,2-dichloroethane. After concentration, the residue was purified by preparative HPLC to give intermediate 5-1, a mixture of diastereomers, which was purified by silica gel column chromatography (EtOAc / hexane = 3 / 2) to give Example 5 (fraction with lower polarity) and Example 6 (fraction with higher polarity).

[0484] Method 3:

[0485]

[0486] Step 1: Preparation of (S)-(1-phenylethyl)-4-nitrophenyl carbonate (5-3-1): A mixture of (1S)-1-(4-phenylphenyl)ethanol (8.7 g, 71.2 mmol) was dissolved in MeTHF (90 mL) and cooled to 0 °C. Pyridine (7.1 mL) was added to the cooled, stirred solution. Then, a solution of 4-nitro-phenyl-chloroformate (14.4 g, 71.2 mmol) in MeTHF (60.0 mL) was added dropwise through a dropping funnel. After the addition, the resulting mixture was removed from the cooling bath and stirred at ambient temperature for 2 hours. TLC showed that (1S)-1-(4-phenylphenyl)ethanol had been consumed, but 4-nitro-phenyl-chloroformate remained. Additional (1S)-1-(4-phenylphenyl)ethanol (2.6 g, 21.3 mmol) and pyridine (1.0 mL) were added, and stirring continued overnight. The reaction mixture was then washed with 1N HCl (2x) and brine (2x), dried over sodium sulfate, filtered, and concentrated. The residue was then dissolved in DCM, mixed with silica gel, concentrated to dryness, and purified twice by normal-phase chromatography (silica gel, 0-20% EtOAc / hexane). The desired fractions were combined and concentrated to give 5-3-1. ¹H NMR (400MHz, chloroform-d) δ 8.34–8.16 (m, 2H), 7.48–7.31 (m, 7H), 5.84 (q, J = 6.6Hz, 1H), 1.70 (d, J = 6.6Hz, 3H).

[0487] Step 2: Cool a solution of N'-(tert-butyldimethylsilyl)pent-4-ene-1-iminosulfonamide (2.0 g, 7.18 mmol) in THF (100 mL) to -50 °C. Add dropwise a solution of 1.6 M n-BuLi in hexane (9.65 mL, 15.4 mmol) to the cooled solution. Stir the newly formed mixture at -50 °C for 20 min, followed by slow dropwise addition of a solution of [(1S)-1-phenylethyl]carbonate (4-nitrophenyl) ester in THF (60 mL). Stir the resulting mixture at -50 °C for 15 min, then transfer it to an ice-water bath and stir at 0 °C for 3 h. Quench the reaction with ice and extract with EtOAc (1x). Wash the organic layer with 1N NaOH (3x) and brine (1x), dry over sodium sulfate, filter, concentrate, and purify by normal phase chromatography (silica gel, 0-20% EtOAc / hexane). The purification was repeated, and the desired fractions were combined and concentrated to give a mixture of diastereomers (5-3-2) and (5-3-3). The mixture of diastereomers was then separated into individual diastereomers by chiral SFC. The first elution peak was designated as chiral as shown in (5-3-2); the second elution peak was designated as chiral as shown in (5-3-3). 1¹H NMR (400 MHz, chloroform-d) for mixtures of diastereomers: δ 7.41–7.29 (m, 5H), 5.84–5.59 (m, 2H), 5.08–4.93 (m, 2H), 3.37–3.16 (m, 2H), 2.19–2.07 (m, 2H), 1.83 (h, J = 7.3, 6.7 Hz, 2H), 1.57 (dq, J = 6.6, 1.8 Hz, 3H), 0.91–0.85 (m, 9H), 0.18 (two sets of s, 3H), 0.12 (two sets of s, 3H). ¹H NMR (400 MHz, chloroform-d) for (5-3-2): δ 7.39–7.30 (m, 5H), 5.86–5.58 (m, 2H), 5.07–4.93 (m, 2H), 3.28 (tq, J = 13.9, 7.9, 7.1 Hz, 2H), 2.13 (p, J = 7.7, 7.2 Hz, 2H), 1.85 (p, J = 7.2 Hz, 2H), 1.57 (dd, J = 6.6, 2.2 Hz, 3H), 0.93–0.91 (m, 9H), 0.19 (both s, 6H).

[0488] Step 3: At room temperature, a solution of intermediate (5-3-2) (858 mg, 2.1 mmol) in THF (24 mL) was treated with a solution of 1.0 M tetrabutylammonium fluoride in THF (6.3 mL, 6.3 mmol) for 60 min. The reaction was then concentrated and purified by normal phase chromatography (silica gel, 0-80% EtOAc / hexane) to give 5-3-3A. ¹H NMR (400 MHz, chloroform-d) δ 7.45–7.31 (m, 4H), 5.83–5.59 (m, 2H), 5.12–4.96 (m, 2H), 3.35–3.21 (m, 2H), 2.28–2.11 (m, 2H), 2.01–1.87 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H).

[0489] Step 4: At 0°C, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (152 mg, 0.98 mmol) was added to a mixture of (3S)-6'-chloro-5-[[(1R,2R)-2-[(1S)-1-methoxyallyl]cyclobutyl]methyl]spiro[2,4-dihydro-1,5-benzoxazetarine-3,1'-tetrahydronaphthalene]-7-carboyl chloride (215 mg, 0.45 mmol) in DCM (20 mL), followed by 4-(dimethylamino)pyridine (120 mg, 0.98 mmol). After stirring for 5 minutes, a solution of intermediate (5-3-3A) (159 mg, 0.54 mmol) in DCM (3 mL) was added. The resulting mixture was removed from the cooling bath and stirred overnight at room temperature. The reaction mixture was further diluted with DCM (30 mL) and washed with 1N HCl (15 mL), saturated sodium bicarbonate (15 mL), and brine (15 mL). After drying with sodium sulfate, the mixture was filtered, concentrated, and purified by normal-phase chromatography (silica gel column, 0-80% EtOAc / hexane) to give intermediate 5-3-4. LCMS-ESI+ (m / z): [M+H]+ Calculated value: 761.0, Measured value: 759.9..1H NMR (400MHz, chloroform-d) δ 7.67 (d, J = 8.5Hz, 1H), 7.50 (s, 1H), 7.39–7.28 (m, 6H), 7.16 (dd, J = 8.5, 2.3Hz, 1H), 7.08 (d, J = 2.3Hz, 1H), 6.91 (d, J = 8.2Hz, 1H), 5.86 (p, J = 6.3Hz, 1H), 5.77–5.48 (m, 2H), 5.21–5.08 (m, 2H), 5 .08–4.96(m,2H),4.14–4.04(m,2H),3.81–3.71(m,2H),3.70–3.48(m,3H),3.39–3.13(m,5H),2.84–2.69 (m,2H),2.52(dd,J=10.7,7.4Hz,1H),2.16(dt,J=13.3,7.6Hz,3H),2.01–1.74(m,7H),1.70–1.39(m,7H).

[0490] Step 5: Nitrogen gas was bubbled into a DCE (10 mL) solution of intermediate 5-3-4 for 5 minutes, followed by the addition of Hoveyda-Grubbs second-generation catalyst (7 mg, 0.011 mmol). The newly formed mixture was degassed for another 2 minutes, then capped and heated at 60 °C for 16 hours. The reaction was then cooled to room temperature, concentrated, and purified by normal-phase chromatography (silica gel, 0-5% DCM / MeOH (containing 2.0 N NH3)) to obtain Example 5 (first elution peak: LCMS-ESI+(m / z): [M+H]+ calculated value: 584.2; measured value: 583.4); and carbamate-protected macrocyclic intermediate 5-3-5 (second elution peak: LCMS-ESI+(m / z): [M+H]+ calculated value: 732.3; measured value: 730.8).

[0491] Step 6: At 0°C, intermediate 5-3-5 (15.8 mg, 0.022 mmol) was dissolved in DCM (1.0 mL). TFA (1.0 mL) was added to this cold solution. The resulting mixture was stirred at 0°C for 2 minutes and then at room temperature for 1 hour. The reaction was cooled back to 0°C and alkalized to pH ~8 with 1N NaOH. The mixture was extracted with DCM (2x). The combined organic layers were washed with brine (1x), dried over sodium sulfate, filtered, concentrated, and purified by Combiflash (silica gel, 0-100% EtOAc / hexane) to obtain Example 5. LCMS-ESI+ (m / z): [M+H]+ Calculated value: 584.2; Measured value: 583.3. 1 ¹H NMR (400MHz, chloroform-d) for (8): δ 7.73 (d, J = 8.6Hz, 1H), 7.44–7.39 (m, 1H), 7.33 (d, J = 1.8Hz, 1H), 7.16 (dd, J = 8.5, 2.3Hz, 1H), 7.06 (d, J = 2.3Hz, 1H), 6.90 (d, J = 8.2Hz, 1H), 6.04–5.93 (m, 1H), 5.73–5.61 (m,1H),4.12–3.94(m,2H),3.88–3.68(m,2H),3.62–3.51(m,2H),3.40–3.17(m,6H),3.00(dd,J=1 5.0,11.0Hz,1H),2.82–2.63(m,4H),2.47–2.20(m,4H),1.99–1.59(m,6H),1.37(t,J=13.1Hz,1H).

[0492] Example 6 was synthesized using the same method as in Example 5 (method 3-step 3-6), with intermediate 5-3-3 used instead of intermediate 5-3-2.

[0493] Examples 7 and 8.

[0494]

[0495] Examples 7 and 8 were prepared using a method similar to that of Examples 3 and 4, with 2-methoxyacetyl chloride used instead of propionyl chloride.

[0496] Example 7: LCMS-ESI+(m / z): [M+H]+C 34 H 42 ClN3O6S: Calculated value: 656.2; Measured value: 656.2.

[0497] Example 8: LCMS-ESI+(m / z): [M+H]+C 34 H 42 ClN3O6S: Calculated value: 656.2; Measured value: 656.2.

[0498] Examples 9 and 10.

[0499]

[0500] Preparation of Examples 9 and 10: In an ice bath, triethylamine (0.004 mL, 0.027 mmol) was added to a CH2Cl2 (5.0 mL) solution of intermediate 5-1 (Example 5 / 6, Method 2, 10.40 mg, 0.018 mmol) under stirring, followed by ethyl chloroformate (2.32 mg, 0.021 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to obtain Example 9 (the more polar fraction) (LCMS-ESI+(m / z): [M+H]+C 34 H 42 ClN3O6S: Calculated value: 656.2; Measured value: 656.2) and Example 10 (fraction with lower polarity).

[0501] Examples 11 and 12.

[0502]

[0503] Step 1: Preparation of Intermediate 11-1: Platinum oxide (IV) (3.48 mg, 0.015 mmol) was added to a 5 mL solution of intermediate 5-1 (Example 5 / 6, Method 2, 17.90 mg, 0.031 mmol) in EtOAc under stirring. The resulting mixture was stirred at room temperature under H2 for 0.5 hours. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc. The filtrate was concentrated. The crude product (18.0 mg) was used directly in the next step.

[0504] Step 2: Preparation of Examples 11 and 12: In an ice bath, triethylamine (0.006 mL, 0.046 mmol) was added to a CH2Cl2 (4.0 mL) solution of intermediate 11-1 (18.0 mg, 0.031 mmol) under stirring, followed by propionyl chloride (3.41 mg, 0.037 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to obtain Example 11 (the more polar fraction) (LCMS-ESI+(m / z): [M+H]+C). 34 H 44 ClN3O5S: Calculated value: 642.3; Measured value: 642.2) and Example 12 (fraction with lower polarity) (LCMS-ESI+(m / z): [M+H]+C 34 H 44 ClN3O5S: Calculated value: 642.3; Measured value: 642.3).

[0505] Examples 13 and 14.

[0506]

[0507] Preparation of Examples 13 and 14: In an ice bath, triethylamine (0.004 mL, 0.028 mmol) was added to a CH2Cl2 (4.0 mL) solution of intermediate 5-1 (method 2 in Examples 5 and 6, 10.9 mg, 0.019 mmol) under stirring, followed by ethyl isocyanate (1.59 mg, 0.022 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC followed by preparative TLC (5% MeOH / CH2Cl2) to obtain Example 13 (the more polar fraction) (LCMS-ESI+(m / z): [M+H]+C). 34 H 43 ClN4O5S: Calculated value: 655.3; Measured value: 655.2), and Example 14 (fraction with lower polarity) ( 1 H NMR (400MHz, chloroform-d) δ7.71(w,1H),7.31(w,1H),7.16(w,2H),7.02(w,1H),6.78(w,1H),5.76( w,2H),4.02-3.94(m,2H),3.72-2.65(m,11H),2.34-0.84(m,17H).LCMS-ESI+(m / z):[M+H]+ C 34 H 43ClN4O5S: Calculated value: 655.3; Measured value: 655.2.

[0508] Example 15.

[0509]

[0510] Et3N (0.01 mL, 0.068 mmol), EDCI (5.32 mg, 0.034 mmol), and DMAP (4.18 mg, 0.034 mmol) were added to a CH2Cl2 (3 mL) solution of 3-(dimethylamino)propionate (3.94 mg, 0.026 mmol) under stirring. Intermediate 5-1 (Example 5 / 6, Method 2, 10.00 mg, 0.017 mmol) was then added. The resulting mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by preparative HPLC to obtain Example 15. LCMS-ESI+ (m / z): [M+H]+ C 36 H 47 ClN4O5S: Calculated value: 683.3; Measured value: 683.3.

[0511] Examples 16 and 17.

[0512]

[0513] Step 1: Preparation of Intermediate 16-1: Pd / C (10 wt%, 0.36 mg, 0.03 mmol) was added to a 5 mL MeOH solution of Intermediate 5-1 (Example 5 / 6, Method 2, 20.00 mg, 0.034 mmol) under stirring. The resulting mixture was stirred at room temperature under H2 for 1.5 hours. The reaction mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was concentrated. The crude product was used directly for the next step.

[0514] Step 2: Preparation of Examples 16 and 17: The crude intermediate 16-1 obtained in Step 1 was then coupled with propionyl chloride and purified in a manner similar to that of Examples 11 and 12 to obtain Example 16 (fraction with lower polarity) (LCMS-ESI+(m / z): [M+H]+C 34 H 45 N3O5S: Calculated value: 607.8; Measured value: 608.3) and Example 17 (fraction with greater polarity) (LCMS-ESI+(m / z): [M+H]+ C 34 H 45 N3O5S: Calculated value: 607.8; Measured value: 608.4.

[0515] Example 18.

[0516]

[0517] EDCI (4.52 mg, 0.029 mmol) and DMAP (3.56 mg, 0.029 mmol) were added to a CH2Cl2 (2 mL) solution of 3-methoxypropionic acid (2.3 mg, 0.022 mmol) under stirring, followed by the addition of Example 5 (8.50 mg, 0.015 mmol). The resulting mixture was stirred at room temperature for 3 hours and then concentrated. The residue was purified by preparative HPLC to obtain Example 18. 1 ¹H NMR (400MHz, chloroform-d) δ 7.73 (d, J = 8.8 Hz, 1H), 7.41 (dd, J = 8.4, 2.0 Hz, 1H), 7.29–7.28 (m, 1H), 7.13 (dd, J = 8.4, 2.4 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.88 (dt, J = 15.8, 5.0 Hz, 1H), 5.75 (dd, J = 15.8, 7.8 Hz, 1H), 4.05 (dd, J = 32.4, 12.0Hz,2H),3.95-3.73(m,6H),3.60(dd,J=8.0,3.2Hz,1H),3.46(s,3H),3.37(d,J=14.4Hz,1H),3.32(s,3H),3.04(dd,J =15.0,11.0Hz,1H),2.80-2.71(m,5H),2.43-2.28(m,4H),2.11-1.69(m,8H),1.42-1.36(m,1H).LCMS-ESI+(m / z):[M+H]+ C 35 H 44 ClN3O6S: Calculated value: 670.3; Measured value: 670.4.

[0518] Example 19.

[0519]

[0520] In an ice bath, triethylamine (0.003 mL, 0.022 mmol) was added to a 2.0 mL solution of CH2Cl2 (8.5 mg, 0.015 mmol) of Example 5 under stirring, followed by isopropyl isocyanate (1.86 mg, 0.022 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC followed by preparative TLC (5% MeOH / CH2Cl2) to obtain Example 19. LCMS-ESI+ (m / z): [M+H]+ C 35 H45 ClN4O5S: Calculated value: 669.3; Measured value: 691.3.

[0521] Example 20.

[0522]

[0523] Example 20 was synthesized using the same method as in Example 18, but with 2-(pyrazin-2-yl)acetic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 37 H 42 ClN5O5S: Calculated value: 704.3; Measured value: 704.4.

[0524] Example 21.

[0525]

[0526] In an ice bath, triethylamine (0.004 mL, 0.026 mmol) was added to a 2.0 mL solution of CH2Cl2 (10.0 mg, 0.017 mmol) of Example 5 under stirring, followed by cyclopropylacetyl chloride (3.04 mg, 0.026 mmol). The resulting mixture was stirred at room temperature for 2 hours. After concentration, the residue was purified by preparative HPLC to obtain Example 21. LCMS-ESI+ (m / z): [M+H]+C 36 H 44 ClN3O5S: Calculated value: 666.3; Measured value: 666.3.

[0527] Example 22.

[0528]

[0529] Example 22 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(1-methyl-1H-pyrazol-5-yl)propionic acid. 1¹H NMR (400MHz, chloroform-d) δ 7.64 (d, J = 2.0Hz, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.29–7.27 (m, 1H), 7.04 (d, J = 2.0Hz, 2H), 6.99 (d, J = 8.0Hz, 1H), 6.64–6.61 (m, 1H), 6.33 (d, J = 2.4Hz, 1H), 5.82 (d,J=4.8Hz,2H),3.99-3.94(m,6H),3.70-3.56(m,4H),3.45-3.28(m,4H),3.11-2.98(m ,4H),2.87-2.72(m,4H),2.58-1.75(m,12H),1.32-1.26(m,1H).LCMS-ESI+(m / z):[M+H]+ C 38 H 46 ClN5O5S: Calculated value: 720.3; Measured value: 720.4.

[0530] Example 23

[0531]

[0532] Example 23 was synthesized using the same method as in Example 21, but instead of cyclopropylacetyl chloride. LCMS-ESI+(m / z): [M+H]+ C 34 H 39 ClF3N3O5S: Calculated value: 694.2; Measured value: 694.4.

[0533] Example 24.

[0534]

[0535] Example 24 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, oxetane-3-carboxylic acid was used. 1¹H NMR (400MHz, methanol-d⁴) δ 7.75 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.0, 2.0 Hz, 1H), 7.17–7.14 (m, 2H), 7.07 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.06 (dt, J = 15.4, 6.2 Hz, 1H), 5.60 (dd, J = 15.6, 8.8 Hz) ,1H),4.90-4.76(m,4H),4.17-3.93(m,4H),3.91-3.79(m,3H),3.72-3.47(m,5H),3.24(s,3H), 3.02(dd,J=15.0,10.6Hz,1H),2.83-2.69(m,2H),2.65-1.37(m,11H).LCMS-ESI+(m / z):[M+H]+ C 35 H 42 ClN3O6S: Calculated value: 668.3; Measured value: 668.6.

[0536] Example 25.

[0537]

[0538] Example 25 was synthesized using acetyl chloride instead of cyclopropylacetyl chloride, following the same method as in Example 21. LCMS-ESI+(m / z): [M+H]+ C 33 H 40 ClN3O5S: Calculated value: 626.2; Measured value: 626.4.

[0539] Example 26.

[0540]

[0541] Example 26 was synthesized using isovaleryl chloride instead of cyclopropylacetyl chloride, following the same method as in Example 21. LCMS-ESI+(m / z): [M+H]+ C 36 H 46 ClN3O5S: Calculated value: 668.3; Measured value: 668.4.

[0542] Example 27.

[0543]

[0544] Example 27 was synthesized using the same method as in Example 21, but instead of cyclopropylacetyl chloride. LCMS-ESI+(m / z): [M+H]+ C 35 H 42ClN3O5S: Calculated value: 652.3; Measured value: 652.4.

[0545] Example 28.

[0546]

[0547] Example 28 was synthesized using the same method as in Example 18, but with 3-(methylsulfonyl)propionic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 35 H 44 ClN3O7S2: Calculated value: 718.3; Measured value: 718.3.

[0548] Example 29.

[0549]

[0550] Example 29 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 2-(1-methyl-1H-pyrazol-5-yl)acetic acid. LCMS-ESI+(m / z): [M+H]+ C 37 H 44 ClN5O5S: Calculated value: 706.3; Measured value: 706.4.

[0551] Example 30.

[0552]

[0553] Example 30 was synthesized using the same method as in Example 18, but with 2-(pyrimidin-2-yl)acetic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 37 H 42 ClN5O5S: Calculated value: 704.3; Measured value: 704.3.

[0554] Example 31.

[0555]

[0556] Example 31 was synthesized using the same method as in Example 21, with cyclobutylformyl chloride used instead of cyclopropylacetyl chloride. 1H NMR (400MHz, methanol-d4) δ7.78(d,J=8.4Hz,1H),7.26(d,J=8.4Hz,1H),7.18(d,J=8. 4Hz,1H),7.12(d,J=8.4Hz,1H),6.82(d,J=8.4Hz,1H),6.10(dt,J=15.6,6.4Hz, 1H),5.60(dd,J=15.6,8.8Hz,1H),4.25-4.13(m,1H),4.03(dd,J=21.6,12.0Hz, 3H),3.94-3.85(m,2H),3.74-3.66(m,2H),3.35-3.30(m,2H),3.27(s,3H),3.22 0 3.14(m,1H),3.04(dd,J=15.2,10.4Hz,1H),2.86-2.72(m,2H),2.39-1.72(m,17H),1.46-1.40(m,1H).LCMS-ESI+(m / z):[M+H]+ C 36 H 44 ClN3O5S: Calculated value: 666.3; Measured value: 666.4.

[0557] Example 32.

[0558]

[0559] Example 32 was synthesized using the same method as in Example 19, but instead of isopropyl isocyanate, 1-isocyano-1-(trifluoromethyl)cyclopropane was used. 1 H NMR (400MHz, methanol-d4) δ7.75(d,J=8.4Hz,1H),7.21(d,J=8.4Hz,1H),7.15(dd,J=8.8,2.4Hz,1H),7.12(s, 1H),7.07(d,J=2.4Hz,1H),6.78(d,J=8.4Hz,1H),6.08-6.02(m,1H),5.62-5.56(m,1H),3.99(dd,J=21. 8,12.2Hz,3H),3.83-3.76(m,2H),3.67-3.64(m,3H),3.34-3.30(m,2H),3.24(s,3H),3.07-3.00(m,1H) ,2.83-2.69(m,2H),2.53-1.68(m,11H),1.44-1.37(m,1H),1.22-1.04(m,4H).LCMS-ESI+(m / z):[M+H]+ C 36 H 42ClF3N4O5S: Calculated value: 735.3; Measured value: 735.3.

[0560] Example 33.

[0561]

[0562] Example 33 was synthesized using the same method as in Example 18, butyrynic acid was used instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 35 H 40 ClN3O5S: Calculated value: 650.2; Measured value: 650.3.

[0563] Example 34.

[0564]

[0565] Example 34 was synthesized using the same method as in Example 19, but with 1,1,1-trifluoro-2-isocyano-2-methylpropane instead of isopropyl isocyanate. LCMS-ESI+(m / z): [M+H]+C 36 H 44 ClF3N4O5S: Calculated value: 737.3; Measured value: 737.3.

[0566] Example 35.

[0567]

[0568] Example 35 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(pyrazin-2-yl)propionic acid was used. 1 ¹H NMR (400MHz, methanol-d⁴) δ 8.58 (s, ¹H), 8.53 (s, ¹H), 8.43 (d, J = 2.8 Hz, ¹H), 7.78 (d, J = 8.4 Hz, ¹H), 7.42–7.35 (m, 2H), 7.24–7.18 (m, ¹H), 7.12 (s, ¹H), 6.91 (d, J = 8.4 Hz, 1H), 5.92–5.80 (m, 2H), 4.11–3 .94(m,3H),3.83-3.68(m,3H),3.60-3.41(m,3H),3.27(s,3H),3.21-3.10(m,3H),2.94(t,J=7.0 Hz,2H),2.85-2.78(m,4H),2.48-1.80(m,10H),1.45(t,J=12.8Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 38 H 44ClN5O5S: Calculated value: 718.3; Measured value: 718.3.

[0569] Example 36.

[0570]

[0571] Example 36 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 4,4-dimethylpentan-2-ynetic acid was used. LCMS-ESI+(m / z): [M+H]+ C 38 H 46 ClN3O5S: Calculated value: 692.3; Measured value: 692.3.

[0572] Example 37.

[0573]

[0574] Example 37 was synthesized using the same method as in Example 19, but instead of isopropyl isocyanate, 4-fluorobenzyl isocyanate was used. 1 H NMR (400MHz, methanol-d4) δ7.76(d,J=8.8Hz,1H),7.36-7.27(m,4H),7.17(d,J=8.4Hz,1H),7.12(d,J=2.4Hz,1H),7.04( t,J=8.6Hz,2H),6.90(d,J=8.0Hz,1H),5.99-5.93(m,1H),5.77-5.71(m,1H),4.36(s,2H),4.05(dd,J=26.4,12.0H z,2H),3.92(w,2H),3.83(d,J=15.2Hz,1H),3.72(d,J=14.0Hz,1H),3.63(d,J=8.8Hz,1H),3.51-3.38(m,3H),3.30 (s,3H),3.15-3.08(m,1H),2.85-2.77(m,3H),2.66-1.79(m,10H),1.44(t,J=12.8Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 39 H 44 ClFN4O5S: Calculated value: 735.3; Measured value: 735.3.

[0575] Example 38.

[0576]

[0577] Example 38 was synthesized using the same method as in Example 18, but with 3-pyrimidin-4-yl-propionic acid instead of 3-methoxypropionic acid. 1H NMR (400MHz, methanol-d4) δ9.04(s,1H),8.62(d,J=5.2Hz,1H),7.78(d,J=8.4Hz,1H),7.47(d,J=5.2Hz,1H),7.42(s,1H) ,7.36(d,J=8.4Hz,1H),7.19(dd,J=9.0,2.2Hz,1H),7.12(d,J=2.4Hz,1H),6.91(d,J=8.4Hz,1H),5.92-5.80(m,2H) ,4.11-3.94(m,3H),3.81(d,J=14.8Hz,1H),3.75(d,J=14.4Hz,1H),3.62-3.42(m,5H),3.27(s,3H),3.19-3.10(m, 3H),2.94(t,J=7.0Hz,2H),2.85-2.77(m,3H),2.54-1.78(m,10H),1.45(t,J=12.4Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 38 H 44 ClN5O5S: Calculated value: 718.3; Measured value: 718.3.

[0578] Example 39.

[0579]

[0580] Example 39 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid. 1H NMR (400MHz, methanol-d4) δ7.77(d,J=8.4Hz,1H),7.65(d,J=2.4Hz,1H),7.49(d,J=1.6Hz,1H),7.40(d,J=2.0Hz,1H),7.34(dd,J=8.2,1.8Hz,1 H),7.19(d,J=8.0Hz,1H),7.12(d,J=2.4Hz,1H),6.90(d,J=8.4Hz,1H),6.26-6.25(m,1H),5.94-5.79(m,2H),4.49(t,J=6.6Hz,2H),4.05 (dd,J=33.4,12.2Hz,2H),3.96-3.91(m,1H),3.81(d,J=15.2Hz,1H),3.75(d,J=14.4Hz,1H),3.68-3.55(m,3H),3.51-3.41(m,2H),3.31( s,3H),3.16-3.10(m,1H),2.96(t,J=6.6Hz,2H),2.85-2.77(m,3H),2.46-1.79(m,10H),1.45(t,J=12.6Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 37 H 44 ClN5O5S: Calculated value: 706.3; Measured value: 706.3.

[0581] Example 40.

[0582]

[0583] Example 40 was synthesized using the same method as in Example 18, but with 3-pyridinepropionic acid instead of 3-methoxypropionic acid. 1H NMR (400MHz, methanol-d4) δ8.78(s,1H),8.65(d,J=5.6Hz,1H),8.50(d,J=8.4Hz,1H),7.90(dd,J=8.0,6.0Hz,1H),7.77(d, J=8.4Hz,1H),7.40(d,J=2.0Hz,1H),7.29(d,J=8.0Hz,1H),7.18(dd,J=8.6,2.2Hz,1H),7.12(d,J=2.4Hz,1H),6.92(d ,J=8.4Hz,1H),5.92-5.81(m,2H),4.11-3.95(m,4H),3.81-3.73(m,2H),3.56-3.43(m,4H),3.32(s,3H),3.25-3.11( m,3H),2.90(t,J=6.8Hz,2H),2.85-2.78(m,2H),2.26-1.80(m,11H),1.44(t,J=12.8Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 39 H 45 ClN4O5S: Calculated value: 717.3; Measured value: 717.4.

[0584] Example 41.

[0585]

[0586] Example 41 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(pyridin-4-yl)propionic acid was used. 1 H NMR (400MHz, methanol-d4) δ8.64(d,J=6.0Hz,2H),7.93(d,J=5.6Hz,2H),7.76(d,J=8.4Hz,1H),7.40(d,J=2.0Hz,1H), 7.31(dd,J=8.2,1.8Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.12(d,J=2.4Hz,1H),6.92(d,J=8.0Hz,1H),5.92-5.8 1(m,2H),4.11-3.97(m,3H),3.81-3.73(m,2H),3.55-3.43(m,3H),3.32(s,3H),3.31-3.20(m,3H),3.17-3.11(m ,1H),2.94(t,J=7.0Hz,2H),2.87-2.77(m,3H),2.54-1.80(m,10H),1.47-1.41(m,1H).LCMS-ESI+(m / z):[M+H]+ C 39H 45 ClN4O5S: Calculated value: 717.3; Measured value: 717.3.

[0587] Example 42.

[0588]

[0589] Example 42 was synthesized using the same method as in Example 18, but with 3-(1H-1,2,4-triazol-1-yl)propionic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 36 H 43 ClN6O5S: Calculated value: 707.3; Measured value: 707.3.

[0590] Example 43.

[0591]

[0592] Example 43 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(1-methyl-1H-imidazol-2-yl)propionic acid. LCMS-ESI+(m / z): [M+H]+ C 38 H 46 ClN5O5S: Calculated value: 720.3; Measured value: 721.3.

[0593] Example 44.

[0594]

[0595] Example 44 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(pyrimidin-2-yl)propionic acid. 1H NMR (400MHz, methanol-d4) δ8.73(d,J=4.8Hz,2H),7.76(d,J=8.8Hz,1H),7.40(d,J=2.0Hz,1H),7.38-7.34(m,2H),7.17(dd,J=8.8 ,2.4Hz,1H),7.11(d,J=2.0Hz,1H),6.91(d,J=8.4Hz,1H),5.93-5.79(m,2H),4.10-3.93(m,3H),3.80(d,J=15.2Hz,1H),3.74 (d,J=14.4Hz,1H),3.67-3.59(m,1H),3.55(dd,J=8.2,3.0Hz,1H),3.43(d,J=14.4Hz,1H),3.35-3.30(m,4H),3.25(s,3H),3 .16-3.09(m,1H),3.00(t,J=6.8Hz,2H),2.86-2.73(m,3H),2.52-1.78(m,10H),1.47-1.41(m,1H).LCMS-ESI+(m / z):[M+H]+C 38 H 44 ClN5O5S: Calculated value: 718.3; Measured value: 719.4.

[0596] Example 45.

[0597]

[0598] Example 45 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(1-ethyl-1H-pyrazol-5-yl)propionic acid. 1¹H NMR (400MHz, methanol-d⁴) δ 7.77 (d, J = 8.4 Hz, 1H), 7.42–7.35 (m, 3H), 7.17 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 5.93–5.81 (m, 2H), 4.17 (q, J = 7.2 Hz) ,2H),4.11-3.94(m,3H),3.81(d,J=14.8Hz,1H),3.74(d,J=14.8Hz,1H),3.63-3.50(m ,2H),3.44(d,J=14.4Hz,1H),3.34-3.31(m,2H),3.31(s,3H),3.17-3.10(m,1H),3.02 -3.00(m,2H),2.87-2.79(m,5H),2.55-1.79(m,10H),1.48-1.35(m,4H).LCMS-ESI+(m / z):[M+H]+ C 39 H 48 ClN5O5S: Calculated value: 734.4; Measured value: 734.4.

[0599] Example 46.

[0600]

[0601] Example 46 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(2-methyl-2H-1,2,3-triazol-4-yl)propionic acid. 1 H NMR (400MHz, methanol-d4) δ7.77(d,J=8.4Hz,1H),7.47(s,1H),7.40(s,1H),7.35(d,J=8.4Hz,1H),7.19(d,J=8.4Hz,1H),7 .12(s,1H),6.90(d,J=8.0Hz,1H),5.96-5.90(m,1H),5.82(dd,J=16.2,8.6Hz,1H),4.10-3.94(m,6H),3.82(d,J=15. 2Hz,1H),3.74(d,J=14.4Hz,1H),3.68-3.50(m,2H),3.42(d,J=14.4Hz,1H),3.34-3.32(m,2H),3.31(s,3H),3.16-3. 09(m,1H),3.01(t,J=7.2Hz,2H),2.85-2.75(m,5H),2.50-1.78(m,10H),1.48-1.42(m,1H).LCMS-ESI+(m / z):[M+H]+ C37 H 45 ClN6O5S: Calculated value: 721.3; Measured value: 721.3.

[0602] Example 47.

[0603]

[0604] Example 47 was synthesized using the same method as in Example 18, but with 2-pyridinepropionic acid instead of 3-methoxypropionic acid. 1 H NMR (400MHz, methanol-d4) δ8.60(d,J=5.6Hz,1H),8.26(t,J=7.8Hz,1H),7.82(d,J=8.0Hz,1H),7.78(d,J=8.4Hz,1H),7.69(t,J= 6.6Hz,1H),7.40(s,1H),7.31(dd,J=8.2,1.8Hz,1H),7.19(d,J=8.8Hz,1H),7.12(s,1H),6.91(d,J=8.0Hz,1H),5.92-5.79( m,2H),4.12-3.92(m,3H),3.82-3.74(m,2H),3.57-3.51(m,2H),3.44(d,J=14.8Hz,1H),3.29(s,3H),3.33-3.24(m,4H),3. 17-3.11(m,1H),2.96(t,J=6.8Hz,2H),2.92-2.78(m,3H),2.49-1.81(m,10H),1.48-1.41(m,1H).LCMS-ESI+(m / z):[M+H]+C 39 H 45 ClN4O5S: Calculated value: 717.3; Measured value: 717.5.

[0605] Example 48.

[0606]

[0607] Example 48 was synthesized using the same method as in Example 18, but with 3-(1-methyl-1H-pyrazol-5-yl)propionic acid and in place of 3-methoxypropionic acid as in Example 6 and Example 5. LCMS-ESI+(m / z): [M+H]+ C 38 H 46 ClN5O5S: Calculated value: 720.3; Measured value: 720.0.

[0608] Example 49.

[0609]

[0610] Step 1: In an ice bath, add triethylamine (0.14 mL, 0.965 mmol) to a CH2Cl2 (15.0 mL) solution of (3S)-N-(amino((2R,3S)-3-methylhex-5-en-2-yl)(oxoyl)-16-thionyl)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxamide 1-6 (309.00 mg, 0.483 mmol), followed by DMAP (23.58 mg, 0.193 mmol) and di-tert-butyl dicarbonate (157.99 mg, 0.724 mmol). The resulting mixture was stirred overnight at room temperature. After concentration, the mixture of diastereomers was separated by preparative HPLC to obtain fractions 49-1 (lower polarity) and 49-2 (higher polarity).

[0611] Step 2: Synthesize intermediate 49-3 from intermediate 49-1 using a similar process to that shown in Step 2 of Method 1 in Example 5.

[0612] Step 3: Following the same method as in Example 18, Example 49 was synthesized using 3-(1-methyl-1H-pyrazol-5-yl)propionic acid and intermediate 49-3. 1 H NMR (400MHz, methanol-d4) δ7.75(d,J=8.8Hz,1H),7.38(s,1H),7.19(d,J=8.4Hz,2H),7.13(d,J=2.0Hz,1H),7.05(s,1 H),6.93(d,J=8.4Hz,1H),6.15(s,1H),6.00-5.93(m,1H),5.60(dd,J=15.4,9.0Hz,1H),4.32-4.28(m,1H),4.09( s,2H),3.85-3.81(m,4H),3.75-3.67(m,3H),3.51-3.79(m,1H),3.25(s,3H),3.16-3.09(m,1H),3.01(t,J=7.2H z,2H),2.85-2.79(m,5H),2.48-1.77(m,10H),1.51-1.44(m,4H),1.06(d,J=5.6Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 40 H 50 ClN5O5S: Calculated value: 748.4; Measured value: 748.0.

[0613] Example 50.

[0614]

[0615] Following the process described in Example 49 (steps 2 and 3), intermediate 49-2 was used instead of intermediate 49-1 to synthesize Example 50. LCMS-ESI+(m / z): [M+H]+ C 40 H 50 ClN5O5S: Calculated value: 748.4; Measured value: 748.0.

[0616] Example 51.

[0617]

[0618] Example 51 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(1-methyl-1H-pyrazol-3-yl)propionic acid. 1 H NMR (400MHz, methanol-d4) δ7.77(d,J=8.4Hz,1H),7.44(d,J=8.4Hz,2H),7.36(d,J=8.0Hz,1H),7.19(d,J=8.4Hz,1H),7.1 2(s,1H),6.90(d,J=8.4Hz,1H),6.12(d,J=2.4Hz,1H),5.94-5.81(m,2H),4.11-3.94(m,3H),3.83-3.80(m,4H),3.75 (d,J=14.4Hz,1H),3.68-3.47(m,2H),3.43(d,J=14.8Hz,1H),3.34-3.31(m,5H),3.16-3.10(m,1H),2.94(t,J=7.8Hz ,2H),2.85-2.78(m,3H),2.74(t,J=7.6Hz,2H),2.53-1.78(m,10H),1.45(t,J=12.6Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 38 H 46 ClN5O5S: Calculated value: 720.3; Measured value: 720.0.

[0619] Example 52.

[0620]

[0621] Example 52 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 41 H 46ClN5O5S: Calculated value: 756.4; Measured value: 756.2.

[0622] Example 53.

[0623]

[0624] Example 53 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(pyrimidin-5-yl)propionic acid. 1 ¹H NMR (400MHz, methanol-d⁴) δ 9.00 (s, ¹H), 8.74 (s, 2H), 7.77 (d, J = 8.4 Hz, ¹H), 7.41 (s, ¹H), 7.34 (dd, J = 8.0, 1.6 Hz, ¹H), 7.17 (d, J = 8.4 Hz, 1H), 7.11 (s, ¹H), 6.90 (d, J = 8.4 Hz, 1H), 5.92–5.81 (m, 2H), 4.11–3.91 (m, 3H), 3 .82-3.68(m,2H),3.60-3.50(m,2H),3.43(d,J=14.4Hz,1H),3.35-3.33(m,5H),3.16-3.10(m,1H),3.02( t,J=7.3Hz,2H),2.87-2.78(m,4H),2.55-1.78(m,10H),1.44(t,J=12.8Hz,1H).LCMS-ESI+(m / z):[M+H]+C 38 H 44 ClN5O5S: Calculated value: 718.3; Measured value: 718.1.

[0625] Example 54.

[0626]

[0627] Example 54 was synthesized using the same method as in Example 18, but with sodium 3-(1H-1,2,3-triazol-1-yl)propionate instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 36 H 43 ClN6O5S: Calculated value: 707.3; Measured value: 707.1.

[0628] Example 55.

[0629]

[0630] Example 55 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(4-chloro-1H-pyrazol-1-yl)propionic acid. 1H NMR (400MHz, methanol-d4) δ7.77(d,J=8.8Hz,1H),7.73(s,1H),7.44(s,1H),7.41(s,1H),7.35(d,J=8.4Hz,1H),7.19(d,J=8.4Hz,1H ),7.12(d,J=2.4Hz,1H),6.90(d,J=8.4Hz,1H),5.94-5.79(m,2H),4.44(t,J=6.2Hz,2H),4.05(dd,J=33.8,12.2Hz,2H),3.97- 3.89(m,1H),3.81(d,J=14.8Hz,1H),3.75(d,J=14.4Hz,1H),3.64-3.50(m,2H),3.43(d,J=14.4Hz,1H),3.34-3.31(m,5H),3.1 6-3.10(m,1H),2.96(t,J=6.4Hz,2H),2.85-2.77(m,3H),2.53-1.79(m,10H),1.45(t,J=12.6Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 37 H 43 Cl2N5O5S: Calculated value: 740.7; Measured value: 740.0.

[0631] Example 56.

[0632]

[0633] Example 56 was synthesized using 3-(5-methyl-1H-pyrazol-1-yl)propionic acid, following the same method as in Example 18. LCMS-ESI+(m / z): [M+H]+ C 38 H 46 ClN5O5S: Calculated value: 720.3; Measured value: 720.1.

[0634] Example 57.

[0635]

[0636] Example 57 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-isoxazol-4-yl-propionic acid was used. 1¹H NMR (400MHz, methanol-d⁴) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.77 (d, J = 8.8Hz, 1H), 7.42 (s, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.17 (d, J = 8.4Hz, 1H), 7.12 (s, 1H), 6.91 (d, J = 8.4Hz, 1H), 5.93–5.81 (m, 2H), 4.11–3.92 (m, 3H), 3.81 (d, J = 15.2Hz) ,1H),3.75(d,J=14.4Hz,1H),3.64-3.49(m,2H),3.44(d,J=14.4Hz,1H),3.36-3.31(m,7H),3.17-3.10(m,1H), 2.87-2.77(m,3H),2.70(t,J=7.2Hz,2H),2.55-1.79(m,10H),1.45(t,J=12.6Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 37 H 43 ClN4O6S: Calculated value: 707.3; Measured value: 707.1.

[0637] Example 58.

[0638]

[0639] Example 58 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(1,2-oxazol-3-yl)propionic acid. 1H NMR (400MHz, methanol-d4) δ8.54(d,J=1.6Hz,1H),7.77(d,J=8.8Hz,1H),7.40(s,1H),7.35(d,J=8.4Hz,1H),7.18(d,J=8.4Hz,1H ),7.12(d,J=2.4Hz,1H),6.90(d,J=8.4Hz,1H),6.43(d,J=1.6Hz,1H),5.95-5.89(m,1H),5.82(dd,J=16.0,8.4Hz,1H),4.1 1-3.92(m,3H),3.82(d,J=15.2Hz,1H),3.74(d,J=14.4Hz,1H),3.68-3.47(m,2H),3.42(d,J=14.4Hz,1H),3.35-3.32(m,2H ),3.31(s,3H),3.16-3.04(m,3H),2.85-2.72(m,5H),2.51-1.78(m,10H),1.45(t,J=12.6Hz,1H).LCMS-ESI+(m / z):[M+H]+C 37 H 43 ClN4O6S: Calculated value: 707.3; Measured value: 707.0.

[0640] Example 59.

[0641]

[0642] Example 59 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(3-methyl-1H-pyrazol-1-yl)propionic acid. ¹H NMR (400 MHz, methanol-d⁴) δ 7.78 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.41 (s, 1H), 7.34 (dd, J = 8.2, 1.8 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.02 (d, J = 2.4 Hz, 1H), 5.95-5.80 (m, 2H), 4.39 (t, J = 6.6 Hz, 2H), 4.06 (dd, J = 34.2, 12.2 Hz, 2H) ),3.98-3.91(m,1H),3.81(d,J=15.2Hz,1H),3.75(d,J=14.4Hz,1H),3.68-3.47(m,2H),3.43(d,J=14.4Hz,1H),3.35-3.31(m,5H) ,3.16-3.10(m,1H),2.93(t,J=6.4Hz,2H),2.85-2.75(m,3H),2.53-1.79(m,13H),1.45(t,J=12.6Hz,1H).LCMS-ESI+(m / z):[M+H]+ C 38 H 46 ClN5O5S: Calculated value: 720.3; Measured value: 720.1.

[0643] Example 60.

[0644]

[0645] Example 60 was synthesized using the same method as in Example 18, but with lithium 3-(5-methyl-1,3,4-oxadiazol-2-yl)propionate instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+C 37 H 44 ClN5O6S: Calculated value: 722.3; Measured value: 722.1.

[0646] Example 61.

[0647]

[0648] Example 61 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(4-methyl-1H-pyrazol-1-yl)propionic acid. 1H NMR (400MHz, methanol-d4) δ7.77(d,J=8.4Hz,1H),7.41(s,2H),7.34(d,J=8.0Hz,1H),7.28(s,1H),7.19(d,J=8.4Hz,1H),7.12( s,1H),6.90(d,J=8.4Hz,1H),5.93-5.80(m,2H),4.40(td,J=6.4,2.4Hz,2H),3.81(dd,J=34.0,12.4Hz,2H),3.97-3.90(m, 1H),3.81(d,J=14.8Hz,1H),3.75(d,J=14.4Hz,1H),3.63-3.47(m,2H),3.43(d,J=14.8Hz,1H),3.35-3.33(m,5H),3.17-3. 10(m,1H),2.92(t,J=6.6Hz,2H),2.85-2.75(m,3H),2.52-1.78(m,13H),1.45(t,J=12.8Hz,1H).LCMS-ESI+(m / z):[M+H]+C 38 H 46 ClN5O5S: Calculated value: 720.3; Measured value: 720.1.

[0649] Examples 62 and 63.

[0650]

[0651] Step 1: Pyridine (1.0 g, 8.5 mmol) and acetic anhydride (1.3 g, 8.5 mmol) were added to a tetrahydrofuran solution of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-hydroxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatrien-3,1'-naphthalene]-7-carboxylic acid (2.0 g, 4.27 mmol) under stirring. The mixture was stirred at room temperature for 48 hours, and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was concentrated to give crude acid anhydride 62-1.

[0652] Step 2: Cool the CH2Cl2 solution of acid anhydride 62-1 (2.0 gr, 3.6 mmol) under stirring to 0°C. Add SOCl2 (2 mL) dropwise to the mixture with vigorous stirring. Stir the mixture at 0°C and slowly warm it to room temperature. After the reaction is complete, evaporate it to remove excess SOCl2 to obtain acyl chloride intermediate 62-2, which can be used directly in the next step.

[0653] Step 3: At room temperature, a racemic mixture of (S)-N'-(tert-butyldimethylsilyl)pent-4-ene-1-iminosulfonamide and (R)-N'-(tert-butyldimethylsilyl)pent-4-ene-1-iminosulfonamide (99 mg, 0.38 mmol) was added to an acetonitrile solution of 62-2 (200 mg, 0.38 mmol) and pyridazine (30 mg, 0.38 mmol) stirred for 5 minutes. After the reaction was complete, the residue was dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by reversed-phase chromatography (acetonitrile-water 50%-90%, 30 minutes) to give a mixture of diastereomers of intermediate IV.

[0654] Step 4: A mixture of iminosulfonamide intermediate IV (150 mg, 0.23 mmol), propionyl chloride (26 mg, 0.29 mmol), and triethylamine (0.29 mmol) was stirred in CH2Cl2 at room temperature for 1 hour. The reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reversed-phase chromatography (acetonitrile-water 50-90%, 30 min) to give 62-3.

[0655] Step 5: Ester intermediate 62-3 (25 mg, 0.036 mmol) and Hoveyda-Grubbs second-generation catalyst (2.2 mg, 0.004 mmol) were sealed in a microwave-safe bottle and purged with argon. Then, 1,2-DCE was added. The bottle was heated at 60 °C for 1 hour. After the reaction was complete, the reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reversed-phase chromatography (acetonitrile-water 50%-90%, 30 min) to give macrocyclic intermediate 62-4, a mixture of diastereomers.

[0656] Step 6: Dissolve intermediate (62-4) in methanol (3 mL) and water (0.3 mL). Add K2CO3 (10.8 mg, 0.08 mmol) to the solution and stir at room temperature for 7 hours. Dissolve the mixture in ethyl acetate and wash with water. Concentrate the organic layer and purify by reversed-phase chromatography (acetonitrile-water 50%-90%, 30 min) to obtain Example 62 (fraction with lower polarity) and Example 63 (fraction with higher polarity).

[0657] Example 62: 1H NMR (400MHz, chloroform-d) δ7.72(d,J=8.5Hz,1H),7.38(d,J=8.9Hz,2H),7.17(dd,J=8.5,2.3Hz,1H),7.07(d,J=2.3Hz,1H),6.92 (d,J=8.0Hz,1H),6.00(dd,J=15.8,7.6Hz,1H),5.80(dt,J=15.8,5.2Hz,1H),4.20–3.95(m,4H),3.78(t,J=14.7Hz,3H),3. 53–3.40(m,3H),3.34(d,J=14.4Hz,2H),3.15–3.00(m,2H),2.88–2.67(m,3H),2.45(q,J=7.5Hz,3H),2.24(dt,J=12.7,6.3 Hz,2H),2.12–1.63(m,4H),1.40(d,J=13.3Hz,1H),1.26(t,J=7.1Hz,1H),1.17(t,J=7.4Hz,2H).LCMS-ESI+(m / z):[M+H]+C 33 H 40 ClN3O5S: Calculated value: 626.2; Measured value: 626.2.

[0658] Example 63: 1 ¹H NMR (400MHz, chloroform-d) δ 8.05 (s, 1H), 7.72 (d, J = 8.5Hz, 1H), 7.44–7.33 (m, 2H), 7.18 (d, J = 8.2Hz, 1H), 7.08 (s, 1H), 6.91 (t, J = 8.1Hz, 1H), 5.91–5.71 (m, 2H), 4.15–4.00 (m, 3H), 3.99–3.85 (m, 1H), 3.71 (d, J = 14.7Hz, 2H), 3. 58(d,J=14.9Hz,1H),3.43(d,J=14.7Hz,1H),3.27(s,2H),3.00(s,2H),2.95–2.87(m,2H),2.80(d,J=19.0Hz ,3H),2.46(tt,J=7.4,3.4Hz,3H),1.90-1.60(m,6H),1.23(dt,J=18.1,7.3Hz,4H).LCMS-ESI+(m / z):[M+H]+ C 33 H 40 ClN3O5S: Calculated value: 626.2; Measured value: 626.2.

[0659] Examples 64 and 65.

[0660]

[0661] Step 1: Preparation of (R)-N-(tert-butyldimethylsilyl)hep-6-ene-3-sulfonamide: In an ice bath, Et3N (1.8 g, 18.3 mmol) was added to a THF solution of (R)-hep-6-ene-3-sulfonamide (prepared according to the procedure in International Publication No. WO17 / 147410, 1.5 g, 11.5 mmol) under stirring, followed by a THF solution of tert-butyldimethylchlorosilane (1.7 g, 11.5 mmol). The resulting mixture was stirred at room temperature for 24 hours. The precipitate was filtered off and washed with diethyl ether. The filtrate was concentrated and purified by normal-phase chromatography (hexane / EtOAc = 3:1) to give (R)-N-(tert-butyldimethylsilyl)hep-6-ene-3-sulfonamide.

[0662] Step 2: Preparation of (3R)-N'-(tert-butyldimethylsilyl)hept-6-ene-3-iminosulfonamide: Under a nitrogen atmosphere, triethylamine (1.2 g, 12.6 mmol) was added to a CH2Cl2 suspension of Ph3PCl2 (4.2 g, 12.6 mmol) under stirring. The mixture was stirred for 10 minutes at room temperature, then cooled to 0 °C, and a CH2Cl2 solution of (R)-N-(tert-butyldimethylsilyl)hept-6-ene-3-sulfonamide (2.2 g, 7.9 mmol) was added. The reaction mixture was stirred for 1 hour at 0 °C. Ammonia was bubbled into the reaction mixture. The mixture was stirred at 0 °C for 2 hours, and then at room temperature for 24 hours. The precipitate was filtered off and washed with CH2Cl2. The filtrate was concentrated and purified by normal phase chromatography (hexane:EtOAc = 7:3) to obtain (3R)-N'-(tert-butyldimethylsilyl)hept-6-ene-3-iminosulfonamide. 1 H NMR(400MHz, chloroform-d)δ5.78(ddt,J=16.9,10.5,6.6Hz,1H),5.13–4.85(m,2H),4.38(s,2H),2.75(tt,J=7.0,4.8Hz,1H),2 .32–2.10(m,2H),2.06–1.86(m,2H),1.79–1.54(m,2H),1.03(td,J=7.5,1.7Hz,3H),0.87(s,9H),0.09(d,J=1.1Hz,6H).

[0663] Step 3: Following the same method as in Examples 3 and 4, Examples 64 and 65 were prepared by replacing N'-(tert-butyldimethylsilyl)hep-6-ene-3-iminosulfonamide with (3R)-N'-(tert-butyldimethylsilyl)pent-4-ene-1-iminosulfonamide.

[0664] Example 64 (a fraction with greater polarity): 1 ¹H NMR (400MHz, chloroform-d) δ 7.70 (t, J = 8.2Hz, 1H), 7.35 (d, J = 8.5Hz, 1H), 7.16 (t, J = 4.2Hz, 2H), 7.07 (s, 1H), 6.87 (d, J = 8.0Hz, 1H), 5.86 (s, 1H), 5.59 (dd, J = 15.8, 7.8Hz, 1H), 4.18–3.95 (m, 3H) ),3.85-3.63(m,3H),3.35-3.21(m,4H),3.07-2.92(m,1H),2.77(s,2H),2.44(t,J=7.9Hz,7 H),2.18-1.57(m,10H),1.25(s,1H),1.13(dt,J=28.4,7.2Hz,6H).LCMS-ESI+(m / z):[M+H]+ C 36 H 46 ClN3O5S: Calculated value: 668.2; Measured value: 668.3.

[0665] Example 65 (fraction with lower polarity): 1 ¹H NMR (400MHz, chloroform-d) δ 7.70 (d, J = 8.5Hz, 1H), 7.17 (d, J = 10.5Hz, 2H), 7.08 (s, 2H), 6.92 (d, J = 8.2Hz, 1H), 6.10–6.00 (m, 1H), 5.50 (dd, J = 15.4, 8.5Hz, 1H), 4.29–3.99 (m, 3H), 3.8 7-3.59(m,3H),3.25(s,4H),3.00(s,1H),2.76(d,J=13.4Hz,2H),2.43(dd,J=19.8,12. 5Hz,6H),2.24-1.54(m,11H),1.41(s,1H),1.28-1.05(m,6H).LCMS-ESI+(m / z):[M+H]+ C 36 H 46 ClN3O5S: Calculated value: 668.2; Measured value: 668.3.

[0666] Example 66.

[0667] Step 1: Preparation of 66-1: A mixture of intermediate IV (900 mg, 1.4 mmol), di-tert-butyl dicarbonate (429 mg, 1.9 mmol), DMAP (17 mg, 0.14 mmol), and triethylamine (0.2 mL) was stirred in CH2Cl2 at room temperature for 1 hour. After the reaction was complete, the reaction mixture was evaporated under reduced pressure and purified by silica gel chromatography (Hex:EtOAc 1:1) to obtain intermediate 66-1.

[0668] Step 2: Add 66-1 (880 mg, 1.26 mmol) and Hoveyda-Grubbs second-generation catalyst (78 mg, 0.13 mmol) to a round flask. Seal the flask, purge with argon, and then add 1,2-DCE. Heat the flask at 60 °C for 1 hour. After the reaction is complete, evaporate the reaction mixture under reduced pressure to obtain intermediate 66-2.

[0669]

[0670] Step 3: Dissolve intermediate 66-2 (600 mg, 0.84 mmol) in methanol (6 mL) and water (0.6 mL). Add K2CO3 (406 mg, 2.94 mmol) to the solution and stir at room temperature for 7 hours. Dissolve the mixture in ethyl acetate and wash with water. Concentrate the organic layer and purify by reversed-phase chromatography (acetonitrile-water 50%-90%, 30 min) to give diastereomers 66-3 (the more polar fraction) and 66-4 (the less polar fraction).

[0671] Step 4: Intermediate 66-3 (15 mg, 0.024 mmol) was dissolved in DMF, and NaH (4 mg, 0.072 mmol) was added at room temperature. The mixture was stirred for 10 minutes, followed by the addition of 2-bromoethyl trifluoromethanesulfonate (12 mg, 0.048 mmol). The reaction mixture was stirred at room temperature for 5 hours and dissolved in ethyl acetate, then washed with water. The organic layer was concentrated to give brominated intermediate 66-5, which could be used further without purification.

[0672] Step 5: Dissolve the brominated intermediate 66-5 (15 mg, 0.02 mmol) in morpholine and stir at 50 °C for 1 hour. Evaporate the mixture under reduced pressure to obtain 66-6, which can be used further without purification.

[0673] Step 6: Morpholine intermediate 66-6 (9 mg, 0.011 mmol) was treated with a mixture of CH2Cl2 (2 mL) and TFA (1 mL) and stirred at room temperature for 1 hour. The mixture was dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was concentrated and purified by reversed-phase chromatography (acetonitrile-water 50%-90%, 30 min) to give intermediate 66-7.

[0674] Step 7: Intermediate 66-7 (5 mg, 0.007 mmol), propionyl chloride (1 mg, 0.007 mmol), and triethylamine (0.021 mmol) were stirred in CH2Cl2 at room temperature for 1 hour. After the reaction was complete, the mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reversed-phase chromatography (acetonitrile-water 50-90%, 30 min) to obtain Example 66. 1H NMR (400MHz, chloroform-d) δ7.72(d,J=8.5Hz,1H),7.46-7.39(m,1H),7.31(s,1H),7.22-7.15(m,1H),7.07(d,J=2.3Hz,1H),6 .92(d,J=8.3Hz,1H),5.94(d,J=15.8Hz,1H),5.73(dd,J=15.9,7.8Hz,1H),4.10(d,J=12.0Hz,1H),4.03-3.75(m,7H),3 .66(t,J=13.1Hz,5H),3.51(d,J=12.0Hz,1H),3.36(d,J=14.4Hz,2H),3.27(s,2H),3.14-2.92(m,3H),2.76(d,J=14.8 Hz,3H),2.53-2.39(m,3H),2.32-1.64(m,10H),1.41(d,J=12.5Hz,2H),1.22(t,J=7.5Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 39 H 51 ClN4O6S: Calculated value: 739.3; Measured value: 739.5.

[0675] Example 67.

[0676]

[0677] Example 67 was synthesized using intermediate 66-4 (a fraction with lower polarity) following the same method as in Example 66. ¹H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.18 (dd, J = 8.6, 2.3 Hz, 1H), 7.08 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.83 (s, 2H), 4.11 (d, J = 12.1 Hz, 1H), 3.99-3.75 (m, 6H), 3.61 (dd... ,J=37.3,15.1Hz,6H),3.49(s,1H),3.40(s,1H),3.32-3.18(m,2H),3.06-2.97(m,1H),2.90(s,2H),2.8 2-2.66(m,3H),2.49(s,4H),2.28-1.62(m,9H),1.37(s,2H),1.27-1.11(m,4H).LCMS-ESI+(m / z):[M+H]+ C 39 H 51 ClN4O6S: Calculated value: 739.3; Measured value: 739.5.

[0678] Example 68.

[0679]

[0680] Example 68 was synthesized using the same method as in Example 67, but with intermediate 67-4 (a fraction with lower polarity) and 1-methylpiperazine instead of morpholine. 1 H NMR (400MHz, chloroform-d) δ7.74(d,J=8.5Hz,1H),7.47-7.30(m,2H),7.21-7.13(m,1H),7.07(d,J=2.3Hz,1H),6.92(d, J=8.3Hz,1H),6.11(dd,J=15.9,9.0Hz,1H),5.75(d,J=15.9Hz,1H),4.12-3.93(m,4H),3.85-3.49(m,8H),3.36( t,J=14.1Hz,4H),3.16-3.00(m,3H),2.87(d,J=10.7Hz,4H),2.82-2.60(m,4H),2.09(td,J=15.4,14.9,8.0Hz,6 H),1.98-1.59(m,6H),1.46(d,J=3.0Hz,1H),1.42-1.20(m,2H),1.12(t,J=7.1Hz,2H).LCMS-ESI+(m / z):[M+H]+ C 40H 54 ClN5O5S: Calculated value: 752.3; Measured value: 752.4.

[0681] Example 69.

[0682] Step 1: Following the same method as in Example 1 (Steps 4 and 5), N'-(tert-butyldimethylsilyl)hex-5-ene-1-iminosulfonamide was prepared by replacing (2R,3S)-3-methylhex-5-ene-2-sulfonamide with hex-5-ene-1-sulfonamide. 1 H NMR (400MHz, chloroform-d) δ5.87–5.63(m,1H),5.07–4.84(m,2H),4.71–4.01(m,2H),3.04(dddd,J=13.4,10.0,8.5, 5.0Hz,2H),2.13–2.01(m,2H),1.92–1.71(m,2H),1.57–1.45(m,2H),0.88(d,J=5.9Hz,9H),0.11–0.2(m,6H).

[0683]

[0684] Step 2: Preparation of Intermediate 69-2: At room temperature, N'-(tert-butyldimethylsilyl)hexyl-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatriene-3,1'-naphthalene]-7-carboxyl chloride (200 mg, 0.40 mmol, obtained from Step 3 of Example 1) and pyridazine (32 mg, 0.40 mmol) in acetonitrile (121 mg, 0.44 mmol) was added. After the reaction was complete, the residue was dissolved in ethyl acetate and washed with water. The organic layer was concentrated and purified by normal-phase chromatography (Hex:AtOAc 1:1) to obtain 69-2, which is a mixture of diastereomers.

[0685] Step 3: Preparation of intermediate 69-3: A mixture of diastereomers, 69-2 (160 mg, 0.25 mmol), propionyl chloride (28 mg, 0.30 mmol), and triethylamine (0.56 mmol), was stirred in CH2Cl2 at room temperature for 1 hour. After the reaction was complete, the reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reversed-phase chromatography (acetonitrile-water 50-90%, 30 min) to obtain 69-3, which is a mixture of diastereomers.

[0686] Step 4: Preparation of Example 69: Intermediate 69-3 (25 mg, 0.037 mmol) and Hoveyda-Grubbs II (2.2 mg, 0.004 mmol) were added to a microwave-safe vial. The vial was sealed and purged with argon, and then 1,2-DCE was added. The vial was heated at 60 °C for 1 hour. After the reaction was complete, the reaction mixture was evaporated under reduced pressure, dissolved in DMF, and purified by reversed-phase chromatography (acetonitrile-water 50-90%, 30 min) to obtain Example 69 (the fraction with lower polarity). 1 ¹H NMR (400MHz, chloroform-d) δ 7.67 (dd, J = 8.6, 4.6Hz, 1H), 7.46 (d, J = 8.1Hz, 1H), 7.32–7.05 (m, 3H), 6.96 (dd, J = 18.1, 8.1Hz, 1H), 5.63–5.30 (m, 2H), 4.25–4.01 (m, 2H), 3.86–3.56 (m, 4H), 3. 49-3.27(m,5H),3.22(d,J=10.0Hz,2H),2.76(d,J=10.8Hz,2H),2.58-2.37(m,4H),2.15-1 .74(m,10H),1.63(dt,J=18.7,9.4Hz,6H),1.23(t,J=7.5Hz,2H).LCMS-ESI+(m / z):[M+H]+ C 35 H 44 ClN3O5S: Calculated value: 654.4; Measured value: 654.2.

[0687] Examples 70 and 71.

[0688]

[0689] Examples 71 and 72 were synthesized using (3R)-N'-(tert-butyldimethylsilyl)hept-6-en-3-iminosulfonamide (step 1 of Examples 64 and 65) and 3-(1-methyl-1H-pyrazol-5-yl)propionic acid, following the same method as in Examples 3 and 4.

[0690] Example 70: 1¹H NMR (400MHz, chloroform-d) δ 7.69 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.16 (td, J = 8.5, 2.3 Hz, 1H), 7.09–7.01 (m, 2H), 7.00–6.87 (m, 2H), 6.16 (d, J = 2.1 Hz, 1H), 5.94–5.80 (m, 1H), 5.51 (dd, J = 15.3, 8.7 Hz, 1H), 4.31 (s, 1H), 4.12–4.02 (m ,2H),3.93(s,2H),3.78(t,J=13.6Hz,1H),3.71-3.59(m,4H),3.25(d,J=15.2Hz,3H),3.05-2.89(m,6H),2.87-2.7 2(m,4H),2.48-2.19(m,4H),2.16-1.57(m,11H),1.49-1.30(m,1H),1.16(t,J=7.5Hz,2H).LCMS-ESI+(m / z):[M+H]+ C 40 H 50 ClN5O5S: Calculated value: 748.2; Measured value: 748.3.

[0691] Example 71: 1 H NMR (400MHz, chloroform-d) δ7.70(d,J=8.5Hz,1H),7.52(d,J=2.1Hz,1H),7.49-7.31(m,2H),7.16(dd,J=8.5,2.4Hz,1H),7.07 (d,J=2.3Hz,1H),6.91(dd,J=11.6,8.3Hz,2H),6.15(d,J=2.1Hz,1H),5.72(td,J=10.8,5.0Hz,1H),5.37(t,J=10.3Hz, 1H),4.10(q,J=9.0,8.0Hz,3H),3.98-3.55(m,5H),3.48-3.35(m,1H),3.35-3.14(m,4H),3.11-2.63(m,9H),2.46-2.14 (m,5H),2.12-1.52(m,10H),1.45-1.34(m,1H),1.14(q,J=5.1,2.9Hz,1H),1.03-0.82(m,2H).LCMS-ESI+(m / z):[M+H]+ C 40 H 50 ClN5O5S: Calculated value: 748.2; Measured value: 748.3.

[0692] Example 72.

[0693]

[0694] Example 72 was synthesized using (S)-3-hydroxy-3-phenylpropionic acid instead of 3-methoxypropionic acid, following the same method as in Example 18. 1 H NMR (400MHz, chloroform-d) δ7.61(d,J=8.5Hz,1H),7.44–7.27(m,6H),7.16(d,J=1.7Hz,1H),7.04(d,J=2.3Hz, 1H),6.92(d,J=8.3Hz,2H),5.88–5.66(m,2H),5.25(dd,J=9.9,2.7Hz,1H),3.99(q,J=12.0Hz,3H),3.71 (dd,J=27.2,14.6Hz,3H),3.56(dd,J=7.5,3.2Hz,1H),3.32(s,4H),3.03(dd,J=15.6,10.2Hz,2H),2.8 7–2.64(m,4H),2.47–2.06(m,5H),2.06–1.66(m,5H),1.29(d,J=30.9Hz,4H).LCMS-ESI+(m / z):[M+H]+C 40 H 46 ClN3O6S: Calculated value: 732.2; Measured value: 732.0.

[0695] Example 73.

[0696]

[0697] A solution of thiomorpholine-4-formyl chloride 1,1-dioxide (8 mg, 0.041 mmol) in 1 mL of dichloromethane was added dropwise to a solution of Example 5 (12 mg, 0.021 mmol) and diisopropylethylamine (0.041 mmol) in 3 mL of dichloromethane, and the mixture was stirred under reflux for 16 hours. LC / MS showed that the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was dissolved in 3 mL of methanol and purified by HPLC to give Example 73. 1¹H NMR (400MHz, chloroform-d) δ 7.77–7.62 (m, 1H), 7.23–7.11 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 7.04–6.81 (m, 2H), 5.93–5.74 (m, 1H), 5.53 (dd, J = 15.5, 8.4 Hz, 1H), 4.28–3.85 (m, 7H). 3.79-3.49(m,4H),3.40-3.20(m,4H),2.99(d,J=34.6Hz,4H),2.85-2.61(m,2H),2.5 5-2.20(m,4H),2.20-1.58(m,9H),1.42(t,J=12.8Hz,2H).LCMS-ESI+(m / z):[M+H]+C 36 H 45 ClN4O7S2: Calculated value: 745.25; Measured value: 745.96.

[0698] Example 74.

[0699]

[0700] Example 74 was synthesized using the same method as Example 73, based on Example 6. LCMS-ESI+(m / z): [M+H]+ C 36 H 45 ClN4O7S2: Calculated value: 745.25; Measured value: 745.96.

[0701] Example 75.

[0702] A solution of Example 5 (12 mg, 0.021 mmol), diphenyl carbonate (5 mg, 0.023 mmol), and DMAP (15 mg, 0.123 mmol) in 3 mL of acetonitrile was stirred at room temperature for 16 hours. (1-Methyl-1H-pyrazol-5-yl)methylamine (6.8 mg, 0.062 mmol) was added, and the mixture was stirred at room temperature for another 1 hour. LC / MS showed that the reaction was complete. The solvent was evaporated under reduced pressure, and the residue was dissolved in 3 mL of methanol and purified by HPLC to give Example 75. 1¹H NMR (400MHz, methanol-d⁴) δ 7.74 (d, J = 8.5Hz, 1H), 7.49–7.20 (m, 3H), 7.20–7.03 (m, 2H), 6.87 (d, J = 8.2Hz, 1H), 6.37 (d, J = 1.9Hz, 1H), 6.00–5.68 (m, 2H), 5.38–5.16 (m, 2H), 4.21–3.90 ( m,2H),3.82-3.47(m,3H),3.46-3.18(m,11H),3.10(dd,J=15.0,10.7Hz,1H),2.93-2.60( m,3H),2.58-2.15(m,3H),2.15-1.64(m,6H),1.52-1.17(m,2H).LCMS-ESI+(m / z):[M+H]+ C 37 H 45 ClN6O5S: Calculated value: 721.29; Measured value: 721.91.

[0703] Example 76.

[0704]

[0705] Example 76 was synthesized using the same method as in Example 75, employing Example 6 and N-methylethylamine. LCMS-ESI+(m / z): [M+H]+ C 35 H 45 ClN4O5S: Calculated value: 669.28; Measured value: 669.88.

[0706] Example 77.

[0707]

[0708] Example 77 was synthesized using N-methylethylamine following the same method as Example 77. LCMS-ESI+(m / z): [M+H]+ C 35 H 45 ClN4O5S: Calculated value: 669.28; Measured value: 669.88.

[0709] Example 78.

[0710]

[0711] Example 78 was synthesized using (1-methyl-1H-pyrazole-5-yl)methanol, following the same method as in Example 76. LCMS-ESI+(m / z): [M+H]+ C 37 H 44 ClN5O6S: Calculated value: 722.27; Measured value: 723.24.

[0712] Example 79.

[0713]

[0714] Example 79 was synthesized using pyridin-4-ylmethylamine following the same method as in Example 76. ¹H NMR (400 MHz, methanol-d⁴) δ 8.70 (d, J = 6.0 Hz, 2H), 7.96 (d, J = 6.0 Hz, 2H), 7.68 (dd, J = 8.9, 6.4 Hz, 1H), 7.41–7.16 (m, 2H), 7.18–6.98 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 5.89 (dt, J = 15.8, 5.3 Hz, 1H), 5 .76(t,J=12.0Hz,1H),4.64(s,2H),4.21-3.46(m,6H),3.39(d,J=14.5Hz,1H),3.34(s,6H),3.10(dd,J=15.1,10.8 Hz,1H),2.97-2.58(m,3H),2.35(d,J=58.3Hz,3H),2.19-1.68(m,6H),1.54-1.17(m,2H).LCMS-ESI+(m / z):[M+H]+ C 38 H 44 ClN5O5S: Calculated value: 718.28; Measured value: 719.76.

[0715] Example 80.

[0716]

[0717] Example 80 was synthesized using pyrazine-2-ylmethylamine in the same manner as in Example 76. 1¹H NMR (400 MHz, methanol-d⁴) δ 8.64 (s, 1H), 8.60–8.41 (m, 2H), 7.74 (dd, J = 8.5, 5.2 Hz, 1H), 7.29 (dd, J = 12.5, 8.1 Hz, 2H), 7.23–7.00 (m, 2H), 6.86 (dd, J = 16.3, 8.1 Hz, 1H), 5.89 (dt, J = 15.8, 5.3 Hz, 1H), 5.76 (t, J = 12.0 Hz, 1H),4.64(s,2H),4.21-3.46(m,6H),3.39(d,J=14.5Hz,1H),3.34(s,6H),3.10(dd,J=15.1,10.8Hz,1H), 2.97-2.58(m,3H),2.35(d,J=58.3Hz,3H),2.19-1.68(m,6H),1.54-1.17(m,2H).LCMS-ESI+(m / z):[M+H]+ C 37 H 43 ClN6O5S: Calculated value: 719.27; Measured value: 719.71.

[0718] Example 81.

[0719]

[0720] Example 81 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid. 1H NMR (400MHz, methanol-d4) δ7.74(d,J=8.5Hz,1H),7.40(d,J=1.9Hz,1H),7.33(dd,J= 8.3,1.9Hz,1H),7.18-7.05(m,2H),6.87(d,J=8.2Hz,1H),5.93-5.76(m,2H),4 .06(d,J=12.1Hz,1H),4.02-3.89(m,2H),3.78(d,J=14.9Hz,1H),3.71(d,J=14 .3Hz,1H),3.67-3.46(m,2H),3.40(d,J=14.4Hz,1H),3.34(s,1H),3.25(s,3H) ,3.11(dd,J=15.3,10.8Hz,1H),2.82-2.72(m,2H),2.47(t,J=7.3Hz,3H),2.26 -2.17(m,1H),2.13-1.98(m,3H),1.93(s,1H),1.77(t,J=6.3Hz,2H),1.53(q,J =7.2Hz,2H),1.41(t,J=13.1Hz,2H),1.28(s,2H),0.89(t,J=6.6Hz,1H),0.80- 0.68(m,1H),0.48-0.39(m,2H),0.08(t,J=4.7Hz,2H).LCMS-ESI+(m / z):[M+H]+ C 37 H 46 ClN3O5S: Calculated value: 680.29; Measured value: 680.98.

[0721] Example 82.

[0722]

[0723] Example 82 was synthesized using the same method as in Example 18, but with 3-cyclopentylpropionic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]+ C 39 H 50 ClN3O5S: Calculated value: 709.32; Measured value: 709.36.

[0724] Examples 83 and 84.

[0725] Step 1: Preparation of ethyl trans-(±)-2-(1-methyl-1H-pyrazole-5-yl)cyclopropane-1-carboxylate: Sodium hydride (0.22 g, 9.1 mmol) and trimethyl sulfoxide (1.4 g, 18.1 mmol) were stirred in 7 mL DMSO at room temperature for 1 hour. Ethyl (E)-3-(1-methyl-1H-pyrazole-5-yl)acrylate (0.65 g, 3.6 mmol) was dissolved in 5 mL DMSO / THF (1:1) and added to the reaction mixture. After the reaction was complete (3 h, LC / MS), 1 N HCl was added, and the reaction mixture was extracted with diethyl ether. The combined organic layers were dried over MgSO4 to remove the solvent. The crude product was ready for use without further purification.

[0726]

[0727] Step 2: Preparation of trans-(±)-2-(1-methyl-1H-pyrazole-5-yl)cyclopropane-1-carboxylic acid: Add 2 mL of 1N NaOH to a solution of ethyl trans-(±)-2-(1-methyl-1H-pyrazole-5-yl)cyclopropane-1-carboxylic acid (0.4 g, 2.4 mmol) in 10 mL of methanol, and stir the reaction at room temperature for 3 hours. Remove methanol under reduced pressure, and acidify the aqueous solution to pH 4 using concentrated HCl. Filter and collect the precipitate, wash with water and air dry to obtain the acid, which can be used directly without further purification.

[0728] Step 3: Preparation of Examples 83 and 84: Two diastereomers, Examples 83 and 84, were synthesized using the same method as in Example 18, with trans-(±)-2-(1-methyl-1H-pyrazol-5-yl)cyclopropane-1-carboxylic acid and Example 5. These two diastereomers were separated by supercritical fluid chromatography (Chiralpak AD-H, 5 μM, 21 x 250 mm, 50% MeOH, flow rate 65 mL / min, 100 bar).

[0729] Example 83 (fractions with lower polarity): 1¹H NMR (400MHz, methanol-d⁴) δ 7.74 (d, J = 8.5Hz, 1H), 7.55–7.24 (m, 3H), 7.24–7.02 (m, 2H), 6.88 (d, J = 8.2Hz, 1H), 6.01 (d, J = 2.0Hz, 1H), 5.85 (qd, J = 15.8, 9.5Hz, 2H), 4.19–3.82 (m, 5H), 3.84–3.36 (m, 6H),3.34(s,3H),3.21-3.00(m,2H),2.93-2.67(m,3H),2.46(dt,J=10.6,5.6Hz,3H),2.24(d,J =8.1Hz,2H),2.15-1.94(m,4H),1.85-1.54(m,3H),1.50-1.14(m,4H).LCMS-ESI+(m / z):[M+H]+ C 39 H 46 ClN5O5S: Calculated value: 732.29; Measured value: 732.00.

[0730] Example 84 (a fraction with greater polarity): 1 H NMR (400MHz, methanol-d4) δ7.78(d,J=8.8Hz,1H),7.31(d,J=2.0Hz,1H),7.25(dd,J=8.2,1.8Hz,1H),7.18(dd,J=8.4,2.4Hz,1H),7.15(d,J=2.0Hz,1H ),7.10(d,J=2.4Hz,1H),6.82(d,J=8.0Hz,1H),6.11(dt,J=15.5,6.4Hz,1H),5.98(d,J=2.0Hz,1H),5.61(dd,J=15.4,9.0Hz,1H),4.19-4.12(m,1 H),4.01(dd,J=21.8,11.8Hz,2H),3.94-3.85(m,5H),3.74-3.66(m,3H), 3.50(p,J=1.6Hz,1H),3.34-3.31(m,2H),3.27(s,3H),3.15(p,J=1.6Hz, 1H),3.08-3.01(m,1H),2.88-2.74(m,3H),2.56-1.70(m,10H),1.59-1.5 4(m,1H),1.46-1.39(m,1H),1.18-1.36(m,1H).LCMS-ESI+(m / z):[M+H]+ C 39 H 46 ClN5O5S: Calculated value: 732.29; Measured value: 732.06.

[0731] Example 85.

[0732]

[0733] Example 85 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 4-(1H-pyrazol-1-yl)butyric acid was used. 1 H NMR (400MHz, methanol-d4) δ7.73(d,J=8.5Hz,1H),7.64(d,J=2.3Hz,1H),7.48(dd,J=1.9,0.7Hz,1H),7.40(d,J=1.9Hz,1H),7. 32(dd,J=8.3,1.9Hz,1H),7.21-7.04(m,2H),6.87(d,J=8.2Hz,1H),6.27(t,J=2.1Hz,1H),5.97-5.74(m,2H),4.20(t,J=6 .8Hz,2H),4.12-3.88(m,3H),3.74(dd,J=26.9,14.7Hz,2H),3.66-3.47(m,2H),3.38(d,J=32.3Hz,4H),3.10(dd,J=15.0, 10.9Hz,1H),2.93-2.60(m,3H),2.61-2.30(m,4H),2.31-1.71(m,12H),1.41(t,J=13.2Hz,1H).LCMS-ESI+(m / z):[M+H]+C 38 H 46 ClN5O5S: Calculated value: 720.29; Measured value: 720.97.

[0734] Example 86.

[0735]

[0736] Example 86 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 2-(imidazo[1,2-a]pyridin-2-yl)acetic acid. LCMS-ESI+(m / z): [M+H]+ C 40 H 44 ClN5O5S: Calculated value: 742.28; Measured value: 742.10.

[0737] Example 87.

[0738]

[0739] Example 87 was synthesized using the same method as in Example 18, but with 3-(2-(trifluoromethyl)phenyl)propionic acid instead of 3-methoxypropionic acid, as in Example 5. LCMS-ESI+(m / z): [M+H]+ C 41 H 45 ClF3N3O5S: Calculated value: 784.2793; Measured value: 784.392.

[0740] Example 88.

[0741]

[0742] Example 88 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(furan-2-yl)propionic acid was used. 1 H NMR (400MHz, chloroform-d) δ7.70(d,J=8.5Hz,1H),7.34–7.29(m,2H),7.22(d,J=1.9Hz,1H),7.12(dd,J=8.2 ,2.2Hz,1H),7.07(d,J=2.3Hz,2H),6.92(d,J=8.2Hz,2H),5.85(dt,J=15.5,5.2Hz,1H),5.69(dd,J= 15.8,7.9Hz,1H),4.12–3.95(m,2H),3.60(dd,J=7.8,3.4Hz,1H),3.30(d,J=1.9Hz,3H),3.08–2.94( m,4H),2.82–2.64(m,6H),2.30(td,J=14.7,13.8,6.2Hz,4H),2.06–1.64(m,12H).LCMS-ESI+(m / z): C 38 H 44 ClN3O6S: Calculated value: 706.2712; Measured value: 706.305.

[0743] Example 89.

[0744]

[0745] Preparation of 3-(1,3-dimethyl-1H-pyrazol-5-yl)propionic acid:

[0746] Step 1: Sodium hydride (70 mg, 3 mmol) was dissolved in THF (6 mL) and then cooled to 0 °C. Ethyl 2-(dimethoxyphosphoryl)ethyl acetate (650 mg, 3 mmol) was added to the mixture, and the mixture was stirred for 20 minutes. Then, 1,3-dimethyl-1H-pyrazole-5-carboxaldehyde (300 mg, 2.417 mmol) was added to the reaction mixture, and the mixture was heated to room temperature for 30 minutes. After the reaction was completed by TLC, the contents were diluted with aqueous solutions of ethyl acetate and ammonium chloride. The organic layer was dried over MgSO4, filtered, and concentrated. The crude reaction mixture was then purified by silica gel chromatography in 2 / 1 hexane:ethyl acetate to give (E)-3-(1,3-dimethyl-1H-pyrazole-5-yl)ethyl acrylate (405 mg). LCMS-ESI+ (m / z): C 10 H 14 N2O2: Calculated value: 195.113; Measured value: 195.132.

[0747] Step 2: Ethyl (E)-3-(1,3-dimethyl-1H-pyrazole-5-yl)acrylate (405 mg, 2 mmol) was added to a reaction flask containing ethanol (7 mL). Palladium / carbon was then added, and the reaction was stirred, with the contents purged and evacuated under nitrogen. Hydrogen was then added from a balloon, and the reaction was stirred for 3 hours. LCMS showed complete conversion to the hydrogenated product. The contents were then filtered through a fritted funnel and diluted with ethyl acetate. The palladium frit was moistened with water. The contents were concentrated, and the product was used directly in the next step without further purification to give ethyl 3-(1,3-dimethyl-1H-pyrazole-5-yl)propionate. LCMS-ESI+ (m / z): [M+H]C 10 H 17 N2O2: Calculated value: 197.129; Measured value: 197.090.

[0748] Step 3: Ethyl 3-(1,3-dimethyl-1H-pyrazole-5-yl)propionate (404 mg, 2 mmol) was dissolved in THF (2 mL), ethanol (1 mL), and water (1 mL), and then sodium hydroxide (412 mg, 10 mmol) was added. The reaction was then stirred for 1 hour. LCMS showed complete conversion. The reaction mixture was diluted with DCM and then acidified with 1N HCl to pH ~4. The organic layer was then dried over MgSO4 and concentrated to give 3-(1,3-dimethyl-1H-pyrazole-5-yl)propionic acid. LCMS-ESI+ (m / z): [M+H]C8H 13 N2O2: Calculated value: 169.0972; Measured value: 169.082.

[0749] Preparation of Example 89: Example 89 was synthesized using the same method as in Example 18, but with 3-(1,3-dimethyl-1H-pyrazol-5-yl)propionic acid instead of 3-methoxypropionic acid. 1 H NMR (400MHz, chloroform-d) δ7.55–7.46(m,2H),7.23(d,J=8.2Hz,1H),7.02(d,J=2.6Hz,2H),6.94(d,J=8.2Hz,1H),6.69(d,J=8.4 Hz,1H),5.77(d,J=7.5Hz,2H),3.99(s,3H),3.89(d,J=15.3Hz,1H),3.65(t,J=12.8Hz,2H),3.56–3.50(m,1H),3.39(d,J= 14.3Hz,1H),3.35(s,3H),3.11–2.98(m,2H),2.96–2.84(m,2H),2.84–2.60(m,4H),2.51–2.35(m,2H),2.31–2.22(m,2H), 2.11(d,J=8.7Hz,2H),2.08(s,3H),1.99(d,J=17.1Hz,4H),1.89–1.73(m,3H),1.36–1.20(m,3H).LCMS-ESI+(m / z):[M+H]C 39 H 48 ClN5O5S: Calculated value: 734.3137; Measured value: 734.400.

[0750] Example 90.

[0751]

[0752] Example 90 was synthesized using the same method as in Example 18, but with 3-(4-chlorophenyl)propionic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]C 39 H 45 Cl2N3O5S: Calculated value: 750.253; Measured value: 750.976.

[0753] Example 91.

[0754]

[0755] Example 91 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(thiazol-2-yl)propionic acid. 1H NMR (400MHz, chloroform-d) δ7.88(d,J=3.6Hz,1H),7.70–7.64(m,1H),7.40(d,J=3.5Hz,1H),7.24(d,J=1.9Hz,1H ),7.18–7.14(m,2H),7.09–7.04(m,2H),6.92(d,J=8.2Hz,1H),5.91–5.62(m,2H),4.09–3.96(m,2H),3.84 –3.67(m,3H),3.62–3.52(m,3H),3.30(s,3H),3.11–2.95(m,3H),2.82–2.71(m,2H),2.45–2.23(m,4H),2. 09–1.99(m,2H),1.94(q,J=9.6Hz,4H),1.88–1.64(m,4H),1.27(d,J=9.8Hz,2H).LCMS-ESI+(m / z):[M+H]C 37 H 43 ClN4O5S2: Calculated value: 723.2436; Measured value: 723.971.

[0756] Example 92.

[0757]

[0758] Preparation of 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propionic acid:

[0759] Step 1: 750 mg (4.16 mmol) of (1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-yl)methanol was added to a round-bottom flask and then dissolved in DCM (10 mL). Dys-Martin periodane reagent (2.2 g, 5 mmol) was then added. The reaction was stirred for 45 minutes. LC-MS indicated the reaction was complete. The contents were diluted with aqueous sodium bicarbonate solution, and the organic layer was dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography in 1 / 1 hexane:ethyl acetate to give 1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxaldehyde. LC-MS-ESI+ (m / z): [M+H]C6H5F3N2O: Calculated value: 179.043; Found value: 179.016.

[0760] Steps 2-4: 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propionic acid was synthesized by the same method as that used in Example 90 (Steps 1-3).

[0761] Preparation of Example 92:

[0762] Example 92 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)propionic acid. 1 H NMR (400MHz, chloroform-d) δ7.60(d,J=2.1Hz,1H),7.49(d,J=8.6Hz,1H),7.10–6.99(m,2H),6.95(d,J=8.4Hz,1 H),6.71(d,J=8.3Hz,1H),6.28(d,J=2.1Hz,1H),5.78(d,J=7.3Hz,2H),4.91(q,J=8.3Hz,2H),3.94(s,3 H),3.72–3.58(m,3H),3.58–3.53(m,1H),3.36(s,3H),3.09–2.91(m,4H),2.88–2.66(m,4H),2.44(s,2H ),2.33–2.21(m,3H),2.04–1.91(m,4H),1.89–1.74(m,4H),1.33–1.21(m,2H).LCMS-ESI+(m / z):[M+H]C 39 H 45 ClN5O5S2: Calculated value: 788.2855; Measured value: 788.261.

[0763] Example 93.

[0764]

[0765] Example 93 was synthesized using the same method as in Example 18, but with 3-(4-methylthiazol-5-yl)propionic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]C 38 H 45 ClN4O5S2: Calculated value: 737.2593; Measured value: 737.220.

[0766] Example 94.

[0767]

[0768] Example 94 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 4,4,4-trifluorobutyric acid was used. 1¹H NMR (400MHz, chloroform-d) δ 7.64 (d, J = 8.5 Hz, 1H), 7.20–7.04 (m, 3H), 7.03–6.97 (m, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.91–5.64 (m, 2H), 4.01 (q, J = 12.0 Hz, 3H), 3.73 (dd, J = 31.3, 14.6 Hz, 3H), 3.59 (dd, J = 8.1, 3.2 Hz, 1H), 3.31 (s, 3H). 3.18(dt,J=12.1,6.0Hz,1H),3.02(dd,J=15.2,10.7Hz,1H),2.80–2.63(m,4H),2.59–2.46(m,2H),2.39–2.27 (m,3H),2.08–1.90(m,5H),1.88–1.78(m,2H),1.76–1.65(m,2H),0.98–0.77(m,2H).LCMS-ESI+(m / z):[M+H]C 35 H 41 ClF3N3O5S: Calculated value: 708.248; Measured value: 708.865.

[0769] Example 95.

[0770]

[0771] Example 95 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 5,5,5-trifluorovaleric acid was used. 1 H NMR (400MHz, chloroform-d) δ7.61(d,J=8.5Hz,1H),7.31(d,J=8.3Hz,1H),7.14(s,1H),7.05(d,J=2.3Hz,1H),6.94( dd,J=8.6,4.0Hz,2H),5.89–5.66(m,2H),3.99(q,J=11.8Hz,2H),3.72(dd,J=29.4,14.8Hz,3H),3.57(dd,J= 7.6,3.1Hz,1H),3.32(s,3H),3.02(dd,J=15.1,10.9Hz,1H),2.80–2.67(m,3H),2.65–2.53(m,2H),2.46–2. 14(m,7H),1.97(dq,J=14.9,7.4Hz,6H),1.86–1.67(m,4H),1.33(t,J=12.9Hz,2H).LCMS-ESI+(m / z):[M+H]C 36 H 43ClF3N3O5S: Calculated value: 722.264; Measured value: 722.274.

[0772] Example 96.

[0773]

[0774] Example 96 was synthesized using the same method as in Example 18, but with 2-phenoxyacetic acid instead of 3-methoxypropionic acid. 1 H NMR (400MHz, chloroform-d) δ7.73(d,J=8.3Hz,1H),7.50–7.27(m,4H),7.18(dd,J=8.5,2.2Hz,1H),7.12–6.97(m,4H),6.9 3(dd,J=8.2,2.8Hz,1H),5.95–5.65(m,2H),4.10(d,J=12.0Hz,1H),4.04–3.91(m,2H),3.91–3.83(m,1H),3.75(q ,J=14.1,13.1Hz,2H),3.61(dd,J=7.7,3.4Hz,1H),3.28(s,3H),3.24–3.16(m,1H),3.07–2.94(m,1H),2.84–2.61 (m,3H),2.46–2.23(m,3H),2.08–1.56(m,8H),1.44–1.29(m,3H),0.88(t,J=8.1Hz,1H).LCMS-ESI+(m / z):[M+H]C 39 H 44 ClN3O6S: Calculated value: 718.271; Measured value: 718.109.

[0775] Example 97.

[0776]

[0777] Example 97 was synthesized using the same method as in Example 18, but with 3-phenylpropionic acid instead of 3-methoxypropionic acid. 1¹H NMR (400MHz, chloroform-d) δ 7.67 (dd, J = 14.8, 8.6Hz, 1H), 7.34–7.27 (m, 3H), 7.25–7.16 (m, 4H), 7.10–7.00 (m, 2H), 6.91 (d, J = 8.3Hz, 1H), 5.95–5.56 (m, 2H), 4.09–3.94 (m, 2H), 3.88 (q, J = 14.4, 11.1Hz, 1H), 3.74 (dd, J = 25.2, 14.8Hz, 3H). 3.59(dd,J=7.9,3.3Hz,1H),3.33(s,3H),3.08–2.91(m,3H),2.86–2.51(m,5H),2.48–2.23(m,2H),2.24–2.14(m,1 H),2.04(t,J=10.7Hz,2H),1.98–1.63(m,6H),1.41–1.23(m,2H),0.86(t,J=10.0Hz,1H).LCMS-ESI+(m / z):[M+H]C 40 H 46 ClN3O5S: Calculated value: 716.292; Measured value: 716.069.

[0778] Example 98.

[0779]

[0780] Example 98 was synthesized using the same method as in Example 18, but with 1-methyl-1H-indole-2-carboxylic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]C 41 H 45 ClN4O5S: Calculated value: 741.287; Measured value: 741.886.

[0781] Example 99.

[0782]

[0783] Example 99 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 3-(2-methylthiazol-4-yl)propionic acid. 1¹H NMR (400MHz, chloroform-d) δ 7.73 (d, J = 8.2Hz, 1H), 7.38 (dd, J = 25.3, 8.7Hz, 1H), 7.23 (s, 1H), 7.21–7.13 (m, 2H), 7.08 (s, 1H), 6.90 (d, J = 8.2Hz, 1H), 5.97–5.63 (m, 2H), 4.09 (d, J = 12.1Hz, 1H), 4.01 (t, J = 10.3Hz, 1H), 3.84 (t, J = 14 .5Hz,1H),3.73(s,3H),3.60(d,J=7.4Hz,1H),3.27(d,J=3.9Hz,3H),3.06–2.91(m,1H),2.78(s,2H),2.65(s, 2H),2.28(d,J=31.5Hz,4H),2.07–1.60(m,8H),1.43–1.12(m,6H),0.94–0.72(m,2H).LCMS-ESI+(m / z):[M+H]C 38 H 45 ClN4O5S2: Calculated value: 737.295; Measured value: 737.040.

[0784] Example 100.

[0785]

[0786] Preparation of 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid:

[0787] Step 1: 1-Methyl-1H-pyrazol-5-ol (250 mg, 3 mmol) was added to a round-bottom flask, followed by potassium carbonate (387 mg, 3 mmol). Then, THF (5 mL) was added. Ethyl bromoacetate (547 mg, 3 mmol) was added, and the reaction was stirred at 50 °C for 1 hour. TLC showed that 1-methyl-1H-pyrazol-5-ol was consumed. The contents were then diluted with ethyl acetate and water, and the organic layer was dried over MgSO4, filtered, and concentrated to give ethyl 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetate.

[0788] Step 2: Then, ethyl 2-((1-methyl-1H-pyrazole-5-yl)oxy)acetic acid (0.265 mg, 1.44 mmol) was diluted in THF (2 mL), water (1 mL), and ethanol (1 mL), followed by the addition of sodium hydroxide (115 mg, 2.88 mmol). The reaction was stirred for 2 hours, then diluted to pH ~4 with sec-butanol and 1N HCl. The organic layer was dried over MgSO4, filtered, and concentrated to obtain 2-((1-methyl-1H-pyrazole-5-yl)oxy)acetic acid. LCMS-ESI+ (m / z): [M+H]C6H8N2O3: Calculated value: 157.061; Measured value: 157.088.

[0789] Preparation of Example 100: Example 100 was synthesized using the same method as in Example 18, but with 2-((1-methyl-1H-pyrazol-5-yl)oxy)acetic acid instead of 3-methoxypropionic acid. 1 H NMR (400MHz, acetone-d6) δ7.77(d,J=8.6Hz,1H),7.43(s,1H),7.32(d,J=8.3Hz,1H),7.22(dd,J=8.5,2.3Hz,1H),7.11(d,J=2.4Hz,2 H),7.04(s,1H),6.88(d,J=8.2Hz,1H),5.96–5.78(m,2H),4.13–3.92(m,4H),3.79(dd,J=23.4,14.6Hz,2H),3.63(dd,J=13.4,7 .6Hz,1H),3.53(dd,J=7.7,3.0Hz,1H),3.45(d,J=14.4Hz,1H),3.26(s,3H),3.04(t,J=7.2Hz,2H),2.90–2.80(m,2H),2.62(s,3 H),2.46(d,J=7.2Hz,2H),2.34–2.18(m,2H),2.01–1.91(m,5H),1.84–1.70(m,3H),1.57–1.39(m,2H).LCMS-ESI+(m / z): [M+H]C 37 H 44 ClN5O6S: Calculated value: 722.277; Measured value: 722.907.

[0790] Example 101.

[0791]

[0792] Example 101 was synthesized using the same method as in Example 18, but with 3-(5-methylthiazol-4-yl)propionic acid instead of 3-methoxypropionic acid. LCMS-ESI+(m / z): [M+H]C38 H 45 ClN4O5S2: Calculated value: 737.2953; Measured value: 737.894.

[0793] Example 102.

[0794]

[0795] Example 102 was synthesized using 3-(5-methyl-1,3,4-thiadiazole-2-yl)propionic acid (prepared from 5-methyl-1,3,4-thiadiazole-2-carboxaldehyde in the same manner as in Example 18). 1 H NMR (400MHz, chloroform-d) δ7.64(d,J=8.5Hz,1H),7.27(d,J=2.7Hz,1H),7.15(s,1H),7.06(d,J=2.3Hz,1H),7.00(d,J=8.5Hz ,1H),6.93(d,J=8.3Hz,1H),5.91–5.64(m,2H),4.01(q,J=12.1Hz,2H),3.89(s,1H),3.83–3.65(m,3H),3.59(dd,J=8. 2,3.1Hz,1H),3.50–3.35(m,2H),3.32(s,3H),3.04(dd,J=16.7,9.6Hz,3H),2.78(s,3H),2.76–2.62(m,3H),2.47–2.2 2(m,4H),2.09–1.91(m,4H),1.81(p,J=9.9Hz,2H),1.71(t,J=9.3Hz,1H),1.43–1.14(m,3H).LCMS-ESI+(m / z):[M+H]C 37 H 44 ClN5O5S2: Calculated value: 738.255; Measured value: 738.054.

[0796] Example 103.

[0797] Example 103 was synthesized using 3-(1,4-dimethyl-1H-pyrazol-5-yl)propionic acid (prepared from 5-methyl-1,3,4-thiadiazole-2-carboxaldehyde in the same manner as in Example 18). 1H NMR (400MHz, chloroform-d) δ7.54(d,J=7.0Hz,2H),7.22(d,J=7.3Hz,1H),7.14–6.99(m,2H),6.94(d,J=8.2Hz,1H),6.80(d,J=8.4 Hz,1H),5.90–5.66(m,2H),4.06–3.94(m,4H),3.85(s,1H),3.66(dd,J=22.7,14.0Hz,2H),3.58–3.50(m,1H),3.37(d,J=23 .2Hz,3H),3.04(t,J=12.4Hz,2H),2.99–2.65(m,5H),2.40(d,J=19.5Hz,2H),2.24(d,J=11.3Hz,2H),2.11(s,2H),2.09(s, 3H),1.99(d,J=12.9Hz,4H),1.90–1.65(m,3H),1.37–1.20(m,3H),0.80(dd,J=55.2,11.8Hz,1H).LCMS-ESI+(m / z):[M+H]C 39 H 48 ClN5O5S: Calculated value: 734.314; Measured value: 734.132.

[0798]

[0799] Example 104.

[0800]

[0801] Example 104 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 1-ethyl-1H-pyrazole-4-carboxylic acid was used. 1H NMR (400MHz, methanol-d4) δ8.43(s,1H),7.93(s,1H),7.65(d,J=8.5Hz,1H),7.34(d,J=8.2Hz,1H),7.26(s,1H),7.06(s,1H ),6.93(dd,J=13.2,8.6Hz,2H),5.97–5.78(m,2H),4.22(q,J=7.3Hz,2H),3.98(d,J=15.3Hz,3H),3.83–3.62(m,2H), 3.58(dd,J=8.3,2.9Hz,1H),3.52–3.40(m,2H),3.35(s,3H),3.19–2.99(m,2H),2.86–2.68(m,3H),2.49(s,2H),2.37 –2.24(m,2H),2.08(d,J=12.7Hz,3H),1.94(s,3H),1.83(t,J=6.7Hz,2H),1.46(t,J=7.3Hz,3H).LCMS-ESI+(m / z):H+ C 37 H 44 ClN5O5S: Calculated value: 706.22824; Measured value: 706.194.

[0802] Example 105.

[0803] Example 105 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid, 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid was used. ¹H NMR (400 MHz, chloroform-d) δ 7.73 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.86 (dt, J = 15.8, 5.2 Hz, 1H), 5.73 (dd, J = 15.9, 7.5 Hz, 1H), 4.15 (s, 2 H),4.12-3.92(m,4H),3.92-3.63(m,4H),3.55(dddd,J=20.5,11.9,6.3,3.2Hz,3H),3.32-3.25(m,4H),3.01(dd,J=14 .9,11.0Hz,1H),2.84-2.66(m,3H),2.50-2.18(m,4H),2.14-1.56(m,12H),1.47-1.18(m,2H).LCMS-ESI+(m / z):[M+H]+ C 38 H 48ClN3O7S: Calculated value: 726.29; Measured value: 726.22.

[0804]

[0805] Example 106.

[0806]

[0807] Step 1: Following the same method as in Example 1 (Steps 4 and 5), N'-(tert-butyldimethylsilyl)hex-5-ene-1-iminosulfonamide was prepared by replacing (2R,3S)-3-methylhex-5-ene-2-sulfonamide with (S)-2-methylpent-4-ene-1-sulfonamide. ¹H NMR (400MHz, chloroform-d) δ 5.75 (ddt, J = 19.5, 9.5, 7.0Hz, ¹H), 5.06 (d, J = 1.4Hz, ¹H), 5.03 (dq, J = 5.1, 1.7Hz, ¹H), 4.75 (d, J = 7.7Hz, 2H), 3.13 (ddd, J = 18.6, 13.7, 4.6Hz, 1H), 2.91 (ddd, J = 22.5, 13.8, 7.1Hz, 1H), 2.32–2.16 (m, 2H), 2.16–2.02 (m, 2H), 1.10 (dd, J = 6.6, 4.2Hz, 3H), 0.88 (s, 9H), 0.10 (d, J = 3.0Hz, 6H).

[0808] Step 2: Preparation of Intermediate 106-2: To a solution of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazacycloheptatriene-3,1'-naphthalene]-7-carboxyl chloride (1.56 g, 3.11 mmol) in acetonitrile (6 mL), a solution of pyridazine (0.22 mL, 3.11 mmol) in acetonitrile (6 mL) was added, followed by a solution of (2S)-N'-(tert-butyldimethylsilyl)-2-methylpent-4-ene-1-iminosulfonamide (0.9 g, 3.27 mmol) in acetonitrile (6 mL). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0-50% hexane solution of EtOAc).

[0809] Step 3: Preparation of Intermediate 106-3: In an ice bath, triethylamine (0.69 mL, 4.92 mmol) was added to a 15 mL solution of intermediate 106-2 (1.54 g, 2.46 mmol) in CH2Cl2 under stirring, followed by di-tert-butyl dicarbonate (0.81 g, 3.69 mmol) and 4-(dimethylamino)pyridine (120.17 mg, 0.98 mmol). The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography. The fraction was concentrated, dissolved in EtOAc, washed with 1% HCl solution, and then washed with saturated NaHCO3 aqueous solution. The organic phase was dried over MgSO4, filtered, concentrated, and the residue was purified again by silica gel column chromatography to obtain the desired product.

[0810] Step 4: Preparation of Intermediate 106-4: The reaction mixture of intermediate 106-3 (330 mg, 0.45 mmol), Hoveyda-Grubbs second-generation catalyst (85.18 mg, 0.14 mmol), and 1,2-dichloroethane (150 mL) was degassed with argon. The reaction mixture was stirred overnight at 60 °C. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography. Two diastereomers were separated (the less polar product was 106-4).

[0811] Step 5: Preparation of Example 106: Example 106 was synthesized using the same method as in Example 18, with 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid (3.61 mg, 0.023 mmol) instead of 3-methoxypropionic acid and the less polar diastereomeric intermediate 106-4 (9 mg, 0.015 mmol). 1H NMR (400MHz, methanol-d4) δ7.76(d,J=8.5Hz,1H),7.27(d,J=8.5Hz,1H),7.19(dd, J=8.5,2.4Hz,1H),7.15-7.06(m,2H),6.91(d,J=8.2Hz,1H),6.10(dt,J=14. 7,7.0Hz,1H),5.63(dd,J=15.3,8.4Hz,1H),4.22(s,2H),4.15(dd,J=14.8,6 .9Hz,1H),4.11-4.01(m,2H),4.00-3.92(m,2H),3.92-3.81(m,2H),3.77(d, J=8.0Hz,1H),3.71(td,J=10.0,9.4,4.9Hz,2H),3.53-3.45(m,2H),3.29(s, 3H),3.07(dd,J=15.1,9.7Hz,2H),2.93-2.69(m,3H),2.48(d,J=21.0Hz,3H) ,2.37-2.06(m,4H),2.06-1.88(m,4H),1.88-1.73(m,3H),1.65(dtt,J=13.4 ,9.0,4.3Hz,2H),1.45(t,J=12.1Hz,1H),1.15(d,J=6.8Hz,3H).LCMS-ESI+:C 39 H 50 ClN3O7S: Calculated value: 740.3 (M+H); Measured value: 740.0 (M+H).

[0812] Example 107.

[0813]

[0814] Example 107 was synthesized using intermediate 106-4 obtained from Example 106 and cyclopropylmethylamine, following the same method as in Example 75. 1H NMR (400MHz, methanol-d4) δ7.73(d,J=8.4Hz,1H),7.24(d,J=8.3Hz,1H),7.12(d,J= 11.4Hz,2H),7.02(s,1H),6.89(d,J=8.2Hz,1H),6.06(dd,J=14.6,7.3Hz,1H) ,5.60(dd,J=15.3,8.8Hz,1H),4.25(dd,J=14.9,6.7Hz,1H),4.11–3.99(m,2H ),3.84(d,J=15.1Hz,2H),3.78(dd,J=8.9,3.5Hz,1H),3.67(d,J=14.2Hz,1H) ,3.28(s,3H),3.13–3.01(m,3H),2.88–2.69(m,2H),2.46(dt,J=23.9,13.6Hz ,3H),2.18(ddd,J=36.0,20.5,10.7Hz,3H),1.99–1.89(m,3H),1.79(dt,J=17 .4,9.2Hz,3H),1.43(t,J=11.9Hz,1H),1.31(s,1H),1.14(d,J=6.6Hz,3H),1. 08–0.97(m,1H),0.57–0.47(m,2H),0.25(dt,J=5.9,4.4Hz,2H).LCMS-ESI+:C 37 H 47 ClN4O5S: Calculated value: 695.3 (M+H); Measured value: 694.8 (M+H).

[0815] Example 108.

[0816]

[0817] Example 108 was synthesized using the same method as in Example 18, but instead of 3-methoxypropionic acid and intermediate 49-3, 2-((tetrahydro-2H-pyran-4-yl)oxy)acetic acid was used. 1¹H NMR (400MHz, methanol-d⁴) δ 7.75 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H), 7.16–7.12 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.00–5.93 (m, 1H), 5.59 (dd, J = 15.2, 9.2 Hz, 1H), 4.38–4.32 (m, 1H), 4.18 (s, 2H), 4.00–3.93 (m, 2H), 3.83 (d, J = 14.8 Hz) z,1H),3.76-3.65(m,3H),3.52-3.45(m,3H),3.37-3.34(m,3H),3.24(s,3H),3.16-3.06(m,1H),2.86-2.73(m,3H),2.49-1 .72(m,12H),1.67-1.58(m,2H),1.54(d,J=6.8Hz,3H),1.50-1.42(m,1H),1.14(d,J=6.8Hz,3H).LCMS-ESI+(m / z):[M+H]+C 40 H 52 ClN3O7S: Calculated value: 754.4; Measured value: 754.2.

[0818] Example 109

[0819] Method 1

[0820]

[0821] Step 1: Under an argon atmosphere, (4S)-5-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonamide]-4-methyl-pent-1-ene (106-1, 14.9 g, 53.9 mmol) was azeotropically dissolved in anhydrous toluene (3 x 50 mL) and dissolved in anhydrous tetrahydrofuran (250 mL). The solution was cooled to -50 °C (internal temperature probe). A 2.5 M n-BuLi hexane solution (46.3 mL, 116 mmol) was added dropwise over 5 minutes. The mixture was stirred for 15 minutes. Simultaneously, (4-nitrophenyl)[(1S)-1-phenylethyl] carbonate (5-3-1, 20.1 g, 70.1 mmol) was azeotropically dissolved in toluene (3 x 50 mL) under an argon atmosphere. The solution was added to the reaction mixture through a sleeve over 5 minutes. The reaction was initially yellow, but turned very dark (green). After 15 minutes, the reaction was heated to 0°C (ice bath). Upon heating, the reactants turned yellow. After 1 hour, TLC (20% ethyl acetate / hexane, observed with KMnO4 staining) showed that the reaction was complete. The reaction was quenched with water (150 mL) at 0°C. Ethyl acetate (150 mL) was added. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 75 mL). The combined organic phases were washed with saturated NaHCO3 (150 mL) and brine (150 mL). The organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure to give crude N-[N-[tert-butyl(dimethyl)silyl]-S-[(2S)-2-methylpent-4-enyl]sulfonamide]carbamate [(1S)-1-phenylethyl] ester (109-1-1).

[0822] Step 2: At 0°C, a tetrabutylammonium fluoride solution in tetrahydrofuran (1.0 M, 63.6 mL, 63.6 mmol) was added to an anhydrous tetrahydrofuran solution of 109-1-1 (22.5 g, 53.0 mmol). The reaction was complete after 90 minutes at 0°C. The solvent was removed under reduced pressure. The residue was diluted with water (150 mL) and ethyl acetate (150 mL). The phases were separated, and the aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to rapid chromatography (0-65% ethyl acetate / hexane 120 g gold Teledyne ISCO column with solid support). Evaporative laser scattering detector (ELSD) and ultraviolet light were used for peak detection. Fractions containing the product were combined and the solvent removed under reduced pressure to give ((2S)-2-methylpent-4-en-1-ylsulfonyl)carbamate, a mixture of diastereomers at the sulfur content. The solid was separated by chiral SFC using a ChiralPak IC column with ethanol as a co-solvent. Alternatively, methanol was used as a co-solvent on a ChiralPak AD-H column. Fractions containing the same diastereomers were combined and the solvent removed under reduced pressure to give ((2S)-2-methylpent-4-en-1-ylsulfonyl)carbamate (S)-1-phenylethyl ester, two diastereomers.

[0823] The first eluted diastereomer (10⁹⁻¹⁻², Rt = 3.05 min, on ChiralPak IC, using 15% ethanol as a co-solvent, as temporarily specified absolute stereochemistry in the figure): 1 H NMR (400MHz, chloroform-d) δ7.43–7.33(m,4H),7.33–7.29(m,1H),5.74(q,J=6.7Hz ,1H),5.62(ddt,J=16.0,11.0,7.1Hz,1H),5.05(d,J=1.3Hz,1H),5.04–4.99 (m,1H),3.43(dd,J=14.4,4.5Hz,1H),3.06(dd,J=14.4,7.9Hz,1H),2.30–2 .20(m,1H),2.20–2.04(m,2H),1.59(d,J=6.7Hz,3H),1.14(d,J=6.7Hz,3H).

[0824] The second eluted diastereomer (10⁹⁻¹⁻³, Rt = 4.92 min, on ChiralPak IC, using 15% ethanol as a co-solvent, as shown in the figure for the provisional absolute stereochemistry): 1H NMR (400MHz, chloroform-d) δ7.44–7.32(m,4H),7.32–7.30(m,1H),5.79–5.73(m,1H),5.73–5.66(m,1H),5.16–5.05(m,2H),3.38(dd,J=14.5,4 .4Hz,1H),3.20(dd,J=14.4,7.7Hz,1H),2.27(dq,J=12.5,6.8Hz,1H),2.22–2.10(m,2H),1.59(d,J=6.7Hz,3H),1.14(d,J=6.7Hz,3H).

[0825] Step 3: i) Preparation of (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptanetriene-3,1'-naphthalene]-7-carboxylic acid (109-1-4): Methyl (S)-6'-chloro-5-(((1R,2R)-2-((S)-1-methoxyallyl)cyclobutyl)methyl)-3',4,4',5-tetrahydro-2H,2'H-spiro[benzo[b][1,4]oxazetane-heptanetriene-3,1'-naphthalene]-7-carboxylic acid 1-3 (11.2 g, 22.5 mmol) was heated in 2N The mixture was stirred overnight at 60°C in a NaOH aqueous solution (10 mL) and a MeOH / THF (1 / 1) mixture (200 mL). After cooling, the mixture was neutralized with HCl and concentrated. The resulting solid was suspended in water and then extracted with DCM. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give 109-1-4, which could be used without further purification. LCMS-ESI+(m / z): [M+H]+ C 28 H 32 ClNO4: Calculated value: 482.20; Measured value: 482.14.

[0826] ii) Preparation of intermediate 109-1-5: Intermediate 109-1-2 (the first eluted diastereomer) (6.17 g, 19.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (7.62 g, 39.75 mmol), and 4-(dimethylamino)pyridine (4.21 g, 34.46 mmol) were added to a 200 mL solution of intermediate 109-1-4 under stirring. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then diluted with DCM and washed with 1N HCl and brine. The organic phase was dried over MgSO4, filtered, and concentrated to give 109-1-5, which could be used further without purification.

[0827] Step 4: Add 25 mL of TFA to a DCM (130 mL) solution of intermediate 109-1-5 (12.7 g, 16.4 mmol). Stir the reaction mixture at room temperature. After the reaction is complete, remove the solvent under vacuum. Dissolve the residue in DCM and wash with saturated NaHCO3 solution. Separate the organic phase, dry over MgSO4, filter, and concentrate to obtain 109-1-6, which can be used further without purification.

[0828] Step 5: Add triethylamine (4.45 mL, 31.94 mmol), 4-(dimethylamino)pyridine (500 mg, 4.09 mmol), and di-tert-butyl dicarbonate (5.23 g, 23.95 mmol) to a DCM solution of intermediate 109-1-6 (10 g, 15.97 mmol). Stir the reaction mixture overnight at room temperature. Wash the reaction mixture with 1N HCl (aqueous solution) and brine. Separate the organic phase, dry to MgSO4, filter, concentrate, and purify by silica gel column chromatography (0-100% EtOAc / hexane) to obtain intermediate 109-1-7.

[0829] Step 6: Intermediate 109-1-7 (1 g, 1.38 mmol) and Hoveyda-Grubbs II (258.13 mg, 0.41 mmol) were degassed with argon in 1,2-dichloroethane (400 mL). The reaction mixture was stirred overnight at 60 °C. The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO2, 0-70% EtOAc / hexane) to obtain Example 109. 1H NMR (400MHz, chloroform-d) δ7.76 (d, J=8.5Hz, 1H), 7.43 (dd, J=8.2, 1.9Hz, 1H), 7.32 ( d,J=2.0Hz,1H),7.20(dd,J=8.5,2.3Hz,1H),7.10(d,J=2.3Hz,1H),6.93(d,J =8.2Hz,1H),6.27(ddd,J=15.1,7.9,5.2Hz,1H),5.99(s,2H),5.56(dd,J=15. 3,8.2Hz,1H),4.20(s,2H),4.06(t,J=11.4Hz,2H),3.92–3.82(m,1H),3.82–3 .69(m,2H),3.47(d,J=5.6Hz,2H),3.36(d,J=14.6Hz,1H),3.28(s,3H),3.02( dd,J=15.0,11.0Hz,1H),2.80(dt,J=11.3,5.1Hz,2H),2.63–2.53(m,1H),2.4 7–2.36(m,2H),2.26(dt,J=14.4,7.3Hz,2H),2.03–1.84(m,3H),1.84–1.57(m ,4H),1.41(t,J=13.4Hz,1H),1.16(d,J=6.1Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 32 H 40 ClN3O4S: Calculated value: 598.2; Measured value: 598.1.

[0830] Method 2

[0831]

[0832] Step 1: At 0°C, triethylamine (1.48 mL, 10.63 mmol) and trifluoroacetic anhydride (1 mL, 7.08 mmol) were added to a 50 mL DCM solution of intermediate 109-1-3 (the second diastereomer eluted from Step 2 of Example 109-Method 1, 1.1 g, 3.54 mmol). The reaction mixture was stirred at 0°C for 30 minutes. The reaction was quenched with brine. The reaction mixture was then diluted with DCM and washed with a saturated NaHCO3 solution. The organic phase was separated, dried over MgSO4, filtered, and concentrated to give intermediate 109-2-1, which could be used further without purification.

[0833] Step 2: Add TFA (10 mL) to a DCM (30 mL) solution of intermediate 109-2-1 (1.4 g, 3.44 mmol). Stir the reaction mixture at room temperature. After completion, concentrate the reaction mixture and purify the residue by silica gel column chromatography (0-50% EtOAc / hexane) to obtain intermediate 109-2-2.

[0834] Step 3: To a DCM (200 mL) solution of intermediate 109-1-4 (1.5 g, 3.11 mmol) under stirring, add intermediate 109-2-2 (790 mg, 3.06 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (1.5 g, 7.78 mmol), and 4-(dimethylamino)pyridine (760 mg, 6.22 mmol). Stir the reaction mixture overnight at room temperature. Then dilute the reaction mixture with DCM and wash with 1N HCl and brine. Dry the organic phase over MgSO4, filter, concentrate, and purify the residue by silica gel column chromatography (0-100% EtOAc / hexane) to obtain intermediate 109-2-3.

[0835] Step 4: Add TFA (0.02 mL, 0.2 mmol) and Hoveyda-Grubbs second-generation catalyst (12.46 mg, 0.02 mmol) to a DCE (10 mL) solution of intermediate 109-2-3 (72 mg, 0.1 mmol). Degas the reaction mixture with argon and then stir overnight at 60 °C. Concentrate the reaction mixture and purify the residue by silica gel column chromatography (0-100% EtOAc / hexane) to obtain intermediate 109-2-4.

[0836] Step 5: Potassium carbonate (129.4 mg, 0.94 mmol) was added to a solution of intermediate 109-2-4 (130 mg, 0.19 mmol) in MeOH (10 mL) and H₂O (2 mL). The reaction mixture was stirred overnight at 60 °C. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with water, and extracted with ethyl acetate. The organic phase was separated, dried over MgSO₄, filtered, concentrated, and purified by silica gel column chromatography (0-70% EtOAc / hexane) to obtain Example 109.

[0837] Method 3

[0838] Step 1: At -40°C, add n-butyllithium (1.6M hexane solution, 1.87mL) to a THF (10mL) solution of intermediate 106-1 (690mg, 2.5mmol). Stir the resulting mixture at -40°C for 20 minutes. Then, add dropwise a THF (6mL) solution of (4-nitrophenyl)[(1S)-1-phenylethyl] carbonate (5-3-1, 1.43g, 4.99mmol), and warm the reaction mixture to room temperature and stir for 3 hours. Quench the reaction with water and extract with EtOAc. Separate the organic layer, dry to MgSO4, filter, and concentrate. Purify the residue by silica gel column chromatography (0-20% EtOAc / hexane). Separate the two diastereomers.

[0839]

[0840] The first eluted diastereomer (109-3-1, tentatively designated absolute stereochemistry as shown in the figure): 1 HNMR (400MHz, chloroform-d) δ7.49–7.29 (m, 5H), 5.84 (dq, J = 23.2, 6.6Hz, 1H), 5. 74–5.47(m,1H),5.08–4.93(m,2H),3.32(dd,J=14.1,4.6Hz,1H),3.18–2. 95(m,1H),2.29–2.10(m,2H),2.03(ddt,J=13.8,6.9,1.3Hz,1H),1.59(d ,J=6.6Hz,3H),1.09(d,J=6.6Hz,3H),0.93(s,9H),0.21(d,J=3.1Hz,6H).

[0841] The second eluted diastereomer (109-3-2, temporarily designated absolute stereochemistry as shown in the figure): 1 HNMR (400MHz, chloroform-d) δ7.45–7.25(m,5H),5.81(t,J=6.6Hz,1H),5.78–5.63(m,1H),5.11–4.95(m,2H),3.40(dd,J=13.9,4.2Hz,1H),3.07(dd, J=14.0,7.5Hz,1H),2.27–2.13(m,2H),2.13–2.07(m,1H),1.59(d,J=6.6Hz,3H),1.09(dd,J=6.7,3.2Hz,3H),0.88(s,9H),0.17–0.09(m,6H).

[0842] Step 2: In an ice bath, tetrabutylammonium fluoride (1.0 M THF, 0.14 mL) was slowly added to a THF (5 mL) solution of intermediate 109-3-1 (40 mg, 0.094 mmol) under stirring. The reaction mixture was stirred at 0 °C for 20 min and then slowly warmed to room temperature. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (0-60% EtOAc / hexane) to give intermediate 109-1-2. 1H NMR (400MHz, chloroform-d) δ7.42-7.37(m,2H),7.37-7.24(m,3H),5.72(q,J=6.6Hz,1H),5.62(ddt,J=15.9,11.1,7.1Hz,1H),5.51(s,2H),5.07- 4.97(m,2H),3.42(dd,J=14.4,4.5Hz,1H),3.06(dd,J=14.4,7.9Hz,1H),2.33-2.01(m,3H),1.57(d,J=6.7Hz,3H),1.12(d,J=6.8Hz,3H).

[0843] Method 4

[0844]

[0845] Step 1: Following a method similar to Step 2 of Method 3 (Example 109), intermediate 109-1-3 was also prepared using intermediate 109-3-2 instead of intermediate 109-3-1. Example 109 was synthesized using intermediate 109-1-3 following the same method as in Example 109 (Method 2).

[0846] Example 110

[0847] Method 1

[0848] Step 1: Under an argon atmosphere, 1-[S-amino-N-[tert-butyl(dimethyl)silyl]sulfonamide]hexane (1-5, 5.9 g, 20.1 mmol) was azeotropically dissolved in anhydrous toluene (3 x 20 mL) and in anhydrous tetrahydrofuran (150 mL). The solution was cooled to -50 °C (internal temperature probe). A 2.5 Mn-BuLi hexane solution (17.3 mL, 43.3 mmol) was added dropwise over 5 minutes. The mixture was stirred for 15 minutes. Simultaneously, (4-nitrophenyl)[(1S)-1-phenylethyl] carbonate (5-3-1, 7.5 g, 26.2 mmol) was azeotropically dissolved in toluene (3 x 20 mL) under an argon atmosphere and in anhydrous tetrahydrofuran (60 mL). The solution was added to the reaction mixture over 5 minutes via a sleeve. The reaction was initially yellow but became very dark (green). After 15 minutes, the reaction was heated to 0°C (ice bath). The reactants turned yellow upon heating. After 1 hour, TLC (20% EtOAc / hexane, observed with KMnO4 staining) showed that the reaction was complete. The reaction was quenched with water (75 mL) at 0°C. EtOAc (50 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaHCO3 (75 mL) and brine (75 mL). The organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure to give crude N-[N-[tert-butyl(dimethyl)silyl]-S-[(1R,2S)-1,2-dimethylpent-4-enyl]sulfonamide]carbamate [(1S)-1-phenylethyl] ester (110-1-1).

[0849] Step 2: At 0°C, TBAF solution (1.0 M, 19.7 mL, 19.7 mmol) was added to anhydrous THF solution of 110-1-1 (6.64 g, 15.1 mmol). The reaction was complete after 1 hour at 0°C. THF was removed under reduced pressure. The residue was diluted with water (80 mL) and EtOAc (80 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to rapid chromatography (0-65% EtOAc / hexane 120 g Gold ISCO column with solid loading). ELSD and UV were used for peak detection. The fractions containing the product were combined and the solvent was removed under reduced pressure to give N-[[(1R,2S)-1,2-dimethylpent-4-enyl]sulfonyl]carbamate [(1S)-1-phenylethyl] ester, a mixture of diastereomers at the sulfur. This solid was then subjected to chiral SFC separation using methanol as a co-solvent and a ChiralPak IC column.

[0850] The first eluted diastereomer (110-1-2, RT = 2.37 min, on ChiralPak IC, using 15% methanol as a co-solvent, as temporarily specified absolute stereochemistry is shown in the figure). 1H NMR (400MHz, chloroform-d) δ7.45–7.33(m,4H),7.33–7.30(m,1H),5.73(q,J=6.7Hz, 1H),5.48(dddd,J=16.4,10.1,8.2,6.0Hz,1H),5.06–4.93(m,2H),3.41(qd,J =7.0,2.2Hz,1H),2.53–2.39(m,1H),2.07(dt,J=14.0,6.2Hz,1H),2.00–1.8 6(m,1H),1.59(d,J=6.7Hz,3H),1.34(d,J=7.0Hz,3H),1.02(d,J=6.8Hz,3H).

[0851] The second eluted diastereomer (110-1-3, Rt = 3.92 min, on ChiralPak IC, using 15% methanol as a co-solvent, as temporarily specified absolute stereochemistry is shown in the figure). 1H NMR (400MHz, chloroform-d) δ7.43–7.32(m,4H),7.33–7.29(m,1H),5.75(q,J=6.6Hz, 1H),5.71–5.62(m,1H),5.13–5.03(m,2H),3.38(qd,J=7.1,2.3Hz,1H),2.47 (dtd,J=8.9,6.9,2.2Hz,1H),2.11(dtt,J=13.1,6.5,1.4Hz,1H),2.07–1.96 (m,1H),1.59(d,J=6.7Hz,3H),1.31(d,J=7.0Hz,3H),1.04(d,J=6.9Hz,3H).

[0852] Example 110 was synthesized using intermediate 110-1-2 instead of intermediate 109-1-2, following the same method as in Example 109 (Method 1-Steps 3-6). ¹H NMR (400MHz, chloroform-d) δ 7.778 (d, J = 8.5Hz, 1H), 7.45 (dd, J = 8.3, 1.9Hz, 1H), 7.30 (d, J = 2.0Hz, 1H), 7.20 (dd, J = 8.5, 2.3Hz, 1H), 7.10 (d, J = 2.4Hz, 1H), 6.93 (d, J = 8.3Hz, 1H), 5.91 (dt, J = 15.8, 5.8Hz, 1H), 5.69 (dd, J = 15.8, 6.8Hz, 1H), 4.18–3.95 ( m,2H),3.87(dd,J=14.9,3.4Hz,1H),3.73(s,5H),3.41–3.23(m,4H),3.01(dd,J=15.0,10.9Hz,1H),2.89–2.72(m,2H),2 .62(s,2H),2.46(s,1H),2.31–2.01(m,3H),1.99–1.64(m,6H),1.46(s,3H),1.11(d,J=6.9Hz,3H).LCMS-ESI+(m / z):H+C 33 H 42 ClN3O4S: Calculated value: 612.26; Measured value: 612.06.

[0853] Method 2:

[0854]

[0855] Step 1: Under argon atmosphere, TEA (2.32 mL, 16.64 mmol) was added to an anhydrous dichloromethane solution of ice-cold intermediate 110-1-3 (the second eluted diastereomer from Example 110-Method 1-Step 2, 3.6 g, 11.10 mmol) and trifluoroacetic anhydride (3.5 g, 16.64 mmol), and the solution was stirred for 30 minutes. The reaction mixture was concentrated to give intermediate 110-2-1.

[0856] Step 2: Add intermediate 110-2-1 (4.2 g, 9.98 mmol) to the stirred dichloromethane / trifluoroacetic acid (3 / 1) (200 mL) mixture. Stir the mixture overnight at room temperature. Remove the solvent under reduced pressure. Then add water and extract the mixture with dichloromethane. Dry the organic phase over anhydrous magnesium sulfate and remove the solvent under reduced pressure. The residue obtained was purified by normal-phase chromatography (SiO2, 1:2Hex:EtOAc) to give intermediate 110-2-2. ¹H NMR (400MHz, chloroform-d) δ 5.70 (dddd, J = 17.0, 10.2, 8.3, 5.8Hz, 1H), 5.58 (s, 2H), 5.22–5.01 (m, 2H), 3.56 (qd, J = 7.0, 2.2Hz, 1H), 2.63–2.42 (m, 1H), 2.19 (dtt, J = 15.1, 6.0, 1.6Hz, 1H), 2.05–1.91 (m, 1H), 1.43 (d, J = 7.0Hz, 3H), 1.08 (d, J = 6.8Hz, 3H).

[0857] Step 3: Add EDCI (2.5 g, 16.6 mmol) and DMAP (2.0 g, 16.6 mmol) to a DCM solution of intermediate 109-1-4 (4.0 g, 8.29 mmol) under stirring. Stir the reaction mixture at room temperature for 10 minutes. Add intermediate 110-2-2 (2.4 g, 9.13 mmol), and stir the resulting suspension overnight at room temperature. Quench the reaction mixture with water and wash with DCM, NaHCO3 aqueous solution, 1N HCl aqueous solution, and brine. Dry the organic layer with Mg2SO4 and remove the solvent under reduced pressure to obtain a crude residue, which is subjected to column chromatography (SiO2, 50-90% Hex / EtOAc) to obtain the desired intermediate 110-2-3.

[0858] Step 4: Intermediate 110-2-3 (1.2 g, 1.57 mmol), TFA (360 mg, 3.15 mmol), and Hoveyda Grubbs second-generation catalyst (196 mg, 0.32 mmol) were stirred at 60 °C for 2 hours in 1,2-dichloroethane (150 mL). More catalyst (196 mg, 0.32 mmol) was added, and the mixture was stirred at 60 °C for 24 hours. After concentration, the residue was purified by silica gel column chromatography (5-95% Hex / EtOAc) to obtain intermediate 110-2-4.

[0859] Step 5: Add water (2 mL) to a 10 mL MeOH solution of intermediate 110-2-4 (200 mg, 0.28 mmol) under stirring, followed by the addition of K₂CO₃ (195 mg, 1.41 mmol). Stir the reaction mixture at 60 °C for 24 hours. Evaporate the mixture under reduced pressure and then dissolve it in DCM. Add water and then extract the mixture with DCM. Wash the combined organic layers with brine, dry to Mg₂SO₄, filter, concentrate, and purify by silica gel column chromatography (50-90% hexane / EtOAc) to obtain Example 110.

[0860] Method 3:

[0861] Step 1: At -50°C, n-butyllithium (1.6M hexane solution, 4.6mL, 7.40mmol) was added dropwise to a THF (50mL) solution of intermediates 1-5 (Example 1-Step 5, 1g, 3.44mmol) over 5 minutes. The mixture was stirred for 15 minutes. Simultaneously, (4-nitrophenyl)[(1S)-1-phenylethyl] carbonate (5-3-1, 1.3g, 4.47mmol) was azeotropically reacted with toluene (3 x 20mL). Under an argon atmosphere, the substance was dissolved in anhydrous tetrahydrofuran (30mL). This solution was added to the reaction mixture through a sleeve over 5 minutes. The reaction was initially yellow but became very dark (green). After 15 minutes, the reaction was warmed to 0°C (ice bath). The reactants turned yellow upon warming. After 3 hours, TLC (20% EtOAc / hexane, observed with KMnO4 staining) showed that the reaction was complete. The reaction was quenched with water (75 mL) at 0 °C. EtOAc (50 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with saturated NaHCO3 (75 mL) and brine (75 mL). The organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was redissolved in hexane and purified by rapid column chromatography (silica gel, 0 to 100% dichloromethane in hexane, ELSD detector). The ELSD-active fraction was determined by silica gel TLC (3:1 hexane: ethyl acetate, KMnO4 staining); the diastereomer was eluted together with the product in 70–100% dichloromethane. The crude product mixture was redissolved in hexane and purified again by rapid column chromatography (silica gel, 0 to 20% ethyl acetate in hexane, ELSD detector). ELSD-active fraction was determined by silica gel TLC (3:1 hexane: ethyl acetate, KMnO4 staining). The first elution peak eluted in 10% ethyl acetate (110-3-1, as shown in the figure, the provisional absolute stereochemistry), while the subsequent elution peak eluted in 15% ethyl acetate (110-3-2, as shown in the figure, the provisional absolute stereochemistry).

[0862]

[0863] Step 2: At 0°C, TBAF solution (1.0 M, 2.84 mL, 2.84 mmol) was added to an anhydrous THF solution of intermediate 110-3-1 (830 mg, 1.89 mmol). The reaction was complete after 60 minutes at 0°C. The solvent was removed under reduced pressure. The residue was diluted with water (80 mL) and EtOAc (80 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to rapid chromatography (0-50% EtOAc / hexane, 80 g silica gel). ELSD and UV were used for peak detection. The fractions containing the product were combined, and the solvent was removed under reduced pressure to obtain intermediate 110-1-2.

[0864] Preparation of Example 110: Example 110 was synthesized using intermediate 110-1-2 in the same manner as in Example 110 (Method 1).

[0865] Method 4:

[0866]

[0867] Step 1: Following a method similar to Step 2 of Method 3 (Example 110), intermediate 110-1-3 was also prepared by using intermediate 110-3-2 instead of intermediate 110-3-1.

[0868] Preparation of Example 110: Example 110 was synthesized using intermediate 110-1-3 in the same manner as in Example 109 (Method 2).

[0869] Example 111

[0870]

[0871] At room temperature, 1.7 mL of ACN was added to a mixture of Example 109 (10 mg, 0.0167 mmol) in DCM (0.6 mL). Then, 10.2 mg of 4-dimethylaminopyridine (0.0836 mmol) and 28.6 mg of diphenyl carbonate (0.134 mmol) were added to the mixture, and the mixture was stirred at room temperature. After 5 hours, 12.7 mg of pyrimidine-2-amine (0.134 mmol) was added, and the reaction was heated at 60 °C for 5 hours, and then allowed to stand overnight at room temperature. The reaction was concentrated, dissolved in DMF (1.2 mL), filtered, and purified by Gilson reversed-phase preparative HPLC, eluting with 60–100% ACN / H₂O containing 0.1% TFA. 1 H NMR (400MHz, methanol-d4) δ8.73(d,J=5.1Hz,2H),7.76(d,J=8.5Hz,1H),7.38–6.82(m,7H),6.14(dq,J=14.4 ,6.6Hz,1H),5.62(dd,J=15.4,8.3Hz,1H),4.21(dd,J=14.8,6.3Hz,1H),4.12–4.01(m,3H),3.91–3.64( m,3H),3.29(s,3H),3.08(dd,J=15.2,10.0Hz,1H),2.89–2.71(m,2H),2.60–2.37(m,3H),2.32–2.06(m ,3H),2.02–1.67(m,7H),1.45(t,J=11.1Hz,1H),1.15(dd,J=8.4,6.3Hz,3H).LCMS-ESI+(m / z):[M+H]+C 37 H 43 ClN6O5S: Calculated value: 719.2; Measured value: 719.5.

[0872] Example 112

[0873]

[0874] Example 112 was synthesized using the same method as in Example 111, with (3S)-tetrahydrofuran-3-amine hydrochloride instead of pyrimidine-2-amine, and Hunig base (8.64 mg, 0.0669 mmol) added to the reaction. ¹H NMR (400 MHz, methanol-d⁴) δ 7.74 (d, J = 8.5 Hz, 1H), 7.24–7.10 (m, 3H), 7.03–6.88 (m, 2H), 6.23–5.97 (m, 1H), 5.64–5.50 (m, 1H), 4.37–4.21 (m, 2H), 4.11–4.01 (m, 2H), 3.98–3.75 (m, 6H), 3.72–3.48 (m, 3H) ),3.28(s,3H),3.08(dd,J=15.3,10.2Hz,1H),2.89–2.71(m,2H),2.57–2.33(m,3H),2.31–2.09( m,3H),1.98–1.73(m,8H),1.44(t,J=11.8Hz,1H),1.14(d,J=6.6Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 37 H 47 ClN4O6S: Calculated value: 711.3; Measured value: 710.8.

[0875] Example 113

[0876]

[0877] To a mixture of 1-methylpyrazol-4-carboxylic acid (3.76 mg, 0.0298 mmol) in DCM (1.0 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (5.71 mg, 0.0298 mmol) and 4-dimethylaminopyridine (3.64 mg, 0.0298 mmol) were added. The mixture was stirred at room temperature for 5 minutes, then Example 5 (8.7 mg, 0.0149 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was then concentrated, dissolved in DMF (1.2 mL), filtered, and purified by Gilson reversed-phase preparative HPLC, eluting with 60–100% ACN / H2O containing 0.1% TFA, to give Example 113. 1H NMR (400MHz, methanol-d4) δ8.42(s,1H),7.91(s,1H),7.65(d,J=8.6Hz,1H),7.36(d,J=8.0Hz,1H),7.26(s,1H),7.07(d,J=2.1Hz ,1H),6.99–6.83(m,2H),5.98–5.90(m,1H),5.86(dd,J=16.0,8.2Hz,1H),3.97(d,J=29.0Hz,6H),3.77(d,J=15.0Hz,1H),3 .71–3.65(m,2H),3.62–3.55(m,2H),3.47(d,J=14.3Hz,1H),3.37(s,3H),3.16(d,J=26.2Hz,1H),2.88–2.74(m,3H),2.50( s,2H),2.30(d,J=9.2Hz,2H),2.10(d,J=14.0Hz,3H),2.00–1.84(m,4H),1.41(d,J=11.9Hz,1H).LCMS-ESI+(m / z):[M+H]+C 36 H 42 ClN5O5S: Calculated value: 692.2; Measured value: 691.973.

[0878] Example 114

[0879]

[0880] Example 114 was synthesized using the same method as in Example 75, with the materials from Example 109 and methyl 3-aminoazacyclobutane-1-carboxylate. 1H NMR (400MHz, methanol-d4) δ7.72(d,J=8.5Hz,1H),7.17–7.12(m,2H),7.09(d,J=2.3Hz,1H),6.94(s,1H),6.90(d,J=8.2Hz,1H),6.07– 5.89(m,1H),5.57(dd,J=15.3,9.0Hz,1H),4.60–4.41(m,1H),4.25(t,J=8.5Hz,3H),4.13–3.98(m,2H),3.96–3.79(m,3H),3.75 (dd,J=9.0,3.7Hz,1H),3.69–3.62(m,1H),3.66(s,3H),3.29–3.23(m,1H),3.25(s,3H),3.06(dd,J=15.3,10.3Hz,1H),2.88–2. 66(m,2H),2.53–2.28(m,3H),2.24–2.05(m,3H),2.00–1.65(m,7H),1.42(t,J=12.4Hz,1H),1.12(d,J=6.5Hz,3H).LCMS-ESI+:C 38 H 48 ClN5O7S: Calculated value: 754.29 (M+H); Measured value: 753.97 (M+H).

[0881] Example 115

[0882]

[0883] Example 115 was synthesized using the same method as in Example 75, with the materials from Example 109 and (1S,2R)-2-fluorocyclopropylamine. 1H NMR (400MHz, methanol-d4) δ7.75(d,J=8.5Hz,1H),7.24–7.15(m,2H),7.12(d,J=2.3Hz,1H),7.03–6.97(m,1H),6.91(d,J=8.2Hz,1H),6.03(d d,J=15.0,7.6Hz,1H),5.59(dd,J=15.2,8.9Hz,1H),4.79–4.54(m,1H),4.29(dd,J=14.9,6.4Hz,1H),4.14–4.01(m,2H),3.91–3.73(m,3 H),3.68(d,J=14.5Hz,1H),3.31–3.24(m,1H),3.27(s,3H),3.07(dd,J=15.2,10.3Hz,1H),2.89–2.72(m,2H),2.68(dt,J=10.2,5.5Hz,1 H),2.57–2.31(m,3H),2.28–2.07(m,3H),2.03–1.65(m,6H),1.44(t,J=12.5Hz,1H),1.24–1.07(m,4H),1.01–0.84(m,1H).LCMS-ESI+: C 36 H 44 ClFN4O5S: Calculated value: 699.27 (M+H); Measured value: 698.73 (M+H).

[0884] Example 116

[0885]

[0886] Example 116 was synthesized using the same method as in Example 75, with the aid of Example 109 and (1R,2S)-2-fluorocyclopropylamine. 1H NMR (400MHz, methanol-d4) δ7.75(d,J=8.5Hz,1H),7.24–7.15(m,2H),7.12(d,J=2.3Hz,1H),7.00(s,1H),6.91(d,J=8.2Hz,1H),6.11–5.97(m,1H),5. 58(dd,J=15.3,8.9Hz,1H),4.66(dtd,J=64.4,5.7,3.2Hz,1H),4.30(dd,J=14.9,6.3Hz,1H),4.15–3.99(m,2H),3.86(d,J=14.8Hz,2H),3.78(dd ,J=9.0,3.7Hz,1H),3.68(d,J=14.6Hz,1H),3.31–3.28(m,1H),3.27(s, 3H),3.07(dd,J=15.2,10.3Hz,1H),2.89–2.71(m,2H),2.67(dt,J=9.4, 5.3Hz,1H),2.55–2.30(m,3H),2.26–2.08(m,3H),2.01–1.67(m,6H),1. 44(t,J=12.2Hz,1H),1.21–1.06(m,4H),1.02–0.87(m,1H).LCMS-ESI+:C 36 H 44 ClFN4O5S: Calculated value: 699.27 (M+H); Measured value: 698.65 (M+H).

[0887] Example 117

[0888]

[0889] Example 117 was prepared using (1S,2R)-2-methylcyclopropyl-1-amine hydrochloride, triethylamine, and the method described in Example 109, similar to that of Example 75. ¹H NMR (400 MHz, methanol-d⁴) δ 7.76 (d, J = 8.5 Hz, 2H), 7.38 (s, 2H), 7.18 (d, J = 9.3 Hz, 2H), 7.12 (s, 2H), 6.85 (s, 2H), 6.24 (s, 2H), 5.59 (s, 2H), 4.60 (s, 1H), 4.11–3.97 (m, 4H), 3.83–3.66 (m, 9H), 2.80 (d, J = 19.4 Hz, 4H), 2.63 (s, 3H), 2 .32(s,4H),2.20-2.03(m,5H),1.96(s,6H),1.77(s,6H),1.46(s,3H),1.31(s,1H),1.07(d,J=6.1Hz,23H),0.8 3(ddt,J=12.2,6.1,3.0Hz,3H),0.61(ddd,J=9.0,5.1,3.6Hz,4H),0.51-0.39(m,6H).LCMS–ESI+(m / z):[M+H]C 37 H 47 ClN4O5S: Calculated value: 695.32; Measured value: 694.99.

[0890] Example 118

[0891]

[0892] Synthesis of 5-chloro-1-methyl-1H-pyrrole-3-carboxylic acid: 5-chloro-1H-pyrrole-3-carboxylic acid (0.075 g);

[0893] Add freshly ground potassium hydroxide (KOH (solid)) to 1.0 mL of DMSO solution containing 0.515 mmol;

[0894] 0.231 g; 4.12 mmol). The heterogeneous slurry was stirred for 50 minutes, followed by the addition of methyl iodide (MeI;

[0895] 0.048 mL; 0.109 g; 0.773 mmol). The mixture was stirred at ambient temperature for 4 hours, then diluted with 10 mL CH₂Cl₂ and 10 mL 1N HCl (aqueous solution). The two-phase mixture was stirred for at least 10 minutes, and then the layers were separated. The aqueous layer was extracted with 10 mL isopropyl acetate and 10 mL ethyl acetate. The combined organic phases were washed with 10 mL H₂O and dried over anhydrous Na₂SO₄. The organic phase was concentrated to dryness under vacuum and used directly for the next step (see below) (62 mg; 82.7% yield).1 ¹H NMR (400MHz, DMSO-d⁶) δ 11.98 (s, 1H), 7.47 (d, J = 2.1Hz, 1H), 6.39 (d, J = 2.1Hz, 1H), 3.60 (s, 3H), 2.55 (s, 1H). LCMS-ESI+ (m / z): [M+H]C₆H₆ClNO₂: Calculated value: 160.01; Measured value: 160.07.

[0896] Example 118 was prepared using 5-chloro-1-methyl-1H-pyrrole-3-carboxylic acid and Example 109, following a method similar to that of Example 106. NMR(400MHz, methanol-d4)δ7.74(d,J=8.5Hz,1H),7.38-7.27(m,2H),7.15(dd,J=8.5, 2.4Hz,1H),7.11-7.01(m,2H),6.81(d,J=8.1Hz,1H),6.48(s,1H),6.17(dd,J=1 4.8,7.4Hz,1H),5.51(dd,J=15.4,8.7Hz,1H),4.15(s,1H),4.10(d,J=7.1Hz,0H ),4.09-3.95(m,2H),3.86-3.70(m,2H),3.60(s,4H),3.25(s,4H),3.03(dd,J=15 .0,9.8Hz,1H),2.86-2.67(m,2H),2.59(d,J=10.4Hz,1H),2.41(s,3H),2.22-2. 05(m,4H),1.99(d,J=9.6Hz,2H),1.91(d,J=7.5Hz,2H),1.79(dd,J=19.5,8.7Hz ,1H),1.73(s,2H),1.69(d,J=8.8Hz,0H),1.41(t,J=12.7Hz,1H),1.33-1.19(m, 2H),1.06(d,J=6.5Hz,3H),0.89(dd,J=7.3,3.8Hz,1H).LCMS-ESI+(m / z):[M+H]C 38 H 44 Cl2N4O5S: Calculated value: 739.24; Measured value: 739.75 (M+H).

[0897] Example 119

[0898]

[0899] Example 119 was prepared using 1-(difluoromethyl)-1H-pyrazole-4-carboxylic acid and Example 109, following a method similar to that of Example 18. 1H NMR (400MHz, methanol-d4) δ8.48(s,1H),8.09(s,1H),7.77(d,J=8.5Hz,1H),7.66(s ,0H),7.52(s,1H),7.40–7.32(m,1H),7.18(dd,J=8.5,2.4Hz,1H),7.10(dd,J= 6.4,2.1Hz,2H),6.84(d,J=8.2Hz,1H),6.22(dt,J=14.4,6.9Hz,1H),5.56(dd ,J=15.4,8.6Hz,1H),4.22–3.98(m,3H),3.87–3.74(m,2H),3.78–3.61(m,4H), 3.55(dt,J=11.6,2.8Hz,0H),3.35(s,0H),3.28(s,3H),3.06(dd,J=15.2,10. 2Hz,1H),2.88–2.70(m,2H),2.70–2.61(m,1H),2.52–2.38(m,1H),2.29(s,1H) ,2.21(dt,J=14.1,7.0Hz,1H),2.12(d,J=13.7Hz,1H),1.94(d,J=7.0Hz,3H), 1.88–1.69(m,2H),1.44(t,J=11.9Hz,1H),1.31(s,0H),1.11(d,J=6.8Hz,3H). 19 F NMR (376MHz, methanol-d4) δ -97.35. LCMS-ESI+ (m / z): [M+H]C 37 H 42 ClF2N5O5S: Calculated value: 742.26; Measured value: 742.13.

[0900] Example 120

[0901]

[0902] Example 118 was prepared using 1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid and Example 109, following a similar method to Example 18. 1¹H NMR (400 MHz, methanol-d⁴) δ 8.11 (s, ¹H), 7.92 (s, ¹H), 7.77 (d, J = 8.6 Hz, ¹H), 7.41–7.24 (m, ³H), 7.18 (dd, J = 8.4, 2.3 Hz, ¹H), 7.13–7.06 (m, 2H), 6.83 (d, J = 8.2 Hz, ¹H), 6.22 (dt, J = 14 .4,6.8Hz,1H),5.75–5.67(m,0H),5.55(dd,J=15.4,8.7Hz,1H),5.07(s,0H),4.31(t,J =5.1Hz,2H),4.22–3.97(m,3H),3.84(d,J=14.8Hz,1H),3.82–3.63(m,7H),3.61–3.51( m,0H),3.29(d,J=12.4Hz,5H),3.06(dd,J=15.0,10.0Hz,1H),2.88–2.74(m,2H),2.64( d,J=13.8Hz,1H),2.43(s,2H),2.27(s,1H),2.23–2.08(m,3H),1.94(d,J=6.3Hz,3H),1 .88–1.68(m,2H),1.52(d,J=6.6Hz,1H),1.50–1.38(m,1H),1.31(s,3H),1.10(dd,J=6. 7,3.6Hz,4H),0.93(d,J=5.7Hz,0H),0.90(s,2H),0.12(s,1H).LCMS-ESI+(m / z):[M+H]C 39 H 48 ClN5O6S: Calculated value: 750.30; Measured value: 750.08.

[0903] Example 121

[0904]

[0905] Example 121 was synthesized using (S)-2-hydroxy-3-phenylpropionic acid and Example 109, following the same method as in Example 18. NMR (400MHz, acetonitrile-d3) δ7.72 (d, J=8.5Hz, 1H), 7.36–7.21 (m, 6H), 7.19 (dd, J= 8.6,2.4Hz,1H),7.16–7.10(m,2H),6.88(d,J=8.2Hz,1H),6.01(dt,J=14.0, 6.5Hz,1H),5.57(dd,J=15.5,7.9Hz,1H),4.43(dd,J=8.1,4.2Hz,1H),4.06( d,J=12.1Hz,1H),4.00(d,J=12.1Hz,1H),3.86(s,1H),3.80(d,J=15.3Hz,1H ),3.74–3.66(m,2H),3.34(d,J=14.3Hz,1H),3.20(s,3H),3.17(dd,J=14.1 ,4.2Hz,1H),3.05(dd,J=15.2,10.1Hz,1H),2.94(dd,J=14.0,8.2Hz,1H),2. 86–2.68(m,2H),2.52–2.34(m,3H),2.14(t,J=8.5Hz,2H),2.10–2.00(m,1H) ,1.90–1.59(m,9H),1.41(dt,J=14.6,7.8Hz,1H),1.05(d,J=6.3Hz,3H).19F NMR (376MHz, acetonitrile-d3) δ -77.38. LCMS-ESI+ (m / z): [M+H]+ C 41 H 48 ClN3O6S: Calculated value: 746.3; Measured value: 746.0.

[0906] Example 122

[0907]

[0908] Example 122 was synthesized using (R)-2-hydroxy-3-phenylpropionic acid and Example 109, following the same method as in Example 18. NMR(400MHz, acetonitrile-d3)δ7.73(d,J=8.5Hz,1H),7.36–7.27(m,4H),7.28–7.22(m,1H) ,7.20(dd,J=8.5,2.4Hz,1H),7.14(dd,J=9.3,2.2Hz,2H),6.88(d,J=8.3Hz,1H), 6.00(dt,J=14.6,6.9Hz,1H),5.55(dd,J=15.6,7.9Hz,1H),4.49(dd,J=7.6,4.1H z,1H),4.06(d,J=12.1Hz,1H),4.00(d,J=12.1Hz,1H),3.83–3.75(m,2H),3.75–3. 64(m,2H),3.34(d,J=14.3Hz,1H),3.20(s,3H),3.15(dd,J=14.1,4.1Hz,1H),3.0 4(dd,J=15.1,10.3Hz,1H),2.96(dd,J=14.1,7.6Hz,1H),2.86–2.64(m,2H),2.49– 2.32 (m, 3H), 2.11–1.99 (m, 2H), 1.92–1.57 (m, 10H), 1.40 (dt, J = 15.1, 8.0 Hz, 1H), 0.99 (d, J = 6.9 Hz, 3H). 19F NMR (376 MHz, acetonitrile-d3) δ -77.38. LCMS-ESI+ (m / z): [M+H]+ C 41 H 48 ClN3O6S: Calculated value: 746.3; Measured value: 746.0.

[0909] Example 123

[0910]

[0911] Example 123 was synthesized using 1-cyclopropyl-1H-pyrazole-4-carboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, acetonitrile-d3) δ8.29(s,1H),7.90(d,J=0.6Hz,1H),7.60(d,J=8.5Hz,1H), 7.23(dd,J=8.2,1.9Hz,1H),7.08(d,J=2.3Hz,1H),7.04–6.92(m,2H),6.83(d,J =8.2Hz,1H),6.01(dt,J=13.7,6.6Hz,1H),5.60(dd,J=15.4,8.4Hz,1H),4.54(h ept,J=6.6Hz,1H),4.12(dd,J=14.8,6.3Hz,1H),3.97(s,2H),3.86–3.67(m,3H) ,3.63(d,J=14.4Hz,1H),3.35(d,J=14.4Hz,1H),3.21(s,3H),3.06(dd,J=15.2, 10.2Hz,1H),2.86–2.65(m,2H),2.59(d,J=13.3Hz,1H),2.47–2.32(m,2H),2.19 (dq,J=14.5,7.2Hz,2H),2.08–1.97(m,2H),1.90(d,J=4.0Hz,2H),1.83–1.63(m ,3H),1.46(t,J=6.8Hz,6H),1.34(dt,J=13.3,8.0Hz,1H),1.08(d,J=6.4Hz,3H). 19 F NMR (376MHz, acetonitrile-d3) δ -77.37. LCMS-ESI+ (m / z): [M+H]+ C 39 H 48 ClN5O5S: Calculated value: 734.3; Measured value: 733.8.

[0912] Example 124

[0913]

[0914] Example 124 was synthesized using 2-((4-methyltetrahydro-2H-pyran-4-yl)oxy)acetic acid and Example 109, following the same method as in Example 18. 1¹H NMR (400MHz, acetonitrile-d³) δ 7.72 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.2, 1.9 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.04 (dt, J =14.7,6.7Hz,1H),5.58(ddd,J=15.5,7.5,1.4Hz,1H),4.08(d,J=1.0Hz,2H),4.05(d,J=12 .1Hz,1H),3.99(d,J=12.1Hz,1H),3.90(dd,J=15.0,5.3Hz,1H),3.81(d,J=7.1Hz,1H),3.7 9–3.75(m,1H),3.75–3.66(m,3H),3.61(dt,J=11.6,4.2Hz,2H),3.36(d,J=14.5Hz,1H),3 .21(s,3H),3.05(dd,J=15.1,10.8Hz,1H),2.85–2.66(m,2H),2.57–2.45(m,2H),2.45–2.3 4(m,1H),2.33–2.21(m,1H),2.15(dt,J=14.7,7.4Hz,1H),2.09–1.99(m,1H),1.92–1.85(m ,3H),1.84–1.56(m,8H),1.40(dt,J=14.9,7.6Hz,1H),1.25(s,3H),1.07(d,J=6.9Hz,3H). 19 F NMR (376MHz, acetonitrile-d3) δ -77.38. LCMS-ESI+ (m / z): [M+H]+C 40 H 52 ClN3O7S: Calculated value: 754.3; Measured value: 753.9.

[0915] Example 125

[0916]

[0917] Example 125 was synthesized using 6-oxaspiro[3.4]octane-2-carboxylic acid and Example 109, following the same method as in Example 18. 1¹H NMR (400MHz, acetonitrile-d³) δ 7.59 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.2, 1.9 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.6, 2.3 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.15–5.99 (m, 1H), 5.64 (dd, J = 15.5, 8.2 Hz, 1H), 4.01–3.90 (m, 3H), 3.85 (ddd, J = 14.7, 4.9, 3.1 Hz, 1H), 3.79– 3.64(m,6H),3.61(d,J=5.6Hz,2H),3.45–3.29(m,2H),3.26(s,4H),3.07(dd,J=15.2,10.1Hz,1H),2.75(dtt,J=43.7,17.9,8.8Hz,4H),2.5 1–2.13(m,7H),2.10–1.99(m,3H),1.95–1.89(m,2H),1.88–1.63(m,2H),1.43–1.23(m,2H),1.10(dd,J=6.8,1.1Hz,3H).LCMS-ESI+(m / z):H+ C 40 H 50 ClN3O6S: Calculated value: 736.3; Measured value: 736.12.

[0918] Example 126

[0919]

[0920] Example 126 was synthesized using 3-chloro-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ8.23(s,1H),7.72(d,J=8.3Hz,1H),7.18(dd,J=8.1,1.9Hz,1H),7.13(s,1H),7.11(s,2H),7.00–6 .87(m,2H),6.04(dd,J=15.0,7.3Hz,1H),5.62(dd,J=15.2,8.9Hz,1H),4.37(dd,J=14.8,6.4Hz,1H),4.07(s,2H),3.89 (s,3H),3.88–3.75(m,3H),3.67(d,J=14.2Hz,1H),3.28(s,3H),3.19–3.00(m,1H),2.91–2.70(m,2H),2.62–2.45(m,1H ),2.44–2.07(m,4H),2.05–1.73(m,3H),1.44(t,J=12.7Hz,1H),1.31(s,1H),1.17(d,J=6.3Hz,3H).LCMS-ESI+(m / z): C 37 H 43 C l2 N5O5S: Calculated value: 739.24; Measured value: 739.99.

[0921] Example 127

[0922]

[0923] Example 127 was synthesized using cis-3-methoxycyclobutanecarboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ7.75(d,J=8.5Hz,1H),7.30(dd,J=8.2,1.9Hz,1H),7.17(dd,J=8.5,2.4Hz,1H),7.10(dd,J=9.1,2.1Hz,2H),6.88(d,J=8.2Hz,1H ),6.13(dt,J=14.4,6.9Hz,1H),5.61(dd,J=15.4,8.5Hz,1H),4.17(dd,J=1 4.8,6.7Hz,1H),4.11–4.00(m,2H),3.96(dd,J=14.8,5.3Hz,1H),3.91–3.80 (m,2H),3.76(d,J=8.6Hz,1H),3.68(d,J=14.2Hz,1H),3.27(d,J=13.7Hz,7 H),3.06(dd,J=15.1,9.8Hz,1H),2.88–2.70(m,3H),2.58–2.47(m,3H),2.4 5(s,2H),2.34–2.19(m,2H),2.14(dd,J=19.5,10.9Hz,3H),1.95(s,3H),1. 90–1.70(m,3H),1.44(t,J=12.4Hz,1H),1.13(d,J=6.8Hz,3H).LCMS-ESI+:C 38 H 48 ClN3O6S: Calculated value: 710.3 (M+H); Measured value: 710.1 (M+H).

[0924] Example 128

[0925]

[0926] Example 128 was synthesized using trans-3-methoxycyclobutanecarboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ7.76 (d, J=8.5Hz, 1H), 7.31 (dd, J=8.1, 1.9Hz, 1H), 7.18 (dd,J=8.5,2.4Hz,1H),7.11(dd,J=4.1,2.2Hz,2H),6.88(d,J=8.2Hz,1H),6.1 4(dt,J=14.5,6.9Hz,1H),5.62(dd,J=15.4,8.4Hz,1H),4.20–4.08(m,2H),4. 06(dd,J=7.6,3.7Hz,2H),4.03–3.93(m,2H),3.85(d,J=15.0Hz,1H),3.77(dd, J=8.5,2.8Hz,1H),3.69(d,J=14.2Hz,1H),3.36(s,1H),3.30(s,3H),3.26(s, 3H),3.21–3.12(m,1H),3.07(dd,J=15.2,9.8Hz,1H),2.89–2.70(m,2H),2.57( qd,J=8.1,4.1Hz,2H),2.46(s,2H),2.36–2.17(m,3H),2.12(d,J=13.9Hz,2H), 2.02–1.67(m,6H),1.45(t,J=12.5Hz,1H),1.14(d,J=6.9Hz,3H).LCMS-ESI+:C 38 H 48 ClN3O6S: Calculated value: 710.3 (M+H); Measured value: 710.1 (M+H).

[0927] Example 129

[0928]

[0929] Example 129 was synthesized using the same method as in Example 75, with the addition of anti-racemic-(1R,2S)-2-(1-methylpyrazol-4-yl)cyclopropylamine hydrochloride and triethylamine. 1H NMR (400MHz, methanol-d4) δ7.67(d,J=8.6Hz,1H),7.42(s,1H),7.34(s,1H),7.22(d,J=8.2Hz,1H),7.09(s,1H),6.98(s,2H),6.88(d ,J=8.2Hz,1H),6.10–6.01(m,1H),5.70–5.59(m,1H),4.23(dd,J=14.8,6.8Hz,1H),4.02(s,2H),3.83(s,5H),3.65(d,J=14.2H z,1H),3.37(s,1H),3.30(s,4H),3.08(dd,J=15.2,9.9Hz,1H),2.92–2.51(m,5H),2.45(s,2H),2.23(s,2H),2.08(t,J=11.5Hz ,2H),2.02–1.85(m,4H),1.81(d,J=7.5Hz,2H),1.40(t,J=12.9Hz,1H),1.19–1.12(m,3H),1.03(q,J=6.3Hz,1H).LCMS-ESI+: C 40 H 49 ClN6O5S: Calculated value: 761.3 (M+H); Measured value: 760.8 (M+H).

[0930] Example 130

[0931]

[0932] Example 130 was synthesized using 1-ethylpyrrole-3-carboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ7.74(d,J=8.4Hz,1H),7.62(t,J=1.9Hz,1H),7.33(d,J=8. 5Hz,1H),7.18–7.08(m,3H),6.90(d,J=8.2Hz,1H),6.81(dd,J=3.0,2.1Hz,1H), 6.64(dd,J=2.9,1.8Hz,1H),6.12(dt,J=14.4,6.6Hz,1H),5.62(dd,J=15.4,8.5 Hz,1H),4.24(dd,J=14.6,6.3Hz,1H),4.12–3.98(m,4H),3.86(d,J=15.0Hz,1H) ,3.82–3.75(m,1H),3.69(d,J=14.3Hz,1H),3.38(s,1H),3.29(s,3H),3.08(dd, J=15.1,10.0Hz,1H),2.89–2.70(m,2H),2.57(dd,J=12.9,6.5Hz,1H),2.46(s,2 H),2.32–2.15(m,2H),2.12(d,J=13.7Hz,1H),1.96(d,J=6.2Hz,3H),1.88–1.69 (m,3H),1.46(t,J=7.3Hz,4H),1.31(s,1H),1.14(d,J=6.5Hz,3H).LCMS-ESI+:C 39 H 47 ClN4O5S: Calculated value: 719.3 (M+H); Measured value: 718.8 (M+H).

[0933] Example 131

[0934]

[0935] Example 131 was synthesized using the same method as in Example 75, employing Example 109 and 1-(methoxymethyl)cyclopropylamine. 1H NMR (400MHz, methanol-d4) δ7.75 (d, J=8.5Hz, 1H), 7.25-7.14 (m, 2H), 7.11 (d, J= 2.3Hz,1H),7.01(s,1H),6.90(d,J=8.2Hz,1H),6.03(dd,J=14.7,7.4Hz,1H ),5.59(dd,J=15.3,8.9Hz,1H),4.31-4.22(m,1H),4.13-4.00(m,2H),3.9 0-3.73(m,3H),3.68(d,J=14.2Hz,1H),3.46(d,J=8.2Hz,1H),3.39(s,3H), 3.27(s,4H),3.07(dd,J=15.3,10.2Hz,1H),2.92-2.70(m,3H),2.48(d,J= 7.6Hz,2H),2.39(d,J=9.2Hz,1H),2.19(dt,J=14.1,7.0Hz,1H),2.12(d,J= 13.1Hz,2H),2.01-1.87(m,3H),1.77(tq,J=17.6,9.3,8.8Hz,3H),1.44(t, J=11.6Hz,1H),1.14(d,J=6.6Hz,3H),0.83(d,J=12.6Hz,3H).LCMS-ESI+:C 38 H 49 ClN4O6S: Calculated value: 725.3 (M+H); Measured value: 724.8 (M+H).

[0936] Example 132

[0937]

[0938] Example 132 was synthesized using the same method as in Example 75, employing the materials from Example 109 and 2-methoxyethyl-1-amine. ¹H NMR (400 MHz, methanol-d⁴) δ 7.75 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.06 (dd, J = 15.0, 6.9 Hz, 1H), 5.58 (dd, J = 15.3, 8.9 Hz, 1H), 4.27 (dd, J = 14.7, 6.5 Hz, 1H), 4.14–3.96 (m, 2H). 3.91-3.62(m,4H),3.49(d,J=5.3Hz,2H),3.38(s,3H),3.27(s,3H),3.07(dd,J=15.2,10.2Hz,1H),2.91-2.66(m,3H),2.57-2.28(m ,3H),2.28-2.04(m,3H),2.02-1.87(m,3H),1.87-1.66(m,3H),1.54-1.36(m,2H),1.31(s,1H),1.13(d,J=6.6Hz,3H).LCMS-ESI+:C 36 H 47 ClN4O6S: Calculated value: 699.3 (M+H); Measured value: 698.6 (M+H).

[0939] Example 133

[0940]

[0941] Following the same method as in Example 18, Example 133 was synthesized using 2-(((3R,4S)-3-fluorotetrahydro-2H-pyran-4-yl)oxy)acetic acid and Example 110. ¹H NMR (400 MHz, methanol-d⁴) δ 7.73 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.2, 1.8 Hz, 1H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.12-6.05 (m, 1H), 5.56 (dd, J = 15.2, 8.8 Hz, 1H), 4.18-4.11 (m, 2H), 4.08-3.83 ( m,4H),3.81-3.72(m,2H),3.68(s,2H),3.61(d,J=14.4Hz,1H),3.55-3.40(m,3H),3.37-3.31(m,2H),3.26(s,3H),3.16-3.08 (m,1H),2.88-2.69(m,3H),2.51-1.61(m,12H),1.54-1.46(m,1H),1.43(d,J=6.8Hz,3H),1.13(d,J=6.8Hz,3H).LCMS-ESI+: C 40 H 51 ClFN3O7S: Calculated value: 772.3 (M+H); Measured value: 772.2 (M+H).

[0942] Example 134

[0943]

[0944] Example 134 was synthesized using 1-ethyl-1H-pyrazole-4-carboxylic acid and Example 109, following the same method as in Example 18. ¹H NMR (400 MHz, methanol-d⁴) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.23 (dd, J = 8.2, 1.8 Hz, 1H), 7.14–7.07 (m, 2H), 6.99 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.07 (dt, J = 14 Hz, 1H). .3,6.7Hz,1H),5.62(dd,J=15.3,8.8Hz,1H),4.34(dd,J=14.8,6.5Hz,1H),4.24(q,J=7.3 Hz,2H),4.06(d,J=1.5Hz,2H),3.92(dd,J=14.7,5.2Hz,1H),3.84(d,J=15.1Hz,1H),3.78 (dd,J=8.8,3.3Hz,1H),3.67(d,J=14.3Hz,1H),3.36(d,J=2.5Hz,1H),3.29(s,3H),3.09( dd,J=15.2,9.9Hz,1H),2.93-2.65(m,3H),2.56(d,J=10.0Hz,1H),2.43(dd,J=17.5,8.9H z,2H),2.25(dt,J=26.4,9.7Hz,2H),2.11(d,J=13.5Hz,1H),1.98(dd,J=16.3,5.2Hz,2H) ,1.82(dt,J=23.0,9.3Hz,4H),1.50(t,J=7.3Hz,3H),1.16(d,J=6.6Hz,3H).LCMS-ESI+:C 38 H 46 ClN5O5S: Calculated value: 720.3 (M+H); Measured value: 719.0 (M+H).

[0945] Example 135

[0946]

[0947] Step 1: Preparation of methyl 3-(2-formyl-1H-pyrrolo-1-yl)propionate: Under a nitrogen atmosphere, a solution of pyrrolocarboxaldehyde (5.0 g, 0.053 mol) in anhydrous DMF (10 mL) was added dropwise to a suspension of 60% sodium hydride (oil suspension) (2.56 g, 0.063 mol) in anhydrous DMF (40 mL) under stirring. The temperature of the mixture was maintained at 0 °C. After the addition was complete, stirring was continued at the same temperature for 30 minutes. Then, a solution of methyl 3-bromopropionate (13.17 g, 0.079 mol) was added dropwise, and the temperature was raised to room temperature. The reaction mixture was stirred at this temperature for 48 hours. Water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the product was purified by normal phase chromatography (silica gel column, 0-80% EtOAc / hexane) to obtain methyl 3-(2-formyl-1H-pyrrole-1-yl)propionate.

[0948] Step 2: Preparation of methyl 3H-pyrrolizine-6-carboxylate: NaOMe (2.62 g, 12.14 mmol) was added to a MeOH (20 mL) solution of methyl 3-(2-formyl-1H-pyrrolo-1-yl)propionate (2.0 g, 11.04 mmol). The reaction mixture was stirred at 45 °C for 48 hours. Water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the mixture was purified by normal-phase chromatography (silica gel column, 0-80% EtOAc / hexane) to give the intermediate methyl 3H-pyrrolizine-6-carboxylate. 1 ¹H NMR (400MHz, chloroform-d) δ 7.58 (p, J = 1.2 Hz, 1H), 6.60 (dtd, J = 6.1, 2.2, 0.7 Hz, 1H), 6.36 (q, J = 0.9 Hz, 1H), 6.31–6.21 (m, 1H), 4.50 (tt, J = 2.2, 1.0 Hz, 2H), 3.83 (s, 3H).

[0949] Step 3: Preparation of 3H-pyrrolizin-6-carboxylic acid: 2N LiOH (1 mL) was added to a methanol (6 mL) solution of methyl 3H-pyrrolizin-6-carboxylate (0.3 g, 1.8 mmol) under stirring, and the reaction mixture was stirred at room temperature for 3 hours. 2N HCl (1 mL) was added to the reaction mixture and the mixture was concentrated. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 3H-pyrrolizin-6-carboxylic acid.

[0950] Step 4: Following the same method as in Example 18, Example 135 was synthesized using 3H-pyrrolizidine-6-carboxylic acid and Example 109. ¹H NMR (400 MHz, chloroform-d) δ 7.86–7.61 (m, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 6.6 Hz, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 6.44 (s, 1H), 6.34 (d, J = 6.1 Hz, 1H), 6.04–5.86 (m, 1H), 5.62 (dd, J = 15.7, 7.7 Hz, 1H). 4.56(s,2H),4.20–3.94(m,3H),3.82(dd,J=42.9,13.7Hz,3H),3.58–3.39(m,1H),3.29(s,3H),3.11–2.88(m,2H),2.88 –2.69(m,2H),2.46(t,J=30.6Hz,4H),2.16–1.66(m,7H),1.28(s,2H),1.13(d,J=6.8Hz,3H).LCMS-ESI+(m / z):[M+H]+C 40 H 45 ClN4O5S: Calculated value: 729.26; Measured value: 729.30.

[0951] Example 136

[0952]

[0953] Step 1: Preparation of methyl 2,3-dihydro-1H-pyrrolizin-6-carboxylate: Methyl 3H-pyrrolizin-6-carboxylate (300 mg, 1.85 mmol) and rhodium (5%, on alumina) were mixed in ethanol (10 mL). The mixture was degassed, injected with hydrogen, and then stirred for 5 hours. The mixture was filtered through silica gel and concentrated. Water was then added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give methyl 2,3-dihydro-1H-pyrrolizin-6-carboxylate. 1 ¹H NMR (400MHz, chloroform-d) δ 7.21 (d, J = 1.4 Hz, 1H), 6.22 (q, J = 1.2 Hz, 1H), 3.99–3.86 (m, 2H), 3.78 (s, 3H), 2.80 (ddd, J = 7.7, 6.7, 1.2 Hz, 2H), 2.48 (tt, J = 8.0, 6.8 Hz, 2H).

[0954] Step 2: Following the same method as in Example 133 (Step 3), methyl 2,3-dihydro-1H-pyrrolizin-6-carboxylate was used instead of methyl 3H-pyrrolizin-6-carboxylate to synthesize 2,3-dihydro-1H-pyrrolizin-6-carboxylic acid.

[0955] Step 3: Following the same method as in Example 18, Example 136 was synthesized using 2,3-dihydro-1H-pyrrolizin-6-carboxylic acid and Example 109. ¹H NMR (400 MHz, chloroform-d) δ 7.76 (d, J = 8.5 Hz, 1H), 7.48–7.37 (m, 2H), 7.25–7.15 (m, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 1.4 Hz, 1H), 6.05–5.89 (m, 1H), 5.62 (dd, J = 15.6, 7.5 Hz, 1H). Hz,1H),4.18–3.69(m,7H),3.30(s,4H),3.08–2.94(m,1H),2.92–2.74(m,3H),2.61–2.32(m,5 H),2.21–1.62(m,13H),1.41(t,J=12.9Hz,1H),1.13(d,J=6.8Hz,2H).LCMS-ESI+(m / z):[M+H]+ C 40 H 47 ClN4O5S: Calculated value: 731.30; Measured value: 731.22.

[0956] Example 137

[0957]

[0958] Example 137 was synthesized using the same method as in Example 18, with 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid and Example 110. NMR (400MHz, chloroform-d) δ7.74(d,J=8.6Hz,1H),7.33(d,J=1.7Hz,1H),7.21(dd,J=8.4,2.5Hz,2H),7.11(d,J=2.3Hz,1H),7.04(s,1H),6.98(d,J= 8.2Hz,1H),6.35(d,J=1.6Hz,1H),5.99(d,J=11.2Hz,1H),5.52(dd,J=15.2,8.9Hz,1H),4.81(dd,J=3.3,1.1Hz,2H),4.57(s,1H),4.18–3.96( m,3H),3.92–3.79(m,2H),3.76–3.65(m,2H),3.26(s,3H),3.02(dd,J=15.2,9.9Hz,1H),2.87–2.70(m,3H),2.42(dt,J=25.8,9.3Hz,3H),2.2 9–1.93(m,5H),1.82(q,J=9.2Hz,3H),1.72–1.55(m,4H),1.41(t,J=12.8Hz,1H),1.28(s,2H),1.01(d,J=6.2Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 41 H 49 ClN4O6S: Calculated value: 761.29; Measured value: 761.22.

[0959] Example 138

[0960]

[0961] Example 138 was synthesized using 1-methyl-1H-pyrazole-4-carboxylic acid and Example 110, following the same method as Example 18. ¹H NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 0.7 Hz, 1H), 7.93 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.5, 2.3 Hz, 1H), 7.18–7.07 (m, 2H), 7.06–6.89 (m, 2H), 5.96 (dd, J = 15.1, 8.6 Hz, 1H), 5.53 (dd, J = 15.2, 9.0 Hz, 1H), 4.67 (d, J = 7.3 Hz, 2H), 4.12 (s, 2H), 3.99 (s, 2H), 3.86 (d, J = 0.7 Hz, 1H), 3.99 (s, 2H), 3.86 (d, J = 0.7 Hz, 1H), 4.12 (s, 2 ... =15.0Hz,2H),3.76-3.61(m,2H),3.26(s,3H),3.02(dd,J=15.2,10.2Hz,2H),2.79(d,J=15.3Hz,3H),2.41(dt,J=45.0,9.2Hz,3H), 2.27-1.92(m,5H),1.84(t,J=8.9Hz,2H),1.70-1.58(m,3H),1.41(t,J=12.4Hz,2H),0.96(d,J=6.2Hz,2H).LCMS-ESI+(m / z):[M+H]+ C 38 H 46 ClN5O5S: Calculated value: 720.29; Measured value: 720.23.

[0962] Example 139

[0963]

[0964] Following the same method as in Example 18, Example 139 was synthesized using 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylic acid and Example 109. ¹H NMR (400 MHz, chloroform-d) δ 7.74 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 15.0, 1.8 Hz, 2H), 7.18 (dd, J = 8.4, 2.3 Hz, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.37 (q, J = 1.2 Hz, 1H), 5.99 (dt, J = 13.7, 6.5 Hz, 1H), 5.62 (dd, J = 15.6, 7.7 Hz, 1H), 4.84 (d, J = 1.1 Hz, 1H). z,2H),4.18–3.95(m,6H),3.94–3.69(m,4H),3.31(s,4H),3.09–2.95(m,2H),2.90–2.68(m,2H),2.59–2.25(m,4H),2.21– 2.03(m,2H),2.02–1.82(m,3H),1.81–1.60(m,3H),1.41(t,J=12.7Hz,1H),1.13(d,J=6.8Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 40 H 47 ClN4O6S: Calculated value: 747.29; Measured value: 747.04.

[0965] Example 140

[0966]

[0967] A mixture of 3-hydroxy-3-methylcyclobutanecarboxylic acid (2.61 mg, 0.02 mmol) and Example 109 (8.0 mg, 0.0134 mmol) in DCM (1.0 mL) was cooled to 0 °C. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (5.11 mg, 0.0268 mmol) was added, followed by DMAP (3.27 mg, 0.0267 mmol). The reaction was removed from the cooling bath and stirred overnight at ambient temperature. The reaction was then concentrated by removing the DCM, diluted with DMF (1 mL), filtered, and purified by Gilson reversed-phase preparative HPLC (60–100% ACN / H₂O containing 0.1% TFA) to give Example 140. 1H NMR (400MHz, methanol-d4) δ7.76–7.67(m,1H),7.31(dd,J=8.2,1.9Hz,1H),7.14–7.04(m,3H),6.86(d,J=8.2Hz,1 H),6.14(dt,J=14.6,7.0Hz,1H),5.63(dd,J=15.4,8.4Hz,1H),4.14(dd,J=14.8,6.9Hz,1H),4.08–3.93(m,3 H),3.88–3.73(m,2H),3.67(d,J=14.3Hz,1H),3.30(s,3H),3.12–2.98(m,1H),2.92–2.70(m,3H),2.59–2.2 0(m,8H),2.16–2.03(m,2H),2.03–1.71(m,7H),1.38(s,4H),1.14(d,J=6.9Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 38 H 48 ClN3O6S: Calculated value: 710.3; Measured value: 710.1.

[0968] Example 141

[0969]

[0970] Example 141 was synthesized using the same method as in Example 140, but instead of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid, racemic 1-methyl-4,5,6,7-tetrahydroindazole-6-carboxylic acid. The peak eluted from the reversed-phase preparative HPLC was arbitrarily designated as "S," and its actual stereochemistry was not determined. 1H NMR (400MHz, methanol-d4) δ7.75(d,J=8.5Hz,1H),7.40(s,1H),7.29(dd,J=8.2,1.8Hz,1H),7.16(dd,J=8.5,2.4Hz,1H),7.10(dd, J=8.5,2.1Hz,2H),6.90(d,J=8.2Hz,1H),6.14(dt,J=14.6,7.0Hz,1H),5.64(dd,J=15.4,8.3Hz,1H),4.15(dd,J=14.8,7.0Hz ,1H),4.11–4.02(m,2H),3.96(dd,J=14.8,4.9Hz,1H),3.88–3.64(m,6H),3.30(s,3H),3.13–3.02(m,1H),2.99–2.66(m,6H) ,2.65–2.29(m,5H),2.26–2.06(m,3H),2.01–1.69(m,8H),1.51–1.38(m,1H),1.18(d,J=6.9Hz,3H).LCMS-ESI+(m / z):[M+H]C 41 H 50 ClN5O5S: Calculated value: 760.3; Measured value: 760.1.

[0971] Example 142

[0972]

[0973] Following the same method as in Example 140, Example 142 was synthesized using 3-(1-methylpyrazol-4-yl)propionic acid instead of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid, with DMF (1.0 mL) added as the co-solvent for the reaction. 1H NMR (400MHz, methanol-d4) δ7.75–7.69(m,1H),7.51(s,1H),7.45–7.41(m,1H),7.31(dd,J=8.3,1.9Hz,1H),7.14–7.05(m,3H),6.8 6(d,J=8.2Hz,1H),6.18–6.06(m,1H),5.62(dd,J=15.5,8.4Hz,1H),4.14–3.97(m,3H),3.92(dd,J=14.8,4.8Hz,1H),3.87–3 .73(m,5H),3.67(d,J=14.2Hz,1H),3.30(s,3H),3.11–3.00(m,1H),2.90–2.74(m,4H),2.74–2.66(m,2H),2.57–2.38(m,3H) ,2.31–2.19(m,1H),2.14–2.05(m,1H),2.03–1.71(m,8H),1.47–1.36(m,1H),1.07(d,J=6.9Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 39 H 48 Calculated value of ClN5O5S: 734.35; Measured value: 734.07.

[0974] Example 143

[0975]

[0976] Example 143 was synthesized using the same method as in Example 140, but instead of 3-hydroxy-3-methyl-cyclobutanecarboxylic acid, isochoric 3-carboxylic acid was used. The earlier eluting peak from the reversed-phase preparative HPLC was arbitrarily designated as "R," without determining the actual stereochemistry. 1H NMR (400MHz, methanol-d4) δ7.76(d,J=8.5Hz,1H),7.28(dd,J=8.2,1.9Hz,1H),7.25–7.15(m,4H),7.14–7.05(m,3H),6.92(d,J=8.2Hz,1H),6.10( dt,J=14.5,6.9Hz,1H),5.64(dd,J=15.4,8.3Hz,1H),5.06-4.89(m,2H)4.44(dd,J=9.7,4.7Hz,1H),4.22–4.01(m,3H),3.95(dd,J=14.9,5.0 Hz,1H),3.85(d,J=14.9Hz,1H),3.77(dd,J=8.4,3.0Hz,1H),3.70(d,J=14.3Hz,1H),3.30(s,3H),3.18–3.02(m,3H),2.90–2.75(m,2H),2.5 6–2.40(m,3H),2.34–2.22(m,1H),2.22–2.07(m,2H),2.00–1.71(m,7H),1.51–1.39(m,1H),1.15(d,J=6.8Hz,3H).LCMS-ESI+(m / z):[M+H]+C 42 H 48 ClN3O6S: Calculated value: 758.37; Measured value: 758.07.

[0977] Example 144

[0978]

[0979] At room temperature, 350 mg (0.59 mmol) of Example 109 was dissolved in DCM (5.9 mL), followed by the addition of triethylamine (0.24 g, 2.34 mmol), and then a solution of isocyanate cyclopropane (107 mg, 1.3 mmol) in DCM (1 mL). The resulting mixture was stirred at room temperature for 2 hours, and then the reaction was concentrated by removing DCM. The resulting residue was reconstituted in EtOAc (30 mL) and washed with 1 N HCl (15 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated NaHCO3 (15 mL) and brine (15 mL), dried over sodium sulfate, filtered, concentrated, reconstituted in DCM, mixed with silica gel, concentrated to dryness, and purified twice by combiflash (12 g silica gel, 0-10% DCM / 2.0 N NH3 in MeOH solution, dry). The desired fractions were combined and concentrated to obtain Example 144. 1 H NMR (400MHz, acetone-d6) δ7.75(d,J=8.5Hz,1H),7.32–7.05(m,4H),6.84(d,J=8.2Hz,1H),6.14(dt,J=14.2,6.6Hz,1H),5.56(dd,J =15.4,8.4Hz,1H),4.04(q,J=11.9Hz,3H),3.85(d,J=15.1Hz,1H),3.71(d,J=14.8Hz,2H),3.39(d,J=14.2Hz,1H),3.23(s,3H) ,3.12(dd,J=15.0,9.8Hz,1H),2.89–2.71(m,3H),2.69–2.60(m,1H),2.58–2.40(m,3H),2.20–2.10(m,3H),2.00–1.89(m,3H), 1.83–1.69(m,3H),1.51–1.34(m,1H),1.08(d,J=6.3Hz,3H),0.66(d,J=6.9Hz,2H),0.56–0.48(m,2H).LCMS-ESI+(m / z):[M+H]+ C 36 H 45 ClN4O5S: Calculated value: 681.28; Measured value: 680.81.

[0980] Example 145

[0981]

[0982] Step 1: At 0°C, tert-butyl butyrate (1.40 mL, 5.75 mmol) was added over 2 minutes via syringe to a solution of 9-boronbicyclo[3.3.1]nonane (0.5 M tetrahydrofuran solution, 17.2 mL, 9 mmol) under stirring. The resulting mixture was then warmed to room temperature. After 4.5 hours, 5-bromo-1H-pyrrole-3-carboxaldehyde (1.00 g, 5.75 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (210 mg, 0.287 mmol), potassium carbonate (1.59 g, 11.5 mmol), and N,N-dimethylformamide (30 mL) were added sequentially, and the resulting mixture was heated to 75°C. After 50 minutes, the reaction mixture was heated to 100°C. After 23 hours, the resulting mixture was cooled to room temperature, and diethyl ether (400 mL) and saturated ammonium chloride aqueous solution (50 mL) were added sequentially. The organic layer was washed with water (2 × 350 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 80% ethyl acetate in hexane) to give 145-1.

[0983] Step 2: At room temperature, an aqueous solution of lithium hydroxide (2.0 M, 11.0 mL, 22 mmol) was added via syringe to a solution of 145-1 (517 mg, 2.18 mmol) in tetrahydrofuran (17 mL), water (5.0 mL), and methanol (5.0 mL) under vigorous stirring. After 1 hour, the resulting mixture was heated to 70 °C. After 3.5 hours, the resulting mixture was cooled to room temperature, and an aqueous solution of hydrogen chloride (2.0 M, 20 mL) and ethyl acetate (100 mL) were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 2 × 80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (24 mL) and N,N-dimethylformamide (4.0 mL), and 4-dimethylaminopyridine (400 mg, 3.27 mmol) was added. The resulting mixture was stirred at room temperature. Two minutes later, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (774 mg, 4.36 mmol) was added. After 14 hours, diethyl ether (120 mL) was added. The organic layer was washed successively with aqueous hydrogen chloride solution (0.05 M, 100 mL) and water (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 80% ethyl acetate in hexane) to give 145-2.

[0984] Step 3: At room temperature, a mixture of sodium chlorite aqueous solution (2.0 M, 469 mL, 0.94 mmol) and sodium dihydrogen phosphate monohydrate (120 mg, 0.868 mmol) was added via syringe to a mixture of 145-2 (22 mg, 0.14 mmol) and 2-methyl-2-butene (143 mL, 1.35 mmol) in tert-butanol (0.4 mL) under vigorous stirring. After 16.5 hours, 20 mL of 2.0 M aqueous hydrogen chloride solution and 100 mL of ethyl acetate were added sequentially. The organic layer was washed with a mixture of water and brine (1:1 v:v, 2 × 80 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 145-3.

[0985] Step 4: Preparation of Example 145: Example 145 was synthesized using 145-3 and Example 109 in the same manner as in Example 18. 1 ¹H NMR (400 MHz, acetone-d6) δ 7.88 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.32–7.21 (m, 2H), 7.19–7.12 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 1.7 Hz, 1H), 6.20–6.06 (m, 1H), 5.60 (dd, J = 15.4, 8.4 Hz) ,1H),4.11(d,J=12.1Hz,1H),4.05(d,J=12.1Hz,1H),3.93–3.65(m,3H),3.40(d,J=14.2Hz, 1H),3.24(s,3H),3.24-3.08(m,1H),2.96–1.22(m,23H),1.13(d,J=6.2Hz,3H).LCMS-ESI+:C 41 H 48 ClN4O6S: Calculated value: 759.3 (M+H); Measured value: 759.0 (M+H).

[0986] Example 146

[0987]

[0988] Example 146 was synthesized using 2-methylthiazol-4-carboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ8.28(s,1H),7.74(d,J=8.5Hz,1H),7.22(dd,J=8.2,1.9Hz,1 H),7.17(dd,J=8.5,2.3Hz,1H),7.10(d,J=2.3Hz,1H),7.03(d,J=2.0Hz,1H),6.94( d,J=8.2Hz,1H),6.04(dt,J=14.4,6.8Hz,1H),5.60(dd,J=15.4,8.7Hz,1H),4.34( dd,J=15.0,6.4Hz,1H),4.13–4.03(m,2H),3.98(dd,J=15.0,5.7Hz,1H),3.85(d,J= 15.0Hz,1H),3.76(dd,J=8.8,3.5Hz,1H),3.69(d,J=14.3Hz,1H),3.33(s,1H),3.2 6(s,3H),3.07(dd,J=15.3,10.0Hz,1H),2.77(s,3H),2.53–2.35(m,3H),2.24(tt,J =14.3,7.2Hz,1H),2.11(d,J=13.9Hz,2H),1.97–1.88(m,1H),1.79(dt,J=20.3,8.5 Hz, 2H), 1.49–1.38 (m, 1H), 1.29 (s, 1H), 1.11 (d, J = 6.7Hz, 3H). LCMS-ESI+ (m / z): H+ C 37 H 43 ClN4O5S2: Calculated value: 723.248; Measured value: 723.221.

[0989] Example 147

[0990]

[0991] Example 147 was synthesized using 1-methyl-1H-pyrrole-3-carboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ7.74(d,J=8.5Hz,1H),7.49(s,1H),7.30(d,J=8.3Hz,1H),7.15(d,J=8.4Hz,1H),7.09(s,2H),6.89(d,J=8.2Hz,1H) ,6.72(d,J=2.7Hz,1H),6.66–6.53(m,1H),6.16–6.00(m,1H),5.59(dd,J=15.3,8.5Hz,1H),4.23(dd,J=16.1,5.8Hz,1H),4.10–3.98(m,2H ),3.85(d,J=14.9Hz,1H),3.77(d,J=8.5Hz,1H),3.72(s,3H),3.68(d,J=14.3Hz,1H),3.27(s,3H),3.10–3.00(m,1H),2.80(s,2H),2.44( s,2H),2.28–2.15(m,1H),2.10(d,J=15.0Hz,1H),1.76(s,2H),1.49–1.38(m,1H),1.29(s,2H),1.12(d,J=6.5Hz,3H).LCMS-ESI+(m / z):H+ C 38 H 45 ClN4O5S: Calculated value: 705.288; Measured value: 705.295.

[0992] Example 148

[0993]

[0994] Example 148 was synthesized using 1-methyl-1H-pyrazole-4-carboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ7.74(d,J=8.5Hz,1H),7.17(t,J=9.6Hz,2H),7.09(d,J=6.8Hz,2H),6.85(d,J=7.6Hz,1H),6.35–6.01(m,1H),5. 55(dd,J=15.2,8.6Hz,1H),4.03(q,J=12.1Hz,2H),3.84(d,J=14.9Hz,1H),3.78(d,J=8.6Hz,1H),3.67(d,J=14.3Hz,1H),3.42(s,2H), 3.27(d,J=1.4Hz,3H),3.11–2.99(m,1H),2.89(s,6H),2.80(s,1H),2.60(s,0H),2.43(s,2H),2.23–2.08(m,1H),2.06–1.97(m,1H),1 .92(d,J=10.7Hz,2H),1.76(d,J=6.9Hz,3H),1.42(t,J=13.0Hz,1H),1.23(d,J=7.5Hz,3H),1.09(d,J=6.5Hz,3H).LCMS-ESI+(m / z):H+ C 37 H 44 ClN5O5S: Calculated value: 706.28; Measured value: 706.27.

[0995] Example 149

[0996]

[0997] Example 149 was synthesized using the same method as in Example 75, employing Example 109 and cis-3-methoxycyclobut-1-amine hydrochloride. ¹H NMR (400 MHz, acetone-d6) δ 7.75 (d, J = 8.5 Hz, 1H), 7.39 (br s, 1H), 7.31–7.15 (m, 2H), 7.10 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.23 (br s, 1H), 5.57 (br s,1H),4.05(q,J=10.0Hz,2H),4.00(m,2H)3.88-3.61(m,4H),3.44(d,J=14.4Hz, 1H),3.26(s,3H),3.19(s,3H),3.13(dd,J=15.2,10.3Hz,1H),2.89-2.68(m,2H),2 .67-2.37(m,2H),2.37-2.16(m,7H),2.16-2.07(m,3H),1.95(m,2H),1.88(m,2H) ,1.74(m,1H),1.48-1.33(m,1H),1.29(s,1H),1.14(d,J=6.4Hz,3H).LCMS-ESI+:C 38 H 50 ClN4O6S: Calculated value: 725.3 (M+H); Measured value: 724.8 (M+H).

[0998] Example 150

[0999]

[1000] Example 150 was synthesized using the same method as in Example 75, employing the materials from Example 109 and trans-3-methoxycyclobut-1-amine hydrochloride. ¹H NMR (400 MHz, acetone-d6) δ 7.64 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.07 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.16–6.02 (m, 1H), 5.67 (dd, J = 15.5, 8.3 Hz, 1H), 4.31 (q, J = 7.1 Hz, 1H), 4.00 (m, 2H) 3.88–3.61 (m, 4H), 3.44 (d, J = 14.4 Hz) ,1H),3.26(s,3H),3.19(s,3H),3.13(dd,J=15.2,10.3Hz,1H),2.89-2.68(m,2H),2.67-2.37(m,2H),2.37-2.16(m,7H),2. 16-2.07(m,3H),1.95(m,2H),1.88(m,2H),1.74(m,1H),1.48-1.33(m,1H),1.29(s,1H),1.14(d,J=6.4Hz,3H).LCMS-ESI+:C 38 H 50 ClN4O6S: Calculated value: 725.3 (M+H); Measured value: 724.5 (M+H).

[1001] Example 151

[1002]

[1003] Example 151 was synthesized using 1-cyclopropyl-1H-pyrazole-4-carboxylic acid and Example 109, following the same method as in Example 18. LCMS-ESI+(m / z): [M+H]+ C 39 H 46 ClN5O5S: Calculated value: 732.3; Measured value: 732.3.

[1004] Example 152

[1005]

[1006] Example 152 was synthesized using 1-(oxetane-3-yl)-1H-pyrazole-4-carboxylic acid and Example 110, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ8.11(s,1H),7.96(s,1H),7.76(d,J=8.4Hz,1H),7.32(dd,J=8.0,2.0Hz,1H),7.17(dd,J=8.4,2.4Hz,1H),7.10(d, J=2.4Hz,1H),7.03(d,J=2.0Hz,1H),6.79(d,J=8.0Hz,1H),6.16-6.09(m,1H),5.59-5.50(m,2H),5.05(d,J=6.8Hz,4H),4.31-4.25(m,1 H),4.15-4.00(m,3H),3.84(d,J=14.8Hz,1H),3.78(d,J=8.4Hz,1H),3.62(d,J=14.4Hz,1H),3.37-3.30(m,2H),3.24(s,3H),3.10-3.04 (m,1H),2.85-2.72(m,2H),2.47-1.68(m,10H),1.51(d,J=6.8Hz,3H),1.48-1.41(m,1H),1.18(d,J=6.8Hz,3H).LCMS-ESI+(m / z):[M+H]+ C 40 H 48 ClN5O6S: Calculated value: 762.3; Measured value: 762.1.

[1007] Example 153

[1008]

[1009] Example 153 was synthesized using the same method as in Example 18, but with 1-ethyl-1H-pyrazole-4-carboxylic acid instead of 3-methoxypropionic acid, and in Example 110. 1H NMR (400MHz, methanol-d4) δ8.00(s,1H),7.84(s,1H),7.72(d,J=8.4Hz,1H),7.38(dd,J=8.0,1.6Hz,1H),7.16(dd,J=8.6,2.2Hz ,1H),7.11(d,J=2.0Hz,2H),6.77(d,J=8.0Hz,1H),6.15-6.08(m,1H),5.57(dd,J=15.6,8.8Hz,1H),4.18(q,J=7.2Hz,2H), 4.12(q,J=7.0Hz,2H),4.07-4.00(m,2H),3.78-3.75(m,2H),3.60(d,J=14.4Hz,1H),3.39-3.33(m,2H),3.25(s,3H),3.16- 3.09(m,1H),2.86-2.73(m,2H),2.50-1.71(m,10H),1.52-1.44(m,7H),1.21(d,J=6.8Hz,3H).LCMS-ESI+(m / z):[M+H]+H+C 39 H 48 ClN5O5S: Calculated value: 734.4; Measured value: 734.2.

[1010] Example 154

[1011]

[1012] Example 154 was synthesized using 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109, following the same procedure as in Example 18. Example 109 (620 mg, 1.04 mmol) was dissolved in dichloromethane (12 mL). 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (324 mg, 2.08 mmol, 2 equivalents) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (400 mg, 2.08 mmol, 2 equivalents) were added. The reaction mixture was stirred at room temperature for 5 minutes, followed by the addition of DMAP (253 mg, 2.08 mmol, 2 equivalents) in a single batch. The reaction mixture was stirred overnight at room temperature, and the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Gilson reversed-phase preparative HPLC (60-100% ACN / H2O containing 0.1% TFA) to obtain Example 154. 1H NMR (400MHz, methanol-d4) δ8.07(s,1H),7.76(d,J=8.6Hz,1H),7.34(d,J=8.2Hz,1H),7.22–7.10(m,3H),6.92(d,J=8.2Hz,1H),6.20–6. 05(m,1H),5.63(dd,J=15.5,8.0Hz,1H),4.10(d,J=12.0Hz,1H),4.06(s,4H),3.91–3.83(m,1H),3.82(s,3H),3.79(s,1H),3.72(d ,J=14.4Hz,1H),3.38(d,J=14.5Hz,1H),3.30(s,3H),3.09(dd,J=15.1,10.0Hz,1H),2.89–2.72(m,2H),2.51(d,J=26.7Hz,2H),2. 24(dd,J=10.9,6.0Hz,2H),2.12(d,J=13.7Hz,1H),2.02–1.70(m,4H),1.54–1.40(m,1H),1.14(d,J=6.1Hz,3H).LCMS-ESI+(m / z): C 38 H 46 ClN5O6S: Calculated value: 735.28; Measured value: 735.94.

[1013] Example 155

[1014]

[1015] Example 155 was synthesized using the same method as in Example 75, employing the materials from Example 109 and (3R)-tetrahydrofuran-3-amine. ¹H NMR (400 MHz, methanol-d⁴) δ 7.73 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 7.17–7.09 (m, 2H), 6.99 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.10–5.98 (m, 1H), 5.60 (dd, J = 15.4, 8.8 Hz, 1H), 4.35–4.23 (m, 2H), 4.10–4.01 (m, 2H), 3.96–3.75 (m,6H),3.72–3.62(m,3H),3.28(s,3H),3.08(dd,J=15.1,10.2Hz,1H),2.84–2.72(m,2H),2.55–2.37(m,3H), 2.32–2.07(m,3H),1.97–1.76(m,8H),1.43(t,J=12.6Hz,1H),1.14(d,J=6.6Hz,3H).LCMS-ESI+(m / z):calcdH+ C 37 H 47 ClN4O6S, calculated value: 711.29; measured value: 710.79.

[1016] Example 156

[1017]

[1018] Example 156 was synthesized using the same method as Example 18, but instead of Example 5, Example 109 was used, and instead of 3-methoxypropionic acid, 1-cyclopropyl-1H-pyrrole-3-carboxylic acid was used. NMR (400MHz, methanol-d4) δ7.76(d,J=8.5Hz,1H),7.62(t,J=2.0Hz,1H),7.32(d,J=8 .0Hz,1H),7.18(dd,J=8.5,2.3Hz,1H),7.15-7.05(m,2H),6.95-6.84(m,2H),6 .61(dd,J=3.0,1.8Hz,1H),6.11(dt,J=14.5,6.8Hz,1H),5.61(dd,J=15.4,8.6 Hz,1H),4.27(dd,J=14.8,6.4Hz,1H),4.14-3.94(m,3H),3.87(d,J=15.1Hz,1H ),3.79(d,J=7.5Hz,1H),3.70(d,J=14.2Hz,1H),3.56-3.46(m,1H),3.36(s,1H ),3.29(s,3H),3.08(dd,J=15.0,9.4Hz,2H),2.89-2.71(m,2H),2.60-2.35(m, 3H),2.32-2.06(m,3H),1.94(d,J=11.6Hz,3H),1.88-1.66(m,3H),1.45(t,J=1 2.1Hz,1H),1.13(d,J=6.7Hz,3H),1.08-0.93(m,4H).LCMS-ESI+(m / z):[M+H]+C 40 H 47 ClN4O5S: Calculated value: 731.35; Measured value: 729.83.

[1019] Example 157

[1020]

[1021] Example 157 was prepared using 3,4-dihydro-1H-2-benzopyran-7-carboxylic acid and Example 109, following a method similar to that of Example 18. 1H NMR (400MHz, acetonitrile-d3) δ7.87(d,J=8.0Hz,1H),7.74(s,1H),7.71(d,J=8.5H z,1H),7.26(d,J=8.0Hz,1H),7.19(dd,J=8.5,2.4Hz,1H),7.16–7.07(m,2 H),6.96(s,1H),6.93(d,J=8.1Hz,1H),5.92(dt,J=14.2,6.5Hz,1H),5.55 (dd,J=15.3,8.9Hz,1H),4.77(s,2H),4.33(dd,J=15.3,5.6Hz,1H),4.05( d,J=2.2Hz,2H),3.94(t,J=5.7Hz,2H),3.84–3.64(m,3H),3.26(d,J=14.3 Hz,1H),3.18(s,3H),3.05(dd,J=15.3,10.4Hz,1H),2.89(t,J=5.7Hz,2H) ,2.84–2.65(m,3H),2.50–2.21(m,3H),2.19–2.00(m,3H),1.91–1.81(m,3 H),1.79–1.63(m,3H),1.47–1.35(m,1H),1.05(d,J=6.3Hz,3H).LCMS-ESI + (m / z): [M+H] + C 42 H 48 ClN3O6S: Calculated value: 758.33; Measured value: 758.0.

[1022] Example 158

[1023]

[1024] Example 158 was prepared using 1,4,6,7-tetrahydropyrano[4,3-b]pyrrole-2-carboxylic acid and Example 109, following a method similar to that of Example 18. 1H NMR(400MHz, acetonitrile-d3)δ9.87(s,1H),7.64(d,J=8.5Hz,1H),7.20(d,J=8.2Hz,1H), 7.09(s,1H),7.06(d,J=8.7Hz,1H),7.01(s,1H),6.85(d,J=8.2Hz,1H),6.78(s, 1H),5.98(dt,J=13.9,6.5Hz,1H),5.58(dd,J=15.4,8.4Hz,1H),4.56(d,J=2.7H z,2H),4.13(dd,J=15.0,5.9Hz,1H),4.00(s,2H),3.87(t,J=5.6Hz,2H),3.82–3 .70(m,3H),3.66(d,J=15.1Hz,1H),3.32(d,J=14.6Hz,1H),3.20(s,3H),3.05(d d,J=15.3,10.1Hz,1H),2.84–2.65(m,3H),2.52(dd,J=11.6,5.3Hz,1H),2.40(d t,J=16.5,6.2Hz,2H),2.27–2.08(m,3H),2.07–1.98(m,1H),1.91–1.81(m,3H), 1.81–1.62(m,3H),1.37(dt,J=15.1,7.8Hz,1H),1.06(d,J=6.3Hz,3H).LCMS-ESI + (m / z): [M+H] + C 40 H 47 ClN4O6S: Calculated value: 747.30; Measured value: 747.0.

[1025] Example 159

[1026]

[1027] Example 109 (11 mg, 0.018 mmol), (1S,2R)-2-methylcyclopropane-1-carboxylic acid (0.014 mL, 0.147 mmol), diphenylphosphoazide (0.032 mL, 0.147 mmol), and trimethylamine (0.028 mL, 0.202 mmol) were suspended in MeCN (2 mL). The reaction mixture was heated to 50 °C overnight and then cooled to room temperature. i-PrOAc (10 mL) and saturated NH4Cl (8 mL) were added, and the mixture was stirred for 10 minutes. The layers were separated, and the aqueous phase was extracted with i-PrOAc. The organic phases were combined, washed twice with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (50% EtOAc / Hex to 40% MeOH / EtOAc) to give Example 159 (6 mg). 1H NMR (400MHz, methanol-d4) δ7.73(d,J=8.5Hz,2H),7.41(s,1H),7.29(s,1H),7.19-7.06(m,4H),6.82(d,J=8.1Hz,2H),6.17(s,2H),5.56(s, 2H),4.08-3.95(m,3H),3.86-3.77(m,4H),3.69(d,J=32.3Hz,4H),3.27(s,3H),3.08(d,J=12.6Hz,1H),2.77(d,J=21.0Hz,3H),2.62( s,3H),2.50(td,J=7.3,4.1Hz,1H),2.38(s,2H),2.26(s,1H),2.19(s,1H),2.09(d,J=13.6Hz,2H),1.93(s,5H),1.78-1.70(m,2H),1. 41(d,J=13.7Hz,1H),1.29(s,1H),1.06(dd,J=18.0,10.9Hz,14H),0.89(ddd,J=15.2,8.9,4.2Hz,6H),0.15-0.06(m,4H).LCMS-ESI+:C 37 H 47 ClN4O5S: Calculated value: 695.3 (M+H); Measured value: 695.2 (M+H).

[1028] Example 160

[1029]

[1030] Example 160, a mixture of diastereomers, was synthesized using the same method as in Example 364, employing Example 109 and racemic-(1S*,2S*)-2-methoxycyclopropane-1-carboxylic acid. LCMS-ESI+(m / z): [M+H] + C 37 H 47 ClN4O6S: Calculated value: 711.2978; Measured value: 710.68. 1 H NMR (400MHz, methanol-d4) δ7.72(dd,J=8.4,2.3Hz,1H),7.22–7.04(m,3H),7.00–6.84(m,2H),6.10–5.92(m,1H),5.58(dd,J=1 5.2,8.9Hz,1H),4.25(d,J=15.3Hz,1H),4.12–3.96(m,2H),3.90–3.71(m,3H),3.66(d,J=14.3Hz,1H),3.43(d,J=1.8Hz, 3H),3.29–3.24(m,1H),3.26(s,3H),3.06(dd,J=15.2,10.2Hz,1H),2.88–2.69(m,2H),2.62(s,1H),2.55–2.28(m,3H),2 .26–2.04(m,3H),2.01–1.67(m,7H),1.41(t,J=12.8Hz,1H),1.12(d,J=6.5Hz,3H),1.06–0.97(m,1H),0.86–0.76(m,1H).

[1031] Example 161

[1032]

[1033] Example 161 was synthesized using the same method as in Example 364, employing the materials from Example 109 and (1R)-2,2-difluorocyclopropanecarboxylic acid. LCMS-ESI+(m / z): [M+H] + C 36 H 43 ClF2N4O5S: Calculated value: 717.2684; Measured value: 716.58. 1¹H NMR (400 MHz, methanol-d⁴) δ 7.73 (d, J = 8.5 Hz, 1H), 7.20–7.07 (m, 3H), 7.00–6.86 (m, 2H), 5.98 (dd, J = 14.7, 7.7 Hz, 1H), 5.58 (dd, J = 15.2, 9.0 Hz, 1H), 4.30 (dd, J = 15.1, 6.2 Hz, 1H), 4.16–3.98 (m, 2H), 3.9 2-3.59(m,4H),3.29-3.24(m,1H),3.25(s,3H),3.06(dd,J=15.3,10.3Hz,1H),2.89-2.64(m,2H), 2.56-2.25(m,3H),2.26-2.05(m,3H),2.00-1.66(m,6H),1.52–1.34(m,2H),1.12(d,J=6.4Hz,3H).

[1034] Example 162

[1035]

[1036] Example 162 was prepared using a method similar to that of Example 159, with (1R,2S)-2-methylcyclopropane-1-carboxylic acid (0.014 mL, 0.147 mmol), diphenylphosphoazide, triethylamine, and the methods described in Example 109. LCMS-ESI+: C 37 H 47 ClN4O5S: Calculated value: 695.3 (M+H); Measured value: 695.2 (M+H).

[1037] Example 163

[1038]

[1039] Example 163 was prepared using pyrrolo[1,2-c]pyrimidine-6-carboxylic acid and Example 109, following a similar method to Example 18. 1H NMR (400MHz, acetonitrile-d3) δ8.97 (s, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.4Hz, 1H), 7.4 2(d,J=6.6Hz,1H),7.36(d,J=6.5Hz,1H),7.18(d,J=8.1Hz,1H),7.13(d,J =8.6Hz,1H),7.12(s,1H),7.00(d,J=1.8Hz,1H),6.91(d,J=8.2Hz,1H),6. 85(s,1H),6.03–5.90(m,1H),5.57(dd,J=15.3,8.6Hz,1H),4.26(d,J=15. 1Hz,1H),4.04(s,2H),3.79(d,J=15.2Hz,2H),3.74–3.64(m,2H),3.30(d, J=14.3Hz,1H),3.19(s,3H),3.06(dd,J=15.3,10.4Hz,2H),2.85–2.66(m, 3H),2.52–2.27(m,4H),2.22–2.13(m,2H),2.05(d,J=13.9Hz,1H),1.83–1 .64(m,3H),1.39(dt,J=14.5,7.4Hz,1H),1.09(d,J=6.1Hz,2H).LCMS-ESI + (m / z): [M+H] + C 40 H 44 ClN5O5S: Calculated value: 742.28; Measured value: 742.0.

[1040] Example 164

[1041]

[1042] Example 164 was synthesized using 3-cyclopropyl-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109, following the same method as in Example 18. 1H NMR (400MHz, methanol-d4) δ8.28(s,1H),7.65(d,J=8.5Hz,1H),7.28(d,J=8.1Hz,1H),7.07(d,J=2.2Hz,1H),6.99(d,J=1.9Hz,1H),6.8 6(d,J=8.3Hz,1H),6.19–6.05(m,1H),5.66(dd,J=15.3,8.7Hz,1H),4.25(s,1H),4.02(s,2H),3.82(s,5H),3.65(d,J=14.3Hz,1H) ,3.39(d,J=14.5Hz,1H),3.31(s,3H),3.18–3.03(m,1H),2.90–2.62(m,3H),2.52(d,J=39.0Hz,3H),2.28(d,J=10.7Hz,2H),2.16– 2.04(m,2H),1.96(m,4H),1.83(s,3H),1.40(t,J=12.5Hz,1H),1.18(d,J=6.2Hz,3H),1.01–0.79(m,5H).LCMS-ESI+(m / z):[M+H]+ C 40 H 48 ClN5O5S: Calculated value: 746.3; Measured value: 746.0.

[1043] Example 165

[1044]

[1045] Example 165 was synthesized using the same method as in Example 18, employing Example 109 and cis-3-hydroxy-3-methyl-cyclobutanecarboxylic acid. ¹H NMR (400 MHz, methanol-d⁴) δ 7.72 (d, J = 9.1 Hz, 1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 7.09 (dt, J = 7.5, 2.0 Hz, 3H), 6.86 (d, J = 8.3 Hz, 1H), 6.14 (dt, J = 14.6, 7.0 Hz, 1H), 5.63 (dd, J = 15.4, 8.4 Hz, 1H), 4.14 (dd, J = 14.8, 7.0 Hz, 1H), 4.08– 3.93(m,3H),3.87–3.74(m,2H),3.67(d,J=14.3Hz,1H),3.30(s,3H),3.11–3.02(m,1H),2.92–2.70(m,3H),2. 58–2.23(m,8H),2.15–2.05(m,2H),2.04–1.72(m,7H),1.38(s,4H),1.14(d,J=6.9Hz,3H).LCMS-ESI+(m / z):H+ C 38 H 48 ClN3O6S: Calculated value: 710.30; Measured value: 710.05.

[1046] Example 166

[1047]

[1048] Example 166 was synthesized using the same method as in Example 18, employing Example 110 and cis-3-hydroxy-3-methyl-cyclobutanecarboxylic acid. ¹H NMR (400 MHz, methanol-d⁴): δ 7.75 (d, J = 8.5 Hz, 1H), 7.25–7.15 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 7.10–7.02 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.03–5.92 (m, 1H), 5.61 (dd, J = 15.3, 8.7 Hz, 1H), 4.38–4.27 (m, 1H), 4.13–4.03 (m, 2H), 3.83 (d, J = 15.1 Hz, 1H), 3.7 7–3.71(m,1H),3.68(d,J=14.3Hz,1H),3.25(s,3H),3.18–3.08(m,1H),2.90–2.71(m,3H),2.50–2.20(m,9H),2.16–2.07( m,1H),2.01–1.72(m,7H),1.55(d,J=7.1Hz,3H),1.52–1.41(m,1H),1.38(s,3H),1.14–1.05(m,3H).LCMS-ESI+(m / z):H+C 39 H 50 ClN3O6S: Calculated value: 724.31; Measured value: 723.99.

[1049] Example 167

[1050]

[1051] Step 1: A mixture of methyl 5-formyl-1H-pyrrole-3-carboxylate (500 mg, 3.27 mmol), (S)-2-methylethylene oxide (458 μL, 6.53 mmol), and cesium carbonate (2.13 g, 6.53 mmol) in acetonitrile (6.0 mL) and methanol (2.0 mL) under vigorous stirring was heated to 60 °C. After 45 minutes, the reaction mixture was cooled to room temperature, and ethyl acetate (60 mL) was added. The organic layer was washed with a mixture of water and brine (1:1 v:v, 40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 70% ethyl acetate in hexane) to give 167-1.

[1052] Step 2: At 0°C, trifluoroacetic acid (163 μL, 2.13 mmol) was added via syringe to a 40 mL solution of 167-1 (150 mg, 0.710 mmol) in dichloromethane under stirring. After 2 minutes, triethylsilane (343 μL, 2.15 mmol) was added via syringe, and the resulting mixture was warmed to room temperature. After 45 minutes, triethylamine (1.0 mL) was added via syringe, and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography (0 to 40% ethyl acetate in hexane) to obtain 167-2.

[1053] Step 3: At room temperature, sodium hydroxide aqueous solution (2....

Claims

1. Compounds selected from formulas C, D, H, J-1, J-2, I-1, and I-2: , , , , , ,and , in: X is O; R 1 C 1-6 Alkyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-12 membered heterocyclic, 5-10 membered heteroaryl, –OR 7 Or –NR 8 R 9 Wherein C 1-6 Alkyl, C 2-6 alkynyl group, C 3-10 Cycloalkyl, 3-12-membered heterocyclic and 5-10-membered heteroaryl groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups; R 2 is hydrogen, C 1-6 alkyl; R 3 is hydrogen, C 1-6 alkyl; R 5 C 1-6 Alkyl, C 1-6 Heteroalkyl, wherein the C 1-6 Alkyl and C 1-6 Heteroalkyl groups are optionally surrounded by 1-5 R groups. 10 Substituted by groups; R 6 is hydrogen or halogen; Each R 7 Independently hydrogen, C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, C 6-10 Aryl and 5-10 heteroaryl groups are optionally coated with 1-5 R groups. 10 Replaced; Each R 8 and R 9 Independently hydrogen, C 1-6 Alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl groups and 3-12-membered heterocyclic groups are optionally surrounded by 1-5 R groups. 10 Replaced; Each R 10 Independently for C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 heteroaryl, halogen, oxo group, –OR a –C(O)R a –C(O)OR a –OC(O)NR a R b –NR a R b –S(O) q R a –CN, where each C 1-6 Alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, 3-12 membered heterocyclic and 5-10 membered heteroaryl, optionally with 1-5 Rs 20 Substituted by groups; Each R a and R b Independently hydrogen, C 1-6 Alkyl, 3-12 membered heterocyclic groups, C 6-10 aryl, 5-10 heteroaryl, or R a and R b Together with the atoms they are attached to, they form 3-12 membered heterocyclic groups, wherein the C 1-6 Alkyl, 3-12 membered heterocyclic groups, C 6-10 Aryl, 5-10 aryl groups, optionally coated with 1-5 R groups 20 Substituted by groups; Each R 20 Independently for C 1-6 Alkyl, C3- 10 Cycloalkyl, C1-6 heteroalkyl, 3-12 membered heterocyclic, C6-C 10 Aryl, hydroxyl, C 1-6 Alkoxy, -CN, -C(O)OC 1-6 Alkyl or halogen; and q is 2.

2. The compound of claim 1, wherein: R 2 is hydrogen or C 1-3 alkyl; R 3 is hydrogen or C 1-3 alkyl; R 5 C 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally replaced by 5-6 membered heterocyclic groups.

3. The compound of claim 1, wherein: R 2 is hydrogen, methyl or ethyl; R 3 is hydrogen or methyl; R 4 is hydrogen; and R 5 is methyl, or .

4. The compound of claim 1, wherein R 2 It is hydrogen.

5. The compound of claim 1, wherein R 3 is methyl.

6. The compound of claim 1, wherein R 5 is methyl.

7. The compound of claim 1, wherein R 6 is Cl.

8. The compound of any one of claims 1-7, wherein R 1 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

9. The compound of any one of claims 1-7, wherein –C(O)R 1 Selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

10. Compounds selected from: , , , and .

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