Cyclin inhibitors

Abstract

Compound of formula (I), JPEG2026521124000638.jpg54170 The intermediate and a method for manufacturing the same are disclosed herein. Furthermore, this specification also describes the use of such compounds and compositions for the treatment of diseases and disorders mediated by at least one or more cyclins, including cancer.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 467,651, filed 19 May 2023; U.S. Provisional Patent Application No. 63 / 612,533, filed 20 December 2023; and U.S. Provisional Patent Application No. 63 / 637,984, filed 24 April 2024, each of which disclosures are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Cyclins are a family of proteins that play a central role in regulating the cell cycle. Certain cyclins, including cyclins D, E, A, and B, are expressed at different stages of the cell cycle, during which they bind to and activate their cognitive cyclin-dependent kinases (CDKs), including CDK1, 2, 4, and 6, forming cyclin-CDK complexes that regulate the progression and transition of different stages of the cell cycle. Disruption of the normal regulatory function of cyclin-CDK complexes is a common driver of tumorigenesis and rapid proliferation of cancer cells. The central roles of cyclins and CDKs in the cell cycle make these proteins and their complexes attractive targets for treating proliferative disorders and cancer. To date, most inhibitors of cyclin-CDK complexes target the kinase activity of CDKs ("CDK inhibitors"), including therapeutics in development and those approved for clinical use. Alternative approaches may include disrupting the association of cyclins and CDKs, or the interaction of specific cyclin-CDK complexes with their substrates or regulators.

[0003] CDK inhibitors have been developed and proven successful in certain cancers, but are currently limited by a relative lack of selectivity, a narrow therapeutic window, and ultimately the development of resistance. Therefore, there is a need to develop agents that provide an alternative approach to inhibiting the function of cyclin-CDK complexes as a means of regulating the cell cycle. Such agents could provide new tools in the treatment of proliferative diseases. The present disclosure addresses this need by providing compounds that inhibit the binding of substrates to various cyclins, thereby disrupting the function of cyclin-CDK complexes. SUMMARY OF THE INVENTION

[0004] In one embodiment, a compound of formula (I):

Chemical formula

[0005] In another embodiment, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure and a pharmaceutically acceptable excipient.

[0006] In another embodiment, the Disclosure provides a method for treating a disease or disorder that is at least partially mediated by cyclin activity, the method comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject in need thereof, thereby treating the disorder or condition.

[0007] In another embodiment, the Disclosure provides a method for treating cancer at least partially mediated by cyclin A, comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject in need thereof, thereby treating the cancer.

[0008] In another embodiment, the present invention provides an intermediate useful for the preparation of a compound of formula (I).

[0009] Other purposes, features, and advantages of this disclosure will be apparent to those skilled in the art from the following detailed description and figures. [Brief explanation of the drawing]

[0010] Not applicable [Modes for carrying out the invention]

[0011] I. General Compounds and compositions that disrupt the typical cellular functions of cyclins are provided herein. For example, methods for treating or preventing diseases, disorders or conditions, or symptoms thereof, that are mediated by cyclin activity are also provided herein.

[0012] The complex between cyclins and cyclin-dependent kinases (CDKs) phosphorylates a wide range of substrates, thereby regulating their activity. Many of these substrates are important in the cell cycle, and therefore, cyclins and CDKs that regulate these substrates, including cyclins D, A, E, and B, and CDKs 1, 2, 4, and 6, play a crucial role in cell cycle regulation. While not bound by any particular theory, certain substrates, including p21, p27, Rb, E2F, and CDC6, initially bind to the cyclin-CDK complex via a conserved RxL motif within the substrate (Adams et al. Mol Cell Biol. 1996.16(12):6223-33), and then bind to a region of the cyclin containing a highly conserved MRAIL motif, referred to as the RxL binding domain or "hydrophobic patch" (Brown et al. Nat Cell Biol. 1999.1(7):438-43). Compounds that disrupt the binding of substrates to cyclins are thought to have potential therapeutic benefits, including the inhibition of cancer cell proliferation (Chen et al. Proc Natl Acad Sci US A.1999.96(8):4325-9).

[0013] While not bound by any particular theory, the compounds of this disclosure are thought to inhibit substrate binding to the hydrophobic patch regions of cyclins A, E, and B, but not limited to these. The compounds of this disclosure include compounds that bind more strongly to one or more cyclins.

[0014] II. Definition As used herein, the term “approximately” means a range of values ​​that includes a specified value, which a person skilled in the art would reasonably consider to be similar to the specified value. In some embodiments, the term “approximately” means within a standard deviation using generally accepted measurements in the art. In some embodiments, “approximately” means a range extending to + / - 10% of the specified value. In some embodiments, “approximately” means the specified value.

[0015] "Alkyl" refers to a linear or branched saturated aliphatic group having the indicated number of carbon atoms. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 It can contain any number of carbon atoms, such as C. 1-6 Alkyls, while not limited to these, include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Alkyls can also refer to alkyl groups having up to 20 carbon atoms, such as heptyl, octyl, nonyl, and decyl, while not limited to these. Alkyl groups can be substituted or unsubstituted.

[0016] "Alkylene" refers to a linear or branched saturated aliphatic group having the indicated number of carbon atoms and linking at least two other groups, i.e., divalent hydrocarbon groups. The two parts linked to the alkylene can be linked to the same or different atoms of the alkylene group. For example, a linear alkylene is -(CH2) n It can be a divalent radical, where n is 1, 2, 3, 4, 5, or 6. Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. The alkylene group may be substituted or unsubstituted.

[0017] "Alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl is C2, C 2-3 , C2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 It can contain any number of carbon atoms, including C6. The alkenyl group can have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl(ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexadienyl. The alkenyl group can be substituted or unsubstituted.

[0018] "Alkenylene" refers to a straight-chain or branched hydrocarbon, i.e., a divalent hydrocarbon radical, that links at least two carbon atoms, one double bond, and at least two other groups. Alkenylene is C2,C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C 3-6 , C 3-7 , C4, C 4-5 , C 4-6 , C 4-7 , C 6-7It can contain any number of carbon atoms, such as C5, C6, and C7. The two parts bonded to the alkenylene can be bonded to the same atom or different atoms of the alkenylene group. Representative alkenylene groups include, but are not limited to, (E)-hexa-2-enylene, (Z)-hexa-2-enylene, (E)-hepta-2-enylene, (Z)-hepta-2-enylene, (E)-hepta-3-enylene, and (Z)-hepta-3-enylene. The alkenylene part may be an E or Z isomer. The alkenylene group may be substituted or unsubstituted.

[0019] "Alkynyl" refers to either a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl is C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 It can contain any number of carbon atoms, including C6. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiinyl, 1-pentynyl, 2-pentynyl, isopentinyl, 1,3-pentadinyl, 1,4-pentadinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadinyl, 1,4-hexadinyl, 1,5-hexadinyl, 2,4-hexadinyl, or 1,3,5-hexatriinyl. The alkynyl group can be substituted or unsubstituted.

[0020] "Alkoxy" refers to an alkyl group that has an oxygen atom bonded to the alkyl group at its bonding site: alkyl-O-. Regarding alkyl groups, the alkoxy group is C 1-6It can have any appropriate number of carbon atoms, such as methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy. The alkoxy group may be substituted or unsubstituted.

[0021] "Alkoxyalkyl" refers to an alkyl group bonded to an oxygen atom further bonded to a second alkyl group, and the second alkyl group is the bonding site with the rest of the molecule: alkyl-O-alkyl. The alkyl part is C 2-6 It can have any appropriate number of carbon atoms, such as methoxymethyl, ethoxymethyl, methoxyethyl, and ethoxyethyl. The alkoxy group can be substituted or unsubstituted.

[0022] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0023] "Haloalkyl" refers to an alkyl group as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to alkyl groups, haloalkyl groups are C 1-6 They can have any appropriate number of carbon atoms, such as trifluoromethyl and fluoromethyl. For example, haloalkyls include trifluoromethyl and fluoromethyl. In some cases, the term "perfluoro" can be used to define a compound or radical in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0024] A "haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. Regarding alkyl groups, haloalkoxy groups are C 1-6It can have any appropriate number of carbon atoms, such as alkoxy groups. The alkoxy group can be substituted with one, two, three or more halogens. If all hydrogens are substituted with halogens, such as fluorine, the compound is oversubstituted, for example, perfluorinated. Haloalkoxys include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and perfluoroethoxy.

[0025] "Cycloalkyl" refers to saturated or partially unsaturated monocyclic, spirocyclic, condensed, or bridging polycyclic ring assemblies containing 3 to 12 ring atoms or the indicated number of atoms. Cycloalkyls can contain any number of carbon atoms, for example, C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 and C 3-12 This may include saturated monocyclic cycloalkyl rings, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. The cycloalkyl group may be partially unsaturated and have one or more double or triple bonds in the ring, but the cycloalkyl group is not aromatic. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl (1,3- and 1,4-isomers), cycloheptenyl, cycloheptadienyl, cyclooctenyl, cyclooctadienyl (1,3-, 1,4- and 1,5-isomers), norborneyl, and norbornadienyl. 3-6When the cycloalkyl group is monocyclic, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl (1,3- and 1,4-isomers). 5-10 In the case of condensed bicyclic cycloalkyl groups, exemplary groups include, but are not limited to, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl, bicyclo[4.2.0]octanyl, and octahydro-1H-indenyl. 5-10 When the cycloalkyl group is crosslinked polycyclic cycloalkyl, exemplary groups include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, and bicyclo[2.1.1]hexane. 5-10 In the case of spirocycloalkyl groups, exemplary groups include, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonanyl, spiro[2.5]octane, and spiro[2.4]heptane. Cycloalkyl groups may be substituted or unsubstituted.

[0026] "Heterocycloalkyl" refers to saturated or partially unsaturated monocyclic, spirocyclic, condensed, or bridging polycyclic ring assemblies having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. The heteroatoms may be oxidized, but are not limited to -S(O)- and -S(O)2-. A heterocycloalkyl group can contain any number of ring atoms, e.g., 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms may be included in heterocycloalkyl groups such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4. Examples of heterocycloalkyl groups include aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), tetrahydropyridine, oxepan, thiirane, thiethane, thiolane (tetrahydrothiophene), thian (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups may be unsubstituted or substituted.

[0027] Heterocycloalkyl groups can be linked at any position on the ring. For example, aziridine may be 1- or 2-aziridine, azetidine may be 1- or 2-azetidine, pyrrolidine may be 1-, 2- or 3-pyrrolidine, piperidine may be 1-, 2-, 3- or 4-piperidine, pyrazolidine may be 1-, 2-, 3- or 4-pyrazolidine, imidazolidine may be 1-, 2-, 3- or 4-imidazolidine, piperazine may be 1-, 2-, 3- or 4-piperazine, tetrahydrofuran may be 1- or 2-tetrahydrofuran, oxazolidine may be 2-, 3-, 4- or 5-oxazolidine, thiazolidine may be isoxazolidine may be 2-, 3-, 4- or 5-thiazolidine, isothiazolidine may be 2-, 3-, 4- or 5-isothiazolidine, and morpholine may be 2-, 3- or 4-morpholine.

[0028] When a heterocycloalkyl is a monocyclic heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, typical members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. Heterocycloalkyls can also be monocyclic heterocycloalkyls having 5 to 6 ring members and 1 to 2 heteroatoms, and typical members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0029] "Aryl" refers to an aromatic ring system having any appropriate number of ring atoms and any appropriate number of rings. An aryl group can contain any appropriate number of ring atoms, e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6-10, 6-12, or 6-14 ring members. An aryl group can be monocyclic, condense to form a bicyclic or tricyclic group, or bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linkage. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, e.g., phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

[0030] A "heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5 to 12 ring atoms, where 1 to 6 of the ring atoms are heteroatoms such as N, O, or S. The heteroatoms are, but are not limited to, -S(O)- and -S(O)2-, and may be oxidized. A heteroaryl group can contain any number of ring atoms, for example, 5 to 6, 5 to 8, 5 to 9, 5 to 10, 5 to 12, or 9 to 12 ring members. Any appropriate number of heteroatoms can be included in a heteroaryl group, such as 1, 2, 3, 4, 5, or 6, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 2 to 6, 3 to 4, 3 to 5, or 3 to 6. A heteroaryl group may have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5 isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also condense with aromatic ring systems such as phenyl rings to form members including, but not limited to, benzopyrroles (e.g., indole and isoindole), benzopyridines (e.g., quinoline and isoquinoline), benzopyrazines (quinoxaline), benzopyrimidines (quinazoline), benzopyridazines (e.g., phthalazine and cinnoline), benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0031] Heteroaryl groups can be linked at any position on the ring. For example, pyrrole contains 1-,2- and 3-pyrrole; pyridine contains 2-,3- and 4-pyridine; imidazole contains 1-,2-,4- and 5-imidazole; pyrazole contains 1-,3-,4- and 5-pyrazole; triazole contains 1-,4- and 5-triazole; tetrazole contains 1- and 5-tetrazole; pyrimidine contains 2-,4-,5- and 6-pyrimidine; pyridazine contains 3- and 4-pyridazine; 1,2,3-triazine contains 4- and 5-triazine; 1,2,4-triazine contains 3-,5- and 6-triazine; thiophene contains 2- and 3-thiophene; and furan contains 2- and 3-furan. The compounds include: thiazoles contain 2-, 4-, and 5-thiazoles; isothiazoles contain 3-, 4-, and 5-isothiazoles; oxazoles contain 2-, 4-, and 5-oxazoles; isoxazoles contain 3-, 4-, and 5-isoxazoles; indole contains 1-, 2-, and 3-indoles; isoindole contains 1-, and 2-isoindoles; quinoline contains 2-, 3-, and 4-quinolines; isoquinoline contains 1-, 3-, and 4-isoquinolines; quinazoline contains 2-, and 4-quinoazolines; sinnoline contains 3-, and 4-sinnolines; benzothiophene contains 2-, and 3-benzothiophene; and benzofuran contains 2-, and 3-benzofurans.

[0032] Some heteroaryl groups have 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5 isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups have 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5 isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those with 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Further, other heteroaryl groups include those with 5 to 6 ring members and 1 to 2 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0033] "Thiophenyl" refers to the thiophene radical.

[0034] As used herein, the term "oxo" refers to an oxygen atom bonded to a bond site by a double bond (=O).

[0035] "Pharmacologically acceptable excipients" refers to substances that assist in the formulation and / or administration of an active agent to a subject. Useful pharmaceutical excipients in this disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, and colorants. Those skilled in the art will recognize that other pharmaceutical excipients may be useful in this disclosure.

[0036] The term "subject" is not limited to animals, but refers to mammals including primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is human.

[0037] "Administering" refers to oral administration, suppository administration, topical contact administration, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intrafocal administration, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained-release device, such as a mini osmotic pump.

[0038] The "therapeutic dose" refers to the dosage administered that produces a therapeutic effect. The exact dosage depends on the purpose of treatment and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0039] "To treat," "to heal," and "treatment" mean indicators of success in treating or improving an injury, pathology, condition, or symptom (e.g., pain), including objective or subjective parameters such as reduction, remission, symptom relief, or making the symptom, injury, pathology, or condition more tolerable to the patient, or reducing the frequency or duration of the symptom or condition. Treatment or improvement of a symptom may be based on any objective or subjective parameters, including, for example, the results of a physical examination.

[0040] III.Compound In some embodiments, the present disclosure relates to a compound of formula (I): [ka] And, R 3 teeth (a) Each of the R's has 0 to 5 3a Replaced with, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl or C 1-6 It is a haloalkyl, (b) 0 to 5 R 3b C replaced by 3-12 It is cycloalkyl, or (c) A heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently being N, O, or S, and 0 to 5 R 3c It is a heterocycloalkyl that is substituted with, (g) A heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently being N, O, or S, with 0, 1, 2, 3, 4, or 5 R 3g It is a heteroaryl that is substituted with, Each R 3a is -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OC(O)C 1-6 It is alkyl, Each R 3b C 1-6 Alkyl, C2-6 Alkenil, C 2-6 Alkinyl, -OH, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy or cyano, Each R 3c Independently, C 1-6 alkyl, halo, C 1-6 Haloalkyl, cyano, C 3-6 It is cycloalkyl or oxo, Each R 3g Independently, C 1-6 alkyl, halo, C 1-6 Haloalkyl or C 3-6 It is a cycloalkyl, R 4a H or C 1-6 It is alkyl, R 4b and R 4c These are H and C, respectively, independently. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 The compounds are alkyl-phenyl, heteroaryl, or C1-6 alkyl-heteroaryl, where each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S, and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S. Alternatively, R 4c and R 4a These, together with the carbon and nitrogen atoms to which they are bonded, form a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms (each independently N, O, or S), and the heterocycloalkyl has 0 to 4 R 4a1 It has been replaced with, Each R 4a1 Independently, C 1-6 alkyl, -OH, C 1-6alkyl-OH, C 1-6 It is an alkoxy or halo, R 5a H or C 1-6 It is alkyl, R 5b and R 5c These are H and C, respectively, independently. 1-6 Alkyl, -C 1-6 alkyl-OH, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, -C 1-6 Alkyl-C(O)NR 5b1 R 5b2 , -C 1-6 Alkyl-C(O)OR 5b1 , C 3-6 Cycloalkyl, C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6 Alkyl-heteroaryl (Each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 5b5 (It is replaced by) Each R 5b1 and R 5b2 H and C are independent of each other. 1-4 Alkyl, or C 1-4 It is a haloalkyl, Alternatively, R 5b1 and R 5b2 Each of these atoms, together with the nitrogen atom to which it is bonded, forms a heterocycloalkyl group having 3 to 6 ring members and 0 to 1 additional heteroatom, and this heterocycloalkyl group has 0 to 2 R 5b3 It has been replaced with, Each R 5b3 and R 5b5 Independently, C1-6 alkyl, halo, C 1-6 It is a haloalkyl or cyano; X 6 C 6-7 Alkylene or C 6-7 It is alkenylene, R 6a H, C 1-6 Alkyl, C 1-6 Alkyl deuterated, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6 Alkyl-heteroaryl compounds are such that heterocycloalkyl compounds have 3 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S), and heteroaryl compounds have 5 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S). R 6b and R 6d These are, independently, H or C 1-6 It is alkyl, R 7a H or C 1-6 It is alkyl, R 7b and R 7c These are H and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 1-6 It is a haloalkyl, C 1-6 alkyl-OH, C 3-6 Cycloalkyl, or -C 1-6 Alkyl-C 3-6 It is a cycloalkyl, R 8a H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl or -C 1-6 Alkyl-C 3-6 It is a cycloalkyl, R 8b , R 8d and R 8e These are, independently, H or C 1-6 It is alkyl, Ring B has 5 to 12 ring members and 1 to 6 heteroatoms. 6-12 It is an aryl or heteroaryl compound, each independently being N, O, or S. The subscript m8 is an integer between 0 and 5. Each R 8f C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, halo, C 1-6 Haloalkyl, cyano, -X 8f -Cyan, C 3-12 It is a cycloalkyl, -X 8f -C 3-6 Cycloalkyl, -CH=CR 8f1 R 8f2 , heterocycloalkyl, -X 8f -heterocycloalkyl, C 6-12 Ariel, -X 8f -C 6-12 Aryl, heteroaryl, or -X 8f - Heteroaryl (Each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0 to 3 R 8f3 (It is replaced by) Alternatively, two R's on adjacent ring vertices 8f The bases combine to form C 3-6A cycloalkyl group or a heterocycloalkyl group having 3 to 6 ring members and 1 to 3 heteroatoms is formed, each independently being N, O, or S, and the cycloalkyl group or heterocycloalkyl group has 0 to 3 R atoms. 8f3 It has been replaced with, each X 8f Independently, C 1-6 Alkilen, C 2-6 Alkenylene, -OC 1-6 Alkylene, C(O), O, or S; Each R 8f1 and R 8f2 These combine with the carbon atoms to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms (each independently being N, O, or S), and the heterocycloalkyl has 0 to 3 R 8f3 And, Each R 8f3 Independently, C 1-6 Alkyl, -Y 8 -C 1-6 Alkyl, C 1-6 It is an alkyl deuterated, -Y 8 -C 1-6 Alkyl deuterated, -OH, -C 1-6 alkyl-OH, -Y 8 -C 1-6 It is alkyl-OH, -C 1-6 Alkyl-Y 8 -C 1-6 Alkyl, -(C 1-2 Alkyl-O)1-4-C 1-2 Alkyl, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, -Y 8 -C 1-6 Haloalkyl, cyano, -C 1-6 Alkyl-cyano, -C 1-6 Alkyl-NR 8g R 8h , oxo, C 3-6 Cycloalkyl, -X 8f3 -C 3-6 Cycloalkyl, heterocycloalkyl, -X 8f3-heterocycloalkyl, phenyl, -X 8f3 -phenyl, heteroaryl, or -X 8f3 -A heteroaryl group, each heterocycloalkyl group has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, S or S(O)2, each heteroaryl group has 5 to 10 ring members and 1 to 4 heteroatoms, or each heterocycloalkyl group and heteroaryl group has 0 to 2 C 1-4 Substituted with alkyl or halo, each X 8f3 Independently, C 1-6 It is alkylene, O, C(O), or S(O)2, Each Y 8 These are independently C(O), C(O)O, and N(R 8f4 ) C(O), O, S, or S(O)2, Each R 8g and R 8h H and C are independent of each other. 1-3 Alkyl or C 1-6 It is a haloalkyl, Alternatively, two R's on the same or adjacent ring vertices 8f3 The groups combine to form a carbon atom with 3 to 6 ring members and 1 to 3 heteroatoms (each independently containing N, O, or S). 3-6 It forms a cycloalkyl or heterocycloalkyl, and the nitrogen atom ring member in the heterocycloalkyl is 0 to 1 C 1-4 It is substituted with alkyl, and Each R 8f4 H or C 1-6 It is alkyl, or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the present disclosure relates to a compound of formula (I): [ka] And, During the ceremony, R 3 teeth (a) Each of the R's has 0 to 5 3a Replaced with, C 1-6Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl or C 1-6 It is a haloalkyl, (b) 0 to 5 R 3b C replaced by 3-12 It is cycloalkyl, or (c) A heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently being N, O, or S, and 0 to 5 R 3c It is a heterocycloalkyl that is substituted with, Each R 3a is -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OC(O)C 1-6 It is alkyl, Each R 3b C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, -OH, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy or cyano, Each R 3c Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 It is a cycloalkyl or oxo, R 4a H or C 1-6 It is alkyl, R 4b and R 4c These are H and C, respectively, independently. 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6Alkyl-heteroaryl compounds, where each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S), and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S). Alternatively, R 4c and R 4a These, together with the carbon and nitrogen atoms to which they are bonded, form a heterocycloalkyl group having 3 to 6 ring members, and the heterocycloalkyl group has 0 to 4 R 4a1 It has been replaced with, Each R 4a1 Independently, C 1-6 alkyl, -OH, C 1-6 alkyl-OH, C 1-6 It is an alkoxy or halo, R 5a H or C 1-6 It is alkyl, R 5b and R 5c These are H and C, respectively, independently. 1-6 Alkyl, -C 1-6 alkyl-OH, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6 Alkyl-heteroaryl (Each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 5b5 (It is replaced by) Each R 5b5 Independently, C 1-6 Alkyl, halo, or C 1-6It is a haloalkyl, X 6 C 6-7 Alkylene or C 6-7 It is alkenylene, R 6a H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6 Alkyl-heteroaryl compounds are such that heterocycloalkyl compounds have 3 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S), and heteroaryl compounds have 5 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S). R 6b and R 6d These are, independently, H or C 1-6 It is alkyl, R 7a H or C 1-6 It is alkyl, R 7b and R 7c These are H and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 1-6 It is a haloalkyl, C 1-6 alkyl-OH, C 3-6 Cycloalkyl, or -C 1-6 Alkyl-C 3-6 It is a cycloalkyl, R 8a H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl or -C 1-6 Alkyl-C 3-6 It is a cycloalkyl, R 8b , R 8d and R 8eThese are, independently, H or C 1-6 It is alkyl, Ring B independently has 5 to 12 ring members and 1 to 6 heteroatoms. 6-12 It is an aryl or heteroaryl, and is N, O, or S. The subscript m8 is an integer between 0 and 5. Each R 8f C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, halo, C 1-6 Haloalkyl, cyano, -X 8f -Cyan, C 3-6 Cycloalkyl, -X 8f -C 3-6 Cycloalkyl, -CH=CR 8f1 R 8f2 , heterocycloalkyl, -X 8f -heterocycloalkyl, C 6-12 Ariel, -X 8f -C 6-12 Aryl, heteroaryl, or -X 8f - Heteroaryl, where each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0 to 3 R 8f3 It has been replaced with, Alternatively, two R's on adjacent ring vertices 8f The bases combine to form C 3-6 A cycloalkyl group or a heterocycloalkyl group having 3 to 6 ring members and 1 to 3 heteroatoms is formed, each independently being N, O, or S, and the cycloalkyl group or heterocycloalkyl group has 0 to 3 R atoms. 8f3 It has been replaced with, each X 8fIndependently, C 1-6 Alkilen, C 2-6 Alkenylene, -OC 1-6 Alkylene, O or S Each R 8f1 and R 8f2 These combine with the carbon atoms to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms (each independently being N, O, or S), and the heterocycloalkyl has 0 to 3 R 8f3 And, Each R 8f3 Independently, C 1-6 Alkyl, -Y 8 -C 1-6 Alkyl, C 1-6 It is an alkyl deuterated, -Y 8 -C 1-6 Alkyl deuterated, -OH, -C 1-6 alkyl-OH, -Y 8 -C 1-6 alkyl-OH, -C 1-6 Alkyl-Y 8 -C 1-6 Alkyl, -(C 1-2 Alkyl-O)1-4-C 1-2 Alkyl, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, -Y 8 -C 1-6 Haloalkyl, cyano, -C 1-6 Alkyl-cyano, oxo, C 3-6 Cycloalkyl, -X 8f3 -C 3-6 Cycloalkyl, heterocycloalkyl, -X 8f3 -heterocycloalkyl, phenyl, -X 8f3 -phenyl, heteroaryl, or -X 8f3-Heteroaryl, each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, S or S(O)2, each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O or S, each heterocycloalkyl and heteroaryl has 0 to 1 C nitrogen atom ring member 1-4 It is substituted with alkyl, each X 8f3 Independently, C 1-6 It is alkylene, O, C(O), or S(O)2, Each Y 8 These are independently C(O), C(O)O, and N(R 8f4 ) C(O), O, S, or S(O)2, Alternatively, two R's on the same or adjacent ring vertices 8f3 The groups combine to form a carbon atom with 3 to 6 ring members and 1 to 3 heteroatoms (each independently containing N, O, or S). 3-6 It forms a cycloalkyl or heterocycloalkyl, and the nitrogen atom ring member in the heterocycloalkyl is 0 to 1 C 1-4 It is substituted with alkyl, and Each R 8f4 H or C 1-6 It is alkyl, or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, the present disclosure relates to a compound of formula (I): [ka] And, During the ceremony, R 3 teeth (a) Each of the R's has 0 to 5 3a Replaced with, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl or C 1-6 It is a haloalkyl, (b) 0 to 5 R 3b C replaced by 3-12 It is cycloalkyl, or (c) A heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently being N, O, or S, and 0 to 5 R 3c It is a heterocycloalkyl that is substituted with, Each R 3a is -OH, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OC(O)C 1-6 It is alkyl, Each R 3b C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, -OH, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, C 1-6 It is a haloalkoxy or cyano, and each R 3c Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 It is a cycloalkyl or oxo, R 4a H or C 1-6 It is alkyl, R 4b and R 4c These are H and C, respectively, independently. 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6 Alkyl-heteroaryl compounds, where each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S), and each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S). Alternatively, R 4c and R 4aThese, together with the carbon and nitrogen atoms to which they are bonded, form a heterocycloalkyl group having 3 to 6 ring members, and the heterocycloalkyl group has 0 to 4 R 4a1 It has been replaced with, Each R 4a1 Independently, C 1-6 alkyl, -OH, C 1-6 alkyl-OH, C 1-6 It is an alkoxy or halo, R 5a H or C 1-6 It is alkyl, R 5b and R 5c These are H and C, respectively, independently. 1-6 Alkyl, -C 1-6 alkyl-OH, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6 Alkyl-heteroaryl (Each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 5b5 (It is replaced by) Each R 5b5 Independently, C 1-6 Alkyl, halo, or C 1-6 It is a haloalkyl, X 6 C 6-7 Alkylene or C 6-7 It is alkenylene, R 6a H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C3-6 Cycloalkyl, -C 1-6 Alkyl-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-6 Alkyl-heterocycloalkyl, phenyl, -C 1-6 Alkylphenyl, heteroaryl, or -C 1-6 Alkyl-heteroaryl compounds are such that heterocycloalkyl compounds have 3 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S), and heteroaryl compounds have 5 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S). R 6b and R 6d These are, independently, H or C 1-6 It is alkyl, R 7a H or C 1-6 It is alkyl, R 7b and R 7c These are H and C, respectively, independently. 1-6 Alkyl, C 2-6 Alkenil, C 1-6 It is a haloalkyl, C 1-6 alkyl-OH, C 3-6 Cycloalkyl, or -C 1-6 Alkyl-C 3-6 It is a cycloalkyl, R 8a H, C 1-6 Alkyl, C 2-6 Alkoxyalkyl, C 3-6 Cycloalkyl or -C 1-6 Alkyl-C 3-6 It is a cycloalkyl, R 8b , R 8d and R 8e These are, independently, H or C 1-6 It is an alkyl group, and ring B is an aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently being N, O, or S. The subscript m8 is an integer between 0 and 5. Each R 8f C1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, halo, C 1-6 Haloalkyl, cyano, -X 8f -Cyan, C 3-12 Cycloalkyl, -X 8f -C 3-6 Cycloalkyl, -CH=CR 8f1 R 8f2 , heterocycloalkyl, -X 8f -heterocycloalkyl, aryl, -X 8f -aryl, heteroaryl, or -X 8f -Heteroaryl, each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; each alkynyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 It has been replaced with, Alternatively, two R's on adjacent ring vertices 8f The groups combine to form a carbon atom with 3 to 6 ring members and 1 to 3 heteroatoms. 3-6 They form cycloalkyl or heterocycloalkyl groups, each independently being N, O, or S. Each X8f operates independently, C 1-6 Alkilen, C 2-6 Alkenylene, O or S. Each R 8f1 and R 8f2 These combine with the carbon atoms to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms (each independently being N, O, or S), where the heterocycloalkyl has 0 to 3 R 8f3 And, Each R 8f3 Independently, C 1-6 Alkyl, -Y 8 -C1-6 Alkyl, C 1-6 Alkyl deuterated, -Y 8 -C 1-6 Alkyl deuterated, -OH, -C 1-6 alkyl-OH, -Y 8 -C 1-6 alkyl-OH, -C 1-6 Alkyl-Y 8 -C 1-6 Alkyl, C 1-6 Alkoxy, Halo, C 1-6 Haloalkyl, -Y 8 -C 1-6 Haloalkyl, cyano, -C 1-6 Alkyl-cyano, oxo, C 3-6 Cycloalkyl, -X 8f3 -C 3-6 Cycloalkyl, heterocycloalkyl, -X 8f3 -heterocycloalkyl, phenyl, -X 8f3 -phenyl, heteroaryl, or -X 8f3 - Heteroaryls, each heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently N, O, S or S(O)2, each heteroaryl having 5 to 10 ring members and 1 to 4 heteroatoms, each independently N, O or S, and each heterocycloalkyl and heteroaryl having 0 to 1 nitrogen atom ring member 1-4 It is substituted with alkyl, each X 8f3 Independently, C 1-6 It is alkylene, O, C(O), or S(O)2, Each Y 8 These are independently C(O), C(O)O, and N(R 8f4 ) C(O), O, S, or S(O)2, Alternatively, two R's on adjacent ring vertices 8f3 The groups combine to form a carbon atom with 3 to 6 ring members and 1 to 3 heteroatoms. 3-6 They form cycloalkyl or heterocycloalkyl groups, each independently being N, O, or S, and Each R 8f4 H or C1-6 It is alkyl, Or provide a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ib): [ka]

[0044] R 3 , R 4a , R 4c , R 5a , R 5c , R 6a , X 6 , R 6d , R 8a , m8, R 8f And ring B may each be independently defined for any embodiment of formula (Ib) described herein.

[0045] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ib1): [ka]

[0046] R 3 , R 4a , R 4c , R 5a , R 5c , R 6a , X 6 , R 6d , R 8a , m8, R 8f And ring B may be independently defined for any embodiment of formula (Ib1) described herein.

[0047] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ic): [ka]

[0048] R 3 , R 4a1 , R 5a , R 5c , R 6a , X 6 , R 6d , R 8a , m8, R 8f And ring B may be independently defined for any embodiment of formula (Ic) described herein.

[0049] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Ic1): [ka]

[0050] R 3 , R 4a1 , R 5a , R 5c , R 6a , X 6 , R 6d , R 8a , m8, R 8f And ring B may be independently defined for any embodiment of formula (Ic1) described herein.

[0051] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Id): [ka] In the equation, bonds indicated by dashed lines are either nonexistent or are single bonds.

[0052] R 3 , R 4a1 , R 5a , R 5c , R 6a , R 6d , R 8a , m8, R 8fRing B and ring B may each be independently defined for any embodiment of formula (Id) described herein. In formula (Id), if the dashed line is a single bond, the wavy bond attached to the double bond represents E, Z, or a mixture of both isomers.

[0053] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I) having the structure of formula (Id1): [ka] In the equation, bonds indicated by dashed lines are either nonexistent or are single bonds.

[0054] R 3 , R 4a1 , R 5a , R 5c , R 6a , R 6d , R 8a , m8, R 8f And ring B may be independently defined for any embodiment of formula (Id1) described herein. Where a dashed line represents a bond in formula (Id1), a wavy line attached to a double bond indicates an E, Z, or mixed or both bond.

[0055] residue 3 In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (a) 0 to 5 R 3a C replaced by 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, or C 1-6 It is a haloalkyl compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (a) 0 to 2 R 3a C replaced by 1-6 Alkyl, or C 1-6It is a haloalkyl compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (a) 0 to 2 R 3a C replaced by 1-6 It is alkyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (a) 0 to 2 R 3a C replaced by 1-6 It is a haloalkyl. 3 These embodiments of R 3a This can be combined with any of the embodiments described herein.

[0056] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 3a is -OH or C 1-6 It is an alkoxy. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 3a It is -OH. 3a These embodiments of R 3 This can be combined with any of the relevant embodiments described herein.

[0057] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (b) 0 to 3 R 3b C replaced by 3-12It is a cycloalkyl compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (b) 0 to 3 R 3b C replaced by 3-7 It is a cycloalkyl compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (b) 0 to 2 R 3b C replaced by 5-6 It is a cycloalkyl compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 (b) 0 to 2 R 3b C replaced by 3-4 It is a cycloalkyl group. 3 These embodiments of R 3b This can be combined with any of the embodiments described herein.

[0058] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 3b Hello, C 1-4 The compound is a haloalkyl or cyano compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 3b is Halo or C 1-4 It is a haloalkyl compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 3b R is fluoromethyl or trifluoromethyl. 3b These embodiments of R 3This can be combined with any of the relevant embodiments described herein.

[0059] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 Each is independently a (c) heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each being N, O, or S, and the heterocycloalkyl has 0 to 5 R 3c It is substituted with. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 Each of these is an (c) heterocycloalkyl having 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S, and the heterocycloalkyl has 0 to 2 R 3c It is replaced with R. 3 These embodiments of R 3c This can be combined with any of the relevant embodiments described herein.

[0060] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3c is Halo or C 1-4 It is a haloalkyl compound. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 3c R is fluoromethyl or trifluoromethyl. 3c These embodiments of R 3 This can be combined with any of the embodiments described herein.

[0061] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), R 3 Each is an (g) heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently being N, O, or S, and the heteroaryl has 0, 1, 2, 3, 4, or 5 R 3g It has been replaced with.

[0062] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3g Independently, C 1-6 alkyl, halo, C 1-6 Haloalkyl, or C 3-6 It is a cycloalkyl group.

[0063] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 teeth [ka] That is the case.

[0064] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 teeth [ka] That is the case.

[0065] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 teeth [ka] is.

[0066] Any of the embodiments described herein for residue 3 can be combined with any of the embodiments described herein for residues 4, 5, 6, 7, and 8. For example, any embodiment of R 3 described herein can be combined with R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8, and any embodiment described herein for R 8f .

[0067] Residue 4 In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), or (Ib1), wherein R 4a , R 4b , and R 4c are each independently H or C 1-6 alkyl, or, R 4c and R 4a together with the carbon and nitrogen to which each is attached form a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each independently N, O, or S, and the heterocycloalkyl is substituted with 0 to 2 R 4a1 ; and each R 4a1 is independently halo.

[0068] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), or (Ib1), where, R 4a , R 4b , and R 4c Each of them is independently H or C 1-6 It is alkyl, Alternatively, R 4c and R 4a These, together with the carbon and nitrogen atoms to which they are bonded, form a heterocycloalkyl group having 4 to 6 ring members, and the heterocycloalkyl group has 0 to 2 R 4a1 It is replaced by; and Each R 4a1 It is a halo in its own right.

[0069] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), or (Ib1), where, R 4a , R 4b , and R 4c Each of them is independently H or C 1-6 It is alkyl.

[0070] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), or (Ib1), where, R 4b H or C 1-6 It is alkyl, and R 4c and R 4a Together with the carbon and nitrogen atoms to which each is bonded, they form a heterocycloalkyl having 4-6 ring members and 1-3 heteroatoms, each independently being N, O, or S, and the heterocycloalkyl has 0-3 R 4a1 It has been replaced with.

[0071] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), or (Ib1), where, R 4b H or C 1-6It is alkyl, and R 4c and R 4a These, together with the carbon and nitrogen atoms to which they are bonded, form a heterocycloalkyl group having 4 to 6 ring members, and the heterocycloalkyl group has 0 to 3 R 4a1 It has been replaced with.

[0072] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), or (Ib1), where, R 4a and R 4b Each of these is H, and R 4c It is ethyl, Alternatively, R 4c and R 4a These atoms, together with the carbon and nitrogen atoms to which they are bonded, form pyrrolidinyl molecules substituted with 0 to 2 fluorocarbons.

[0073] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), or (Ib1), where, R 4b is H and R 4c and R 4a Each of these, together with the carbon and nitrogen to which it is bonded, forms 0 to 2 R atoms. 4a1 It forms pyrrolidinyl substituted with it.

[0074] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), (Id1), where R 4a1 C 1-6 It is alkyl or halo. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), (Id1), and R 4a1is a halo. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), (Id1), and R 4a1 is fluoro. R 4a1 These embodiments of R 4 can be combined with any of the related embodiments described herein for R

[0075] R 4a , R 4b and R 4c The embodiments described herein for R 4a , R 4b and R 4c Any embodiment of R 3 , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8 and R 8f can be combined with any of the embodiments described herein for R

[0076] Residue 5 In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), wherein R 5a is H or C 1-6 alkyl, R 5b and R 5c are each independently H, C 1-6Alkyl, -C 1-6 alkyl-OH, C 2-6 Alkoxyalkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, or C 1-4 Alkyl-C 3-6 It is a cycloalkyl group, and each cycloalkyl group has 0 to 3 R atoms. 5b5 It is replaced by; and Each R 5b5 Independently, C 1-4 Alkyl, halo, or C 1-4 It is a haloalkyl group.

[0077] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 5a H or C 1-6 It is alkyl, R 5b and R 5c These are H and -C, respectively, independently. 1-6 Alkyl-C(O)NR 5b1 R 5b2 , or -C 1-6 Alkyl-C(O)OR 5b1 And, Each R 5b1 and R 5b2 H and C are independent of each other. 1-4 Alkyl, or C 1-4 It is a haloalkyl, Alternatively, R 5b1 and R 5b2 Each of these atoms, together with the nitrogen atom to which it is bonded, forms a heterocycloalkyl group having 3 to 6 ring members and 0 to 1 additional heteroatom, and the heterocycloalkyl group has 0 to 2 R 5b3 Replaced with and Each R 5b3 Independently, C 1-6 alkyl, halo, C 1-6 It is a haloalkyl or cyano, and each R 5b5 Independently, C 1-4 Alkyl, halo, or C 1-4 It is a haloalkyl group.

[0078] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 5a H or C 1-6 It is alkyl, and R 5b and R 5c These are H and C, which are independent of each other. 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-4 Alkyl-C 3-6 It is a cycloalkyl group.

[0079] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 5a H or C 1-6 It is alkyl, R 5b is H and R 5c C 3-6 Cycloalkyl or C 1-4 Alkyl-C 3-6 It is a cycloalkyl group.

[0080] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 5a and R 5b Each of them is H; and R 5c H, methyl, ethyl, [ka] That is the case.

[0081] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 5a and R 5b Each of them is H; and R 5c H, methyl, ethyl, [ka] That is the case.

[0082] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 5a H or C 1-6 It is alkyl, R 5b is H and R 5c teeth, [ka] That is the case.

[0083] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 5a H or C 1-6 It is alkyl, R 5b is H and R 5c teeth, [ka] That is the case.

[0084] R 5a , R 5b and R 5cThe embodiments described herein for residue 5 may exist in any combination. Furthermore, the embodiments described herein for residue 5 may exist in combination with any of the embodiments described herein for residues 3, 4, 6, 7, and 8. For example, the embodiments described herein for R 5a , R 5b and R 5c Any embodiment of R 3 , R 4a , R 4b , R 4c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8 and R 8f This can be combined with any embodiment described herein.

[0085] residue 6 In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), or (Ic1), and X 6 is C 6-7 It is alkylene. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), or (Ic1), and X 6 is C 6-7 It is alkenylene. 6 These embodiments of R 6a , R 6b and R 6d This can be combined with any of the embodiments described herein.

[0086] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), or (Ic1), where X 6 teeth [ka] And, Bonds indicated by wavy lines attached to a double bond represent E, Z, or a mixture of both isomers. X 6 These embodiments of R 6a , R 6b and R 6d This can be combined with any of the embodiments described herein.

[0087] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), or (Ic1), where X 6 teeth [ka] And, Bonds indicated by wavy lines attached to a double bond represent E, Z, or a mixture of both isomers. X 6 This embodiment of R 6a , R 6b and R 6d This can be combined with any of the embodiments described herein.

[0088] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), or (Ic1), and X 6 teeth [ka] That is the case. X 6 This embodiment of R 6a , R 6b and R 6d This can be combined with any of the embodiments described herein.

[0089] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 6a H, C 1-4 Alkyl, C 1-4 Alkyl deuterated, or -C 1-4 Alkyl-C 3-6 It is cycloalkyl; and R 6b and R 6d Each of them is independently H or C 1-6 It is alkyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 6a H, C 1-4 Alkyl, or -C 1-4 Alkyl-C 3-6 It is cycloalkyl; and R 6b and R 6d Each of them is independently H or C 1-6 It is alkyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 6a C 1-4 It is alkyl; R 6b H is; and R 6d C 1-4 It is alkyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 6a C 1-4 It is alkyl; and R 6b and R 6d Each of these is H. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), and R 6a , R 6b , and R 6dThese are H, respectively. 6a , R 6b , and R 6d These embodiments of X 6 This can be combined with any of the embodiments described herein.

[0090] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 6a H, methyl, ethyl [ka] And; R 6b is H; and R 6d R is H, methyl, or ethyl. 6a , R 6b and R 6d This embodiment of X 6 This can be combined with any of the embodiments described herein.

[0091] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 6a is H, methyl, ethyl, or [ka] And; R 6b is H; and R 6d R is H, methyl, or ethyl. 6a , R 6b and R 6d This embodiment of X 6 This can be combined with any of the embodiments described herein.

[0092] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 6a is H, methyl, ethyl, or [ka] And; R 6b is H; and R 6d R is H or methyl. 6a , R 6b and R 6d This embodiment of X 6 This can be combined with any of the embodiments described herein.

[0093] X 6 , R 6a , R 6b and R 6d The embodiments described herein for residue 6 may exist in any combination. Furthermore, the embodiments described herein for residue 6 may exist in combination with any of the embodiments described herein for residues 3, 4, 5, 7, and 8. For example, X described herein 6 , R 6a , R 6b and R 6d Any of the embodiments is R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e , ring B, m8 and R 8f This can be combined with any of the embodiments described herein.

[0094] residue 7 In some embodiments, the compound or a pharmaceutically acceptable salt thereof is the compound of formula (I), where R 7a and R 7b Each of them is independently H or C 1-6 Alkyl and R 7c C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Haloalkyl, C 1-6 Alkyl-OH or -C 1-6 Alkyl-C 3-6 It is a cycloalkyl group.

[0095] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is the compound of formula (I), where R 7a and R 7b Each of them is independently H or C 1-6 Alkyl and R 7c C 1-6 Alkyl or C 1-6 It is a haloalkyl group.

[0096] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is the compound of formula (I), where R 7a and R 7b Each of them is H, and R 7c is C 1-6 It is alkyl.

[0097] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is the compound of formula (I), where R 7a and R 7b Each of them is H, and R 7c isobutyl, [ka] That is the case.

[0098] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is the compound of formula (I), where R 7a and R 7b Each of them is H, and R7c It is isobutyl.

[0099] R 7a , R 7b and R 7c The embodiments described herein for residue 7 may exist in any combination. Furthermore, the embodiments described herein for residue 7 may exist in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 8. For example, the embodiments described herein for R 7a , R 7b and R 7c Any embodiment of R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 8a , R 8b , R 8d , R 8e , ring B, m8 and R 8f This can be combined with any embodiment described herein.

[0100] residue 8 In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where, R 8a , R 8b , R 8d , and R 8e Each of them is independently H or C 1-6 It is alkyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), R 8a is H or methyl; and R 8b , R 8d , and R 8e These are H, respectively. 8a , R8b , R 8d , and R 8e These embodiments of m8, ring B, R 8f , and R 8f3 This can be combined with any of the embodiments described herein.

[0101] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is a phenyl or heteroaryl having 5-6 ring members and 1-3 heteroatoms, each heteroatom being N, O, or S. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is phenyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is naphthyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is biphenyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is a heteroaryl having 5-6 ring members and 1-3 heteroatoms, each heteroatom being N, O, or S. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is thiophenyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is a heteroaryl having 5-6 ring members and 1-3 heteroatoms, each heteroatom being N. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is pyridyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is benzofuranyl.In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is indolyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is indazolyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is quinolinyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is pyrido-3-yl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is phenyl or pyridyl. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where ring B is phenyl or pyrido-3-yl. These embodiments of ring B are R. 8a , R 8b , R 8d , R 8e , m8, R 8f and R 8f3 This can be combined with any of the embodiments described herein.

[0102] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where the subscript m8 is 1, 2, or 3. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where the subscript m8 is 0. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where the subscript m8 is 1. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where the subscript m8 is 2. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where the subscript m8 is 3. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where the subscript m8 is 4. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where the subscript m8 is 5. These embodiments of m8 are R 8a , R 8b , R 8d , R 8e , R 8f , R 8f3 Ring B can be combined with any of the embodiments described herein.

[0103] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), and this part [ka] teeth [ka] That is the case. These embodiments are R 8a , R 8b , R 8d , R 8e , R 8f , R 8f3 m8 and ring B can be combined with any of the embodiments described herein.

[0104] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), and this part [ka] teeth [ka] That is the case. These embodiments are R 8a , R 8b , R 8d , R 8e , R 8f , R 8f3 m8 and ring B can be combined with any of the embodiments described herein.

[0105] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), and this part [ka] teeth [ka] That is the case. These embodiments are R 8a , R 8b , R 8d , R 8e , R 8f , R 8f3m8 and ring B can be combined with any of the embodiments described herein.

[0106] In some embodiments, at least one R 8f is a halo. In some embodiments, at least one R 8f R is fluoro or chloro. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0107] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f Independently, C 1-6 Alkyl, C 2-6 Alkenil, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, halo, C 1-6 Haloalkyl, cyano, or -X 8f - It is cyano. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0108] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f It is independently, Halo, C 3-6 Cycloalkyl, -X 8f -C 3-6 Cycloalkyl, -CH=CR 8f1 R 8f2 , Heterocycloalkyl, -X8f -heterocycloalkyl, phenyl, -X 8f -phenyl, heteroaryl, or -X 8f -Heteroaryl, each heterocycloalkyl independently has N, O, or S, with 3 to 10 ring members and 1 to 3 heteroatoms, each heteroaryl independently has N, O, or S, with 5 to 10 ring members and 1 to 3 heteroatoms, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 It is replaced with each X 8f Independently, C 1-6 Alkilen, C 2-6 Alkenylene, O, or S, and each R 8f1 and R 8f2 These atoms bond to the carbon atoms to form heterocycloalkyl groups, each independently having 3 to 10 ring members and 1 to 3 heteroatoms, and the heterocycloalkyl groups have 0 to 3 R atoms. 8f3 It is replaced with R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0109] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f It is independently, Halo, C 3-6 Cycloalkyl, -X 8f -C 3-6 Cycloalkyl, -CH=CR 8f1 R 8f2 , Heterocycloalkyl, -X 8f -heterocycloalkyl, heteroaryl, or -X 8f-A heteroaryl, where each heterocycloalkyl is independently N, O, or S, and has 3 to 10 ring members and 1 to 3 heteroatoms, and each heteroaryl is independently N, O, or S, and has 5 to 10 ring members and 1 to 3 heteroatoms, where each cycloalkyl, heterocycloalkyl, and heteroaryl has 0 to 3 R 8f3 It is replaced with each X 8f Independently, C 1-6 Alkilen, C 2-6 Alkenylene, O, or S, and each R 8f1 and R 8f2 These atoms bond to the carbon atoms to form heterocycloalkyl groups, each independently having 3 to 10 ring members and 1 to 3 heteroatoms, where the heterocycloalkyl group has 0 to 3 R atoms. 8f3 It is replaced with R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0110] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f C is independent 1-6 It is an alkylene. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f C is independent 2-6 The compound is an alkenylene. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f -OC is independent 1-6It is an alkylene. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f is independently C(O). In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f Independently, is S. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f Independently, C 1-6 It is alkylene or O. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B, and R 8f3 This can be combined with any of the embodiments described herein.

[0111] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f It is independently, Halo, C 3-6 Cycloalkyl, -CH=CR 8f1 R 8f2 Each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group has 3 to 10 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; each heteroaryl group has 5 to 10 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl group has 0 to 3 R8f3 It is replaced by each R 8f1 and R 8f2 These atoms bond to the carbon atoms to form a heterocycloalkyl group having 3 to 10 ring members and 1 to 3 heteroatoms, each independently being N, O, or S, and the heterocycloalkyl group having 0 to 3 R atoms. 8f3 It is replaced with R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0112] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f Independently, C 1-4 Alkyl, C 2-4 Alkenil, C 1-4 Alkoxy, C 1-4 Deuterated alkoxy, halo, C 1-4 Haloalkyl, cyano, or -C 1-2 It is alkyl-cyano. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0113] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f It is independently, Halo, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocycloalkyl, -C 2-4Alkenyl heterocycloalkyl, -O-heterocycloalkyl, -CH=CR 8f1 R 8f2 phenyl, -O-phenyl, heteroaryl, or -O-heteroaryl, each heterocycloalkyl is independently N, O, or S, and has 3 to 9 ring members and 1 to 3 heteroatoms, each heteroaryl has 5 to 9 ring members and 1 to 3 heteroatoms, each heteroaryl is independently N, O, or S, and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 It is replaced with and R 8f1 and R 8f2 These combine with the carbon atoms to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently being N, O, or S, and the heterocycloalkyl has 0 to 3 R 8f3 It is replaced with R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0114] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f It is independently, Halo, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocycloalkyl, -C 2-4The compounds are alkenyl heterocycloalkyl, -O-heterocycloalkyl, phenyl, -O-phenyl, heteroaryl, or -O-heteroaryl, where each heterocycloalkyl is independently N, O, or S, and has 3 to 6 ring members and 1 to 2 heteroatoms; each heteroaryl is independently N, O, or S, and has 5 to 6 ring members and 1 to 3 heteroatoms; and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R 8f3 It is replaced with R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0115] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f It is independently, Halo, C 3-6 Cycloalkyl, -OC 3-6 The compounds are cycloalkyl, heteroaryl, or -O-heteroaryl, each heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently being N, O, or S, and each cycloalkyl and heteroaryl has 0-3 R 8f3 It is replaced by R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0116] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8fEach is independently a halo, heterocycloalkyl, -O-heterocycloalkyl, phenyl, or -O-phenyl, and each heterocycloalkyl has independently 3 to 6 ring members and 1 to 2 heteroatoms, each being N, O, or S, and each heterocycloalkyl and phenyl has 0 to 3 R 8f3 It is replaced by R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0117] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f Each is independently a halo, heterocycloalkyl, or -O-heterocycloalkyl, and each heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently being N, O, or S, and each heterocycloalkyl has 0 to 3 R 8f3 It is replaced by R. 8f These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f3 This can be combined with any of the embodiments described herein.

[0118] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 1-6 Alkyl, -Y 8 -C 1-6 Alkyl, C 1-6 It is an alkyl deuterated, -Y 8 -C 1-6 Alkyl deuterated, -OH, -C 1-6alkyl-OH, -Y 8 -C 1-6 It is an alkyl-OH group. -C 1-6 Alkyl-Y 8 -C 1-6 alkyl, halo, C 1-6 Haloalkyl, -Y 8 -C 1-6 It is a haloalkyl or oxo; each Y 8 These are independently C(O), C(O)O, and N(R 8f4 ) C(O), O, S, or S(O)2; and each R 8f4 H or C 1-6 It is alkyl. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0119] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 1-6 Alkyl, -Y 8 -C 1-6 Alkyl, C 1-6 It is an alkyl deuterated, -Y 8 -C 1-6 Alkyl deuterated, -OH, -C 1-6 alkyl-OH, -Y 8 -C 1-6 It is an alkyl-OH group. -C 1-6 Alkyl-Y 8 -C 1-6 alkyl, halo, C 1-6 Haloalkyl, -Y 8 -C 1-6 Haloalkyl, -C 1-6 Alkyl-NR 8g R 8h , or oxo; each Y 8These are independently C(O), C(O)O, and N(R 8f4 ) C(O), O, S, or S(O)2; and each R 8f4 H or C 1-6 It is alkyl. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0120] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8g and R 8h These are H and C, respectively, independently. 1-3 Alkyl, or C 1-3 It is a haloalkyl group.

[0121] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each Y 8 -Y is independent 8 -C 1-6 It is alkyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), each Y 8 -Y is independent 8 -methyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), each Y 8 is independently C(O). In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each Y 8is independently C(O)O. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each Y 8 is independently NHC(O). In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each Y 8 In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each Y 8 Independently, is S. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each Y 8 It is independently S(O)2. 8 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B, R 8f and R 8f3 This can be combined with any of the embodiments described herein.

[0122] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 1-6 Alkyl, C 1-6 Alkyl deuterated, -OH, -C 1-6 alkyl-OH, halo, C 1-6 It is a haloalkyl or oxo. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0123] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 1-6 Alkyl or -Y 8 -C 1-6 It is alkyl. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), each Y 8 R is independently C(O) or C(O)O. 8f3 and Y 8 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0124] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 3-6 Cycloalkyl, -X 8f3 -C 3-6 Cycloalkyl, heterocycloalkyl, or -X 8f3 -A heterocycloalkyl group, each heterocycloalkyl group independently having 3-6 members and 1-2 heteroatoms, each being N, O, S, or S(O)2; and each X 8f3 Each of them is independent of C 1-6 It is alkylene, C(O), or S(O)2. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0125] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f3 C is independent 1-6 It is an alkylene. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f3 C(O) is independently. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each X 8f3 X is independently S(O)2. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B, R 8f and R 8f3 This can be combined with any of the embodiments described herein.

[0126] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 3-6 The cycloalkyl or heterocycloalkyl group is such that each heterocycloalkyl group independently has 3 to 6 members of N, O, S, or S(O)2 and 1 to 2 heteroatoms. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0127] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where two R vertices are adjacent to each other. 8f3 The groups combine to form a heterocycloalkyl group having 3 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0128] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-6 Alkoxyalkyl, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkyl-S(O)2-C 1-4 alkyl, halo, C 1-4 Haloalkyl, oxo, -C(O)-C 1-4 Alkyl, or -C(O)OC 1-4 It is alkyl. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0129] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where each R 8f3 Independently, C 1-4Alkyl, C 1-4 Alkoxy, C 2-6 Alkoxyalkyl, halo, C 1-4 Haloalkyl, oxo, -S(O)2-C 1-4 Alkyl, -C 1-4 Alkyl-S(O)2-C 1-4 Alkyl, -C(O)-C 1-4 Alkyl, -C(O)OC 1-4 Alkyl, C 3-6 Cycloalkyl, -C(O)-C 3-6 Cycloalkyl, -S(O)2-C 3-6 Cycloalkyl, heterocycloalkyl, -C 1-4 Alkyl-heterocycloalkyl or -S(O)2-heterocycloalkyl, where each heterocycloalkyl has 4-6 ring members and 1-2 heteroatoms, each independently of N, O, S, or S(O)2; or two R atoms on adjacent ring vertices. 8f3 The groups bond to form a non-aromatic cyclic moiety having 3 to 6 ring members, each independently being N, O, or S, and 0 to 2 additional heteroatoms. 8f3 These embodiments of R 8a , R 8b , R 8d , R 8e , m8, ring B and R 8f This can be combined with any of the embodiments described herein.

[0130] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where m8 is 1, 2, or 3, and Each R 8f These are independently methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, and cyano compounds. [ka] [ka] [ka] [ka] Alternatively, ring B and the three R 8f The base is a part [ka] Forming, The wavy line represents the bond with the rest of the molecule.

[0131] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where m8 is 1, 2, or 3, and Each R 8f These are independently methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, and cyano compounds. [ka] [ka] [ka] [ka] Alternatively, ring B and the three R 8f The base is a part [ka] Forming, The wavy line represents the bond with the rest of the molecule.

[0132] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where m8 is 1, 2, or 3, and Each R 8fThese are independently methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, and chloro. [ka] [ka] [ka] Alternatively, ring B and the three R 8f The base is a part [ka] Forming, The wavy line represents the bond with the rest of the molecule.

[0133] R 8a , R 8b , R 8d , R 8e , m8, R 8f The embodiments described herein for ring B may exist in any combination. Furthermore, the embodiments described herein for residue 8 may exist in combination with any of the embodiments described herein for residues 3, 4, 5, 6, and 7. For example, the embodiments described herein for R 8a , R 8b , R 8d , R 8e , m8, R 8f And any embodiment of ring B is R 3 , R 4a , R 4b , R 4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b and R 7c This can be combined with any of the embodiments described herein.

[0134] residue 3-8 In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 teeth [ka] And, R 4a and R 4b These are H, R 4c It is ethyl, Alternatively, R 4c and R 4a These, together with the carbon and nitrogen atoms to which they are bonded, form pyrrolidinyl molecules substituted with 0 to 2 fluorocarbons. R 5a and R 5b These are H, R 5c H, methyl, ethyl, [ka] And, X 6 teeth [ka] And, R 6a H, methyl, ethyl, [ka] And, R 6b H is H, R 6d is H, methyl, or ethyl, R 7a and R 7b These are H, R 7c isobutyl, [ka] And, R8a is H or methyl, R 8b , R 8d and R 8e These are H, Ring B is phenyl, naphthyl, biphenyl, thiophenyl, pyridyl, benzofuranyl, indolyl, indazolyl, or quinolinyl. m8 is 1, 2, or 3, and Each R 8f These are independently methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, and cyano compounds. [ka] [ka] [ka] [ka] And, Alternatively, ring B and the three R 8f The base is a part [ka] Forming, The wavy lines indicate bonding to the rest of the molecule.

[0135] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 teeth [ka] And, R 4a and R 4b These are H, R 4c It is ethyl, Alternatively, R 4c and R4a These, together with the carbon and nitrogen atoms to which they are bonded, form pyrrolidinyl molecules substituted with 0 to 2 fluorocarbons; R 5a and R 5b These are H, R 5c H, methyl, ethyl, [ka] And, X 6 teeth [ka] And, R 6a is H, methyl, ethyl, or [ka] And, R 6b H is H, R 6d is H, methyl, or ethyl, R 7a and R 7b These are H, R 7c isobutyl, [ka] And, R 8a is H or methyl, R 8b , R 8d and R 8e These are H, Ring B is phenyl, biphenyl, or pyrido-3-yl. m8 is 1, 2 or 3, and Each R 8f These are independently methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, and cyano compounds. [ka] [ka] [ka] [ka] And, Alternatively, ring B and the three R 8f The base is a part [ka] Forming, The wavy lines indicate bonding to the rest of the molecule.

[0136] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1), where R 3 teeth [ka] And, R 4a and R 4b These are H, R 4c It is ethyl, Alternatively, R 4c and R 4a These, together with the carbon and nitrogen atoms to which they are bonded, form pyrrolidinyl molecules substituted with 0 to 2 fluorocarbons; R 5a and R 5b These are H, R 5c H, methyl, ethyl, [ka] And, X 6 teeth [ka] And, R6a is H, methyl, ethyl, or [ka] And, R 6b H is H, R 6d is H or methyl, R 7a and R 7b These are H, R 7c isobutyl, [ka] And, R 8a is H or methyl, R 8b , R 8d and R 8e These are H, Ring B is phenyl or pyrido-3-yl, m8 is 1, 2 or 3, and Each R 8f These are independently methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, and cyano compounds. [ka] [ka] [ka] And, Alternatively, ring B and the three R 8f The base is a part [ka] Forming, The wavy lines indicate bonding to the rest of the molecule.

[0137] Regarding the above embodiment, R 3 , R 4a , R 4b , R4c , R 5a , R 5b , R 5c , X 6 , R 6a , R 6b , R 6d , R 7a , R 7b , R 7c , R 8a , R 8b , R 8d , R 8e Ring B, m8, and R 8f These may each be independently defined for any embodiment of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) as described herein.

[0138] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 1 to 426. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 1 to 389. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 1 to 334. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 1 to 50. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 51 to 100. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 101 to 150. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 151 to 200. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 201 to 250. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 251 to 300.In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 301 to 334. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 335 to 389. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) having one of the structures of Examples 390 to 426.

[0139] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0140] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0141] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0142] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0143] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0144] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0145] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0146] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0147] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0148] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0149] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0150] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0151] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0152] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is structured [ka] That is the case.

[0153] This disclosure includes all tautomers and stereoisomers of the compounds described herein, either in mixtures or in pure or substantially pure forms. Compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) may have a chiral center on one or more carbon atoms, and therefore compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) may exist in diastereomer or enantiomer forms or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers and other mixtures of such isomers, as well as solvates, hydrates, and tautomers are within the scope of this disclosure. Compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) can be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Furthermore, diastereomers and enantiomer products can be separated by chromatography, fractional crystallization, or other methods known to those skilled in the art. Unless otherwise indicated, where a stereochemical description is given, it means that isomers having the indicated stereochemistry exist and that there are substantially no other isomers. "Substantially no other isomers" means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10 or 95 / 5 or higher. If the structure contains a wavy bond attached to a double bond, this indicates E, Z, or a mixture of both isomers.

[0154] Compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) may be in salt form, e.g., acid salts or base salts of compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1). Examples of pharmaceutically acceptable salts include mineral acid salts (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid salts (e.g., acetic acid, propionic acid, glutamic acid, citrate), and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide). Pharmaceutically acceptable salts are understood to be non-toxic. For further information on appropriate pharmaceutically acceptable salts, see Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0155] pharmaceutically acceptable salts of the acidic compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) are salts formed using a base, i.e., cationic salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, and magnesium, and ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris-(hydroxymethyl)-methylammonium salts.

[0156] Similarly, when a basic group such as pyridyl constitutes part of the structure, acid addition salts of inorganic acids, organic carboxylic acids, and organic sulfonic acids, such as hydrochloric acid, methanesulfonic acid, and maleic acid, are also possible.

[0157] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional methods. The parent form of a compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents; otherwise, the salt is equivalent to the parent form of the compound for the purposes of this disclosure.

[0158] This disclosure also includes isotope-labeled compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1), in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Examples include, but are not limited to, Cl. Isotope-labeled compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) may be useful in assays of the tissue distribution of compounds and their prodrugs and metabolites. Preferred isotopes for such assays include, 3 H and 14 C is one example. Furthermore, in certain situations, deuterium ( 2 Substitution with heavier isotopes such as H) can provide increased metabolic stability, which offers therapeutic benefits such as increased in vivo half-life or reduced dose required. Isotope-labeled compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) can generally be prepared according to methods known in the art.

[0159] IV. Composition The compounds of formulas (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein are useful in the manufacture of pharmaceutical compositions or pharmaceuticals for modulating one or more cyclins (e.g., cyclin A, cyclin B, cyclin E). In some embodiments, the present disclosure provides pharmaceutical compositions comprising the compounds of the present disclosure and pharmaceutically acceptable excipients. In some embodiments, a pharmaceutical composition or pharmaceutical comprising one or more compounds of formulas (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) can be administered to a subject for the treatment of cancer.

[0160] Pharmaceutical compositions or pharmaceuticals for use in this disclosure can be formulated by standard techniques or methods well known in the field of pharmacy, using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and, for example, in "Remington's Pharmaceutical Sciences" by E.W. Martin. Compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1), and their physiologically acceptable salts and solvates can be formulated for administration by any suitable route, including but not limited to oral, topical, nasal, rectal, pulmonary, parenteral (e.g., intravenous, subcutaneous, intramuscular, etc.), and combinations thereof. In some embodiments, compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) are dissolved in a liquid, for example, water. The most appropriate route of administration for compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) in any given case depends, in part, on the nature, severity, and, in a discretionary manner, on the stage of the cancer.

[0161] The pharmaceutical compositions or pharmaceuticals of this disclosure may include compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) as active ingredients, as well as pharmaceutically acceptable carriers and / or excipients or diluents. Any carrier and / or excipient suitable for the form of a preparation desired for administration is intended to be used in conjunction with the compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) disclosed herein.

[0162] In some embodiments, the pharmaceutical compositions or pharmaceuticals described herein are suitable for systemic administration. Systemic administration includes enteral administration (e.g., absorption of the compound through the gastrointestinal tract) or parenteral administration (e.g., injection, infusion, or transplantation). In some embodiments, the pharmaceutical compositions or pharmaceuticals may be administered via syringe or intravenously. In preferred embodiments, the pharmaceutical compositions or pharmaceuticals are administered by subcutaneous injection.

[0163] For oral administration, the pharmaceutical composition or pharmaceutical may take the form of tablets or capsules prepared by conventional means, for example, with pharmaceutically acceptable excipients. Preferably, tablets and gelatin capsules containing (one or more) active ingredients together with (a) diluents or fillers, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethylcellulose, microcrystalline cellulose), glycine, pectin, polyacrylate and / or calcium hydrogen phosphate, calcium sulfate, and (b) lubricants, such as silica, anhydrous colloidal silica, talc, stearic acid, its magnesium or calcium salt (e.g., magnesium stearate or calcium stearate), metal stearate, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate and / or polyethylene glycol are preferred. The tablets are also tablets and gelatin capsules comprising (c) a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and / or hydroxypropyl methylcellulose; optionally (d) a disintegrant, e.g., starch (e.g., potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, or a foaming mixture; (e) a wetting agent, e.g., sodium lauryl sulfate; and / or (f) an absorbent, coloring agent, flavoring agent and sweetener. In some embodiments, the tablets contain a mixture of hydroxypropyl methylcellulose, polyethylene glycol 6000 and titanium dioxide. The tablets may be either film-coated or enterically coated according to methods known in the art.

[0164] Liquid formulations for oral administration may take the form of solutions, syrups, or suspensions, or may be provided as dry products to be prepared with water or other suitable solvents before use. Such liquid formulations may be prepared by conventional methods using pharmaceutically acceptable additives, such as suspending agents, e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible oils; emulsifiers, e.g., lecithin or acacia; non-aqueous solvents, e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, e.g., methyl or propyl-p-hydroxybenzoic acid esters or sorbic acid. The preparations may also contain buffer salts, flavorings, colorants, and / or sweeteners as needed. If desired, the preparations for oral administration may be appropriately formulated to provide controlled release of the active compound.

[0165] Typical formulations for topical administration include creams, ointments, sprays, lotions, and patches. However, pharmaceutical compositions can be formulated using syringes or other devices for any type of administration, such as intradermal, subcutaneous, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intra-arterial, intraperitoneal, intravesical, intrapleural, intra-coronary, or intratumoral injection. Formulations for administration by inhalation (e.g., aerosol) or for oral, rectal, or vaginal administration are also being considered.

[0166] Examples of pharmaceutical compositions for pulmonary administration include, but are not limited to, dry powder compositions comprising a powder of the compound or a salt thereof described herein and a powder of a suitable carrier and / or lubricant. Compositions for pulmonary administration can be inhaled from any suitable dry powder inhalation device known to those skilled in the art. In certain examples, the composition may be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dose unit can be determined by providing a valve for delivering a measured amount. Capsules and cartridges, for example, gelatin capsules and cartridges for use in inhalers or injectors, may be formulated containing a powder mixture of the compound and a suitable powder base, e.g., lactose or starch.

[0167] Compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) can also be formulated into rectal compositions, such as suppositories or retained enemas, such as conventional suppository bases, such as cocoa butter or other glycerides.

[0168] The compounds of formulas (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein can be formulated for parenteral administration by injection, for example, by bolus injection. The injectable formulations can be provided in unit dosage forms, such as ampoules or multi-dose containers, with added preservatives. The injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from lipid emulsions or suspensions. The compositions may be sterile and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution enhancers, salts and / or buffers for adjusting osmotic pressure. Alternatively, the compounds may be in powder form for reconstitution with a suitable solvent, such as sterile pyrogenic substance-removed water, before use. Furthermore, they may also contain other therapeutically valuable substances. Each composition is prepared according to conventional mixing, granulation, or coating methods and contains about 0.1 to 75%, preferably about 1 to 50%, of the compound.

[0169] In some embodiments, the compositions described herein are prepared using polysaccharides, such as chitosan or its derivatives (e.g., chitosan succinate, chitosan phthalate, etc.), pectin and its derivatives (e.g., amidated pectin, calcium pectate, etc.), chondroitin and its derivatives (e.g., chondroitin sulfate), and alginates.

[0170] In some embodiments, the compositions described herein further comprise a pharmaceutical surfactant. In other embodiments, the compositions further comprise a cryoprotectant. Non-limiting examples of cryoprotectants include glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, cyclodextrin, 2-hydroxypropyl-13-cyclodextrin (HPI3CD) glycerol, maltose, mannitol, saccharose, and mixtures thereof.

[0171] V. Method This disclosure intends to utilize compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein in the treatment or prevention of a disease or disorder at least partially modulated by one or more cyclins. In some embodiments, the cyclin-mediated disease is a proliferative condition or proliferative disorder, including cancer. In some embodiments, this disclosure provides a method for treating cancer at least partially mediated by cyclin activity, comprising administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure to a subject in need thereof, thereby treating the cancer.

[0172] In some embodiments, compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) for therapeutic use are provided herein.

[0173] This disclosure intends to utilize the compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein in the treatment or prevention of diseases or disorders at least partially regulated by cyclin A. In some embodiments, cyclin A-mediated diseases are proliferative conditions or proliferative disorders, including cancer. In some embodiments, this disclosure provides a method for treating cancer at least partially regulated by cyclin A, comprising administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure to a subject in need thereof, thereby treating the cancer.

[0174] In some embodiments, methods for treating a proliferative condition or proliferative disorder at least partially mediated by cyclin A are provided herein, comprising administering a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) as described herein.

[0175] In some embodiments, compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) are provided herein for use in methods of treating proliferative conditions or proliferative disorders mediated at least partially by cyclin A.

[0176] In some embodiments, the use of compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) for the manufacture of pharmaceuticals for treating proliferative conditions or proliferative disorders at least partially mediated by cyclin A is provided herein.

[0177] This disclosure intends to utilize the compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein in the treatment or prevention of diseases or disorders at least partially regulated by cyclin B. In some embodiments, cyclin B-mediated diseases are proliferative conditions or proliferative disorders, including cancer. In some embodiments, this disclosure provides a method for treating cancer at least partially mediated by cyclin B, comprising administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure to a subject in need thereof, thereby treating the cancer.

[0178] In some embodiments, methods for treating a cyclin B-mediated proliferative condition or proliferative disorder are provided herein, comprising administering a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) as described herein.

[0179] In some embodiments, compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) are provided herein for use in methods of treating proliferative conditions or proliferative disorders that are at least partially mediated by cyclin B.

[0180] In some embodiments, the use of compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) for the manufacture of pharmaceuticals for treating proliferative conditions or proliferative disorders at least partially mediated by cyclin B is provided herein.

[0181] This disclosure intends to utilize the compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein in the treatment or prevention of diseases or disorders at least partially regulated by cyclin E. In some embodiments, cyclin E-mediated diseases are proliferative conditions or proliferative disorders, including cancer. In some embodiments, this disclosure provides a method for treating cancer at least partially regulated by cyclin E, comprising administering a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure to a subject in need thereof, thereby treating the cancer.

[0182] In some embodiments, methods for treating a cyclin E-mediated proliferative condition or proliferative disorder are provided herein, comprising administering a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) as described herein.

[0183] In some embodiments, compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) are provided herein for use in methods of treating proliferative conditions or proliferative disorders that are at least partially mediated by cyclin E.

[0184] In some embodiments, the use of compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1), (Id), or (Id1) for the manufacture of pharmaceuticals for treating proliferative conditions or proliferative disorders at least partially mediated by cyclin E is provided herein.

[0185] In some embodiments, compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein can be used to treat or prevent proliferative conditions or proliferative disorders, including cancers of the uterus, cervix, breast, prostate, testes, gastrointestinal tract (e.g., esophagus, cervix, breast, prostate, testes, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon, or rectum), kidney, renal cells, bladder, bone, bone marrow, skin, head and neck, liver, gallbladder, bile duct, heart, lung (e.g., non-small cell lung cancer, small cell lung cancer), pancreas, salivary glands, adrenal glands, thyroid, brain, ganglia, central nervous system (CNS) and peripheral nervous system (PNS), and cancers of the hematopoietic and immune systems (e.g., spleen or thymus).

[0186] This disclosure also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions, including, for example, virus-induced cancers (e.g., epithelial cell carcinoma, endothelial cell carcinoma, squamous cell carcinoma, and papillomavirus), adenocarcinoma, lymphoma, carcinoma, melanoma, leukemia, myeloma, sarcoma, teratoma, chemoinducible carcinoma, metastasis, and angiogenesis.

[0187] In some embodiments, the tumor or cancer is colon cancer, ovarian cancer, breast cancer, melanoma, lung cancer, glioblastoma, or leukemia.

[0188] In some embodiments, the tumor or cancer is small cell lung cancer (SCLC).

[0189] The use of the term "cancer-related diseases, disorders, and conditions" means a broad range of conditions that are directly or indirectly related to cancer, including, for example, precancerous conditions such as angiogenesis and dysplasia.

[0190] In some embodiments, the cancer is a blood cancer (e.g., leukemia, lymphoma, multiple myeloma).

[0191] In some embodiments, leukemia is acute lymphoblastic leukemia, chronic lymphoblastic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or hairy cell leukemia.

[0192] In some embodiments, the lymphoma is non-Hodgkin lymphoma, Hodgkin lymphoma, B-cell lymphoma, or Burkitt lymphoma.

[0193] In some embodiments, the cancer is an Rb-mutated cancer. In some embodiments, the cancer has a mutation in the Rb / E2F pathway.

[0194] VI. Administration This disclosure intends to administer compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) and compositions thereof by any suitable method. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implant), intraperitoneal, subarachnoid, intra-articular, intraperitoneal, intracerebral (intraparenchymal) and intraventricular), transnasal, transvaginal, sublingual, intraocular, rectal, topical (e.g., transdermal), buccal mucosa, and inhalation.

[0195] Pharmaceutical compositions comprising compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) are preferably in unit dosage forms. A unit dosage form may be a packaged preparation and may include individual quantities of preparations such as packaged tablets, capsules, and powders in vials or ampoules. Alternatively, a unit dosage form may be the capsules, tablets, cachets, or lozenges themselves, or an appropriate number of any of these in packaging form.

[0196] Compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1), or their pharmaceutical compositions or pharmaceuticals, may be administered to subjects diagnosed or suspected of having a disease or disorder at least partially mediated by cyclin A, in an amount sufficient to induce an effective therapeutic response in the subject.

[0197] The dosage of a compound administered depends on various factors, including the subject's body weight, age, individual condition, and / or form of administration. The dosage is also determined by the presence, nature, and degree of any adverse effects associated with the administration of a particular compound in a given subject. Typically, the dosage of an active compound is sufficient to achieve the desired effect. The optimal administration schedule can be calculated from measurements of compound accumulation in the subject's body. Generally, dosages may be given once or more daily, once or more weekly, or once or more monthly. Those skilled in the art can easily determine the optimal dosage, method of administration, and repetition rate.

[0198] In some embodiments, a unit dose for orally administering a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein to a subject weighing about 50 to about 70 kg (e.g., a human) may consist of about 1 to about 5,000 mg, about 1 to about 3,000 mg, about 1 to about 2,000 mg, or about 1 to about 1,000 mg of the compound(s).

[0199] In some embodiments, a unit dose for subcutaneous administration of a compound of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) described herein to a subject weighing about 50 to about 70 kg (e.g., a human) may include about 0.1 to about 500 mg, about 0.5 to about 300 mg, about 0.5 to about 200 mg, about 0.5 to about 100 mg, or about 0.5 to about 50 mg.

[0200] The dose may be administered once daily or divided into subdoses, and may be administered in multiple doses, for example, two, three, or four times daily. However, as will be understood by those skilled in the art, different amounts may be administered at different times depending on the route of administration.

[0201] In some embodiments, the compound is administered for about 1 to 31 days or about 1 to 12 months. In some embodiments, the compound is administered for more than one week, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 weeks or more. In some embodiments, the compound is administered for one month or more, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months or longer.

[0202] The optimal dosage, toxicity, and therapeutic efficacy of such compounds may vary depending on the relative potency of each compound, and can be determined by standard pharmaceutical procedures in experimental animals, for example, LD 50 (A lethal dose for 50% of the population) and ED 50 This can be determined by determining the dose that is therapeutically effective in 50% of the population. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, or ratio LD50. 50 / ED 50 This can be expressed as follows. Compounds exhibiting a large therapeutic index are preferred. Compounds exhibiting toxic side effects can be used, but care should be taken to design a delivery system that targets such compounds to the affected area in order to minimize potential damage to normal cells and thereby reduce side effects.

[0203] The dosage of the pharmaceutical composition or pharmacopoeia of this disclosure may be monitored and adjusted throughout treatment in accordance with the severity of symptoms, the frequency of recurrence, and / or the physiological response to the treatment regimen. Those skilled in the art will generally engage in such adjustments in the treatment regimen.

[0204] A single or multiple dose of a pharmaceutical composition or pharmacopoeia may be administered according to the dosage and frequency required and tolerated by the patient. In any case, the composition or pharmacopoeia should provide an amount of the compound of this disclosure sufficient to effectively treat the patient. Generally, when treating cancer, the dose is sufficient to halt tumor growth or induce tumor regression without causing unacceptable toxicity or side effects to the patient.

[0205] VII. Intermediate In some embodiments, the Disclosure provides intermediates useful for preparing compounds of formula (I). Specific intermediates useful for preparing compounds of formula (I) can be found, for example, in the Examples section of the Disclosure.

[0206] In some embodiments, the intermediate is an external construction block as described herein. In some embodiments, the intermediate is a compound produced by any one of methods A to D or methods 1 to 14 for any one of the compounds exemplified herein. In some embodiments, the intermediate is any of Int. 1 to 438. In some embodiments, the intermediate is any of Int. 1 to 405. In some embodiments, the intermediate is any of Int. 1 to 154.

[0207] In some embodiments, the intermediate is Int.7 [ka] That is the case.

[0208] In some embodiments, the intermediate is Int.30 [ka] That is the case.

[0209] In some embodiments, the intermediate is Int.142 [ka] That is the case.

[0210] In some embodiments, the intermediate is a combination of one or more covalently bonded external components.

[0211] VIII. Kit This disclosure envisions a kit comprising compounds of formula (I), (Ib), (Ib1), (Ic), (Ic1)(Id), or (Id1) as described herein, and pharmaceutical compositions thereof. The kit generally takes the form of a physical structure containing various components, as described below, and can be used, for example, when carrying out the above method.

[0212] A kit may contain one or more of the compounds disclosed herein (e.g., provided in sterile containers) and may be in the form of a pharmaceutical composition suitable for administration to a subject. The compounds described herein may be provided in a ready-to-use form (e.g., tablets, capsules, syringes) or in a form that requires, for example, reconstitution or dilution (e.g., powder) before administration. If the compounds described herein are in a form that requires reconstitution or dilution by the user, the kit may also include diluents (e.g., sterile water), buffers, pharmaceutically acceptable excipients, etc., packaged together with or separately from the compounds described herein. Each component of the kit may be sealed in an individual container, and all of the various containers may be contained in a single package. The kits of this disclosure may be designed for conditions necessary to properly maintain the components contained therein (e.g., refrigeration or freezing).

[0213] The kit may include labels or packaging inserts containing identification information for its components and instructions for their use (e.g., administration parameters, clinical pharmacology of the active ingredients (including mechanism of action, pharmacokinetics and pharmacodynamics, adverse effects, contraindications, etc.)). The labels or inserts may also include manufacturer information such as lot number and expiration date. The labels or packaging inserts may be, for example, integrated into the physical structure containing the components, housed separately within the physical structure, or affixed to the components of the kit (e.g., ampoules, tubes, or vials).

[0214] The label or insert may further include, or be incorporated into, computer-readable media such as disks (e.g., hard disks, cards, memory disks), optical discs such as CD-ROMs or DVD-ROM / RAM, DVDs, MP3s, magnetic tapes, or electrical storage media such as RAM and ROM, or hybrids thereof such as magnetic / optical storage media, FLASH media, or memory cards. In some embodiments, actual instructions are not present in the kit, but means are provided for obtaining instructions from a remote source, for example, via the Internet. [Examples]

[0215] IX. Examples The following examples illustrate how various intermediates and exemplary compounds of formula (I) are prepared. The following examples are provided to illustrate the present disclosure, but are not intended to limit it.

[0216] A. External Components The compounds of formula (I) described herein are prepared by covalently bonding the external components described in this section. The external components of this disclosure are identified in Table 1 below by the intermediate number (INT#), IUPAC name, and CAS number, if known. For those without a CAS number, experimental writings are provided herein. The sequence and details of covalently bonding these external components are described in a separate section. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] [Table 1-15] [Table 1-16] Int.6: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(2,5-dichlorophenyl)propanoic acid [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)amino]-3-(2,5-dichlorophenyl)propanoate: [ka]

[0217] To a stirred mixture of Zn (29.95 g, 458.06 mmol, 2.5 equivalents) and TMSCl (1.33 g, 12.28 mmol, 0.067 equivalents) in DMA, methyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (1.03 g, 3.11 mmol, 1.7 equivalents) was added dropwise under a nitrogen atmosphere at less than 45°C. The resulting mixture was stirred under a nitrogen atmosphere at rt for 16 hours. The above mixture was added under nitrogen at rt to a solution of 1,4-dichloro-2-iodobenzene (50 g, 183.22 mmol, 1 equivalent), CuI (6.96 g, 36.64 mmol, 0.2 equivalents), and Pd(dppf)Cl2·CH2Cl2 (14.93 g, 18.32 mmol, 0.10 equivalents). The resulting mixture was stirred at 85°C for a further 16 hours. The desired product was detected by LC-MS. The reaction was quenched by adding water (1.5 L) at rt. The aqueous layer was extracted with RINKAN (3 × 500 mL). The combined organic layers were washed with water (5 × 300 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (25:1) to obtain methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2,5-dichlorophenyl)propanoate (40 g, 63%) as a white solid. LCMS(ESI+): m / z 292.15(M-56) + ). 1 H NMR (300MHz, DMSO-d6): δ 1.11-1.47(m,12H),2.89(dd,1H),3.22(dd,1H),3.64(d,4H),3.91-4.37(m,1H),6.87-7.89(m,4H). Step 2: (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5-dichlorophenyl)propanoate: [ka]

[0218] To a stirred solution of methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2,5-dichlorophenyl)propanoate (200 mg, 0.574 mmol, 1 equivalent) and methyl iodide (214.00 g, 1507.67 mmol, 15 equivalents) in DMF (350 mL), (algentiooxy)silver (93.17 g, 402.04 mmol, 4 equivalents) was added in fractions at 25°C under a nitrogen atmosphere. The reaction mixture was stirred at 25°C for 16 hours. The desired product was detected by LC-MS. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (3 × 100 mL). The filtrate was diluted with water (500 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with water (4 × 200 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.05% TFA), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. This yielded methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5-dichlorophenyl)propanoate as a white solid. LCMS(ESI+): m / z 262.20(M+Na + ). Step 3: Cont.6: [ka]

[0219] A solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(2,5-dichlorophenyl)propanoate (35 g, 96.62 mmol, 1 equivalent) and LiOH (4.63 g, 193.24 mmol, 2 equivalents) in THF (500 mL) / H2O (300 mg) was stirred at 25°C for 16 hours. The desired product was detected by LC-MS. The mixture was acidified to pH=4 with dilute HCl (aqueous solution). The aqueous layer was extracted with ELISA (3 × 500 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. As a result, Int.6 (25.26g, 75.07%) was obtained as a pale yellow solid. LCMS(ESI+): m / z 346.00 (MH) - ). 1 H NMR (400MHz, DMSO-d6): δ 1.23(d,9H),2.66(d,3H),3.06-3.39(m,2H),7.24-7.56(m,3H),13.00(s,1H). Preparation of Int.7:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-cyclopropoxypyridine-3-yl)propanoic acid [ka] Step 1: 3-bromo-5-chloro-2-cyclopropoxypyridine: [ka]

[0220] In a 1000 mL round-bottom flask, 3-bromo-5-chloro-2-fluoropyridine (50 g, 237.61 mmol, 1 equivalent) was added in 400 mL of DMF, and Cs2CO3 (232.97 g, 712.83 mmol, 3 equivalents) was added under nitrogen atmosphere at rt. The mixture was stirred at rt for 50 minutes. Cyclopropanol (9.94 g, 171.08 mmol, 1.2 equivalents) was added dropwise at rt over 2 minutes. The resulting mixture was stirred at 80°C for 16 hours. The reaction product was quenched with ice water (700 mL) and extracted with EA (3 × 100 mL). The organic layers were washed together with brine (300 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (0-20%). This yielded 3-bromo-5-chloro-2-cyclopropoxypyridine (40g, 68%) as a colorless oil. LCMS(ESI+): m / z 249.95. 1 H NMR(400MHz,DMSO-d6)δ 0.76(ddd,J=5.7,4.5,3.1Hz,2H),0.96-0.78(m,2H),4.32(tt,J=6.4,3.1Hz,1H),8.17(d,J=2.5Hz,1H),8.26(d,J=2.4Hz,1H). Step 2: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridine-3-yl)propanoate: [ka]

[0221] To a mixture of DMA (135 mL) containing Zn (26.84 g, 410.46 mmol, 1.7 equivalents), 1,2-dibromoethane (6.80 g, 36.22 mmol, 0.15 equivalents) was added all at once under N2. Then, chlorotrimethylsilane (2.62 g, 24.15 mmol, 0.1 equivalent) was slowly added, and the mixture was stirred at 25°C for 30 minutes. A solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (95.36 g, 289.74 mmol, 1.2 equivalents) in DMA (135 mL) was slowly added dropwise (60 minutes), maintaining the temperature below 50°C, and the resulting mixture was stirred at rt for 2 hours. Then, a cannula was placed in a 1000 mL three-necked round-bottom flask and 3-bromo-5-chloro-2-silane was added. When clopropoxypyridine (60 g, 241.45 mmol, 1 equivalent), Pd(dppf)Cl2CH2Cl2 (19.67 g, 24.14 mmol, 0.1 equivalent), and CuI (9.20 g, 48.29 mmol, 0.2 equivalents) were added to a DMA (135 ml) solution under N2 conditions, the mixture turned brown. The mixture was then heated and stirred at 80°C for 2 hours under N2 conditions. The mixture was quenched with ice water (700 ml) and extracted with EA (3 × 500 ml). The organic layers were combined, washed with brine (300 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. Purification of the crude product by silica gel chromatography eluted with PE / EA (0-50%) yielded methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridine-3-yl)propanoate (30 g, 34%) as a white solid. LCMS (ESI+): m / z 371.10. Step 3: Methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclopropoxypyridine-3-yl)propanoate: [ka]

[0222] In a 1000 mL round-bottom flask, methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclopropoxypyridine-3-yl)propanoate (25 g, 67.42 mmol, 1 equivalent) was added to DMF (400 mL), and Ag2O (78.11 g, 337.08 mmol, 5 equivalents) was added under a nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes, and CH3I (95.69 g, 674.16 mmol, 10 equivalents) was added dropwise over 2 minutes at 0°C. The resulting mixture was stirred at rt for 16 hours. The reaction product was quenched with ice water (500 mL) and extracted with ELISA (3 × 500 mL). The organic layers were washed together with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography eluted with PE / EA (7:1) yielded methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclopropoxypyridine-3-yl)propanoate (22 g, 85%) as a colorless oil. LCMS(ESI+): m / z 385.10. 1 H NMR(400MHz,DMSO-d6)δ 0.83-0.62(m,2H),1.19(t,J=7.1Hz,2H),1.28(s,9H),2.65(d,J=3.3Hz,3H),2.95(dd,J=13.6,10.4Hz,1H),3. 07(ddd,J=14.2,4.9,1.9Hz,2H),3.73-3.61(m,3H),4.69(dd,J=10.5,4.6Hz,1H),8.12(dd,J=17.7,2.6Hz,2H). Step 4: Int.7: [ka]

[0223] In a 1000 mL round-bottom flask, methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclopropoxypyridine-3-yl)propanoate (20 g, 51.97 mmol, 1 equivalent) and NaOH in water (10.39 g, 259.84 mmol, 5 equivalents) (50 ml) were added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at rt for 2 hours. The solvent was removed by reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18; mobile phase, ACN in water (0.5% FA), gradient from 0% to 100% over 40 minutes; detector, UV 254 nm. As a result, Int.7 (13.95 g, 72%) was obtained as a yellow oil. LCMS (ESI+): m / z 371.00. 1 H NMR(400MHz,DMSO-d6)δ 0.79-0.61(m,4H),1.21(s,9H),2.95-2.84(m,2H),3.00(s,3H),3.09-3.01(m,1H) ,4.86(dd,J=11.3,4.6Hz,1H),7.67(d,J=2.6Hz,1H),8.11(dd,J=18.4,2.6Hz,1H). Preparation of Int.8:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl)propanoic acid [ka] Step 1: 4-Chloro-2-iodobenzohydrazide: [ka]

[0224] To a stirred mixture of 4-chloro-2-iodobenzoic acid (10 g, 35.40 mmol, 1 equivalent) and 2-methylpropylcarbonochloridic acid (4.84 g, 35.40 mmol, 1 equivalent) in THF (100 mL), TEA (10.75 g, 106.21 mmol, 3 equivalents) and hydrazine (5.67 g, 177.02 mmol, 5 equivalents) were added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for a further 4 hours at rt. The desired product was detected by LC-MS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with HCl (3 × 100 mL). The combined organic layers were washed with 0.5 N HCl solution (3 × 50 mL). The combined aqueous layer was basicized to pH 8 with NaOH (0.5 N). The resulting mixture was extracted with HCl (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 5% to 100% over 30 minutes; detector, UV 254 nm. This yielded 4-chloro-2-iodobenzohydrazide (7.5 g, 72%) as a white solid. LCMS (ESI+): m / z 296.90 (M+H + ). Step 2: 2-(4-chloro-2-iodophenyl)-5-methyl-1,3,4-oxadiazole: [ka]

[0225] 4-chloro-2-iodobenzohydrazide (8 g, 26.98 mmol, 1 equivalent) and triethyl orthoacetate (80 mL) were added to a 200 mL vial at rt. The resulting mixture was stirred overnight at 140 °C. The desired product was detected by LC-MS. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% TFA), gradient from 5% to 100% over 30 minutes; detector, UV 254 nm. This yielded 2-(4-chloro-2-iodophenyl)-5-methyl-1,3,4-oxadiazole (10.2 g, 118%) as a yellow solid. LC-MS (ESI+): m / z 320.85 (M+H + ). Step 3: Methyl(2S)-2-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]-3-propanoate: [ka]

[0226] To a stirred solution of Zn (3.84 g, 58.73 mmol, 2 equivalents) in DMA (30 mL), 1,2-dibromoethane (0.55 g, 2.937 mmol, 0.1 equivalent) and TMSCl (0.21 g, 1.967 mmol, 0.067 equivalents) were added dropwise under a nitrogen atmosphere at rt. To the above mixture, DMA (30 mL) containing methyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (9.66 g, 29.37 mmol, 1 equivalent) was added dropwise. The resulting mixture was stirred further at rt for 3 hours. To a stirred mixture of 2-(4-chloro-2-iodophenyl)-1,3,4-oxadiazole (9 g, 29.37 mmol, 1 equivalent) in DMA (30 mL), Pd(dppf)Cl2CH2Cl2 (2.39 g, 2.94 mmol, 0.10 equivalent) and CuI (1.12 g, 5.87 mmol, 0.2 equivalent) were added in separate portions under nitrogen atmosphere at rt. Then, the two mixtures were added together. The resulting mixture was stirred for a further 16 hours at rt. The resulting mixture was stirred for a further 3 hours at 80°C. The desired product was detected by LC-MS. The reaction mixture was quenched with water (100 mL) at rt. The resulting mixture was filtered, and the filter cake was washed with siRNA (3 × 150 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with siRNA (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 5% to 100% over 30 minutes; detector, UV 254 nm. This yielded methyl(2S)-2-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]-3-(4.5 g, 39%) propanoate as a yellow solid. LCMS(ESI+): m / z 396.1(M+H) + ). Step 4: (2S)-2-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]-3-propanoic acid: [ka]

[0227] A solution of methyl(2S)-2-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]-3-propanoate (5 g, 12.63 mmol, 1 equivalent) in THF (40 mL) and water (10 mL) was treated with LiOH (1.51 g, 63.16 mmol, 5 equivalents) at rt for 4 hours. The desired product was detected by LC-MS. The mixture was diluted with water and EA. The aqueous phase was acidified with dilute HCl (0.5 N) and extracted with EA. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. This yielded (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]propanoic acid (4.5 g) as a pale yellow solid. LCMS(ESI+): m / z 404.0(M+Na) + ). Step 5: Methyl(2S)-3-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]-2-[(isopropoxycarbonyl)(methyl)amino]propanoate: [ka]

[0228] A solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]propanoic acid (4.5 g, 11.79 mmol, 1 equivalent) in DMF (50 mL) was treated with Ag2O (13.66 g, 58.93 mmol, 5 equivalents) under a nitrogen atmosphere at rt for 20 minutes, followed by the dropwise addition of CH3I (25.09 g, 176.79 mmol, 15 equivalents) at rt. The resulting mixture was stirred at rt for 4 hours. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with RINKAN (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 5% to 100% over 50 minutes; detector, UV 220 nm. This yielded methyl(2S)-3-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]-2-[(isopropoxycarbonyl)(methyl)amino]propanoate (3.7 g, 79%) as a yellow solid. LCMS(ESI+): m / z 410.1(M+H + ). Step 6: Int.8: [ka]

[0229] A solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(5-methyl-1,3,4-oxadiazole-2-yl)phenyl]propanoate (2.6 g, 6.34 mmol, 1 equivalent) in THF (40 mL) and H2O (10 mL) was treated with LiOH (1.08 g, 45.14 mmol, 5 equivalents) under a nitrogen atmosphere at rt for 4 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with water (20 mL) and acidified to pH 6 with HCl (0.5 mol / L). The mixture was concentrated under reduced pressure and extracted with HCl (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% TFA), gradient from 5% to 100% over 30 minutes; detector, UV 254 nm. As a result, Int.8 (3.4289 g, 96%) was obtained as a yellow solid. LCMS (ESI+): m / z 390.10 (M+H + ). 1 H NMR(300MHz,DMSO-d6):δ 1.26(s,4H),1.39(s,5H)2.67(d,J=1.9Hz,3H),2.84(d,J=8.8Hz,3H),3.33(ddd,J=14.3,10.9,3.4Hz,1H),3.91(dt,J=14.6,2.9Hz,1H ),5.06(ddd,J=18.1,10.8,3.8Hz,1H),7.34-7.26(m,1H),7.40(ddd,J=8.5,6.1,2.1Hz,1H),7.90(dd,J=8.4,3.8Hz,1H),10.00(s,1H). Preparation of Int.9:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(2-cyclopropoxy-5-fluoropyridine-3-yl)propanoic acid [ka] Step 1: 3-bromo-2-cyclopropoxy-5-fluoropyridine: [ka]

[0230] To a solution of cyclopropanol (15.55 g, 268.10 mmol, 1.3 equivalents) in THF (500 mL), sodium hydride (16.6 g, 691.67 mmol, 2 equivalents) was gradually added at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 1 hour. 3-bromo-2,5-difluoropyridine (40 g, 206.21 mmol, 1 equivalent) was added dropwise over 30 minutes at 0°C. The resulting mixture was stirred at rt for 16 hours. The reaction product was quenched with ice water (700 mL) and extracted with DCM (3 × 100 mL). The organic layers were washed with brine (300 mL) and dried on anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to obtain 3-bromo-2-cyclopropoxy-5-fluoropyridine (34 g, crude) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI+): m / z 233.90(M+H + ). Step 2: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-cyclopropoxy-5-fluoropyridine-3-yl)propanoate: [ka]

[0231] To a mixture of DMA (80 mL) containing Zn (15.94 g, 249.06 mmol, 1.7 equivalents), 1,2-dibromoethane (4.13 g, 21.98 mmol, 0.15 equivalents) was added all at once under N2 conditions. Then, chlorotrimethylsilane (1.58 g, 14.66 mmol, 0.1 equivalent) was slowly added, and the mixture was stirred at 25°C for 30 minutes. A DMA (80 mL) solution of methyl 2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (57.86 g, 175.86 mmol, 1.2 equivalents) was slowly added dropwise (60 minutes), maintaining the temperature below 50°C. The resulting mixture was stirred under rt for 2 hours. Then, a cannula was placed in a 250 mL three-necked round-bottom flask and added to a DMA (80 mL) solution of 3-bromo-2-cyclopropoxy-5-fluoropyridine (34 g, 146.55 mmol, 1 equivalent), Pd(dppf)Cl2CH2Cl2 (23.94 g, 29.31 mmol, 0.2 equivalents) and CuI (5.57 g, 29.31 mmol, 0.2 equivalents) under N2. The mixture turned brown, and the mixture was then heated and stirred under N2 at 80°C for 2 hours. The mixture was quenched with ice water (400 ml) and extracted with EA (3 × 500 ml). The organic layers were combined, washed with brine (300 ml), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography with PE / Â=0~50% elution to obtain methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-cyclopropoxy-5-fluoropyridine-3-yl)propanoate (11.2 g, 23%) as a yellow oil. LCMS(ESI+): m / z 355.10(M+H + ). Step 3: Int.9: [ka]

[0232] In a 1000 mL round-bottom flask, methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(2-cyclopropoxy-5-fluoropyridine-3-yl)propanoate (11 g, 31.07 mmol, 1 equivalent) was added to DMF (150 mL), and Ag2O (35.89 g, 155.37 mmol, 5 equivalents) was added under a nitrogen atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes, and methyl iodide (44.12 g, 310.73 mmol, 10 equivalents) was added dropwise over 2 minutes at 0°C. The resulting mixture was stirred at rt for 16 hours. The reaction product was quenched with ice water (100 mL) and extracted with RINKAN (3 × 300 mL). The organic layers were combined, washed with brine (3 × 200 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using PE / EA (7:1) elution, and Int.9 (10.8g, 94%) was obtained as yellow oil. LCMS (ESI+): m / z 369.15 (M+H + ). 1 H NMR(400MHz,DMSO-d6):δ 8.06(dd,J=18.7,3.0Hz,1H),7.55(ddd,J=18.5,8.7,3.0Hz,1H),4.68(dd,J=10.6,4.5Hz,1H),4.24(ddt,J=11.7,8.6, 4.0Hz,1H),3.68(d,J=7.6Hz,3H),3.13-2.84(m,2H),2.63(d,J=7.7Hz,3H),1.24(d,J=18.3Hz,9H),0.80-0.63(m,4H). Preparation of Int.10:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoic acid [ka] Step 1: 3-Bromo-5-chloro-2-isopropoxypyridine: [ka]

[0233] A mixture of 3-bromo-5-chloro-2-fluoropyridine (50 g, 237.61 mmol, 1 equivalent) and K2CO3 (98.52 g, 712.83 mmol, 3 equivalents) in IPA (500 mL, 5261.52 mmol, 22.14 equivalents) was stirred at 20°C. The resulting mixture was stirred at 80°C for 48 hours. The resulting mixture was concentrated under reduced pressure and dissolved in DCM (300 mL). The resulting mixture was filtered, and the filter cake was washed with DCM (3 × 50 mL). The filtrate was concentrated under reduced pressure. This yielded 3-bromo-5-chloro-2-isopropoxypyridine (50 g, 84.0%) as a yellow oil. LCMS(ESI+): m / z 252.05(M+H + ). Step 2: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoate: [ka]

[0234] To a stirred mixture of 3-bromo-5-chloro-2-isopropoxypyridine (50 g, 199.59 mmol, 1 equivalent), Pd(dppf)Cl2DCM adduct (16.26 g, 19.96 mmol, 0.1 equivalent), and CuI (7.60 g, 39.92 mmol, 0.2 equivalents) in DMA (500 mL), methyl(2S)-2-[(tert-butoxycarbonyl)amino]-2-(iododinthio)acetate (162.6 mL, 199.59 mmol, 10 equivalents) was added dropwise at 20°C under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with ELISA (3 × 500 mL). The filtrate was extracted with ELISA (3 × 800 mL). The combined organic layers were washed with H2O (3 × 1000 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and eluted with CH2Cl2 / PE (5:1) to obtain methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoate (110 g) as a yellow oil. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), gradient from 10% to 80% over 35 minutes; detector, UV 280 nm. The resulting mixture was concentrated under reduced pressure. This yielded methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoate (53 g, 77%) as a white solid. LCMS(ESI+): m / z 373.25(M+H + ). Step 3: Methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoate: [ka]

[0235] A stirred mixture of methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoate (20 g, 53.64 mmol, 1 equivalent) and Ag2O (62.15 g, 268.21 mmol, 5 equivalents) in DMF (500 mL) was mixed with MeI (77.66 g, 536.41 mmol, 10 equivalents) at 20°C. The resulting mixture was stirred at 60°C for 16 hours. The resulting mixture was filtered, and the filtered cake was washed with ELISA (3 × 500 mL). The filtrate was dissolved in H2O (800 mL), and the mixture was extracted with ELISA (3 × 1000 mL). The combined organic layers were washed with H2O (4 × 1200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoate (20.5g, 99%) as a yellow oil. LCMS(ESI+):m / z 387.15(M+H + ). Step 4: Int.10: [ka]

[0236] To a stirred mixture of EtOH (30 mL) containing methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-isopropoxypyridine-3-yl)propanoate (20 g, 51.70 mmol, 1 equivalent) and THF (60 mL), H2O (120 mL) containing NaOH (6.20 g, 155.09 mmol, 3 equivalents) was added dropwise at 0°C. The resulting mixture was stirred at 20°C for 16 hours. The resulting mixture was extracted with ELISA (2 × 100 mL). The combined organic layer was washed with H2O (1 × 150 mL). The combined aqueous phase was acidified to pH=6 with diluted citric acid (1 N). The resulting mixture was extracted with ELISA (2 × 200 mL). The combined organic layer was washed with H2O (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain Int.10 (14.2g, 74%) as yellow oil. LCMS(ESI+): m / z 373.15(M+H + ). Preparation of Int.11:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-(pyrimidine-2-yloxy)phenyl)propanoic acid [ka] Step 1: 5-(2-bromo-4-chlorophenyl)pyrimidine: [ka]

[0237] Pyrimidine-5-ylboronic acid (10 g, 80.70 mmol, 1 equivalent) and 2-bromo-4-chloro-1-iodobenzene (25.61 g, 80.70 mmol, 1 equivalent) were mixed in 1,4-dioxane (80 mL) and H2O (20 mL). Pd(dppf)Cl2CH2Cl2 (6.57 g, 8.06 mmol, 0.10 equivalent) and Na2CO3 (25.66 g, 242.11 mmol, 3 equivalents) were added in rt division under a nitrogen atmosphere. The resulting mixture was stirred at 80°C for a further 4 hours. The desired product was detected by LC-MS. The resulting mixture was filtered, and the filter cake was washed with siRNA (3 × 10 mL). The resulting mixture was diluted with water and extracted with siRNA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 5% to 100% over 30 minutes; detector, UV 220 nm. This yielded 5-(2-bromo-4-chlorophenyl)pyrimidine (9.6 g, 44%) as a brown oily substance. LCMS (ESI+): m / z 270.90 (M+H + ). Step 2: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(pyrimidine-5-yl)phenyl]propanoate: [ka]

[0238] To a stirred solution of Zn (6.31 g, 96.46 mmol, 2 equivalents) in DMA (30 mL), 1,2-dibromoethane (0.91 g, 4.82 mmol, 0.1 equivalent) and TMSCl (0.35 g, 3.23 mmol, 0.067 equivalents) were added dropwise at rt under a nitrogen atmosphere. To the above mixture, DMA (30 mL) containing methyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (15.87 g, 48.23 mmol, 1 equivalent) was added dropwise. The resulting mixture was stirred further at rt for 3 hours. To a stirred solution of 5-(2-bromo-4-chlorophenyl)pyrimidine (13 g, 48.23 mmol, 1 equivalent) in DMA (40 mL), Pd(dppf)Cl2CH2Cl2 (3.93 g, 4.82 mmol, 0.1 equivalent) and CuI (1.84 g, 9.65 mmol, 0.2 equivalent) were added in separate portions at rt under a nitrogen atmosphere. The two mixtures were then added together. The resulting mixture was stirred at 80°C for a further 3 hours. The desired product was detected by LC-MS. The reaction was quenched by adding water (100 mL) at rt. The resulting mixture was filtered, and the filter cake was washed with EA (3 × 100 mL). The residue was diluted with water and EA. The organic phase was washed with brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 5% to 100% over 30 minutes; detector, UV 220 nm. This yielded methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(pyrimidine-5-yl)phenyl]propanoate (8 g, 42%) as a yellow solid. LCMS (ESI+): m / z 392.05 (M+H + ). Step 3: Methyl(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-(pyrimidine-2-yloxy)phenyl)propanoate: [ka]

[0239] A solution of methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(pyrimidine-2-yloxy)phenyl]propanoate (1.3 g, 3.19 mmol, 1 equivalent) in DMF (15 mL) was treated with Ag2O (3.69 g, 15.94 mmol, 5 equivalents) under a nitrogen atmosphere using rt, followed by dropwise addition of CH3I (6.79 g, 47.81 mmol, 15 equivalents) using rt. The resulting mixture was stirred for a further 3 hours using rt. The desired product was detected by LC-MS. The resulting mixture was filtered, and the filter cake was washed with DMF (30 mL). The filtrate was used directly in the next step without further purification. LC-MS (ESI+): m / z 378.0 (M+H + ). Step 4: Int.11: [ka]

[0240] A solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(pyrimidine-2-yloxy)phenyl]propanoate (3 g, 7.111 mmol, 1 equivalent) in DMF (45 mL) and H2O (10 mL) was treated with NaOH (0.85 g, 21.333 mmol, 3 equivalents) at rt. The resulting mixture was stirred at rt for a further 16 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with SiO2 (3 × 50 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 5% to 100% over 10 minutes; detector, UV 220 nm. As a result, Int.11 (1.86 g, 62%) was obtained as a yellow solid. LCMS (ESI+): m / z 408.05 (M+H + ). Preparation of Int.12:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-cyclobutoxypyridine-3-yl)propanoic acid [ka] Step 1: 3-bromo-5-chloro-2-cyclobutoxypyridine: [ka]

[0241] To a suspension of NaH (6.35 g, 158.67 mmol, 1.2 equivalents, 60% of oil) in THF (250 mL), cyclobutanol (10.49 g, 145.45 mmol, 1.1 equivalents) in THF (20 mL) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1 hour under a nitrogen atmosphere. 30.0 g, 132.23 mmol, 1.0 equivalent of 3-bromo-2,5-dichloropyridine (30.0 g, 132.23 mmol, 1.0 equivalent) in THF (30 mL) was added, and the mixture was stirred at 60°C for 16 hours under a nitrogen atmosphere. The reaction was quenched at 0°C by adding saturated NH4Cl (aqueous solution) (100 mL). The resulting mixture was diluted with water (500 mL) and then extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (40:1) to obtain 3-bromo-5-chloro-2-cyclobutoxypyridine (31.0 g, 89%) as a colorless oil. LCMS(ESI+): m / z 262(M+H + ). Step 2: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclobutoxypyridine-3-yl)propanoate: [ka]

[0242] To a stirred mixture of 3-bromo-5-chloro-2-cyclobutoxypyridine (15 g, 57.14 mmol, 1.0 equivalent), Pd(dppf)Cl2.CH2Cl2 (2.33 g, 2.86 mmol, 0.05 equivalent), and CuI (1.09 g, 5.71 mmol, 0.1 equivalent) in N,N-dimethylacetamide (300 mL), methyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-(iododinthio)propanoate (171.41 mL, 171.41 mmol, 3.00 equivalent) was added all at once under a nitrogen atmosphere using rt. The resulting mixture was stirred under a nitrogen atmosphere at 80°C for 16 hours. The resulting mixture was diluted with water (600 mL) and ethyl acetate (200 mL), and then filtered. The filtered cake was washed with ethyl acetate (1 × 20 mL). The filtrate was separated, and the aqueous layer was extracted with ELISA (2 × 200 mL). The combined organic layers were washed with saturated NH4Cl (aqueous solution) (2 × 300 mL) and brine (1 × 300 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN, gradient from 10% to 80% over 20 minutes; detector, UV 220 nm. This yielded methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclobutoxypyridine-3-yl)propanoate (16.4 g, 75%) as a colorless oil. LCMS (ESI+): m / z 385 (M+H + ). Step 3: Methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclobutoxypyridine-3-yl)propanoate: [ka]

[0243] To a stirred mixture of methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-cyclobutoxypyridine-3-yl)propanoate (16.4 g, 42.61 mmol, 1 equivalent) and Ag2O (39.50 g, 170.45 mmol, 4.0 equivalents) in DMF (200 mL), CH3I (96.8 g, 681.81 mmol, 16.0 equivalents) was added in one batch at rt under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at 50°C for 16 hours. The starting materials were completely converted. The resulting mixture was diluted with water (500 mL) and ethyl acetate (200 mL), and then filtered. The filtered cake was washed with ethyl acetate (1 × 20 mL). The resulting mixture was separated, and the aqueous layer was extracted with ethyl acetate (2 × 150 mL). The combined organic layers were washed with saturated NH4Cl (aqueous solution) (2 × 300 mL) and brine (1 × 300 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (20:1) to obtain methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclobutoxypyridine-3-yl)propanoate (17.0 g, 95%) as a colorless oil. Step 4: Int.12: [ka]

[0244] A solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-(5-chloro-2-cyclobutoxypyridine-3-yl)propanoate (17 g, 42.62 mmol, 1 equivalent) in THF (300 mL) and H2O (100 mL) was stirred, and a solution of LiOH (3.06 g, 127.86 mmol, 3.00 equivalent) in H2O (100 mL) was added dropwise at 0°C. The resulting mixture was stirred at rt for 16 hours. The resulting mixture was diluted with water (300 mL) and then acidified to pH 2 with HCl (2 M aqueous solution). The resulting mixture was extracted with ELISA (3 × 150 mL). The combined organic layers were washed with brine (1 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution, 10% to 60% gradient over 25 minutes; detector, UV 220 nm. As a result, Int.12 (15.7 g, 95%) was obtained as a white solid. LCMS(ESI+): m / z 385(M+H + ). 1 H NMR(300MHz,DMSO-d6)δ 1.23(d,J=21.1Hz,9H),1.54-1.88(m,2H),1.93-2.20(m,2H),2.28-2.47(m,2H),2.68(d,J=1.4Hz,3H),2.86-3.03( m,1H),3.04-3.19(m,1H),4.66-5.03(m,1H),5.05-5.21(m,1H),7.49-7.81(m,1H),7.88-8.23(m,1H),12.95(s,1H). Preparation of Int.13: (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-methoxypyridine-3-yl)propanoic acid [ka] Step 1: 5-Chloro-2-methoxy-3-iodopyridine: [ka]

[0245] A solution of 2,5-dichloro-3-iodopyridine (5.0 g, 1 equivalent, 18 mmol) in THF (26 mL) was brought to 0°C, and NaH (1.5 g, 60% by weight, 2 equivalents, 37 mmol) was added as a solid. MeOH was then added dropwise, and the mixture was stirred at 0°C for 1 hour. The mixture was then stirred at 50°C until LC-MS analysis showed complete consumption of the starting materials. The reaction product was added to 100 mL of ice water, then extracted with siRNA (150 mL x 2), and the combined organic layer was washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, siRNA:hexane; 0-60%) to obtain 5-chloro-2-methoxy-3-iodopyridine (4.3 g, 16 mmol, yield 87%) as a yellow solid. Step 2: Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-methoxypyridine-3-yl)propanoate: [ka]

[0246] Zinc (2.4 g, 3 equivalents, 37 mmol) and DMF (15 mL) were added to a dry flask and degassed with Ar. Then, Boc-β-iodo-Ala-OMe (4.0 g, 1 equivalent, 12 mmol) and iodine (0.47 g, 0.15 equivalents, 1.8 mmol) were added as solids. In a separate vial, 5-chloro-3-iodo-2-methoxypyridine (4.3 g, 1.3 equivalents, 16 mmol) and 2-dicyclohexylphosphino-2,6-dimethoxy-1,1-biphenyl (0.13 g, 0.025 equivalents, 0.31 mmol) were dissolved in DMF (15 mL) and degassed with Ar. Then, Pd2dba3 (0.14 g, 0.013 equivalents, 0.15 mmol) was added. The first solution was transferred to the second solution and stirred at rt until LC-MS analysis showed complete consumption of the starting materials. The reaction mixture was added to 50 mL of ice water, then extracted with RINKAN (100 mL x 2), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (SiO2, RINKAN:hexane; 0-60%) to obtain methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-methoxypyridine-3-yl)propanoate (1.8 g, 8.1 mmol, yield 66%) as a white solid. LC-MS (ESI+): m / z 345.3 (M+H + ) Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-methoxypyridine-3-yl)propanoic acid: [ka]

[0247] Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-methoxypyridine-3-yl)propanoate (2.8 g, 1 equivalent, 8.1 mmol) was dissolved in THF (20 mL), H2O (14 mL), and MeOH (6.8 mL), and then brought to 0°C. Lithium hydroxide monohydrate (1.0 g, 0.68 mL, 3 equivalents, 24 mmol) was added, and the mixture was stirred at 25°C until LC-MS analysis showed complete consumption of the starting material. Then, 10% citric acid was added to the mixture at 0°C until the pH became acidic. The reaction mixture was concentrated in a rotary evaporator, extracted with RINKAN (80 mL x 2), washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to yield (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-methoxypyridine-3-yl)propanoic acid (2.3 g, 7.0 mmol, yield 86%). LCMS(ESI+): m / z 331.4(M+H + ) Step 4: Int.13: [ka]

[0248] (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-methoxypyridine-3-yl)propanoic acid (2.3 g, 1 equivalent, 7.0 mmol) solid was dissolved in THF (35 mL) and brought to 0°C under Ar. Then, NaH (0.56 g, 60% by weight, 2 equivalents, 14 mmol) was added as a solid, and MeI (5.9 g, 2.6 mL, 6 equivalents, 42 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour. Then, the mixture was stirred at 25°C until LC-MS analysis showed complete consumption of the starting materials. The reaction was quenched with 100 mL of ice water, and 10% citric acid was added to the mixture at 0°C until the pH became acidic. The reaction mixture was concentrated in a rotary evaporator, extracted with Depositphotos (80 mL x 2), the combined organic layers were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain Int.13 (2.3 g, 6.7 mmol, 96% yield) as a white solid. LCMS (ESI+): m / z 345.3 (M+H + ). Int.14:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-ethoxypyridine-3-yl)propanoic acid: [ka]

[0249] This material was synthesized using ethanol as the starting alcohol, following the procedure in Int. 13. LCMS(ESI+): m / z 359.3(M+H + ) Int.15:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-isobutoxypyridine-3-yl)propanoic acid [ka]

[0250] This material was synthesized using 2-methylpropan-1-ol as the starting alcohol, following the procedure in Int. 13. LCMS(ESI+): m / z 387.3(M+H + ) Int.16: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)phenyl)propanoic acid [ka] Step 1: 4-Chloro-N'-cyclopropancarbonyl-2-iodobenzohydrazide: [ka]

[0251] To a stirred solution of 4-chloro-2-iodobenzoic acid (1 g, 3.54 mmol, 1 equivalent) and NMI (0.87 g, 10.62 mmol, 3 equivalents) in ACN (40 mL), cyclopropanecarborazide (354.45 mg, 3.540 mmol, 1 equivalent) and TCFH (1.19 g, 4.25 mmol, 1.2 equivalents) were added in fractions at 0°C. The resulting mixture was stirred at rt for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with siRNA (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% FA), gradient from 0% to 60% over 30 minutes; detector, UV 254 nm. This yielded 4-chloro-N'-cyclopropanecarbonyl-2-iodobenzohydrazide (815 mg, 62%) as an off-white solid. LCMS(ESI+): m / z 364.80(M+H + ). Step 2: 2-(4-chloro-2-iodophenyl)-5-cyclopropyl-1,3,4-oxadiazole: [ka]

[0252] A solution of 4-chloro-N'-cyclopropanecarbonyl-2-iodobenzohydrazide (5 g, 13.72 mmol, 1 equivalent) in POCl3 (100 mL) was stirred at 85°C for 2 hours. The resulting mixture was concentrated under reduced pressure and extracted with CH2Cl2 (3 × 200 mL). The combined organic layer was washed with NaHCO3 (aqueous solution) (1 × 200 mL) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 2-(4-chloro-2-iodophenyl)-5-cyclopropyl-1,3,4-oxadiazole (4.5 g, 82%) as a brown solid. The crude product was used directly in the next step without further purification. LCMS (ESI+): m / z 347.00 (M+H + ). Step 3: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)phenyl]propanoate: [ka]

[0253] To a stirred solution of Zn (4.98 g, 76.18 mmol, 2.4 equivalents) and 1,2-dibromoethane (609.07 mg, 3.17 mmol, 0.1 equivalent) in DMA (20 mL), TMSCl (231.04 mg, 2.13 mmol, 0.067 equivalents) was added dropwise at 25°C under a nitrogen atmosphere. The resulting mixture was stirred for 30 minutes, and methyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (20.89 g, 63.48 mmol, 2.00 equivalents) in DMA (20 mL) was added to the solution. The temperature was increased and maintained below 50°C. After 30 minutes, the mixture was added dropwise to a solution of DMA (200 mL) containing 2-(4-chloro-2-iodophenyl)-5-cyclopropyl-1,3,4-oxadiazole (11 g, 31.74 mmol, 1 equivalent), CuI (1.21 g, 6.35 mmol, 0.2 equivalents), and Pd(dppf)Cl2 (2.32 g, 3.174 mmol, 0.1 equivalents), and stirred at 80°C for 2 hours. The reaction was quenched at 0°C with saturated NH4Cl (aqueous solution). The resulting mixture was filtered, the filter cake was washed with CH2Cl2 (500 mL), and the filtrate was extracted with CH2Cl2 (1000 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% FA), gradient from 0% to 100% over 40 minutes; detector, UV 254 nm. This yielded methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)phenyl]propanoate (7.2 g, 197%) as a brown solid. LCMS(ESI+): m / z 422.20(M+H + ). Step 4: Methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)phenyl]propanoate: [ka]

[0254] Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(5-cyclopropyl-1,3,4-oxadia-2-yl)]propanoate (7 g, 16.59 mmol, 1 equivalent) and Ag2O (15.38 g, 66.37 mmol, 4 equivalents) were stirred in DMF (140 mL), to which CH3I (23.55 g, 165.9 mmol, 10 equivalents) was added dropwise at 0°C. The resulting mixture was stirred at rt for 72 hours. The resulting mixture was filtered, the filter cake was washed with siRNA (3 × 100 mL), and the filtrate was extracted with siRNA (3 × 100 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (7g) was purified by preparative HPLC under the following conditions (column: XBridge C18 OBD Prep Column, 100Å 10μm, 19mm × 250mm; mobile phase A: water (10 mmol / LNH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 60% B to 60% B in 24 minutes; wavelength: 220 nm; RT1 (min): 18; number of runs: 0) to obtain methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)phenyl]propanoate (3.6g, 50%) as a brown oily substance. LCMS (ESI+): m / z 565.60 (M+H + ). Step 5: Int.16: [ka]

[0255] A stirred solution of methyl(2S)-2-[5-chloro-2-(5-cyclopropyl-1,3,4-oxadiazole-2-yl)phenyl]-3-propanoate (2.6 g, 5.97 mmol, 1 equivalent) in THF (24 mL) / H2O (8 mL) was mixed with NaOH solution (715.69 mg, 17.90 mmol, 3.00 equivalent) in water (10 mL) at 0°C. The mixture was acidified to pH=5 with HCl (1 N). The resulting mixture was extracted with  (3 × 200 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile (0.1% FA), gradient from 5% to 100% over 30 minutes; detector, UV 254 nm. This yielded Int.16 (2.73 g, 108%) as an off-white solid. LCMS(ESI+): m / z 421.95(M+H + ). Int.17: Preparation of (S)-3-(2-((1-acetylpiperidine-4-yl)oxy)-5-chlorophenyl)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid: [ka] Step 1: 1-(4-(4-chloro-2-iodophenoxy)piperidine-1-yl)ethane-1-one: [ka]

[0256] To a solution of THF (200 mL) containing 4-chloro-2-iodophenol (20 g, 78.60 mmol, 1 equivalent), 1-(4-hydroxy-1-piperidyl)ethanone (12.38 g, 86.46 mmol, 1.1 equivalents), and PPh3 (24.74 g, 94.32 mmol, 1.2 equivalents), DIAD (19.07 g, 94.32 mmol, 18.34 mL, 1.2 equivalents) was added dropwise at 0°C under an N2 atmosphere. The reaction mixture was then slowly heated to 20°C and stirred at 20°C for 12 hours. LC-MS showed that the starting materials were completely consumed and the mass of the target product was detected. The reaction mixture was quenched with water (200 mL) and extracted with siRNA (150 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® silica flash column, eluent 0-55% Â1 / PE gradient @ 200 mL / min) to obtain 1-(4-(4-chloro-2-iodophenoxy)piperidine-1-yl)ethane-1-one (21.49 g, 39.55 mmol, yield 50%, purity 70%) as a pale yellow solid. Step 2: Methyl(S)-3-(2-((1-acetylpiperidine-4-yl)oxy)-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate [ka]

[0257] The mixture of Zn (6.95 g, 106.34 mmol, 3.5 equivalents) in DMF (50 mL) was degassed, purged three times with N2, and the mixture was stirred at 120°C for 10 minutes under an N2 atmosphere. Then, I2 (2.31 g, 9.11 mmol, 1.84 mL, 0.3 equivalents) in DMF (10 mL) was added dropwise at 20°C, methyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (10 g, 30.38 mmol, 1 equivalent) in DMF (30 mL) was added dropwise, and I2 (2.31 g, 9.11 mmol, 1.84 mL, 0.3 equivalents) in DMF (10 mL) was added dropwise, and the reaction mixture was stirred at 20°C for 1 hour. In TLC (PE:siRNA=5:1, Rf=0.5), the starting material was completely consumed, and new major spots were detected. (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II)iodide (11.99 g, crude) was obtained as a gray liquid and used in the next step without further purification.

[0258] A solution of 1-(4-(4-chloro-2-iodophenoxy)piperidine-1-yl)ethane-1-one (5.58 g, 14.70 mmol, 1 equivalent), sPhos (603.43 mg, 1.47 mmol, 0.1 equivalent), and Pd2(dba)3 (673.00 mg, 734.95 μmol, 0.05 equivalent) in DMF (50 mL) was degassed and purged three times with N2. Then, (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II)iodide (11.99 g, 30.39 mmol, 2.07 equivalents) was added dropwise to the DMF. The reaction mixture was then stirred at 65°C for 12 hours. LC-MS showed that the starting material was completely consumed and the mass of the target product was detected. The reaction mixture was cooled to rt, quenched with water (150 mL), and extracted with RINKAN (100 mL x 2). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: 800 g Agela C18; mobile phase: [water-ACN]; B%: 20-50% 30 min; 50% 20 min) to obtain methyl(S)-3-(2-((1-acetylpiperidine-4-yl)oxy)-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (3.62 g, 7.66 mmol, yield 52%, purity 96%) as a white solid. Step 3: (S)-3-(2-((1-acetylpiperidine-4-yl)oxy)-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid: [ka]

[0259] To a solution of methyl(S)-3-(2-((1-acetylpiperidine-4-yl)oxy)-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (3.62 g, 7.96 mmol, 1 equivalent) in THF (40 mL), a solution of LiOH·H2O (400.69 mg, 9.55 mmol, 1.2 equivalents) in H2O (20 mL) was added. The reaction mixture was then stirred at 25°C for 1 hour. LC-MS showed that the starting material was completely consumed and the mass of the target product was detected. The reaction mixture was concentrated under reduced pressure to remove THF. The mixture was then acidified to pH=2-3 with 1N HCl at 0°C and extracted with ELISA (15 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound (S)-3-(2-((1-acetylpiperidine-4-yl)oxy)-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.35 g, 7.60 mmol, yield 95%, purity 100%) as a white solid. Step 4: Int.17: [ka]

[0260] (S)-3-(2-((1-acetylpiperidine-4-yl)oxy)-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.35 g, 7.60 mmol, 1 equivalent) was dissolved in THF (40 mL) and NaH (759.71 mg, 18.99 mmol, 60% purity, 2.5 equivalents) was added at 0°C under an N2 atmosphere. The mixture was stirred at 20°C for 30 minutes. Then, MeI (14.02 g, 98.77 mmol, 6.15 mL, 13 equivalents) was added at 0°C, and the reaction mixture was stirred at 20°C for 12 hours. LCMS showed that 38% of the starting material remained and 26% of the target mass was detected. The reaction mixture was cooled to 0°C, quenched with NH4Cl (40 mL), and extracted with siRNA (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by reverse-phase HPLC (column: 800 g Agela C18; mobile phase: [water (FA)-ACN]; B%: 25-55% 30 min; 55% 20 min) to obtain Int. 17 (3.02 g, 6.41 mmol, purity 97%) as a pale yellow solid. Spectrum: 1 H NMR(400MHz,DMSO-d6)δ=12.80(br s,1H),7.28-6.99(m,3H),4.90-4.60(m,2H),3.73-3.54(m,2H),3.39(td,J=3.8,13.3Hz,2H),3.18(br dd,J=3.8,13.8Hz,1H),2.95-2.82(m,1H),2.66(s,3H),2.01(s,3H),1.97-1.80(m,2H),1.74-1.50(m,2H),1.30-1.15(m,9H) Int.18: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid [ka] Step 1: 5-Fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine: [ka]

[0261] To a solution of 2-bromo-5-fluoropyridine-3-amine (12 g, 62.83 mmol, 1 equivalent) in dioxane (96 mL) and H2O (18 mL), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, Pd(dppf)Cl2 (2.30 g, 3.14 mmol, 0.05 equivalent), and K2CO3 (17.37 g, 125.65 mmol, 2 equivalents) were added, and the mixture was stirred under N2 at 90°C for 12 hours. Monitoring the reaction by LC-MS showed that 2-bromo-5-fluoropyridine-3-amine was consumed and one peak with the mass of the target product was detected. Five other reactions of the same size were set up, and all six reactions were combined and worked up. After cooling to rt, the mixture was filtered. The filtrate was diluted with water (500 mL) and extracted with siRNA (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (200 mL) and 250 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry liquid solid, which was then loaded onto Biotage® using a 400 g Agela flash silica gel column and eluted with 0% to 50% siRNA PE solution at a flow rate of 75 mL / min. The product fractions were combined and concentrated to obtain 5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine (63 g, crude) as a yellow solid. Step 2: 5-Fluoro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine: [ka]

[0262] To a solution of MeCN (450 mL) containing 5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine (15.75 g, 81.95 mmol, 1 equivalent), CuI (18.73 g, 98.34 mmol, 1.2 equivalents), KI (68.02 g, 409.75 mmol, 5 equivalents), and tert-butyl nitrite (42.25 g, 409.75 mmol, 48.73 mL, 5 equivalents) were added, and the mixture was stirred under N2 at 60°C for 12 hours. Monitoring the reaction by LC-MS showed that 5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine was consumed, and one peak with the mass of the target product was detected. Three other reactions of the same size were set up, all four reactants were combined, filtered, and the filtered cake was rinsed with siRNA (100 mL x 3). The combined filtrate was concentrated under reduced pressure to obtain the residue. The filtrate was diluted with water (200 mL) and extracted with dichloromethane (80 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (100 mL) and 200 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry liquid solid, which was then loaded onto Biotage® using a 300 g Agela flash silica gel column and eluted with 0% to 20% siRNA in PE at a flow rate of 75 mL / min. The product fractions were combined and concentrated to obtain 5-fluoro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine (30 g, 98.99 mmol, yield 60%, purity 100%) as a yellow solid. Step 3: Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoate: [ka]

[0263] A solution of 5-fluoro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine (30 g, 98.99 mmol, 1 equivalent), SPhos (4.06 g, 9.90 mmol, 0.1 equivalent), and Pd2(dba)3 (4.83 g, 5.28 mmol, 0.05 equivalent) in DMF (330 mL) was degassed and purged three times with N2. Then, (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II)iodide (78.10 g, 197.97 mmol, 2 equivalents) in DMF (200 mL) was added dropwise. The reaction mixture was then stirred at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that 5-fluoro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine was consumed, and one peak with the mass of the target product was detected. The mixture was filtered. The filtrate was diluted with water (200 mL) and extracted with siRNA (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250 × 100 mm #10 μm; mobile phase: [water (NH₄HCO₃)-ACN]; B%: 30%~60%, 36 min), the HPLC fractions were combined, and lyophilized. The product fractions were combined and concentrated to obtain methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoate (4.2 g, 11.10 mmol, yield 11%, purity 100%) as a yellow solid. Step 4: (S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid: [ka]

[0264] To a solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoate (4.2 g, 11.10 mmol, 1 equivalent) in THF (60 mL), a solution of LiOH.H2O (558.93 mg, 13.32 mmol, 1.2 equivalents) in H2O (30 mL) was added, and the mixture was stirred at 20°C for 1 hour. The mixture was acidified to pH=5 by adding hydrochloric acid (0.1 M, 10 mL) dropwise at 20°C. The filtrate was diluted with water (30 mL) and extracted with ELISA (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid (3.7 g, 10.15 mmol, yield 91%, purity 100%) as a yellow solid. Step 5: Int.18: [ka]

[0265] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid (1.85 g, 5.08 mmol, 1 equivalent) in THF (76 mL), NaH (1.02 g, 25.39 mmol, 60% purity, 5 equivalents) was added at 0°C, and the mixture was stirred under N2 at 0°C for 1 hour. MeI (7.21 g, 50.77 mmol, 3.16 mL, 10 equivalents) was added to the reaction mixture, and the mixture was stirred under N2 at 20°C for 12 hours. LC-MS showed that (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-fluoro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid was consumed and the mass of the target product was detected. Another reaction of the same size was set up and both reactions were combined and worked up. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution (20 mL), acidified to pH=5 by dropwise addition of hydrochloric acid (0.1 M, 10 mL) at 0°C, and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain Int. 18 (2.5 g, 6.53 mmol, 64.3% yield, 99% purity) as a yellow solid. 1 H NMR(400MHz,MeOD-d4)δ=8.34(dd,J=2.4,15.3Hz,1H),8.02(d,J=7.0Hz,1H),7.84(d,J=3.1Hz,1H),7.52(dt,J=2.6,9.2Hz ,1H),4.74-4.62(m,1H),4.02-3.92(m,3H),3.64-3.54(m,1H),3.28-3.12(m,1H),2.66(d,J=6.9Hz,3H),1.42-1.18(m,9H). Int.19: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid [ka] Step 1: 5-Chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine: [ka]

[0266] To a solution of dioxane (720 mL) containing 2-bromo-5-chloropyridine-3-amine (30 g, 144.61 mmol, 1 equivalent) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (36.11 g, 173.53 mmol, 1.2 equivalents) and H2O (120 mL), K2CO3 (39.97 g, 289.22 mmol, 2 equivalents) and Pd(dppf)Cl2 (3.17 g, 4.34 mmol, 0.03 equivalents) were added, and the mixture was stirred under N2 at 90°C for 12 hours. Monitoring the reaction by LC-MS showed that 2-bromo-5-chloropyridine-3-amine was consumed and one peak with the mass of the target product was detected. The reaction mixture was filtered, the filtered cake was washed with toluene (50 mL x 3), diluted with water (10 mL), and extracted with toluene (200 mL x 3). The combined organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (80 mL) and 40 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry liquid solid, which was then loaded onto Biotage® using an Agela flash silica gel column and eluted with a 0% to 40% toluene PE solution at a flow rate of 75 mL / min. The product fractions were combined and concentrated to obtain 5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine (30 g, 142.35 mmol, yield 98%, purity 99%) as a brown solid. Step 2: 5-Chloro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine: [ka]

[0267] To a solution of 5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine (9 g, 43.14 mmol, 1 equivalent) in MeCN (300 mL), CuI (9.86 g, 51.76 mmol, 1.2 equivalents), KI (35.80 g, 215.68 mmol, 5 equivalents) and tert-butyl nitrite (22.24 g, 215.68 mmol, 25.65 mL, 5 equivalents) were added, and the mixture was stirred under N2 at 60°C for 12 hours. Monitoring the reaction by LC-MS showed that 5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-amine was consumed, and one peak with the mass of the target product was detected. After cooling to rt, the solid was recovered by filtration, washed with siRNA (100 mL × 3), and dried under reduced pressure to obtain a brown solid. The solid was triturated with siRNA at 20°C for 30 minutes. The crude product was then triturated with aqueous ammonia at 20°C for 30 minutes, filtered, and the filtered cake was concentrated to obtain 5-chloro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine (20.5 g, 50.04 mmol, yield 58%, purity 78%), a brown solid. Step 3: Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoate: [ka]

[0268] To a solution of DMF (200 mL) containing 5-chloro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine (20.5 g, 64.16 mmol, 1 equivalent), (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II)iodide (50.62 g, 128.31 mmol, 2 equivalents), Pd2(dba)3 (2.94 g, 3.21 mmol, 0.05 equivalents) and sPhos (2.63 g, 6.42 mmol, 0.1 equivalents) were added, and the mixture was stirred under N2 at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that 5-chloro-3-iodo-2-(1-methyl-1H-pyrazole-4-yl)pyridine was consumed, and one peak with the mass of the target product was detected. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with brine (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (50 mL) and 40 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry liquid solid, which was then loaded onto Biotage® using a 120 g Agela flash silica gel column and eluted with 0% to 55% ethyl acetate in PE at a flow rate of 75 mL / min. When the product fractions were combined and concentrated, methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoate (8g, 19.86 mmol, yield 31%, purity 98%) was obtained as a yellow solid. Step 4: (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid: [ka]

[0269] To a solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoate (8 g, 20.26 mmol, 1 equivalent) in THF (100 mL), a solution of LiOH.H2O (1.02 g, 24.31 mmol, 1.2 equivalents) in H2O (50 mL) was added, and the mixture was stirred at 20°C for 1 hour. Monitoring the reaction by LC-MS showed that methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoate was consumed, and one peak with the mass of the target product was detected. The mixture was extracted with ELISA (100 mL). The aqueous phase was acidified to pH=4 by dropwise addition of hydrochloric acid (1M, 50 mL) at 0°C and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid (7 g, 18.01 mmol, yield 89%, purity 98%) as a yellow solid. Step 5: Int.19: [ka]

[0270] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid (3.7 g, 9.72 mmol, 1 equivalent) in THF (100 mL), NaH (1.94 g, 48.58 mmol, 60% purity, 5 equivalents) was added at 0°C, and the mixture was stirred under N2 at 0°C for 1 hour. MeI (13.79 g, 97.16 mmol, 6.05 mL, 10 equivalents) was added to the reaction mixture, and the mixture was stirred under N2 at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methyl-1H-pyrazole-4-yl)pyridine-3-yl)propanoic acid was consumed, and one of the peaks containing the mass of the target product was detected. The reaction mixture was cooled to 0°C, quenched with NH4Cl (30 mL), and extracted with RINKAN (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain Int. 19 (3 ​​g, 7.51 mmol, 77% yield, 98% purity) as a yellow solid. 1 1H NMR (400MHz, MeOD-d4) 1 H NMR(400MHz,METHANOL-d4)δ=8.48-8.32(m,1H),8.08(d,J=6.8Hz,1H),7.92(s,1H),7.76-7.64(m,1H), 4.80-4.66(m,1H),3.98(s,3H),3.64-3.56(m,1H),3.28-3.16(m,1H),2.66(d,J=9.8Hz,3H),1.24(s,9H) Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-(1-methylcyclopropoxy)phenyl)propanoic acid [ka] Step 1: 4-Chloro-1-(1-methylcyclopropoxy)-2-nitrobenzene: [ka]

[0271] Cs2CO3 (58.47 g, 179.44 mmol, 1.5 equivalents) was added to a solution of 4-chloro-1-fluoro-2-nitrobenzene (21 g, 119.63 mmol, 1 equivalent) and 1-methylcyclopropanol (11.16 g, 131.59 mmol, 85% purity, 1.1 equivalents) in DMF (150 mL). The reaction mixture was then stirred at 75 °C for 3 hours. HPLC showed that the starting material was completely consumed and a new major peak was detected. The reaction mixture was cooled to rt, quenched with water (200 mL), and extracted with SiO2 (150 mL x 2). The combined organic layers were washed with water (100 mL x 3) and brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-chloro-1-(1-methylcyclopropoxy)-2-nitrobenzene (25 g, 104.54 mmol, yield 87%, purity 95.2%) as a brown oil. Step 2: 5-Chloro-2-(1-methylcyclopropoxy)aniline: [ka]

[0272] To a solution of EtOH (200 mL) and H2O (100 mL) containing 4-chloro-1-(1-methylcyclopropoxy)-2-nitrobenzene (25 g, 109.82 mmol, 1 equivalent), NH4Cl (5.87 g, 109.82 mmol, 1 equivalent) and Fe (18.40 g, 329.46 mmol, 3 equivalents) were added. The reaction mixture was then stirred at 80°C for 2 hours. LC-MS showed that the starting material was completely consumed and the mass of the target product was detected. The resulting mixture was filtered, and the filter cake was rinsed with EtOH (100 mL x 3). The combined filtrate was then concentrated under reduced pressure to remove the EtOH. The aqueous phase was then extracted with SiO2 (150 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-chloro-2-(1-methylcyclopropoxy)aniline (20.9 g, 104.54 mmol, yield 95%, purity 99%) as a black, brownish oil. Step 3: 4-Chloro-2-iodo-1-(1-methylcyclopropoxy)benzene: [ka]

[0273] To a solution of 5-chloro-2-(1-methylcyclopropoxy)aniline (20.9 g, 105.74 mmol, 1 equivalent) in HCl (2.5 M, 209.00 mL, 4.94 equivalents) and ACN (100 mL), a solution of NaNO2 (8.02 g, 116.31 mmol, 1.1 equivalents) in H2O (100 mL) was slowly added at 0°C. Then, a solution of KI (43.88 g, 264.34 mmol, 2.5 equivalents) in H2O (100 mL) was slowly added. The reaction mixture was then heated to 25°C and stirred at 25°C for 12 hours. LC-MS showed that the starting material was completely consumed and a new major spot was detected. The reaction mixture was adjusted to pH=7 by slowly adding saturated NaHCO3 aqueous solution at 0°C and extracted with siRNA (60 mL × 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® silica flash column, eluent 0-0% siRNA / PE gradient @ 150 mL / min) to obtain 4-chloro-2-iodo-1-(1-methylcyclopropoxy)benzene (23 g, 73.84 mmol, yield 70%, purity 99.1%) as a pale yellow oil. Step 4: Methyl(S)-2-((tert-butoxycarbonylamino)-3-(5-chloro-2-(1-methylcyclopropoxy)phenyl)propanoate: [ka]

[0274] A mixture of DMF (50 mL) containing 4-chloro-2-iodo-1-(1-methylcyclopropoxy)benzene (15 g, 48.62 mmol, 1 equivalent), sPhos (2.00 g, 4.86 mmol, 0.1 equivalent), and Pd2(dba)3 (2.23 g, 2.43 mmol, 0.05 equivalent) was degassed, purged three times with N2, and then [(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxopropyl]iodo-zinc (41.95 g, 106.34 mmol, 2.19 equivalents) was added to the mixture. The mixture was then stirred at 65°C for 12 hours under an N2 atmosphere. LCMS showed that the starting material was completely consumed and the mass of the target product was detected. The reaction mixture was cooled to rt, quenched with water (300 mL), and extracted with Âxa (150 mL x 2). The combined organic layer was washed with water (200 mL x 2) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm #10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%~80%, 20 min) to obtain methyl(S)-2-((tert-butoxycarbonylamino)-3-(5-chloro-2-(1-methylcyclopropoxy)phenyl)propanoate (15 g, 36.75 mmol, yield 76%, purity 94.0%) as a pale yellow solid. Step 5: (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methylcyclopropoxy)phenyl)propanoic acid: [ka]

[0275] A solution of methyl(S)-2-((tert-butoxycarbonylamino)-3-(5-chloro-2-(1-methylcyclopropoxy)phenyl)propanoate (15 g, 39.08 mmol, 1 equivalent) in THF (200 mL) was added to a solution of LiOH·H2O (2.46 g, 58.61 mmol, 1.5 equivalents) in H2O (100 mL) at 0-10°C. The reaction mixture was then stirred at 20°C for 0.5 hours. LC-MS showed that the starting material was completely consumed and the mass of the target product was detected. The reaction mixture was concentrated under reduced pressure. The THF was removed and extracted with ELISA (80 mL x 2). The aqueous phase was acidified by adding hydrochloric acid (1N) dropwise to pH = 2-3 at 0°C. The aqueous phase was extracted with ELISA (100 mL x 2). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methylcyclopropoxy)phenyl)propanoic acid (12.7 g, 33.65 mmol, yield 86%, purity 98.1%) as a pale yellow oil. Step 6: Int.20: [ka]

[0276] (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-(1-methylcyclopropoxy)phenyl)propanoic acid (12.7 g, 34.34 mmol, 1 equivalent) was dissolved in THF (400 mL) and NaH (6.87 g, 171.70 mmol, 60% purity, 5 equivalents) was added at 0°C under an N2 atmosphere. The mixture was stirred at 20°C for 0.5 hours. Then, MeI (48.74 g, 343.39 mmol, 21.38 mL, 10 equivalents) was added and the reaction mixture was stirred at 20°C for 12 hours. LCMS showed that the starting material was completely consumed and the mass of the target product was detected. The reaction mixture was cooled to 0°C, quenched with NH4Cl (150 mL), acidified to pH 2-3 by adding hydrochloric acid (1N) dropwise at 0°C, and extracted with siRNA (200 mL x 2). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain Int.20 (9.98 g, 26.00 mmol, yield 76%, purity 100%) as a pale yellow solid. 1 H NMR(400MHz,DMSO-d6)δ=7.28-7.04(m,3H),4.83-4.39(m,1H),3.15-2.97(m,1H),2.89-2.71(m,1H),2.61(br d,J=3.3Hz,3H),1.49(d,J=11.1Hz,3H),1.30-1.12(m,9H),0.95-0.81(m,2H),0.81-0.69(m,2H) Int.22: Preparation of (S)-3-(1'-acetyl-5-chloro-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-3-yl)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid [ka] Step 1: 2-Bromo-3-(bromomethyl)-5-chloropyridine: [ka]

[0277] To a stirred mixture of 2-bromo-5-chloro-3-methylpyridine (25 g, 121.08 mmol, 1 equivalent) and NBS (23706.05 mg, 133.19 mmol, 1.1 equivalents) in ACN (200 mL), AIBN (1988.33 mg, 12.11 mmol, 0.1 equivalent) was added at rt under a nitrogen atmosphere. The resulting mixture was stirred overnight at 80°C. The resulting mixture was concentrated under reduced pressure and diluted with water. The mixture was extracted with  (2 × 200 mL), and the combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. This yielded 2-bromo-3-(bromomethyl)-5-chloropyridine (30 g, 87%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS(ESI+): m / z 282.4. Step 2: tert-butyl(2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(diphenylmethylidene)amino]propanoate: [ka]

[0278] 2-Bromo-3-(bromomethyl)-5-chloropyridine (15g, 52.57 mmol, 1 equivalent), (2S,4S,5R)-1-[(anthracene-9-yl)methyl]-5-ethenyl-2-[(R)-(propa-2-en-1-yloxy)(quinoline-4-yl)methyl]-1-azabicyclo[2.2.2]octan-1-ium bromide (1591. To a stirred mixture of 69 mg, 2.63 mmol, 0.05 equivalents of (29578.95 mg, 105.13 mmol, 2 equivalents) and isopropyl 2-[(diphenylmethylidene)amino]acetate (29578.95 mg, 105.13 mmol, 2 equivalents) in DCM (100 mL), KOH (29.49 g, 525.65 mmol, 10 equivalents) was added in H2O (30 mL) under an air atmosphere at -10°C in divided portions. The resulting mixture was stirred further at -10°C for 4 hours. The resulting mixture was extracted with siRNA (2 × 200 mL), and the combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography eluting with PE / EA (10:1) yielded tert-butyl(2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(diphenylmethylidene)amino]propanoate (25g, 95%) as a yellow oil. LCMS(ESI+): m / z 501.1. Step 3: (S)-2-amino-3-(2-bromo-5-chloropyridine-3-yl)propanoic acid: [ka]

[0279] A mixture of tert-butyl(2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(diphenylmethylidene)amino]propanoate (5 g, 10.0 mmol, 1 equivalent) and HCl (6 M) (30 mL) in THF (10 mL) was stirred overnight at 55°C. The resulting mixture was concentrated under reduced pressure. This yielded (2S)-2-amino-3-(2-bromo-5-chloropyridine-3-yl)propanoic acid (2.6 g, 93%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI+): m / z 278.9. Step 4: (2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(tert-butoxycarbonyl)amino]propanoic acid: [ka]

[0280] To a stirred mixture of H2O (60 mL) containing (2S)-2-amino-3-(2-bromo-5-chloropyridine-3-yl)propanoic acid (9 g, 32.20 mmol, 1 equivalent) and Na2CO3 (10.24 g, 96.59 mmol, 3 equivalents), Boc2O (14.05 g, 64.40 mmol, 2 equivalents) was added in a fractional manner under air atmosphere at rt. The resulting mixture was stirred overnight at rt. The mixture was acidified to pH=6 with dilute HCl (1N aqueous solution). The resulting mixture was extracted with ELISA (2 × 100 mL), and the combined organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 100% over 30 minutes; detector, UV 210 nm. This yielded (2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (12 g, 98%) as a white solid. LC-MS (ESI+): m / z 380.90. Step 5: (2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid: [ka]

[0281] NaH (6.32 g, 263.41 mmol, 10 equivalents) was gradually added under nitrogen at 0°C to a stirred mixture of THF (100 mL) containing (2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(tert-butoxycarbonyl)amino]propanoic acid (10 g, 26.34 mmol, 1 equivalent), and the resulting mixture was stirred at 0°C for 1 hour. MeI (56.08 g, 395.12 mmol, 15 equivalents) was added dropwise under a nitrogen atmosphere at 0°C. The resulting mixture was stirred overnight at rt. The reaction was quenched with water at 0°C. The mixture was acidified to pH=6 with HCl (aqueous solution). The resulting mixture was extracted with ELISA (2 × 120 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN (0.1% FA), gradient from 10% to 100% over 30 minutes; detector, UV 220 nm. This yielded (2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (7.3 g, 70%) as a yellow oil. Step 6: Int.22: [ka]

[0282] To a stirred mixture of (2S)-3-(2-bromo-5-chloropyridine-3-yl)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (2.5 g, 6.35 mmol, 1 equivalent) and 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-yl]ethanone (2392.26 mg, 9.53 mmol, 1.5 equivalents) in 20 mL of dioxane, Na2CO3 (2019.28 mg, 19.05 mmol, 3 equivalents) and Pd(dppf)Cl2.DCM adduct (517.34 mg, 0.635 mmol, 0.1 equivalent) were added in fractional amounts by rt ​​under a nitrogen atmosphere. The resulting mixture was stirred further at 80°C for 3 hours. The mixture was acidified to pH=6 with HCl (1N aqueous solution). The resulting mixture was extracted with ELISA (2 × 60 mL), and the combined organic layer was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 100% over 30 minutes; detector, UV 254 nm. As a result, Int.22 (1.94 g, 66%) was obtained as a brown solid. LCMS (ESI+): m / z 438.2. 1 1H NMR (400MHz, DMSO-d6)δ 12.99(s,1H),8.45(dd,J=15.5,2.4Hz,1H),7.81(dd,J=53.7,2.4Hz,1H),5.86 (d,J=33.1Hz,1H),4.85-4.50(m,1H),4.09(tt,J=30.1,13.7Hz,2H),3.90-3.4 7(m,2H),3.42-3.24(m,2H),3.11(dt,J=26.2,13.1Hz,1H),2.58-2.37(m,4H), 2.41-2.15(m,1H),2.05(dd,J=12.3,2.5Hz,3H),1.23(dd,J=31.0,3.0Hz,9H). Int.23: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid [ka] Step 1: 4-Chloro-1-cyclopropoxy-2-nitrobenzene: [ka]

[0283] To a solution of 4-chloro-1-fluoro-2-nitrobenzene (40 g, 227.86 mmol, 1 equivalent) in DMF (400 mL), cyclopropanol (19.85 g, 341.79 mmol, 1.5 equivalents) and Cs2CO3 (111.36 g, 341.79 mmol, 1.5 equivalents) were added, and the mixture was stirred under N2 at 75°C for 12 hours. Monitoring the reaction by LC-MS showed that 4-chloro-1-fluoro-2-nitrobenzene was consumed and one peak with the mass of the target product was detected. After cooling to rt, the filtrate was diluted with water (400 mL) and extracted with siRNA (200 mL x 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. 4-Chloro-1-cyclopropoxy-2-nitrobenzene (35 g, crude) was obtained as a black-brown oily substance. Step 2: 5-Chloro-2-cyclopropoxyaniline: [ka]

[0284] To a solution of 4-chloro-1-cyclopropoxy-2-nitrobenzene (35 g, 163.84 mmol, 1 equivalent) in H2O (280 mL) and ethanol (280 mL), Fe (45.75 g, 819.22 mmol, 5 equivalents) and NH4Cl (4.38 g, 81.92 mmol, 0.5 equivalents) were added, and the mixture was stirred at 80°C for 1 hour. Monitoring the reaction by LC-MS showed that 4-chloro-1-cyclopropoxy-2-nitrobenzene was consumed and one peak with the mass of the target product was detected. After cooling to rt, the reaction mixture was filtered, and the filter cake was rinsed with siRNA (100 mL x 3). The combined filtrate was then concentrated under reduced pressure to obtain a residue, from which 5-chloro-2-cyclopropoxyaniline (26 g, 115.93 mmol, yield 71%, purity 82%) was obtained as a yellow oil. Step 3: 4-Chloro-1-cyclopropoxy-2-iodobenzene: [ka]

[0285] To a solution of 5-chloro-2-cyclopropoxyaniline (20 g, 108.91 mmol, 1 equivalent) in H2O (216 mL), hydrogen chloride (12 M, 27.23 mL, 3 equivalents) adjusted to pH 2 was added dropwise at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Then, a solution of NaNO2 (8.27 g, 119.80 mmol, 1.1 equivalents) in H2O (36 mL) was added dropwise to the mixture at 0°C, and the mixture was stirred for 1 hour. Subsequently, the reaction mixture was added to a solution of KI (54.24 g, 326.74 mmol, 3 equivalents) in H2O (200 mL), and the mixture was stirred at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that 5-chloro-2-cyclopropoxyaniline was consumed, and one peak with the mass of the target product was detected. The mixture was filtered, the filtrate was diluted with water (300 mL), and extracted with siRNA (150 mL x 3). The combined organic layer was washed with brine (150 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (100 mL) and 60 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry, fluid solid, which was then loaded onto Biotage® using a 120 g Agela flash silica gel column and eluted with a 0%-12% siRNA solution in PE at a flow rate of 75 mL / min. The product fractions were combined and evaporated. 4-Chloro-1-cyclopropoxy-2-iodobenzene (20 g, 65.46 mmol, yield 60%, purity 96.4%) was obtained as a black-brown oil. Step 4: Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoate: [ka]

[0286] The mixture of Zn (34.77 g, 531.70 mmol, 3.5 equivalents) in DMF (210 mL) was degassed, purged three times with N2, and the mixture was stirred at 120°C for 10 minutes under an N2 atmosphere. Then, I2 (11.57 g, 45.57 mmol, 9.18 mL, 0.3 equivalents) from DMF (120 mL) was added dropwise at 20°C, methyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (50 g, 151.92 mmol, 1 equivalent) from DMF (40 mL) was added dropwise, and I2 (11.57 g, 45.57 mmol, 9.18 mL, 0.3 equivalents) from DMF (40 mL) was added dropwise, and the reaction mixture was stirred at 20°C for 1 hour. Monitoring the reaction by TLC (PE:Â=5:1, Rf=0.5) showed that the starting material was completely consumed and a new major spot was detected. The crude product was used in the next step without further purification. (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II)iodide (59.93 g, crude) was obtained as a gray liquid. The zincate was used without further purification.

[0287] A solution of 4-chloro-1-cyclopropoxy-2-iodobenzene (20 g, 67.91 mmol, 1 equivalent), sPhos (4.18 g, 10.19 mmol, 0.15 equivalents), and Pd2(dba)3 (6.22 g, 6.79 mmol, 0.1 equivalents) in DMF (400 mL) was degassed and purged three times with N2. Then, (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc(II)iodide (53.58 g, 135.82 mmol, 2 equivalents) was added dropwise to the DMF. The reaction mixture was then stirred at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that 4-chloro-1-cyclopropoxy-2-iodobenzene was consumed and one peak with the mass of the target product was detected. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (200 mL), filtered, diluted with water (100 mL), and extracted with toluene (100 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250 × 70 mm × 10 μm; mobile phase: [water (NH₄HCO₃)-ACN]; B%: 50%~80%, 18 min), the HPLC fractions were combined, and freeze-dried. Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoate (8 g, 19.53 mmol, yield 29%, purity 98%) was obtained as a yellow oil. Step 5: (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid: [ka]

[0288] To a solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoate (8 g, 21.63 mmol, 1 equivalent) in THF (112 mL), LiOH.H2O (1.09 g, 25.96 mmol, 1.2 equivalents) in H2O (56 mL) was added, and the mixture was stirred at 20°C for 1 hour. Monitoring the reaction by LC-MS showed that methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoate was consumed, and one peak with the mass of the target product was detected. The mixture was acidified to pH=5 by dropwise addition of hydrochloric acid (0.1 M, 15 mL) at 0°C. The residue was diluted with water (100 mL) and extracted with ELISA (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid (5 g, 13.77 mmol, yield 64%, purity 98%) was obtained as a yellow solid. Step 6: Int.23: [ka]

[0289] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid (5 g, 14.05 mmol, 1 equivalent) in THF (50 mL), NaH (2.81 g, 70.26 mmol, 60% purity, 5 equivalents) was added at 0°C. The mixture was stirred under N2 at 0°C for 1 hour. MeI (19.95 g, 140.52 mmol, 8.75 mL, 10 equivalents) was added to the reaction mixture, and the mixture was stirred at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-cyclopropoxyphenyl)propanoic acid was consumed, and one peak with the mass of the target product was detected. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution (20 mL), and the mixture was acidified to pH=5 by dropwise addition of hydrochloric acid (0.1 M, 10 mL) at 0°C. The residue was extracted with toluene (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain residue Int.23 (3 g, 7.71 mmol, 54% yield, 95% purity) as yellow oil. 1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ=7.31-7.08(m,3H),4.85-4.52(m,1H),3.91-3.80(m,1H),3.12-2.99(m,1H),2.94-2.80(m,1H),2.65-2.55(m,3H),1.24(br d,J=19.6Hz,9H),0.87-0.58(m,4H) Preparation of Int.24:(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(morpholine-4-yl)phenyl]propanoic acid [ka] Step 1: (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(morpholine-4-yl)phenyl]propanoate [ka]

[0290] A solution of methyl(2S)-3-(2-bromo-5-chlorophenyl)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoate (3 g, 7.376 mmol, 1 equivalent), Cs2CO3 (7232.46 mg, 22.128 mmol, 3 equivalents), morpholine (771.18 mg, 8.851 mmol, 1.2 equivalents), SPhos (605.66 mg, 1.475 mmol, 0.2 equivalents), and Pd2(dba)3 (675.48 mg, 0.738 mmol, 0.1 equivalent) in dioxane (50 mL) was stirred at 80°C for 3 hours under a nitrogen atmosphere. Residual Cs2CO3 was removed by filtration. Purification of the residue by silica gel column chromatography eluted with PE / EA (5:1) yielded methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(morpholine-4-yl)phenyl]propanoate (1.15 g, 38%) as a brown oil. LCMS(ESI+): m / z 413(M+H + ). Step 2: Int.24: [ka]

[0291] To a stirred solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(morpholine-4-yl)phenyl]propanoate (1.2 g, 2.906 mmol, 1 equivalent) in tetrahydrofuran (15 mL), caustic soda (0.58 g, 14.530 mmol, 5 equivalents) in water (5 mL) was added dropwise at 0°C. The resulting mixture was stirred at rt for 16 hours. The resulting mixture was concentrated under reduced pressure and then diluted with water (20 mL). The resulting mixture was acidified to pH=3 with diluted citric acid (1 N) and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous sodium 2SO4. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 50% over 10 minutes; detector, UV 220 nm. After filtration, the filtrate was concentrated under reduced pressure. As a result, Int.24 (0.81 g, 70%) was obtained as a brownish-yellow solid. LCMS(ESI+): m / z 399(M+H + ). Preparation of Int.25:(S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-morpholinopyridine-3-yl)propanoic acid [ka] Step 1: 4-(3-bromo-5-chloropyridine-2-yl)morpholine: [ka]

[0292] A solution of 3-bromo-5-chloro-2-fluoropyridine (10 g, 47.52 mmol, 1 equivalent) in DMF (600 mL) was treated with Cs2CO3 (46.45 g, 142.57 mmol, 3 equivalents) under a nitrogen atmosphere at rt, followed by the addition of morpholine (6.21 g, 71.28 mmol, 1.5 equivalents) in fractional amounts at rt. The resulting mixture was stirred at rt under a nitrogen atmosphere for 16 hours. The desired product was detected by LC-MS. The resulting mixture was diluted with ice water (1 L) and extracted with SiO2 (2 × 1 L). The combined organic layers were washed with brine (500 mL × 3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 100% over 40 minutes; detector, UV 200-210 nm. This yielded 4-(3-bromo-5-chloropyridine-2-yl)morpholine (3 g, 23%) as a pale yellow solid. LC-MS (ESI+): m / z 279.00. Step 2: Methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(morpholine-4-yl)pyridine-3-yl]propanoate: [ka]

[0293] A DMA (30 mL) solution of 4-(3-bromo-5-chloropyridine-2-yl)morpholine (3.3 g, 11.89 mmol, 1 equivalent) was treated with CuI (0.45 g, 2.38 mmol, 0.2 equivalents) and Pd(dppf)Cl2.CH2Cl2 (0.87 g, 1.19 mmol, 0.1 equivalent) under a nitrogen atmosphere via rt, followed by the addition of methyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-(iododinthio)propanoate (33 mL) via rt. The resulting mixture was stirred at 80°C for 16 hours under a nitrogen atmosphere. The desired product was detected by LC-MS. The reaction mixture was quenched with water (200 mL) and diluted with EA (200 mL). The precipitated solid was removed by filtration and washed with RINKAN (2 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 100% over 40 minutes; detector, UV 200-210 nm. The residue was purified by Prep-TLC (PE / EA2:1) to obtain methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(morpholine-4-yl)pyridine-3-yl]propanoate (1 g, 21%) as a pale yellow oil. LC-MS (ESI+): m / z 400.15. Step 3: Methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(morpholine-4-yl)pyridine-3-yl]propanoate: [ka]

[0294] A solution of methyl(2S)-2-[(tert-butoxycarbonyl)amino]-3-[5-chloro-2-(morpholine-4-yl)pyridine-3-yl]propanoate (700 mg, 1.75 mmol, 1 equivalent) in DMF (10 mL, 129.22 mmol) was treated with Ag2O (2 g, 8.76 mmol, 5 equivalents) under a nitrogen atmosphere at rt, followed by the addition of CH3I (2.4 g, 17.51 ​​mmol, 10 equivalents) at rt. The resulting mixture was stirred at rt under a nitrogen atmosphere for 16 hours. The desired product was detected by LC-MS. The resulting mixture was extracted with SiO2 (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA2:1) to obtain methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(morpholine-4-yl)pyridine-3-yl]propanoate (500 mg, 69%) as a pale yellow oil. LCMS (ESI+): m / z 414.15. 1 H NMR(400MHz,DMSO-d6):δ 1.15-1.34(m,8H),2.61(d,J=8.9Hz,2H),2.94-3.13(m,4H),3.23(dd,J=14.7,4.5Hz ,1H),3.66-3.75(m,5H),7.69(dd,J=34.4,2.6Hz,1H),8.22(dd,J=13.9,2.6Hz,1H). Step 4: Int.25: [ka]

[0295] A solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-[5-chloro-2-(morpholine-4-yl)pyridine-3-yl]propanoate (660 mg, 1.60 mmol, 1 equivalent) in THF (10 mL) was treated with NaOH (318.89 mg, 7.98 mmol, 5 equivalents) in water (10 mL) at 0°C. The resulting mixture was stirred at rt for 2 hours. The desired product was detected by LC-MS. The mixture was neutralized to pH=2 with dilute HCl (1N). The resulting mixture was extracted with ELISA (2 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 100% over 40 minutes; detector, UV 200-210 nm. As a result, Int.25 (423 mg, 66%) was obtained as a white solid. LC-MS (ESI+): m / z 400-15. 1 H NMR(400MHz,DMSO-d6):δ 1.26(s,9H),2.61(d,J=8.7Hz,3H),3.00(tq,J=13.5,8.6,7.2Hz,4H),3.63-3.78(m,4H),5.03(ddd, J=148.8,11.4,4.2Hz,1H),7.67(dd,J=35.8,2.6Hz,1H),8.21(dd,J=14.5,2.6Hz,1H),12.91(s,1H). Int.26: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propanoic acid [ka] Step 1: 5-Chloro-2-hydroxy-3-nitrophenylacetate: [ka]

[0296] TFAA (409.17 g, 1.95 mol, 270.97 mL, 10 equivalents) was added to a three-necked flask, and H2O2 (110.44 g, 974.07 mmol, 93.59 mL, 30% purity, 5 equivalents) was added dropwise at -10°C. After 10 minutes, a solution of 1-(5-chloro-2-hydroxy-3-nitrophenyl)ethane-1-one (42 g, 194.81 mmol, 1 equivalent) in DCM (250 mL) was added dropwise. The reaction mixture was stirred at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that the starting material was consumed and one peak with the mass of the target product was detected. The reaction mixture was diluted with water (100 mL) and extracted with DCM (300 mL x 3). The combined organic layers were washed with aqueous sodium sulfite solution (100 mL, 1 M) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-chloro-2-hydroxy-3-nitrophenyl acetate (30 g, 124.36 mmol, yield 64%, purity 96%) as a yellow solid. LCMS(ESI+): m / z 230.0(M+H + ). Step 2: 5-Chloro-3-nitrobenzene-1,2-diol: [ka]

[0297] To a solution of 5-chloro-2-hydroxy-3-nitrophenyl acetate (30 g, 129.54 mmol, 1 equivalent) in EtOH (300 mL), NaOH (12.95 g, 129.54 mmol, 40 mL, 40% purity in H2O, 1 equivalent) was added, and the mixture was stirred at 20°C for 2 hours. Monitoring the reaction by LC-MS showed that the starting material was consumed and one peak with the mass of the target product was detected. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was acidified to pH=4 by dropwise addition of hydrochloric acid (1 M, 50 mL) at 0°C. The mixture was extracted with ELISA (200 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-chloro-3-nitrobenzene-1,2-diol (22 g, 113.74 mmol, yield 87.80%, purity 98%) as a yellow solid. LCMS(ESI+): m / z 188.0(M+H) + ). Step 3: 7-Chloro-5-nitro-2,3-dihydrobenzo[b][1,4]dioxin: [ka]

[0298] To a solution of 5-chloro-3-nitrobenzene-1,2-diol (10 g, 52.76 mmol, 1 equivalent) in DMF (100 mL), 1,2-dibromoethane (9.91 g, 52.76 mmol, 3.98 mL, 1 equivalent) and K2CO3 (14.58 g, 105.51 mmol, 2 equivalents) were added at 20°C. The mixture was stirred at 80°C for 12 hours. Monitoring the reaction by LC-MS showed that the starting material was consumed and one of the main peaks was detected. The reaction mixture was cooled to rt, diluted with water (100 mL), and extracted with siRNA (60 mL x 3). The combined organic layers were washed with water (100 mL x 2). Next, the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and the reaction mixture was concentrated under reduced pressure to obtain 7-chloro-5-nitro-2,3,-dihydrobenzo[b][1,4]dioxin (11 g, 51.0 mmol, 97% yield) as a black-brown oil. Step 4: 7-Chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine: [ka]

[0299] To a solution of 7-chloro-5-nitro-2,3,-dihydrobenzo[b][1,4]dioxin (16 g, 74.21 mmol, 1 equivalent) in EtOH (80 mL) and H2O (80 mL), Fe (20.72 g, 371.07 mmol, 5 equivalents) and NH4Cl (19.85 g, 371.07 mmol, 5 equivalents) were added at 20°C. The reaction mixture was stirred at 80°C for 2 hours. Monitoring the reaction by LC-MS showed that the starting material was consumed and one of the main peaks, representing the mass of the target product, was detected. The reaction mixture was filtered through a Celite pad, and the Celite was rinsed with SiO4 (100 mL). The filtrate was diluted with water (100 mL) and extracted with SiO4 (120 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (200 mL) and 50 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry liquid solid, which was then loaded onto Biotage® using an 80 g Agela flash silica gel column and eluted with a 30%-40% siRNA PE solution at a flow rate of 75 mL / min. The product fractions were combined and evaporated to obtain 7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (8.6 g, 43.84 mmol, yield 30%, purity 94%) as a brown oil. LCMS (ESI+): m / z 186.3 (M+H + ). Step 5: 7-Chloro-5-iodo-2,3-dihydrobenzo[b][1,4]dioxin: [ka]

[0300] To a solution of 7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-amine (4.6 g, 24.78 mmol, 1 equivalent) in MeCN (24 mL), hydrogen chloride (2.5 M, 49.57 mL, 5 equivalents) was added at 0°C. The mixture was stirred at 0°C for 0.5 hours. Next, a solution of NaNO2 (1.88 g, 27.26 mmol, 1.1 equivalents) in H2O (20 mL) was added to the reaction mixture, and the mixture was stirred at 0°C for 0.5 hours. Next, a solution of KI (12.34 g, 74.35 mmol, 3 equivalents) in H2O (100 mL) was added to the reaction mixture, and the reaction mixture was stirred at 0°C for 2 hours. Monitoring the reaction by LC-MS showed that the starting material was consumed and one of the main peaks with the mass of the target product was detected. The pH of the mixture was adjusted to 7-8 by slowly adding saturated NaHCO3 aqueous solution at 0°C. The mixture was extracted with siRNA (50 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (50 mL) and 20 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry, flowing solid, which was then loaded onto Biotage® using a 40 g Agela flash silica gel column and eluted with a 15-20% siRNA PE solution at a flow rate of 75 mL / min. The product fractions were combined and evaporated to obtain 7-chloro-5-iodo-2,3-dihydrobenzo[b][1,4]dioxin (6.5 g, 21.71 mmol, yield 88%, purity 99%) as a black-purple solid. LCMS(ESI+): m / z 298.1(M+H + ). Step 6: Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propanoate: [ka]

[0301] The mixture of Zn (13.91 g, 212.68 mmol, 3.5 equivalents) in DMF (100 mL) was degassed, purged three times with N2, and the mixture was stirred at 120°C for 10 minutes under an N2 atmosphere. Then, I2 (4.63 g, 18.23 mmol, 3.7 mL, 0.3 equivalents) in DMF (40 mL) was added dropwise at 20°C, methyl(2R)-2-(tert-butoxycarbonylamino)-3-iodopropanoate (20 g, 60.77 mmol, 1 equivalent) in DMF (30 mL) was added dropwise, and I2 (4.63 g, 18.23 mmol, 3.67 mL, 0.3 equivalents) in DMF (30 mL) was added dropwise, and the reaction mixture was stirred at 20°C for 1 hour. The zincate was used in the next step without further purification. [(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxopropyl]iodo-zinc (23.95 g, 60.71 mmol, yield 99.9%) was obtained as a gray liquid. To a solution of 7-chloro-5-iodo-2,3-dihydrobenzo[b][1,4]dioxin (9 g, 30.36 mmol, 1 equivalent) in DMF (90 mL), [(2R)-2-(tert-butoxycarbonylamino)-3-methoxy-3-oxopropyl]iodo-zinc (23.95 g, 60.71 mmol, 2 equivalents), Pd2(dba)3 (1.39 g, 1.52 mmol, 0.05 equivalents) and SPhos (1.25 g, 3.04 mmol, 0.1 equivalents) were added at 20°C. The mixture was stirred at 20°C for 12 hours. Monitoring the reaction by LC-MS showed that the starting material was consumed and one of the main peaks, representing the mass of the target product, was detected. The reaction mixture was diluted with water (90 mL) and extracted with pharmaceutically acceptable ammonium compounds (100 mL x 3). The combined organic layer was washed with water (150 mL x 2). The combined organic layer was then washed with brine (200 mL), dried over Na2SO4, filtered, and the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in DCM (30 mL) and 18 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry, liquid solid, which was then loaded onto Biotage® using a 40 g Agela flash silica gel column and eluted with 0% to 20% pharmaceutically acceptable ammonium compounds in PE at a flow rate of 75 mL / min.When the product fractions were combined and evaporated, methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propanoate (6g, 15.55 mmol, yield 51%, purity 96%) was obtained as a yellow oil. Step 7: (S)-2-((tert-butoxycarbonyl)amino)-3-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propanoic acid: [ka]

[0302] A solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propanoate (5.5 g, 14.79 mmol, 1 equivalent) in THF (36 mL) was added to a solution of LiOH.H2O (744.89 mg, 17.75 mmol, 1.2 equivalents) in H2O (18 mL) at 0°C. The mixture was stirred at 20°C for 2 hours. Monitoring the reaction by LC-MS showed that the starting material was consumed and one of the main peaks, representing the mass of the target product, was detected. The mixture was acidified by adding hydrochloric acid (1 M) dropwise at 0°C to pH=3. The mixture was extracted with ELISA (50 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was dissolved in DCM (30 mL) and 10 g of silica gel was added. The resulting mixture was evaporated under reduced pressure to obtain a dry liquid solid, which was then loaded onto Biotage® using a 40 g Agela flash silica gel column and eluted with 0% to 35% ethyl acetate in PE at a flow rate of 75 mL / min. The product fractions were combined and evaporated to obtain (S)-2-((tert-butoxycarbonyl)amino)-3-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propanoic acid (5.2 g, 14.53 mmol, yield 98%, purity 100%) as a yellow oil. LCMS (ESI+): m / z 380.2 (M+Na +). Step 8: Int.26: [ka]

[0303] (S)-2-((tert-butoxycarbonyl)amino)-3-(7-chloro-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)propanoic acid (2.6 g, 7.27 mmol, 1 equivalent) was dissolved in THF (60 mL) and NaH (1.45 g, 36.33 mmol, 60% purity, 5 equivalents) was added at 0°C. The mixture was stirred under N2 at 0°C for 1 hour. MeI (10.31 g, 72.67 mmol, 4.52 mL, 10 equivalents) was added to the reaction mixture and the mixture was stirred under N2 at 20°C for 12 hours. (Batch 2) Monitoring the reaction by LC-MS showed that the starting material was consumed and one of the main peaks with the mass of the target product was detected. The reactants were quenched with saturated ammonium chloride (30 mL) at 0°C and extracted with SiO2 (60 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and the reaction mixture was concentrated under reduced pressure to obtain Int.26 (3.9 g, 10.0 mmol, yield 69%, purity 96%) as a pale yellow solid. LCMS(ESI+): m / z 394.1(M+Na + ). 1 H NMR(400MHz,CHLOROFORM-d).δ ppm 1.40(d,J=10.8Hz,9 H)2.67-2.82(m,3 H)3.00-3.13(m,1 H)3.15-3.35(m,1 H)4.18-4.34(m,4 H)4.61-4.91(m,1 H)6.68(d,J=11.6Hz,1 H)6.79(d,J=2.0Hz,1 H). Int.27: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-methylpyridine-3-yl)propanoic acid [ka] Step 1: (5-chloro-2-methylpyridine-3-yl)methanol: [ka]

[0304] NaBH4 (6.11 g, 161.63 mmol, 3 equivalents) was added to a mixture of MeOH (200 mL) containing methyl 5-chloro-2-methylpyridine-3-carboxylate (10 g, 53.88 mmol, 1 equivalent) at 0°C under an air atmosphere. The mixture was stirred overnight at rt. The reaction product was then quenched with water (100 mL) and concentrated under reduced pressure. The residual aqueous phase was extracted with ÂTED (2 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to obtain (5-chloro-2-methylpyridine-3-yl)methanol (6.1 g, 72%) as a yellow oil. LCMS (ESI+): m / z 158.0. Step 2: 3-(bromomethyl)-5-chloro-2-methylpyridine: [ka]

[0305] PBr3 (31431.18 mg, 116.12 mmol, 3 equivalents) was added dropwise to a mixture of DCM (50 mL) containing (5-chloro-2-methylpyridine-3-yl)methanol (6.1 g, 38.71 mmol, 1 equivalent) at 0°C under a nitrogen atmosphere. The mixture was stirred at 0°C for 3 hours. The resulting mixture was quenched with water (50 mL) at 0°C and extracted with  (2 × 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. This yielded 3-(bromomethyl)-5-chloro-2-methylpyridine (7 g, 82%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI+): m / z 222.1. Step 3: tert-butyl(2S)-3-(5-chloro-2-methylpyridine-3-yl)-2-[(diphenylmethylidene)amino]propanoate: [ka]

[0306] To a stirred mixture in DCM (60 mL) containing 3-(bromomethyl)-5-chloro-2-methylpyridine (6.1 g, 27.67 mmol, 1 equivalent) and tert-butyl 2-[(diphenylmethylidene)amino]acetate (12257.90 mg, 41.50 mmol, 1.5 equivalents), H2O (15 mL) containing KOH (15521.82 mg, 276.66 mmol, 10 equivalents) was added in divided portions at -10°C under an air atmosphere. The resulting mixture was stirred overnight at -10°C. The resulting mixture was extracted with DCM (2 × 100 mL), the combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. Purification of the residue by silica gel column chromatography using PE / EA (10:1) elution yielded tert-butyl(2S)-3-(5-chloro-2-methylpyridine-3-yl)-2-[(diphenylmethylidene)amino]propanoate (6.4 g, 53%) as a yellow oil. LCMS(ESI+): m / z 435.0. Step 4: (S)-2-amino-3-(5-chloro-2-methylpyridine-3-yl)propanoic acid: [ka]

[0307] A mixture of tert-butyl(2S)-3-(5-chloro-2-methylpyridine-3-yl)-2-[(diphenylmethylidene)amino]propanoate (300 mg, 0.69 mmol, 1 equivalent) and HCl (6 M) (100.00 mL, 3291.28 mmol, 119.30 equivalents) in THF (10 mL) was stirred overnight at 55°C under an air atmosphere. The resulting mixture was concentrated under reduced pressure. This yielded (2S)-2-amino-3-(5-chloro-2-methylpyridine-3-yl)propanoic acid (5 g, 84.43%) as a yellow oil. The crude product was used directly in the next step without further purification. LCMS (ESI+): m / z 215.0. Step 5: (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-methylpyridine-3-yl)propanoic acid: [ka]

[0308] To a stirred mixture of H2O (100 mL) containing (2S)-2-amino-3-(5-chloro-2-methylpyridine-3-yl)propanoic acid (4 g, 18.64 mmol, 1 equivalent) and Boc2O (12.20 g, 55.91 mmol, 3.00 equivalent), Na2CO3 (5.93 g, 55.91 mmol, 3 equivalents) was gradually added at rt under an air atmosphere. The resulting mixture was stirred overnight at rt. The mixture was acidified to pH=6 with dilute HCl (1N aqueous solution). The resulting mixture was stirred overnight at 0°C. The resulting mixture was extracted with ELISA (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), gradient from 10% to 100% over 35 minutes; detector, UV 220 nm. This yielded (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-methylpyridine-3-yl)propanoic acid (5.6 g, 95%) as a white solid. LC-MS (ESI+): m / z 315.10. 1 H NMR(400MHz,DMSO-d6):δ12.82(s,1H),8.33(d,J=2.4Hz,1H),7.65(d,J=2.5Hz,1H),7.21(d,J=8.8Hz,1H) ,4.28-4.10(m,1H),3.11(dd,J=14.3,4.4Hz,1H),2.81(dd,J=14.4,11.0Hz,1H),2.47(s,3H),1.30(s,9H). Step 6: Int.27: [ka]

[0309] NaH (1.19 g, 49.56 mmol, 6 equivalents) was gradually added under nitrogen at 0°C to a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(5-chloro-2-methylpyridine-3-yl)propanoic acid (2.6 g, 8.26 mmol, 1 equivalent) in THF (25 mL). The mixture was stirred at 0°C for 1 hour. MeI (11.72 g, 82.60 mmol, 10 equivalents) was added to the above solution at 0°C under a nitrogen atmosphere. The resulting mixture was stirred overnight at rt. The reaction was quenched at 0°C by adding saturated NH4Cl (aqueous solution) (20 mL). The mixture was acidified to pH=6 with dilute HCl (aqueous solution 1 N). The resulting mixture was extracted with ELISA (2 × 50 mL), and the combined organic layers were dried over anhydrous Na2SO4 and filtered. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 10% to 100% over 35 minutes; detector, UV 210 nm. As a result, Int. 27 (3.71 g, 133% mass recovery) was obtained as a yellow solid. LC-MS (ESI+): m / z 329.10. 1 H NMR(400MHz,DMSO-d6):δ 12.98(s,1H),8.34(dd,J=16.6,2.4Hz,1H),7.59(dd,J=21.9,2.4Hz,1H),4.72(ddd,J=53.9,1 1.2,4.4Hz,1H),3.27-2.92(m,2H),2.65(d,J=2.0Hz,3H),2.50(s,3H),1.25(d,J=34.2Hz,9H). Int.28: Preparation of (S)-2-((tert-butoxycarbonyl)(methyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoic acid [ka] Step 1: 5-Chloro-3-iodo-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine: [ka]

[0310] To a solution of 2,5-dichloro-3-iodopyridine (10 g, 36.51 mmol, 1 equivalent) in DMF (140 mL), Cs2CO3 (23.79 g, 73.02 mmol, 2 equivalents) and 1-methylpyrazole-4-ol (4.30 g, 43.81 mmol, 1.2 equivalents) were added. The mixture was stirred at 80°C for 1 hour. LC-MS showed that 2,5-dichloro-3-iodopyridine was completely consumed and the mass of the target product was detected. After cooling to rt, the reaction mixture was diluted with water (200 mL) and extracted with siRNA (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The resulting crude product was purified by flash chromatography on silica gel (0-22% siRNA in PE). 5-Chloro-3-iodo-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine (10.9 g, 29.59 mmol, yield 81%, purity 91%) was obtained as a yellow solid. Step 2: Methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoate [ka]

[0311] The mixture of Zn (18.08 g, 276.49 mmol, 3.5 equivalents) in DMF (150 mL) was degassed, purged three times with N2, and the mixture was stirred at 120°C for 10 minutes under an N2 atmosphere. Then, I2 (6.01 g, 23.70 mmol, 4.77 mL, 0.3 equivalents) in DMF (20 mL) was added dropwise at 20°C, methyl(R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (26 g, 79.00 mmol, 1 equivalent) in DMF (70 mL) was added dropwise, and I2 (6.01 g, 23.70 mmol, 4.77 mL, 0.3 equivalents) in DMF (20 mL) was added dropwise, and the reaction mixture was stirred at 20°C for 1 hour. Zinc salt was used directly.

[0312] To a solution of 5-chloro-3-iodo-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine (9.9 g, 29.51 mmol, 1 equivalent) in DMF (260 mL), Pd2(dba)3 (1.35 g, 1.48 mmol, 0.05 equivalent) and sPhos (1.21 g, 2.95 mmol, 0.1 equivalent) were added under an N2 atmosphere. Then, under an N2 atmosphere, (R)-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)zinc iodide(II) (24.33 g, 61.67 mmol, 2.09 equivalents in DMF) was added dropwise, and the reaction mixture was stirred under N2 at 65°C for 12 hours. LC-MS showed that 5-chloro-3-iodo-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine was completely consumed and the mass of the target product was detected. The mixture was quenched with NH4Cl (200 mL) and extracted with siRNA (200 mL x 3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by flash chromatography on silica gel (0-21% siRNA in PE) to obtain methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoate (5.6 g, 11.97 mmol, yield 41%, purity 87.8%) as a pale yellow rubbery substance. Step 3: (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoic acid: [ka]

[0313] To a solution of methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoate (4.6 g, 11.20 mmol, 1 equivalent) in THF (40 mL), LiOH·H2O (704.75, 16.79 mol, 1499.99 equivalents) in H2O (20 mL) was added at 0°C, and the reaction was stirred at 25°C for 0.5 hours. LCMS showed that the methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoate was completely consumed and the mass of the target product was detected. The reaction mixture was washed with MTBE (10 mL x 2), and then the aqueous phase was adjusted to pH 3-4 with 1 M HCl and extracted with siRNA (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue, from which (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoic acid (4 g, 9.37 mmol, yield 84%, purity 93%) was obtained as a pale yellow rubber without purification. Step 4: Int.28: [ka]

[0314] (S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoic acid (3 g, 7.56 mmol, 1 equivalent) was dissolved in THF (90 mL), to which NaH (1.51 g, 37.80 mmol, 60% purity, 5 equivalents) was added under an N2 atmosphere at 0°C. The mixture was stirred at 0°C for 30 minutes, and then MeI (10.73 g, 75.60 mmol, 4.71 mL, 10 equivalents) was added. The mixture was heated to 25°C and stirred at 25°C for 12 hours. LC-MS showed that methyl(S)-2-((tert-butoxycarbonyl)amino)-3-(5-chloro-2-((1-methyl-1H-pyrazole-4-yl)oxy)pyridine-3-yl)propanoate was completely consumed and the mass of the target product was detected. The reaction mixture was quenched with NH4Cl (100 mL), the pH was adjusted to 3-4 with 1 M HCl, and extracted with siRNA (30 mL x 4). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was diluted with MeOH (50 mL) and washed with PE (20 mL x 4). The residue was concentrated under reduced pressure to obtain a pale yellow solid. Int. 28 (2.6 g, 6.10 mmol, yield 81%, purity 92.8%) was obtained as a pale yellow solid without purification. Int.29:(S)-3-(2-((1-acetylazetidine-3-yl)oxy)-5-chloropyridine-3-yl)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid: [ka]

[0315] This material was synthesized using 1-(3-hydroxyazetidine-1-yl)ethane-1-one as the starting alcohol, following the procedure in Int. 13. LCMS(ESI+): m / z 428.1(M+H + ) Preparation of Int.30: (S)-3-(2-bromo-5-chlorophenyl)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid [ka] Step 1: (2S, 5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine: [ka]

[0316] To a solution of (R)-3,6-diethoxy-2-isopropyl-2,5-dihydropyrazine (151 g, 711 mmol, 1.00 equivalent) in THF (1500 mL), n-BuLi (2.5 M, 285 mL, 1.00 equivalent) was added under N2 at -70°C. Then, to the above solution, a solution of 1-bromo-2-(bromomethyl)-4-chlorobenzene (222.5 g, 782 mmol, 1.10 equivalent) in THF (220 mL) was added at -70°C. The mixture was stirred at 25°C for 12 hours. TLC showed that 1-bromo-2-(bromomethyl)-4-chlorobenzene remained, and several new spots were detected. The reaction mixture was poured into saturated NH4Cl (aqueous solution). 6000 mL of the reaction mixture was partitioned into 6000 mL of aqueous phase and 6000 mL of THF. The organic phase was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE / siRNA = 100 / 0~1 / 1) to obtain the desired (2S,5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (620 g, 1.48 mol, yield 104%, purity 99.3%) as a yellow rubbery substance. LCMS (ESI+): m / z 415 / 417 (M+H + ) Step 2: Ethyl(S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate: [ka]

[0317] To a solution of (2S, 5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (100 g, 240 mmol, 1.00 equivalent) in ACN (1500 mL), HCl (0.20 M, 1.40 L, 1.16 equivalents) was added at 0°C, and the mixture was stirred at 25°C for 48 hours. TLC showed that (2S, 5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine was completely consumed. The reaction mixture was concentrated under reduced pressure to remove the ACN, extracted with 4000 mL (2000 mL x 2) of DCM, and the organic layer was concentrated under reduced pressure to obtain the residue. The aqueous phase was then basicized with saturated aqueous solution. NaHCO3 was added to adjust the pH to 7, and the mixture was extracted with 4.00 L (2.00 L x 2) of DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the desired ethyl(S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate (143 g, 466 mmol, yield 49%) as a white solid, and (2S,5R)-2-(2-bromo-5-chlorobenzyl)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazine (200 g, crude) as a yellow rubber. Step 3: (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid: [ka]

[0318] To a solution of ethyl(S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate (143 g, 466 mmol, 1.00 equivalent) in THF (715 mL) and EtOH (715 mL), LiOH·H2O (58.7 g, 1.40 mol, 3.00 equivalent) was added at 0°C, and the reaction was stirred at 25°C for 12 hours. TLC showed that the ethyl(S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoate was completely consumed. The reaction mixture was concentrated under reduced pressure at 30°C to remove half of the solvent. This was added to a saturated solution of citric acid (1.50 L) at 5-10°C, and the entire reaction was allowed to proceed under acidic conditions. Some solid precipitated, and the suspension was then filtered, and the filter cake was washed with MTBE (1.00 L). The filtered cake was collected and dried in a vacuum to obtain the desired (S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid (130 g, crude) as a yellow solid, which was confirmed by LC-MS and SFC, and then used in the next step without further purification. Step 4: (S)-3-(2-bromo-5-chlorophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid: [ka]

[0319] A mixture of THF (750 mL) containing (2S)-2-amino-3-(2-bromo-5-chlorophenyl)propanoic acid (70.00 g, 251.32 mmol, 1 equivalent) and NaOH (1N, 750 mL) was mixed with Boc₂O (109.70 g, 502.64 mmol, 115.47 mL, 2 equivalents) at 0°C, and the mixture was stirred at 20°C for 12 hours. LC-MS showed that reactant 1 was completely consumed and the desired product was detected. The mixture was poured into saturated citric acid (4 L) and extracted with SiO₂ (1 L x 3 times). The organic layer was washed with water (2 L) and brine (2 L), dried over Na₂SO₄, filtered, and concentrated. The mixture was suspended in PE (1 L) and stirred at 20°C for 0.5 hours. Next, the mixture was filtered, the white solid was recovered, and dried to obtain compound 2(2S)-3-(2-bromo-5-chlorophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (124 g, 320.9 mmol, yield 64%, purity 98%) as a white solid. 1 H NMR:ET53616-98-P1Z(400MHz,MeOD)δ 7.54(d,J=8.4Hz,1H),7.33(d,J=2.4Hz,1H),7.17-7.15(m,1H),4.49(dd,J=4.4,10.4Hz,1H),3.39(br dd,J=4.4,9.6Hz,1H),2.94-2.88(m,1H),1.36-1.28(m,9H).LCMS(ESI+):m / z 277.9 / 279.9(M+H + ) Step 5: Int.30: [ka]

[0320] To a mixture of THF (90 mL × 10) containing (2S)-3-(2-bromo-5-chlorophenyl)-2-(tert-butoxycarbonylamino)propanoic acid (3.00 g × 10, 7.92 mmol, 1 equivalent), NaH (1.58 g × 10, 39.61 mmol, 60% purity, 5 equivalents) was added at 0°C, and the mixture was stirred at 0°C for 0.5 hours. Then, MeI (11.25 g × 10, 79.23 mmol, 4.93 mL, 10 equivalents) was added at 0°C, and the mixture was stirred at 15°C for 12 hours. LC-MS showed that (2S)-3-(2-bromo-5-chlorophenyl)-2-(tert-butoxycarbonylamino)propanoic acid was completely consumed, and the desired product was detected. The mixture was quenched with saturated citric acid (1.5 L) and extracted with toluene (1.5 L x 2). The organic layer was washed with brine (1.5 L), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (SiO2, PE / toluene / THF = 20 / 1 / 0 to 6 / 1 / 1) to obtain the crude product. The mixture was combined with ET53616-100 and 104. The residue was dissolved in DCM (1 L) and concentrated under reduced pressure to obtain the target product Int.30 (114.0 g, 285.70 mmol, purity 98%) as a yellow solid. 1 H NMR:ET53616-105-P1Z2(400MHz,CHLOROFORM-d)δ 11.44(brs,1H),7.50-7.47(m,1H),7.20-7.19(m,1H),7.13-7.11(m,1H),4.83-4.71(m,1H), 3.48-3.43(m,1H),3.31-3.06(m,1H),2.81-2.70(m,3H),1.44-1.37(m,9H).LCMS(ESI+):m / z 291.9 / 293.9(M+H + ). Int.31:(S)-3-(2-bromo-5-fluorophenyl)-2-((tert-butoxycarbonyl)(methyl)amino)propanoic acid: [ka]

[0321] This material was synthesized using 1-bromo-2-(bromomethyl)-4-fluorobenzene as the starting material, following the acid procedure in Int. 30. Int.33:((2S,4R)-4-fluoro-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)pyrrolidine-2-carbonyl)glycine: [ka]

[0322] This material was synthesized using commercially available FMOC-protected amino acids in the same manner as Int.34. LCMS(ESI+): m / z 327.1(M+H + ). Preparation of Int.34: ((S)-2-(1-(trifluoromethyl)cyclopropane-1-carboxamide)butanoyl)-L-alanine [ka] Steps 1-4: Int.34: [ka] [ka] [ka] [ka]

[0323] A mixture of TEA (7.61 g, 10.5 mL, 6 equivalents, 75.2 mmol) and (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alanine (3.90 g, 1 equivalent, 12.5 mmol) in DCM (50 mL) was added to a pre-swollen 2-chlorotrityl chloride resin (5 g). The reaction mixture was stirred for 1 hour and then filtered. The supported resin was washed with DMF (3 × 50 mL). Next, 20% piperidine in DMF (50 mL) was added to the resin, stirred for 1 hour, and then washed with DMF (3 × 50 mL). Next, the newly deprotected resin was subjected to a pre-activation solution in DMF (50 mL) of Fmoc-protecting amino acids consisting of (S)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)amino)butanoic acid (4.08 g, 1 equivalent, 12.5 mmol), HATU (5.24 g, 1.1 equivalent, 13.8 mmol), and DIPEA (13.0 g, 17.5 mL, 8 equivalents, 100 mmol). The resin was stirred for 1 hour and then washed with DMF (3 × 50 mL). Deprotection was repeated by adding 20% ​​piperidine in DMF (50 mL). The resin was stirred for 1 hour and then washed with DMF (3 × 50 mL). The final coupling was performed in DMF (50 mL) This was done by adding another pre-activated carboxylic acid solution consisting of 1-(trifluoromethyl)cyclopropane-1-carboxylic acid (1.93 g, 1 equivalent, 12.5 mmol), HATU (5.24 g, 1.1 equivalent, 13.8 mmol), and DIPEA (13.0 g, 17.5 mL, 8 equivalents, 100 mmol) to the resin. This was stirred for 1 hour, and then washed with DMF (3 × 50 mL), methanol (3 × 50 mL), and then DCM (3 × 50 mL). The tripeptides were then cleaved by stirring the resin with an HFIP / DCM mixture (1:1, 2 × 50 mL). The combined cleaved filtrate was concentrated, and the crude residue was collected from FCC (SiO2, MeOH in DCM). Purified by 0-20% for 10 minutes. Int.34 (500 mg, 0.5 mmol / 80% based on resin loading) was isolated as a white solid. LC-MS (ESI+): m / z 311.1 (M+H + ). Int.35:(S)-2-((2S,4R)-4-fluoro-1-(1-trifluoromethyl)cyclopropane-1-carbonyl)pyrrolidine-2-carboxamide)butanoic acid: [ka]

[0324] This material was synthesized using commercially available FMOC-protected amino acids in the same manner as Int.34. LCMS(ESI+): m / z 355.4(M+H + ). Int.39: Preparation of (2S,4R)-4-fluoro-1-(2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylic acid: [ka]

[0325] Int.39 was synthesized according to Int.148 and Int.149, but the diastereomer was not separated. Preparation of Int.40: 1-(4-((4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-yl)ethane-1-one [ka] Step 1: Int.40: [ka]

[0326] tert-butyl 4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene)piperidine-1-carboxylate (1.0 g, 1 equivalent, 3.1 mmol) was dissolved in 10 mL of DCM / TFA (3:1) and stirred until the starting material was consumed (monitored by LC-MS). The volatile solvent was completely removed, and residual TFA was removed by co-evaporation with toluene. The deprotected amine was used directly without further purification. The crude material was dissolved in DCM (20 mL), cooled to 0°C, and then TEA (0.94 g, 1.3 mL, 3 equivalents, 9.3 mmol) and AcCl (0.29 g, 0.26 mL, 1.2 equivalents, 3.7 mmol) were added and stirred at 0°C. Once complete, the volatile solvent was removed, and the resulting solid was left overnight under high pressure. The obtained solid Int.40 (750 mg, 2.83 mmol, 91%) was used in subsequent reactions without further purification. LCMS(ESI+): m / z 266.1(M+H) + ). Preparation of Int.41:(S)-2-((tert-butoxycarbonyl)(ethyl)amino)penta-4-enoic acid [ka] Step 1: (2S)-2-(ethylamino)penta-4-enoic acid: [ka]

[0327] (2S)-2-aminopenta-4-enoic acid (5 g, 43.43 mmol, 1 equivalent) was stirred in MeOH (50 mL), to which NaBH3CN (3.41 g, 54.29 mmol, 1.25 equivalents) was added under a nitrogen atmosphere at 0°C. The resulting solution was stirred at 0°C for 10 minutes. Acetaldehyde (10.97 mL, 195.43 mmol, 1.5 equivalents) was added, and the resulting solution was stirred at 0°C for 1 hour. After heating to rt, the mixture was stirred at rt for 16 hours. The resulting mixture was quenched with water at 0°C and extracted with ELISA (2 × 10 mL). This yielded (2S)-2-(ethylamino)penta-4-enoic acid (15 g, 76%), and the resulting crude mixture was used directly in the next step without further purification. LCMS (ESI+): m / z 144.09 (M+H + ). Step 2: Int.41: [ka]

[0328] To a stirred solution of (2S)-2-(ethylamino)penta-4-enoic acid (15 g, 104.76 mmol, 1 equivalent) and NaOH (29.33 g, 733.31 mmol, 7 equivalents) in dioxane (150 mL) / H2O (150 mL), Boc2O (45.73 g, 209.52 mmol, 2 equivalents) was added under a nitrogen atmosphere at 0°C. The resulting solution was stirred at rt for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the dioxane. The aqueous layer was acidified to pH=5 with 1N HCl. The aqueous layer was extracted with SiO2 (3 × 200 mL). The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN aqueous solution (0.1% FA), gradient from 0% to 100% over 40 minutes; detector, UV 210 nm. As a result, Int. 41 (11.9 g, 46%) was obtained as a white solid. LCMS (ESI+): m / z 244.15 (M+H + ). 1H NMR(400MHz,DMSO-d6):δ 1.05(dt,J=7.0,7.0,14.3Hz,3H),1.38(d,J=14.8Hz,9H),2.51-2.69(m,2H),3.03(dq,J=6.8,6.8,6.8,18.6Hz,1H),3.26(ddq ,J=6.9,7.0,7.0,14.0,28.9Hz,1H),4.18(ddd,J=5.1,9.9,114.9Hz,1H),4.97-5.18(m,2H),5.64-5.90(m,1H),12.52(s,1H). Preparation of Int.42:(S)-2-((tert-butoxycarbonyl)(methyl)amino)hexa-5-enoic acid [ka] Step 1: (S)-1-[(2R)-1-benzylpyrrolidine-2-carbonyl]-5-(buta-3-en-1-yl)-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one: [ka]

[0329] A solution of 1-[(2R)-1-benzylpyrrolidine-2-carbonyl]-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one (75.31 g, 151.17 mmol, 1 equivalent) and NaOH (60.46 g, 1511.67 mmol, 10 equivalents) in DMF (600 mL) was stirred at rt for 15 minutes under a nitrogen atmosphere. 4-bromo-1-butene (20 g, 148.14 mmol, 0.98 equivalents) was added dropwise to the solution and stirred at rt for 1.5 hours. The mixture was acidified to pH=6 with HOAc (5%) and extracted with SiO2 (3 × 1 L). The combined organic layers were washed with NH4Cl (aqueous solution) (3 × 1 L) and dried on anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography. Elution with CH2Cl2 / MeOH (20:1) yielded the crude product (5S)-1-[(2R)-1-benzylpyrrolidine-2-carbonyl]-5-(buta-3-en-1-yl)-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one (80g, 86%) as a red solid. LCMS (ESI+): m / z 552.3(M+H + ). 1 H NMR(400MHz,DMSO-d6):δ 1.19(t,J=7.1Hz,7H),1.59(dtd,J=13.3,6.6,3.3Hz,1H),1.99(s,5H),2.07(s,6H),2.02-2.25(m,3H),2.48(s,1H),3.33(s,4H) ),3.34-3.48(m,1H),3.48-3.62(m,2H),3.64(td,J=10.6,9.7,3.7Hz,1H),3.99-4.13(m,5H),4.82(dd,J=10.2,1.9Hz,1H),4.8 5-4.97(m,1H),5.49(s,1H),5.95(s,1H),6.55(dd,J=8.2,1.7Hz,1H),6.61-6.74(m,1H),7.03-7.16(m,2H),7.13-7.27(m,1H), 7.36(t,J=7.7Hz,2H),7.39-7.49(m,1H),7.45-7.53(m,1H),7.50-7.64(m,3H),7.98(dd,J=8.7,1.2Hz,1H),8.32-8.43(m,2H). Step 2: (2S)-2-aminohexa-5-enoic acid: [ka]

[0330] (5S)-1-[(2R)-1-benzylpyrrolidine-2-carbonyl]-5-(buta-3-en-1-yl)-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one (100 g, 181.06 mmol, 1 equivalent) and HCl (600 mL, 3N) were mixed in THF (600 mL) and stirred at 80°C for 2 hours. The mixture was basicized to pH=7 with NaOH / Na2CO3. The resulting mixture was extracted with CH2Cl2 (3 × 500 mL). 2-aminohexa-5-enoic acid (25 g, 427%) in the (2S) aqueous layer was used directly in the next step without further purification. LCMS (ESI+): m / z 130.15 (M+H + ). Step 3: (2S)-2-[(tert-butoxycarbonyl)amino]hexa-5-enoic acid: [ka]

[0331] To the above aqueous solution (1.5 L) containing (2S)-2-aminohexa-5-enoic acid (25 g, 193.56 mmol, 1 equivalent), Boc2O (84.50 g, 387.12 mmol, 2 equivalents) was added and the mixture was stirred at rt for 16 hours. The mixture was acidified to pH=6 with citric acid and extracted with CH2Cl2 (3 × 500 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile, gradient from 5% to 100% over 30 minutes; detector, UV 210 nm. This yielded (2S)-2-[(tert-butoxycarbonyl)amino]hexa-5-enoic acid (12 g, 135%) as a pale yellow oily substance. LCMS(ESI+): m / z 130.15(M+H + ). 1 H NMR(400MHz,DMSO-d6):δ 1.18(t,J=7.1Hz,1H),1.35(s,1H),1.39(s,8H),1.57-1.69(m,1H),1.66 -1.78(m,1H),1.91(s,2H),1.99(s,1H),2.06(dq,J=13.9,7.2Hz,2H),3.8 8(ddd,J=9.5,8.1,4.7Hz,1H),4.03(q,J=7.1Hz,1H),4.94-5.06(m,2H), 5.78(ddt,J=16.9,10.2,6.6Hz,1H),7.08(d,J=8.1Hz,1H),12.26(s,2H). Step 4: Methyl(S)-2-((tert-butoxycarbonyl)(methyl)amino)hexa-5-enoate: [ka]

[0332] (2S)-2-[(tert-butoxycarbonyl)amino]hexa-5-enoic acid (6 g, 26.17 mmol, 1 equivalent) and Ag2O (24.26 g, 104.68 mmol, 4 equivalents) were stirred in DMF (90 mL), to which CH3I (55.72 g, 392.54 mmol, 15 equivalents) was added dropwise at 0°C. The resulting mixture was stirred overnight at rt. The resulting mixture was filtered, and the filter cake was washed with DMF (3 × 50 mL). The filtrate was used directly in the next step without further purification. LCMS (ESI+): m / z 258.20 (M+H + ). Step 5: Int.42: [ka]

[0333] To a stirred solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]hexa-5-enoate (20 g, 77.72 mmol, 1 equivalent) in H2O (500 mL) / DMF (500 mL), NaOH (18.65 g, 466.33 mmol, 6 equivalents) was added in fractions at 0°C. The resulting mixture was stirred at rt for 16 hours and acidified to pH 6 with HCl (3N). The mixture was extracted with CH2Cl2 (3 × 0.5 L). The combined organic layers were washed with brine (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous acetonitrile, 5% to 50% gradient over 30 minutes; detector, UV 200 nm. As a result, a racemic product (20g) was obtained, which was purified by Prep-CHIRAL-HPLC under the following conditions (column: CHIRALPAK IC-3, 4.6×50mm, 3μm; mobile phase A: Hex (0.1% TFA): IPA = 98:2; flow rate: 1mL / min; gradient: 0%B to 0%B; injection volume: 5ulmL), and Int.42 (15.78g, 83%) was obtained as a pale yellow oil. LCMS (ESI+): m / z 242.10 (M+H + ). 1H NMR(300MHz,DMSO-d6)δ 1.38(d,J=13.4Hz,17H),1.71-1.86(m,1H),1.89(s,1H),1.94(d,J=4.9Hz,1H),1.94-2.12(m,3H),2.72(s,6H),4.26(dd,J=10.4, 4.6Hz,1H),4.50(dd,J=10.8,4.4Hz,1H),4.93-5.05(m,3H),5.02-5.10(m,1H),5.81(ddd,J=16.9,10.2,3.6Hz,1H),12.73(s,2H). Preparation of Int.43:(S)-2-((tert-butoxycarbonyl)(methyl)amino)hepta-6-enoic acid [ka] Step 1: (5S)-1-[(2S)-1-benzylpyrrolidine-2-carbonyl]-5-(penta-4-en-1-yl)-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one: [ka]

[0334] To a solution of NaOH (80.51 g, 2013.0 mmol, 10 equivalents) in DMF (270 mL), 1-[(2S)-1-benzylpyrrolidine-2-carbonyl]-7-phenyl-1H,4H,5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one (102.29 g, 205.33 mmol, 1.02 equivalents) was added under a nitrogen atmosphere at 25°C. The reaction mixture was stirred at 25°C for 15 minutes. 5-bromopenta-1-ene (30 g, 201.30 mmol, 1 equivalent) was added dropwise at below 25°C. The reaction mixture was stirred at 25°C for 5 hours. The reaction mixture was purified together with pages EB2141275-183 and EB2141275-184. The mixture was acidified to pH=3 with acetic acid (5%), and the resulting mixture was extracted with siRNA (2 × 250 mL). The combined organic layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and eluted with CH₂Cl₂ / MeOH (20:1) to obtain (5S)-1-[(2S)-1-benzylpyrrolidine-2-carbonyl]-5-(penta-4-en-1-yl)-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one (88 g, 77%) as a yellow oil. LCMS(ESI+): m / z 566(M+H + ). 1 H NMR(400MHz,DMSO-d6):δ 1.54(dddd,2H),1.76-2.04(m,3H),2.12-2.34(m,3H),2.45(t,2H),3.32(d,2H),3.50-3.71(m,3H),4.07(d,1H),4.85-5.09(m,2H),5 .76(ddt,1H),6.53(dd,1H),6.66(ddd,1H),7.01-7.24(m,3H),7.36(t,2H),7.45-7.66(m,4H),7.91-8.09(m,1H),8.27-8.46(m,2H). Step 2: (S)-2-aminohepta-6-enoic acid: [ka]

[0335] (5S)-1-[(2S)-1-benzylpyrrolidine-2-carbonyl]-5-(penta-4-en-1-yl)-7-phenyl-5H-benzo[d]1-oxa-3,7-diaza-2-nickelacyclononan-4-one (88 g, 155.39 mmol, 1 equivalent) was dissolved in THF (880.0 g, 12204.1 mmol, 78.54 equivalents), to which HCl (517.96 mL, 1553.87 mmol, 10 equivalents) was added at 25°C. The reaction mixture was stirred at 60°C for 2 hours. The resulting mixture was diluted with water (1500 mL). The mixture was basicized to pH=8 with NaOH (2N aqueous solution). The resulting mixture was extracted with ELISA (2 × 500 mL). The aqueous phase (containing approximately 22 g of product) was used in the next step without further purification. LCMS(ESI+): m / z 144(M+H + ). Step 3: (2S)-2-[(tert-butoxycarbonyl)amino]hepta-6-enoic acid: [ka]

[0336] To a solution of (2S)-2-aminohepta-6-enoic acid (22 g, 153.65 mmol, 1 equivalent) and Na2CO3 (97.71 g, 921.88 mmol, 6 equivalents) in water (2000 mL), Boc2O (100.60 g, 460.94 mmol, 3 equivalents) was added at 25°C. The reaction mixture was stirred at 25°C for 6 hours. The mixture was acidified to pH=6 with diluted citric acid. The resulting mixture was extracted with Depositphotos (3 × 150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (20:1) to obtain (2S)-2-[(tert-butoxycarbonyl)amino]hepta-6-enoic acid (30 g, 80%) as a yellow oil. LCMS(ESI+):m / z 266(M+Na + ). 1H NMR(400MHz,DMSO-d6):δ 1.38(s,11H),1.50-1.59(m,1H),1.66(dddd,1H),2.74(s,1H),2.90(s,1H),3.86(d dd,1H),4.95(ddt,1H),5.00(dt,1H),5.68-5.88(m,1H),7.07(d,1H),12.38(s,1H). Step 4: Methyl(S)-2-((tert-butoxycarbonyl)(methyl)amino)hepta-6-enoate: [ka]

[0337] MeI (175.02 g, 1233.03 mmol, 10 equivalents) was added to a solution of (2S)-2-[(tert-butoxycarbonyl)amino]hepta-6-enoic acid (30 g, 123.30 mmol, 1 equivalent) and Ag2O (142.87 g, 616.52 mmol, 5 equivalents) in DMF (200 mL). The reaction mixture was stirred at 25°C for 6 hours. The desired product was detected by LC-MS. The resulting mixture was filtered, and the filter cake was washed with DMF (2 × 5 mL). The filtrate was used in the next step without further purification (approximately 35 g). LC-MS (ESI+): m / z 172(M+H-Boc + ). Step 5: Int.43: [ka]

[0338] NaOH (25.79 g, 644.91 mmol, 5 equivalents) in water (350.00 mL, 19428.41 mmol, 150.63 equivalents) was added at 25°C to a solution of methyl(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]hepta-6-enoate (35 g, 128.98 mmol, 1 equivalent) in DMF (20 mL). The reaction mixture was stirred at 25°C for 5 hours. The desired product was detected by LC-MS. The reaction mixture was purified using pages EB2206983-001, EB2206983-002, EB2206983-003, and EB2206983-004. The resulting mixture was diluted with water (500 mL). The mixture was acidified to pH=6 with HCl (2N aqueous solution). The resulting mixture was extracted with toluene (3 × 1000 mL). The combined organic layers were washed with saturated ammonium chloride (2 × 500 mL) and dried on anhydrous sodium 2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, aqueous MeCN, gradient from 10% to 60% over 20 minutes; detector, UV 254 nm. (2S)-2-[(tert-butoxycarbonyl)(methyl)amino]hepta-6-enoic acid (31 g, 93.40%) was obtained as a pale yellow oil. Column: CHIRAL ART Cellulose-SC, 2*25cm, 5μm; Mobile phase A: Hex (0.1% FA) -- HPLC, Mobile phase B: IPA -- HPLC; Flow rate: 20 mL / min; Gradient: 17 mins from 2% B to 2% B; Wavelength: 220 / 254 nm; RT1 (min): 6.939; RT2 (min): 12.248; Sample solvent: EtOH -- Int. 43 (21.4 g, 66%) was obtained as a pale yellow oil by HPLC. LCMS (ESI+): m / z 280 (M+Na + ). 1 H NMR(400MHz,DMSO-d6):δ 1.39(d,11H),1.56-1.88(m,2H),2.05(qp,2H),2.70(s,3H),4.41(ddd,1H),4.92-5.09(m,2H),5.71-5.88(m,1H),12.65(s,1H). Int.44:1-(methylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole: [ka]

[0339] This material was synthesized using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate and methanesulfonyl chloride as starting materials, following the procedure in Int. 40. LCMS(ESI+): m / z 274.2(M+H + ). Int.45:1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]octa-2-en-8-yl)ethane-1-one: [ka]

[0340] This material was synthesized using tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]octo-2-en-8-carboxylate as the starting material, following the procedure in Int. 40. LCMS(ESI+): m / z 278.2(M+H + ). Int.122:1-(3,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-yl)ethane-1-one: [ka]

[0341] Int.122 was synthesized using tert-butyl 3,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate as the starting material, following the procedure for Int.40. LCMS(ESI+): m / z 280.5(M+H + ). Int.127:(S)-2-Cyclopropyl-2-((2S,4R)-1-(3,3-Difluoro-1-(trifluoromethyl)cyclobutene-1-carbonyl)-4-Fluoropyrrolidine-2-Carboxamide)acetic acid: [ka]

[0342] This material was synthesized using commercially available FMOC-protected amino acids in the same manner as Int.34. LCMS(ESI+): m / z 417.1(M+H + ). Int.129:(S)-2-cyclopropyl-2-((2S,4R)-4-fluoro-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)pyrrolidine-2-carboxamide)acetic acid: [ka]

[0343] This material was synthesized using commercially available FMOC-protected amino acids in the same manner as Int.34. LCMS(ESI+): m / z 367.4(M+H + ). Preparation of Int.140: (2S,4R)-4-fluoro-1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0344] This compound was prepared using 1-(trifluoromethyl)cyclopropane-1-carboxylic acid as a starting material, following the general synthetic sequence described for the preparation of Int. 141. LCMS(ESI+): m / z 417.99(M+H + ). Preparation of Int.141: (2S,4R)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylic acid [ka] Step 1: (2S,4R)-4-fluoropyrrolidine-2-carboxylate methyl: [ka]

[0345] 1,4-Dioxane (758.29 mL, 505.53 mmol, 5 equivalents) containing 1-tert-butyl 2-methyl (2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (150 g, 101.1 mmol, 1 equivalent) and HCl (ガス) The solution was stirred at rt for 0.5 hours, and then concentrated under reduced pressure to obtain methyl(2S,4R)-4-fluoropyrrolidine-2-carboxylate (110 g, yield, 99%, purity 80%) as a white solid. The crude product was used directly in the next step without further purification. LCMS(ESI+): m / z 148.15(M+H) + ). Step 2: (2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate methyl: [ka]

[0346] (2S,4R)-4-fluoropyrrolidine-2-carboxylate methyl (110 g, 103.3 mmol, 1 equivalent, 80%), 3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carboxylate (122.06 g, 103.3 mmol, 1 equivalent), and TCFH (251.69 g, 154.95 mmol, 1.5 equivalents) were stirred in ACN (1100 mL), to which NMI (245.51 g, 516.49 mmol, 5 equivalents) was added dropwise for 45 minutes at 0°C. The mixture was slowly warmed to rt and stirred overnight at rt. The mixture was concentrated under reduced pressure at 28°C, diluted with HCl (900 mL), and washed with HCl (0.5 N, 1400 mL × 1). The aqueous layer was extracted again with HCl (1 × 500 mL). The combined organic layers were washed with saturated NaHCO3 (1000 mL x 1). The aqueous layer was extracted again with toluene (300 mL x 1). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain (2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylatemethyl 180 g, 81%) as a pale yellow solid. The crude product was used directly in the next step without further purification. LCMS(ESI+): m / z 334.15(M+H + ). Step 3: Int.141: [ka]

[0347] To a stirred solution of MeOH (1400 mL) containing methyl(2S,4R)-1-[3,3-difluoro-1-(trifluoromethyl)cyclobutanecarbonyl]-4-fluoropyrrolidine-2-carboxylate (180 g, 82.15 mmol, 1 equivalent, 90%), H2O (400 mL) containing NaOH (58.33 g, 246.45 mmol, 3 equivalents) was added dropwise over 30 minutes at 0-20°C. The mixture was stirred at rt for 2 hours. The MeOH was evaporated under reduced pressure. The residue was diluted with water (2500 mL) and acidified with HCl (3N, 400 mL) at 0-20°C. The precipitated solid was then collected by filtration and washed with water (3 × 200 mL). HCl (3N, 100 mL) was added to the filtrate. The precipitated solid was collected by filtration and washed with water (3 × 100 mL). The combined solid was dried in an oven at 40°C for 16 hours. As a result, Int.40 (150.7g, 97%) was obtained as a white solid. LCMS(ESI+): m / z 319.95(M+H + ). Preparation of Int.142: (2S,4R)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidine-2-carboxylic acid [ka]

[0348] This compound was prepared according to the general synthetic sequence described for the preparation of Int. 141. (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid was used as the starting material. LCMS(ESI+): m / z 421.08 Preparation of Int.143:(2S,4R)-4-fluoro-1-(2-(trifluoromethyl)spiro[3.3]heptan-2-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0349] This compound was prepared using 2-(trifluoromethyl)spiro[3.3]heptane-2-carboxylic acid as a starting material, following the general synthetic sequence described for the preparation of Int. 141. LCMS(ESI+):m / z 323.11(M+H + ). Preparation of Int.144: (2S,4R)-4-fluoro-1-(1-(trifluoromethyl)cyclobutan-1-carbonyl)pyrrolidine-2-carboxylic acid [ka]

[0350] This compound was prepared using 1-(trifluoromethyl)cyclobutane-1-carboxylic acid as a starting material, following the general synthetic sequence described for the preparation of Int. 141. LCMS(ESI+): m / z 283.08(M+H + ). Int.145: Preparation of (1-(trifluoromethyl)cyclobutan-1-carbonyl)-L-proline: [ka]

[0351] This compound was prepared using (tert-butoxycarbonyl)-L-proline and 1-(trifluoromethyl)cyclobutane-1-carboxylic acid as starting materials, following the general synthetic sequence described for the preparation of Int. 141. LCMS(ESI+): m / z 266.1(M+H + ). Int.146:(3,3-difluoro-1-(trifluoromethyl)cyclobutan-1-carbonyl)-L-proline: [ka]

[0352] This compound was prepared using (tert-butoxycarbonyl)-L-proline as a starting material, following the general synthetic sequence described for the preparation of Int. 141. LCMS(ESI+): m / z 302.2(M+H + ). Preparation of Int.147: (2S,4R)-1-(1-cyanocyclobutane-1-carbonyl)-4-fluoropyrrolidine-2-carboxylic acid [ka]

[0353] This compound was prepared using 1-cyanocyclobutane-1-carboxylic acid as a starting material, following the general synthetic sequence described for the preparation of Int. 141. LCMS(ESI+): m / z 240.09(M+H + ). Preparation of (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylic acid and (2S,4R)-4-fluoro-1-((S)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylic acid [ka] Step 1: (2S,4R)-4-fluoropyrrolidine-2-carboxylate methyl: [ka]

[0354] A mixture of 1-(tert-butyl)2-methyl(2S,4R)-4-fluoropyrrolidine-1,2-dicarboxylate (20 g, 80.9 mmol, 1 equivalent) in HCl / siRNA (200 mL) (4 M) was stirred at 25°C for 2 hours. LC-MS showed that the starting material was consumed and one main peak with the mass of the target product was detected. The reaction mixture was concentrated to obtain (2S,4R)-4-fluoropyrrolidine-2-carboxylate methyl (15 g, crude, HCl) as a pale yellow solid. This was used in the next reaction without further purification. Step 2: (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate and (2S,4R)-4-fluoro-1-((S)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate: [ka]

[0355] To a solution of 2-(trifluoromethyl)tetrahydro-2H-pyran-2-carboxylate (13 g, 65.61 mmol, 1 equivalent) in DCM (200 mL), DIEA (8.48 g, 65.61 mmol, 11.43 mL, 1 equivalent) was added, and the mixture was stirred for 10 minutes. Then, BOP-Cl (18.37 g, 72.17 mmol, 1.1 equivalents), methyl(2S,4R)-4-fluoropyrrolidine-2-carboxylate, and DIEA (16.96 g, 131.22 mmol, 22.86 mL, 2 equivalents) were added. The mixture was stirred at 25°C for 12 hours. LC-MS showed the detection of one main peak with the mass of the target product. The reaction mixture was concentrated under reduced pressure to remove the DCM, and then siRNA (30 mL) was added. The solution was washed three times with 5% NaHCO3 solution (15 mL), and then washed once consecutively with water (15 mL), 2 M HCl solution (15 mL), water (15 mL), and saturated brine (15 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. When the residue was purified by column chromatography (SiO2, PE:HCl = 10:1~2:1), methyl (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate (10.7g, 31.7mmol, yield 48%, purity 96.8%) was obtained as a pale yellow oil, and methyl (2S,4R)-4-fluoro-1-((S)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate (11g, 32.0mmol, yield 49%, purity 95.2%) was obtained as a pale yellow oil. Step 3: (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylic acid: [ka]

[0356] LiOH.H2O (2.66 g, 63.32 mmol, 2 equivalents) was added to a solution of THF (100 mL) and H2O (100 mL) containing methyl(2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate (10.7 g, 31.66 mmol, purity 96.83%, 1 equivalent). The mixture was stirred at 25°C for 1 hour. LC-MS showed that methyl(2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate was consumed and a single main peak with the mass of the target product was detected. The mixture was acidified with HCl (1N) at 0°C until the pH was 2-3. Next, the mixture was extracted with 300 mL (100 mL x 3) of toluene. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, PE:toluene = 10:1~2:1) to obtain (2S,4R)-4-fluoro-1-((R)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylic acid (8.9 g, 28.33 mmol, yield 89%, purity 99%) as a white solid. LCMS (ESI+): m / z 314.0 (M+H + ). Step 4: Int.149: [ka]

[0357] A similar hydrolysis procedure was performed on methyl(2S,4R)-4-fluoro-1-((S)-2-(trifluoromethyl)tetrahydro-2H-pyran-2-carbonyl)pyrrolidine-2-carboxylate, yielding the target product Int.149 (9.1g, 28.97 mmol, 90.5% yield, 99.7% purity) as a white solid. LCMS(ESI+): m / z 314.0(M+H + ). Preparation of Int.150: (2S,4R)-4-fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidine-2-carboxylic acid [ka]

[0358] Int.150 was prepared according to the general synthesis sequence described for the preparation of Int.141. LCMS(ESI+): m / z 271.08(M+H + ). Preparation of Int.154:tert-butyl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)penta-4-enoate [ka] Step 1: Int.154: [ka]

[0359] A solution of Int. 152 (250 g, 1.09 mol, 1 equivalent) was prepared in HCl / Ã (2500 mL). The mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the deprotected HCl salt (180.5 g, crude, HCl) was obtained as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 14.33-13.58(m,1H),10.10-8.94(m,2H),5.84-5.69(m,1H),5.31-5.11(m,2H),3.99(br t,J=5.2Hz,1H),2.68(br t,J=6.4Hz,2H),2.60-2.52(m,3H).

[0360] To a solution of crude HCl salt (170 g, 1.03 mol, 1 equivalent) in H2O (860 mL) and dioxane (1140 mL), FmocOSu (346 g, 1.03 mol, 1 equivalent) and DIEA (398 g, 3.08 mol, 536 mL, 3 equivalents) were added. The mixture was stirred until LCMS showed consumption of the starting materials. The reaction was quenched with citric acid solution (800 mL) at 25 °C, and then extracted with HCl (500 mL x 4). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (using a 0-40% siRNA / PE eluent) to obtain (S)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)pento-4-enoic acid (290 g, 815 mmol, yield 80%, purity 99%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 13.13-12.72(m,1H),7.89(dd,J=3.7,7.2Hz,2H),7.63(br d,J=7.6Hz,2H),7.45-7.27(m,4H),5.73-5.46(m,1H),5.17-4.95(m,2H),4.67-4.44(m,1H),4.40-4.21(m,3H),2.80-2.70(m,3H),2.53(br s,1H),2.48-2.32(m,1H). Step 2: Int.154: [ka]

[0361] (S)-2-(((((9H-fluoren-9-yl)methoxy)carbonyl)(methyl)amino)penta-4-enoic acid (10 g, 1 equivalent, 28 mmol) was dissolved in DCM (20 mL) and brought to 0°C under argon. DCC (6.5 g, 1.1 equivalent, 31 mmol) and DMAP (0.35 g, 0.1 equivalent, 2.8 mmol) were added as solids. tert-butanol (8.4 g, 11 mL, 4 equivalents, 0.11 mol) was added by syringe. The mixture was stirred overnight under rt. Diluted with water and DCM, and extracted three times with DCM. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated. Purified by normal-phase chromatography (0-100% siRNA in hexane), Int. 154 (9.8 g, 24 mmol, 85%) was obtained as a pale oil. Preparation of Int.162:(S)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid [ka] Step 1: 2-benzyl 1-(tert-butyl)(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate: [ka]

[0362] To a solution of (S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (2.50 g, 9.95 mmol, 1.0 equivalent) in DMF (50 mL), Na2CO3 (2.11 g, 19.9 mmol, 2.0 equivalent) was added and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was then cooled to 0°C and BnBr (1.87 g, 10.9 mmol, 1.30 mL, 1.1 equivalent) was added. The mixture was stirred at 0°C for a further 2.5 hours. Water (80 mL) was added, the aqueous phase was extracted with ELISA (30 mL x 3), the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (PET ether / siRNA, 30:1) to obtain 2-benzyl 1-(tert-butyl)(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.80 g, 8.20 mmol, yield 82.4%) as a clear oil. 1 H NMR(400MHz,DMSO-d6):δ7.37(d,J=4.8Hz,5H),5.23-5.10(m,2H),4.59-4.50(m, 1H),3.83-3.70(m,2H),3.02-2.87(m,1H),2.59-2.50(m,1H),1.41-1.25(m,9H). Step 2: Benzyl(S)-4,4-difluoropyrrolidine-2-carboxylate: [ka]

[0363] To a solution of 10 mL of HCl containing 2-benzyl 1-(tert-butyl)(S)-4,4-difluoropyrrolidine-1,2-dicarboxylate (2.00 g, 5.86 mmol, 1.0 equivalent), HCl / HCl (4 M, 40 mL, 27.3 equivalents) was added and the mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated to obtain benzyl(S)-4,4-difluoropyrrolidine-2-carboxylate (2.14 g, crude) as a white solid. 1H NMR (400MHz, DMSO-d6): δ10.78-10.59(m,1H),7.48-7.33(m,5H),5.30-5.22(m,2H),4. 86(t,J=8.8Hz,1H),3.83-3.64(m,2H),2.97-2.85(m,1H),2.75(dq,J=8.8,14.8Hz,1H). Step 3: Benzyl(S)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4,4-difluoropyrrolidine-2-carboxylate [ka]

[0364] To a solution of DMF (30 mL) containing benzyl(S)-4,4-difluoropyrrolidine-2-carboxylate (1.90 g, 7.88 mmol, 1.0 equivalent), DIPEA (3.05 g, 23.6 mmol, 4.12 mL, 3.0 equivalent), 3,3-difluoro-1-(trifluoromethyl)cyclobutanecarboxylate (2.41 g, 11.8 mmol, 1.5 equivalent), and HATU (4.49 g, 11.8 mmol, 1.5 equivalent) were added, and the mixture was stirred at 20°C for 2 hours. Water (60 mL) was added, and the aqueous phase was extracted with SiO2 (20 mL x 3). The organic layer was then washed with brine (30 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by silica gel column chromatography and eluted with petroleum ether / RINKAN (10:1~3:1) to obtain benzyl(S)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4,4-difluoropyrrolidine-2-carboxylate (2.30 g, 5.38 mmol, yield 68.3%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):δ7.41-7.32(m,5H),5.15(s,2H),4.83(dd,J=4.4,10.0Hz ,1H),4.13-4.00(m,2H),3.34-3.20(m,4H),2.99-2.83(m,1H),2.59-2.51(m,1H). Step 4: Int.162 [ka]

[0365] To a solution of benzyl(S)-1-(3,3-difluoro-1-(trifluoromethyl)cyclobutane-1-carbonyl)-4,4-difluoropyrrolidine-2-carboxylate (2.30 g, 5.38 mmol, 1.0 equivalent) in MeOH (30 mL), 10% Pd / C (572 mg, 538 μmol, 0.1 equivalent) was added under an Ar atmosphere. The suspension was degassed and purged with H2. The mixture was stirred under H2 (15 Psi) at 20°C for 2 hours. The reaction product was filtered through diatomaceous earth, and the filter cake was rinsed with MeOH (10 mL x 3). The combined filtrate was then concentrated under reduced pressure. The obtained residue was purified by reverse-phase flash chromatography (C18, MeCN in water (0.2% formic acid), 35%-65% gradient (10 minutes)), and after lyophilization, Int.162 (1.08 g, 3.03 mmol, 56.2% yield, 94.5% purity) was obtained as a white solid. LCMS: m / z 336.0 (MH) + ). 1 H NMR(400MHz,DMSO-d6):δ13.03(s,1H),4.68-4.61(m,1H),3.99(t,J=11.6Hz,2H), 3.33-3.23(m,4H),2.94-2.80(m,1H),2.50-2.40(m,1H).17(s,12H),1.12(s,6H). Int.172: Preparation of 1-methyl-5'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3'H-spiro[azetidine-3,1'-isobenzofuran]: [ka] Step 1: 5'-Bromo-3'H-Spiro[azetidine-3,1'-isobenzofuran]: [ka]

[0366] 300 mg, 1 equivalent, 882 μmol of tert-butyl 5'-bromo-3'h-spiro[azetidine-3,1'-isobenzofuran]-1-carboxylate was dissolved in 3 mL of 3N HCl in MeOH and stirred at 50°C until deprotection was complete (monitored by LC-MS). The volatile solvent was completely removed to obtain the crude deprotected product as an HCl salt. The material can be used in subsequent reactions without further purification. LC-MS (ESI+): m / z 240.37 (M+H). Step 2: 5'-Bromo-1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]: [ka]

[0367] Crude 5'-bromo-3'H-spiro[azetidine-3,1'-isobenzofuran] hydrochloride, formaldehyde (98.2 mg, 90.1 μL, 37% Wt, 1.5 equivalents, 1.21 mmol) and DIPEA (313 mg, 421 μL, 3 equivalents, 2.42 mmol) were dissolved in THF (8.67 mL) and stirred at 25°C for 15 minutes. Then, NaBH(OAc)3 (305 mg, 2 equivalents, 1.61 mmol) was gradually added to the reaction mixture. The reaction mixture was stirred at room temperature until all starting materials were consumed (monitored by LC-MS). The reaction mixture was diluted with water (20 mL) and extracted with RINKAN (2 × 20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The crude mixture was purified by silica gel column chromatography and eluted with DCM / MeOH (95:5). After removing the solvent, 5'-bromo-1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran] (185 mg, 728 μmol, 90.3%) was obtained as a white solid. LC-MS (ESI+): m / z 253.96 (M+H). Step 3: Int.172: [ka]

[0368] In a sealed tube, 5'-bromo-1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran] (185 mg, 1 equivalent, 544 μmol), potassium acetate (213 mg, 136 μL, 4 equivalents, 2.18 mmol), and bis(pinacolato)diborane (414 mg, 3 equivalents, 1.63 mmol) were added in dioxane (2.72 mL). The reaction mixture was degassed with Ar for 15 minutes, and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloro (22.2 mg, 0.05 equivalents, 27.2 μmol) was added. The reaction mixture was sealed and heated to 80°C until all starting materials were consumed (monitored by LC-MS). The reaction mixture was then cooled to room temperature, quenched with water, and the organic layer was extracted with SiO2 (3 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and brine (10 mL), dried, concentrated, purified by flash column chromatography (DCM:MeOH, 95:5), and concentrated again. As a result, Int. 172 (149 mg, 495 μmol, 68.0%) was obtained as a brown...

Claims

1. Compound of formula (I), 【Chemistry 1】 And in the formula, R ３ but, (a) Each has 0 to 5 R ３ａ Replaced with C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl or C １－６ It is a haloalkyl, (b) 0 to 5 R ３ｂ C replaced by ３－１２ It is cycloalkyl, or (c)A heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently being N, O or S, wherein the heterocycloalkyl is substituted with 0 to 5 R ３ｃ and is a heterocycloalkyl, (g) A heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S, wherein the heteroaryl has 0, 1, 2, 3, 4, or 5 R ３ｇ It has been replaced with, Each R ３ａ However, -OH, C １－６ Alkoxy, C １－６ Haloalkoxy, or -O-C(O)C １－６ It is alkyl, Each R ３ｂ C is independent １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -OH, C １－６ Alkoxy, Halo, C １－６ Haloalkyl, C １－６ It is a haloalkoxy or cyano, Each R ３ｃ C is independent １－６ Alkyl, Halo, C １－６ Haloalkyl, cyano, C ３－６ It is a cycloalkyl or oxo, Each R ３ｇ C is independent １－６ Alkyl, Halo, C １－６ Haloalkyl, or C ３－６ It is a cycloalkyl, R ４ａ is H or C １－６ It is alkyl, R ４ｂ and R ４ｃ These are H and C, which are independent of each other. １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, -C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ Alkyl-heteroaryl compounds, each heterocycloalkyl group having 3 to 6 ring members and 1 to 3 heteroatoms, each heteroatom independently being N, O, or S; each heteroaryl group having 5 to 6 ring members and 1 to 3 heteroatoms, each heteroatom independently being N, O, or S; Or, R ４ｃ and R ４ａ Together with the carbon and nitrogen atoms to which each is bonded, each has 3 to 6 ring members and 1 to 3 heteroatoms, each independently forming a heterocycloalkyl group which is N, O, or S, and the heterocycloalkyl group has 0 to 4 R ４ａ１ It has been replaced with, Each R ４ａ１ Independently, C １－６ Alkyl, -OH, C １－６ Alkyl-OH, C １－６ It is an alkoxy or halo, R ５ａ is H or C １－６ It is alkyl, R ５ｂ and R ５ｃ These are H and C, which are independent of each other. １－６ Alkyl, -C １－６ Alkyl-OH, C ２－６ Alkoxyalkyl, C １－６ Haloalkyl, -C １－６ Alkyl-C(O)NR ５ｂ１ R ５ｂ２ , -C １－６ Alkyl-C(O)OR ５ｂ１ , C ３－６ Cycloalkyl, C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ Alkyl-heteroaryl (Each heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S; Each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R ５ｂ５ (It is replaced by) Each R ５ｂ１ and R ５ｂ２ H and C are independent of each other. １－４ Alkyl, or C １－４ It is a haloalkyl, Or, R ５ｂ１ and R ５ｂ２ Each of these, together with the nitrogen to which it is bonded, forms a heterocycloalkyl having 3 to 6 ring members and 0 to 1 further heteroatom, and the heterocycloalkyl has 0 to 2 R ５ｂ３ It has been replaced with, Each R ５ｂ３ and R ５ｂ５ Independently, C １－６ Alkyl, Halo, C １－６ It is a haloalkyl or cyano; X ６ C ６－７ Alkylene or C ６－７ It is alkenylene, R ６ａ is H, C １－６ alkyl, C １－６ deuterated alkyl, C ２－６ alkoxyalkyl, C ３－６ cycloalkyl, -C １－６ alkyl-C ３－６ cycloalkyl, heterocycloalkyl, -C １－６ alkyl-heterocycloalkyl, phenyl, -C １－６ alkyl-phenyl, heteroaryl or -C １－６ alkyl-heteroaryl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms (each independently, N, O or S), and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms (each independently, N, O or S). R ６ｂ and R ６ｄ These are, independently, H or C １－６ It is alkyl, R ７ａ is H or C １－６ and is alkyl, R ７ｂ and R ７ｃ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C １－６ It is a haloalkyl, C １－６ Alkyl-OH, C ３－６ Cycloalkyl, or -C １－６ Alkyl-C ３－６ It is a cycloalkyl, R ８ａ H, C １－６ Alkyl, C ２－６ Alkoxyalkyl, C ３－６ Cycloalkyl or -C １－６ Alkyl-C ３－６ It is a cycloalkyl, R ８ｂ , R ８ｄ and R ８ｅ These are, independently, H or C １－６ It is alkyl, Ring B has 5 to 12 ring members and 1 to 6 heteroatoms. ６－１２ It is an aryl or heteroaryl compound, each independently being N, O, or S. The subscript m8 is an integer between 0 and 5. Each R ８ｆ C is independent １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Alkoxy, C １－６ Deuterated alkoxy, halo, C １－６ Haloalkyl, cyano, -X ８ｆ - Cyano, C ３－１２ It is a cycloalkyl, -X ８ｆ -C ３－６ Cycloalkyl, -CH=CR ８ｆ１ R ８ｆ２ , heterocycloalkyl, -X ８ｆ - Heterocycloalkyl, C ６－１２ Ariel, -X ８ｆ -C ６－１２ Aryl, heteroaryl, or -X ８ｆ - Heteroaryl (Each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0 to 3 R ８ｆ３ (It is replaced by) Alternatively, two R's on adjacent ring vertices ８ｆ The bases combine to form C ３－６ A cycloalkyl or heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms is formed, each independently being N, O, or S, and the cycloalkyl or heterocycloalkyl has 0 to 3 R ８ｆ３ It has been replaced with, Each X ８ｆ Independently, C １－６ Alkylene, C ２－６ Alkenylene, -O-C １－６ Alkylene, C(O), O, or S, Each R ８ｆ１ and R ８ｆ２ These combine with the carbon to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms (each independently being N, O, or S), and the heterocycloalkyl has 0 to 3 R ８ｆ３ And, Each R ８ｆ３ Independently, C １－６ Alkyl, -Y ８ -C １－６ Alkyl, C １－６ It is an alkyl deuterated, -Y ８ -C １－６ Alkyl deuterated, -OH, -C １－６ Alkyl-OH, -Y ８ -C １－６ It is an alkyl-OH group, -C １－６ Alkyl-Y ８ -C １－６ Alkyl, -(C １－２ Alkyl-O) １－４ -C １－２ Alkyl, C １－６ Alkoxy, Halo, C １－６ Haloalkyl, -Y ８ -C １－６ Haloalkyl, cyano, -C １－６ Alkyl-cyano, -C １－６ Alkyl-NR ８ｇ R ８ｈ , oxo, C ３－６ Cycloalkyl, -X ８ｆ３ -C ３－６ Cycloalkyl, heterocycloalkyl, -X ８ｆ３ - Heterocycloalkyl, phenyl, -X ８ｆ３ - Phenyl, heteroaryl, or - X ８ｆ３ - A heteroaryl compound, where each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently containing N, O, S, or S(O) ２ Each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, or each heterocycloalkyl and heteroaryl has 0 to 2 C １－４ Substituted with alkyl or halo, Each X ８ｆ３ Independently, C １－６ Alkylene, O, C(O), or S(O) ２ And, Each Y ８ These are independently C(O), C(O)O, N(R) ８ｆ４ ) C(O), O, S or S(O) ２ And, Each R ８ｇ and R ８ｈ H and C are independent of each other. １－６ Alkyl or C １－６ It is a haloalkyl, Alternatively, two R's on the same or adjacent ring vertices ８ｆ３ The groups combine to form a carbon atom having 3 to 6 ring members and 1 to 3 heteroatoms (each independently containing N, O, or S). ３－６ It forms a cycloalkyl or heterocycloalkyl, and the nitrogen atom ring member in the heterocycloalkyl is 0 to 1 C １－４ It is substituted with alkyl, and Each R ８ｆ４ H or C １－６ Alkyl compounds, or a pharmaceutically acceptable salt thereof.

2. R ３ but (a) 0 to 5 R ３ａ C replaced by １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl or C １－６ Haloalkyl (b) 0 to 5 R ３ｂ C replaced by ３－１２ Cycloalkyl, or (c) A heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently being N, O, or S, wherein the heterocycloalkyl has 0 to 5 R ３ｃ It has been replaced with, Each R ３ａ is -OH, C １－６ Alkoxy, C １－６ Haloalkoxy, or -O-C(O)C １－６ It is alkyl, and each R ３ｂ Independently, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -OH, C １－６ Alkoxy, Halo, C １－６ Haloalkyl, C １－６ It is a haloalkoxy or cyano, Each R ３ｃ Independently, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ It is a cycloalkyl or oxo, R ４ａ is H or C １－６ It is alkyl, R ４ｂ and R ４ｃ These are H and C, which are independent of each other. １－６ Alkyl, C ３－６ Cycloalkyl, -C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ The alkyl-heteroaryl group is an alkyl group having 3 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S), and the heteroaryl group has 5 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S). Or, R ４ｃ and R ４ａ These, together with the carbon and nitrogen to which they are bonded, form a heterocycloalkyl having 3 to 6 ring members, and the heterocycloalkyl has 0 to 4 R ４ａ１ It has been replaced with, Each R ４ａ１ Independently, C １－６ Alkyl, -OH, C １－６ Alkyl-OH, C １－６ It is an alkoxy or halo, R ５ａ is H or C １－６ It is alkyl, R ５ｂ and R ５ｃ These are H and C, which are independent of each other. １－６ Alkyl, -C １－６ Alkyl-OH, C ２－６ Alkoxyalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ The alkyl-heteroaryl compounds are alkyl-heteroaryl compounds, each heterocycloalkyl compound independently having 3 to 6 ring members and 1 to 3 heteroatoms, each heteroaryl compound independently having 5 to 6 ring members and 1 to 3 heteroatoms, each cycloalkyl compound, heterocycloalkyl compound, phenyl compound, and heteroaryl compound having 0 to 3 R atoms. ５ｂ５ It has been replaced with, Each R ５ｂ５ Independently, C １－６ Alkyl, halo, or C １－６ It is a haloalkyl, X ６ C ６－７ Alkylene or C ６－７ It is alkenylene, R ６ａ H, C １－６ Alkyl, C ２－６ Alkoxyalkyl, C ３－６ Cycloalkyl, -C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ The alkyl-heteroaryl is an alkyl-heteroaryl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S, and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S. R ６ｂ and R ６ｄ Each of these is independently H or C １－６ It is alkyl, R ７ａ is H or C １－６ It is alkyl, R ７ｂ and R ７ｃ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C １－６ It is a haloalkyl, C １－６ Alkyl-OH, C ３－６ Cycloalkyl, or -C １－６ Alkyl-C ３－６ It is a cycloalkyl, R ８ａ H, C １－６ Alkyl, C ２－６ Alkoxyalkyl, C ３－６ Cycloalkyl or -C １－６ Alkyl-C ３－６ It is a cycloalkyl, R ８ｂ , R ８ｄ and R ８ｅ These are, independently, H or C １－６ It is alkyl, Ring B has 5 to 12 ring members and 1 to 6 heteroatoms. ６－１２ It is an aryl or heteroaryl compound, each independently being N, O, or S. The subscript m8 is an integer between 0 and 5. Each R ８ｆ C is independent １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Alkoxy, C １－６ Deuterated alkoxy, halo, C １－６ Haloalkyl, cyano, -X ８ｆ - Cyano, C ３－１２ It is a cycloalkyl, -X ８ｆ -C ３－６ Cycloalkyl, -CH=CR ８ｆ１ R ８ｆ２ , heterocycloalkyl, -X ８ｆ - Heterocycloalkyl, C ６－１２ Ariel, -X ８ｆ -C ６－１２ Aryl, heteroaryl, or -X ８ｆ - Heteroaryl (Each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl has 0 to 3 R ８ｆ３ (It is replaced by) Alternatively, two R's on adjacent ring vertices ８ｆ The bases combine to form C ３－６ A cycloalkyl or heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms is formed, each independently being N, O, or S, and the cycloalkyl or heterocycloalkyl has 0 to 3 R ８ｆ３ It has been replaced with, Each X ８ｆ Independently, C １－６ Alkylene, C ２－６ Alkenylene, -O-C １－６ Alkylene, C(O), O, or S, Each R ８ｆ１ and R ８ｆ２ These combine with the carbon to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms (each independently being N, O, or S), and the heterocycloalkyl has 0 to 3 R ８ｆ３ And, Each R ８ｆ３ Independently, C １－６ Alkyl, -Y ８ -C １－６ Alkyl, C １－６ It is an alkyl deuterated, -Y ８ -C １－６ Alkyl deuterated, -OH, -C １－６ Alkyl-OH, -Y ８ -C １－６ alkyl-OH, -C １－６ Alkyl-Y ８ -C １－６ Alkyl, -(C １－２ Alkyl-O) １－４ -C １－２ Alkyl, C １－６ Alkoxy, Halo, C １－６ Haloalkyl, -Y ８ -C １－６ Haloalkyl, cyano, -C １－６ Alkyl-cyano, oxo, C ３－６ Cycloalkyl, -X ８ｆ３ -C ３－６ Cycloalkyl, heterocycloalkyl, -X ８ｆ３ - Heterocycloalkyl, phenyl, -X ８ｆ３ - Phenyl, heteroaryl, or - X ８ｆ３ - A heteroaryl group, where each heterocycloalkyl group has 3 to 12 ring members and 1 to 4 heteroatoms, each independently comprising N, O, S, or S(O) ２ Each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, and each independently contains N, O, or S, and each heterocycloalkyl and heteroaryl has 0 to 1 C in its ring member. １－４ It is substituted with alkyl, Each X ８ｆ３ Independently, C １－６ Alkylene, O, C(O), or S(O) ２ And, Each Y ８ These are independently C(O), C(O)O, N(R) ８ｆ４ ) C(O), O, S or S(O) ２ And, Alternatively, two R's on the same or adjacent ring vertices ８ｆ３ The groups combine to form a carbon atom having 3 to 6 ring members and 1 to 3 heteroatoms (each independently containing N, O, or S). ３－６ It forms a cycloalkyl or heterocycloalkyl, and the nitrogen atom ring member in the heterocycloalkyl is 0 to 1 C １－４ It is substituted with alkyl, and Each R ８ｆ４ H or C １－６ A compound that is alkyl, or a pharmaceutically acceptable salt thereof. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R ３ but (a) 0 to 5 R ３ａ C replaced by １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl or C １－６ Haloalkyl (b) 0 to 5 R ３ｂ C replaced by ３－１２ Cycloalkyl, or (c) A heterocycloalkyl having 3 to 12 ring members and 1 to 4 heteroatoms, each independently being N, O, or S, wherein the heterocycloalkyl has 0 to 5 R ３ｃ It has been replaced with, Each R ３ａ is -OH, C １－６ Alkoxy, C １－６ Haloalkoxy, or -O-C(O)C １－６ It is alkyl, and each R ３ｂ Independently, C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -OH, C １－６ Alkoxy, Halo, C １－６ Haloalkyl, C １－６ It is a haloalkoxy or cyano, Each R ３ｃ Independently, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ It is a cycloalkyl or oxo, R ４ａ is H or C １－６ It is alkyl, R ４ｂ and R ４ｃ These are H and C, which are independent of each other. １－６ Alkyl, C ３－６ Cycloalkyl, -C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ The alkyl-heteroaryl group is an alkyl group having 3 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S), and the heteroaryl group has 5 to 6 ring members and 1 to 3 heteroatoms (each independently of N, O, or S). Or, R ４ｃ and R ４ａ These, together with the carbon and nitrogen to which they are bonded, form a heterocycloalkyl having 3 to 6 ring members, and the heterocycloalkyl has 0 to 4 R ４ａ１ It has been replaced with, Each R ４ａ１ Independently, C １－６ Alkyl, -OH, C １－６ Alkyl-OH, C １－６ It is an alkoxy or halo, R ５ａ is H or C １－６ It is alkyl, R ５ｂ and R ５ｃ These are H and C, which are independent of each other. １－６ Alkyl, -C １－６ Alkyl-OH, C ２－６ Alkoxyalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ The alkyl-heteroaryl compounds are alkyl-heteroaryl compounds, each heterocycloalkyl group independently having 3 to 6 ring members and 1 to 3 heteroatoms, each heteroaryl group independently having 5 to 6 ring members and 1 to 3 heteroatoms, each cycloalkyl group, heterocycloalkyl group, phenyl group, and heteroaryl group have 0 to 3 R atoms. ５ｂ５ It has been replaced with, Each R ５ｂ５ Independently, C １－６ Alkyl, halo, or C １－６ It is a haloalkyl, X ６ C ６－７ Alkylene or C ６－７ It is alkenylene, R ６ａ H, C １－６ Alkyl, C ２－６ Alkoxyalkyl, C ３－６ Cycloalkyl, -C １－６ Alkyl-C ３－６ Cycloalkyl, heterocycloalkyl, -C １－６ Alkyl-heterocycloalkyl, phenyl, -C １－６ Alkylphenyl, heteroaryl, or -C １－６ The alkyl-heteroaryl is an alkyl-heteroaryl, wherein the heterocycloalkyl has 3 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S, and the heteroaryl has 5 to 6 ring members and 1 to 3 heteroatoms, each independently of N, O, or S. R ６ｂ and R ６ｄ Each of these is independently H or C １－６ It is alkyl, R ７ａ is H or C １－６ It is alkyl, R ７ｂ and R ７ｃ These are H and C, respectively, independently. １－６ Alkyl, C ２－６ Alkenil, C １－６ It is a haloalkyl, C １－６ Alkyl-OH, C ３－６ Cycloalkyl, or -C １－６ Alkyl-C ３－６ It is a cycloalkyl, R ８ａ H, C １－６ Alkyl, C ２－６ Alkoxyalkyl, C ３－６ Cycloalkyl or -C １－６ Alkyl-C ３－６ It is a cycloalkyl, R ８ｂ , R ８ｄ and R ８ｅ These are, independently, H or C １－６ It is alkyl, Ring B is an aryl or heteroaryl having 5 to 12 ring members and 1 to 6 heteroatoms, each independently being N, O, or S. The subscript m8 is an integer between 0 and 5. Each R ８ｆ C is independent １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C １－６ Alkoxy, C １－６ Deuterated alkoxy, halo, C １－６ Haloalkyl, cyano, -X ８ｆ - Cyano, C ３－１２ It is a cycloalkyl, -X ８ｆ -C ３－６ Cycloalkyl, -CH=CR ８ｆ１ R ８ｆ２ , heterocycloalkyl, -X ８ｆ - Heterocycloalkyl, aryl, - X ８ｆ - Aryl, heteroaryl, or -X ８ｆ - Heteroaryl (Each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O, or S; Each alkynyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R ８ｆ３ (It is replaced by) Alternatively, two R's on adjacent ring vertices ８ｆ The bases combine to form C ３－６ Having a cycloalkyl group or 3 to 6 ring members and 1 to 3 heteroatoms, Each X ８ｆ Independently, C １－６ Alkylene, C ２－６ Alkenylene, O, or S, Each R ８ｆ１ and R ８ｆ２ These combine with the carbon to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms (each independently being N, O, or S), and the heterocycloalkyl has 0 to 3 R ８ｆ３ And, Each R ８ｆ３ Independently, C １－６ Alkyl, -Y ８ -C １－６ Alkyl, C １－６ Alkyl deuterated, -Y ８ -C １－６ Alkyl deuterated, -OH, -C １－６ Alkyl-OH, -Y ８ -C １－６ alkyl-OH, -C １－６ Alkyl-Y ８ -C １－６ Alkyl, C １－６ Alkoxy, Halo, C １－６ Haloalkyl, -Y ８ -C １－６ Haloalkyl, cyano, -C １－６ Alkyl-cyano, oxo, C ３－６ Cycloalkyl, -X ８ｆ３ -C ３－６ Cycloalkyl, heterocycloalkyl, -X ８ｆ３ - Heterocycloalkyl, phenyl, -X ８ｆ３ - Phenyl, heteroaryl, or - X ８ｆ３ - A heteroaryl compound, where each heterocycloalkyl has 3 to 12 ring members and 1 to 4 heteroatoms, each independently comprising N, O, S, or S(O) ２ Each heteroaryl has 5 to 10 ring members and 1 to 4 heteroatoms, each independently of N, O, or S, and each heterocycloalkyl and heteroaryl has 0 to 1 nitrogen atom ring member. １－４ It is substituted with alkyl, Each X ８ｆ３ Independently, C １－６ Alkylene, O, C(O), or S(O) ２ And, Each Y ８ These are independently C(O), C(O)O, N(R) ８ｆ４ ) C(O), O, S or S(O) ２ And, Alternatively, two R's on adjacent ring vertices ８ｆ３ The groups combine to form a carbon atom with 3 to 6 ring members and 1 to 3 heteroatoms. ３－６ They form cycloalkyl or heterocycloalkyl groups, each independently being N, O, or S, and Each R ８ｆ４ H or C １－６ It is alkyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R ３ However, (a) 0 to 5 R ３ａ C replaced by １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkinyl, or C １－６ A compound according to any one of claims 1 to 3, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

5. R ３ However, (a) 0 to 2 R ３ａ C replaced by １－６ Alkyl or C １－６ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

6. Each R ３ａ A compound according to any one of claims 1 to 5, wherein the compound is -OH, or a pharmaceutically acceptable salt thereof.

7. R ３ However, (b) 0 to 3 R ３ｂ C replaced by ３－７ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

8. R ３ However, (b) 0 to 2 R ３ｂ C replaced by ３－４ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

9. Each R ３ｂ is Halo or C １－４ A compound according to claim 7 or claim 8, or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

10. R ３ (c) is a heterocycloalkyl having 3 to 6 ring members and 1 to 3 heteroatoms, each independently being N, O, or S, wherein the heterocycloalkyl has 0 to 5 R ３ｃ A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is substituted with.

11. Each R ３ｃ is Halo or C １－４ A compound according to claim 10 or a pharmaceutically acceptable salt thereof, which is a haloalkyl compound.

12. Each R ３ｃ The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein is fluoro or trifluoromethyl.

13. R ３ but 【Chemistry 2】 The compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. R ４ａ , R ４ｂ , and R ４ｃ Each of these is independently H or C １－６ It is alkyl, Or, R ４ｃ and R ４ａ Together with the carbon and nitrogen atoms to which each is bonded, each independently forms a heterocycloalkyl having 4 to 6 ring members and 1 to 3 heteroatoms, each being N, O, or S, and the heterocycloalkyl has 0 to 2 R ４ａ１ It is replaced by; and Each R ４ａ１ It is a halo independently. A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. R ４ａ , R ４ｂ and R ４ｃ These are, independently, H or C １－６ It is alkyl. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

16. R ４ｂ is H or C １－６ It is alkyl, and R ４ｃ and R ４ａ These, together with the carbon and nitrogen atoms to which they are bonded, form a heterocycloalkyl group having 4 to 6 ring members, and the heterocycloalkyl group has 0 to 3 R ４ａ１ It is replaced by A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

17. R ４ａ and R ４ｂ Each of these is H, and R ４ｃ It is ethyl, Or, R ４ｃ and R ４ａ These, together with the carbon and nitrogen atoms to which they are bonded, form pyrrolidinyl molecules substituted with 0 to 2 fluorocarbons. A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

18. R ５ａ is H or C １－６ It is alkyl, R ５ｂ and R ５ｃ These are H and C, which are independent of each other. １－６ Alkyl, -C １－６ Alkyl-OH, C ２－６ Alkoxyalkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, or C １－４ Alkyl-C ３－６ It is a cycloalkyl group, and each cycloalkyl group has 0 to 3 R atoms. ５ｂ５ It is replaced by; and Each R ５ｂ５ Independently, C １－４ Alkyl, halo, or C １－４ It is a haloalkyl, A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. R ５ａ is H or C １－６ It is alkyl, R ５ｂ is H, and R ５ｃ C ３－６ Cycloalkyl or C １－４ Alkyl-C ３－６ It is a cycloalkyl, A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

20. R ５ａ and R ５ｂ These are H, R ５ｃ H, methyl, ethyl, 【Transformation 3】 That is, A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

21. X ６ C ６－７ It is alkylene. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

22. X ６ C ６－７ It is alkenylene. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

23. X ６ but, 【Chemistry 4】 The compound according to any one of claims 1 to 22, wherein the wavy bond attached to the double bond in the formula represents E, Z, or a mixture of both isomers, or a pharmaceutically acceptable salt thereof.

24. X ６ but, 【Transformation 5】 The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein the wavy bond attached to the double bond in the formula represents E, Z, or a mixture of both isomers.

25. X ６ but, 【Transformation 6】 The compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

26. R ６ａ H, C １－４ Alkyl, or -C １－４ Alkyl-C ３－６ It is cycloalkyl, and R ６ｂ and R ６ｄ These are, independently, H or C １－６ It is alkyl. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

27. R ６ａ However, H, methyl, ethyl, or 【Transformation 7】 And, R ６ｂ However, H is and R ６ｄ However, it is H, methyl, or ethyl. A compound according to any one of claims 1 to 26 or a pharmaceutically acceptable salt thereof.

28. R ７ａ and R ７ｂ However, each independently, H or C １－６ Alkyl; and R ７ｃ However, C １－６ Alkyl, C ２－６ Alkenil, C １－６ Haloalkyl, C １－６ Alkyl-OH, or -C １－６ Alkyl-C ３－６ It is a cycloalkyl, A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. R ７ａ and R ７ｂ However, each is H; and R ７ｃ However, C １－６ Alkyl The compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

30. R ７ａ and R ７ｂ However, each is H; and R ７ｃ However, isobutyl, 【Transformation 8】 The compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

31. R ７ａ and R ７ｂ However, each is H; and R ７ｃ However, it is isobutyl. A compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof.

32. R ８ａ , R ８ｂ , R ８ｄ and R ８ｅ These are, independently, H or C １－６ It is alkyl. A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

33. R ８ａ is H or methyl, and R ８ｂ , R ８ｄ and R ８ｅ These are H, A compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof.

34. A compound according to any one of claims 1 to 33, wherein ring B is phenyl, or a pharmaceutically acceptable salt thereof.

35. A compound according to any one of claims 1 to 33, wherein ring B is biphenyl, or a pharmaceutically acceptable salt thereof.

36. The compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, wherein ring B is a heteroaryl having 5 to 6 ring members and 1 to 3 heteroatoms, and each heteroatom is N.

37. A compound according to any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, wherein ring B is naphthyl, thiophenyl, benzofuranyl, indolyl, indazolyl, or quinolinyl.

38. A compound according to any one of claims 1 to 33, wherein ring B is pyrido-3-yl, or a pharmaceutically acceptable salt thereof.

39. A compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein the subscript m8 is 1, 2, or 3.

40. at least one R ８ｆ A compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof, wherein the compound is a halo.

41. Each R ８ｆ C is independent １－６ Alkyl, C ２－６ Alkenil, C １－６ Alkoxy, C １－６ Deuterated alkoxy, halo, C １－６ Haloalkyl, cyano, or -X ８ｆ - It is cyano, A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

42. Each R ８ｆ It is independent, Haro, C ３－６ Cycloalkyl, -X ８ｆ -C ３－６ Cycloalkyl, -CH=CR ８ｆ１ R ８ｆ２ , Heterocycloalkyl, -X ８ｆ - Heterocycloalkyl, phenyl, -X ８ｆ - Phenyl, heteroaryl, or - X ８ｆ -A heteroaryl, where each heterocycloalkyl is independently N, O, or S, and has 3 to 10 ring members and 1 to 3 heteroatoms; each heteroaryl is independently N, O, or S, and has 5 to 10 ring members and 1 to 3 heteroatoms; each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R ８ｆ３ It has been replaced with, Each X ８ｆ Independently, C １－６ Alkylene, C ２－６ Alkenylene, O, or S, and Each R ８ｆ１ and R ８ｆ２ These atoms bond to the carbon atoms to which they are bonded, forming a heterocycloalkyl group having 3 to 10 ring members and 1 to 3 heteroatoms, each being independently N, O, or S, and the heterocycloalkyl group has 0 to 3 R atoms. ８ｆ３ It is replaced by A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

43. Each X ８ｆ C １－６ A compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, which is an alkylene.

44. Each R ８ｆ It is independent, Haro, C ３－６ Cycloalkyl, -CH=CR ８ｆ１ R ８ｆ２ Each cycloalkyl, heterocycloalkyl, phenyl, or heteroaryl group has 3 to 10 ring members and 1 to 3 heteroatoms, each independently comprising N, O, or S atoms; each heteroaryl group has 5 to 10 ring members and 1 to 3 heteroatoms, each independently comprising N, O, or S atoms; and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl group has 0 to 3 R atoms. ８ｆ３ It has been replaced with, Each R ８ｆ１ and R ８ｆ２ These combine with the carbon atoms to which they are bonded to form a heterocycloalkyl having 3 to 10 ring members and 1 to 3 heteroatoms, each independently being N, O, or S, and the heterocycloalkyl having 0 to 3 R ８ｆ３ It is replaced by A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

45. Each R ８ｆ C is independent １－４ Alkyl, C ２－４ Alkenil, C １－４ Alkoxy, C １－４ Deuterated alkoxy, halo, C １－４ Haloalkyl, cyano, or -C １－２ It is alkyl-cyano. A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

46. Each R ８ｆ It is independent, Haro, C ３－６ Cycloalkyl, -O-C ３－６ Cycloalkyl, heterocycloalkyl, -C ２－４ The compounds are alkenyl-heterocycloalkyl, -O-heterocycloalkyl, phenyl, -O-phenyl, heteroaryl, or -O-heteroaryl, where each heterocycloalkyl is independently N, O, or S, and has 3 to 6 ring members and 1 to 2 heteroatoms; each heteroaryl is independently N, O, or S, and has 5 to 6 ring members and 1 to 3 heteroatoms; and each cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl has 0 to 3 R ８ｆ３ It is replaced by A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

47. Each R ８ｆ It is independent, Haro, C ３－６ It is a cycloalkyl, -O-C ３－６ The compounds are cycloalkyl, heteroaryl, or -O-heteroaryl, each heteroaryl having 5-6 ring members and 1-3 heteroatoms, each independently being N, O, or S, and each cycloalkyl and heteroaryl has 0-3 R ８ｆ３ Replaced by, A compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof.

48. Each R ８ｆ These are independently halo, heterocycloalkyl, -O-heterocycloalkyl, phenyl, or -O-phenyl. It is -O-phenyl, and each heterocycloalkyl has 3 to 6 ring members and 1 to 2 heteroatoms, each independently being N, O, or S, and each heterocycloalkyl and phenyl has 0 to 3 R ８ｆ３ It is replaced by A compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof.

49. Each R ８ｆ３ Independently, C １－６ Alkyl, -Y ８ -C １－６ Alkyl, C １－６ It is an alkyl deuterated, -Y ８ -C １－６ Alkyl deuterated, -OH, -C １－６ Alkyl-OH, -Y ８ -C １－６ It is an alkyl-OH group, -C １－６ Alkyl-Y ８ -C １－６ Alkyl, Halo, C １－６ Haloalkyl, -Y ８ -C １－６ It is a haloalkyl or oxo, Each Y ８ These are independently C(O), C(O)O, N(R) ８ｆ４ ) C(O), O, S, or S(O) ２ and Each R ８ｆ４ H or C １－６ It is alkyl. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof.

50. Each R ８ｆ３ Independently, C １－６ Alkyl, C １－６ Alkyl deuterated, -OH, -C １－６ Alkyl-OH, halo, C １－６ It is a haloalkyl or oxo. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof.

51. Each R ８ｆ３ C is independent １－６ Alkyl or -Y ８ -C １－６ It is alkyl. A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof.

52. Each Y ８ They are independently C(O) or C(O)O. A compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof.

53. Each R ８ｆ３ Independently, C ３－６ Cycloalkyl, -X ８ｆ３ -C ３－６ Cycloalkyl, heterocycloalkyl, or -X ８ｆ３ - It is a heterocycloalkyl, and each heterocycloalkyl is independently N, O, S, or S(O) ２ It has 3 to 6 members and 1 to 2 heteroatoms, and Each X ８ｆ３ Each of them is independent of C １－６ Alkylene, C(O), or S(O) ２ That is, A compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof.

54. Each R ８ｆ３ Independently, C ３－６ It is a cycloalkyl or heterocycloalkyl, and each heterocycloalkyl is independently N, O, S, or S(O) ２ It has 3 to 6 members and 1 to 2 heteroatoms A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof.

55. Each X ８ｆ３ C １－６ It is alkylene. A compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof.

56. Two R's on adjacent ring vertices ８ｆ３ The groups bond to form a heterocycloalkyl group having 3 to 6 ring members, each independently being N, O, or S, and 1 to 3 heteroatoms. A compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof.

57. Each R ８ｆ３ Independently, C １－４ Alkyl, C １－４ Alkoxy, C ２－６ Alkoxyalkyl, -S(O) ２ -C １－４ It is alkyl. -C １－４ Alkyl-S(O) ２ -C １－４ Alkyl, Halo, C １－４ Haloalkyl, oxo, -C(O)-C １－４ Alkyl, or -C(O)O-C １－４ It is alkyl. A compound according to any one of claims 1 to 48 or a pharmaceutically acceptable salt thereof.

58. m8 is 1, 2, or 3, and Each R ８ｆ However, independently, methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, cyano, 【Chemistry 9-1】 【Chemistry 9-2】 【Chemistry 9-3】 【Chemistry 9-4】 And, Alternatively, ring B and the three R ８ｆ The base is a part 【Chemistry 10】 Forming, The compound according to any one of claims 1 to 57 or a pharmaceutically acceptable salt thereof, wherein the wavy line represents a bond with the rest of the molecule.

59. R ３ but 【Chemistry 11】 And, R ４ａ and R ４ｂ These are H, R ４ｃ It is ethyl, Or, R ４ｃ and R ４ａ However, together with the carbon and nitrogen atoms to which they are bonded, they form pyrrolidinyl molecules substituted with 0 to 2 fluorocarbons. R ５ａ and R ５ｂ These are H, R ５ｃ H, methyl, ethyl, 【Chemistry 12】 And, X ６ but 【Chemistry 13】 And, R ６ａ H, methyl, ethyl, 【Chemistry 14】 And, R ６ｂ H is, R ６ｄ is H, methyl or ethyl, R ７ａ and R ７ｂ These are H, R ７ｃ isobutyl, 【Chemistry 15】 And, R ８ａ is H or methyl, R ８ｂ , R ８ｄ and R ８ｅ These are H, Ring B is phenyl, naphthyl, biphenyl, thiophenyl, pyridyl, benzofuranyl, indolyl, indazolyl, or quinolinyl. m8 is 1, 2, or 3, and Each R ８ｆ However, independently, methyl, isopropyl, isobutyl, methoxy, ethoxy, fluoro, chloro, cyano, 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 【Chemistry 16-4】 And, Alternatively, ring B and the three R ８ｆ The base is part 【Chemistry 17】 Forming, The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the wavy line indicates bonding to the rest of the molecule.

60. Compound of formula (Ib), [Chemistry 18] A compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, having the above.

61. Compound of formula (Ic), 【Chemistry 19】 A compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, having the above.

62. Compound of formula (Id), 【Chemistry 20】 The compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, wherein the dashed bond in the formula is absent or is a single bond, and if the dashed bond is a single bond in formula (Id), the wavy bond attached to the double bond represents E, Z, or a mixture of both isomers.

63. A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the structure of any one of Examples 1 to 426.

64. structure 【Chemistry 21】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

65. structure 【Chemistry 22】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

66. structure 【Chemistry 23】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

67. structure 【Chemistry 24】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

68. structure 【Chemistry 25】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

69. structure 【Chemistry 26】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

70. structure 【Chemistry 27】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

71. structure 【Chemistry 28】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof having the above.

72. A pharmaceutical composition comprising a compound according to any one of claims 1 to 71 and a pharmaceutically acceptable excipient.

73. A method for treating cancer at least partially mediated by cyclin A, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 72, thereby treating the disorder or condition.

74. A compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 72, for use in a method of treating cancer at least partially mediated by cyclin A.

75. Use of a compound according to any one of claims 1 to 71, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 72, for the manufacture of a pharmaceutical for treating cancer at least partially mediated by cyclin A.

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