Di-cyclopropyl based il-17a modulators and uses thereof

Abstract

To provide potent small molecule IL-17A modulators for the treatment of inflammatory diseases and other associated disorders.SOLUTION: The disclosure herein provides compounds and pharmaceutical compositions of Formula (I) for the modulation of IL-17A. Compounds and pharmaceutical compositions of Formula (I) are useful for the treatment of inflammatory conditions, such as psoriasis.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross-reference) This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 314,257, filed on February 25, 2022, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] The IL-17 family consists of six cytokines (IL-17A through IL-17F). Interleukin-17A (IL-17A) is an established pro-inflammatory cytokine and is involved in the induction of IL-6, IL-8, G-CSF, TNF-α, IL-1β, PGE2, and IFN-γ, as well as numerous chemokines and other effectors. IL-17A can form homodimers or heterodimers with its family member IL-17F and can bind to both the IL-17 receptors IL-17RA and IL-17RC to mediate signaling. IL-17A is a major pathological cytokine expressed by Th17 cells, as well as CD8+ T cells, γδ cells, NK cells, NKT cells, macrophages, and dendritic cells, which are involved in the pathology of inflammation and autoimmunity. Furthermore, IL-17A and Th17 are required for defense against various microorganisms despite their involvement in inflammation and autoimmune disorders. Additionally, IL-17A can act in concert with other inflammatory cytokines such as TNF-α, IFN-γ, and IL-1β to mediate a pro-inflammatory effect.

[0003] To date, there are several biologics (secukinumab and ixekizumab) that have been approved for modulating IL-17A for the treatment of inflammatory diseases such as psoriasis, ankylosing spondylitis, and psoriatic arthritis. These treatments require injection into patients because they are not readily absorbed by the intestine when taken orally. Furthermore, these approved biological treatments are costly for patients to participate in and limit availability to the patient populations that need them. There are several small molecule modulators of IL-17A that are approved for oral administration. However, while these have the convenience of oral administration and lower invasive cost to patients, they lack the efficacy of the approved biologics. Thus, there is a need for the development of potent small molecule IL-17A modulators for the treatment of inflammatory diseases and other related disorders.

SUMMARY OF THE INVENTION

[0004] In certain aspects, the present disclosure provides a compound represented by formula (I):

CHEMICAL

Chemical formula

[0005] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of formula (I) and a pharmaceutically acceptable excipient.

[0006] In certain aspects, the present disclosure provides a method of modulating IL-17A in a subject in need thereof, the method comprising administering to the subject a compound or salt of formula (I) or a pharmaceutical composition thereof.

[0007] In certain aspects, the present disclosure provides a method of treating an inflammatory disease or condition, the method comprising administering to a subject in need thereof a compound or salt of formula (I) or a pharmaceutical composition thereof. In some aspects, the inflammatory disease or condition is selected from psoriasis vulgaris, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

[0008] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent that the incorporated publications and patents or patent applications conflict with the disclosure contained herein, this specification is intended to supersede and / or take precedence over any such conflicting material.

Best Mode for Carrying Out the Invention

[0009] Preferred embodiments of the present invention have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Those skilled in the art will envision numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in practicing the present invention. The following claims define the scope of the present invention, and it is intended that methods and structures within these claims and their equivalents be encompassed thereby.

[0010] Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications cited herein are incorporated by reference.

[0011] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0012] "Alkyl" refers to a monovalent radical of a straight-chain or branched-chain hydrocarbon chain consisting only of carbon and hydrogen atoms, containing no unsaturation, and preferably having from 1 to 12 carbon atoms (i.e., C 1 ~C 12 alkyl). Alkyl is attached to the remainder of the molecule via a single bond. In certain embodiments, alkyl contains from 1 to 12 carbon atoms (i.e., C 1 ~C 12 alkyl). In certain embodiments, alkyl contains from 1 to 8 carbon atoms (i.e., C 1 ~C 8 alkyl). In other embodiments, alkyl contains from 1 to 5 carbon atoms (i.e., C 1 ~C5 (alkyl). In other embodiments, the alkyl contains 1 to 4 carbon atoms (i.e., C 1 ~C 4 (alkyl). In other embodiments, the alkyl contains 1 to 3 carbon atoms (i.e., C 1 ~C 3 (alkyl). In other embodiments, the alkyl contains 1 to 2 carbon atoms (i.e., C 1 ~C 2 (alkyl). In other embodiments, the alkyl contains 1 carbon atom (i.e., C 1 (alkyl). In other embodiments, the alkyl contains 5 to 15 carbon atoms (i.e., C 5 ~C 15 (alkyl). In other embodiments, the alkyl contains 5 to 8 carbon atoms (i.e., C 5 ~C 8 (alkyl). In other embodiments, the alkyl contains 2 to 5 carbon atoms (i.e., C 2 ~C 5 (alkyl). In other embodiments, the alkyl contains 3 to 5 carbon atoms (i.e., C 3 ~C 5 (alkyl). For example, the alkyl group can be bonded to the rest of the molecule by a single bond, for example, methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.

[0013] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon chain radical group consisting of only carbon atoms and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having 2 to 12 carbon atoms (i.e., C 2 ~C 12 (alkenyl). In certain embodiments, the alkenyl contains 2 to 8 carbon atoms (i.e., C 2 ~C 8 (alkenyl). In certain embodiments, the alkenyl contains 2 to 6 carbon atoms (i.e., C 2~C 6 alkenyl). In other embodiments, the alkenyl contains 2 to 4 carbon atoms (i.e., C 2 ~C 4 alkenyl). The alkenyl is bonded to the remainder of the molecule by a single bond and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, etc.

[0014] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon radical group consisting of only carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having 2 to 12 carbon atoms (i.e., C 2 ~C 12 alkynyl). In certain embodiments, the alkynyl contains 2 to 8 carbon atoms (i.e., C 2 ~C 8 alkynyl). In other embodiments, the alkynyl contains 2 to 6 carbon atoms (i.e., C 2 ~C 6 alkynyl). In other embodiments, the alkynyl contains 2 to 4 carbon atoms (i.e., C 2 ~C 4 alkynyl). The alkynyl is bonded to the remainder of the molecule by a single bond and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0015] "Alkylene" refers to a straight-chain divalent hydrocarbon chain consisting of only carbon and hydrogen, containing no unsaturation, bonding the remainder of the molecule to a radical group, and preferably having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, butylene, etc. The alkylene chain is bonded to the remainder of the molecule via a single bond and to the radical group via a single bond. The points of attachment of the alkylene chain to the remainder of the molecule and to the radical group are via terminal carbons, respectively. The alkylene chain may be optionally substituted by one or more substituents such as those described herein. In certain embodiments, the alkylene contains 1 to 10 carbon atoms (i.e., C 1 ~C 10(alkylene). In certain embodiments, alkylene contains from 1 to 8 carbon atoms (i.e., C 1 ~C 8 alkylene). In other embodiments, alkylene contains from 1 to 5 carbon atoms (i.e., C 1 ~C 5 alkylene). In other embodiments, alkylene contains from 1 to 4 carbon atoms (i.e., C 1 ~C 4 alkylene). In other embodiments, alkylene contains from 1 to 3 carbon atoms (i.e., C 1 ~C 3 alkylene). In other embodiments, alkylene contains from 1 to 2 carbon atoms (i.e., C 1 ~C 2 alkylene). In other embodiments, alkylene contains 1 carbon atom (i.e., C 1 alkylene). In other embodiments, alkylene contains from 5 to 8 carbon atoms (i.e., C 5 ~C 8 alkylene). In other embodiments, alkylene contains from 2 to 5 carbon atoms (i.e., C 2 ~C 5 alkylene). In other embodiments, alkylene contains from 3 to 5 carbon atoms (i.e., C 3 ~C 5 alkylene).

[0016] "Alkenylene" refers to a straight-chain divalent hydrocarbon chain consisting of only carbon and hydrogen, containing at least one carbon-carbon double bond, preferably having from 2 to 12 carbon atoms, and connecting the remainder of the molecule to a radical group. The alkenylene chain is bonded to the remainder of the molecule via a single bond and to the radical group via a single bond. The points of attachment of the alkenylene chain to the remainder of the molecule and to the radical group are via terminal carbons, respectively. The alkenylene chain may be optionally substituted by one or more substituents such as those described herein. In certain embodiments, alkenylene contains from 2 to 10 carbon atoms (i.e., C 2 ~C 10 alkenylene). In certain embodiments, alkenylene contains from 2 to 8 carbon atoms (i.e., C2 ~C 8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (i.e., C 2 ~C 5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (i.e., C 2 ~C 4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (i.e., C 2 ~C 3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (i.e., C 2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (i.e., C 5 ~C 8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (i.e., C 3 ~C 5 alkenylene).

[0017] "Alkenylene" refers to a straight-chain divalent hydrocarbon chain consisting of only carbon and hydrogen, containing at least one carbon-carbon triple bond, preferably having 2 to 12 carbon atoms, and connecting the rest of the molecule to a radical group. The alkynylene chain is bonded to the rest of the molecule via a single bond and to the radical group via a single bond. The bonding points of the alkynylene chain to the rest of the molecule and the radical group are via terminal carbons respectively. The alkynylene chain can be optionally substituted by one or more substituents such as those described herein. In certain embodiments, alkynylene contains 2 to 10 carbon atoms (i.e., C 2 ~C 10 alkynylene). In certain embodiments, alkynylene contains 2 to 8 carbon atoms (i.e., C 2 ~C 8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (i.e., C 2 ~C 5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (i.e., C 2 ~C 4(alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (i.e., C 2 ~C 3 (alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (i.e., C 2 (alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (i.e., C 5 ~C 8 (alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (i.e., C 3 ~C 5 (alkynylene).

[0018] The term "C x~y ", when used in combination with a chemical moiety such as alkyl, alkenyl, or alkynyl, means a group containing x to y carbons in the chain. For example, the term "C 1~6 alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing straight-chain alkyl and branched-chain alkyl groups having 1 to 6 carbons. C x~y The term alkylene refers to a substituted or unsubstituted alkylene chain having x to y carbons in the alkylene chain. For example, C 1~6 alkylene can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which is optionally substituted.

[0019] The terms "C x~y alkenyl" and "C x~y alkynyl" are similar in length and possible substitution to the above alkyl, but refer to unsaturated aliphatic groups each containing at least one double bond or triple bond. C x~y The term alkenylene refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the alkenylene chain. For example, C 2~6 alkenylene can be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any of which is optionally substituted. The alkenylene chain can have one double bond or two or more double bonds in the alkenylene chain. C x~yThe term "alkynylene" refers to a substituted or unsubstituted alkynylene chain having from x to y carbons in the alkynylene chain. For example, C 2~6 The alkynylene may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any of which may be optionally substituted. The alkynylene chain may have one triple bond or two or more triple bonds in the alkynylene chain.

[0020] As used herein, the term "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocyclic rings include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of the bicyclic carbocyclic ring may be selected from saturated, unsaturated, and aromatic rings. The bicyclic carbocyclic ring may be a fused, bridged, or spiro ring system. In some embodiments, the carbocyclic ring is aryl. In some embodiments, the carbocyclic ring is cycloalkyl. In some embodiments, the carbocyclic ring is cycloalkenyl. In an exemplary embodiment, an aromatic ring, such as phenyl, may be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocyclic, as long as valency permits. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The carbocyclic ring may be optionally substituted by one or more substituents such as those described herein.

[0021] "Cycloalkyl" refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting only of carbon atoms and hydrogen atoms, including fused ring systems or bridged ring systems, preferably having from 3 to 12 carbon atoms (i.e., C 3~12 cycloalkyl). In certain embodiments, cycloalkyl contains from 3 to 10 carbon atoms (i.e., C 3~10 cycloalkyl). In other embodiments, cycloalkyl contains from 5 to 7 carbon atoms (i.e., C 5~7cycloalkyl). The cycloalkyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. The cycloalkyl can be optionally substituted by one or more substituents such as those described herein.

[0022] "Cycloalkenyl" preferably refers to a stable unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting only of carbon and hydrogen atoms, having 3 to 12 carbon atoms and containing at least one double bond, and including a fused or bridged ring system (i.e., C 3~12 cycloalkenyl). In certain embodiments, the cycloalkenyl contains 3 to 10 carbon atoms (i.e., C 3~10 cycloalkenyl). In other embodiments, the cycloalkenyl contains 5 to 7 carbon atoms (i.e., C 5~7 cycloalkenyl). The cycloalkenyl can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The cycloalkenyl can be optionally substituted by one or more substituents such as those described herein.

[0023] "Aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon, as well as 5 to 18 carbon atoms, and at least one of the rings in the ring system is aromatic, that is, it contains a cyclic delocalized (4n + 2)π - electron system according to Hückel's theory. Examples of ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Aryl may be optionally substituted by one or more substituents such as those described herein.

[0024] "C" x~y "carbocyclic ring" means including a group containing x to y carbons in the ring. For example, the term "C" 3~6 "carbocyclic ring" can be a saturated, unsaturated or aromatic ring system containing 3 to 6 carbon atoms, and any of those carbon atoms can be optionally substituted as provided herein.

[0025] As used herein, the term "heterocyclic ring" refers to a saturated, unsaturated, non-aromatic, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocyclic rings include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of the bicyclic heterocyclic ring can be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocyclic ring contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclic ring contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocyclic ring contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocyclic ring contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocyclic ring can be attached to the remainder of the molecule via any atom of the heterocyclic ring whose valence is acceptable, such as a carbon or nitrogen atom of the heterocyclic ring. In some embodiments, the heterocyclic ring is a heteroaryl. In some embodiments, the heterocyclic ring is a heterocycloalkyl. Exemplary heterocyclic rings include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. The heterocyclic ring can be optionally substituted by one or more substituents such as those described herein. The bicyclic heterocyclic ring can be a fused, bridged, or spiro ring system. In an exemplary embodiment, a heterocyclic ring, e.g., pyridyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. The heterocyclic ring can be optionally substituted by one or more substituents such as those described herein.

[0026] "Heterocycloalkyl" refers to a stable 3- to 12-membered non-aromatic ring radical containing 2 to 12 carbon atoms and at least 1 heteroatom, where each heteroatom can be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl contains at least 1 heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl contains at least 1 heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl contains at least 1 heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl contains at least 1 heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl can be selected from monocyclic or bicyclic, and fused or bridged ring systems. The heteroatoms in the heteroaryl radical are optionally oxidized. When present, one or more nitrogen atoms are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the remainder of the molecule via any atom of the heterocycloalkyl whose valence is permitted, such as any carbon or nitrogen atom of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The heterocycloalkyl can be optionally substituted by one or more substituents such as those described herein.

[0027] The term "heteroaryl" refers to a radical derived from a 3- to 12-membered aromatic ring radical containing 1 to 11 carbon atoms and at least 1 heteroatom, each heteroatom being optionally selected from N, O, and S. In some embodiments, heteroaryl contains at least 1 heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, heteroaryl contains at least 1 heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, heteroaryl contains at least 1 heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, heteroaryl contains at least 1 heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, a heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems, with at least 1 of the rings in the ring system being aromatic, i.e., containing a cyclic delocalized (4n + 2)π-electron system according to Hückel's theory. The heteroatom(s) in a heteroaryl radical may optionally be oxidized. When present, one or more nitrogen atoms are optionally quaternized. Heteroaryl may be attached to the remainder of the molecule via any atom of the heteroaryl for which the valence is permissible, such as a carbon or nitrogen atom of the heteroaryl. Heteroaryl includes an aromatic monocyclic structure, preferably a 5- to 6-membered ring, the ring structure containing at least 1 heteroatom, preferably 1 to 4 heteroatoms, more preferably 1 or 2 heteroatoms. Examples of heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl may optionally be substituted by one or more substituents such as those described herein. Heteroaryl also includes a polycyclic ring system having two or more rings in which two or more atoms are common to two adjacent rings, with at least 1 of the rings being heteroaromatic, and for example, the other rings may be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may optionally be substituted by one or more substituents such as those described herein.

[0028] The "X-membered heterocyclic ring" refers to the number of ring atoms within the ring, i.e., it refers to X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocyclic ring has 5 ring atoms, such as triazole, oxazole, thiophene, etc.

[0029] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is the alkyl chain defined above.

[0030] "Halo" or "halogen" refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.

[0031] As used herein, the terms "haloalkyl" or "haloalkane" refer to an alkyl radical as defined above substituted by one or more halogen radicals, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, and I). When an alkyl group is substituted with two or more halogen radicals, each halogen can be independently selected, for example, from 1-chloro, 2-fluoroethane.

[0032] The term "substituted" refers to hydrogen on one or more carbons or substitutable heteroatoms, such as NH or NH of a compound2 Refers to a moiety having a substituent to replace. "Substituted" or "substituted with" is understood to include the implicit condition that such substitution results in a stable compound, i.e., a compound that does not spontaneously undergo conversions such as rearrangement, cyclization, elimination, etc., in accordance with the acceptable valences of the substituted atom and the substituent. In certain embodiments, substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all acceptable substituents of an organic compound. In a broad sense, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. The acceptable substituents can be one or more and can be the same or different for a suitable organic compound.

[0033] In some embodiments, the substituent may include any substituent described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO 2 ), imino (=N-H), oxime (=N-OH), hydrazine (=N-NH 2 ), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a ) 2 , -R b -O-R c -C(O)N(R a ) 2 , -Rb -N(R a )C(O)OR a 、-R b -N(R a )C(O)R a 、-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), -R b -S(O) t N(R a ) 2 (t is 1 or 2); alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, any of them, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO 2 )、imino(=N-H), oxime(=N-OH), hydrazine(=N-NH 2 )、-R b -OR a -R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a ) 2 、-R b -N(R a ) 2 、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a ) 2 、-R b -O-R c -C(O)N(R a )2 , -R b , -N(R a )C(O)OR a , -R b , -N(R a vC(O)R a , -R b , -N(R a )S(O) t R a (t is 1 or 2), -R b , -S(O) t R a (t is 1 or 2), -R b , -S(O) t OR a (t is 1 or 2), and -R b , -S(O) t N(R a ) 2 (t is 1 or 2) is optionally substituted, and each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, where each R a is, to the extent permitted by valence, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO 2 ), imino(=N-H), oximo(=N-OH); hydrazine(=N-NH 2 ), -R b , -OR a , -R b , -OC(O)-R a , -R b , -OC(O)-OR a , -R b , -OC(O)-N(R a ) 2 , -R b , -N(R a ) 2 , -R b , -C(O)R a , -R b , -C(O)OR a , -R b , -C(O)N(Ra ) 2 -R b -O-R c -C(O)N(R a ) 2 -R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2) is optionally substituted, and each R b is independently selected from a direct bond or a linear or branched alkylene chain, alkenylene chain or alkynylene chain, and each R c is a linear or branched alkylene chain, alkenylene chain or alkynylene chain. It will be understood by those skilled in the art that the substituents themselves can be substituted as appropriate.

[0034] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed using inorganic bases and / or organic bases.

[0035] As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, or commensurate with a reasonable benefit / risk ratio.

[0036] As used herein, the terms "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.

[0037] The terms "subject", "individual", and "patient" may be used interchangeably and refer to humans, as well as non-human mammals (e.g., non-human primates, dogs, horses, cats, pigs, cows, ungulates, rabbits, etc.). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) who is under the care of a physician or other patient in a hospital as an external healthcare provider or in other clinical situations. In certain embodiments, the subject may not be under the care or prescription of a physician or other healthcare provider.

[0038] As used herein, the phrase "subject in need" refers to a subject as described herein who has or is at risk of having a medical condition to be prophylactically or therapeutically treated with a compound or salt described herein.

[0039] The terms "administer", "administered", "administering", and "administration" are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, an oral route of administering the composition can be used. The terms "administer", "administered", "administering", and "administration" of a compound are to be understood to mean providing the compound of the invention or a salt of the compound of the invention to an individual in need thereof.

[0040] As used herein, "treatment" or "treating" refers to an approach for obtaining a beneficial or desired result, including but not limited to therapeutic and / or prophylactic benefits, with respect to a disease, disorder, or medical condition. In certain embodiments, treatment or treating involves administering to a subject a compound or composition disclosed herein. Therapeutic benefits can include eradication or amelioration of the underlying disease being treated. Additionally, a therapeutic benefit can be achieved by eradication or amelioration of one or more of the physiological symptoms associated with the underlying disease, such as observing an improvement in the subject even though the subject may still be afflicted with the underlying disease. In certain embodiments, for prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease or to a subject reporting one or more of the physiological symptoms of a disease, even in the absence of a diagnosis of that disease. Treating can include, for example, reducing, delaying, or alleviating the severity of one or more symptoms of a disease or condition, or reducing the frequency with which symptoms, such as a disease, defect, disorder, or adverse condition, are experienced by a patient. Treating can be used herein to refer to a method that provides a level of treatment or amelioration of a disease or condition, and can contemplate a range of results directed thereto, including but not limited to complete prevention of the condition.

[0041] In certain embodiments, the term “prevent” or “prevention” related to a disease or disorder can refer to a compound that, in a statistical sample, reduces the occurrence of a disorder or condition in a treated sample compared to an untreated control sample, or delays or reduces the severity of the onset of one or more symptoms of a disorder or condition compared to an untreated control sample.

[0042] The terms “inhibit,” “selectively inhibit,” or “selectively inhibit” refer to the (chemical or biological) ability of an agent to preferentially reduce target signaling activity compared to off-target signaling activity through direct or indirect interaction with the target.

[0043] “Therapeutic effect,” as used herein, encompasses the above-described therapeutic and / or prophylactic benefits. Prophylactic effects include the appearance of a disease or condition, the delay or elimination of the onset of symptoms of a disease or condition, the slowing, stopping, or reversal of the progression of a disease or condition, or any combination thereof.

[0044] Compound In some embodiments, the present disclosure provides a compound of Formula I,

Chemical Formula

[0045] In some embodiments, for the compound or salt of formula (I), n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments, n is selected from 0 and 1. In some embodiments, n is selected from 1, 2, 3, and 4. In some embodiments, n is selected from 2, 3, and 4. In some embodiments, n is selected from 3 and 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0046] In some embodiments, for the compound or salt of formula (I), each R 3 is independently selected from halogen, -OR 14 , -N(R 14 ), -C(O)R 2 , -C(O)OR 14 , -NO 14 , and -CN. In some embodiments, each R 2 is independently selected from halogen, -OR 3 , -NO 14 , and -CN. In some embodiments, each R 2 is independently selected from chlorine, fluorine, bromine, and -OR 3 . In some embodiments, each R 14 is independently selected from chlorine, fluorine, bromine, and -OR3 is independently selected from chlorine, fluorine, and bromine. In some embodiments, each R 3 is independently selected from chlorine and fluorine. In some embodiments, each R 3 is fluorine.

[0047] In some embodiments, for the compound or salt of formula (I), each R 3 is selected from C 1~6 alkyl and C 3~6 carbocyclic ring, and each C 1~6 alkyl and C 3~6 carbocyclic ring is optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 , and -CN. In some embodiments, each R 3 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)OR 14 , -NO 2 , and -CN.

[0048] In some embodiments, for the compound or salt of formula (I), each R 3 is independently selected from halogen, -OR 14 , -N(R 14 ) 2 , -CN, C 1~3 alkyl, C 1~3 haloalkyl, and optionally substituted C 3~6 saturated carbocyclic ring. In some embodiments, each R 3 is halogen, -OR 14 , -N(R 14 ) 2is independently selected from -CN, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, each R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -CN, C 1~3 alkyl, and C 1~3 haloalkyl, independently selected. In some embodiments, each R 3 is fluorine, chlorine, -OR 14 , -N(R 14 ) 2 , -CN, C 1~3 alkyl, and C 1~3 haloalkyl, independently selected. In some embodiments, each R 3 is fluorine, chlorine, -OR 14 , -N(R 14 ) 2 , and -CN, independently selected. In some embodiments, each R 3 is independently selected from fluorine or chlorine. In some embodiments, each R 3 is selected from fluorine.

[0049] In some embodiments, for the compound or salt of formula (I), n is selected from 1, 2, and 3, and each R 3 is halogen, -OR 14 , -N(R 14 ) 2 , -CN, C 1~3 alkyl, and C 1~3 haloalkyl, independently selected. In some embodiments, n is selected from 1, 2, and 3, and each R 3 is fluorine, chlorine, -OR 14 , -N(R 14 ) 2 , -CN, C 1~3 alkyl, and C 1~3 haloalkyl, independently selected. In some embodiments, n is selected from 1, 2, and 3, and each R 3 is selected from fluorine.

[0050] In some embodiments, for the compound or salt of formula (I), n is 1, and R 3 is selected independently from halogen, -OR 14 , -N(R 14 ), -CN, C 2 alkyl, and C 1~3 haloalkyl. In some embodiments, n is 1, and R 1~3 is selected independently from fluorine, chlorine, -OR 3 , -N(R 14 ), -CN, C 14 alkyl, and C 2 haloalkyl. In some embodiments, n is 1, and R 1~3 is selected from the following. 1~3 3

[0051] In some embodiments, for the compound or salt of formula (I) or (I-A), R 1 is selected from hydrogen, halogen, -OR 12 , -N(R 12 ), -C(O)R 2 , -C(O)OR 12 , -NO 12 , and -CN. In some embodiments, R 2 is selected from halogen, -OR 1 , -N(R 12 ), -C(O)R 12 , -C(O)OR 2 , -NO 12 , and -CN. In some embodiments, R 12 is selected independently from halogen, -OR 2 , -N(R 1 ), -C(O)R 12 , -C(O)OR 12 , -NO 2 , and -CN and is optionally substituted with one or more substituents selected therefrom and is selected from C 12 alkyl. In some embodiments, R 12 is selected from hydrogen, halogen, -OR 2 , -N(R 1~6 ), -C(O)R 1 , -C(O)OR 12 , -NO12 ) 2 、 -CN, C 1~3 alkyl, and C 1~3 is selected from haloalkyl. In some embodiments, R 1 is halogen, -OR 12 , -N(R 12 ) 2 , -CN, C 1~3 alkyl, and C 1~3 is selected from haloalkyl. In some embodiments, R 1 is selected from methyl, ethyl, propyl, and isopropyl, any of which is optionally substituted with halogen, -OR 12 , -N(R 12 ) 2 , and -CN. In some embodiments, R 1 is selected from methyl, ethyl, propyl, isopropyl, and trifluoromethyl. In some embodiments, R 1 is selected from methyl, ethyl, propyl, and isopropyl. In some embodiments, R 1 is selected from methyl and trifluoromethyl. In some embodiments, R 1 is selected from methyl. In some embodiments, R 1 is selected from trifluoromethyl.

[0052] In some embodiments, for the compound or salt of formula (I) or (I-A), A is selected from saturated C 3~6 carbocyclic ring and 5-membered heteroaryl, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11,-C(O)OR 11 ,-NO 2 ,-CN,C 3~6 A carbon ring, and a C optionally substituted with one or more substituents independently selected from 5- to 6-membered heterocyclic rings 1~3 alkyl, wherein each C 3~6 The carbon ring and the 5- to 6-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from halogen, -OR 11 ,-N(R 11 ) 2 ,-C(O)R 11 ,-C(O)OR 11 ,-NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from: C 1~3 alkyl, and (c) each is optionally substituted with one or more substituents selected from halogen, -OR 11 ,-N(R 11 ) 2 ,-C(O)R 11 ,-C(O)OR 11 ,-NO 2 , and -CN, and is optionally substituted with one or more substituents selected from: C 3~6 carbon ring.

[0053] In some embodiments, for the compound or salt of formula (I) or (I-A), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) halogen, -OR 11 ,-N(R 11 ) 2 ,-C(O)R 11 ,-C(O)OR 11 ,-NO 2 , and -CN; (b) halogen, -OR 11 ,-N(R 11 ) 2 ,-C(O)R 11 ,-C(O)OR 11 ,-NO 2 ,-CN,C3~6 A C optionally substituted with one or more substituents independently selected from a carbocyclic ring and one or more 5- to 6-membered heterocyclic rings 1~3 alkyl, each C 3~6 The carbocyclic ring and 5- to 6-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, a C 1~3 alkyl, and (c) each being a C optionally substituted with one or more substituents selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, a C 3~6 carbocyclic ring.

[0054] In some embodiments, for a compound or salt of formula (I) or (I-A), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c). (a) halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, C 3~6 a C optionally substituted with one or more substituents independently selected from a carbocyclic ring and one or more 5- to 6-membered heterocyclic rings 1~3 alkyl, each C 3~6The carbon ring and 5- to 6-membered heterocyclic rings are each optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, and C 1~3 alkyl, and (c) each of which is optionally substituted with one or more substituents selected from halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, and a C 3~6 heterocyclic ring optionally substituted with one or more substituents selected from halogen, -OR

[0055] In some embodiments, for the compound or salt of formula (I) or (I-A), A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from (a), (b), and (c): (a) halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; (b) halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, C 3~6 carbon ring, and C 1~3 alkyl optionally substituted with one or more substituents independently selected from 5- to 6-membered heterocyclic rings, where each C 3~6 carbon ring and 5- to 6-membered heterocyclic ring are halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R11 、 -C(O)OR 11 、 -NO 2 、 and optionally substituted with one or more substituents independently selected from -CN, C 1~3 alkyl, and (c) each independently being -OR 11 、 -N(R 11 ) 2 、 -C(O)R 11 、 -C(O)OR 11 、 -NO 2 、 and optionally substituted with one or more substituents selected from -CN, C 3~6 carbocyclic ring.

[0056] In some embodiments, for the compound or salt of formula (I) or (I-A), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 、 -N(R 11 ) 2 、 -C(O)R 11 、 -C(O)OR 11 、 -NO 2 、 and -CN. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 、 -N(R 11 ) 2 、 -C(O)R 11 、 -C(O)OR 11 、 -NO 2 、 and -CN. In some embodiments, A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 、 -N(R 11 ) 2 、 -C(O)R 11 、 -C(O)OR11 、 -NO 2 and is optionally substituted with one or more substituents independently selected from -CN.

[0057] In some embodiments, for a compound or salt of formula (I) or (I-A), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is C 1~3 halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, C 3~6 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles, each C 3~6 carbocycle and 5- to 6-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected therefrom. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, C 3~6 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 6-membered heterocycles, and C 1~3 optionally substituted with one or more substituents independently selected from alkyls, each C 3~6 carbocycle and 5- to 6-membered heterocycle is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11, -C(O)OR 11 , -NO 2 and is optionally substituted with one or more substituents independently selected from -CN. In some embodiments, A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, C 3~6 carbon ring, and C optionally substituted with one or more substituents independently selected from 5- to 6-membered heterocycles 1~3 is optionally substituted with one or more substituents independently selected from, and each C 3~6 carbon ring and 5- to 6-membered heterocycle are halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and is optionally substituted with one or more substituents independently selected from -CN.

[0058] In some embodiments, for the compound or salt of formula (I) or (I-A), A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is optionally substituted with one or more substituents independently selected from C 3~6 carbon ring, and each of those carbon rings is halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2and is optionally substituted with one or more substituents selected from -CN. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any of which is C 3~6 optionally substituted with one or more substituents independently selected from carbocycles, each of which is halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN. In some embodiments, A is selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is C 3~6 optionally substituted with one or more substituents independently selected from carbocycles, each of which is halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN.

[0059] In some embodiments, for the compound or salt of formula (I) or (I-A), A is a saturated C 11 carbocycle optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 2 ), -CN, C 1~3 alkyl, and C 1~3 haloalkyl. In some embodiments, A is a C 3~6 carbocycle selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is halogen, -OR 3~6 , -N(R 11 ), -CN, C 11 alkyl, and C 2 , and C 1~3 alkyl, and C 1~3It is optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, A is a saturated C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6 carbocyclic ring, any of which is halogen, -OR 11 , -N(R 11 ), -CN, C 2 alkyl, and C 1~3 haloalkyl, and is optionally substituted with one or more substituents independently selected therefrom. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is halogen, -OR 11 , -N(R 11 ), -CN, C 2 alkyl, and C 1~3 haloalkyl, and is optionally substituted with one or more substituents independently selected therefrom. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is halogen, -OR 1~3 , -N(R 11 ), -CN, C 1~3 alkyl, and C 1~3 haloalkyl, and is optionally substituted with one or more substituents independently selected therefrom. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is fluorine, chlorine, bromine, C 1~3 alkyl, and C 1~3 haloalkyl, and is optionally substituted with one or more substituents independently selected therefrom. In some embodiments, A is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, any of which is optionally substituted with one or more substituents independently selected from fluorine, chlorine and bromine.

[0060] In some embodiments, for the compound or salt of formula (I) or (I-A), A is an optionally substituted C 3~6 carbocyclic ring. In some embodiments, A is a C 3~5 carbocyclic ring, C 3~4 carbocyclic ring, C3~4 Carbon ring, C 4~6 Carbon ring, and C 5~6 Selected from carbon rings, any of which is optionally substituted. In some embodiments, A is C 3 Carbon ring, C 4 Carbon ring, C 5 Carbon ring, and C 6 Selected from carbon rings, any of which is optionally substituted. In some embodiments, A is optionally substituted C 3~6 A saturated carbon ring and optionally substituted unsaturated C 3~6 Is a carbon ring. In some embodiments, A is C selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl 3~6 Is a carbon ring, any of which is optionally substituted. In some embodiments, A is C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6 Is a saturated carbon ring, and any of these may also be optionally substituted.

[0061] In some embodiments, for the compound or salt of formula (I) or (I-A), A is saturated C 3~6 Is a carbon ring, any of which is halogen, -OR 11 , -N(R 11 ) 2 , -CN, C 1~3 Alkyl, and C 1~3 Optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, A is saturated C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6 Is a carbon ring, any of which is halogen, -OR 11 , -N(R 11 ) 2 , -CN, C 1~3 Alkyl, and C 1~3 Optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, A is saturated C selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl 3~6It is a carbon ring, and any of them is optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, -OR 11 , -N(R 11 ), 2 , -CN, C 1~3 alkyl, and C 1~3 haloalkyl. In some embodiments, A is a saturated C 3~6 carbon ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and any of them is optionally substituted with one or more substituents independently selected from fluorine, chlorine, bromine, -OR 11 , C 1~3 alkyl, and C 1~3 haloalkyl. In some embodiments, A is a cyclopropyl optionally substituted with halogen, C 1~3 alkyl, and C 1~3 haloalkyl. In some embodiments, A is a cyclopropyl optionally substituted with fluorine, chlorine, bromine, C 1~3 alkyl, and C 1~3 haloalkyl. In some embodiments, A is a cyclopropyl optionally substituted with fluorine, chlorine, and bromine. In some embodiments, A is

Chemical formula

[0062] In some embodiments, for a compound or salt of formula (I) or (I-A), A is a 5- to 6-membered heterocyclic ring containing at least one heteroatom selected from nitrogen, oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5- to 6-membered heterocyclic ring containing at least one heteroatom selected from nitrogen, oxygen, and combinations thereof. In some embodiments, A is a 5- to 6-membered heterocyclic ring containing at least one heteroatom selected from nitrogen, sulfur, and combinations thereof. In some embodiments, A is a 5- to 6-membered heterocyclic ring containing at least one heteroatom selected from oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5- to 6-membered heterocyclic ring containing at least one nitrogen heteroatom. In some embodiments, A is a 5- to 6-membered heterocyclic ring containing at least one oxygen heteroatom. In some embodiments, A is a 5- to 6-membered heterocyclic ring containing at least one sulfur heteroatom. In some embodiments, A is a 5- to 6-membered saturated heterocyclic ring. In some embodiments, A is a 5- to 6-membered unsaturated heterocyclic ring. In some embodiments, A is a 5- to 6-membered heteroaryl.

[0063] In some embodiments, for a compound or salt of formula (I) or (I-A), A is a 5- to 6-membered heteroaryl containing at least one heteroatom selected from nitrogen, oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5- to 6-membered heteroaryl containing at least one heteroatom selected from nitrogen, oxygen, and combinations thereof. In some embodiments, A is a 5- to 6-membered heteroaryl containing at least one heteroatom selected from nitrogen, sulfur, and combinations thereof. In some embodiments, A is a 5- to 6-membered heteroaryl containing at least one heteroatom selected from oxygen, sulfur, and combinations thereof. In some embodiments, A is a 5- to 6-membered heteroaryl containing at least one nitrogen heteroatom. In some embodiments, A is a 5- to 6-membered heteroaryl containing at least one oxygen heteroatom. In some embodiments, A is a 5- to 6-membered heteroaryl containing at least one sulfur heteroatom.

[0064] In some embodiments, for a compound or salt of formula (I) or (I-A), A is a 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and a C 11 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 11 ), -N(R 2 ), -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN; and a C 1~6 carbocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR , -N(R 11 ), -C(O)R 11 ), -C(O)OR 2 , -NO 11 , and -CN. 11 2 3~6 3~6

[0065] In some embodiments, for a compound or salt of formula (I) or (I-A), A is pyrazole, imidazole, triazole, tetrazole, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, or triazine, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -N(R 11 ), -C(O)R 2 , -C(O)OR 11 , -NO 11 , -NO 2 ​​, -CN, and each independently selected from halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and optionally substituted with one or more substituents independently selected from a 5- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 alkyl; and each independently selected from halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and optionally substituted with one or more substituents selected from a C 3~6 carbocyclic ring.

[0066] In some embodiments, for the compound or salt of formula (I) or (I-A), A is a 6-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each independently selected from halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and optionally substituted with one or more substituents independently selected from a 5- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 alkyl; and each independently selected from halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2and C optionally substituted with one or more substituents selected from -CN 3~6 carbocyclic ring.

[0067] In some embodiments, for a compound or salt of formula (I) or (I-A), A is pyridine, pyridazine, pyrimidine, pyrazine, or triazine, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and C optionally substituted with one or more substituents independently selected from a 5- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 alkyl; and each is optionally substituted with one or more substituents selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and C optionally substituted with one or more substituents selected from -CN 3~6 carbocyclic ring.

[0068] In some embodiments, for a compound or salt of formula (I) or (I-A), A is a 5-membered heteroaryl optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each is optionally substituted with one or more substituents independently selected from halogen, -OR 11, -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and one or more substituents independently selected from 5- to 6-membered heterocycles optionally substituted with one or more substituents selected from -CN, optionally substituted C 1~6 alkyl; and each independently being a carbon ring optionally substituted with one or more substituents selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, and each independently being a carbon ring optionally substituted with one or more substituents selected from halogen, -OR 3~6 .

[0069] In some embodiments, for the compound or salt of formula (I) or (I-A), A is pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, tetrazole, any of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each independently being a carbon ring optionally substituted with one or more substituents selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and -CN, and one or more substituents independently selected from 5- to 6-membered heterocycles optionally substituted with one or more substituents selected from -CN, optionally substituted C 1~6 alkyl; and each independently being a carbon ring optionally substituted with one or more substituents selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2and C optionally substituted with one or more substituents selected from -CN 3~6 carbocyclic ring.

[0070] In some embodiments, for a compound or salt of formula (I) or (I-A), A is pyrazole and oxadiazole, each of which is optionally substituted with one or more substituents independently selected from: halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and each is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and C optionally substituted with one or more substituents independently selected from 5- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 alkyl; and each is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , and C optionally substituted with one or more substituents selected from -CN 3~6 carbocyclic ring.

[0071] In some embodiments, for a compound or salt of formula (I) or (I-A), A is selected from pyrazole and oxadiazole, each of which is optionally substituted with one or more substituents independently selected from C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkyl-OR 11 , and C optionally substituted with one or more substituents independently selected from 5- to 6-membered saturated heterocyclic rings. 1~3 alkyl.

[0072] In some embodiments, for a compound or salt of formula (I) or (I-A), A is selected from pyrazole and oxadiazole, each of which is optionally substituted with methyl, ethyl, propyl, and isopropyl.

[0073] In some embodiments, for a compound or salt of formula (I) or (I-A), A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0074] In some embodiments, for a compound or salt of formula (I) or (I-A), A is selected from pyrazole and oxadiazole, each of which is C 1~3 haloalkyl and C1~3 alkyl-OR 11 is optionally substituted. In some embodiments, A is [Chemical formula] selected from. In some embodiments, A is [Chemical formula] selected from. In some embodiments, A is [Chemical formula] is. In some embodiments, A is [Chemical formula] is. In some embodiments, A is [Chemical formula] is. In some embodiments, A is [Chemical formula] is.

[0075] In some embodiments, for the compound or salt of formula (I) or (I-A), A is selected from pyrazole and oxadiazole, each of which is a C substituted with a 5- to 6-membered saturated heterocycle 1~3 alkyl optionally substituted with. In some embodiments, A is selected from pyrazole and oxadiazole, each of which is a C substituted with pyrrolidine, pyrazolidine, imidazolidine, tetrahydrofuran, tetrahydrothiophene, oxathiolane, piperidine, piperazine, tetrahydropyran, thiane, dithiane, morpholine, and thiomorpholine 1~3 alkyl optionally substituted with. In some embodiments, A is [Chemical formula] is.

[0076] In some embodiments, for a compound or salt of formula (I) or (I-A), A is selected from pyrazole and oxadiazole, each of which is optionally substituted with one or more substituents selected from halogen, -OR 11 , -N(R 11 ), -C(O)R 2 , -C(O)OR 11 , -NO 11 , and -CN, and is optionally substituted with one or more substituents independently selected from saturated C 2 carbocycles. In some embodiments, A is selected from pyrazole and oxadiazole, each of which is optionally substituted with cyclopropyl, and the cyclopropyl is optionally substituted with one or more fluorine or chlorine atoms. In some embodiments, A is 3~6 selected from [Chemical formula] . In some embodiments, A is [Chemical formula] . In some embodiments, A is [Chemical formula] .

[0077] In some embodiments, for a compound or salt of formula (I) or (I-A), R 2 is selected from -N(R C )C(O)N(R D )(R E ). In some embodiments, R 2 is selected from -N(R C )C(O)N(R D )(R E ), wherein R C is selected from hydrogen, R D is C 1~6Alkyl and saturated C 3~6 selected from carbocycles, any of which is independently selected from one or more substituents selected from halogen, -OR 18 , -N(R 18 ), -C(O)R 2 , -C(O)OR 18 , -NO 18 , and -CN, and is optionally substituted, 2 R E is selected from C 1~6 alkyl and saturated C 3~6 carbocycles, any of which is independently selected from one or more substituents selected from halogen, -OR 19 , -N(R 19 ), -C(O)R 2 , -C(O)OR 19 , -NO 19 , and -CN, and is optionally substituted. 2

[0078] In some embodiments, for a compound or salt of formula (I) or (I-A), R 2 is selected from -N(R C )C(O)N(R D )(R E ). In some embodiments, R 2 is selected from -N(R C )C(O)N(R D )(R E ), wherein R C is selected from hydrogen, R D is selected from C 1~6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is independently selected from one or more substituents selected from halogen, -OR 18 , -N(R 18 ), -C(O)R 2 , -C(O)OR 18 , -NO 18 , and -CN, and is optionally substituted, 2 R E is C 1~6 ​​​Selected from alkyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 19 、-N(R 19 ) 2 、-C(O)R 19 、-C(O)OR 19 、-NO 2 、and -CN.

[0079] In some embodiments, for a compound or salt of formula (I) or (I-A), R D is selected from C 1~3 alkyl and cyclopropyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 18 、-N(R 18 ) 2 、-NO 2 、and -CN; R E is selected from C 1~3 alkyl. In some embodiments, R E is selected from C 1~3 alkyl and cyclopropyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 19 、-N(R 19 ) 2 、-NO 2 、and -CN; and R D is selected from C 1~3 alkyl. In some embodiments, R 2 is

Chemical formula

Chemical formula

Chemical formula

[0080] In some embodiments, for a compound or salt of formula (I) or (I-A), R 2 is selected from -N(R A )C(O)(R B ); R A is C 15 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -N(R 2 ), -C(O)R 15 , -C(O)OR 15 , -NO 2 , and -CN. In some embodiments, R 1~6 is selected from -N(R 2 )C(O)(R A ), R B is C A alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 15 , and -N(R 15 ). In some embodiments, R 2 is selected from -N(R 1~6 )C(O)(R 2 ), R A is C B alkyl optionally substituted with one or more substituents independently selected from -C(O)R A , -C(O)OR 15 , -NO 15 , and -CN. In some embodiments, R 2 is selected from -N(R 1~6 )C(O)(R 2 ), R A is hydrogen. B A is hydrogen.

[0081] In some embodiments, for a compound or salt of formula (I) or (I-A), R 2 is selected from -N(R A )C(O)(R B ); R Bis one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , and -CN, and is optionally substituted with C 1~6 alkyl selected. In some embodiments, R 2 is selected from -N(R A )C(O)(R B ), R B is C 3~6 alkyl optionally substituted with one or more substituents independently selected from carbocyclic rings and 5- to 6-membered heterocyclic rings, and each of them is halogen, -OR 1~6 , -N(R 16 ), 16 , -C(O)R 2 , -C(O)OR 16 , -NO 16 , and -CN, and is optionally substituted with one or more substituents independently selected. In some embodiments, R 2 is selected from -N(R 2 )C(O)(R A ), R B is selected from C B a carbocyclic ring or a 4- to 6-membered heterocyclic ring, each of which is halogen, -OR 3~6 , -N(R 13 ), 16 , -C(O)R 2 , -C(O)OR 16 , -NO 16 , and -CN, and is optionally substituted with one or more substituents independently selected. In some embodiments, R 2 is selected from -N(R 2 )C(O)(R A ), R B is selected from C B a carbocyclic ring or a 4- to 6-membered heterocyclic ring, each of which is halogen, -OR 3~6 , -N(R 16 ), 16 ​2 、 -C(O)R 16 、 -C(O)OR 16 、 -NO 2 、 and one or more substituents independently selected from -CN, optionally substituted C 1~6 alkyl is optionally substituted with one or more substituents independently selected therefrom.

[0082] In some embodiments, for a compound or salt of formula (I) or (I-A), R 2 is selected from -N(R A )C(O)(R B ), R A is hydrogen, R B is halogen, -OR 16 、 -N(R 16 ) 2 、 -C(O)R 16 、 -C(O)OR 16 、 -N(R 16 )C(O)OR 16 、 -NO 2 、 and one or more substituents independently selected from -CN, optionally substituted C 1~6 alkyl is selected. In some embodiments, R 2 is selected from -N(R A )C(O)(R B ), R A is hydrogen, R B is C 3~6 alkyl optionally substituted with one or more substituents independently selected from carbocyclic rings and 5- to 6-membered heterocyclic rings, each of which is independently selected from halogen, -OR 1~6 alkyl is selected, and any of them is optionally substituted with one or more substituents independently selected from -N(R 16 ), -C(O)R 16 ) 2 、 -C(O)R 16 、 -C(O)OR 16 、 -NO 2 、 and -CN. In some embodiments, R 2 is selected from -N(R A )C(O)(R B ), R A is hydrogen, R B is C3~6 Selected from a carbon ring or a 4- to 6-membered heterocyclic ring, each of which is independently selected from one or more substituents selected from halogen, -OR 13 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN. In some embodiments, R 2 is selected from -N(R A )C(O)(R B ), R A is hydrogen, and R B is selected from a C 3~6 carbon ring or a 4- to 6-membered heterocyclic ring, each of which is independently selected from one or more substituents selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN and is optionally substituted with one or more substituents independently selected from a C 1~6 alkyl optionally substituted with one or more substituents independently selected from the above.

[0083] In some embodiments, for the compound or salt of formula (I) or (I-A), R 2 is selected from -N(R A )C(O)(R B ), R A is selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , -CN and is a C 1~6 alkyl optionally substituted with one or more substituents independently selected from the above, and R B is selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR16 , -N(R 16 )C(O)OR 16 , -NO 2 , and one or more substituents independently selected from -CN, optionally substituted C 1~6 selected from. In some embodiments, R 2 is selected from -N(R A )C(O)(R B ), R A is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , -CN, optionally substituted with one or more substituents independently selected from C 1~6 alkyl, R B is C 3~6 alkyl optionally substituted with one or more substituents independently selected from carbocyclic and 5- to 6-membered heterocyclic rings, C 1~6 alkyl, any of which are halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN, optionally substituted with one or more substituents independently selected from. In some embodiments, R 2 is selected from -N(R A )C(O)(R B ), R A is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 ), -N(R 16 C(O)OR 16 , -NO 2 , -CN, optionally substituted with one or more substituents independently selected from C 1~6 alkyl, R B is C 3~6Selected from a carbon ring or a 4- to 6-membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 13 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN. In some embodiments, R 2 is selected from -N(R A )C(O)(R B ), R A is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , -CN, and is C 1~6 alkyl, and R B is selected from C 3~6 a carbon ring or a 4- to 6-membered heterocyclic ring, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from C 1~6 alkyl.

[0084] In some embodiments, for the compound or salt of formula (I) or (I-A), R 2 is -N(R A )C(O)(R B ), wherein R A is selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, R B is selected from: halogen, -OR16 ,-N(R 16 ) 2 ,-C(O)R 16 ,-C(O)OR 16 ,-N(R 16 )C(O)OR 16 ,-NO 2 ,-CN,C 3~6 An alkyl optionally substituted with one or more substituents independently selected from a carbon ring and a 5- to 6-membered heterocyclic ring, wherein the carbon ring and the 5- to 6-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 ,-N(R 3~6 ),-C(O)R 16 ,-C(O)OR 16 ),-NO 2 ,and -CN; and 16 ,-C(O)OR 16 ,-NO 2 ,and -CN, and an optionally substituted 4- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 ),-N(R ),-C(O)R 13 ,-N(R 16 ),-C(O)R 2 ,-C(O)OR 16 ,-NO 16 ,-CN, and halogen, -OR 2 ),-N(R 16 ),-C(O)R 16 ),-C(O)OR 2 ,-NO 16 ,and -CN. 16 ,-NO 2 ,and -CN, and an optionally substituted 4- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 alkyl.

[0085] In some embodiments, for the compound or salt of formula (I) or (I-A), R 2 is -N(R A )C(O)(R B ), wherein R A is selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, RB is selected from one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , and -CN, and is optionally substituted with one or more substituents selected from C 1~6 alkyl selected from

[0086] In some embodiments, for a compound or salt of formula (I) or (I-A), R 2 is -N(R A )C(O)(R B ), wherein R A is selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, R B is selected from C 3~6 alkyl optionally substituted with one or more substituents independently selected from carbocyclic rings and 5- to 6-membered heterocyclic rings, and any of them is optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 , -N(R 16 ), -C(O)R 16 ), -C(O)OR 2 , -NO 16 , and -CN 16 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from

[0087] In some embodiments, for a compound or salt of formula (I) or (I-A), R A is hydrogen, and R B is selected from halogen, -OR 16 , -N(R 16 ), -C(O)R 2 , -C(O)OR 16 , -N(R 16 ), -C(O)OR 16 ), -NO 16 , -NO 2 , -CN, C 3~6A C optionally substituted with one or more substituents independently selected from a carbon ring and a 5- to 6-membered heterocyclic ring 1~6 selected from C alkyl, each C 3~6 The carbon ring and the 5- to 6-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN.

[0088] In some embodiments, for a compound or salt of formula (I) or (I-A), R A is hydrogen, and R B is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , and -CN and is selected from C 1~6 alkyl. In some embodiments, R A is hydrogen, and R B is selected from methyl, ethyl, propyl, and isobutyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , and -CN.

[0089] In some embodiments, for a compound or salt of formula (I) or (I-A), R B is selected from C 1~6 alkyl and C 1~6 haloalkyl. In some embodiments, R Ais hydrogen, and R B is selected from C 1~6 alkyl and C 1~6 haloalkyl. In some embodiments, R A is hydrogen, and R B is C 1~6 alkyl optionally substituted with one or more substituents independently selected from chlorine, fluorine, and bromine. In some embodiments, R A is hydrogen, and R B is C 1~6 alkyl optionally substituted with one or more fluorine atoms. In some embodiments, R 2 is

Chemical formula

Chemical formula

Chemical formula

[0090] In some embodiments, for the compound or salt of formula (I) or (I-A), R B is C 16 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 ), and N(R 16 )C(O)OR 1~6 . In some embodiments, R A is hydrogen, and R B is C 16 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 16 ), and N(R 16 )C(O)OR 1~6 . In some embodiments, R Ais hydrogen, and R B is one or more substituents independently selected from chlorine, fluorine, bromine, -OR 16 , and -N(R 16 )C(O)OR 16 , and is optionally substituted with an optionally substituted C 1~6 alkyl selected therefrom. In some embodiments, R A is hydrogen, and R B is one or more substituents independently selected from chlorine, fluorine, bromine, and -N(R 16 )C(O)OR 16 , and is optionally substituted with an optionally substituted C 1~6 alkyl selected therefrom. In some embodiments, R A is hydrogen, and R B is -OR 16 and -N(R 16 )C(O)OR 16 , and is optionally substituted with an optionally substituted C 1~6 alkyl selected therefrom. In some embodiments, R A is hydrogen, and R B is one or more substituents independently selected from chlorine, fluorine, bromine, and -OR 16 , and is optionally substituted with an optionally substituted C 1~6 alkyl selected therefrom.

[0091] In some embodiments, for the compound or salt of formula (I) or (I-A), R 2 is

Chemical formula

Chemical formula

Chemical formula

[0092] In some embodiments, for the compound or salt of formula (I) or (I-A), R B is C 16 alkyl optionally substituted with -OR 1~6 . In some embodiments, R A is hydrogen, and R B is C 16 alkyl optionally substituted with -OR 1~6 . In some embodiments, R A is hydrogen, R B is C 16 alkyl optionally substituted with -OR 1~6 , and R 16 is C 1~6 alkyl substituted with -O-C 1~6 alkyl. In some embodiments, R 2 is [Chemical formula] is as follows.

[0093] In some embodiments, for the compound or salt of formula (I) or (I-A), R B is C 3~6 alkyl optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 5- to 6-membered heterocyclic ring, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 , -N(R 16 ) 16 , -NO 2 , and -CN. In some embodiments, R 2 is hydrogen, and R A is C B alkyl optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 5- to 6-membered heterocyclic ring, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 3~6 , -N(R 1~6Selected from alkyl, any of which is halogen, -OR 16 、-N(R 16 ) 2 、-NO 2 、and -CN, and is optionally substituted with one or more substituents independently selected therefrom.

[0094] In some embodiments, for the compound or salt of formula (I) or (I-A), R A is hydrogen, and R B is C 3~6 optionally substituted with one or more substituents independently selected from optionally substituted carbocycles, and is selected from C 1~6 alkyl. In some embodiments, R A is hydrogen, and R B is C 1~6 alkyl optionally substituted with one or more substituents independently selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In some embodiments, R A is hydrogen, and R B is C 1~6 alkyl optionally substituted with one or more cyclopropyl substituents. In some embodiments, R 2 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0095] In some embodiments, for a compound or salt of formula (I) or (I-A), R B is selected from one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from a 5-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 alkyl. In some embodiments, R A is hydrogen and R B is selected from one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from a 5-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, -OR 1~6 alkyl.

[0096] In some embodiments, for a compound or salt of formula (I) or (I-A), R A is hydrogen and R B is selected from C 1~6 alkyl optionally substituted with one or more of pyrazole, imidazole, triazole, tetrazole, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, and thiadiazole, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -NO 2 , and -CN. In some embodiments, R A is hydrogen and R B is selected from C 1~6 alkyl optionally substituted with one or more of pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 16, -N(R 16 ) 2 , -NO 2 , and is optionally substituted with one or more substituents independently selected from -CN. In some embodiments, R 2 is

Chemical formula

[0097] In some embodiments, for the compound or salt of formula (I) or (I-A), R B is C 16 ) 2 alkyl optionally substituted with -N(R 1~6 ), R 16 is, each occurrence, selected from hydrogen, C 1~3 alkyl, and 3- to 6-membered heterocycles, and each C 1~3 alkyl and 3- to 6-membered heterocycle is optionally substituted. In some embodiments, R A is hydrogen, R B is C 16 ) 2 alkyl optionally substituted with -N(R 1~6 ), R 16 is, each occurrence, selected from hydrogen, C 1~3 alkyl, and 3- to 6-membered heterocycles, and each C 1~3 alkyl and 3- to 6-membered heterocycle is optionally substituted. In some embodiments, R 2 is

Chemical formula

Chemical formula

Chemical formula

[0098] In some embodiments, for a compound or salt of formula (I) or (I-A), R B is halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from a 4- to 6-membered heterocyclic ring optionally substituted with one or more substituents independently selected from C 1~6 . In some embodiments, R B is selected from 4- to 6-membered saturated heterocyclic rings, any of which is halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from C 1~6 alkyl. In some embodiments, R B is selected from azetidine and pyrrolidine, each of which is optionally substituted with halogen, -OR 13 , -C(O)R 16 , -C(O)OR 16 .

[0099] In some embodiments, for a compound or salt of formula (I) or (I-A), R A is hydrogen, and R B is halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from C 1~6 alkyl optionally substituted with one or more substituents independently selected from a 4- to 6-membered heterocyclic ring. In some embodiments, R A is hydrogen, and R B is selected from a 4- to 6-membered saturated heterocyclic ring, any of which is halogen, -OR 13 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , -CN, and one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -NO 2 , and -CN, and is optionally substituted with one or more substituents independently selected from C 1~6 alkyl optionally substituted with one or more substituents independently selected from. In some embodiments, R A is hydrogen, and R B is selected from azetidine and pyrrolidine, each of which is optionally substituted with halogen, -OR 13 , -C(O)R 16 , -C(O)OR 16 .

[0100] In some embodiments, for a compound or salt of formula (I) or (I-A), R 2 is

Chemical formula

Chemical formula

Chemical formula

[0101] In some embodiments, for a compound or salt of formula (I) or (I-A),

Chemical formula

[0102] In some embodiments, for a compound or salt of formula (I) or (I-A),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0103] In some embodiments, for the compound or salt of formula (I) or (I-A),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0104] In some embodiments, for the compound or salt of formula (I) or (I-A)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0105] In some embodiments, for the compound or salt of formula (I) or (I-A)

Chemical formula

Chemical formula

Chemical formula

[0106] In some embodiments, for the compound or salt of formula (I), formula (I) is represented by formula (I-A),

Chemical formula

[0107] In some embodiments, formula (I) or formula (I-A) is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

[0108] In certain embodiments, the present disclosure provides a compound or salt represented by the structure of formula (I), wherein A is a 5-membered heteroaryl selected from pyrazole, imidazole, oxazole, isoxazole, oxadiazole, triazole, and tetrazole, any of which is halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 , -C(O)OR 11 , -NO 2 , -CN, and one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ), 2 , -C(O)R 11 -, C(O)OR 11 , -NO 2 , and -CN, optionally substituted with one or more substituents independently selected from C 1~6 alkyl, optionally substituted with one or more substituents independently selected from, for example, A is pyrazole optionally substituted with one or more halogen, C 1~6 alkyl or C 1~6 haloalkyl, R 1 is hydrogen, halogen, -OR 12 , -N(R 12 ), 2 , -NO 2 , -CN, C 1~6 alkyl, and C 1~6 haloalkyl, selected from, for example, R 1 is C 1~6 alkyl or C 1~6 haloalkyl, R 2 is -N(R A )C(O)(R B ), R A is hydrogen, C 1~6Alkyl, and C 1~6 selected from haloalkyl, for example, R A is hydrogen, R B is halogen, -OR 16 , -N(R 16 ) 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , and CN, and is optionally substituted with one or more substituents independently selected from C 1~6 alkyl, for example, R B is one or more halogens, -OR 16 , or -C(O)OR 16 and is optionally substituted with C 1~6 alkyl,

Chemical formula

Chemical formula

[0109] In certain embodiments, the present disclosure provides a compound or salt represented by the structure of formula (I), wherein A is a saturated C 3~6 carbocyclic ring selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, any of which is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -N(R 11 ) 2 , -CN, C 1~6 alkyl, and C 1~6 haloalkyl, for example, A is cyclopropyl optionally substituted with one or more halogen, C 1~6 alkyl, or C 1~6 haloalkyl, R 1 is hydrogen, halogen, -OR 12 , -N(R 12 ) 2 , -NO 2 , -CN, C 1~6 alkyl, and C1~6 Selected from haloalkyl, for example, R 1 is C 1~6 alkyl or C 1~6 haloalkyl, and R 2 is -N(R A )C(O)(R B ), and R A is selected from hydrogen, C 1~6 alkyl, and C 1~6 haloalkyl, for example, R A is hydrogen, and R B is one or more substituents independently selected from halogen, -OR 16 , -N(R 16 ), 2 , -C(O)R 16 , -C(O)OR 16 , -N(R 16 )C(O)OR 16 , -NO 2 , and CN, and is optionally substituted with one or more substituents selected from C 1~6 alkyl, for example, R B is one or more halogen, -OR 16 , or -C(O)OR 16 , and is optionally substituted C 1~6 alkyl, and

Chemical formula

Chemical formula

[0110] A chemical substance having a carbon-carbon double bond or a carbon-nitrogen double bond may exist in the Z or E form (or cis or trans form). Further, some chemical substances may exist in various tautomeric forms. Unless otherwise specified, all compounds described herein are intended to include all Z-, E-, and tautomeric forms alike.

[0111] "Isomers" are different compounds having the same molecular formula. "Stereoisomers" are isomers that differ only in terms of the arrangement of atoms in space. "Enantiomers" are a pair of stereoisomers that are mirror images that cannot be superimposed on each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used, where appropriate, to designate a racemic mixture. "Diastereomeric isomers" or "diastereomers" are stereoisomers that have at least two chiral atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be designated by either R or S. A resolved compound of unknown absolute configuration can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) in which it rotates plane-polarized light at the wavelength of the sodium D line. The specific compounds described herein contain one or more chiral centers and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms, and the chiral centers can be defined as (R)- or (S)- with respect to absolute stereochemistry. The optically active (R)- and (S)-isomers can be prepared using a chiral synthon or chiral reagent or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method including, but not limited to, chiral chromatography and polarimetry, and the preponderance of one stereoisomer over the other can be determined.

[0112] When the stereochemistry is not specified in the chemical structure, molecules having the stereocenters described herein include isomers such as enantiomers and diastereomers, mixtures of enantiomers including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent that they can be prepared by routine experimentation by those skilled in the art. In certain embodiments, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by resolution of a racemate or a mixture of diastereomers. Resolution of a racemate or a mixture of diastereomers can be achieved, if possible, by conventional methods such as crystallization in the presence of a resolving agent or chromatography using, for example, a chiral high performance liquid chromatography (HPLC) column. Further, a mixture of two enantiomers enriched in one of the two enantiomers can be purified to obtain a more optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0113] In certain embodiments, the compositions of the present disclosure can include two or more enantiomers or diastereomers of a compound, where a single enantiomer or diastereomer comprises at least about 70 wt%, at least about 80 wt%, at least about 90 wt%, at least about 98 wt%, or at least about 99 wt% or more of the total weight of all stereoisomers. Methods for producing substantially pure enantiomers are well known to those skilled in the art. For example, a single stereoisomer substantially free of its stereoisomers, e.g., an enantiomer, can be obtained by resolution of a racemic mixture using methods such as formation of diastereomers using an optically active resolving agent (Stereochemistry of Carbon Compounds, (1962) by E.L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method including, but not limited to, (1) formation and fractional crystallization or other means of separation of ionic diastereomeric salts with a chiral compound, (2) formation of diastereomeric compounds with a chiral derivatizing reagent, separation of the diastereomers, and conversion to the pure stereoisomer, and (3) direct separation under chiral conditions of substantially pure or enriched stereoisomers. Another approach for separation of enantiomers is to use a Diacel chiral column and elute with an organic mobile phase as performed for a fee by Chiral Technologies (www.chiraltech.com).

[0114] "Tautomers" refer to molecules in which proton transfer is possible from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. Where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria are included below.

Chem.

[0115] The compounds disclosed in this specification, in some embodiments, are in different enriched isotopic forms, e.g., 2 H, 3 H, 11 C, 13 C, and / or 14 C in an enriched form. In certain embodiments, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, and thus extend the duration of action of the drug.

[0116] In certain embodiments, the compounds disclosed herein 1 have some or all of the 2 H atoms replaced by

[0117] Deuterium-substituted compounds are synthesized using a variety of methods as described in Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601 - 21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1 - 2), 9 - 32.

[0118] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A number of deuterium-containing reagents and components are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0119] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes in one or more of the atoms that make up such compounds. For example, the compounds may be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine - 125 ( 125 I) or carbon - 14 ( 14 C), etc. 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, and 125 All isotopic substitutions with F, Cl, Br, and I are contemplated. All isotopic variants of the compounds of the present disclosure are intended to be included within the scope of the present disclosure, whether or not radioactive.

[0120] The present disclosure includes salts of the compounds of formula (I), particularly pharmaceutically acceptable salts. The compounds of the present disclosure can have sufficiently acidic functional groups, sufficiently basic functional groups, or both functional groups, and can react with some inorganic bases and either inorganic or organic acids to form salts. Alternatively, a compound that is essentially charged (e.g., a compound having a quaternary nitrogen) can form a salt with a suitable counterion (e.g., a halide (e.g., bromide, chloride, or fluoride)).

[0121] Synthetic chemical transformations and methodologies useful for synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. 1991, Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, 1994; and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, (1995).

[0122] Pharmaceutical preparation In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of formula (I) and at least one pharmaceutically acceptable excipient.

[0123] The pharmaceutical composition can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries. The formulation can be modified according to the selected route of administration. The pharmaceutical composition containing the compound, salt or conjugate can be produced, for example, by lyophilizing the compound, salt or conjugate and mixing, dissolving, emulsifying, encapsulating or enclosing the conjugate. The pharmaceutical composition can also contain the compound, salt, or conjugate in free base form or in pharmaceutically acceptable salt form.

[0124] Any one of the compounds or salts of formula (I) can be formulated into any suitable pharmaceutical formulation. The pharmaceutical formulations of the present disclosure typically contain an active ingredient (e.g., any one of the compounds or salts of formula (I)) and one or more pharmaceutically acceptable excipients or carriers including, but not limited to, inert solid diluents and fillers, diluents, sterile aqueous solutions and various organic solvents, permeation enhancers, antioxidants, solubilizers, and adjuvants.

[0125] The pharmaceutical composition can also be prepared from any one compound or salt of formula (I), and one or more pharmaceutically acceptable excipients suitable for transdermal, inhalation, sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999).

[0126] Treatment method In certain embodiments, the compound or salt of formula (I), or a salt thereof, can be used to treat or prevent a disease or condition mediated directly or indirectly by IL-17A. Such diseases include inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases, and other diseases described herein. The method generally involves administering to a subject a therapeutically effective amount of a compound or a pharmaceutical composition thereof disclosed herein.

[0127] Increased levels of IL-17A have been associated with several conditions including airway inflammation, rheumatoid arthritis (RA), osteoarthritis, bone erosion, intra-abdominal abscesses and adhesions, inflammatory bowel disease (IBD), allograft rejection, psoriasis, psoriatic arthritis, ankylosing spondylitis, certain types of cancer, angiogenesis, atherosclerosis, and multiple sclerosis (MS). Both IL-17A and IL-17R are upregulated in synovial tissue from patients with RA. IL-17A plays its role in the pathogenesis of RA via both IL-1-β and TNF-α-dependent and -independent pathways. IL-17A stimulates the secretion of other cytokines and chemokines, such as TNF-α, IL-1β, IL-6, IL-8, and Gro-α. IL-17A directly contributes to disease progression in RA. Injection of IL-17A into the mouse knee promotes joint destruction independent of IL-1β activity (Ann Rheum Dis 2000, 59:529-32). Anti-IL-1β antibodies have no effect on IL-17A-induced inflammation and joint damage (J Immunol 2001, 167:1004-1013). In the SCW-induced mouse arthritis model, IL-17A induced inflammatory cell infiltration and proteoglycan depletion in wild-type and IL-1β knockout and TNF-α knockout mice. IL-17A knockout mice are phenotypically normal in the absence of antigen challenge but show a marked reduction in arthritis after immunization with type II collagen (J Immunol 2003, 171:6173-6177). Increased levels of IL-17 A-secreting cells have also been observed in the facet joints of patients suffering from ankylosing spondylitis (see H Appel et al., Arthritis Res Therap 2011, 13:R95).

[0128] In certain aspects, the disclosure provides a method of modulating IL-17A in a subject in need thereof, the method comprising administering to the subject a compound or salt of formula (I). In certain embodiments, the compound or salt of formula (I) inhibits the activity of IL-17A in a subject in need thereof.

[0129] In certain embodiments, the compound or salt of formula (I) is used to treat or prevent an inflammatory disease or condition. In certain embodiments, the compound or salt of formula (I) is administered to a subject in need thereof to treat an inflammatory disease or condition, such as psoriasis.

[0130] In certain embodiments, the compound or salt of formula (I) is used to treat or prevent an inflammatory disease or condition selected from plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis. In certain embodiments, the compound or salt of formula (I) is used to treat or prevent psoriasis.

Examples

[0131] Although the invention has been generally described, it will be more readily understood by reference to the following examples. These examples are included for the purpose of illustration of specific aspects and embodiments of the invention only and are not intended to limit the invention.

[0132] The following synthetic schemes are provided for purposes of illustration and not limitation. The following examples illustrate various methods for making the compounds described herein. It will be understood by those skilled in the art that these compounds can be made by similar methods or by combining other methods known to those skilled in the art. It will also be understood by those skilled in the art that appropriate starting materials can be used and the synthetic routes can be modified as necessary to make the compounds in a manner similar to that described below. Generally, starting materials and reagents can be obtained from commercial suppliers or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0133] Examples 1-8 illustrate the general procedures for the preparation of the claimed IL-17A modulators. Examples 9-10 exemplify the bioassay procedures for IL-17A / A and IL-17A / F inhibition. Example 11 exemplifies the comparative data of selected claimed IL-17A modulators against reference compounds.

[0134] Table 1 shows the spectroscopic data, bioassay inhibition, and synthetic procedures for the claimed IL-17A modulators. Table 2 shows selected claimed IL-17A modulators and selected comparative compounds. Table 2.6 shows the microsomal stability data for selected claimed IL-17A modulators and selected comparative compounds. Table 2.6 shows the rat pharmacokinetic data for selected claimed IL-17A modulators and selected comparative compounds.

[0135] Example 1 - Synthesis of Intermediates A and B

Chemical formula

[0136] Step 1: To a solution of (methoxymethyl)triphenylphosphonium chloride (140.04 g, 408.52 mmol, 1.5 eq) in THF (1000 mL) was added dropwise n-BuLi (2.5 M, 163.41 mL, 1.5 eq) at 5 °C under N 2 2. After the addition, the mixture was stirred at 5 °C for 1 hour, then dicyclopropylmethanone (30 g, 272.35 mmol, 30.71 mL, 1 eq) was added dropwise. The resulting mixture was stirred at 60 °C for 12 hours. H 2 2O (200 mL) was added to the reaction, and the mixture was extracted with ethyl acetate (500 mL × 2). The combined organic layers were dried over Na 2 2SO 4 4, filtered, and concentrated. The residue was purified by column chromatography (SiO 2 2, petroleum ether / ethyl acetate = 100 / 1 - 50 / 1). Compound 1 (30 g, 217.07 mmol, 79.70% yield) was obtained as a yellow oil. 11H NMR: (400 MHz, CDCl 3 ) δ 5.87 (s, 1H), 3.58 (s, 3H), 1.84 - 1.78 (m, 1H), 0.85 - 0.73 (m, 1H), 0.73 - 0.72 (m, 2H), 0.61 - 0.57 (m, 2H), 0.47 - 0.45 (m, 2H), 0.25 - 0.23 (m, 2H).

[0137] Step 2: To a solution of Compound 1 (30 g, 217.07 mmol, 1 equiv) in dioxane (500 mL) and H 2 2O (50 mL) was added TsOH (149.52 g, 868.27 mmol, 4 equiv). The mixture was stirred at 110 °C for 3 h. To the reaction was added saturated NaHCO 3 3 (1000 mL), and the mixture was extracted with ethyl acetate (1000 mL × 2). The combined organic layers were dried over Na 2 2SO 4 4, filtered, and concentrated. The crude product was distilled in vacuo (120 °C, pressure 0.1 Mpa). Compound 2 (21 g, 169.11 mmol, yield 77.91%) was obtained as a colorless oil. 1 1H NMR: (400 MHz, CDCl 3 ) δ 9.76 - 9.72 (m, 1H), 1.04 - 0.96 (m, 1H), 0.87 - 0.85 (m, 2H), 0.58 - 0.53 (m, 4H), 0.26 - 0.24 (m, 4H).

[0138] Step 3: To a mixture of Compound 2 (7 g, 56.37 mmol, 1 equiv) in MeOH (35 mL) and H 2 2O (35 mL) were added KCN (5.51 g, 84.55 mmol, 3.62 mL, 1.5 equiv) and (NH 4 ) 2 2CO 3 3 (16.25 g, 169.11 mmol, 18.05 mL, 3 equiv). The mixture was stirred at 60 °C for 12 h. To the reaction was added saturated NaHCO 3 3 (200 mL), and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic layers were dried over Na 2 2SO 4 4, filtered, and concentrated. The residue was purified by column chromatography (SiO2 , petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound 3 (6 g, 30.89 mmol, yield 54.80%, purity 100%) was obtained as a white solid. LC-MS: rt = 0.87 min; [M+H] + In the case of, m / z: 195.1. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.52 (s, 1H), 6.51 (s, 1H), 4.26 (s, 1H), 0.87 - 0.79 (m, 3H), 0.75 - 0.72 (m, 1H), 0.52 - 0.50 (m, 2H), 0.50 - 0.49 (m, 2H), 0.24 - 0.21 (m, 3H).

[0139] Step 4: H 2 To a mixture of compound 3 (10 g, 51.49 mmol, purity 100%, 1 equivalent) in H 2 O (200 mL), NaOH (5 M, 102.97 mL, 10 equivalents) was added. The mixture was stirred at 100 °C for 12 h. Then the mixture was cooled to 20 °C, and then the pH of the mixture was adjusted to 7 - 8 with 5 M HCl (1 mL). Boc 2 O (16.85 g, 77.23 mmol, 17.74 mL, 1.5 equivalents) and THF (100 mL) were slowly added dropwise to the above mixture. The mixture was stirred at 25 °C for 4 h. H 2 O (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over Na 4 SO 2 , filtered, and concentrated. The residue was purified by column chromatography (SiO + , petroleum ether / ethyl acetate = 10 / 1 to 1 / 1). Compound 4 (11 g, 38.02 mmol, yield 73.85%, purity 93.1%) was obtained as a yellow oil. LC-MS: rt = 0.93 min; [M+Na] 1 H NMR: (400 MHz, CDCl 3 ) δ 10.03 (s, 1H), 6.04 - 5.27 (m, 1H), 4.56 - 4.37 (m, 1H), 1.45 (s, 9H), 0.78 - 0.52 (m, 3H), 0.27 - 0.25 (m, 4H), 0.23 - 0.20 (m, 4H).

[0140] Step 5: A mixture of Compound 4 (2.0 g, 6.92 mmol, purity 93.1%, 1 equiv) in DCM (50 mL), 4-methoxybenzyl alcohol (1.15 g, 8.30 mmol, 1.03 mL, 1.2 equiv), DCC (2.14 g, 10.38 mmol, 2.10 mL, 1.5 equiv), and DMAP (845.49 mg, 6.92 mmol, 1 equiv) was stirred at 20 °C for 16 h. To the reaction mixture was added H 2 O (100 mL), and the mixture was extracted with DCM (100 mL × 2). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 (250×70 mm, 10 um); mobile phase: [water (0.1% TFA)-ACN]; B%: 58% - 86%, 21 min). Compound 5 (2 g, 5.07 mmol, yield 73.31%, purity 98.8%) was obtained as a white solid. LC-MS: rt = 1.10 min; [M+Na] + +, m / z = 412.2. 1 H NMR: (400 MHz, CDCl 3 3) δ 7.30 - 7.27 (m, 2H), 6.90 - 6.87 (m, 2H), 5.26 (d, J = 9.2 Hz, 1H), 5.09 (s, 2H), 4.55 - 4.36 (m, 1H), 3.82 (s, 3H), 1.45 (s, 9H), 0.73 - 0.63 (m, 3H), 0.48 - 0.47 (m, 3H), 0.19 - 0.18 (m, 1H), 0.17 - 0.15 (m, 3H), 0.14 - 0.01 (m, 1H).

[0141] Step 6: The residue of Compound 5 was purified by Prep-SFC (column: DAICEL CHIRALPAK AY-H (250 mm×30 mm, 10 um); mobile phase: [0.1% NH 3 H 2 3 ETOH]; B%: 70% - 70%, 10.5; 160 min). Compound 6 (0.9 g, 2.30 mmol, yield 45.36%, purity 99.6%) was obtained as a yellow oil. LC-MS: rt = 1.09 min; [M+Na] +In the case of, m / z = 412.2. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.30 - 7.27 (m, 2H), 6.90 - 6.87 (m, 2H), 5.26 (d, J = 8.8 Hz, 1H), 5.09 (s, 2H), 4.55 - 4.36 (m, 1H), 3.81 (s, 3H), 1.45 (s, 9H), 0.73 - 0.63 (m, 3H), 0.48 - 0.47 (m, 3H), 0.19 - 0.18 (m, 1H), 0.17 - 0.15 (m, 3H), 0.14 - 0.01 (m, 1H). Compound 7 (0.9 g, 2.30 mmol, yield 45.36%, purity 99.7%) was obtained as a yellow oil. LC-MS: rt = 1.09 min; [M+Na] + In the case of, m / z = 412.2. 1 H NMR: (400 MHz, CDCl 3 ) δ 7.30 - 7.27 (m, 2H), 6.90 - 6.87 (m, 2H), 5.26 (d, J = 9.2 Hz, 1H), 5.09 (s, 2H), 4.55 - 4.36 (m, 1H), 3.82 (s, 3H), 1.45 (s, 9H), 0.73 - 0.63 (m, 3H), 0.48 - 0.47 (m, 3H), 0.19 - 0.18 (m, 1H), 0.17 - 0.15 (m, 3H), 0.14 - 0.01 (m, 1H).

[0142] Step 7a: To a solution of compound 6 (250 mg, 641 μmol, 1.00 equivalent) in DCM (2.00 mL), Pd / C (100 mg, purity 10.0%) was added under N 2 atmosphere. The suspension was degassed under vacuum and purged several times with H 2 . The reaction was stirred at 25 °C for 24 h under H 2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated under vacuum. Intermediate A (0.170 g, 631 μmol, yield 98.3%) was obtained as a colorless oil. LC-MS: rt = 0.85 min; [M+Na] + In the case of, m / z = 292.2.

[0143] The following absolute stereochemistry was confirmed by X-ray crystallographic analysis of Intermediate A.

Chemical Structure

[0144] Step 7b: To a solution of compound 7 (250 mg, 641 μmol, 1.00 equiv) in DCM (2.00 mL) was added Pd / C (100 mg, purity 10.0%) under N 2 atmosphere. The suspension was degassed under vacuum and purged several times with H 2 . The reaction was stirred at 25 °C for 24 h under H 2 (15 Psi). The reaction mixture was filtered and the filtrate was concentrated. Intermediate B (0.170 g, 631 μmol, 98.3% yield) was obtained as a colorless oil and used without further characterization.

[0145] Example 2. General Scheme - Synthesis of Intermediate C [Chemical formula]

[0146] Step 1: To a solution of compound 8 (25.0 g, 73.0 mmol, 1.00 equiv) in DCM (200 mL) was added HCl / dioxane (4 M, 182 mL, 10.0 equiv) at 0 °C. The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated to give the product. Compound 9 (17.0 g, 61.0 mmol, 83.5% yield, HCl) was obtained as a yellow solid. LC-MS: rt = 0.16 min; [M+H] + in the case of, m / z: 243.2. The synthetic procedure of compound 8 can be found in US Patent Application No. 17 / 118,947 and US Patent Application No. 16 / 783,268.

[0147] Step 2: To a solution of compound 9 (17.0 g, 61.0 mmol, 1.00 equiv, HCl) in dioxane (170 mL) was added H 2 O (170 mL) containing Na 2 CO 3(19.4 g, 183 mmol, 3.00 equivalents) and a solution of Cbz-OSu (30.4 g, 122 mmol, 2.00 equivalents) were added at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding 100 mL of 1 M aqueous HCl at 0 °C to pH = 4 and extracted with 400 mL of ethyl acetate (200 mL×2). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue. Compound 10 (22.0 g, 58.4 mmol, 95.8% yield) was obtained as a yellow oil. LC-MS: rt = 0.84 min; [M+H] + in the case of, m / z: 375.1.

[0148] Step 3: To a solution of Compound 10 (22.0 g, 58.4 mmol, 1.00 equivalent) in MeOH (22.0 mL) and DCM (220 mL), TMSCHN 2 (2 M, 43.8 mL, 1.50 equivalents) was added at 0 °C and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding 50.0 mL of 10% AcOH at 0 °C and then diluted with 200 mL of H 2 O and extracted with 400 mL of DCM (200 mL×2). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100:1 to 10:1), and Compound 11 (21.0 g, 53.8 mmol, 92.0% yield) was obtained as a yellow oil. LC-MS: rt = 0.92 min; [M+Na] + in the case of, m / z = 413.1.

[0149] Step 4: To a solution of Compound 11 (21.0 g, 53.8 mmol, 1.00 equivalent) in EtOH (300 mL), NH 2 in H 4 (100 mL)A solution of Cl (14.3 g, 268 mmol, 5.00 equiv) and Fe (15.0 g, 268 mmol, 5.00 equiv) was added. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to remove EtOH, then diluted with H 2 O (100 mL) and extracted with DCM (200 mL × 2). The combined organic layers were washed with brine (200 mL × 2) and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. Compound 12 (19.0 g, 52.7 mmol, 98.0% yield) was obtained as a white solid. LC-MS: rt = 0.96 min; [M+H] + , m / z: 361.3 for this case.

[0150] Step 5: To a solution of Compound 12 (2.50 g, 6.94 mmol, 1.00 equiv) and Intermediate A (2.39 g, 8.88 mmol, 1.28 equiv) in pyridine (20.0 mL) was added EDCI (3.99 g, 20.8 mmol, 3.00 equiv). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (50.0 mL) and extracted with DCM (50.0 mL × 3). The combined organic layers were washed with Na 2 SO 4 (50.0 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The crude product was triturated with MTBE (50.0 mL) at 25 °C for 2 hours. The residue was purified by Prep-HPLC (basic conditions, column: Waters Xbridge 150×25mm×5um; mobile phase: [water (0.05% ammonia hydroxide v / v) - ACN]; B%: 53% - 83%, 10 min). Compound 13 (4.20 g, 6.87 mmol, 98.9% yield) was obtained as a white solid. LC-MS: rt = 1.14 min; [M+H] + , m / z: 512.4 for this case.

[0151] Step 6: To a solution of Compound 13 (3.00 g, 4.90 mmol, 1.00 eq) in DCM (20.0 mL) was added HCl / dioxane (4 M, 12.2 mL, 10.0 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. Compound 14 (2.60 g, 4.74 mmol, yield 96.7%, HCl) was obtained as a white solid. LC-MS: rt = 1.09 min; [M+H] + In the case of, m / z: 512.4.

[0152] Step 7: To a solution of Compound 14 (2.10 g, 3.83 mmol, 1.00 eq, HCl) and 1-ethyl-1H-pyrazole-5-carboxylic acid (「A-COOH」

Chemical formula

[0153] Step 8: To a solution of Compound 15 (2.00 g, 3.16 mmol, 1.00 eq) in MeOH (10.0 mL) and THF (10.0 mL) was added a solution of NaOH (378 mg, 9.47 mmol, 3.00 eq) in H 2 O (2.00 mL) at 0 °C. The mixture was stirred at 30 °C for 2 h. The reaction mixture was H 2It was diluted with O (30.0 mL), 1 M HCl was added to adjust the pH to 2. The mixture was extracted with DCM (50.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. Compound 16 (1.90 g, 3.07 mmol, yield 97.1%) was obtained as a white solid. LC-MS: rt = 0.96 min; [M+H] + In the case of, m / z: 620.3.

[0154] Step 9: To a solution of compound 16 (80.0 mg, 129 μmol, 1.00 equiv), (2S,6R)-126-trimethylpiperazine ("H-B") (24.8 mg, 193 μmol, 1.50 equiv), and DIEA (83.4 mg, 645.4 μmol, 112.3 μL, 5.00 equiv) in DCM (5.00 mL) was added T3P (246 mg, 387 μmol, 230 μL, purity 50%, 3.00 equiv) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by SFC (EW27685-21-P1A_c10) (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [0.1% NH 3 H 2 O IPA]; B%: 35% - 35%, 3; 40 min, Rt = 1.929). Compound 17 (50.0 mg, 68.5 μmol, yield 53.0%) was obtained as a white solid. LC-MS: rt = 1.06 min; [M+H] + In the case of, m / z: 730.6.

[0155] Step 10: To a solution of compound 17 (50.0 mg, 68.5 μmol, 1.00 equiv) in DCM (5.00 mL) was added Pd / C (5.00 mg, purity 10.0%) under N 2 atmosphere. The suspension was, H2 It was degassed and purged three times with. The mixture was H 2 Under, it was stirred at 25 °C for 2 hours. The reaction mixture was filtered, the cake was washed with 100 mL of MeOH, and then concentrated under reduced pressure to obtain a residue. Intermediate C (40.0 mg, 67.1 μmol, yield 98.0%) was obtained as a white solid. LC-MS: rt = 0.91 min; [M+H] + In the case of, m / z: 596.5.

[0156] As described in Example 2,

Chemical formula

Chemical formula

Chemical formula

[0157] As described in Example 2, H-B is

Chemical formula

Chemical formula

Chemical formula

[0158] Example 3. Exemplary Scheme - Synthesis of Selected Compounds [Chemical formula]

[0159] Example 3.1.1 - Synthesis of Compound 223 [Chemical formula]

[0160] To intermediate C (40.0 mg, 67.0 μmol, 1.00 equivalent) and TEA (20.3 mg, 201 μmol, 28.0 μL, 3.00 equivalents) in DCM (5.00 mL), propionic anhydride (17.4 mg, 134 μmol, 17.3 μL, 2.00 equivalents) was added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 223 (35.2 mg, 51.4 μmol, yield 76.6%, purity 95.3%) was obtained as a white solid. LC-MS: rt = 0.95 min; [M+H] + In the case of, m / z: 652.6.

[0161] Compounds 202, 203, 204, 205, 208, 209, 212, 213, 214, 216, 217, 231, 232, 235, 236, 237, 238, 239, 240, 241, 242, 245, 250, 251, 252, 253, 257, 258, 264, 265, 266, 267, 268, 288, and 304 were similarly synthesized using appropriate anhydride reagents under similar reaction conditions.

[0162] Example 3.1.2 - Synthesis of Compound 204 To a solution of the appropriately substituted Intermediate C (50.0 mg, 87.7 μmol, 1.00 eq) and TEA (26.6 mg, 263 μmol, 36.6 μL, 3.00 eq) in DCM (3.00 mL) was added propionic anhydride (13.7 mg, 105 μmol, 13.5 μL, 1.20 eq) at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 204 (34.6 mg, 53.5 μmol, yield 60.9%, purity 96.7%) was obtained as a white solid. LC-MS: rt = 0.84 min; [M+H] + In the case of, m / z: 626.2.

[0163] Example 3.1.3 - Synthesis of Compound 205 To a solution of the appropriately substituted Intermediate C (40.0 mg, 66.9 μmol, 1.00 eq) and TEA (20.3 mg, 200 μmol, 27.9 μL, 3.00 eq) in DCM (5.00 mL) was added propionic anhydride (13.0 mg, 100 μmol, 12.9 μL, 1.50 eq) at 25 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 205 (41.8 mg, 63.3 μmol, yield 94.6%, purity 99.1%) was obtained as a white solid. LC-MS: rt = 0.84 min; [M+H] + In the case of, m / z: 654.3.

[0164] Example 3.1.4 - Synthesis of Compound 208 To a solution of the appropriately substituted Intermediate C (30.0 mg, 51.5 μmol, 1.00 eq) and TEA (26.0 mg, 257 μmol, 35.8 μL, 5.00 eq) in DCM (2.0 mL) was added propionic anhydride (10.0 mg, 77.3 μmol, 9.97 μL, 1.50 eq) at 0 °C. Then, the mixture was stirred at 25 °C for 2 h. The reaction mixture was H 2Dilute with O (20.0 mL), extract with DCM (20.0 mL × 3), and dry the combined organic phases over anhydrous Na 2 SO 4 and filter. Concentrate under reduced pressure to obtain a residue. Purify the residue by Prep-TLC (SiO 2 , DCM:EtOAc = 10:1). Compound 208 (34.0 mg, 50.0 μmol, yield 93.8%, purity 99.6%) was obtained as a white solid. LC-MS: rt = 0.73 min; [M+H] + In the case of, m / z: 638.4.

[0165] Example 3.1.5 - Synthesis of Compound 209 To a solution of appropriately substituted intermediate C (50.0 mg, 85.9 μmol, 1.00 equiv) and TEA (26 mg, 257 μmol, 35.8 μL, 3.00 equiv) in DCM (5.00 mL), add propionic anhydride (22.3 mg, 171 μmol, 22.1 μL, 2.00 equiv) at 0 °C. Stir the mixture at 25 °C for 2 h. Dilute the reaction mixture with H 2 O (30.0 mL) and extract with DCM (30.0 mL × 3). Dry the combined organic layers over Na 2 SO 4 filter, and concentrate under reduced pressure to obtain a residue. Purify the residue by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Purify the residue by Prep-HPLC (column: Phenomenex Gemini-NX C18 75 × 30 mm × 3 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 23% - 53%, 7 min). Compound 209 (20.6 mg, 31.6 μmol, yield 36.8%, purity 97.9%) was obtained as a white solid. LC-MS: rt = 0.95 min; [M+H] + In the case of, m / z: 638.6.

[0166] Example 3.1.16 - Synthesis of Compound 212 To a solution of appropriately substituted Intermediate C (40.0 mg, 67.0 μmol, 1.00 eq) and TEA (20.3 mg, 201 μmol, 28.0 μL, 3.00 eq) in DCM (5.00 mL), propionic anhydride (11.3 mg, 87.2 μmol, 11.2 μL, 1.30 eq) was added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, then concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 212 (21.8 mg, 32.8 μmol, yield 48.9%, purity 98.1%) was obtained as a white solid. LC-MS: rt = 0.81 min; [M+H] + in the case of, m / z: 652.2.

[0167] Example 3.1.17 - Synthesis of Compound 213 To a solution of appropriately substituted Intermediate C (35.0 mg, 60.2 μmol, 1.00 eq) and TEA (18.3 mg, 181 μmol, 25.1 μL, 3.00 eq) in DCM (2.00 mL), propionic anhydride (8.61 mg, 66.2 μmol, 8.52 μL, 1.10 eq) was added at 0 °C. The mixture was stirred at 15 °C for 1 h. The reaction mixture was diluted with H 2 O (10.0 mL) and extracted with DCM (10.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, then concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 213 (28.0 mg, 41.8 μmol, yield 69.4%, purity 95.1%) was obtained as a white solid. LC-MS: rt = 0.84 min; [M+H] + in the case of, m / z: 638.4.

[0168] Example 3.1.8 - Synthesis of Compound 214 To a solution of appropriately substituted Intermediate C (120 mg, 205 μmol, 1.00 equiv) and TEA (62.4 mg, 616 μmol, 85.8 μL, 3.00 equiv) in DCM (5.00 mL) was added acetic anhydride (41.9 mg, 411 μmol, 38.5 μL, 2.00 equiv) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 214 (37.1 mg, 57.7 μmol, yield 28.1%, purity 97.4%) was obtained as a white solid. LC-MS: rt = 0.88 min; [M+H] + in the case of, m / z: 626.1.

[0169] Example 3.1.9 - Synthesis of Compound 216 To a solution of appropriately substituted Intermediate C (50.0 mg, 85.3 μmol, 1.00 equiv) and TEA (25.9 mg, 256 μmol, 35.6 μL, 3.00 equiv) in DCM (5.0 mL) was added propionic anhydride (14.4 mg, 111 μmol, 14.3 μL, 1.30 equiv) at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 216 (54.0 mg, 80.6 μmol, yield 94.5%, purity 95.8%) was obtained as a white solid. LC-MS: rt = 0.73 min; [M+H] + in the case of, m / z: 642.5.

[0170] Example 3.1.10 - Synthesis of Compound 217 To a solution of appropriately substituted Intermediate C (65.0 mg, 108 μmol, 1.00 equiv) and TEA (32.9 mg, 325 μmol, 45.2 μL, 3.00 equiv) in DCM (5.0 mL), propionic anhydride (21.1 mg, 162 μmol, 20.9 μL, 1.50 equiv) was added at 25 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H 2 O (40.0 mL) and extracted with DCM (40.0 mL × 3). The combined organic layers were washed with brine (40.0 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 217 (69.6 mg, 103 μmol, yield 95.4%, purity 97.5%) was obtained as a white solid. LC-MS: rt = 0.73 min; [M+H] + for, m / z: 656.5.

[0171] Example 3.1.11 - Synthesis of Compound 232 To a solution of appropriately substituted Intermediate C (60.0 mg, 99.3 μmol, 1.00 equiv) and TEA (30.1 mg, 298 μmol, 41.5 μL, 3.00 equiv) in DCM (5.0 mL), propionic anhydride (15.5 mg, 119 μmol, 15.3 μL, 1.20 equiv) was added. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H 2 O (40.0 mL) and extracted with DCM (40.0 mL × 3). The combined organic layers were washed with brine (40.0 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 232 (49.4 mg, 72.5 μmol, yield 73.0%, purity 96.8%) was obtained as a white solid. LC-MS: rt = 0.81 min; [M+H] + for, m / z: 674.2.

[0172] Example 3.1.12 - Synthesis of Compound 239 To a solution of appropriately substituted Intermediate C (89.0 mg, 149 μmol, 1.00 equiv) and TEA (45.5 mg, 449 μmol, 62.5 μL, 3.00 equiv) in DCM (5.0 mL), propionic anhydride (39.0 mg, 299 μmol, 38.6 μL, 2.00 equiv) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 239 (43.5 mg, 66.4 μmol, yield 44.2%, purity 99.0%) was obtained as a white solid. LC-MS: rt = 0.84 min; [M+H] + for, m / z: 650.3.

[0173] Example 3.1.13 - Synthesis of Compound 245 To a solution of appropriately substituted Intermediate C (80.0 mg, 146 μmol, 1.00 equiv) and TEA (14.8 mg, 146 μmol, 20.4 μL, 1.00 equiv) in DCM (5.00 mL), propionic anhydride (28.6 mg, 219 μmol, 28.3 μL, 1.50 equiv) was added at 15 °C. The mixture was stirred at 15 °C for 12 h. The reaction mixture was diluted with H 2 O (10.0 mL) and extracted with DCM (20.0 mL × 2). The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 245 (49.3 mg, 76.6 μmol, yield 52.2%, purity 93.5%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + for, m / z: 602.4.

[0174] Example 3.1.14 - Synthesis of Compound 250 To a solution of appropriately substituted Intermediate C (50.0 mg, 87.7 μmol, 1.00 eq) and TEA (26.6 mg, 263 μmol, 36.6 μL, 3.00 eq) in DCM (3.00 mL), propionic anhydride (13.7 mg, 105 μmol, 13.5 μL, 1.20 eq) was added at 0 °C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 250 (34.6 mg, 53.5 μmol, yield 60.9%, purity 96.7%) was obtained as a white solid. LC-MS: rt = 0.84 min; [M+H] + , m / z: 626.2 in the case of

[0175] Example 3.1.15 - Synthesis of Compound 257 To a solution of appropriately substituted Intermediate C (100.0 mg, 172 μmol, 1.00 eq) and TEA (34.7 mg, 343 μmol, 47.8 μL, 2.00 eq) in DCM (1.0 mL), propionic anhydride (33.5 mg, 257 μmol, 33.2 μL, 1.50 eq) was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL×3), the combined organic layers were washed with brine (5.0 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , EtOAc:MeOH = 10:1). Compound 257 (38.4 mg, 58.7 μmol, yield 34.1%, purity 97.6%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + , m / z: 638.4 in the case of

[0176] Example 3.1.16 - Synthesis of Compound 258 To a solution of appropriately substituted Intermediate C (100.0 mg, 168 μmol, 1.00 equiv) and TEA (33.9 mg, 335 μmol, 46.7 μL, 2.00 equiv) in DCM (1.0 mL), propionic anhydride (32.7 mg, 252 μmol, 32.4 μL, 1.50 equiv) was added at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL × 3), the combined organic layers were washed with brine (5.0 mL), dried over Na 2 SO 4 and filtered, concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC [column: Phenomenex Synergi C18 150×25 mm×10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 13% - 43%, 10 min], to afford the desired product. Compound 258 (60.2 mg, 91.5 μmol, yield 54.5%, purity 99.1%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + for, m / z: 652.5.

[0177] Example 3.1.17 - Synthesis of Compound 264 To a solution of appropriately substituted Intermediate C (100.0 mg, 164 μmol, 1.00 equiv) and TEA (33.3 mg, 329 μmol, 45.8 μL, 2.00 equiv) in DCM (1.0 mL), propionic anhydride (32.1 mg, 247 μmol, 31.8 μL, 1.50 equiv) was added at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL × 3), the combined organic layers were washed with brine (5.0 mL), dried over Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC [Column: Phenomenex Synergi C18 150×25mm×10um; Mobile phase: [Water (0.225% FA)-ACN]; B%: 14%~44%, 10 min], and the desired product was obtained. Compound 264 (75.1 mg, 111 umol, yield 67.7%, purity 98.5%) was obtained as a white solid. LC-MS: rt = 0.75 min; [M+H] + In the case of, m / z: 664.4.

[0178] Example 3.1.18 - Synthesis of Compound 265 To a solution of the appropriately substituted intermediate C (100.0 mg, 168 umol, 1.00 equiv) and TEA (33.9 mg, 336 umol, 46.7 uL, 2.00 equiv) in DCM (1.0 mL) was added propionic anhydride (32.7 mg, 252 umol, 32.4 uL, 1.50 equiv). The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL×3), the combined organic layers were washed with brine (5.0 mL), and dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , EtOAc:MeOH = 10:1). Compound 265 (32.0 mg, 47.6 umol, yield 28.3%, purity 97.0%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + In the case of, m / z: 652.5.

[0179] Example 3.1.19 - Synthesis of Compound 288 To a solution of the appropriately substituted intermediate C (130.0 mg, 232 umol, 1.00 equiv) and TEA (47.0 mg, 464 umol, 64.6 uL, 2.00 equiv) in DCM (2.0 mL) was added propionic anhydride (45.3 mg, 348 umol, 44.8 uL, 1.50 equiv) at 20 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCO 3Washed with (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL × 3), the combined organic layers were washed with brine (5.0 mL), and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , plate 1, EtOAc:MeOH = 5:1, Rf f = 0.5). The residue was purified by Prep-HPLC [column: Phenomenex Synergi C18 150 × 25 mm × 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 13% - 43%, 10 min], and the desired product was obtained. Compound 288 (57.4 mg, 92.6 umol, yield 39.8%, purity 99.3%) was obtained as a white solid. LC-MS: rt = 0.73 min; m / z: 616.4 [M+H] + .

[0180] Example 3.2.1 - Synthesis of Compound 224

Chemical Structure

[0181] To intermediate C (80.0 mg, 140 umol, 1.00 equivalent) and N-cyclopropyl-N-methylcarbamoyl chloride (37.5 mg, 280 umol, 2.00 equivalents) in DCM (3.00 mL), DMAP (85.7 mg, 702 umol, 5.00 equivalents) was added. The mixture was stirred at 25 °C for 8 h. The reaction mixture was diluted with H 2 O (40.0 mL) and extracted with DCM (40.0 mL × 3). The combined organic layers were washed with brine (40.0 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , ethyl acetate:methanol = 5:1). Compound 224 (37.0 mg, 54.1 umol, yield 38.5%, purity 97.5%) was obtained as a white solid. LC-MS: rt = 0.79 min; for [M+H] + , m / z: 667.4.

[0182] Compounds 225, 270, 271, 291, 295, 313, and 316 were similarly synthesized using appropriate carbamoyl chloride reagents under similar reaction conditions.

[0183] Example 3.2.2 - Synthesis of Compound 225 To a solution of the appropriately substituted intermediate C (200 mg, 352 μmol, 1.00 equivalent) and N-cyclopropyl-N-methylcarbamoyl chloride (470 mg, 3520 μmol, 10.00 equivalents) in DCM (5.00 mL) was added DMAP (150 mg, 1230 μmol, 3.50 equivalents). The mixture was stirred at 20 °C for 52 h. The reaction mixture was diluted with H 2 O (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (40.0 mL) and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:methanol = 10:1). Compound 225 (120 mg, 177 μmol, 50.4% yield, 98.3% purity) was obtained as a white solid. LC-MS: rt = 0.90 min; for [M+H] + , m / z: 665.1.

[0184] Example 3.3.1 - Synthesis of Compound 206

Chemical Structure

[0185] To a solution of intermediate C (50.0 mg, 87.7 μmol, 1.00 equiv) and methoxyacetic acid (10.2 mg, 114 μmol, 8.71 μL, 1.30 equiv) in pyridine (3.00 mL) was added EDCI (50.4 mg, 263 μmol, 3.00 equiv). The mixture was stirred at 25 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 35% - 62%, 9 min). Compound 206 (30.8 mg, 46.9 μmol, yield 53.5%, purity 97.6%) was obtained as a white solid. LC-MS: rt = 0.83 min; [M+H] + In the case of, m / z: 642.2.

[0186] Compounds 207, 210, 211, 215, 218, 219, 220, 221, 222, 226, 227, 228, 254, 255, 256, 259, 260, 261, 262, 263, 269, 272 - 287, 289, 290, 292 - 294, 298 - 303, 307 - 312, 314, 315, 317 - 342, 345 - 349, 361, 362, 343, and 344 were synthesized similarly using appropriate carboxylic acid reagents under similar reaction conditions.

[0187] Example 3.3.2 - Synthesis of Compound 207 To a solution of appropriately substituted intermediate C (50.0 mg, 85.9 μmol, 1.00 equiv) and methoxyacetic acid (11.6 mg, 128 μmol, 9.84 μL, 1.50 equiv) in pyridine (5.00 mL) was added EDCI (49.4 mg, 257 μmol, 3.00 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL×3). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2, DCM:MeOH = 10:1). Compound 207 (49.3 mg, 71.2 μmol, yield 82.9%, purity 94.4%) was obtained as a white solid. LC-MS: rt = 0.94 min; [M+H] + In the case of, m / z: 654.6.

[0188] Example 3.3.3 - Synthesis of Compound 210 To the appropriately substituted intermediate C (50.0 mg, 85.9 μmol, 1.00 equivalent) and N-(ethoxycarbonyl)-N-methyl-L-alanine (18.0 mg, 103 μmol, 1.20 equivalent) in pyridine (5.0 mL), EDCI (49.4 mg, 257 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Then, the residue was purified by Prep-HPLC (basic conditions, column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 20% - 50%, 7 min). Compound 210 (13.2 mg, 17.0 μmol, yield 19.8%, purity 94.8%) was obtained as a white solid. LC-MS: rt = 0.99 min; [M+H] + In the case of, m / z: 739.6.

[0189] Example 3.3.4 - Synthesis of Compound 211 To the appropriately substituted intermediate C (60.0 mg, 105 μmol, 1.00 equivalent) and N-(ethoxycarbonyl)-N-methyl-L-alanine (24.1 mg, 137 μmol, 1.30 equivalent) in pyridine (2.0 mL), EDCI (40.5 mg, 211 μmol, 2.00 equivalents) was added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with DCM (30.0 mL) and washed with water (20.0 mL × 3) and brine (20.0 mL × 2), Na 2 SO4 It was dried and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 211 (42.0 mg, 57.9 μmol, yield 54.8%, purity 91.7%) was obtained as a white solid. LC-MS: rt = 0.97 min; [M+H] + In the case of, m / z: 725.6.

[0190] Example 3.3.5 - Synthesis of Compound 215 To a solution of the appropriately substituted intermediate C (60.0 mg, 106 μmol, 1.00 equiv) and methoxyacetic acid (14.3 mg, 159 μmol, 12.1 μL, 1.50 equiv) in pyridine (1.00 mL), EDCI (60.8 mg, 318 μmol, 3.00 equiv) was added. The mixture was stirred at 15 °C for 3 h. The reaction mixture was diluted with H 2 O (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 215 (43.7 mg, 67.9 μmol, yield 64.2%, purity 99.4%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + In the case of, m / z: 640.4.

[0191] Example 3.3.6 - Synthesis of Compound 219 To a solution of the appropriately substituted intermediate C (45.0 mg, 77.3 μmol, 1.00 equiv) and the sodium salt of 2-fluoropropanoic acid (10.6 mg, 92.8 μmol, 1.20 equiv) in DMF (5.0 mL), HOBT (20.9 mg, 154 μmol, 2.00 equiv), DIEA (20.0 mg, 154 μmol, 26.9 μL, 2.00 equiv), and EDCI (29.6 mg, 154 μmol, 2.00 equiv) were added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were saturated with NaHCO3 Washed with aqueous solution (30.0 mL×2), and Na 2 SO 4 dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 219 (39.0 mg, 57.2 μmol, yield 74.0%, purity 96.1%) was obtained as a white solid. LC-MS: rt = 0.96 min; [M+H] + in the case of, m / z: 656.5.

[0192] Example 3.3.7 - Synthesis of Compound 220 To a solution of appropriately substituted intermediate C (50.0 mg, 87.7 μmol, 1.00 equivalent) and (S)-2-methoxypropanoic acid (11.8 mg, 114 μmol, 1.30 equivalents) in pyridine (4.0 mL), EDCI (50.4 mg, 263 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 37% - 64%, 9 min). Compound 220 (33.6 mg, 51.1 μmol, yield 58.3%, purity 99.8%) was obtained as a white solid. LC-MS: rt = 0.85 min; [M+H] + in the case of, m / z: 656.3.

[0193] Example 3.3.8 - Synthesis of Compound 221 To a solution of appropriately substituted intermediate C (50.0 mg, 85.9 μmol, 1.00 equivalent) and (S)-2-methoxypropanoic acid (13.4 mg, 128 μmol, 1.50 equivalents) in pyridine (5.00 mL), EDCI (49.4 mg, 257 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL×3). The combined organic layers were washed with Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 221 (37.7 mg, 54.1 μmol, yield 62.9%, purity 95.7%) was obtained as a white solid. LC-MS: rt = 0.94 min; [M+H] + In the case of, m / z: 668.5.

[0194] Example 3.3.9 - Synthesis of Compound 222 To a solution of the appropriately substituted intermediate C (60.0 mg, 106 μmol, 1.00 equivalent) and (S)-2-methoxypropanoic acid (22.0 mg, 211 μmol, 2.00 equivalents) in pyridine (2.00 mL), EDCI (60.8 mg, 317 μmol, 3.00 equivalents) was added. The mixture was stirred at 15 °C for 3 h. The reaction mixture was diluted with H 2 O (15 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 222 (40.4 mg, 60.8 μmol, yield 57.5%, purity 98.4%) was obtained as a white solid. LC-MS: rt = 0.75 min; [M+H] + In the case of, m / z: 654.4.

[0195] Example 3.3.10 - Synthesis of Compound 226 To a solution of the appropriately substituted intermediate C (50.0 mg, 85.9 μmol, 1.00 equivalent) and 2-cyclopropylacetic acid (12.9 mg, 128 μmol, 1.50 equivalents) in pyridine (5.0 mL), EDCI (49.4 mg, 257 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2 、 DCM:MeOH = 10:1). Compound 226 (45.4 mg, 66.8 μmol, yield 77.7%, purity 97.7%) was obtained as a white solid. LC-MS: rt = 0.97 min; [M+H] + In the case of, m / z: 664.6.

[0196] Example 3.3.11 - Synthesis of Compound 227 To a solution of the appropriately substituted Intermediate C (60.0 mg, 85.9 μmol, 1.00 equiv) and 2-cyclopropylacetic acid (13.7 mg, 137 μmol, 1.30 equiv) in pyridine (2.0 mL), EDCI (40.5 mg, 211 μmol, 2.00 equiv) was added. The mixture was stirred at 20 °C for 1 h. The reaction mixture was diluted with DCM (30.0 mL) and washed with water (20.0 mL × 3) and brine (20.0 mL × 2), dried over Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 227 (60.0 mg, 92.3 μmol, yield 87.3%, purity 96.6%) was obtained as a white solid. LC-MS: rt = 0.95 min; [M+H] + In the case of, m / z: 650.6.

[0197] Example 3.3.12 - Synthesis of Compound 228 To a solution of the appropriately substituted Intermediate C (70.0 mg, 120 μmol, 1.00 equiv) and the sodium salt of 2-fluoroacetic acid (19.1 mg, 180 μmol, 1.50 equiv) in DMF (5.0 mL), HOBT (32.5 mg, 240 μmol, 2.00 equiv), DIEA (31.1 mg, 240 μmol, 41.9 μL, 2.00 equiv), and EDCI (46.1 mg, 240 μmol, 2.00 equiv) were added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2) and dried over Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (FA conditions, column: Phenomenex Gemini-NX C18 75×30mm×3um; mobile phase: [water (0.225% FA)-ACN]; B%: 15% - 45%, 7 min). Compound 228 (26.7 mg, 39.3 umol, yield 32.7%, purity 94.4%) was obtained as a white solid. LC-MS: rt = 0.94 min; [M+H] + In the case of, m / z: 642.5.

[0198] Example 3.3.13 - Synthesis of Compound 260 To a solution of appropriately substituted intermediate C (100.0 mg, 168 umol, 1.00 equiv) and (S)-2-methoxypropanoic acid (20.9 mg, 201 umol, 1.20 equiv) in pyridine (1.0 mL), EDCI (64.3 mg, 335 umol, 2.00 equiv) was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with saturated NaHCO 3 aqueous solution (3.0 mL) and H 2 O (3.0 mL), and extracted with DCM (3.0 mL×3). The combined organic layers were dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC [column: Phenomenex Synergi C18 150×25mm×10um; mobile phase: [water (0.225% FA)-ACN]; B%: 14 - 44%, 10 min], and the desired product was obtained. Compound 260 (61.8 mg, 88.9 umol, yield 52.9%, purity 98.2%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + In the case of, m / z: 682.6.

[0199] Example 3.3.14 - Synthesis of Compound 261 A solution of appropriately substituted Intermediate C (100.0 mg, 164 μmol, 1.00 equiv) and (S)-2-methoxypropanoic acid (20.5 mg, 197 μmol, 25.4 μL, 1.20 equiv) in pyridine (1.0 mL) was added with EDCI (63.0 mg, 329 μmol, 2.00 equiv). The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL × 3), the combined organic layers were washed with brine (5.0 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25 mm×10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 14 - 44%, 10 min) to give the desired product. Compound 261 (72.9 mg, 104 μmol, yield 63.5%, purity 99.4%) was obtained as a white solid. LC-MS: rt = 0.75 min; [M+H] + In the case of, m / z: 694.4.

[0200] Example 3.3.15 - Synthesis of Compound 269 A solution of appropriately substituted Intermediate C (70.0 mg, 131 μmol, 1.00 equiv) and (ethoxycarbonyl)-L-proline (42.4 mg, 263 μmol, 2.00 equiv) in pyridine (5.0 mL) was added with EDCI (75.7 mg, 395 μmol, 3.00 equiv). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 269 (34.5 mg, 50.8 μmol, yield 38.6%, purity 99.2%) was obtained as a white solid. LC-MS: rt = 0.83 min; [M+H]+ In the case of, m / z: 675.5.

[0201] Example 3.3.16 - Synthesis of Compound 272 To a solution of the appropriately substituted Intermediate C (50.0 mg, 94.0 μmol, 1.00 equivalent) and (S)-2-methoxypropanoic acid (14.6 mg, 141 μmol, 1.50 equivalents) in pyridine (5.0 mL), EDCI (54.0 mg, 282 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2) and dried over Na 2 SO 4 filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 272 (29.5 mg, 45.5 μmol, yield 48.4%, purity 95.2%) was obtained as a white solid. LC-MS: rt = 0.82 min; [M+H] + In the case of, m / z: 618.2.

[0202] Example 3.3.17 - Synthesis of Compound 273 To a solution of the appropriately substituted Intermediate C (50.0 mg, 91.6 μmol, 1.00 equivalent) and (S)-2-methoxypropanoic acid (14.3 mg, 137 μmol, 1.50 equivalents) in DCM (5.00 mL), EDCI (52.7 mg, 274 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 273 (32.5 mg, 48.8 μmol, yield 53.3%, purity 94.7%) was obtained as a white solid. LC-MS: rt = 0.83 min; [M+H] +In the case of, m / z: 632.2.

[0203] Example 3.3.18 - Synthesis of Compound 274 To a solution of the appropriately substituted Intermediate C (60.0 mg, 112 μmol, 1.00 equivalent) and (S)-1-(ethoxycarbonyl)azetidine-2-carboxylic acid (29.3 mg, 169 μmol, 1.50 equivalents) in pyridine (5.0 mL), EDCI (64.9 mg, 338 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 274 (32.8 mg, 46.7 μmol, yield 41.4%, purity 97.9%) was obtained as a white solid. LC-MS: rt = 0.97 min; [M+H] + In the case of, m / z: 687.5.

[0204] Example 3.3.19 - Synthesis of Compound 275 To a solution of the appropriately substituted Intermediate C (190.0 mg, 348 μmol, 1.00 equivalent) and (S)-1-(ethoxycarbonyl)azetidine-2-carboxylic acid (90.4 mg, 522 mmol, 1.50) in pyridine (5.0 mL), EDCI (200 mg, 1.04 mmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2, DCM:MeOH = 10:1). Compound 275 (85.9 mg, 118 μmol, yield 34.1%, purity 97.0%) was obtained as a white solid. LC-MS: rt = 0.82 min; [M+H] + In the case of, m / z: 701.3.

[0205] Example 3.3.20 - Synthesis of Compound 276 To a solution of the appropriately substituted Intermediate C (70.0 mg, 131 μmol, 1.00 equivalent) and (ethoxycarbonyl)-L-proline (49.2 mg, 263 μmol, 2.00 equivalents) in pyridine (5.0 mL) was added EDCI (75.7 mg, 395 μmol, 3.00 equivalents). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 276 (52.2 mg, 72.2 μmol, yield 54.8%, purity 96.9%) was obtained as a white solid. LC-MS: rt = 0.98 min; [M+H] + In the case of, m / z: 701.5.

[0206] Example 3.3.21 - Synthesis of Compound 278 To a solution of the appropriately substituted Intermediate C (70.0 mg, 128 μmol, 1.00 equivalent) and (S)-1-(methoxycarbonyl)azetidine-2-carboxylic acid (30.6 mg, 192 μmol, 1.50 equivalents) in pyridine (2.0 mL) was added EDCI (49.2 mg, 257 μmol, 2.00 equivalents). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with DCM (20.0 mL) and extracted with saturated NaHCO 3 aqueous solution (10.0 mL) and DCM (10.0 mL × 2), and the organic phase was washed with water (20.0 mL) and brine (20.0 mL), then dried over Na 2 SO 4It was dried and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 278 (55.0 mg, 78.9 μmol, yield 61.5%, purity 98.5%) was obtained as a white solid. LC-MS: rt = 0.73 min; [M+H] + In the case of, m / z: 687.4.

[0207] Example 3.3.22 - Synthesis of Compound 279 To a solution of appropriately substituted intermediate C (70.0 mg, 128 μmol, 1.00 equivalent) and (ethoxycarbonyl)-L-proline (48.0 mg, 256 μmol, 2.00 equivalents) in pyridine (5.0 mL), EDCI (73.7 mg, 384 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 279 (54.1 mg, 72.6 μmol, yield 56.6%, purity 96.0%) was obtained as a white solid. LC-MS: rt = 0.99 min; [M+H] + In the case of, m / z: 715.5.

[0208] Example 3.3.23 - Synthesis of Compound 280 To a solution of appropriately substituted intermediate C (70.0 mg, 132 μmol, 1.00 equivalent) and (methoxycarbonyl)-L-proline (34.2 mg, 198 μmol, 1.50 equivalents) in pyridine (2.0 mL), EDCI (50.5 mg, 263 μmol, 2.00 equivalents) was added. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with saturated NaHCO 3 aqueous solution (10.0 mL), extracted with DCM (10.0 mL × 5), and the combined organic phases were washed with water (10.0 mL) and brine (10.0 mL), then Na2 SO 4 It was dried with SO and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 280 (60.0 mg, 87.4 μmol, yield 66.4%, purity 98.3%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + In the case of, m / z: 687.4.

[0209] Example 3.3.24 - Synthesis of Compound 281 To a solution of the appropriately substituted intermediate C (70.0 mg, 128 μmol, 1.00 equivalent) and (methoxycarbonyl)-L-proline (33.3 mg, 192 μmol, 1.50 equivalents) in pyridine (2.0 mL), EDCI (49.2 mg, 257 μmol, 2.00 equivalents) was added. The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with saturated NaHCO 3 aqueous solution (10.0 mL), extracted with DCM (10.0 mL × 5), and the combined organic phases were washed with water (10.0 mL) and brine (10.0 mL), then dried over Na 2 SO 4 and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 281 (55.0 mg, 77.9 μmol, yield 60.7%, purity 99.3%) was obtained as a white solid. LC-MS: rt = 0.81 min; [M+H] + In the case of, m / z: 701.2.

[0210] Example 3.3.25 - Synthesis of Compound 282 To a solution of the appropriately substituted intermediate C (70.0 mg, 128 μmol, 1.00 equivalent) and (ethoxycarbonyl)-L-alanine (41.3 mg, 256 μmol, 2.00 equivalents) in pyridine (5.0 mL), EDCI (73.7 mg, 384 μmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were saturated with NaHCO 3Wash with aqueous solution (30.0 mL×2), and dry over Na 2 SO 4 , filter, concentrate under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 282 (39.1 mg, 55.6 μmol, yield 43.3%, purity 98.1%) was obtained as a white solid. LC-MS: rt = 0.83 min; [M+H] + In the case of, m / z: 689.5.

[0211] Example 3.3.26 - Synthesis of Compound 286 To a solution of appropriately substituted intermediate C (90.0 mg, 151 μmol, 1.00 equiv) and 2-methoxyacetic acid (20.4 mg, 226 μmol, 1.50 equiv) in pyridine (5.0 mL), EDCI (86.8 mg, 453 μmol, 3.00 equiv) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL), and extracted with ethyl acetate (30.0 mL×3). The combined organic layers were washed with saturated aqueous NaHCO 3 , and dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 286 (100 mg, 148 μmol, yield 98.0%, purity 97.9%) was obtained as a white solid. LC-MS: rt = 0.82 min; [M+H] + In the case of, m / z: 668.3.

[0212] Example 3.3.27 - Synthesis of Compound 287 To a solution of appropriately substituted intermediate C (90.0 mg, 151 μmol, 1.00 equiv) and (S)-2-methoxypropanoic acid (23.5 mg, 226 μmol, 1.50 equiv) in pyridine (5.0 mL), EDCI (86.8 mg, 453 μmol, 3.00 equiv) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2It was diluted with O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), and dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 287 (39.3 mg, 57.3 umol, yield 37.9%, purity 99.4%) was obtained as a white solid. LC-MS: rt = 0.82 min; [M+H] + In the case of, m / z: 682.3.

[0213] Example 3.3.28 - Synthesis of Compound 289 To a solution of the appropriately substituted intermediate C (130.0 mg, 232 umol, 1.00 equivalent) and methoxyacetic acid (25.1 mg, 278 umol, 21.2 uL, 1.20 equivalent) in pyridine (5.0 mL), EDCI (89.0 mg, 464 umol, 2.00 equivalent) was added. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with saturated NaHCO 3 aqueous solution (3.0 mL) and H 2 O (3.0 mL), and extracted with DCM (3.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 , filtered, concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , plate 1, EtOAc:MeOH = 5:1, Rf f = 0.5). The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25 mm×10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 14~44%, 10 min) to obtain the desired product. Compound 289 (27.7 mg, 43.1 umol, yield 18.6%, purity 98.4%) was obtained as a white solid. LC-MS: rt = 0.73 min; [M+H] + In the case of, m / z: 632.4.

[0214] Example 3.3.29 - Synthesis of Compound 290 A solution of appropriately substituted Intermediate C (130.0 mg, 232 μmol, 1.00 eq) and (S)-2-methoxypropanoic acid (29.0 mg, 279 μmol, 1.20 eq) in pyridine (2.0 mL) was added with EDCI (89.0 mg, 464 μmol, 2.00 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with saturated NaHCO 3 aqueous solution (3.0 mL) and H 2 O (3.0 mL), and extracted with DCM (3.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2 , plate 1, EtOAc:MeOH = 5:1, Rf f = 0.5). The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150×25 mm×10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 14 - 44%, 10 min) to obtain the desired product. Compound 290 (52.9 mg, 81.1 μmol, yield 34.9%, purity 99.0%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + in the case of, m / z: 646.4.

[0215] Example 3.3.30 - Synthesis of Compound 308 A solution of appropriately substituted Intermediate C (70.0 mg, 122 μmol, 1.00 eq) and (S)-2-methoxypropanoic acid (25.5 mg, 245 μmol, 2.00 eq) in pyridine (5.0 mL) was added with EDCI (70.6 mg, 368 μmol, 3.00 eq). The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H 2 O (40.0 mL), and extracted with DCM (40.0 mL × 3). The combined organic layers were washed with brine (40.0 mL × 3), dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO 2, DCM:MeOH = 10:1). Compound 308 (63.5 mg, 93.5 μmol, yield 76.0%, purity 96.5%) was obtained as a white solid. LC-MS: rt = 0.76 min; [M+H] + In the case of, m / z: 656.3.

[0216] Example 3.3.31 - Synthesis of Compound 319 To a solution of the appropriately substituted intermediate C (70.0 mg, 120 μmol, 1.00 equiv) and 2,2-dicyclopropylacetic acid (20.2 mg, 144 μmol, 1.20 equiv) in pyridine (1.0 mL), EDCI (46.1 mg, 240 μmol, 2.00 equiv) was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was washed with saturated NaHCO 3 (3.0 mL) and water (3.0 mL), extracted with DCM (3.0 mL × 3), the combined organic layers were washed with brine (5 mL), and dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , EtOAc:MeOH = 10:1). Compound 319 (50.6 mg, 69.4 μmol, yield 57.6%, purity 96.5%) was obtained as a white solid. LC-MS: rt = 0.78 min; [M+H] + In the case of, m / z: 704.4.

[0217] Example 3.3.32 - Synthesis of Compound 342 To a solution of the appropriately substituted intermediate C (120.0 mg, 202 μmol, 1.00 equiv) and (S)-2-methoxypropanoic acid (31.5 mg, 303 μmol, 1.50 equiv) in pyridine (5.0 mL), EDCI (116 mg, 606 μmol, 3.00 equiv) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO2 、 DCM:MeOH = 10:1). Compound 342 (84.7 mg, 119 μmol, yield 59.0%, purity 95.7%) was obtained as a white solid. LC-MS: rt = 0.82 min; [M+H] + In the case of, m / z: 680.5.

[0218] Example 3.3.33 - Synthesis of Compound 347 To a solution of appropriately substituted Intermediate C (100.0 mg, 179 μmol, 1.00 equiv) and (S)-2-methoxypropanoic acid (28.1 mg, 269 μmol, 1.50 equiv) in pyridine (5.0 mL), EDCI (103 mg, 539 μmol, 3.00 equiv) was added. The mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with DCM (30.0 mL), and the combined organic phases were washed with water (10.0 mL) and brine (10.0 mL), then dried over Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 347 (34.4 mg, 52.9 μmol, yield 29.4%, purity 98.6%) was obtained as a white solid. LC-MS: rt = 0.98 min; [M+H] + In the case of, m / z: 642.5.

[0219] Example 3.3.34 - Synthesis of Compound 348 To a solution of appropriately substituted Intermediate C (80.0 mg, 140 μmol, 1.00 equiv) and 2-methoxyacetic acid (18.9 mg, 210 μmol, 16.0 μL, 1.50 equiv) in pyridine (5.0 mL), EDCI (80.7 mg, 421 μmol, 3.00 equiv) was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with DCM (30.0 mL), and the combined organic phases were washed with water (10.0 mL) and brine (10.0 mL), then dried over Na 2 SO 4 and concentrated under reduced pressure to give a residue. The residue was purified by Prep-TLC (SiO 2, DCM:MeOH = 10:1). Compound 348 (45.0 mg, 68.2 μmol, yield 48.5%, purity 97.3%) was obtained as a white solid. LC-MS: rt = 0.97 min; [M+H] + In the case of, m / z: 642.5.

[0220] Example 3.3.35 - Synthesis of Compound 361 To a solution of the appropriately substituted Intermediate C (75.0 mg, 134 μmol, 1.00 equiv) and (ethoxycarbonyl)-L-alanine (43.5 mg, 269 μmol, 2.00 equiv) in pyridine (3.0 mL), EDCI (51.7 mg, 269 μmol, 2.00 equiv) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (neutral conditions; column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (10 mM NH4HCO3)-ACN]; B%: 40% - 70%, 10 min). Compound 361 (17.6 mg, 23.1 μmol, yield 17.1%, purity 92.1%) was obtained as a white solid. LC-MS: rt = 0.75 min; [M+H] + In the case of, m / z: 699.4.

[0221] Example 3.3.36 - Synthesis of Compound 362 To a solution of the appropriately substituted Intermediate C (75.0 mg, 131 μmol, 1.00 equiv) and (ethoxycarbonyl)-L-alanine (42.4 mg, 263 μmol, 2.00 equiv) in pyridine (2.0 mL), EDCI (75.7 mg, 394 μmol, 3.00 equiv) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were dried over Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-HPLC (neutral conditions; column: Waters Xbridge 150×25mm×5um; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 42% - 72%, 10 min). Compound 362 (22.8 mg, 30.8 umol, yield 23.4%, purity 96.1%) was obtained as a white solid. LC-MS: rt = 0.85 min; [M+H] + In the case of, m / z: 713.3.

[0222] Example 3.4 - Synthesis of Compound 360

Chem.

[0223] Step A: To a solution of intermediate C (70.0 mg, 122 umol, 1.00 equivalent) and (2R)-2-{[(benzyloxy)carbonyl]amino}-3-fluoropropanoic acid (59.2 mg, 245 umol, 2.00 equivalents) in pyridine (2.00 mL), EDCI (70.6 mg, 368 umol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 h. The reaction was diluted with H 2 O (20.0 mL), filtered, and concentrated in vacuo. Compound 360, step A (90.0 g, 113 umol, 92.3% yield) was obtained as a yellow solid. LC-MS: rt = 0.87 min; [M+H] + In the case of, m / z: 779.2.

[0224]

Chem.

[0225] Step B: To a solution of compound 360, step A (90.0 mg, 113 umol, 1.00 equivalent) in DCM (2.00 mL), N 2 under, Pd / C (10.0 mg, purity 10%) was added. The suspension was degassed under vacuum and purged with H 2 several times. The mixture was, H 2It was stirred at 25 °C for 2 hours at low pressure (15 psi). The reaction product was filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (neutral conditions; column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 36% - 66%, min). Compound 360, step B (70.0 mg, 106 μmol, 93.6% yield) was obtained as a white solid. LC-MS: rt = 0.68 min; [M+H] + In the case of, m / z: 645.4.

[0226]

Chemical formula

[0227] Step C: To a solution of Compound 360, step B (70.0 mg, 108 μmol, 1.00 equivalent) in DCM (2.00 mL), TEA (32.9 mg, 325 μmol, 45.3 μL, 3.00 equivalents) and ethyl chloroformate (17.6 mg, 162 μmol, 15.5 μL, 1.50 equivalents) were added at 0 °C. The mixture was stirred at 0 °C for 0.5 hour. LC-MS (EW24650-429-P1A1) indicated that the desired mass was detected. The reaction product was diluted with H 2 O (30.0 mL), extracted with EtOAc (30.0 mL×3), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by Prep-TLC (SiO2, DCM:MeOH = 10:1). 360 (30.6 mg, 41.9 μmol, yield 38.6%, purity 98.0%) was obtained as a white solid. LC-MS: rt = 0.83 min; [M+H] + In the case of, m / z: 717.4.

[0228] Compounds 358, 359, and 363 were similarly synthesized using appropriate carboxylic acids and haloformate reagents under similar reaction conditions.

[0229] Example 3.5 - Synthesis of Compound 306

Chemical formula

[0230] Process A: To a mixture of compound intermediate CC (500 mg, 860 μmol, 1.00 equiv) and (2S)-2-{[(tert-butoxy)carbonyl]amino}propanoic acid (244 mg, 1.29 mmol, 1.50 equiv) in pyridine (4.00 mL) was added EDCI (330 mg, 1.72 mmol, 2.00 equiv), and the mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was then diluted with DCM (20.0 mL). The combined organic phases were washed with water (10.0 mL) and brine (10.0 mL), then dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (plate 1, DCM:MeOH = 10:1, R f = 0.48). The desired product, compound 306, Process A (458 mg, 608 μmol, yield 70.8%, purity 100%) was obtained as a white solid. LC-MS: rt = 0.95 min; [M+H] + In the case of, m / z: 753.3.

[0231]

Chemical Structure

[0232] Process B: To a solution of compound 306, Process A (450 mg, 598 μmol, 1.00 equiv) in DCM (4.00 mL) was added TFA (2.04 g, 17.9 mmol, 1.33 mL, 30.0 equiv) at 0 °C, then the mixture was warmed to 20 °C and stirred for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was washed with saturated NaHCO 3 (20.0 mL), then extracted with DCM (10.0 mL × 5). The combined organic phases were washed with water (10.0 mL) and brine (10.0 mL), then dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to give a residue of the desired product, compound 306, Process B (340 mg, 521 μmol, yield 87.1%) as a white solid. LC-MS: rt = 0.85 min; [M+H]+ In the case of, m / z: 653.3.

[0233]

Chem.

[0234] Step C: To a mixture of Compound 306, Step B (150 mg, 230 μmol, 1.00 equivalent) and 2-chloropyrimidine (52.6 mg, 460 μmol, 2.00 equivalents) in NMP (2.00 mL), DIEA (149 mg, 1.15 mmol, 200 μL) was added. uL, 5.00 equivalents) was added and heated at 170 °C for 20 h with microwave. The reaction mixture was diluted with water (20.0 mL), extracted with DCM (10.0 mL × 4), and the combined organic layers were washed with water (20.0 mL) and brine (20.0 mL), and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150×25 mm, 5 μm; mobile phase: [water (10 mM NH 4 HCO 3 )-ACN]; B%: 32% - 62%, min), and the desired product Compound 306 (80.0 mg, 109 μmol, yield 47.6%) was obtained as a white solid. LC-MS: rt = 0.95 min; [M+H] + In the case of, m / z: 731.5.

[0235] Compound 305 was synthesized under the same reaction conditions using appropriate reagents.

[0236] Example 3.6 - Synthesis of Compound 296

Chem.

[0237] Procedure A: To a solution of Intermediate C (150 mg, 257 μmol, 1.00 equiv) and (2S)-2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (78.6 mg, 386 μmol, 1.50 equiv) in pyridine (5.00 mL) was added EDCI (148 mg, 773 μmol, 3.00 equiv). The mixture was stirred at 15 °C for 12 h. The reaction mixture was diluted with H 2 O (10.0 mL) and extracted with DCM (20.0 mL × 2). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (40 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. Compound 296, Procedure A (200 mg, crude product) was obtained as a white solid. LC-MS: rt = 0.78 min; [M+H] + for, m / z: 767.5.

[0238]

Chemical formula

[0239] Procedure B: To a solution of Compound 296, Procedure A (200 mg, 260 μmol, 1.00 equiv) in DCM (5.00 mL) was added TFA (594 mg, 5.22 mmol, 386 μL, 20.0 equiv) at 0 °C. The mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with H 2 O (10.0 mL) and saturated NaHCO 3 aqueous solution was added to adjust the pH to 9. The mixture was extracted with DCM (50.0 m × 2). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (100 mL × 4), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. Compound 296, Procedure B (150 mg, 224 μmol, 86.2% yield) was obtained as a yellow solid. LC-MS: rt = 0.92 min; [M+H] + for, m / z: 667.5.

[0240]

Chemical formula

[0241] To a solution of Compound 296 in Project C: DCM (2.00 mL), Project B (130 mg, 194 μmol, 1.00 equivalent) and TEA (59.1 mg, 584 μmol, 81.4 μL, 3.00 equivalents), 2-chloroethyl isocyanate (30.8 mg, 292 μmol, 1.50 equivalents) was added. The mixture was stirred at 25 °C for 12 hours. To the reaction mixture was added H 2 O (10.0 mL), and the mixture was extracted with DCM (20.0 mL × 2). The combined organic layers were washed with a saturated aqueous solution of NaHCO 3 (40.0 mL), dried over saturated Na 2 SO 4 aqueous solution, filtered, and concentrated under reduced pressure to obtain a residue. Compound 296, Project C (120 mg, 155 μmol, 79.7% yield) was obtained as a yellow oil. LC-MS: rt = 0.95 min; [M + H] + In the case of, m / z: 772.5.

[0242] [Chemical Structure]

[0243] Project D: To a solution of Compound 296 in Project C: MeCN (10.0 mL), Project C (120 mg, 155 μmol, 1.00 equivalent), K 2 CO 3 (64.4 mg, 466 μmol, 3.00 equivalents) was added. The mixture was stirred at 70 °C for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product. The residue was purified by prep-HPLC (neutral conditions; column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (10 mM NH 4 HCO 3 ) - ACN]; B%: 26% - 56%, 2 min). The residue was separated by SFC (conditions: column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); mobile phase: [0.1% of NH 3 H 2O ETOH]; B%: 25% - 25%, 5.0 min; 40 min). Compound 296 (24.38 mg, 31.84 μmol, yield 20.49%, purity 96.1%) was obtained as a white solid. LC-MS: rt = 0.95 min; [M + H] + In the case of, m / z: 736.6.

[0244] Example 4. Exemplary Scheme - Synthesis of Compounds 200, 229 - 230, 233 - 234, 243 - 244, 246 - 249, and 297

Chemical Structure

[0245] Step 1: To a solution of compound 8 (5.00 g, 14.6 mmol, 1.00 equiv), (2R)-1,2-dimethylpiperazine (1.83 g, 16.0 mmol, 1.10 equiv), and DIEA (9.65 g, 74.6 mmol, 13.0 mL, 5.11 equiv) in DCM (50.0 mL) was added T3P (11.7 g, 18.5 mmol, 11.0 mL, purity 50%, 1.27 equiv) at -20 °C, and then the mixture was stirred for 12 h. The reaction mixture was diluted with DCM (200 mL) and washed with saturated NaHCO 3 (100 mL), H 2 O (100 mL), and brine (50.0 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue, giving the desired product compound 18, which was used without further purification or analysis.

[0246] Step 2: To a solution of compound 18 (6.31 g, 14.3 mmol, 1.00 equiv) in DCM (70.0 mL) was added TFA (16.4 g, 143 mmol, 10.6 mL, 10.0 equiv) at 0 °C, and then the mixture was warmed to 20 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The crude product, compound 19 (6.51 g, crude product, TFA), was obtained as a yellow oil and used in the next step.

[0247] Procedure 3: To a solution of Compound 19 (6.51 g, 14.3 mmol, 1.00 equiv., TFA) in DCM (100 mL) were added TEA (14.5 g, 143 mmol, 20.0 mL, 10.0 equiv.) and propionic anhydride (3.75 g, 28.7 mmol, 3.71 mL, 2.00 equiv.) at 0 °C, and then the mixture was stirred at 20 °C for 1 h. The reaction mixture was washed with saturated NaHCO 3 aqueous solution (50.0 mL), H 2 O (50.0 mL), and brine, and the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Welch Ultimate XB-CN 250×70×10um; mobile phase: [heptane-EtOH (0.1% NH 3 H 2 O)]; B%: 5% - 45%, 12 min), and the desired product Compound 20 (4.00 g, 10.1 mmol, yield 70.4%) was obtained as a yellow solid. LC-MS: rt = 0.56 min; [M+H] + for, m / z: 395.1.

[0248] Procedure 4: To a solution of Compound 20 (4.00 g, 10.1 mmol, 1.00 equiv.) in THF (40.0 mL) was added Pd / C (400 mg, purity 10%) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was stirred at 15 °C for 12 h under H 2 (15.0 psi). The reaction mixture was filtered, the cake was washed with MeOH (100 mL), and then concentrated under reduced pressure to give a residue. Compound 21 (3.20 g, 8.78 mmol, yield 86.5%) was obtained as a white solid and used without further characterization.

[0249] Procedure 5: To Compound 21 (310 mg, 1.15 mmol, 1.20 equiv.) and Intermediate A (350 mg, 960 umol, 1.00 equiv.) in pyridine (5.00 mL) was added EDCI (368 mg, 1.92 mmol, 2.00 equiv.). The mixture was stirred at 15 °C for 10 h. The reaction mixture was H2 It was diluted with O (50.0 mL) and extracted with EtOAc (50.0 mL × 2). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (70.0 mL × 2), and Na 2 SO 4 dried, filtered, and concentrated under reduced pressure to obtain a residue. Compound 22 (400 mg, 649.59 μmol, yield 67.64%, purity N / A) was obtained as a white solid. LC-MS: rt = 1.00 min; [M + H] + In the case of, m / z: 616.6.

[0250] Step 6: To a solution of Compound 22 (400 mg, 649 μmol, 1.00 equivalent) in DCM (5.00 mL) was added TFA (1.48 g, 12.9 mmol, 961 μL, 20.0 equivalents) at 0 °C. The mixture was stirred at 15 °C for 2 h. The reaction mixture was diluted with H 2 O (10.0 mL), and saturated NaHCO 3 aqueous solution was added to adjust the pH to 9. The mixture was extracted with DCM (20 mL × 2). The combined organic layers were dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. Compound 23 (288 mg, 558.51 μmol, yield 85.98%) was obtained as a yellow solid. LC-MS: rt = 0.90 min; [M + H] + In the case of, m / z: 516.5.

[0251] Example 4.1.1 - Synthesis of Compound 229 Step 7: To a solution of Compound 23 (50.0 mg, 96.9 μmol, 1.00 equivalent) and 1-cyclopropyl-1H-pyrazole-5-carboxylic acid (22.1 mg, 145 μmol, 1.50 equivalents) in pyridine (3.00 mL) was added EDCI (37.1 mg, 193 μmol, 2.00 equivalents). The mixture was stirred at 15 °C for 10 h. The reaction mixture was diluted with H 2 O (10.0 mL) and extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (20 mL × 3), and Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 229 (37.6 mg, 55.9 μmol, yield 57.6%, purity 96.4%) was obtained as a white solid. LC-MS: rt = 0.74 min; [M+H] + In the case of, m / z: 650.4.

[0252] Compounds 200, 230, 233, 234, 243, 244, 246 - 249, and 297 were synthesized using similar reaction conditions with appropriate carboxylic acid reagents.

[0253] Example 4.3.2 - Synthesis of Compound 200 To a solution of appropriately substituted compound 23 (50.0 mg, 96.9 μmol, 1.00 equiv) and 1-ethyl-1H-pyrazole-5-carboxylic acid (16.7 mg, 119 μmol, 1.20 equiv) in pyridine (5.00 mL), EDCI (37.1 mg, 193 μmol, 2.00 equiv) was added. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with NaHCO 3 (30.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with brine (30 mL × 3) and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 20% - 50%, 7 min). Compound 200 (31.0 mg, 49.7 μmol, yield 49.8%, purity 100%) was obtained as a white solid. LC-MS: rt = 0.93 min; [M+H] + In the case of, m / z: 624.4.

[0254] Example 4.2.3 - Synthesis of Compound 246 A solution of appropriately substituted Compound 23 (50.0 mg, 96.9 μmol, 1.00 equiv) and 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (18.6 mg, 145 μmol, 1.50 equiv) in pyridine (3.00 mL) was added with EDCI (37.1 mg, 193 μmol, 2.00 equiv). The mixture was stirred at 15 °C for 10 h. The reaction mixture was diluted with H 2 O (10.0 mL) and extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with saturated aqueous NaHCO 3 (20 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO 2 , DCM:MeOH = 10:1). Compound 246 (27.3 mg, 41.6 μmol, yield 42.9%, purity 95.4%) was obtained as a white solid. LC-MS: rt = 0.76 min; [M+H] + in the case of, m / z: 626.4.

[0255] As described in Example 4,

Chemical formula

Chemical formula

[0256] In some embodiments, B of Example 4 is of formula (I) or (I-A)

Chemical formula

[0257] Example 5 - Synthesis of Compound 201

Chem.

[0258] Step 1: To a solution of Intermediate B (140 mg, 519 μmol, 1.01 eq) and Compound 21 (accompanied by 1-methylpiperazine) (180 mg, 513 μmol, 1.00 eq) in pyridine (5.00 mL) was added EDCI (200 mg, 1.04 mmol, 2.03 eq) at 25 °C, and then the mixture was stirred at 25 °C for 12 h. The mixture was combined with a similar reaction carried out on a 30.0 mg scale. The residue was diluted with H 2 O (40.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (200 mL × 3), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 25% - 55%, 7 min). Compound 24 (0.150 g, 249 μmol, 40.0% yield) was obtained as a white solid. LC-MS: rt = 0.76 min; for [M+H] + , m / z: 602.4.

[0259] Step 2: To a solution of Compound 24 (120 mg, 199 μmol, 1.00 eq) in DCM (3.00 mL) was added dropwise TFA (454 mg, 3.99 mmol, 295 μL, 20.0 eq) at 0 °C, and then the mixture was stirred at 25 °C for 2 h. The mixture was combined with a similar reaction carried out on a 30.0 mg scale. The reaction mixture was concentrated at 30 °C under reduced pressure to remove DCM. The residue was diluted with saturated aqueous NaHCO 3 (20.0 mL) and extracted with ethyl acetate (20.0 mL × 3). The combined organic layers were washed with brine (20.0 mL × 3), dried over Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. Compound 25 (110 mg) was obtained as a white solid. LC-MS: rt = 0.91 min; [M+H] + In the case of, m / z: 502.5.

[0260] Step 3: To a solution of compound 25 (80.0 mg, 159 μmol, 1.00 equiv) and 1-ethyl-1H-pyrazole-5-carboxylic acid (27.0 mg, 192 μmol, 1.21 equiv) in pyridine (5.00 mL), EDCI (61.1 mg, 318 μmol, 2.00 equiv) was added at 25 °C, and then the mixture was stirred at 25 °C for 6 h. The residue was diluted with saturated NaHCO 3 aqueous solution (30.0 mL) and extracted with ethyl acetate (30.0 mL × 3). The combined organic layers were washed with brine (30.0 mL × 3), and Na 2 SO 4 dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep-TLC (SiO2, DCM:MeOH = 10:1). The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX C18 75×30 mm×3 μm; mobile phase: [water (0.05% ammonia hydroxide v / v)-ACN]; B%: 18% - 48%, 7 min). Compound 201 (35.0 mg, 56.1 μmol, yield 35.1%, purity 100%) was obtained as a white solid. LC-MS: rt = 0.93 min; [M+H] + In the case of, m / z: 624.5.

[0261] Example 6 - Synthesis of Intermediate D

Chemical Structure

[0262] To a solution of acetic acid (52 g, 290.22 mmol, 1 equiv) in dichloromethane (400 mL), EDCI (61.20 g, 319.25 mmol, 1.1 equiv) was added. The mixture was stirred at 25 °C for 2 h. Water (200 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with brine (100 L), and Na2 SO 4 It was dried with SO, filtered, and concentrated in vacuo to obtain the product. The product was slurried with a mixture of dichloromethane and petroleum ether (V:V = 1:4, 500 mL) at 20 °C for 30 minutes, and the filter cake was obtained as the product, and the filtrate was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 50 / 1 to 5 / 1). Intermediate D (42 g, 258.01 mmol, yield 88.90%, purity 99%) was obtained as a yellow solid. LC-MS: rt = 0.93 min; [M+H] + In the case of, m / z: 624.5. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.01-7.99 (m, 2H), 7.59-7.52 (m, 1H), 7.51-7.48 (m, 2H), 4.43 (s, 2H).

[0263] Example 7 - Synthesis of Intermediate E

Chemical Structure

[0264] Step 1: To a solution of 4-bromo-3-fluorobenzaldehyde (115 g, 566.48 mmol, 1 equiv) in THF (1000 mL), TMSCF 3 (96.66 g, 679.78 mmol, 1.2 equiv) was added, and then TBAF (1 M, 11.33 mL, 0.02 equiv) was added at 0 °C. The mixture was stirred at 20 °C for 1 hour. HCl (3 M, 283.24 mL, 1.5 equiv) was added at 10 °C, and then the mixture was stirred at 20 °C for 12 hours. MTBE (200 mL) was added to the mixture, and the aqueous phase was extracted with MTBE (100 mL). The combined organic layers were washed with brine (100 mL) and dried with Na 2 SO 4 filtered, and then concentrated in vacuo to obtain the crude product. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1). Compound 26 (150 g, 533.47 mmol, yield 94.17%, purity 97.1%) was obtained as a colorless oil. LC-MS: rt = 0.98 min; [M+H] + In the case of, m / z: 271.0. 1 H NMR: (400 MHz, CDCl 3 ) δ: 7.62 - 7.58 (m, 1H), 7.32 - 7.29 (m, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.04 - 5.01 (m, 1H), 2.78 - 2.77 (d, J = 3.6 Hz, 1H).

[0265] Step 2: To a solution of compound 26 (75 g, 274.70 mmol, 1 equiv) in dichloromethane (700 mL) was added DMP (139.82 g, 329.64 mmol, 102.06 mL, 1.2 equiv) at 0 °C. The reaction mixture was stirred at 20 °C for 4 h. H 2 O (500 mL) was added to the reaction mixture, which was then filtered. The filtrate was successively washed with saturated NaHCO 3 (200 mL), saturated Na 2 SO 3 (100 mL × 2), brine (100 mL). The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to give the crude product. The crude product 27 was used in the next step without purification.

[0266] Step 3: To a THF solution (600 mL) of TiCl 4 (60.89 g, 321.03 mmol, 1.5 equiv) was added a THF solution (100 mL) of compound 27 (58 g, 214.02 mmol, 1 equiv) at -10 °C. A solution of intermediate D (41.39 g, 256.82 mmol, 1.2 equiv) in THF (100 mL) was added to the mixture at -10 °C. The mixture was stirred at -10 to 0 °C for 30 min. Pyridine (33.86 g, 428.03 mmol, 34.55 mL, 2 equiv) was added at 0 °C, and then the mixture was stirred at 20 °C for 12 h. H 2O (200 mL) was added to the mixture, and the aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (200 mL) and dried over Na 2 SO 4 . The mixture was filtered and concentrated in vacuo to give the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 10 / 1 to 20 / 1). Compound 28 (54 g, 130.39 mmol, yield 60.92%, purity 100%) was obtained as a yellow solid. LC-MS: rt = 1.09 min; [M+H] + , m / z: 414.1. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.21 - 8.19 (m, 2H), 7.70 - 7.66 (m, 2H), 7.59 - 7.57 (m, 2H), 7.17 - 7.15 (m, 1H), 7.07 - 7.05 (m, 1H).

[0267] Step 4: A solution of compound 28 (40 g, 96.58 mmol, 1 equiv) in MeOH (100 mL) was stirred at 50 °C for 4 h. The mixture was concentrated in vacuo to give the product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 to 5 / 1). Compound 29 (40 g, 88.75 mmol, yield 91.89%, purity 99%) was obtained as a white solid. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.46 (s, 1H), 7.85 - 7.83 (m, 2H), 7.64 - 7.52 (m, 4H), 7.12 - 7.10 (d, J = 8.8 Hz, 1H), 7.01 - 6.81 (d, J = 8.0 Hz, 1H), 3.60 (s, 3H).

[0268] Step 5: To a solution of compound 29 (10 g, 22.41 mmol, 1 equiv) in MeOH (100 mL) was added PtO 2 (1.00 g, 4.40 mmol, 1.96e-1 equiv) under N 2 . The suspension was degassed under vacuum and purged with H 2 several times. The mixture was purged with H 2(At 50 psi), it was stirred at 20 °C for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to obtain the crude product. The crude product was used in the next step without purification. Compound 30 (10 g, crude product) was obtained as a white solid. LC-MS: rt = 1.10 min; [M+H] + In the case of, m / z: 452.0.

[0269] Step 6: A solution of compound 30 (10 g, 22.01 mmol, 1 equiv) in HCl (6 M, 98.67 mL, 26.89 equiv) and AcOH (51.80 g, 862.60 mmol, 49.33 mL, 39.18 equiv) was stirred at 120 °C for 12 hours. The reaction mixture was concentrated in vacuo to obtain the crude product. The crude product was used in the next step without purification. Compound 31 (8 g, crude product, HCl) was obtained as a yellow oil. LC-MS: rt = 0.70 min; [M+H] + In the case of, m / z: 330.1.

[0270] Step 7: To a solution of compound 31 (8 g, 21.83 mmol, 1 equiv, HCl) in THF (90 mL) was added a solution of K 2 O (20 mL) in 2 CO 3 (12.07 g, 87.30 mmol, 4 equiv). Boc 2 O (7.15 g, 32.74 mmol, 7.52 mL, 1.5 equiv) was added to the mixture. The mixture was stirred at 20 °C for 12 hours. The mixture was adjusted to pH 4 with HCl (1 M), and then extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered, and concentrated in vacuo to obtain the crude product. The crude product was used in the next step without purification. Compound 32 (9 g, crude product) was obtained as a yellow solid.

[0271] Step 8: To a solution of compound 32 (9 g, 20.92 mmol, 1 equiv) in dichloromethane (150 mL) and MeOH (15 mL) was added TMSCHN 2(2M, 11.51 mL, 1.1 eq) was added dropwise. The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under vacuum to obtain the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 - 5 / 1). Compound 33 (9 g, 19.33 mmol, yield 92.39%, purity 95.4%) was obtained as a pale yellow oil.

[0272] Step 9: To a mixture of compound 33 (12.5 g, 28.14 mmol, 1 eq), diphenylmethanimine (7.65 g, 42.21 mmol, 7.08 mL, 1.5 eq), and Cs 2 CO 3 (18.34 g, 56.28 mmol, 2 eq) in dioxane (200 mL) was added Pd 2 (dba) 3 (1.29 g, 1.41 mmol, 0.05 eq) and Xantphos (1.63 g, 2.81 mmol, 0.1 eq). The mixture was stirred at 100 °C for 14 h. The mixture was filtered and the filtrate was concentrated in vacuo to obtain the crude product. The crude product was used in the next step without purification. Compound 34 (20 g, crude product) was obtained as a black-brown oil. LC-MS: rt = 1.12 min; [M+H] + in the case of, m / z: 545.3.

[0273] Step 10: To a solution of compound 34 (20 g, 36.73 mmol, 1 eq) in THF (150 mL) was added citric acid (10 M, 140.00 mL, 38.12 eq). The mixture was stirred at 20 °C for 16 h. The mixture was extracted with ethyl acetate (150 mL×2), and the organic layer was successively washed with saturated NaHCO 3 (150 mL), brine (100 mL), dried over Na 2 SO 4 , and concentrated in vacuo to obtain the crude product. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 100 / 1 - 3 / 1). Intermediate E (5 g, 12.90 mmol, yield 35.11%, purity 98.1%) was obtained as a yellow oil. LC-MS: rt = 0.92 min; [M+H-boc]+ In this case, m / z = 281.1. 1 1H NMR: (400 MHz, CDCl 3 ) δ 7.02 - 6.98 (m, 1H), 5.95 - 6.88 (m, 1H), 6.77 - 6.75 (m, 1H), 5.18 - 5.04 (m, 1H), 4.87 - 4.81 (m, 1H), 3.86 - 3.79 (m, 1H), 3.71 - 3.68 (m, 3H), 1.43 (s, 9H).

[0274] Example 8. Exemplary Scheme - Synthesis of Compounds 350 - 357

Chemical formula

[0275] Step 1: To a solution of Intermediate E (500 mg, 1.31 mmol, 1.00 equivalent) and Cbz - amino (518 mg, 1.71 mmol, 1.30 equivalents) in pyridine (10.0 mL), EDCI (756 mg, 3.94 mmol, 3.00 equivalents) was added at 25 °C for 2 hours. 40.0 mL of H 2 O was added to the reaction mixture, and it was extracted with 100 mL of EtOAc (50.0 mL × 2). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (100 mL × 2), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by Prep - HPLC (basic conditions, column: Welch Ultimate XB - CN 250×50×10um; mobile phase: [hexane - EtOH (0.1% NH 3 . H 2 O)]; B%: 1% - 40%, 15 min). Compound 35 (400 mg, 600 umol, yield 45.7%) was obtained as a white solid. LC - MS: rt = 1.08 min; [M + H - Boc] + In this case, m / z: 566.3.

[0276] Step 2: To a solution of Compound 35 (400 mg, 600 umol, 1.00 equivalent) in DCM (5.00 mL), Pd / C (40.0 mg, purity 10.0%) was added under N 2It was added under an atmosphere. The suspension was degassed and purged three times with H 2 It was degassed and purged three times with H. The mixture was stirred at 25 °C for 2 hours under H 2 (15 Psi). The reaction mixture was filtered, the cake was washed with 100 mL of MeOH, and concentrated under reduced pressure to obtain a residue. Compound 36 (319 mg, 600 μmol, yield 99.8%) was obtained as a white solid. LC-MS: rt = 0.84 min; [M+H] + In the case of, m / z: 554.1.

[0277] Step 3: To a solution of compound 36 (319 mg, 600 μmol, 1.00 equivalent) and 1-ethyl-1H-pyrazole-5-carboxylic acid (126 mg, 900 μmol, 1.50 equivalents) in pyridine (5.00 mL), EDCI (345 mg, 1.80 mmol, 3.00 equivalents) was added. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. Compound 37 (340 mg, 520 μmol, yield 86.6%) was obtained as a white solid. LC-MS: rt = 0.99 min; [M+H] + In the case of, m / z: 654.5.

[0278] Step 4: To a solution of compound 37 (340 mg, 520 μmol, 1.00 equivalent) in MeOH (2.00 mL) and THF (2.00 mL), NaOH (83.2 mg, 2.08 mmol, 4.00 equivalents) in H 2 O (1.00 mL) was added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (10.0 mL), 1 M HCl was added to adjust the pH to 2. The mixture was extracted with DCM (20.0 mL × 3). The combined organic layers were dried over Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure to obtain a residue. Compound 38 (320 mg, 500 μmol, yield 96.1%) was obtained as a yellow solid. LC-MS: rt = 0.59 min; [M + H] + In the case of, m / z: 640.4.

[0279] Step 5: To a solution of compound 38 (160 mg, 250 μmol, 1.00 equivalent) and 1-methylpiperazine (37.5 mg, 375 μmol, 41.6 μL, 1.50 equivalents) in DCM (5.00 mL), DIEA (161 mg, 1.25 mmol, 217 μL, 5.00 equivalents) and T3P (477 mg, 750 μmol, 446 μL, purity 50.0%, 3.00 equivalents) were added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with DCM (30.0 mL × 3). The combined organic layers were washed with saturated NH 4 Cl aqueous solution (30.0 mL × 2) and dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. Compound 39 (having B = 1-methylpiperazine) (180 mg, 249 μmol, yield 99.7%) was obtained as a yellow solid. LC-MS: rt = 0.84 min; [M + H] + In the case of, m / z: 722.5.

[0280] Step 6: To a solution of compound 39 (having B = 1-methylpiperazine) (180 mg, 249 μmol, 1.00 equivalent) in DCM (5.00 mL), TFA (568 mg, 4.99 mmol, 369 μL, 20.0 equivalents) was added at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with H 2 O (10.0 mL), and saturated NaHCO 3 was added to adjust the pH to 9. The mixture was extracted with DCM (20.0 mL × 2). The combined organic layers were dried over Na 2 SO 4 filtered, and concentrated under reduced pressure to obtain a residue. Compound 40 (having B = 1-methylpiperazine) (150 mg, 241 μmol, yield 96.7%) was obtained as a white solid. LC-MS: rt = 0.77 min; [M + H]+ In the case of, m / z: 622.3.

[0281] Step 7: To a solution of Compound 40 (having 1-methylpiperazine) (140 mg, 225 μmol, 1.00 equivalent) in DCM (5.00 mL), TEA (45.5 mg, 450 μmol, 62.6 μL, 2.00 equivalents) and propanoyl propanoate (37.6 mg, 289 μmol, 37.3 μL, 1.20 equivalents) were added at 0 °C. The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with H 2 O (30.0 mL) and extracted with EtOAc (30.0 mL × 3). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (30.0 mL × 2), and dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure to obtain a residue.

[0282] The residue was purified by SFC (column: DAICEL CHIRALPAK IE (250 mm × 30 mm, 10 μm); mobile phase: [hexane - IPA]; B%: 25% - 25%, 15 min) to obtain Compound 350. The residue was further purified by SFC (column: DAICEL CHIRALCEL OD - H (250 mm × 30 mm, 5 μm; mobile phase: [0.1% NH 3 H 2 O ETOH]; B%: 15% - 15%, 2.2; 90 min, Rt = 1.143, 1.191 min) to obtain Compound 352. The residue was further purified by SFC (column: DAICEL CHIRALCEL AD - H (250 mm × 30 mm, 5 μm; mobile phase: [0.1% NH 3 H 2 O IPA]; B%: 20% - 20%, 5.2 min; 70 min, Rt = 1.216, 1.348 min) to obtain Compound 354. The residue was further purified by SFC (column: DAICEL CHIRALCEL AD - H (250 mm × 30 mm, 5 μm; mobile phase: [0.1% NH 3 H 2 O IPA]; B%: 20% - 20%, 5.2 min; 40 min, Rt = 1.324 min) to obtain Compound 356.

[0283] Compound 350 (9.10 mg, 12.4 μmol, yield 5.53%, purity 92.7%) was obtained as a white solid. LC-MS: rt = 0.97 min; [M+H] + In the case of, m / z: 678.5. 1 H NMR: (400 MHz, CDCl 3 ) δ 8.48 - 8.44 (t, J = 8.8 Hz, 1H), 8.35 - 8.31 (m, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.40 (s, 1H), 7.25 - 7.19 (m, 2H), 6.73 (d, J = 2.0 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H), 5.80 - 5.75 (t, J = 10 Hz, 1H), 4.99 - 4.96 (m, 1H), 4.76 - 4.70 (m, 2H), 4.09 - 3.98 (m, 1H), 3.70 - 3.65 (m, 1H), 3.57 - 3.53 (m, 1H), 3.47 - 3.42 (m, 1H), 2.40 - 2.35 (m, 3H), 2.27 (s, 3H), 2.13 - 2.00 (m, 1H), 1.59 - 1.55 (t, J = 7.2 Hz, 3H), 1.39 (s, 3H), 1.31 - 1.27 (t, J = 8.0 Hz, 3H), 1.07 - 0.91 (m, 3H), 0.62 - 0.66 (m, 4H), 0.54 - 0.36 (m, 4H).

[0284] Compound 352 (22.67 mg, 31.2 μmol, yield 13.8%, purity 93.4%) was obtained as a white solid. LC-MS: rt = 0.98 min; [M+H] + In the case of, m / z: 678.4. 1 H NMR: (400 MHz, CDCl 3)δ 8.29 - 8.25 (m, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.17 - 7.08 (m, 3H), 6.59 (d, J = 2.0 Hz, 1H), 6.17 - 6.15 (m, 1H), 5.72 - 5.67 (t, J = 9.6 Hz, 1H), 4.90 - 4.87 (m, 1H), 4.60 - 4.54 (m, 2H), 4.07 - 3.99 (m, 1H), 3.78 - 3.63 (m, 3H), 2.48 - 2.39 (m, 3H), 2.31 (s, 3H), 2.02 - 1.83 (m, 4H), 1.43 - 1.39 (t, J = 6.8 Hz, 3H), 1.28 - 1.24 (m, 1H), 0.91 - 0.80 (m, 5H), 0.67 - 0.52 (m, 4H), 0.42 - 0.23 (m, 4H).

[0285] Compound 354 (16.3 mg, 23.6 μmol, yield 10.5%, purity 98.4%) was obtained as a white solid. LC-MS: rt = 0.98 min; [M + H] + in the case of, m / z: 678.4. 1 H NMR: (400 MHz, CDCl 3 )δ 8.39 (s, 1H), 8.28 - 8.24 (t, J = 8.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.09 - 7.06 (m, 2H), 6.65 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 9.2 Hz, 1H), 5.75 - 5.70 (t, J = 9.6 Hz, 1H), 4.94 - 4.91 (m, 1H), 4.65 - 4.52 (m, 2H), 4.06 - 3.97 (m, 1H), 3.81 - 3.71 (m, 2H), 3.64 - 3.58 (m, 1H), 2.47 - 2.39 (m, 3H), 2.32 (s, 3H), 1.96 - 1.82 (m, 3H), 1.44 - 1.40 (t, J = 7.2 Hz, 3H), 1.31 - 1.25 (m, 2H), 0.88 - 0.76 (m, 5H), 0.67 - 0.49 (m, 4H), 0.43 - 0.17 (m, 4H).

[0286] Compound 356 (11.94 mg, 17.4 μmol, yield 7.76%, purity 99.2%) was obtained as a white solid. LC-MS: rt = 0.82 min; [M + H] + in the case of, m / z: 678.6. 11H NMR: (400 MHz, CD 3 CN) δ 8.76 (s, 1H), 7.99 - 7.94 (t, J = 8.4 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.39 - 7.31 (m, 1H), 7.26 - 7.18 (m, 2H), 7.06 (d, J = 9.6 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 5.64 - 5.59 (t, J = 10.8 Hz, 1H), 4.93 - 4.89 (m, 1H), 4.57 - 4.51 (m, 2H), 4.13 - 4.03 (m, 1H), 3.82 (s, 2H), 3.56 (s, 1H), 2.60 - 2.55 (m, 2H), 2.52 (s, 3H), 2.20 - 2.15 (m, 2H), 1.45 - 1.37 (m, 3H), 1.27 - 1.24 (m, 2H), 1.00 - 1.11 (m, 3H), 0.93 - 0.82 (m, 4H), 0.51 - 0.36 (m, 4H), 0.29 - 0.22 (m, 4H).

[0287] Using (R)-1,2-dimethylpiperazine as B from Example 8, Compounds 351, 353, 355, and 357 were similarly synthesized and purified.

[0288] In some embodiments, B of Example 8 is a optionally substituted 4- to 12-membered heterocyclic ring represented by Formula (I) or (I-A)

Chemical Formula

[0289] Example 9: IL-17A / A HEK-Blue Cell Assay The HEK-Blue IL-17 reporter cell line (Fisher#NC1408637) was used in a cell-based IL-17A / A inhibition assay. The cells were grown and prepared for the assay according to the manufacturer's instructions. This cell line consists of HEK 293 cells engineered to express IL-17RA, IL-17RC, and the ACTi adapter molecule, and their combination activates the NFκB promoter and drives the expression of recombinant secreted alkaline phosphatase (SEAP) protein when stimulated by IL-17A / A. Next, the medium from the cells was added to a chromogenic reagent (Quanti-Blue Substrate, Fisher#NC9711613) and read at A 630 .

[0290] Compounds were titrated in DMSO at a maximum final compound concentration of 10 μM and added to the cells immediately prior to the addition of IL-17A / A (Genscript#Z03228). The cells, compounds, and IL-17A / A were then incubated for 20 hours, after which the medium was removed for SEAP analysis. The resulting inhibition curves were then analyzed using the Dotmatics screening protocol, and the IC 50 values were determined using a four-parameter non-linear fit. DMSO was added to a common final concentration of 0.1% to optimize the background. The IL-17A / A inhibition data for the selected compounds are shown in Table 1.

[0291] Example 10: IL-17A / F HEK-Blue Cell Assay The HEK-Blue IL-17 reporter cell line (Fisher #NC1408637) was used in a cell-based IL-17A / F inhibition assay. The cells were grown and prepared for the assay according to the manufacturer's instructions. This cell line consists of HEK 293 cells designed to express the IL-17RA, IL-17RC, and ACTi adapter molecules, and their combination activates the NFκB promoter and drives the expression of the recombinant secreted alkaline phosphatase (SEAP) gene protein when stimulated by IL-17A / A. Subsequently, the medium from the cells was added to a chromogenic reagent (Quanti-Blue Substrate, Fisher #NC9711613) and read at A 630 .

[0292] Compounds were titrated in DMSO and added to the cells immediately before adding IL-17A / A (Custom from R&D systems, IL-17A / F + BSA without tag as carrier protein). The cells, compounds, and IL-17A / A were then incubated for 20 hours, after which the medium was removed for SEAP analysis. The resulting inhibition curves were then analyzed using the Dotmatics screening protocol, and the IC 50 values were determined using a four-parameter non-linear fit. DMSO was added to an optimal final concentration of 0.1% to optimize the background. The IL-17A / F inhibition data for the selected compounds are shown in Table 1. Table 1 includes the pIC 50 values for the IL-17A / A and IL-17A / F inhibition of the selected compounds, and the compounds have pIC 50 with 8 or more as A, 8 > B ≥ 7, and 7 > C ≥ 5. Table 1 also includes the synthetic and spectroscopic data for the claimed IL-17 monomer.

[0293]

Table 1-1

[0294]

Table 1-2

[0295]

Table 1-3

[0296]

Table 1-4

[0297]

Table 1-5

[0298]

Table 1-6

[0299]

Table 1-7

[0300]

Table 1-8

[0301]

Table 1-9

[0302]

Table 1-10

[0303]

Table 1-11

[0304]

Table 1-12

[0305]

Table 1-13

[0306]

Table 1-14

[0307]

Table 1-15

[0308]

Table 1-16

[0309]

Table 1-17

[0310]

Table 1-18

[0311]

Table 1-19

[0312]

Table 1-20

[0313]

Table 1-21

[0314]

Table 1-22

[0315]

Table 1-23

[0316]

Table 1-24

[0317]

Table 1-25

[0318]

Table 1-26

[0319]

Table 1-27

[0320]

Table 1-28

[0321]

Table 1-29

[0322]

Table 1-30

[0323]

Table 1-31

[0324]

Table 1-32

[0325]

Table 1-33

[0326]

Table 1-34

[0327]

Table 1-35

[0328]

Table 1-36

[0329]

Table 1-37

[0330]

Table 1-38

[0331]

Table 1-39

[0332]

Table 1-40

[0333]

Table 1-41

[0334]

Table 1-42

[0335]

Table 1-43

[0336]

Table 1-44

[0337]

Table 1-45

[0338]

Table 1-46

[0339] Example 11: Comparison of Selected IL-17 Modulators Against Reference Compounds A - M Microsome Stability Test Preparation of test compound and control working solution. 5 μL of the compound and control stock solution (10 mM in dimethyl sulfoxide (DMSO)) was diluted with 495 μL of acetonitrile (ACN).

[0340] Preparation of NADPH cofactor. An appropriate amount of NADPH powder was weighed and diluted in 10 mM MgCl 2 solution (working solution concentration: 10 mM; final concentration in the reaction system: 1 mM). Materials: NADPH powder: β-Nicotinamide adenine dinucleotide phosphate, reduced, tetrasodium salt; NADPH·4Na (Supplier: Chem-Impex International, Catalog No. 00616).

[0341] Preparation of liver microsomes. An appropriate concentration of microsome working solution was prepared in 100 mM potassium phosphate buffer. Materials: Human liver microsomes (HLM) Catalog No. 452117 and Lot No. 38295 (Corning); Sprague-Dawley (SD) rat liver microsomes (RLM) Catalog No. R1000 and Lot No. 1910100 (Xenotech).

[0342] Preparation of the stop solution. Cold (4 °C) acetonitrile (ACN) containing 200 ng / mL tolbutamide and 200 ng / mL labetalol as internal standards (IS) was used as the stop solution.

[0343] Assay procedure. Empty incubation plates (T60 and NCF60) were warmed for 10 minutes before use. Liver microsomes were diluted to 0.56 mg / mL with 100 mM phosphate buffer. 445 μL of the microsome working solution (0.56 mg / mL) was transferred to the pre-warmed "Incubation" plates T60 and NCF60. The "Incubation" plates T60 and NCF60 were then pre-incubated at 37 °C for 10 minutes with constant shaking. 54 μL of liver microsomes was transferred to a blank plate, then 6 μL of nAPDH cofactor was added to the blank plate, followed by 180 μL of quenching solution added to the blank plate. 5 μL of the compound working solution (100 μM) was added to the "Incubation" plates (T60 and NCF60) containing microsomes and mixed thoroughly 3 times. 50 μL of buffer was added to the NCF60 plate and mixed thoroughly 3 times. Start timing; the plates were incubated at 37 °C for 60 minutes with shaking. To the "Quench" plate T0, 180 μL of quenching solution and 6 μL of NAPDH cofactor were added. The plates were cooled to prevent evaporation. The T60 plate was mixed thoroughly 3 times and immediately 54 μL of the mixture was removed at the 0-minute time point to the "Quench" plate. Then, 44 μL of NAPDH cofactor was added to the incubation plate (T60). Start timing; the plates were incubated at 37 °C for 60 minutes with shaking. Final concentrations of each component in the incubation medium: microsomes (0.5 mg protein / mL); test compound (1 μM); control compound (1 μM); ACN (0.99%); and DMSO (0.01%). At 5, 15, 30, 45, and 60 minutes, 180 μL of quenching solution was added to the "Quench" plate, mixed once, and 60 μL of sample was continuously transferred from the T60 plate to the "Quench" plate at each time point. For the NCF60 plate, it was mixed once and at the 60-minute time point (start time 1:00:00 and end time 0:00:00), 60 μL of sample was transferred from the NCF60 incubation to the "Quench" plate containing the quenching solution. Table 2.1 provides the reaction plate incubation times.

[0344]

Table 2

[0345] All sampling plates were shaken for 10 minutes and then centrifuged at 4000 rpm for 20 minutes at 4°C. 80 μL of the supernatant was transferred to 240 μL of HPLC water and mixed on a plate shaker for 10 minutes. Each bioanalysis plate was sealed and shaken for 10 minutes, followed by LC-MS / MS analysis. Using the first-order kinetics, the half-life and CL were calculated as reported in Table 2.6. int(mic) (μL / min / mg)

[0346] Rat pharmacokinetics Formulation for PO. Weigh an appropriate amount of the test substance and mix it with an appropriate volume of vehicle to obtain a clear solution or a homogeneous suspension, although vortexing or sonication in a water bath may be used. Administer the animals within 4 hours after preparing the formulation. Take formulation samples from each of the formulation solutions or suspensions, transfer them to 1.5 mL polypropylene microcentrifuge tubes, and verify the dose by LC / UV or LC-MS / MS.

[0347] Dose administration. For PO administration, administer the dose formulation by oral gavage.

[0348] Blood collection. From the carotid artery cannula (CAC) of each animal, perform each blood collection (about 0.2 mL per time point) into a pre-cooled commercially available EDTA-K2 tube as an anticoagulant, and then place it on wet ice until centrifuged. Process the blood samples for plasma by centrifugation at about 4°C and 3200 g for 10 minutes. Collect the plasma respectively, transfer a certain amount of plasma from the rats to pre-labeled 96-well plates or polypropylene tubes, rapidly freeze them on dry ice, and maintain them at -60°C or below until LC-MS / MS analysis. After the final collection, store all the plasma in a freezer at about -80°C until the final analysis.

[0349] Plot the plasma concentration-time data on a graph and analyze it by a non-compartmental approach using the Phoenix WinNonlin 6.3 software program. The PO AUC calculation method used is linear / logarithmic trapezoid, and the values from this method are reported in Table 2.6. Trapezoid: before tMAX (linear); after Tmax (logarithmic). Sub-region interpolation: before tMAX (linear); after Tmax (logarithmic).

[0350] Table 2.2 provides the study design for determining rat pharmacokinetics. Table 2.3 provides the dosing schedule for PK analysis. Table 2.4 provides the sampling schedule.

[0351]

Table 3

[0352] Is cassette: True means administration of the cassette compound to this group. False means administration of a single compound. Is Diff: True means that the cassette compound administration and dose levels are different for each compound. False means that the dose levels are the same for each compound or for single compound administration.

[0353]

Table 4

[0354]

Table 5

[0355] Table 2.5 provides a list of selected IL-17 modulators disclosed herein that are used for comparative studies against reference compounds A - M.

[0356] Table 2.6 provides microsomal stability data and rat pharmacokinetic data for selected IL-17 modulators against reference compounds A - M. The data demonstrate improved microsomal stability and rat pharmacokinetics for the selected IL-17 modulators against reference compounds A - M.

[0357]

Table 6-1

[0358]

Table 6-2

[0359]

Table 6-3

[0360]

Table 7

Claims

[Claim 1] The invention described herein.