Condensed bicyclic heterocyclyl compounds as CCR4 modulators. This application claims priority and benefit of Indian Patent Application No. IN 202341031205, filed 2 May 2023, and Indian Patent Application No. IN 202341084043, filed 9 December 2023. These applications are incorporated herein by reference in their entirety.

Abstract

This application provides condensed bicyclic heterocyclyl compounds represented by formula (I) and derivatives thereof that are therapeutically useful as CCR4 modulators. These compounds are useful in the treatment and / or prevention of diseases and / or disorders in which modulation of CCR4 activity is involved. The compounds of this disclosure are particularly useful in the treatment of cancer and inflammatory diseases and disorders. This disclosure further provides a process for preparing the compounds and pharmaceutical formulations comprising at least one compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. [Formula 1] TIFF2026517794000113.tif47134

Description

[Technical Field]

[0001] This application relates to condensed bicyclic heterocyclyl compounds represented by formula (I) and their derivatives as CCR4 modulators useful for treating cancer and inflammatory diseases or disorders. The disclosure further provides pharmaceutically acceptable compositions comprising the compounds of this application and methods of using said compositions in the treatment of CCR4-related diseases. [Background technology]

[0002] Innate and adaptive immune responses, as well as their coordinated interactions, are essential for maintaining homeostasis and for effective immune surveillance against pathogens and inflammatory diseases. Key mediators of the immune system include immune cells and the cytokines they produce. Chemokines are a family of secreted small cytokines that regulate multiple processes, including cell adhesion, localization, migration, and cell-cell interactions (Clemens Esche, J Invest Dermatol. 2005 Oct;125(4):615-28).

[0003] Inflammatory chemokines, secreted by various cell types, regulate the recruitment of inflammatory effector cells such as leukocytes in response to infection, inflammation, tissue damage, and within the tumor microenvironment (Anna E Vilgelm, Front Immunol. 2019 Feb 27;10:333). They exert their effects through the activation of chemokine receptors on the cell surface of effector cells. Chemokine receptors belong to the large family of G protein-coupled receptors (GPCRs). Cells expressing chemokine receptors migrate in the direction of the respective chemokine gradient secreted by tissue-resident cells. CCR4 (CC chemokine receptor) is an important member of the GPCR family that plays a crucial role in the migration of immune cells in response to inflammatory chemokines CCL22 and CCL17 (Hongyi Li, MedComm (2020). 2022 Jun 8;3(2):e147).

[0004] Tumor cells and tumor-associated macrophages secrete CCL22, which recruits regulatory T cells (Tregs) expressing CCR4 into the tumor microenvironment. Increased infiltration of these Tregs leads to an immunosuppressive tumor microenvironment and is associated with a poor prognosis (Osamu Yoshie, Cancers (Basel). 2021 Nov 4;13(21):5542).

[0005] Therefore, CCR4 is involved in the pathogenesis of various immune-related diseases. Consequently, effectively modulating CCR4 is crucial for therapeutic interventions in inflammatory diseases and cancer. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Clemens Esche, J Invest Dermatol. 2005 Oct;125(4):615-28 [Non-Patent Document 2] Anna E Vilgelm, Front Immunol. 2019 Feb 27;10:333 [Non-Patent Document 3] Hongyi Li, MedComm (2020). 2022 Jun 8;3(2):e147 [Non-Patent Document 4] Osamu Yoshie, Cancers (Basel). 2021 Nov 4;13(21):5542 [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] This specification provides a compound represented by formula (I) and a pharmaceutical composition thereof that can modulate CCR4. [Means for solving the problem]

[0008] In one aspect of this disclosure, it is given by formula (I): [ka]

[0009] [During the ceremony, W1 is C, N, or O; X1 and X2 are independently CH, N, and NR. x , O, S, or -S(O)-; X3, X4, and X5 are each independently either C or N; R x is hydrogen or a C1-C6 alkyl group; Y1, Y2, Y3, and Y4 are each independently either C or N; In each occurrence, R1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR 1a , -C(O)R 1b or C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl may each be substituted with one or more substituents independently selected from halo, hydroxy, and C1-C6 alkoxy; R2 and R 2’ Each of these is independently hydrogen, a C1-C6 alkyl group, or a halo; R3 is hydrogen or a C1-C6 alkyl group; In each occurrence, R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR 4a , -C(O)R 4b or C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl may each be substituted with one or more substituents independently selected from halo, hydroxyl, and C1-C6 alkoxy; In each occurrence, R5 is independently a halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -C(O)R5a and; R6 at each occurrence is independently C1-C6 alkyl, halo, C1-C6 haloalkyl, cyano, -C(O)R 6a , -(C1-C3 alkyl)C(O)R 6a or -OR 6b and; R 1a and R 4a are each independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl; R 1b , R 4b and R 5a are each independently hydrogen, C1-C6 alkyl, hydroxy, amino, C1-C6 alkylamino, C1-C6 haloalkyl, C3-C6 cycloalkyl or C3-C6 heterocycloalkyl; R 6a is hydrogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, C1-C6 alkylamino or C3-C6 cycloalkyl; R 6b is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; “m” is selected from 0 to 5; “n” is selected from 0 to 3; “j” is selected from 0 to 4; “k” is selected from 0 to 2; “p” and “q” are each independently selected from 1 and 2; and, “z” is selected from 0 to 4〕 including a compound represented by the formula or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0010] In yet another aspect, the present application provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent).

[0011] In yet another embodiment, this application relates to the preparation of a compound represented by formula (I).

[0012] In yet another embodiment of this application, a compound represented by formula (I) capable of modulating CCR4 and its therapeutic use are provided. [Modes for carrying out the invention]

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art in the field to which the subject matter of the present invention pertains. Where used herein and in the appended claims, unless otherwise stated, the following terms have the meanings provided for the convenience of understanding this disclosure.

[0014] Where used herein, unless otherwise defined, the term "alkyl," alone or in combination with other terms, means a saturated aliphatic hydrocarbon chain, which is C1-C 10 Linear alkyl group or C1-C 10 This includes branched alkyl groups. Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl, and neopentyl.

[0015] Where used herein, unless otherwise defined, the term “alkenyl,” either alone or in combination with other terms, means an unsaturated aliphatic hydrocarbon chain, which is C1-C 10 Linear alkyl group or C1-C 10 It includes branched alkyl groups. Alkenyls may contain one or more double bonds, as well as two or more double bonds and / or one or more triple bonds. Examples of "alkenyls," though not limited to them, include vinyl, 2-propenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, and 3-(1,4-pentadienyl).

[0016] Where used herein, unless otherwise defined, the term “alkynyl,” either alone or in combination with other terms, means an unsaturated aliphatic hydrocarbon chain, which is C1-C 10 Linear alkyl group or C1-C 10 It includes branched alkyl groups. Alkynnyls can contain one or more triple bonds, as well as two or more triple bonds and / or one or more double bonds. Examples of "alkynyls," though not limited to them, include ethynyl, 1-propynyl, 3-propynyl, and 3-butynyl.

[0017] As used herein, the terms “halo” or “halogen,” either alone or in combination with other terms, mean fluorine, chlorine, bromine, or iodine.

[0018] Where used herein, the term “haloalkyl” means an alkyl group substituted with one or more halogen atoms, where alkyl groups are as defined above. The term “halo” is used herein interchangeably with the term “halogen” and means F, Cl, Br, or I. Examples of “haloalkyl” include, but are not limited to, fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, and 2,2,2-trifluoroethyl.

[0019] Where used herein, the terms "hydroxy" or "hydroxyl," either alone or in combination with other terms, mean -OH.

[0020] Where used herein, the term "hydroxyalkyl" refers to the group HO-alkyl-, where alkyl and hydroxyl groups are as defined herein.

[0021] As used herein, the term "alkoxy," either alone or in combination with other terms, refers to an alkyl-O- or -O-alkyl group, where alkyl is as defined above. Representative C1-C groups containing an alkoxy group. 10 Examples of alkyl groups, though not limited to them, include methoxy, ethoxy, n-propoxy, n-butoxy, and t-butoxy. The alkoxy group may be unsubstituted or substituted with one or more suitable groups.

[0022] Where used herein, the term “haloalkoxy” refers to an alkoxy group substituted with one or more halogen atoms (i.e., a halo-C substituted 1-8 alkoxy). Examples of “haloalkoxy” include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and 1-bromoethoxy.

[0023] Where used herein, the term "alkoxyalkyl" refers to the alkyl-O-alkyl- group, where alkyl and alkoxy groups are as defined above. Typical alkoxyalkyl- groups include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, and isopropoxymethyl.

[0024] The term "amino" or "amine" can be used alone or in combination with other terms to refer to a primary amine (-NH2) group, a secondary amine ( [ka]

[0025] Here, "N" is a group (substituted with two substituents other than hydrogen) or a tertiary amine ( [ka]

[0026] Here, "N" represents a group that is substituted with three substituents other than hydrogen.

[0027] As used herein, the term “alkylamino” means, alone or in combination with other terms, an amino group as defined above, which is substituted with one or more “alkyl” groups, where the alkyl and amino groups are as defined above. Examples of “alkylamino” groups include, but are not limited to, -NHCH3, -NHCH2CH3, -N(CH3)2, and -N(CH3)(CH2CH3).

[0028] As used herein, the term "cyano" means -CN; and the term "cyanoalkyl" means alkyl substituted with -CN; where the alkyl group is as defined above.

[0029] Where used herein, the term "nitro" refers to -NO2.

[0030] Where used herein, the term "cycloalkyl" is used alone or in combination with other terms as -C3-C 10 This refers to a saturated cyclic hydrocarbon ring. A cycloalkyl can be a single ring, which typically contains 3 to 7 carbon ring atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Alternatively, cycloalkyls can be polycyclic or contain multiple rings. Examples of polycyclic cycloalkyls include bridging carbon rings, fused carbon rings, and spirocyclic carbon rings.

[0031] As used herein, the term “aryl” refers to an unsubstituted or substituted monocyclic, bicyclic, or polycyclic aromatic hydrocarbon ring system of approximately 6 to 14 carbon atoms. C6-C 14Examples of aryl groups, though not limited to them, include phenyl, naphthyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthyl. The aryl group may be unsubstituted or substituted with one or more suitable groups.

[0032] Where used herein, the term "carbocyryl," either alone or in combination with other terms, encompasses both "cycloalkyl" and "aryl," where "cycloalkyl" and "aryl" are as defined above. Examples of "carbocyryl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and naphthyl.

[0033] The term "heterocycloalkyl" refers to a 3- to 15-membered non-aromatic saturated or partially saturated monocyclic or polycyclic ring system, where the ring system has at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)2, NH, or C(O), and the remaining ring atoms are independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. Monocyclic heterocycloalkyls typically contain 4 to 7 ring atoms. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, azepanyl, and their N-oxides. The bonding of heterocycloalkyl substituents can occur via either a carbon atom or a heteroatom. Heterocycloalkyl groups may be unsubstituted or may be substituted with one or more suitable groups by one or more of the aforementioned groups.

[0034] As used herein, the term “heteroaryl,” either alone or in combination with other terms, means a fully unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of these ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), and the remaining ring atoms / groups are independently selected from the group consisting of carbon, oxygen, nitrogen, or sulfur. Heteroaryls can be monocyclic or polycyclic ring systems. Examples of “heteroaryls,” but are not limited to, pyridyl, indolyl, benzimidazolyl, and benzothiazolyl.

[0035] Where used herein, the term “heterocyclyl,” either alone or in combination with other terms, encompasses both “heterocycloalkyl” and “heteroaryl” groups, where these groups are as defined above. Examples of “heterocyclyls,” but not limited to, include azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, indolyl, benzimidazolyl, and benzothiazolyl.

[0036] As used herein, the term "heteroatom" means a sulfur atom, a nitrogen atom, or an oxygen atom.

[0037] Where used in the above definition, the terms "optionally substituted," "substituted," or "optionally substituted with suitable" The term "groups)" indicates that one or more hydrogen radicals in a given structure are replaced by radicals of a particular substituent, where the particular substituents include, but are not limited to, halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that any of these substituents may be further substituted.

[0038] Where used herein, the term “compound” includes the compounds disclosed herein.

[0039] Where used herein, the terms “comprise” or “comprising” are generally used to mean “include,” that is, to allow the presence of one or more features or components.

[0040] Where used herein, the term "or" means "and / or" unless otherwise indicated.

[0041] As used herein, the term "including" and other forms, such as "include," "includes," and "included," are not limited to this specification.

[0042] Where used herein, the term “composition” is intended to encompass products containing specific amounts of specific components, and any products obtained directly or indirectly from specific amounts of specific combinations of components. “Pharmacologically acceptable” means that a carrier, diluent, or excipient is compatible with the other components of the formulation and is not harmful to its recipient.

[0043] Where used herein, the terms “treat,” “treating,” and “treatment” refer to methods of alleviating or suppressing a disease and / or its associated symptoms.

[0044] As used herein, the terms “prevent,” “preventing,” and “prevention” refer to methods of preventing the onset of a disease and / or its associated symptoms, or methods of preventing a person from contracting the disease. As used herein, “prevent,” “preventing,” and “prevention” also include delaying the onset of a disease and / or its associated symptoms, or reducing the risk of a person contracting the disease.

[0045] As used herein, the term “therapeutic effective amount” refers to the amount of compound administered that is sufficient to prevent or, to some extent, alleviate one or more symptoms of the condition or disorder being treated.

[0046] "Pharmacopoecitable" means useful in the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and such pharmaceutical composition includes those that are acceptable for veterinary and human pharmaceutical use.

[0047] Where used herein, the term “pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic, and not biologically or otherwise undesirable, and include those that are acceptable for veterinary and human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defined herein. For example, see the following: Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

[0048] Where used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound, where the parent compound is modified by converting an existing acidic or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts of this disclosure include, for example, conventional non-toxic salts of the parent compound formed from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of this disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or free base form of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of water and an organic solvent. Generally, non-aqueous media such as ether, ethyl acetate, alcohol, or acetonitrile (ACN) are preferred.

[0049] The term "stereoisomer" refers to any enantiomer, diastereoisomer, or geometric isomer of a compound represented by formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), and (IM) when the compound is chiral or has one or more double bonds. When the compounds represented by formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), and (IM) are chiral, they may exist in racemic form or in an optically active form. It should be understood that this disclosure encompasses all stereochemical isomer forms, including diastereomers, enantiomers, and epimers, as well as d-isomers, l-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials containing chiral centers, or by preparing a mixture of enantiomer products and then separating them, for example, by separation after conversion to a mixture of diastereomers, by recrystallization, by chromatographic techniques, by direct separation of enantiomers on a chiral chromatography column, or by any other suitable method known to those skilled in the art. Starting compounds having specific stereochemistry are commercially available or can be manufactured and divided by techniques known to those skilled in the art. Furthermore, the compounds of this disclosure may also exist as geometric isomers. This disclosure encompasses all cis isomers, trans isomers, syn isomers, anti isomers, R and S isomers, entgegen (E) and tuzamen (Z) isomers, and suitable mixtures thereof.

[0050] This disclosure provides compounds represented by formula (I) that are useful for modulating CCR4.

[0051] The disclosure further provides pharmaceutical compositions comprising compounds represented by formula (I) and derivatives thereof as therapeutic agents.

[0052] It will be readily apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of the various embodiments disclosed herein. For example, features illustrated or described as part of one embodiment can be applied to another embodiment to obtain yet another embodiment. Accordingly, this application is intended to encompass such modifications and variations and their equivalents. Other objects, features, and aspects of this application are disclosed in or evident from the following detailed description. It will be understood to those skilled in the art that this description is an exemplary description of embodiments and should not be construed as limiting broader aspects of this disclosure.

[0053] The following embodiments are illustrative and not intended to limit the claims to any specific embodiment described herein.

[0054] In the first embodiment, this application is, Equation (I): [ka]

[0055] [During the ceremony, W1 is C, N, or O; X1 and X2 are independently CH, N, and NR. x , O, S, or -S(O)-; X3, X4, and X5 are each independently either C or N; R x is hydrogen or a C1-C6 alkyl group; Y1, Y2, Y3, and Y4 are each independently either C or N; In each occurrence, R1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR 1a , -C(O)R 1bor C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl may each be substituted with one or more substituents independently selected from halo, hydroxy, and C1-C6 alkoxy; R2 and R 2’ Each of these is independently hydrogen, a C1-C6 alkyl group, or a halo; R3 is hydrogen or a C1-C6 alkyl group; In each occurrence, R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR 4a , -C(O)R 4b or C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl may each be substituted with one or more substituents independently selected from halo, hydroxyl, and C1-C6 alkoxy; In each occurrence, R5 is independently a halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -C(O)R 5a and; In each appearance, R6 is independently C1-C6 alkyl, halo, C1-C6 haloalkyl, cyano, -C(O)R 6a -(C1-C3 alkyl)C(O)R 6a OR 6b and; R 1a and R 4a These are, independently, hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl; R 1b , R 4b and R 5a Each of these is independently hydrogen, C1-C6 alkyl, hydroxy, amino, C1-C6 alkylamino, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl; R 6aThese are hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, or C3-C6 cycloalkyl; R 6b These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; "m" is selected from 0 to 5; "n" is selected from 0 to 3; "j" is selected from 0 to 4; "k" is selected from 0 to 2; "p" and "q" are independently selected from 1 and 2, respectively; and, "z" is selected from 0 to 4. The present invention provides a compound represented by [formula], or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0056] In another embodiment, this application relates to formula (I) [wherein, W1 is CH2, NH, or O; X1 and X2 are independently CH, N, and NR. x , O, S, or -S(O)-; X3, X4, and X5 are each independently either C or N; R x is hydrogen or alkyl; Y1, Y2, Y3, and Y4 are each independently either C or N; In each occurrence, R1 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR 1a , -C(O)R 1b or C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl may each be substituted with one or more substituents independently selected from halo, hydroxy, and C1-C6 alkoxy; R2 and R 2’ Each of these is independently hydrogen, a C1-C6 alkyl group, or a halo; R3 is hydrogen or a C1-C6 alkyl group; In each occurrence, R4 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR 4a , -C(O)R 4b or C3-C6 cycloalkyl; where C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl may each be substituted with one or more substituents independently selected from halo, hydroxyl, and C1-C6 alkoxy; In each occurrence, R5 is independently a halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or -C(O)R 5a and; In each appearance, R6 is independently C1-C6 alkyl, halo, C1-C6 haloalkyl, cyano, -C(O)R 6a -(C1-C3 alkyl)C(O)R 6a OR 6b and; R 1a and R 4a These are, independently, hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl; R 1b , R 4b and R 5a Each of these is independently hydrogen, C1-C6 alkyl, hydroxy, amino, C1-C6 alkylamino, C1-C6 haloalkyl, C3-C6 cycloalkyl, or C3-C6 heterocycloalkyl; R 6a These are hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, amino, C1-C6 alkylamino, or C3-C6 cycloalkyl; R 6b These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C3-C6 cycloalkyl; "m" is selected from 0 to 5; "n" is selected from 0 to 3; "j" is selected from 0 to 4; "k" is selected from 0 to 2; "p" and "q" are independently selected from 1 and 2, respectively; and, "z" is selected from 0 to 4. The present invention provides a compound represented by [formula], or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0057] In another embodiment of this application, formula (IA): [ka]

[0058] The present invention provides a compound represented by [formula], or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0059] In another embodiment of this application, formula (IB): [ka]

[0060] The present invention provides a compound represented by [formula], or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0061] In another embodiment of this application, formulas (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), and (IL): [ka] TIFF2026517794000009.tif130157

[0062] The present invention provides a compound represented by [formula], or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0063] In another embodiment of this application, formulas (IA-1), (IB-1), (IC-1), (ID-1), (IE-1), (IF-1), and (IG-1): [ka] TIFF2026517794000011.tif205158

[0064] The present invention provides a compound represented by [formula], or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0065] In another embodiment of this application, formulas (IA-2), (IB-2), (IC-2), (ID-2), (IE-2), (IF-2), (IG-2), and (IH-2): [ka] TIFF2026517794000013.tif73152

[0066] The present invention provides a compound represented by [formula], or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0067] In one embodiment of this application, compounds represented by formulas (I) to (IL), (IA-1) to (IG-1), and (IA-2) to (IH-2) are provided, where, [ka]

[0068] The ring represented by is [ka]

[0069] Here, the asterisk indicates the bond point with the azetidine ring.

[0070] In one embodiment of this application, compounds represented by formulas (I) to (IL), (IA-1) to (IG-1), and (IA-2) to (IH-2) are provided, where, [ka]

[0071] The ring represented by is [ka]

[0072] Here, the asterisk indicates the bond point with the azetidine ring.

[0073] In one embodiment, [ka]

[0074] The ring represented by is [ka]

[0075] Here, the asterisk indicates the bond point with the azetidine ring.

[0076] In one embodiment, [ka]

[0077] The ring represented by is [ka]

[0078] Here, the asterisk indicates the bond point with the azetidine ring.

[0079] In one embodiment, [ka]

[0080] The ring represented by is [ka]

[0081] Here, the asterisk indicates the bond point with the azetidine ring.

[0082] In one embodiment, [ka]

[0083] The ring represented by is [ka]

[0084] Here, the asterisk indicates the bond point with the azetidine ring.

[0085] In one embodiment, [ka]

[0086] The ring represented by is [ka]

[0087] Here, the asterisk indicates the bond point with the azetidine ring.

[0088] In one embodiment, [ka]

[0089] The ring represented by is [ka]

[0090] Here, the asterisk indicates the bond point with the azetidine ring.

[0091] In one embodiment of this application, a ring [ka]

[0092] Independently, [ka]

[0093] And here, the asterisk indicates R2 groups and R 2’ This represents the bond point with the carbon atom that has the group.

[0094] In one embodiment, X1 is N, NR x It is O, S, or -S(O)-.

[0095] In one embodiment, X2 is CH, N, O, S, or NR x That is the case.

[0096] In one embodiment, X1 is N, NR x , is O, S or -S(O)-, and X2 is N.

[0097] In one embodiment, X2 is CH, N, NR x , is O or S or -S(O)-, and X1 is N.

[0098] In one embodiment, X1 is N, O, or S; and X2 is N.

[0099] In one embodiment, X1 is N, O, S, or -S(O)-.

[0100] In one embodiment, X1 is N, O, or S.

[0101] In one embodiment, X1 is S or -S(O)-.

[0102] In one embodiment, X1 is S.

[0103] In one embodiment, X2 is CH, N, O, or NR x That is the case.

[0104] In one embodiment, X2 is CH, N, or O.

[0105] In one embodiment, X2 is N, O, or NR x That is the case.

[0106] In one embodiment, X2 is N or O.

[0107] In one embodiment, X2 is N.

[0108] In one embodiment, X1 is S and X2 is N.

[0109] In one embodiment, X1 is N, NR x It is either O or S.

[0110] In one embodiment, X1 is N, O, or S.

[0111] In one embodiment, X1 is N or O.

[0112] In one embodiment, X1 is O.

[0113] In one embodiment, X2 is C, N, or O.

[0114] In one embodiment, X1 is O and X2 is N.

[0115] In one embodiment, R1 in each occurrence is a halo.

[0116] In one embodiment, R1 in each occurrence is a halo, and "m" is between 0 and 3.

[0117] In one embodiment, R1 in each occurrence is a halo, and "m" is 2.

[0118] In one embodiment, R2 is a C1-C6 alkyl group or a halo, and R 2’ It is hydrogen.

[0119] In one embodiment, R2 is a C1-C6 alkyl group, and R 2’ It is hydrogen.

[0120] In one embodiment, R3 is hydrogen.

[0121] In one embodiment, R4 in each occurrence is independently a halo, C1-C6 alkyl, cyano, or -OR 4a or -C(O)R 4b And here, R 4a These are hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and R 4b These are hydrogen, C1-C6 alkyl, amino, C1-C6 alkylamino, or C1-C6 haloalkyl.

[0122] In one embodiment, R4 in each appearance is independently a halo, C1-C6 alkyl, cyano, and -OR 4a And here, R 4a These are hydrogen, a halo, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0123] In one embodiment, R4 in each occurrence is independently a halo, C1-C6 alkyl, or -OR 4a That is the case.

[0124] In one embodiment, R4 in each appearance is independently a halo, a C1-C6 alkyl, or a C1-C6 haloalkyl.

[0125] In one embodiment, R4 in each appearance is independently a halo or a C1-C6 haloalkyl.

[0126] In one embodiment, R4 in each appearance is a halo, C1-C6 alkyl, and -OR 4a Selected from; where R 4ais hydrogen, halo, C1-C6 alkyl or C1-C6 haloalkyl.

[0127] In one embodiment, R6 at each occurrence is independently C1-C6 alkyl, -(C1-C3 alkyl)C(O)R 6a or -C(O)R 6a where R 6a is hydroxy.

[0128] In one embodiment, R6 at each occurrence is independently C1-C6 alkyl or -C(O)R 6a where R 6a is hydroxy.

[0129] In one embodiment, each R6 at each occurrence is independently selected from -CH3, -CH2C(O)OH and -C(O)OH.

[0130] In one embodiment, each R6 at each occurrence is independently selected from -CH3 and -C(O)OH.

[0131] In one embodiment, W1 is C, N or O.

[0132] In one embodiment, X1 and X2 are each independently N, NR x , O, S or -S(O)-; X3, X4 and X5 are each independently C or N; R x is C1-C6 alkyl; Y1, Y2, Y3 and Y4 are each independently C or N; R1 at each occurrence is independently halo; R2 and R 2’ are each independently hydrogen, C1-C6 alkyl or halo; R3 is hydrogen; R4 at each occurrence is independently C1-C6 alkyl, cyano, halo, -OR 4a or C(O)R 4band wherein C1-C6 alkyl may be independently substituted with one or more substituents selected from one or more of halo and hydroxy; R 4a is hydrogen, halo, C1-C6 alkyl or C1-C6 haloalkyl; R 4b is hydrogen, C1-C6 alkyl, hydroxy, amino, C1-C6 alkylamino; R6 in each occurrence is independently C1-C6 alkyl or -C(O)R 6a ; R 6a is hydroxy; "m" is selected from 0 to 3; "n" is selected from 0 to 2; "j" is from 0 to 2; "k" is 1; "p" and "q" are each 1; and, "z" is selected from 0 to 4.

[0133] In one embodiment, X1 and X2 are each independently N, NR x , O, S or -S(O)-; X3, X4 and X5 are each independently C or N; R x is C1-C6 alkyl; Y1, Y2, Y3 and Y4 are each independently C or N; R1 in each occurrence is independently halo; R2 and R 2’ are each independently hydrogen, C1-C6 alkyl or halo; R3 is hydrogen; R4 in each occurrence is independently C1-C6 alkyl, halo or -OR 4a ; where R 4a is hydrogen, halo, C1-C6 alkyl or C1-C6 haloalkyl; R6 in each occurrence is independently C1-C6 alkyl or -C(O)R 6a ; R 6a It is hydroxyl; "m" is selected from 0 to 3; "n" is selected from 0 to 2; "j" is between 0 and 2; "k" is 1; "p" and "q" are each 1; and, "z" is selected from 0 to 4.

[0134] In one embodiment, X1 and X2 are independently N, NR x , O or S; X3, X4, and X5 are each independently either C or N; R x It is a C1-C6 alkyl group; In each occurrence, R1 is independently a halo; R2 and R 2’ Each of these is independently either hydrogen or a C1-C6 alkyl group; R3 is hydrogen; In each occurrence, R4 is independently a C1-C6 alkyl, halo, or -OR 4a And; here, the C1-C6 alkyl group may be independently substituted with one or more halos; R 4a These are C1-C6 alkyl or C1-C6 haloalkyl; In each occurrence, R6 is independently a C1-C6 alkyl or -C(O)R 6a and; R 6a It is hydroxyl; "m" is selected from 0 to 3; "n" is selected from 0 to 2; "j" is 0; "k" is 1; "p" and "q" are each 1; and, "z" is selected from 0 to 4.

[0135] In one embodiment, j is 0.

[0136] In one embodiment, k is 1.

[0137] In one embodiment, m is from 1 to 3.

[0138] In one embodiment, n is from 0 to 2.

[0139] In one embodiment, p and q are each 1.

[0140] In certain embodiments, the present application is [Table 1] TIFF2026517794000033.tif248150TIFF2026517794000034.tif227151TIFF2026517794000035.tif215151TIFF2026517794000036.tif215151TIFF2026517794000037.tif224151TIFF2026517794000038.tif220150TIFF2026517794000039.tif244150TIFF2026517794000040.tif103151

[0141] provides a compound selected from or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

[0142] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof described herein and at least one pharmaceutically acceptable excipient (e.g., a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in the present disclosure can be combined with a pharmaceutically acceptable excipient (e.g., a carrier or diluent), or diluted with a carrier, or encapsulated in a carrier that can be in the form of a capsule, sachet, paper or other container.

[0143] In yet another embodiment, the compounds of the present disclosure are CCR4 modulators.

[0144] In yet another embodiment, the compounds represented by formula (I) are CCR4 modulators.

[0145] In another embodiment, the present disclosure provides a pharmaceutical composition for use in the treatment and / or prevention of diseases and / or disorders responsive to modulation of CCR4 activity.

[0146] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof for use in the manufacture of a medicament for treating and / or preventing a disease and / or disorder responsive to modulation of CCR4 activity.

[0147] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.

[0148] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) for use in the treatment of a subject suffering from a disease or condition associated with CCR4.

[0149] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound represented by formula (I) for use in the manufacture of a medicament for treating a subject suffering from a disease or condition associated with CCR4.

[0150] The compounds of this disclosure are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared using procedures well known in the pharmaceutical field and contain at least one of the compounds of this disclosure. Pharmaceutical compositions of this disclosure contain one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, pharmaceutically acceptable excipients are approved by regulatory authorities or are generally considered safe for use in humans or animals. Examples of pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, flow enhancers and lubricants, preservatives, buffers, chelating agents, polymers, gelling agents, thickeners, and solvents.

[0151] The pharmaceutical composition can be administered orally, parenterally, or by inhalation. Examples of parenteral administration include administration by injection, transdermal administration, transmucosal administration, transnasal administration, and transpulmonary administration.

[0152] Examples of suitable carriers, though not limited to them, include water, salt solutions, alcohol, polyethylene glycol, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters, and polyoxyethylenes.

[0153] The pharmaceutical composition may also contain one or more pharmaceutically acceptable adjuvants, humectants, suspendants, preservatives, buffers, sweeteners, flavorings, colorants, or any combination thereof.

[0154] The pharmaceutical composition may be in conventional forms, such as tablets, capsules, solutions, suspensions, injections, or products for topical application. Furthermore, the pharmaceutical composition of this disclosure may be formulated to provide a desired release profile.

[0155] The compounds of this disclosure, whether in pure form or contained in a suitable pharmaceutical composition, may be administered using any of the permissible routes of administration of the pharmaceutical composition. Such routes may be any routes that effectively deliver the active compound of this disclosure to a suitable or desired site of action. Suitable routes of administration include, but are not limited to, oral, intranasal, oral cavity, intracutaneous, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, ​​intramuscular, or topical administration.

[0156] Examples of solid oral preparations include, but are not limited to, tablets, capsules (soft gelatin or hard gelatin), sugar-coated tablets (containing active ingredients in powder or pellet form), lozenges, and other similar preparations.

[0157] Liquid formulations include, but are not limited to, syrups, emulsions, and sterile injection solutions (e.g., suspensions or solutions).

[0158] Topical administration forms of the compound include ointments, pastes, creams, lotions, powders, solutions, eye drops or ear drops, and impregnated bandages, and may contain appropriate conventional additives such as preservatives and solvents to aid drug penetration.

[0159] The pharmaceutical compositions of this disclosure can be prepared by conventional techniques known in the literature.

[0160] Appropriate dosages of compounds for use in the treatment of diseases or disorders described herein can be determined by those skilled in the art. Therapeutic doses are generally determined through dose-finding studies in humans, based on preliminary evidence from animal studies. The dosage must be sufficient to produce the desired therapeutic benefit without causing undesirable side effects. Methods of administration, dosage forms, and appropriate pharmaceutically acceptable excipients can also be appropriately used and modified by those skilled in the art. All changes and modifications are assumed to be within the scope of this disclosure.

[0161] In one embodiment, the compounds disclosed in the present disclosure are formulated for pharmaceutical administration. Yet another embodiment of the present disclosure provides for the use of the compounds disclosed in this application in the treatment and prevention of diseases and / or disorders responsive to modulation of CCR4 activity.

[0162] Yet another embodiment of the present disclosure provides for the use of the compound or a pharmaceutically acceptable salt thereof in the treatment and / or prevention of diseases whose symptoms are treated, ameliorated, reduced, and / or prevented by modulation of CCR4.

[0163] According to yet another embodiment, the disorder and / or disease or condition mediated by CCR4 is cancer or an inflammatory disease or disorder.

[0164] According to yet another embodiment, the disorder and / or disease or condition mediated by CCR4 is cancer.

[0165] In yet another aspect of the embodiment, the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer, or colorectal cancer.

[0166] In yet another aspect of the embodiment, the cancer is colorectal cancer, pancreatic cancer, or intestinal cancer.

[0167] According to yet another embodiment, the disorder and / or disease or condition mediated by CCR4 is an inflammatory disease or disorder.

[0168] In yet another aspect of the embodiment, the inflammatory disease or disorder is dermatitis.

[0169] In yet another aspect of the embodiment, the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.

[0170] In yet another aspect of the embodiment, the inflammatory disease or disorder is atopic dermatitis.

[0171] In yet another embodiment of the embodiment, the inflammatory disease or disorder is contact dermatitis.

[0172] In yet another embodiment of the embodiment, the inflammatory disease or disorder is nodular prurigo.

[0173] In yet another embodiment of the embodiments, the inflammatory disease or disorder is related to Th2-related inflammation in various mucosal barriers, including, but not limited to, the lung and upper respiratory tract tissues. Accordingly, the present disclosure provides compounds for use in respiratory allergies, or for use in asthma, or for use in chronic sinusitis with or without nasal polyps (CRSwNP).

[0174] In yet another embodiment, the inflammatory disease or disorder is related to Th2-related inflammation in various mucosal barriers, including, but not limited to, upper and lower gastrointestinal tissues. Accordingly, the Disclosure provides compounds for use in eosinophilic esophagitis (EoE) and, but not limited to, inflammatory bowel disease (IBD). In yet another embodiment, the Disclosure provides compounds for the treatment of ulcerative colitis (UC) (which includes, but not limited to, Th2-related UC).

[0175] In yet another embodiment, the present disclosure provides a compound represented by formula (I) for use in the treatment of cancer.

[0176] In yet another embodiment, the subject is a mammal, including humans.

[0177] In yet another embodiment, the disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof for use as a pharmaceutical.

[0178] In yet another embodiment, the present disclosure provides the use of the compounds of the present disclosure in the manufacture of pharmaceuticals.

[0179] In yet another embodiment, the Disclosure provides compounds or pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of cancer or inflammatory diseases or disorders. In yet another embodiment, the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer, or colorectal cancer. In yet another embodiment, the cancer is skin cancer, which includes, but is not limited to, melanoma or invasive adenocarcinoma.

[0180] In yet another embodiment, the Disclosure provides compounds for use in the treatment of hematological cancers (which include, but are not limited to, T-cell lymphomas and leukemias). The Disclosure further provides compounds for use in established HTLV-1 virus-induced T-cell leukemias and lymphomas, or for use in preventing the development of leukemia in HTLV-1-positive patients.

[0181] In yet another embodiment, the Disclosure provides compounds for use in the treatment and / or prevention of CCR4 activity that promotes metastasis by tumor cells expressing CCR4 migrating to distant target organs expressing CCL17 or CCL22 via lymphatic vessels or blood circulation. Accordingly, the Disclosure provides compounds for use in suppressing metastasis to secondary lymphoid tissues (which include, but are not limited to, discharging lymph nodes, downstream lymph nodes, thymus, lungs, liver, bone marrow, skin, intestines, kidneys and brain).

[0182] In yet another embodiment, the disclosure provides compounds for use in the treatment and / or prevention of CCR4 activity, which promotes the migration of leukemia cells to sites resulting in the development of cutaneous lymphoma or thymic lymphoma through the recruitment of immunosuppressive regulatory T cells (Treg cells) that can inhibit tumor immunity and tumor removal.

[0183] In yet another embodiment, the Disclosure provides the use of the compounds of the Disclosure in the manufacture of pharmaceuticals for treating diseases and / or disorders that respond to modulation of CCR4 activity.

[0184] In yet another embodiment, the Disclosure provides a compound or a pharmaceutically acceptable salt or stereoisomer thereof for use in the treatment of a disease or disorder mediated by CCR4. In yet another embodiment, the Disclosure provides the use of the compounds of the Disclosure in the manufacture of a pharmaceutical for the treatment of cancer or an inflammatory disease or disorder.

[0185] In yet another embodiment, the disclosure provides the use of the compounds of the disclosure in the manufacture of a pharmaceutical product for the treatment of cancer.

[0186] In yet another embodiment, the Disclosure provides the use of the compounds of the Disclosure in the manufacture of a medicament for the treatment of cancer, wherein the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer, or colorectal cancer.

[0187] In yet another embodiment, the Disclosure provides the use of the compounds of the Disclosure in the manufacture of a pharmaceutical product for treating an inflammatory disease or disorder.

[0188] In yet another embodiment, the Disclosure provides the use of a compound of the Disclosure in the manufacture of a medicament for the treatment of an inflammatory disease or disorder, wherein the inflammatory disease or disorder is dermatitis. In yet another embodiment, the Disclosure provides the use of a compound of the Disclosure in the manufacture of a medicament for the treatment of an inflammatory disease or disorder, wherein the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.

[0189] In yet another embodiment, the application provides a compound for use as a pharmaceutical for treating subjects suffering from diseases and / or disorders that respond to modulation of CCR4 activity.

[0190] In yet another embodiment, the application provides a compound for use in the manufacture of a pharmaceutical for treating subjects suffering from diseases and / or disorders that respond to modulation of CCR4 activity.

[0191] In yet another embodiment, the Disclosure provides a compound of the Disclosure for use in the manufacture of a pharmaceutical product for the treatment of cancer.

[0192] In yet another embodiment, the Disclosure provides a compound of the Disclosure for use in the manufacture of a pharmaceutical product for treating inflammation.

[0193] In yet another embodiment, the Disclosure provides a compound of the Disclosure for use in the manufacture of a pharmaceutical for the treatment of cancer, wherein the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer, or colorectal cancer.

[0194] In yet another embodiment, the Disclosure provides a compound of the Disclosure for use in the manufacture of a pharmaceutical product for treating an inflammatory disease or disorder.

[0195] In yet another embodiment, the Disclosure provides a compound of the Disclosure for use in the manufacture of a pharmaceutical for treating an inflammatory disease or disorder, wherein the inflammatory disease or disorder is dermatitis.

[0196] In yet another embodiment, the Disclosure provides a compound of the Disclosure for use in the manufacture of a pharmaceutical for treating an inflammatory disease or disorder, wherein the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.

[0197] In yet another embodiment, the present disclosure includes administering a therapeutically effective amount of the compound of the present disclosure to a subject in need, together with one or more additional chemotherapeutic agents independently selected from antiproliferative agents, anticancer agents, immunosuppressants, and analgesics.

[0198] In yet another embodiment, the present disclosure includes administering a therapeutically effective dose of the compound of the present disclosure together with one or more additional anti-inflammatory agents to a subject in need.

[0199] The therapeutic methods disclosed herein include administering to patients (in particular humans) in need a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in a safe and effective quantity.

[0200] In certain embodiments, the Disclosure provides a method for treating a CCR4-mediated disease and / or disorder in a subject, the method comprising administering a therapeutically effective dose of a compound represented by formula (I) to the subject in need.

[0201] In certain embodiments, the Disclosure provides a method for modulating CCR4 in a subject, the method comprising contacting CCR4 with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0202] In certain embodiments, the Disclosure provides a method for treating or preventing a CCR4-mediated disease or disorder, the method comprising administering a therapeutically effective dose of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0203] In certain embodiments, the Disclosure provides a method for treating or preventing a disease or disorder mediated by CCR4, wherein the disease or disorder is cancer or an inflammatory disease or disorder.

[0204] According to certain embodiments, the present disclosure provides a method in which the disease or disorder is inflammation.

[0205] According to certain embodiments, the present disclosure provides a method in which the disease or disorder is dermatitis.

[0206] According to certain embodiments, the present disclosure provides a method in which the disease or disorder is atopic dermatitis or contact dermatitis.

[0207] According to certain embodiments, the present disclosure provides a method in which the disease or disorder is cancer.

[0208] According to certain embodiments, the Disclosure provides a method in which the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, stomach cancer, liver cancer, or colorectal cancer.

[0209] According to certain embodiments, the Disclosure provides a method comprising administering a therapeutically effective dose of the Compound of the Disclosure to a subject in need, together with one or more chemotherapeutic agents or anti-inflammatory agents.

[0210] The compounds described herein are indicated for both therapeutic and / or prophylactic treatment of the conditions described above. With regard to the therapeutic uses described above, the dose administered will naturally vary depending on the compound used, the method of administration, the desired treatment, and the disease or disorder to which the indication is directed.

[0211] The compounds of this disclosure can be used as single agents or as pharmaceutical compositions in which the compounds are mixed with various pharmacologically acceptable materials.

[0212] According to one embodiment, the present disclosure provides compounds for use in combination with other compounds or biological entities to treat inflammatory diseases or cancer. Appropriate combinations and doses of compounds for combination therapies used in the treatment of the diseases or disorders described herein can be determined by those skilled in the art. Combination therapies relating to the compounds of the present disclosure can be used to treat inflammatory diseases or cancer.

[0213] According to one embodiment, the compounds of the Disclosure may also contain isotopes of an unnatural ratio in one or more of the atoms constituting the compound. For example, the Disclosure also includes isotope-labeled variants of the Disclosure which are identical to the compounds described herein except that one or more atoms of the compound are replaced by atoms having an atomic weight or mass number different from the major atomic weight or mass number commonly found in nature with respect to those atoms. All isotopes of any identified atom or element are included within the scope of the compounds of the Disclosure and their uses. Representative isotopes that can be incorporated into the compounds of the Disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, for example, 2 H ("D") 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I and 125 Examples include I. The isotope-labeled compounds of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with isotope-labeled reagents, following procedures similar to those disclosed in the schemes and / or examples below.

[0214] Experimental section This application provides a method for preparing the compound represented by formula (I) in accordance with the description herein, using appropriate methods and / or materials. Those skilled in the art will understand that these intermediates and compounds can be prepared using known variations of the conditions and processes of the following procedure. Furthermore, by utilizing the procedure described in detail, those skilled in the art can prepare further compounds of this disclosure.

[0215] The following general guidelines apply to all experimental procedures described herein. Unless otherwise indicated, experiments are conducted under positive nitrogen pressure, and temperatures mentioned are external temperatures (i.e., oil bath temperatures). Reagents and solvents obtained from suppliers are used as is, without further drying or purification. Molar concentrations of reagents in solution mentioned herein are approximate values ​​as they have not been confirmed by pre-titration with standard solutions. All reactants are stirred under a magnetic stirring bar. Cooling to sub-zero temperatures was performed using acetone / dry ice or wet ice / salt. Magnesium sulfate and sodium sulfate were used as solvent dehydrators after workup of the reaction, but these are interchangeable. Removal of the solvent under reduced pressure or vacuum means distillation of the solvent in a rotary evaporator.

[0216] The compounds of this disclosure can be prepared by synthetic chemical processes (examples of which are shown herein). It should be understood that the order of the steps in the process is modifiable, the reagents, solvents and reaction conditions specifically described are substituted, and fragile substructures can be protected and deprotected as needed.

[0217] Details of the process for preparing the compounds of this disclosure are described in the Experiments section.

[0218] This disclosure is illustrated by several embodiments, but these embodiments should not be construed as limiting the scope of this disclosure.

[0219] Unless otherwise specified, post-treatment includes partitioning the reaction mixture between the organic and aqueous phases, separating the layers, dehydrating the organic layer with anhydrous sodium sulfate, filtering, and evaporating the solvent. Unless otherwise specified, purification includes purification by silica gel chromatography (which generally uses an ethyl acetate / petroleum ether mixture with appropriate polarity as the mobile phase).

[0220] The analysis of the compounds of this disclosure was carried out by general methods well known to those skilled in the art, unless otherwise described. While this disclosure has been described with reference to certain preferred embodiments, other embodiments will also be apparent to those skilled in the art from the considerations herein. This disclosure is further defined with reference to the following examples, which detail the analysis of the compounds of this disclosure.

[0221] Those skilled in the art will readily understand that many modifications can be made to both the materials and methods without departing from the scope of this disclosure. Unless otherwise indicated, some of the intermediates were moved to the next stage based on the TLC results without further characterization.

[0222] Abbreviation: DIPA - Diisopropylamine; NBS - N-bromosuccinimide; DMF - N,N-dimethylformamide; ACN - Acetonitrile; Â - Acetyl acetate; THF - Tetrahydrofuran; ACOH - Acetic acid; TFAA - Trifluoroacetic anhydride; Et2O - Diethyl ether; MeMgBr - Methylmagnesium bromide; mCPBA - Methachloroperoxybenzoic acid; 1,2-DME - 1,2-dimethoxyethane; MeI - Methyl iodide; DCM - Dichloromethane; MeNH2 - Methylamine; MeOH - methanol; EtOH - Ethanol; DMSO - Dimethyl sulfoxide; MeI - Methyl iodide; NaOtBu - sodium tert-butoxide; KOtBu - potassium tert-butoxide; t-BuOH - tert-butyl alcohol; CsF - Cesium fluoride; BINAP - 2,2'-bis(diphenylphosphin)-1,1'-binaphthyl; DEA - Diethanolamine; DIPEA - N,N-diisopropylethylamine; TFA - Trifluoroacetic acid; TLC - Thin-layer chromatography; LC-MS - Liquid Chromatography-Mass Spectrometry; HPLC - High-performance liquid chromatography; DMSO-d6-Deuterated Dimethyl Sulfoxide; NMR - nuclear magnetic resonance; s - single line; d - double line; t - triple line; q - quadruple line; app.quint - an apparent quintuplet; dd - double line of double lines; td - double line, triple line; SM - Starting material; Int - intermediate; Comp. - Compound; RB - round bottom; RT - room temperature; MHz - Megahertz; RM - reaction mixture; DMP - Desmartin Periodinaan; Et3N - Triethylamine.

[0223] Synthesis of intermediates Intermediate I-1: Synthesis of 7-bromo-6-chlorobenzo[d]oxazole-2-thiol [ka]

[0224] Step 1: Synthesis of tert-butyl (4-chloro-2-hydroxyphenyl)carbamate (1b) 2-amino-5-chlorophenol (5 g, 34.8 mmol) was dissolved in THF (50 mL) and, while stirring, anhydrous Boc (11.4 g, 52.2 mmol) was added at 0°C. The resulting reaction mixture was raised to room temperature and stirred at that temperature for 4 hours. After the reaction was complete, it was diluted with ice-cold water, extracted with ethyl acetate, and the layers were separated. The organic layer was dehydrated with anhydrous Na₂SO₄, filtered, and concentrated to obtain the crude compound. The crude compound was purified by combi-flash chromatography using 10% ethyl acetate in hexane as the eluent to obtain the pure title compound 1b (5 g, 58.9% yield).

[0225] LC-MS: 242.0 [MH] - . Step 2: Synthesis of tert-butyl (3-bromo-4-chloro-2-hydroxyphenyl)carbamate (1c) A solution of tert-butyl (4-chloro-2-hydroxyphenyl)carbamate (0.5 g, 2.052 mmol) was dissolved in CH2Cl2 (10 mL). While stirring, diisopropylamine (0.441 g, 4.1 mmol) and NBS (0.29 g, 1.64 mmol) were added at 0°C. The reaction mixture was heated to room temperature and stirred for 4 hours. After the reaction was complete, the mixture was quenched with saturated sodium thiosulfate aqueous solution, extracted with CH2Cl2, and the layers were separated. The organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by combi-flash chromatography using 5% ethyl acetate in hexane as the eluent to obtain the pure title compound 1c (0.2 g, 30.2%).

[0226] LC-MS: 321.9 [MH] - . Step 3: Synthesis of 6-amino-2-bromo-3-chlorophenol (1d) A solution of tert-butyl (3-bromo-4-chloro-2-hydroxyphenyl)carbamate (0.12 g, 0.37 mmol) was dissolved in CH2Cl2 (1 mL), and 4 M HCl (1 mL) in dioxane was added at 0°C while stirring. The resulting reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete, the mixture was quenched with saturated aqueous NaHCO3, extracted with ethyl acetate, and the layers were separated. The organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the title compound 1d (0.1 g).

[0227] LC-MS: 223.9 [M+H] + . Step 4: Synthesis of 7-bromo-6-chlorobenzo[d]oxazole-2-thiol (I-1) 6-amino-2-bromo-3-chlorophenol (0.5 g, 2.24 mmol) was dissolved in acetonitrile (10 mL), and while stirring, di(1H-imidazole-1-yl)methanethion (0.8 g, 4.49 mmol) was added at 0°C. The resulting reaction mixture was heated to room temperature and stirred at 85°C for 4 hours. After the reaction was complete, it was cooled to room temperature, quenched with 1N HCl, extracted with ethyl acetate, and the layers were separated. The organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the title compound I-1 (0.55 g).

[0228] LC-MS: 263.8 [MH] - . Intermediate I-2: Synthesis of 7-bromobenzo[d]oxazole-2-thiol [ka]

[0229] Stage 1: 7-bromobenzo[d]oxazole-2-thiol (I-2) 2-amino-6-bromophenol (3 g, 15.9 mmol) was dissolved in methanol (50 mL). While stirring, potassium ethylxanthate (2.83 g, 17.8 mmol) was added to the solution at room temperature, and the resulting reaction mixture was stirred at 65 °C for 7 hours. After the reaction was complete, the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was dissolved in water and acidified with 1 N HCl. The precipitated solid was filtered and washed with water. The resulting residue was dissolved with ethyl acetate, washed with water, and the two layers were separated. The organic layer was dehydrated with anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a dark brown solid I-2 (2.36 g). This was used as is without further purification.

[0230] LC-MS: 229.8 [MH] - . The intermediates listed in Table A below were prepared using the same procedure as described in the synthesis of I-1 and I-2, with appropriate modifications to the cyclization method, reactants, reagents, solvent amounts, and reaction conditions. The characteristic data of these compounds are summarized in the table below. [Table 2]

[0231] TIFF2026517794000044.tif92163

[0232] Intermediate I-3: Synthesis of 4-bromo-2-chloro-1-methyl-1H-benzo[d]imidazole [ka]

[0233] Step 1: Synthesis of 4-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (3b) 3-Bromo-N 1-Methylbenzene-1,2-diamine (0.75 g, 3.73 mmol) was dissolved in THF (15 mL) and, while stirring, triphosgene (0.332 g, 1.11 mmol) was added at room temperature. The resulting reaction mixture was stirred at the same temperature for 20 minutes. After the reaction was complete, the reaction mixture was quenched with water, extracted with ethyl acetate, and the layers were separated. The organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the title compound 3b (0.79 g).

[0234] LC-MS: 228.8 [M+H] + . Step 2: Synthesis of 4-bromo-2-chloro-1-methyl-1H-benzo[d]imidazole (I-3) In an RB flask, a mixture of 4-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one (1.5 g, 6.6 mmol) and POCl3 (20.2 g) was heated at 100°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, quenched with ice water, extracted with ethyl acetate, and the layers were separated. The organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the title compound I-3 (0.8 g, 49.3%).

[0235] 1 H-NMR (400 MHz, CDCl3): δ 7.5 (d, 1H), 7.48 (d, 1H), 7.26-7.18 (m, 1H), 3.82 (s, 3H). Intermediate I-4: Synthesis of 7-bromo-2-chloro-1-methyl-1H-benzo[d]imidazole [ka]

[0236] Step 1: Synthesis of 2-bromo-N-methyl-6-nitroaniline (4b) Compound 4a (9 g, 40.9 mmol) in methylamine in MeOH (90 mL) was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain crude solid 4b (10 g crude yield). This was used without further purification.

[0237] LC-MS: 232.1 [M+H]+ . Stage 2: 6-Bromo-N 1 Synthesis of methylbenzene-1,2-diamine(4c) 2-Bromo-N-methyl-6-nitroaniline (4b) (3 g, 12.9 mmol) was dissolved in AcOH:siRNA:water (3:1:0.1, 42 mL). Iron powder (2.9 g, 51.9 mmol) was added to the solution while stirring, and the mixture was heated at 80°C for 1 hour. The reaction was monitored by TLC. After the reaction was complete, the mixture was quenched with ice water and extracted with CH2Cl2. The organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound 4c (1.6 g, 62% yield).

[0238] LC-MS: 202.2 [M+H] + . Step 3: Synthesis of 7-bromo-1-methyl-1H-benzo[d]imidazole-2-thiol (4d) 6-Bromo-N 1 -Methylbenzene-1,2-diamine (4c) (1.6 g, 7.9 mmol) was dissolved in ACN (60 mL) and, while stirring, 1,1'-carbonyldiimidazole (2.67 g, 14.9 mmol) was added, and the mixture was stirred at 100 °C for 6 hours. The progress of the reaction was monitored by TLC. After the starting materials were complete, the reaction mixture was quenched with 1(N)HCl, extracted with ethyl acetate, and concentrated to obtain the title compound 4d (crude yield of 1.3 g).

[0239] LC-MS: 244.1 [M+H] + . Step 4: Synthesis of 7-bromo-2-chloro-1-methyl-1H-benzo[d]imidazole (I-4) 7-Bromo-1-methyl-1H-benzo[d]imidazole-2-thiol (4d) (0.5 g, 2.05 mmol) was dissolved in thionyl chloride (2.1 mL, 28.7 mmol) under argon at room temperature, followed by the addition of 2 drops of DMF as a catalyst. The reaction mixture was heated at 80°C for 30 minutes. After cooling to room temperature, toluene was added, and the mixture was evaporated to remove excess SOCl2. The residue was poured into cold water and extracted with toluene. The organic phase was dehydrated with Na2SO4, filtered, and evaporated to obtain the crude product. This was purified by flash chromatography using 15% ethyl acetate in hexane to obtain the title compound I-4 (0.4 g, 85% yield).

[0240] LC-MS: 246.5 [M+H] + . Intermediate I-5: Synthesis of 7-bromobenzo[d]thiazole-2-thiol [ka]

[0241] Potassium ethylxanthate (3.73 g, 23.1 mmol) was added to a solution of 5a (2 g, 10.52 mmol) dissolved in DMF (20 mL) while stirring, at room temperature. The resulting reaction mixture was stirred at 120 °C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and acidified with 1 N HCl. The precipitated solid was filtered, washed with water, and dried to obtain the title compound (crude yield of 1.9 g). This was used directly in the next step.

[0242] LC-MS: 248.0 [M+H+1] + . The intermediates listed in Table B below were prepared using the same procedure as described in the synthesis of I-5, with appropriate modifications to the cyclization method, reactants, reagents, solvent amounts, and reaction conditions. The characteristic data of these compounds are summarized in the table below. [Table 3]

[0243] Intermediate I-6: [ka]

[0244] Step 1: Synthesis of 2,6-dibromo-3-fluoroaniline (6b) A solution of 3-fluoroaniline (1 g, 8.99 mmol) dissolved in acetonitrile (30 mL) was stirred, and 1-bromopyrrolidine-2,5-dione (3.2 g, 17.9 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product. This was purified by flash chromatography using 1% ethyl acetate in hexane as the eluent to obtain the pure title compound 6b (2 g, 82.5% yield).

[0245] LC-MS: 269.9 [M+H] + . Step 2: Synthesis of 4-bromo-7-fluorobenzo[d]thiazole-2-thiol(I-6) 2,6-Dibromo-3-fluoroaniline (6b) (2 g, 7.44 mmol) was dissolved in DMF (20 mL) and, while stirring, ethyl xanthogenic acid (2 g, 16.36 mmol) was added and the mixture was stirred at 120 °C for 12 hours. After the reaction was complete, the reaction mixture was quenched with 1 N HCl solution to obtain a solid. This was filtered to obtain the pure title compound I-6. This was used in the next step without further purification.

[0246] LC-MS: 266.1 [M+1+H] + . Intermediate I-7: Synthesis of (1R,3r)-3-((R)-3-(azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutan-1-carboxylic acid [ka]

[0247] Step 1: Synthesis of (1R,3r)-3-((R)-3-(1-(tert-butoxycarbonyl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (7d) A solution of tert-butyl (R)-3-(piperidine-3-yl)azetidine-1-carboxylate (7a) (15 g, 62.4 mmol) and 1-methyl-3-oxocyclobutane-1-carboxylic acid (7b) (6.39 g, 49.9 mmol) dissolved in toluene (300 mL) was stirred, and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (7c) (18.9 g, 74.8 mmol) was added to it. The mixture was refluxed for 16 hours in a round-bottomed container equipped with a Dean-Stark condenser. The reaction mixture was cooled to room temperature, quenched with water, washed with ethyl acetate, and the aqueous layer was concentrated to obtain the title compound 7d (crude yield of 21 g).

[0248] LC-MS: 353.15 [M+H] + . Stage 2: (1R,3r)-3-((R)-3-(azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutan-1-carboxylic acid (I-7) (1R,3r)-3-((R)-3-(1-(tert-butoxycarbonyl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutan-1-carboxylic acid (7d) (20 g, 56.7 mmol) was dissolved in water (160 mL), and concentrated HCl (40 mL) was added at 0°C. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. The reaction mixture was then washed with diethyl ether, followed by ethyl acetate, and the aqueous portion was neutralized with 6N NaOH aqueous solution. The aqueous portion was concentrated, and 20% methanol in CH2Cl2 was added to the resulting residue and filtered. The filtrate was concentrated, and the residue was washed with diethyl ether to obtain the title compound I-7 in quantitative yield.

[0249] LC-MS: 253.2 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d 6) 3.70-3.59 (m, 2H), 3.55-3.45 (m, 2H), 2.67-2.52 (m, 2H), 2.48-2.30 (m, 3H), 1.68-1.42 (m, 6H), 1.4-1.2 (m, 3H), 1.77 (s, 3H), 0.80-0.65 (m, 1H). Intermediate A-23: 2-(1-(3-(azetidine-3-yl)piperidine-1-yl)cyclobutyl)acetic acid hydrochloride: [ka]

[0250] Step 1: Synthesis of ethyl 2-cyclobutylidene acetate Reagent A was dissolved in THF, and while stirring, ethyl 2-diethoxyphosphoryl acetate (B) and potassium hydroxide were added at 0°C under an argon atmosphere. The reaction mixture was slowly heated to room temperature and stirred for 12 hours. The reaction was then monitored by TLC, and after completion, it was quenched with water and extracted with diethyl ether. The organic layers were combined and concentrated to obtain crude intermediate C of compound A-23. This was used in the next step.

[0251] LC-MS: 141.2 [M+H] + Step 2: Synthesis of tert-butyl 3-(1-(1-(2-ethoxy-2-oxoethyl)cyclobutyl)piperidine-3-yl)azetidine-1-carboxylate Intermediate C and intermediate D were dissolved in ACN, and while stirring, 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine was added, and the mixture was stirred at 65°C for 72 hours under an argon atmosphere. After the reaction was complete, the mixture was monitored by TLC, and the crude product was obtained by evaporation to dryness. This was purified by combiflash column chromatography (elution with 0-20% MeOH:DCM) to obtain the pure intermediate E of compound A-23.

[0252] LC-MS: 381.5 [M+H] + Step 3: Synthesis of 2-(1-(3-(1-(tert-butoxycarbonyl)azetidine-3-yl)piperidine-1-yl)cyclobutyl)acetic acid Intermediate E was dissolved in THF:EtOH:H2O (2:2:1), and while stirring, sodium hydroxide (3 eq.) was added at 0°C and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, washed with 1N HCl, and extracted with 10% MeOH:DCM. The organic layers were combined and concentrated to obtain crude intermediate F of compound A-23. This was used in the next step.

[0253] LC-MS: 353.5 [M+H] + Step 4: Synthesis of 2-(1-(3-(azetidine-3-yl)piperidine-1-yl)cyclobutyl)acetic acid hydrochloride Intermediate F was dissolved in DCM, and while stirring, 4M HCl in 1,4-dioxane was added to the solution at 0°C under an argon atmosphere. The resulting reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, it was concentrated under reduced pressure to obtain crude salt A-23, which was used in the next step.

[0254] LC-MS: 252.5 [M] + Intermediate A-24: Synthesis of (1r,3r)-3-(2-(azetidine-3-yl)morpholino)-1-methylcyclobutan-1-carboxylic acid: [ka]

[0255] Step 1: Synthesis of tert-butyl 3-formylazetidine-1-carboxylate tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (5 g, 26.70 mmol) was dissolved in DCM (50 mL), and desmartin periodinane (13.59 g, 32.04 mmol) was added to the solution at 0°C while stirring. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored by TLC, which showed that no starting material was present. The reaction mixture was cooled to 0°C, poured into a saturated NaHCO3 solution, extracted with DCM, the organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (elution with 0-60% siRNA in hexane) to obtain intermediate B (4.5 g, 91%) of compound A-24.

[0256] 1 H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 4.164-4.081 (m, 4H), 1.460 (S, 9H) Step 2: Synthesis of tert-butyl 3-(1-hydroxy-2-nitroethyl)azetidine-1-carboxylate A solution of tert-butyl 3-formylazetidine-1-carboxylate (4.5 g, 24.25 mmol) was dissolved in MeOH (50 mL). Triethylamine (7.3 g, 72.80 mmol) and nitromethane (4.45 g, 72.88 mmol) were added at 0°C while the solution was stirred. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC, which showed that no starting materials were present. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (elution with 0-60% siRNA in hexane) to obtain intermediate C (4.40 g, 91%) of compound A-24.

[0257] LC-MS: 245.0 [M+H] + Step 3: Synthesis of tert-butyl 3-(2-amino-1-hydroxyethyl)azetidine-1-carboxylate A solution of tert-butyl 3-(1-hydroxy-2-nitroethyl)azetidine-1-carboxylate (4 g, 16.24 mmol) was dissolved in MeOH (50 mL), and Pd / C (10%) (1.3 g) was added at room temperature while stirring. The resulting reaction mixture was stirred at room temperature for 16 hours under an H2 balloon pressure (30 psi). The reaction was monitored by TLC, which showed that no starting material was present. The reaction mixture was filtered through a Celite pad and further washed with excess MeOH. The filtrate was concentrated under reduced pressure to obtain crude intermediate D (4.0 g) of compound A-24.

[0258] LC-MS: 217.2 [M+H] + Step 4: Synthesis of tert-butyl 3-(2-(2-chloroacetamide)-1-hydroxyethyl)azetidine-1-carboxylate 3.7 g, 17.11 mmol of tert-butyl 3-(2-amino-1-hydroxyethyl)azetidine-1-carboxylate was dissolved in 40 mL of DCM. Triethylamine (5.19 g, 51.32 mmol) and chloroacetyl chloride (2.13 g, 18.81 mmol) were added to the solution at 0°C while stirring. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC, which showed that no starting materials were present. The reaction mixture was cooled to 0°C, poured into a saturated NaHCO3 solution, extracted with DCM, the organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by flash chromatography (elution with 0-80% siRNA in hexane) to obtain intermediate F (2.8, 56%) of compound A-24.

[0259] LC-MS: 193.1[M-Boc] + Step 5: Synthesis of tert-butyl 3-(5-oxomorpholin-2-yl)azetidine-1-carboxylate A solution of tert-butyl 3-(2-(2-chloroacetamide)-1-hydroxyethyl)azetidine-1-carboxylate (2.7 g, 9.22 mmol) was dissolved in tBuOH (25 mL), and KOtBu (2.07 g, 18.44 mmol) was added at 0°C while stirring. The resulting reaction mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC, which showed that no starting material was present. The reaction mixture was cooled to 0°C, poured into ice water, extracted with SiO2, the organic layer was washed with brine, dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure to obtain intermediate G (2.2 g) of compound A-24.

[0260] LC-MS: 157.1[M-Boc] + Step 6: Synthesis of tert-butyl 3-(morpholine-2-yl)azetidine-1-carboxylate A solution of tert-butyl 3-(5-oxomorpholin-2-yl)azetidine-1-carboxylate (0.9 g, 3.51 mmol) was dissolved in THF (15 mL). While stirring, BH3 (1 M) (0.91 g, 10.53 mmol) from THF was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 6 hours. The reaction was monitored by TLC, which showed that no starting material was present. The reaction mixture was cooled to 0°C, gradually quenched with MeOH, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash chromatography (elution with 0-20% MeOH in DCM) to obtain intermediate H (0.35 g, 41%) of compound A-24.

[0261] LC-MS: 243.2 [M+1] + Step 7: Synthesis of 3-(2-(1-(tert-butoxycarbonyl)azetidine-3-yl)morpholino)-1-methylcyclobutane-1-carboxylic acid A solution of tert-butyl 3-(morpholine-2-yl)azetidine-1-carboxylate (0.15 g, 0.62 mmol) dissolved in toluene (5 mL) was stirred, and 1-methyl-3-oxocyclobutane-1-carboxylic acid (0.087 g, 0.68 mmol) and Hanch ester (0.2 g, 0.8 mmol) were added at room temperature. The resulting reaction mixture was stirred at 110 °C for 16 hours. The reaction was monitored by TLC, which showed that no starting materials were present. The reaction mixture was cooled to room temperature, poured into water, and washed with ethyl acetate to remove impurities. The aqueous layer was then concentrated under reduced pressure to obtain intermediate J (0.25 g) of compound A-24.

[0262] LC-MS: 355.2[M+1] + Step 8: Synthesis of 3-(2-(azetidine-3-yl)morpholino)-1-methylcyclobutan-1-carboxylic acid hydrochloride 3-(2-(1-(tert-butoxycarbonyl)azetidine-3-yl)morpholino)-1-methylcyclobutane-1-carboxylic acid (0.15 g, 0.62 mmol) was dissolved in water (5 mL), and concentrated HCl (2.5 mL) was added at 0°C while stirring. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by TLC, which showed that no starting material was present. The reaction mixture was cooled to room temperature, poured into water, and washed with ethyl acetate to remove impurities. The aqueous layer was then concentrated under reduced pressure to obtain crude compound A-24 (0.2 g).

[0263] LC-MS: 255.2[M+1] + . Intermediate I-8 to Intermediate I-10: [ka]

[0264] Step 1: Synthesis of 4-amino-2-(methylthio)thiazole-5-carbonitrile (8c) A suspension of Na2S (5.4 g, 68.4 mmol, 1 eq.) in DMF (80 mL) was stirred, and dimethyl cyanodithioiminocarbonate (10 g, 68.4 mmol, 1 eq.) was added to it. The reaction mixture was heated at 70°C for 2 hours. Next, chloroacetonitrile (10.3 g, 136.8 mmol, 2 eq.) was slowly added to the reaction mixture at 70°C and stirred at the same temperature for 2 hours. Subsequently, potassium carbonate was added to the reaction mixture and stirred at the same temperature for 1 hour. After the reaction was complete, the mixture was poured into water with stirring to obtain a solid precipitate. This precipitate was filtered, washed with water, and dried under reduced pressure to obtain the title compound 8c (crude yield of 7.8 g).

[0265] LC-MS: 172.2 [M+H] + . Step 2: Synthesis of 2-(methylthio)thiazolo[4,5-d]pyrimidine-7(6H)-one(8d) A solution of 4-amino-2-(methylthio)thiazole-5-carbonitrile (8c) (1.1 g, 6.42 mmol) was dissolved in formic acid (4 mL). While stirring, water (1 drop) was added, and the mixture was heated under reflux for 4 hours. The progress of the reaction was monitored by TLC. The mixture was allowed to stand at room temperature until the reaction was complete, then added to ice water to obtain a precipitate. This precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain compound 8d (crude yield of 0.85 g).

[0266] LC-MS: 200.2 [M+H] + . Step 3: Synthesis of 7-chloro-2-(methylthio)thiazolo[4,5-d]pyrimidine (I-8) A solution of 2-(methylthio)thiazolo[4,5-d]pyrimidine-7(6H)-one (8d) (0.1 g, 0.5 mmol) dissolved in POCl3 (1 mL) was heated at 110°C for 1 hour with stirring. The progress of the reaction was monitored by TLC analysis. After the reaction was complete, the solution was added to ice water to obtain a precipitate. This precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain compound I-8 (crude yield of 0.05 g).

[0267] LC-MS: 218.7 [M+H] + . The procedure for synthesizing I-9 was the same as for I-8.

[0268] Step 4: Synthesis of N-(5-cyano-2-(methylthio)thiazole-4-yl)-2,2,2-trifluoroacetamide (10a) A solution of 4-amino-2-(methylthio)thiazole-5-carbonitrile (8c) (2 g, 11.7 mmol, 1 eq.) was dissolved in THF (20 mL). While stirring, pyridine (1.03 mL, 12.8 mmol, 1.1 eq.) was added, followed by the addition of anhydrous trifluoroacetic acid (1.64 mL, 11.7 mmol, 1 eq.) at 0°C. Stirring was continued at room temperature for 3 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under high vacuum, the crude product was diluted with ice-cold water, extracted with CH2Cl2 (twice), the organic layers were combined and further washed with brine, dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude 10a (crude yield of 4.8 g). This was used without further purification.

[0269] LC-MS: 268.2 [M+H] + . Step 5: Synthesis of 2-(methylthio)-5-(trifluoromethyl)thiazolo[4,5-d]pyrimidine-7-ol (10b) AcOH (40 mL) was added to N-(5-cyano-2-(methylthio)thiazole-4-yl)-2,2,2-trifluoroacetamide (10a) (3 g) at 0°C, and the mixture was stirred at 150°C for 16 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under high vacuum to obtain a crude solid. This was ground with pentane and dried under reduced pressure to obtain 10b (crude yield of 1.2 g).

[0270] LC-MS: 268.2 [M+H] + . Step 6: Synthesis of 2-(methylthio)-5-(trifluoromethyl)thiazolo[4,5-d]pyrimidine-7-ol (I-10) 2-(methylthio)-5-(trifluoromethyl)thiazolo[4,5-d]pyrimidine-7-ol (10b) (1.1 g, 4.1 mmol) was mixed with phosphorus oxychloride (V) (19.2 mL, 205.8 mmol, 50 eq.) at 0°C, and the mixture was stirred at 110°C for 3 hours. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under high vacuum to obtain the crude product. This was diluted with ice-cold water, extracted with Et2O (twice), the organic layers were combined and further washed with brine, dehydrated with anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude solid. This was ground with pentane and dried under reduced pressure to obtain I-10 (crude yield of 1.3 g).

[0271] LC-MS: 286.7 [M+H] + . Intermediate I-11: Synthesis of 1-(3,5-dichloropyridine-2-yl)ethane-1-amine: [ka]

[0272] Step 1: Synthesis of 1-(3,5-dichloropyridine-2-yl)ethane-1-one A solution of 3,5-dichloropicolinonitrile (5 g, 28.90 mmol) was dissolved in dry THF (50 mL). While stirring, a solution of 2 M methylmagnesium bromide in THF (6.89 g, 57.80 mmol) was added to this solution at -78°C for no more than 15 minutes. The resulting reaction mixture was allowed to continue for 2 hours. The reaction was monitored by TLC, which showed that no starting material was present. The reaction mixture was quenched with saturated aqueous NH4Cl solution, extracted with siRNA, washed with brine, dehydrated with anhydrous Na2SO4, and the organic layer was evaporated to dryness under reduced pressure to obtain the crude compound. The crude compound was purified by combiflapping with 0-5% ethyl acetate in hexane to obtain the title compound 11a (3.3 g, 60%).

[0273] LC-MS: 190.0 [M+H] + . Step 2: Synthesis of 1-(3,5-dichloropyridine-2-yl)ethane-1-amine A solution of 1-(3,5-dichloropyridine-2-yl)ethane-1-one (11a) (1.0 g, 5.26 mmol) was dissolved in MeOH (20 mL). Hydroxylamine hydrochloride (0.55 g, 7.89 mmol) was added to the solution while stirring, followed by sodium carbonate (0.84 g, 7.89 mmol) at room temperature. The resulting reaction mixture was heated at 60 °C for 3 hours. The reaction was monitored by TLC, which showed that the starting material was absent. The reaction mixture was cooled to room temperature, and NH4Cl (1.41 g, 53.49 mmol) in water (5 mL) was added, followed by zinc (3.44 g, 52.61 mmol) at room temperature, and the reaction was continued for up to 12 hours. After the reaction was complete, the RM was filtered through a sintered funnel packed with Celite, and the solid was washed with excess ethyl acetate. The filtrate was evaporated to dryness under reduced pressure to obtain the crude compound. The crude compound was purified by combi-flush using 0-5% MeOH in DCM to obtain the title compound I-11 (0.65 g, 65%).

[0274] LC-MS: 191.0 [M+H] +, 1H-NMR (400 MHz, DMSO-d6) δ 8.65 (d, 1H), 8.28 (d, 1H), 4.52-4.51 (m, 3H), 1.32 (d, 3H). The intermediates listed in Table C below were prepared using the same procedure as described in the synthesis of I-11, with appropriate modifications to the amounts of reactants, reagents, and solvents, as well as the reaction conditions. The characteristic data of these compounds are summarized in the table below. [Table 4]

[0275] General synthesis scheme General scheme-1: [ka]

[0276] Here, X1, X2, X3, X4, X5, Y1, Y2, Y3, Y4, R1, R2, R 2’ R3, R4, R5, R6, j, k, m, n, and p are as defined in equation (I).

[0277] Some representative compounds of this application can generally be synthesized using the process outlined in general Scheme-1. GS-1B was obtained by reacting commercially available or synthesized GS-1 with GS-1A (alkyl halide) in the presence of appropriate reagents and solvents (K2CO3, DMF, room temperature). GS-1B was then reacted with GS-1C in the presence of appropriate reagents and solvents (toluene, Xantphos, Pd2(dba)3, sodium tert-butoxide) to obtain GS-1D. GS-1D was then treated with mCPBA in the presence of appropriate reagents and solvents (chloroform) to obtain a mixture of GS-1E and GS-1F. The mixture of GS-1E and GS-1F was then treated with GS-1G in the presence of appropriate reagents and solvents (DMF, dioxane, DIPEA) to obtain the compound represented by formula (I).

[0278] General Scheme-2: [ka]

[0279] Some representative compounds of this application can generally be synthesized using the process outlined in General Scheme-2. GS-2A was obtained by reacting commercially available or synthesized GS-1 with appropriate reagents and solvents (SOCl2, DMF). GS-2B was then reacted with GS-1G in the presence of appropriate reagents and solvents (dioxane, DIPEA) to obtain GS-2B. GS-2B was then treated with GS-1C in the presence of appropriate reagents and solvents (CS2CO3, X-Phos, Pd2(dba)3, 1,2-DME, tert-butanol) to obtain the compound represented by formula (I).

[0280] General Scheme-3: [ka]

[0281] Here, X1, X2, X3, X4, X5, R1, R2, R 2’ R3, R4, R5, R6, j, k, m, n, and p are as defined in equation (I).

[0282] Some representative compounds of this application can generally be synthesized using the process outlined in general Scheme-3. GS-1B was obtained by reacting commercially available or synthesized GS-1 with GS-1A (alkyl halide) in the presence of appropriate reagents and solvents (K2CO3, DMF, room temperature). GS-1B was then reacted with GS-3A in the presence of appropriate reagents and solvents (toluene, Xantphos, Pd2(dba)3, sodium tert-butoxide) to obtain GS-3B. GS-3C was then treated with mCPBA in the presence of appropriate reagents and solvents (chloroform) to obtain GS-3C. GS-3C was then treated with GS-3D in the presence of appropriate reagents and solvents (DMF, dioxane, DIPEA) to obtain the compound represented by formula (IB).

[0283] General Scheme-4: [ka]

[0284] Some representative compounds of this application can generally be synthesized using the process outlined in general Scheme-4. GS-2A was obtained by reacting commercially available or synthesized GS-1 with appropriate reagents and solvents (SOCl2, DMF). GS-2A was then reacted with GS-3D in the presence of appropriate reagents and solvents (dioxane, DIPEA) to obtain GS-4A. GS-4A was then treated with GS-3A in the presence of appropriate reagents and solvents (CS2CO3, X-Phos, Pd2(dba)3, 1,2-DME, tert-butanol) to obtain the compound represented by formula (IB). [Examples]

[0285] Examples: Example 1: Synthesis of (1R,3r)-3-((R)-3-(1-(6-chloro-7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)benzo[d]oxazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (Compound 1) [ka]

[0286] Step 1: Synthesis of 7-bromo-6-chloro-2-(methylthio)benzo[d]oxazole (1A) 7-Bromo-6-chlorobenzo[d]oxazole-2-thiol (2 g, 7.56 mmol) was dissolved in DMF (20 mL) and, while stirring, anhydrous K2CO3 (2.09 g, 15.12 mmol) was added at 0°C and the mixture was stirred at the same temperature for 10 minutes. Iodomethane (1.61 g, 11.34 mmol) was added at the same temperature and the reaction mixture was gradually heated to room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was poured into cold water and extracted with ethyl acetate. The organic portion was washed with water (twice) and the layers were separated. The organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by flash chromatography using 0-10% ethyl acetate in hexane as the eluent to obtain the pure title compound 1A (1.5 g, 71.2%).

[0287] LC-MS: 279.6 [M+H] + . Step 2: Synthesis of (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(methylthio)benzo[d]oxazole-7-amine(1C) In a sealed tube, 7-bromo-6-chloro-2-(methylthio)benzo[d]oxazole (0.1 g, 0.35 mmol) and (R)-1-(2,4-dichlorophenyl)ethane-1-amine (0.102 g, 0.538 mmol) were dissolved in toluene (6 mL) and stirred at room temperature. Then, the mixture was purged with argon gas for 5 minutes, followed by the sequential addition of Xantphos (0.042 g, 0.07 mmol), Pd2(dba)3 (0.033 g, 0.03 mmol), and sodium tert-butoxide (0.069 g, 0.71 mmol), and the argon purging was continued for another 5 minutes. The resulting reaction mixture was stirred at 100 °C for 1.5 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated to obtain the crude compound. The crude compound was purified by silica gel column flash chromatography using 0-10% ethyl acetate in hexane as the eluent to obtain pure title compound 1C (0.08 g, 71.8%).

[0288] LC-MS: 388.0 [M+H] + . Step 3: Synthesis of 6-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(methylsulfinyl)benzo[d]oxazole-7-amine(1D) (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2-(methylthio)benzo[d]oxazole-7-amine (0.07 g, 0.181 mmol) was dissolved in chloroform (3 mL) and, while stirring, m-CPBA (0.047 g, 0.27 mmol) was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was quenched with saturated aqueous solution NaHCO3 and extracted with DCM. The organic portion was washed again with water, dehydrated with Na2SO4, filtered, and concentrated to obtain the title compound 1D (0.15 g).

[0289] LC-MS: 404.9 [M+H] + . Step 4: Synthesis of (1R,3r)-3-((R)-3-(1-(6-chloro-7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)benzo[d]oxazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-1) A mixture of 6-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2-(methylsulfinyl)benzo[d]oxazole-7-amine (0.13 g, 0.31 mmol) and (1R,3r)-3-((R)-3-(azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutan-1-carboxylic acid (0.156 g, 0.62 mmol) in DMF (1 mL) and dioxane (1 mL) was mixed with DIPEA (0.16 g, 1.24 mmol) at 0°C. The resulting reaction mixture was allowed to cool to room temperature and then stirred at 100°C for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with saturated NH4Cl solution, extracted with ethyl acetate, and the layers were separated. The organic portion was dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the crude compound. The crude compound was purified by preparative TLC using 15% methanol in CH2Cl2 to obtain title compound 1 (0.09 g, 49.04%).

[0290] LC-MS: 591.2 [M+H] + ; 1H-NMR (400 MHz, CD3OD) δ 7.47 (d, 1H), 7.37 (d, 1H), 7.27-7.25 (dd, 1H), 7.11 (d, 1H), 6.60 (d, 1H), 5.53-5.46 (m, 1H), 4.29 (t, 1H), 4.20 (t, 1H), 3.99 (t, 1H), 3.83 (t, 1H), 3.29-3.20 (m, 3H), 3.13-3.07 (m, 1H), 2.74-2.69 (m, 2H), 2.68-2.61 (m, 1H), 2.35-2.28 (m, 1H), 2.08-2.02 (m, 1H), 1.98-1.84 (m, 4H), 1.75-1.64 (m, 1H), 1.59 (d, 3H), 1.39 (s, 3H), 1.10-1.03 (m, 1H). Example 2: Synthesis of (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)benzo[d]oxazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (Compound 2) [ka]

[0291] Step 1: Synthesis of 7-bromo-2-chlorobenzo[d]oxazole (2A) A solution of 7-bromobenzo[d]oxazole-2-thiol (1 g, 4.34 mmol) was dissolved in thionyl chloride (7.2 g, 60.8 mmol). While stirring, a few drops of DMF were added to the solution, and the resulting reaction mixture was stirred at 80°C. After 30 minutes, the reaction mixture was cooled to 50°C, toluene (5 mL) was added, and the resulting mixture was concentrated to obtain a residue. The residue was added to cold water, extracted with toluene, and the layers were separated. The organic portion was dehydrated with anhydrous Na2SO4, filtered, and concentrated. The crude compound was purified by flash chromatography using 10% ethyl acetate in hexane as the eluent to obtain pure title compound 2A (0.53 g, 52.4%).

[0292] LC-MS: 229.8 [MH] - . Step 2: Synthesis of (1R, 3r)-3-((R)-3-(1-(7-bromobenzo[d]oxazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (2B) (1R,3r)-3-((R)-3-(azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutan-1-carboxylic acid (0.261 g, 1.03 mmol) was dissolved in dioxane (4 mL). While stirring, DIPEA (0.154 g, 1.19 mmol) and 7-bromo-2-chlorobenzo[d]oxazole (0.185 g, 0.79 mmol) were added at room temperature. The resulting mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was then cooled to room temperature and concentrated. The residue was washed with ether to obtain crude title compound 2B (0.4 g). This was used directly in the next step.

[0293] LC-MS: 450.3 [M+H+2] + . Step 3: Synthesis of (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)benzo[d]oxazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-2) In a sealed tube, (1R,3r)-3-((R)-3-(1-(7-bromobenzo[d]oxazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutan-1-carboxylic acid (0.15 g, 0.33 mmol) and (R)-1-(2,4-dichlorophenyl)ethane-1-amine (0.083 g, 0.436 mmol) were dissolved in 1:1 ratio 1,2-DME (3.5 mL) and tert-butanol (3.5 mL) and stirred at room temperature. Subsequently, the reaction mixture was purged with argon gas for 5 minutes, and then Cs2CO3 (0.437 g, 1.34 mmol), X-Phos (0.048 g, 0.1 mmol), and Pd2(dba)3 (0.031 g, 0.3 mmol) were added sequentially. The mixture was then purged again with argon gas for 5 minutes at room temperature. The resulting mixture was heated to 110°C and stirred for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated to obtain the crude compound. The crude compound was purified by preparative HPLC to obtain the title compound 2 (0.005 g).

[0294] Method: Column: LUNA OMEG PS C-18 (250 × 21.2 mm) 5 μm; Eluent: A is 0.05% TFA in water, B is acetonitrile; Flow rate: 16 mL / min; Gradient program: 20% B at 0 min, 30% B at 2 min, 80% B at 8 min.

[0295] LC-MS: 557.3 [M+H] + ; 1 H-NMR (400 MHz, CD3OD) δ 7.48-7.46 (dd, 2H), 7.25-7.22 (dd, 1H), 6.90 (t, 1H), 6.62-6.60 (dd, 1H), 6.22 (d, 1H), 5.17-5.12 (m, 1H), 4.40-4.30 (m, 2H), 4.09-4.01 (m, 2H), 3.85-3.75 (m, 1H), 3.58-3.51 (m, 1H), 3.44-3.36 (m, 1H), 3.28-3.24 (m, 1H), 2.91-2.84 (m, 2H), 2.80-2.70 (m, 2H), 2.58-2.51 (m, 1H), 2.28-2.18 (m, 3H), 2.10-1.98 (m, 3H), 1.53 (d, 3H), 1.47 (s, 3H). The following compounds were prepared using the same synthesis routes as in Examples 1 and 2, starting from the starting materials listed in Table D, with appropriate modifications to the coupling method, reactants, reagent amounts, and solvent as needed. The characteristic data of these compounds are summarized in the table below. [Table 5] TIFF2026517794000063.tif247167TIFF2026517794000064.tif216166TIFF20265177940 00065.tif246166TIFF2026517794000066.tif238166TIFF2026517794000067.tif249167 TIFF2026517794000068.tif231165TIFF2026517794000069.tif244165TIFF20265177940 00070.tif248166TIFF2026517794000071.tif223166TIFF2026517794000072.tif158166

[0296] Example 3: Synthesis of (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)thiazolo[4,5-d]pyrimidine-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (Compound 32) [ka]

[0297] Stage 1: (R)-N-(1-(2,4-dichlorophenyl)ethyl)-2-(methylthio)thiazolo[4,5-d]pyrimidine-7-amine(3A): 7-chloro-2-(methylthio)thiazolo[4,5-d]pyrimidine (I-8) (0.6 g, 2.75 mmol, 1 eq.) and 1B (0.78 g, 4.1 mmol, 1.5 eq.) were suspended in DMSO (12 mL). CsF (1.25 g, 8.26 mmol, 3 eq.) was added to the suspension, and the reaction mixture was stirred at room temperature for 2 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the mixture was dissolved in ice water, extracted with SiO2 (3 times), and the organic layers were combined and dehydrated with anhydrous Na2SO4. The mixture was concentrated under high vacuum to obtain the crude product. This was purified by silica gel column flash chromatography using 30-40% SiO2 in hexane as the eluent to obtain the pure title compound 3A (0.65 g, 63% yield).

[0298] LC-MS: 372.3 [M+H] + . Step 2: Synthesis of (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)thiazolo[4,5-d]pyrimidine-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-32): A solution of 3A (0.05 g, 0.13 mmol, 1 eq.) and (1R,3r)-3-((R)-3-(azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutan-1-carboxylic acid (I-7) (0.06 g, 0.27 mmol, 2 eq.) dissolved in DMSO (3 mL) was stirred, and cesium fluoride (0.06 g, 0.4 mmol, 3 eq.) was added at room temperature. The mixture was heated at 100 °C for 3 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, ice water was added to the reaction mixture to obtain a crude solid. This was purified by preparative TLC using 15% methanol in CH2Cl2 to obtain the title compound (0.03 g, 39% yield).

[0299] LC-MS: 575.1 [M+H]+; 1H-NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.47 (d, 1H), 7.42 (d, 1H), 7.29-7.27 (dd, 1H), 5.71-5.66 (m, 1H), 4.35-4.31 (m, 2H), 4.12-4.08 (m, 2H), 3.84-3.72 (m, 1H), 3.55-3.46 (m, 1H), 3.44-3.36 (m, 1H), 2.89-2.74 (m, 4H), 2.58-2.48 (m, 1H), 2.28-2.19 (m, 3H), 2.10-1.93 (m, 2H), 1.90-1.72 (m, 1H), 1.58 (d, 3H), 1.44 (s, 3H), 1.32-1.18 (m, 1H). The following compounds were prepared using the same synthetic route as in Example-3, starting from the starting materials listed in Table-E, with appropriate modifications to the coupling method, reactants, reagent amounts, and solvent as needed. The characteristic data of these compounds are summarized in the table below. [Table 6]

[0300] Example-4: (1R,3r)-3-((3R)-3-(1-(7-((1-(3,5-dichloropyridine-2-yl)ethyl)amino)-6-fluorobenzo[d]thiazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-35), (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(3,5-dichloropyridine-2-yl)ethyl)amino)-6-fluorobenzo[ Synthesis of [d]thiazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-36) and (1R,3r)-3-((R)-3-(1-(7-(((S)-1-(3,5-dichloropyridine-2-yl)ethyl)amino)-6-fluorobenzo[d]thiazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-37) [ka]

[0301] Step 1: Synthesis of 7-bromo-6-fluoro-2-(methylthio)benzo[d]thiazole (4A) A solution of A-19 (12 g, 45.43 mmol) was dissolved in DMF (120 mL). While stirring, anhydrous K2CO3 (12.56 g, 90.86 mmol) was added at 0°C and the mixture was stirred at the same temperature for 10 minutes. Then, iodomethane (9.67 g, 68.14 mmol) was added at the same temperature, and the reaction mixture was gradually heated to room temperature. Next, the reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was poured into cold water, the resulting precipitate was filtered, washed with excess ice-cold water, and dried under line vacuum to obtain crude compound 4A (10 g).

[0302] LC-MS: 277.9 [M+H] + . Step 2: Synthesis of N-(1-(3,5-dichloropyridine-2-yl)ethyl)-6-fluoro-2-(methylthio)benzo[d]thiazole-7-amine(4C) In a sealed tube, 7-bromo-6-fluoro-2-(methylthio)benzo[d]thiazole (4A) (0.5 g, 1.80 mmol) and I-11 (0.51 g, 2.70 mmol) were dissolved in toluene (15 mL) and stirred at room temperature. Then, the mixture was purged with argon gas for 5 minutes, and subsequently, BINAP (0.22 g, 0.36 mmol), Pd2(dba)3 (0.29 g, 0.36 mmol), and sodium tert-butoxide (0.35 g, 3.60 mmol) were added sequentially, and the argon purging was continued for another 5 minutes. The resulting reaction mixture was stirred at 100 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated to obtain the crude compound. The crude compound was used as the eluent and purified by silica gel column flash chromatography using 0-20% ethyl acetate in hexane to obtain the pure title compound 4C (0.22 g, 31%).

[0303] LC-MS: 388.0 [M+H] + . Step 3: Synthesis of N-(1-(3,5-dichloropyridine-2-yl)ethyl)-6-fluoro-2-(methylsulfinyl)benzo[d]thiazole-7-amine (4D) and N-(1-(3,5-dichloropyridine-2-yl)ethyl)-6-fluoro-2-(methylsulfonyl)benzo[d]thiazole-7-amine (4E) N-(1-(3,5-dichloropyridine-2-yl)ethyl)-6-fluoro-2-(methylthio)benzo[d]thiazole-7-amine (4C) (0.2 g, 0.51 mmol) was dissolved in dichloromethane (5 mL). While stirring the solution, m-CPBA (0.18 g, 1.03 mmol) was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 6 hours. After the reaction was complete, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with CH2Cl2 (twice). The organic layer was washed again with water, dehydrated with anhydrous Na2SO4, filtered, and concentrated to obtain the crude compound (a mixture of 4D and 4E) (0.24 g).

[0304] LC-MS: 403.85 [M+H] + and 420.1 [M+H] + . Step 4: Synthesis of (1R,3r)-3-((3R)-3-(1-(7-((1-(3,5-dichloropyridine-2-yl)ethyl)amino)-6-fluorobenzo[d]thiazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-35) A mixture of 4D (0.2 g, 0.49 mmol) and 4E (0.25 g, 0.99 mmol) in DMSO (3 mL) was mixed with CsF (0.24 g, 1.56 mmol) at 0°C. The resulting reaction mixture was allowed to cool to room temperature and stirred at 100°C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with saturated NH4Cl solution, and extracted with 10% MeOH in CH2Cl2. The organic layer was dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude compound. This was purified by preparative TLC using 15% methanol in CH2Cl2 to obtain the title compound 35 (0.1 g, 34%).

[0305] LC-MS: 592.2 [M+H] + ; 1H-NMR (400 MHz, CD3OD) δ 8.53 (d, 1H), 7.95-7.94 (dd, 1H), 7.07-7.02 (dd, 1H), 6.97-6.94 (dd, 1H), 5.39-5.37 (m, 1H), 4.33-4.30 (m, 2H), 4.08-4.05 (m, 2H), 3.85-3.75 (m, 1H), 3.60-3.55 (m, 1H), 3.45-3.34 (m, 1H), 2.92-2.82 (m, 2H), 2.80-2.72 (m, 2H), 2.54 (t, 1H), 2.27-2.21 (m, 2H), 2.15-1.98 (m, 2H), 1.83-1.70 (m, 1H), 1.48 (d, 3H), 1.46 (s, 3H), 1.30-1.15 (m, 1H). LC-MS: 592.2 [M+H] + This racemic mixture was separated using chiral HPLC to obtain both isomers. The details of the method are as follows.

[0306] column :CHIRALPAK IG(250mm×4.6mm, 5μ); mobile phase A: n-hexane, B: 0.1% DEA in EtOH, DEA: 0.5% TFA in water, and B was acetonitrile; flow rate :15mL / min.

[0307] (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(3,5-dichloropyridine-2-yl)ethyl)amino)-6-fluorobenzo[d]thiazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-36): LC-MS: 592.2 [M+H] + ; 1H-NMR (400 MHz, CD3OD): δ 8.52 (d, 1H), 7.93 (d, 1H), 7.04-6.99 (dd, 1H), 6.98-6.93 (dd, 1H), 5.40-5.37 (m, 1H), 4.31-4,24 (m, 2H), 4.02-3.96 (m, 2H), 3.34-3.21 (m, 2H), 2.76-2.73 (m, 3H), 2.52-2.42 (m, 1H), 2.32-2.22 (m, 1H), 2.06-1.94 (m, 5H), 1.78-1.68 (m, 1H), 1.46 (d, 3H), 1.43 (s, 3H), 1.20-1.10 (m, 1H), 0.90 (m, 1H), HPLC: 98.21% and Chiral HPLC: 93.35%. (1R,3r)-3-((R)-3-(1-(7-(((S)-1-(3,5-dichloropyridine-2-yl)ethyl)amino)-6-fluorobenzo[d]thiazole-2-yl)azetidine-3-yl)piperidine-1-yl)-1-methylcyclobutane-1-carboxylic acid (compound-37): LC-MS: 592.2 [M+H] + ; 1 H-NMR (400 MHz, CD3OD): δ 8.52(d, 1H), 7.93 (d, 1H), 7.04-6.99 (dd, 1H), 6.98-6.93 (dd, 1H), 5.40-5.36 (m, 1H), 4.29-4,24 (m, 2H), 4.03-3.97 (m, 2H), 2.76-2.71 (m, 3H), 2.01-1.92 (m, 6H), 1.47 (d, 3H), 1.44-1.42 (m,2H), 1.39 (s, 3H), 1.32-1.27 (m, 2H), 0.93-0.89 (m, 2H), HPLC: 97.16% and Chiral HPLC: 98.30% The following compounds were prepared using the same synthetic route as in Example-4, starting from the starting materials listed in Table-F, with appropriate modifications to the coupling method, reactants, reagent amounts, and solvent as needed. The characteristic data of these compounds are summarized in the table below. [Table 7] TIFF2026517794000077.tif239170TIFF2026517794000078.tif210170TIFF2026517794000079.tif240170TIFF2026517794000080.tif153170

[0308] While this application has been illustrated by several embodiments described above, it should not be construed as being limited thereto. Rather, this application encompasses the general area disclosed above. For example, the following compounds, which can be prepared by following procedures similar to those described in the schemes / examples above and with appropriate modifications known to those skilled in the art, are also included in the scope of this application: [ka] TIFF2026517794000082.tif208153TIFF2026517794000083.tif229152

[0309] Biology: β-arrestin recruitment assay protocol CHO-K1 CCR4 β-arrestin cells were seeded and incubated overnight at 37°C in a CO2 incubator to allow adhesion. The following day, the cells were pretreated with various concentrations of CCR4 modulator at 37°C for 30 minutes. The cells were stimulated with recombinant human CCL22 (10 nM) and incubated for a further 90 minutes. Working detection solution was added, and the cells were incubated at room temperature for 1 hour, after which the chemiluminescence signal was read using a luminometer.

[0310] Representative compounds of this application were screened using the above assay, and the results are summarized in the table.

[0311] The CCR4 inhibition values ​​at 5 μM and 30 μM for representative specific compounds are summarized in Table G below. [Table 8]

[0312] CCR4 antagonistic IC4 activity of some representative compounds 50 The values ​​are summarized in Table H below. Here, "A" represents ICs smaller than 0.25 μM. 50 The values ​​are shown, and "B" indicates an IC in the range of 0.25 μM to 0.5 μM (including both ends). 50 The value is shown, and "C" indicates an IC larger than 0.5 μm. 50 It shows the value. [Table 9]

[0313] Embedding by citation All publications and patents described herein are incorporated in whole by reference as if each individual publication or patent were specifically indicated to be incorporated by reference. In the event of any inconsistency, this application (including the definitions herein) shall prevail.

[0314] Equivalents While specific embodiments of this disclosure have been discussed, the above specification is illustrative and not limiting. By examining this specification and the following claims, many variations of this disclosure will be readily apparent to those skilled in the art. The full scope of this disclosure should be determined by referring to the full scope of the claims and their equivalents, as well as this specification and such variations.

Claims

1. Equation (I): 【Chemistry 1】 [During the ceremony, W １ is C, N, or O; X １ and X ２ These are CH, N, and NR, respectively, independently. ｘ , O, S or -S(O)-; X ３ , X ４ and X ５ Each of these is independently either C or N; R ｘ is hydrogen or C １ -C ６ alkyl; Y １ , Y ２ , Y ３ and Y ４ Each of these is independently either C or N; R in each appearance １ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, Halo, Cyano, Amino, Nitro, -OR １ａ , -C(O)R １ｂ or C ３ -C ６ It is a cycloalkyl; where C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl and C ３ -C ６ Cycloalkyls are, respectively, halo, hydroxy, and C. １ -C ６ It may also be substituted with one or more substituents independently selected from the alkoxy; R ２ and R ２’ These are, independently, hydrogen and C １ -C ６ Alkyl or halo; R ３ is hydrogen or C １ -C ６ It is alkyl; R in each appearance ４ Independently, C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, Halo, Cyano, Amino, Nitro, -OR ４ａ , -C(O)R ４ｂ or C ３ -C ６ It is a cycloalkyl; where C １ -C ６ Alkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl and C ３ -C ６ Each cycloalkyl group consists of one or more halo, hydroxy, and C atoms. １ -C ６ It may also be substituted with one or more substituents independently selected from the alkoxy; R in each appearance ５ It is independent, Haro, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy or -C(O)R ５ａ And; R in each appearance ６ Independently, C １ -C ６ Alkyl, Halo, C １ -C ６ Haloalkyl, cyano, -C(O)R ６ａ , - (C １ -C ３ Alkyl)C(O)R ６ａ OR ６ｂ And; R １ａ and R ４ａ are each independently hydrogen, halo, C １ -C ６ -alkyl, C １ -C ６ -haloalkyl, C ３ -C ６ -cycloalkyl or C ３ -C ６ -heterocycloalkyl; R １ｂ 、 R ４ｂ and R ５ａ are each independently hydrogen, C １ -C ６ -alkyl, hydroxy, amino, C １ -C ６ -alkylamino, C １ -C ６ -haloalkyl, C ３ -C ６ -cycloalkyl or C ３ -C ６ -heterocycloalkyl; R ６ａ is hydrogen, hydroxyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Alkoxy, C １ -C ６ Haloalkoxy, amino, C １ -C ６ Alkylamino or C ３ -C ６ It is a cycloalkyl; R ６ｂ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl or C ３ -C ６ It is a cycloalkyl; "m" is selected from 0 to 5; "n" is selected from 0 to 3; "j" is selected from 0 to 4; "k" is selected from 0 to 2; "p" and "q" are independently selected from 1 and 2, respectively; and, "z" is selected from 0 to 4. A compound represented by , or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

2. Formula (IA): 【Chemistry 2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having the above characteristics.

3. Formula (IB): 【Transformation 3】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having the above characteristics.

4. Formula (IC) to formula (IL): 【Chemistry 4】 【change】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having the above characteristics.

5. Formula (IA-1) to formula (IG-1): 【Transformation 5】 【change】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having the above characteristics.

6. Formula (IA-2) to formula (IH-2): 【Transformation 6】 【change】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, having the above characteristics. 【Request Item 7】 【Chemistry 7】 The ring represented by is 【Transformation 8】 The compound according to any one of claims 1 to 6, wherein the asterisk indicates a bond point with the azetidine ring. [Request Item 8] [Chemistry 9] The ring represented by is 【Chemistry 10】 The compound according to any one of claims 1 to 6, wherein the asterisk indicates a bond point with the azetidine ring. 【Request Item 9】 【Chemistry 11】 The ring represented by is 【Chemistry 12】 The compound according to claims 1 to 7, wherein the asterisk indicates a bond point with the azetidine ring.

10. ring 【Chemistry 13】 Independently, 【Chemistry 14】 【change】 And here, the star is R ２ Base and R ２’ The compound according to claims 1 to 6, representing a bond point with a carbon atom having a group.

11. X １ The compound according to any one of claims 1 to 6, wherein is N, O, or S.

12. X ２ is N, O, or NR ｘ The compound according to any one of claims 1 to 6.

13. X １ is N, O, or S; and X ２ The compound according to any one of claims 1 to 6, wherein is N.

14. R in each appearance １ The compound according to any one of claims 1 to 6, wherein the compound is a halo.

15. R in each appearance ４ It is independent, Haro, C １ -C ６ Alkyl, cyano, -OR ４ａ or -C(O)R ４ｂ And here, R ４ａ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ It is a haloalkyl and R ４ｂ is hydrogen, C １ -C ６ Alkyl, amino, C １ -C ６ Alkylamino or C １ -C ６ A compound according to any one of claims 1 to 6, which is a haloalkyl compound.

16. R in each appearance ６ Independently, C １ -C ６ Alkyl or -C(O)R ６ａ And here, R ６ａ The compound according to any one of claims 1 to 6, wherein is hydroxyl.

17. W １ is C, N, or O; X １ and X ２ These are N and NR, respectively, independently. ｘ , O, S or -S(O)-; X ３ , X ４ and X ５ Each of these is independently either C or N; R ｘ C １ -C ６ It is alkyl; Y １ , Y ２ , Y ３ and Y ４ Each of these is independently either C or N; R in each appearance １ It is, independently, a halo; R ２ and R ２’ These are, independently, hydrogen and C １ -C ６ Alkyl or halo; R ３ is hydrogen; R in each appearance ４ Independently, C １ -C ６ Alkyl, cyano, halo, -OR ４ａ or -C(O)R ４ｂ And here, C １ -C ６ The alkyl group may be independently substituted with one or more substituents selected from one or more halo and hydroxyl groups; R ４ａ is hydrogen, halo, C １ -C ６ Alkyl or C １ -C ６ It is a haloalkyl; R ４ｂ is hydrogen, C １ -C ６ Alkyl, hydroxy, amino, C １ -C ６ It is an alkylamino; R in each appearance ６ Independently, C １ -C ６ Alkyl or -C(O)R ６ａ And; R ６ａ It is hydroxyl; "m" is selected from 0 to 3; "n" is selected from 0 to 2; "j" is between 0 and 2; "k" is 1; "p" and "q" are each 1; and, "z" is selected from 0 to 4; The compound according to any one of claims 1 to 16.

18. The compound according to any one of claims 1 to 17, wherein j is 0.

19. The compound according to any one of claims 1 to 17, wherein k is 1.

20. The compound according to any one of claims 1 to 17, wherein m is 1 to 3.

21. The compound according to any one of claims 1 to 17, wherein n is 0 to 2.

22. The compound according to any one of claims 1 to 17, wherein p and q are each 1.

23. R ２ C １ -C ６ It is alkyl, and R ２’ The compound according to any one of claims 1 to 17, wherein is hydrogen.

24. R ３ The compound according to any one of claims 1 to 17, wherein is hydrogen.

25. R in each appearance ６ is, -CH ３ A compound according to any one of claims 1 to 17, independently selected from and -C(O)OH.

26. R in each appearance ４ It is independent, Haro, C １ -C ６ Alkyl, cyano and -OR ４ａ And here, R ４ａ is hydrogen, halo, C １ -C ６ Alkyl or C １ -C ６ The compound according to any one of claims 1 to 17, wherein it is a haloalkyl compound. 【Request Item 27】 【Table 1】 A compound selected from the above, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.

29. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use as a pharmaceutical.

30. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in the treatment of a disease or disorder mediated by CCR4.

31. A method for modulating CCR4 in a subject, comprising administering to the subject a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

32. A method for treating or preventing a disease or disorder mediated by CCR4 in a subject who needs treatment or prevention of such a disease or disorder, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

33. The method according to claim 32, wherein the disease or disorder is cancer or an inflammatory disease or disorder.

34. The method according to claim 32, wherein the disease or disorder is inflammation.

35. The method according to claim 34, wherein the disease or disorder is dermatitis.

36. The method according to claim 34, wherein the disease or disorder is atopic dermatitis or contact dermatitis.

37. The method according to claim 32, wherein the disease or disorder is cancer.

38. The method according to claim 37, wherein the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, stomach cancer, liver cancer, or colorectal cancer.

39. The method according to any one of claims 31 to 38, further comprising administering a therapeutically effective amount of the compound according to claim 1 to the subject together with one or more chemotherapeutic agents or anti-inflammatory agents.

40. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a pharmaceutical product for treating a disease or disorder mediated by CCR4.

41. Use of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, in the manufacture of a pharmaceutical product for the treatment of cancer or an inflammatory disease or disorder.

42. The use according to claim 41, wherein the inflammatory disease or disorder is dermatitis.

43. The use according to claim 42, wherein the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.

44. The use according to claim 41, wherein the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, stomach cancer, liver cancer, or colorectal cancer.

45. A method for treating or preventing an inflammatory disease or disorder in a person who needs treatment or prevention of such a disease or disorder, comprising administering to the person a therapeutically effective amount of a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

46. The method according to claim 45, wherein the inflammatory disease or disorder is inflammation.

47. The method according to claim 46, wherein the inflammatory disease or disorder is dermatitis.

48. The method according to claim 46, wherein the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.

49. A method for treating or preventing cancer in a person who needs to be treated or prevented from having cancer, comprising administering to the person a therapeutically effective amount of a compound described in any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

50. The method according to claim 49, wherein the cancer is colorectal cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, stomach cancer, liver cancer, or colorectal cancer.

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