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WO2024228132A1 - Composés hétérocyclyle bicycliques condensés utilisés en tant que modulateurs de ccr4 - Google Patents

Composés hétérocyclyle bicycliques condensés utilisés en tant que modulateurs de ccr4 Download PDF

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Publication number
WO2024228132A1
WO2024228132A1 PCT/IB2024/054242 IB2024054242W WO2024228132A1 WO 2024228132 A1 WO2024228132 A1 WO 2024228132A1 IB 2024054242 W IB2024054242 W IB 2024054242W WO 2024228132 A1 WO2024228132 A1 WO 2024228132A1
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Prior art keywords
alkyl
cancer
independently
compound
halo
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PCT/IB2024/054242
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English (en)
Inventor
Chandrasekhar ABBINENI
Susanta Samajdar
Krishna Chaitanya TALLURI
Subhendu MUKHERJEE
Chandrasekhar V MIDUTURU
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Aurigene Oncology Ltd
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Aurigene Oncology Ltd
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Priority to AU2024266044A priority Critical patent/AU2024266044A1/en
Priority to CN202480029392.6A priority patent/CN121039119A/zh
Publication of WO2024228132A1 publication Critical patent/WO2024228132A1/fr
Priority to MX2025012881A priority patent/MX2025012881A/es
Priority to IL324308A priority patent/IL324308A/en
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings

Definitions

  • the present application is directed to fused bicyclic heterocyclyl compounds and their derivatives of formula (I) as CCR4 modulators, useful for the treatment of cancer and inflammatory diseases or disorders.
  • the disclosure also provides pharmaceutically acceptable compositions comprising compounds of the present application and methods of using said compositions in the treatment of diseases associated with CCR4.
  • Innate and adaptive immune responses and their coordinated interplay are essential to maintain homeostasis and for effective immune surveillance against pathogens and inflammatory diseases.
  • the key mediators of the immune system include the immune cells and the cytokines produced by them.
  • Chemokines are a family of small, secreted cytokines that control several processes such as cellular adhesion, localization, migration and cell-cell interaction (Clemens Esche, J Invest Dermatol. 2005 Oct; 125(4):615-28).
  • Inflammatory chemokines secreted by various types of cells control the recruitment of inflammatory effector cells such as leukocytes in response to infection, inflammation, tissue injury and in the tumor microenvironment (Anna E Vilgelm, Front Immunol. 2019 Feb 27; 10:333). They exert their effect through the activation of chemokine receptors on the cell surface of the effector cells.
  • Chemokine receptors belong to the large family of G-protein coupled receptors (GPCR). Cells expressing the chemokine receptors migrate in the direction of the respective chemokine gradient secreted by the tissue resident cells.
  • CCR4 C-C chemokine receptor
  • CCL22 and CCL17 Hongyi Li, MedComm (2020). 2022 Jun 8;3(2):el47.
  • Tregs regulatory T cells
  • CCR4 is implicated in the pathology of various immune-associated disorders. Effective modulation of CCR4 is hence crucial for the therapeutic intervention of inflammatory disorders and cancer.
  • W 1 is C, N or O;
  • X1 and X2 are each independently CH, N, NRx, O, S or -S(O)-;
  • X3, X4 and X5 are each independently C or N;
  • R x is hydrogen or C 1 -C 6 alkyl;
  • Y1, Y2, Y3, and Y4 are each independently C or N;
  • R1 at each occurrence is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR1a, -C(O)R1b or C3-C6 cycloalkyl; wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is optionally substituted
  • the present application provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the present application relates to the preparation of compounds of formula (I).
  • compounds of formula (I) which are capable of modulating CCR4 and therapeutic use thereof.
  • alkyl alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including C1-C10 straight or C1- C 10 branched alkyl groups.
  • alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl and the like.
  • alkenyl alone or in combination with other term(s) means unsaturated aliphatic hydrocarbon chains, including C1-C10 straight or C1-C10 branched alkyl groups.
  • alkenyl may include more than one double bond and/or one or more triple bonds in addition to the one or more double bonds.
  • alkenyl include but are not limited to vinyl, 2-propenyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl) and the like.
  • alkynyl alone or in combination with other term(s) means unsaturated aliphatic hydrocarbon chains, including C1-C10 straight or C 1 -C 10 branched alkyl groups.
  • An alkynyl may include more than one triple bond and/or one or more double bonds in addition to the one or more triple bonds.
  • alkynyl examples include but are not limited to ethynyl, 1- and 3-propynyl, 3-butynyl and the like.
  • halo or “halogen” alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
  • haloalkyl means alkyl substituted with one or more halogen atoms, wherein the alkyl groups are as defined above
  • halo is used herein interchangeably with the term “halogen” means F, Cl, Br or I.
  • haloalkyl examples include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and the like.
  • hydroxy or “hydroxyl” alone or in combination with other 5 term(s) means –OH.
  • hydroxyalkyl refers to the group HO-alkyl-, wherein alkyl and hydroxy groups are as defined herein.
  • alkoxy alone or in combination with other term(s) refers to the group alkyl-O- or –O-alkyl, where alkyl groups are as defined above.
  • Exemplary C 1 -C 10 alkyl group containing alkoxy- groups include but are not limited to methoxy, ethoxy, n- propoxy, n-butoxy, t-butoxy and the like.
  • An alkoxy group can be unsubstituted or substituted with one or more suitable groups.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms (i.e., haloC.sub.1-8alkoxy).
  • haloalkoxy examples include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1-bromoethoxy.
  • alkoxyalkyl refers to the group alkyl-O-alkyl-, wherein alkyl and alkoxy groups are as defined above.
  • Exemplary alkoxyalkyl- groups include but are not limited to methoxymethyl, ethoxymethyl, methoxyethyl, isopropoxymethyl and the like.
  • amino or "amine” alone or in combination with other term(s) refers to a primary amine (–NH2), secondary amine , wherein ‘N’ is substituted with two substituents other than hydrogen) or tertiary amine , wherein ‘N’ is substituted with three substituents other than hydrogen) group.
  • alkylamino alone or in combination with other term(s) means an amino group as defined above, substituted with one or more "alkyl” group, wherein the alkyl group and amino group is as defined above.
  • alkylamino groups include but are not limited to -NHCH3, -NHCH2CH3, -N(CH3)2, -N(CH3)(CH2CH3) and the like.
  • cyano refers to —CN; and the term “cyanoalkyl” refers to 30 alkyl substituted with -CN; wherein the alkyl groups are as defined above
  • nitro refers to –NO2;
  • cycloalkyl alone or in combination with other term(s) means -C3-C10 saturated cyclic hydrocarbon ring.
  • a cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms.
  • single-ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • a cycloalkyl may alternatively be polycyclic or contain more than one ring.
  • polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls and the like.
  • aryl is unsubstituted or substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms.
  • Examples of a C 6 - C14 aryl group include, but are not limited to phenyl, naphthyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl and acenaphthyl.
  • An aryl group may be unsubstituted or substituted with one or more suitable groups.
  • the term "carbocyclyl” alone or in combination with other term(s) includes both "cycloalkyl” and "aryl” groups which are as defined above.
  • heterocycloalkyl refers to a non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O) 2 , NH or C(O) with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur.
  • a monocyclic heterocycloalkyl may typically contain 4 to 7 ring atoms.
  • heterocycloalkyl examples 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 N-oxides thereof.
  • heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom.
  • a heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups by one or more aforesaid groups.
  • heteroaryl alone or in combination with other term(s) means a completely unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms/groups being independently selected from the group consisting of carbon, oxygen, nitrogen or sulfur.
  • a heteroaryl may be a single-ring (monocyclic) or polycyclic ring system.
  • heteroaryl include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl and the like.
  • heterocyclyl alone or in combination with other term(s) includes both “heterocycloalkyl” and “heteroaryl” groups which are as defined above.
  • Heterocyclyl examples include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, indolyl, benzimidazolyl, benzothiazolyl and the like.
  • heteroatom designates a sulfur, nitrogen or oxygen atom.
  • the term "optionally substituted” or “substituted” or “optionally substituted with suitable groups” refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alky
  • the term 'compound(s)' comprises the compounds disclosed in the present disclosure.
  • the term “comprise” or “comprising” is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
  • the term “or” means “and/or” unless stated otherwise.
  • the term “including” as well as other forms, such as “include”, “includes” and “included” is not limiting.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • the term “pharmaceutically acceptable” it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the term “treat”, “treating” and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
  • the term “prevent”, “preventing” and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
  • “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
  • the term “therapeutically effective amount” refers to that amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
  • “Pharmaceutically acceptable” means that, which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • 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 neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use.
  • each component is "pharmaceutically acceptable” as defined herein. See, e.g., 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.
  • pharmaceutically acceptable salt(s) refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric 5 amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols or acetonitrile (ACN) are preferred.
  • stereoisomers refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL) and (IM) wherever they are chiral or when they bear one or more double bonds.
  • compounds of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL) and (IM) are chiral, they can exist in racemic or in optically active form.
  • the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as d-isomers and l-isomers and mixtures thereof.
  • Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
  • Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present disclosure may exist as geometric isomers.
  • the present disclosure includes all cis, trans, syn, anti, R and S,
  • Alternative mixtures thereof The present disclosure provides compounds of formula (I), which are useful for the modulation of CCR4.
  • the present disclosure further provides pharmaceutical compositions comprising the said compounds of formula (I), and their derivatives as therapeutic agents. It will be 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 various embodiments disclosed herein. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present application includes such modifications and variations and their equivalents.
  • the present application provides compounds of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, W1 is C, N or O; X 1 and X 2 are each independently CH, N, NR x , O, S or -S(O)-; X3, X4 and X5 are each independently C or N; Rx is hydrogen or C1-C6 alkyl; Y 1 , Y 2 , Y 3, and Y 4 are each independently C or N; R1 at each occurrence is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR1a, -C(O)R1b or C3-C6 cycloalkyl; wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is optional
  • the present application provides compounds of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, W1 is CH2, NH or O; X1 and X2 are each independently CH, N, NRx, O, S or -S(O)-; X 3, X 4 and X 5 are each independently C or N; Rx is hydrogen or alkyl; Y1, Y2, Y3, and Y4 are each independently C or N; R1 at each occurrence is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo, cyano, amino, nitro, -OR1a, -C(O)R1b or C3-C6 cycloalkyl; wherein each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and C3-C6 cycloalkyl is optionally substituted with one or more substituents independently selected
  • asterisk mark represents the point of attachment with azetidine ring.
  • the ring represented by, , ; wherein the asterisk mark represents the point of attachment with azetidine ring.
  • the ring represented by, , ; wherein the asterisk mark represents the point of attachment with azetidine ring.
  • X1 is N, NRx, O, S or -S(O)-.
  • X2 is CH, N, O, S or NRx.
  • X 1 is N, NR x , O, S or -S(O)- and X 2 is N.
  • X2 is CH, N, NRx, O, or S or -S(O)- and X1 is N.
  • X1 is N, O or S; and X2 is N.
  • X1 is N, O, S or -S(O)-.
  • X 1 is N, O or S.
  • X1 is S or -S(O)-.
  • X1 is S.
  • X 2 is CH, N, O or NR x .
  • X2 is CH, N or O.
  • X 2 is N, O or NR x .
  • X2 is N or O.
  • X2 is N.
  • X1 is S and X2 is N.
  • X1 is N, NRx, O or S.
  • X1 is N, O or S.
  • X1 is N or O.
  • X 1 is O.
  • X2 is C, N or O.
  • X1 is O and X2 is N.
  • R 1 at each occurrence is halo.
  • R1 at each occurrence is halo and ‘m’ is 0 to 3.
  • R1 at each occurrence is halo and ‘m’ is 2.
  • R 2 is C 1 -C 6 alkyl or halo and R 2 ' is hydrogen.
  • R2 is C1-C6 alkyl and R2' is hydrogen.
  • R3 is hydrogen.
  • R4 at each occurrence is independently halo, C1-C6 alkyl, cyano, - OR 4a or -C(O)R 4b ; wherein R 4a is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and R 4b is hydrogen, C1-C6 alkyl, amino, C1-C6 alkylamino, or C1-C6 haloalkyl.
  • R4 at each occurrence is independently halo, C1-C6 alkyl, cyano and -OR 4a ; wherein R 4a is hydrogen, halo, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • R4 at each occurrence is independently halo, C1-C6 alkyl or -OR4a. In one embodiment, R4 at each occurrence is independently halo, C1-C6 alkyl or C1-C6 haloalkyl. In one embodiment, R4 at each occurrence is independently halo or C1-C6 haloalkyl. In one embodiment, R 4 at each occurrence is selected from halo, C 1 -C 6 alkyl and -OR 4a ; wherein R4a is hydrogen, halo, C1-C6 alkyl or C1-C6 haloalkyl.
  • R6 at each occurrence is independently C1-C6 alkyl, -(C1-C3 alkyl)C(O)R 6a or -C(O)R 6a ; wherein R 6a is hydroxy. In one embodiment, R6 at each occurrence is independently C1-C6 alkyl or -C(O)R6a; wherein R6a is hydroxy. In one embodiment, each R6 at each occurrence is independently selected from -CH3, - CH 2 C(O)OH and -C(O)OH. In one embodiment, each R6 at each occurrence is independently selected from -CH3 and -C(O)OH. In one embodiment, W 1 is C, N or O.
  • X1 and X2 are each independently N, NRx, O or S; 25 X 3 , X 4 and X 5 are each independently C or N; Rx is C1-C6 alkyl; R 1 at each occurrence is independently halo; R2 and R2' are each independently hydrogen or C1-C6 alkyl; R3 is hydrogen; R4 at each occurrence is independently C1-C6 alkyl, halo or -OR4a; wherein the C1-C6 alkyl is optionally independently substituted with one or more halo; R4a is C1-C6 alkyl or C1-C6 haloalkyl; R6 at each occurrence is independently C1-C6 alkyl or -C(O)R6a; R 6a is hydroxy; ‘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
  • j is 0. In one embodiment, k is 1. In one embodiment, m is 1 to 3. In one embodiment, n is 0 to 2. In one embodiment, p and q are each 1. In certain embodiments, the present application provides a compound selected from:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present disclosure may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds of the present disclosure are CCR4 modulators. In yet another embodiment, the compound of formula (I) is a CCR4 modulator.
  • the present disclosure provides pharmaceutical composition for use in treating and/or preventing a disease and/or disorder responsive to the modulation of CCR4 activity.
  • the present disclosure provides pharmaceutical composition
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable carrier or excipient.
  • the present disclosure provides pharmaceutical composition comprising the compound of formula (I), for use in treating a subject suffering from a disease or condition associated with CCR4.
  • the present disclosure provides pharmaceutical composition comprising the compound of formula (I), for use in the manufacture of a medicament for treating a subject suffering from a disease or condition associated with CCR4.
  • the compounds of the disclosure are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the present disclosure.
  • the pharmaceutical composition of the present disclosure comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
  • the pharmaceutical composition can be administered by oral, parenteral or inhalation routes.
  • parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, 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 polyoxyethylene.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
  • compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present disclosure may be formulated to provide desired release profile.
  • Administration of the compounds of the disclosure, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
  • the route of administration may be any route which effectively transports the active compound of the present disclosure to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
  • Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.
  • Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
  • compositions of the present disclosure may be prepared by conventional techniques known in literature.
  • Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present disclosure.
  • the compounds as disclosed in the present disclosure are formulated for pharmaceutical administration.
  • Yet another embodiment of the present disclosure provides use of the compounds as disclosed in the present application in the treatment and prevention of diseases and/or disorder responsive to the modulation of CCR4 activity.
  • Yet another embodiment of the present disclosure provides use of the compound or a pharmaceutically acceptable salt thereof, in treating and/or preventing a disease for which the symptoms thereof are treated, improved, diminished and/or prevented by modulation of CCR4.
  • the CCR4 mediated disorder and/or disease or condition is cancer or an inflammatory disease or disorder.
  • the CCR4 mediated disorder and/or disease or condition is cancer.
  • the cancer is colon cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer or colorectal cancer.
  • the cancer is colon cancer, pancreatic cancer or intestinal cancer.
  • the CCR4 mediated disorder and/or disease or condition is an inflammatory disease or disorder.
  • the inflammatory disease or disorder is dermatitis.
  • the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.
  • the inflammatory disease or disorder is atopic dermatitis. In yet another aspect of an embodiment, the inflammatory disease or disorder is contact dermatitis.
  • the inflammatory disease or disorder is prurigo nodularis.
  • the inflammatory disease or disorder is related to but not limited to Th2-associated inflammation in various mucosal barriers including lung and upper respiratory tissues. Accordingly, the present disclosure provides compounds for the use in respiratory allergies or for asthma or for chronic rhinosinusitis with or without nasal polyposis (CRSwNP).
  • CRSwNP nasal polyposis
  • the inflammatory disease or disorder is related to but not limited to Th2-associated inflammation in various mucosal barriers including upper and lower alimentary tract tissues.
  • the present disclosure provides compounds for the use in eosinophilic esophagitis (EoE) as well as but not limited to inflammatory bowel disease (IBD).
  • the present disclosure provides compounds for treatment of ulcerative colitis (UC) including but not limited to Th2-associated UC.
  • the present disclosure provides compound of formula (I) for use in the treatment of cancer.
  • the subject is a mammal including human.
  • the present disclosure provides compounds or pharmaceutically acceptable salts or stereoisomers thereof, for use as a medicament.
  • the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament.
  • the present disclosure provides compounds or pharmaceutically acceptable salts or stereoisomers thereof, for use in the treatment of cancer or an inflammatory disease or disorder.
  • the cancer is colon cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer or colorectal cancer.
  • the cancer is skin cancer including but not limited to melanoma or invasive adenocarcinoma.
  • the present disclosure provides compounds for use in the treatment of haematological cancers including but not limited to T cell lymphomas and leukaemia.
  • the present disclosure further provides compounds for use in established HTLV- 1 viral induced T cell leukaemia and lymphoma or for the prevention of leukaemogenesis in HTLV-1 positive patients.
  • the present disclosure provides compounds for use in the treatment and/or prevention of CCR4 activity that promotes metastasis due to migration of tumor cells expressing CCR4 to remote target organs that express CCL17 or CCL22 through lymphatics or blood circulation. Accordingly, the present disclosure provides compounds for use to inhibit metastasis to secondary lymphoid structures including but not limited to draining lymph nodes, downstream lymph nodes, thymus, lung, liver, bone marrow, skin, intestines, kidney and brain.
  • the present disclosure provides compounds for use in the treatment and/or prevention of CCR4 activity that promotes migration of leukaemia cells to sites resulting in development of cutaneous or thymic lymphomas through recruitment of immunosuppressive regulatory T-cells (Treg) cells that can inhibit tumor immunity and clearance.
  • Treg immunosuppressive regulatory T-cells
  • the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of diseases and/or disorder responsive to the modulation of CCR4 activity.
  • the disclosure provides a compound or a pharmaceutical acceptable salt or a stereoisomer thereof, for use in the treatment of CCR4 mediated disease or disorder.
  • the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer or an inflammatory disease or disorder.
  • the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer.
  • the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer wherein the cancer is colon cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer or colorectal cancer.
  • the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of inflammatory disease or disorder.
  • the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of inflammatory disease or disorder wherein the inflammatory disease or disorder is dermatitis. In yet another embodiment, the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of inflammatory disease or disorder wherein the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.
  • the present application provides compounds for use as a medicament for treating a subject suffering from diseases and/or disorder responsive to the modulation of CCR4 activity.
  • the present application provides compounds for use in the manufacture of a medicament for treating a subject suffering from diseases and/or disorder responsive to the modulation of CCR4 activity.
  • the disclosure provides compounds of the present disclosure for use in the manufacture of a medicament for the treatment of cancer.
  • the disclosure provides compounds of the present disclosure for use in the manufacture of a medicament for the treatment of inflammation.
  • the disclosure provides compounds of the present disclosure for use in the manufacture of a medicament for the treatment of cancer wherein the cancer is colon cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer or colorectal cancer.
  • the disclosure provides compounds of the present disclosure for use in the manufacture of a medicament for the treatment of inflammatory disease or disorder.
  • the disclosure provides compounds of the present disclosure for use in the manufacture of a medicament for the treatment of inflammatory disease or disorder wherein the inflammatory disease or disorder is dermatitis. In yet another embodiment, the disclosure provides compounds of the present disclosure for use in the manufacture of a medicament for the treatment of inflammatory disease or disorder wherein the inflammatory disease or disorder is atopic dermatitis or contact dermatitis.
  • the present disclosure comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more additional chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain- relieving agents.
  • additional chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain- relieving agents.
  • the present disclosure comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more additional anti-inflammatory agents.
  • the method(s) of treatment of the present disclosure comprises administering a safe and effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient (particularly a human) in need thereof.
  • the present disclosure provides a method of treating diseases and/or disorder mediated by CCR4 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • the present disclosure provides a method of modulating CCR4 in a subject, comprising contacting CCR4 with a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder mediated by CCR4, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating or preventing a disease or disorder mediated by CCR4, the disease or disorder is cancer or an inflammatory disease or disorder.
  • the present disclosure provides a method wherein the disease or disorder is inflammation. According to certain foregoing embodiments, the present disclosure provides a method wherein the disease or disorder is dermatitis.
  • the present disclosure provides a method wherein the disease or disorder is atopic dermatitis or contact dermatitis.
  • the present disclosure provides a method wherein the disease or disorder is cancer.
  • the present disclosure provides a method wherein the cancer is colon cancer, pancreatic cancer, intestinal cancer, breast cancer, lung cancer, gastric cancer, liver cancer or colorectal cancer.
  • the present disclosure provides a method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more chemotherapeutic agents or antiinflammatory agents.
  • the compounds of the present disclosure may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.
  • the present disclosure provides compounds for use in combination with other compounds or biologic entities for treatment of inflammatory diseases or cancer. Suitable combinations and doses of compounds for combination therapy used in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Combination therapies for compounds of the present disclosure can be used for treatment of inflammatory diseases or cancer.
  • the compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the disclosure and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2 H (“D”), 3 H, U C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • work-up includes distribution of the reaction mixture between the organic and aqueous phases, separation of layers and drying the organic layer over anhydrous sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.
  • quint-Apparent quintet dd-doublet of doublets, td-Triplet of doublets, SM-starting material, Int-Intermediate, Comp. -Compound, RB- Round bottom, RT- Room temperature, MHz-Megahertz, RM-Reaction mixture, DMP- Dess martin periodinane, EtsN- Triethylamine.
  • Step-1 Synthesis of tert-butyl (4-chloro-2-hydroxyphenyl)carbamate (lb)
  • Step-2 Synthesis of tert-butyl (3-bromo-4-chloro-2-hydroxyphenyl)carbamate (1c)
  • Step-3 Synthesis of 6-amino-2-bromo-3-chlorophenol (Id)
  • tert-butyl (3-bromo-4-chloro-2-hydroxyphenyl)carbamate (0.12 g, 0.37 mmol) in CH 2 Cl 2 (1 mL)
  • 4M HCl in dioxane (1 mL)
  • the resulting reaction mixture was stirred at RT for 4 h.
  • quenched with saturated aq. NaHCO3 solution extracted with ethyl acetate and the layers were separated.
  • the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated to afford the title compound 1d (0.1 g).
  • Step-4 Synthesis of 7-bromo-6-chlorobenzo[d]oxazole-2-thiol (I-1) To the stirred solution of 6-amino-2-bromo-3-chlorophenol (0.5 g, 2.24 mmol) in acetonitrile (10 mL) was added di(1H-imidazol-1-yl)methanethione (0.8 g, 4.49 mmol) at 0 °C. The resulting reaction mixture was warmed to RT and stirred at 85 °C for 4 h.
  • Step-1 Synthesis of 4-bromo-l-methyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (3b)
  • THF 15 mL
  • triphosgene 0.332 g, 1.11 mmol
  • the resulting reaction mixture was stirred for 20 minutes at the same temperature.
  • the reaction mixture was quenched with water, extracted with ethyl acetate and the layers were separated. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to get the title compound 3b (0.79 g).
  • Step-2 Synthesis of 4-bromo-2-chloro-l-methyl-lH-benzo[d]imidazole (1-3)
  • ACN 100 °C, 6 h 80 °C, 3 h
  • Step-1 Synthesis of 2,6-dibromo-3-fluoroaniline (6b) To a stirred solution of 3 -fluoroaniline (1 g, 8.99 mmol) in acetonitrile (30 mL), 1- bromopyrrolidine-2, 5-dione (3.2 g, 17.9 mmol) was added at 0 °C and stirred at RT for 2 hrs. After the completion of the reaction concentrated under reduced pressure to get the crude which was purified by flash chromatography using 1% ethyl acetate in hexane as an eluent to afford the pure title compound 6b (2 g, 82.5% yield). LC-MS: 269.9 [M+H] + .
  • Step-2 Synthesis of 4-bromo-7-fluorobenzo[d]thiazole-2-thiol (1-6)
  • Step-1 Synthesis of (lR,3r)-3-((R)-3-(l-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-l- yl)-l-methylcyclobutane-l-carboxylic acid (7d)
  • Step-2 (lR,3r)-3-((R)-3-(azetidin-3-yl)piperidin-l-yl)-l-methylcyclobutane-l-carboxylic acid (1-7)
  • Step-1 Synthesis of ethyl 2-cyclobutylideneacetate
  • Step-2 Synthesis of tert-butyl 3-(l-(l-(2-ethoxy-2-oxoethyl)cyclobutyl)piperidin-3- yl)azetidine-l-carboxylate
  • Step-3 Synthesis of 2-(l-(3-(l-(tert-butoxycarbonyl)azetidin-3-yl)piperidin-l- yl)cyclobutyl)acetic acid
  • Step-2 Synthesis of tert-butyl 3-(l-hydroxy-2-nitroethyl) azetidine-l-carboxylate
  • Step-3 Synthesis of tert-butyl 3-(2-amino-l-hydroxyethyl) azetidine-l-carboxylate
  • Step-4 Synthesis of tert-butyl 3-(2-(2-chloroacetamido)-l-hydroxyethyl) azetidine-l- carboxylate
  • Step-5 Synthesis of tert-butyl 3-(5-oxomorpholin-2-yl) azetidine-l-carboxylate
  • tert-butyl 3 -(2-(2-chloroacetamido)-l -hydroxy ethyl) azetidine-1- carboxylate 2.7 g, 9.22 mmol
  • KO’Bu 2.07 g, 18.44 mmol
  • Step-6 Synthesis of tert-butyl 3-(morpholin-2-yl) azetidine-l-carboxylate
  • Step-7 Synthesis of 3-(2-(l-(tert-butoxy carbonyl) azetidin-3-yl) morpholino)-!- methylcyclobutane-l-carboxylic acid
  • Step-8 Synthesis of 3-(2-(azetidin-3-yl) morpholino)-l-methylcyclobutane-l-carboxylic acid hydrochloride
  • Step-3 Synthesis of 7-chloro-2-(methylthio)thiazolo [4, 5-d] pyrimidine (1-8)
  • Step-4 Synthesis of N-(5-cyano-2-(methylthio)thiazol-4-yl)-2,2,2-trifluoroacetamide (10a)
  • Phosphorus(V) oxychloride (19.2 mL, 205.8 mmol, 50 eq.) was added to 2-(methylthio)-5- (trifluoromethyl)thiazolo[4,5-d]pyrimidin-7-ol (10b) (1.1 g, 4.1 mmol) at 0 °C and continued stirring at 110 °C for 3h. The progress of the reaction was monitored by TLC.
  • Step-1 Synthesis of l-(3,5-dichloropyridin-2-yl)ethan-l-one
  • Step-2 Synthesis of l-(3,5-dichloropyridin-2-yl)ethan-l-amine
  • GS-1A alkyl halide
  • suitable reagents and solvents K2CO3, DMF, room temperature
  • suitable reagents and solvents K2CO3, DMF, room temperature
  • suitable reagents and solvents toluene, Xantphos, Pd2(dba)3, sodium tertiary butoxide
  • GS-1D on treatment with mCPBA in presence of suitable reagents and solvents (chloroform) afforded mixture of GS-1E and GS-1F.
  • GS-1A alkyl halide
  • suitable reagents and solvents K2CO3, DMF, room temperature
  • suitable reagents and solvents K2CO3, DMF, room temperature
  • suitable reagents and solvents toluene, Xantphos, Pd 2 (dba) 3 , sodium tertiary butoxide
  • GS-3B on treatment with mCPBA in presence of suitable reagents and solvents (chloroform) afforded GS-3C.
  • Treatment of GS-3C with GS-3D in presence of suitable reagents and solvents DMF, dioxane, DIPEA
  • Some exemplary compounds of the present application may be generally synthesized utilizing the process outlined in General Scheme-4.
  • the commercially available or synthesized GS-1 was reacted with suitable reagents and solvents (SOCl2, DMF) to obtain GS-2A which upon reacting with GS-3D in presence of suitable reagents and solvents (dioxane, DIPEA) afforded GS-4A.
  • GS-4A on treatment with GS-3A in presence of suitable reagents and solvents (CS 2 CO 3 , X-Phos, Pd 2 (dba) 3 , 1,2-DME, tert-butanol) afforded compound of formula (IB).
  • Step-2 Synthesis of (R)-6-chloro-N-(1-(2,4-dichlorophenyl)ethyl)-2- (methylthio)benzo[d]oxazol-7-amine (1C)
  • 7-bromo-6-chloro-2-(methylthio)benzo[d]oxazole 0.1 g, 0.35 mmol
  • (R)- 1-(2,4-dichlorophenyl)ethan-1-amine (0.102 g, 0.538 mmol) were taken, dissolved using toluene (6 mL) and stirred at RT.
  • Step-3 Synthesis of 6-chloro-N-((R)-1-(2,4-dichlorophenyl)ethyl)-2- (methylsulfinyl)benzo[d]oxazol-7-amine (1D)
  • m-CPBA 0.047 g, 0.27 mmol
  • reaction mixture was cooled to RT, quenched with saturated NH 4 Cl solution, extracted with ethyl acetate and the layers were separated. The organic portion was dried over anhydrous Na2SO4, filtered, and concentrated to get crude compound.
  • the crude compound was purified by preparative TLC using 15% methanol in CH 2 Cl 2 to afford the title compound 1 (0.09 g, 49.04%).
  • Step-2 Synthesis of (1R, 3r)-3-((R)-3-(1-(7-bromobenzo[d]oxazol-2-yl)azetidin-3- yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (2B)
  • (1R,3r)-3-((R)-3-(azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane- 1-carboxylic acid 0.261g, 1.03 mmol
  • DIPEA 0.154g, 1,19 mmol
  • 7-bromo-2-chlorobenzo[d]oxazole (0.185g, 0.79 mmol
  • Step-3 Synthesis of (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4- dichlorophenyl)ethyl)amino)benzo[d]oxazol-2-yl)azetidin-3-yl)piperidin-1-yl)-1- methylcyclobutane-1-carboxylic acid (Compound-2)
  • (1R,3r)-3-((R)-3-(1-(7-bromobenzo[d]oxazol-2-yl)azetidin-3-yl)piperidin-1- yl)-1-methylcyclobutane-1-carboxylic acid (0.15g, 0.33 mmol)
  • (R)-1-(2,4- dichlorophenyl)ethan-1-amine 0.083g, 0.436 mmol
  • reaction mixture was purged with argon gas for 5 minutes, then were added Cs2CO3 (0.437g, 1.34 mmol), X-Phos (0.048g, 0.1 mmol), Pd2(dba)3 (0.031g, 0.3 mmol) one followed by another and again purged with argon gas for another 5 minutes at RT.
  • the resultant mixture was heated to 110 °C and stirred for 16 h. After the completion of reaction, the reaction mixture was cooled to RT and concentrated to get the crude compound.
  • the crude compound is purified by preparative HPLC-method to get the title compound 2 (0.005 g).
  • Step-2 Synthesis of (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4- dichlorophenyl)ethyl)amino)thiazolo[4,5-d]pyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)- 1-methylcyclobutane-1-carboxylic acid (Compound-32): To the stirred solution of 3A (0.05 g, 0.13 mmol, 1 eq.) and (1R,3r)-3-((R)-3-(azetidin-3- yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid (I-7) (0.06 g, 0.27 mmol, 2 eq.) in DMSO (3 mL) was added cesium fluoride (006 g 04 mmol 3 eq) at RT and heated at 100 o completion of the r ich was purified by
  • Example-4 Synthesis of (1R,3r)-3-((3R)-3-(1-(7-((1-(3,5-dichloropyridin-2- yl)ethyl)amino)-6-fluorobenzo[d]thiazol-2-yl)azetidin-3-yl)piperidin-1-yl)-1- methylcyclobutane-1-carboxylic acid (Compound-35), (1R,3r)-3-((R)-3-(1-(7-(((R)-1- (3,5-dichloropyridin-2-yl)ethyl)amino)-6-fluorobenzo[d]thiazol-2-yl)azetidin
  • Step-2 Synthesis of N-(1-(3,5-dichloropyridin-2-yl)ethyl)-6-fluoro-2- (methylthio)benzo[d]thiazol-7-amine (4C)
  • 7-bromo-6-fluoro-2-(methylthio)benzo[d]thiazole (4A) 0.5 g, 1.80 mmol
  • I-11 0.51 g, 2.70 mmol
  • Step-3 Synthesis of N-(1-(3,5-dichloropyridin-2-yl)ethyl)-6-fluoro-2- (methylsulfinyl)benzo[d]thiazol-7-amine (4D) and N-(1-(3,5-dichloropyridin-2-yl)ethyl)- 6-fluoro-2-(methylsulfonyl)benzo[d]thiazol-7-amine (4E) To the stirred solution of N-(1-(3,5-dichloropyridin-2-yl)ethyl)-6-fluoro-2- (methylthio)benzo[d]thiazol-7-amine (4C) (0.2 g, 0.51 mmol) in dichloromethane (5 mL) was added m-CPBA (0.18 g, 1.03 mmol) at 0 °C and the resulting reaction mixture was stirred at RT for 6 h
  • Step-4 Synthesis of (1R,3r)-3-((3R)-3-(1-(7-((1-(3,5-dichloropyridin-2-yl)ethyl)amino)-6- fluorobenzo[d]thiazol-2-yl)azetidin-3-yl)piperidin-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) and was added CsF (0.24 g, 1.56 mmol) at 0 °C and the resulting reaction mixture was allowed to reach to RT and stirred at 100 °C for 16 h.
  • reaction mixture was cooled to RT, quenched with saturated NH 4 Cl solution, extracted with 10% MeOH in CH2Cl2. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get crude compound which was purified by preparative TLC using 15% methanol in CH 2 Cl 2 to afford the title compound 35 (0.1 g, 34%).
  • Table-G % inhibition values of exemplary compounds
  • the CCR4 antagonistic activity IC50 values of some exemplary compounds are summarized below in table-H, wherein “A” refers to an IC50 value less than 0.25 ⁇ M, “B” refers to an IC50 value in range of 0.25 ⁇ M to 0.5 ⁇ M (both inclusive) and “C” refers to an IC 50 value greater than 0.5 ⁇ M.
  • Table-H IC 50 values of exemplary compounds Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

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Abstract

La présente divulgation concerne des composés hétérocyclyle bicycliques condensés et leurs dérivés de formule (I), qui sont thérapeutiquement utiles en tant que modulateurs de CCR4. Ces composés sont utiles dans le traitement et/ou la prévention de maladies et/ou de troubles sensibles à la modulation de l'activité de CCR4. Les composés selon la présente divulgation sont particulièrement utiles pour le traitement du cancer et de maladies et de troubles inflammatoires. La présente divulgation concerne également la préparation des composés et des formulations pharmaceutiques comprenant au moins l'un des composés de formule (I) ou un sel ou un stéréoisomère pharmaceutiquement acceptable de ceux-ci.
PCT/IB2024/054242 2023-05-02 2024-05-02 Composés hétérocyclyle bicycliques condensés utilisés en tant que modulateurs de ccr4 Pending WO2024228132A1 (fr)

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AU2024266044A AU2024266044A1 (en) 2023-05-02 2024-05-02 Fused bicyclic heterocyclyl compounds as ccr4 modulators
CN202480029392.6A CN121039119A (zh) 2023-05-02 2024-05-02 作为ccr4调节剂的稠合双环杂环基化合物
MX2025012881A MX2025012881A (es) 2023-05-02 2025-10-28 Compuestos heterociclicos biciclicos fusionados como moduladores del receptor tipo 4 de quimiocina c-c (ccr4)
IL324308A IL324308A (en) 2023-05-02 2025-10-29 Compressed bicyclic heterocyclyl compounds as CCR4 modulators

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Publication number Priority date Publication date Assignee Title
WO2018187509A1 (fr) * 2017-04-04 2018-10-11 Flx Bio, Inc. Composés hétérocycliques utilisés en tant que modulateurs du récepteur de chimiokine
WO2019090272A1 (fr) * 2017-11-06 2019-05-09 Flx Bio, Inc. Modulateurs du récepteur de chimiokine pour le traitement de cancers positifs au virus epstein-barr
WO2019147862A1 (fr) * 2018-01-26 2019-08-01 Flx Bio, Inc. Modulateurs des récepteurs de la chimiokine et leurs utilisations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018187509A1 (fr) * 2017-04-04 2018-10-11 Flx Bio, Inc. Composés hétérocycliques utilisés en tant que modulateurs du récepteur de chimiokine
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