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WO2024114561A1 - Composé pyrimidine substitué par spiro-hétérocycle, son procédé de préparation et son utilisation - Google Patents

Composé pyrimidine substitué par spiro-hétérocycle, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024114561A1
WO2024114561A1 PCT/CN2023/134260 CN2023134260W WO2024114561A1 WO 2024114561 A1 WO2024114561 A1 WO 2024114561A1 CN 2023134260 W CN2023134260 W CN 2023134260W WO 2024114561 A1 WO2024114561 A1 WO 2024114561A1
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membered
alkyl
formula
compound
halogen
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姚元山
胡玮
栾林波
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Shanghai Meiyue Biotech Development Co Ltd
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Shanghai Meiyue Biotech Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a spiroheterocyclic substituted pyrimidine compound, a preparation method and use thereof.
  • Chemokines are a family of cytokines that guide leukocytes to move as chemical attractants. They are secreted by a variety of cells, and can be functionally divided into two categories: hemostatic chemokines and inflammatory chemokines. Hemostatic chemokines are produced in certain tissues in a compositional manner, and control the cells of the immune system during the immune surveillance process, such as directing lymphocytes to lymph nodes so that they can screen for the invasion of pathogens.
  • Inflammatory chemokines are released by cell response pathological events (for example, proinflammatory stimulants, such as IL-1 or viruses). It mainly acts as a chemical attractant as a part of inflammatory response, and is used to guide the cells of the innate immune system and the adaptive immune system to the inflammatory site.
  • proinflammatory stimulants such as IL-1 or viruses.
  • CCR4 C-C chemokine receptor type 4
  • Th2 cells C-C chemokine receptor type 4
  • cytokines such as IL4, IL5 and IL13.
  • CCR4 has attracted widespread research and development interest as a potential drug development target, the development of small molecule compounds that regulate CCR4 function is an ongoing challenge. So far, no small molecule drug has entered the market, so it is still necessary to actively explore new, excellent and selective CCR4 small molecule antagonists.
  • CCR4-related patents that have been disclosed so far include WO2019090272A1 and WO2019147862A1.
  • the present disclosure provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof,
  • G is CR 5 or N
  • R 1 is LR 9 ;
  • L is a chemical bond, NR 10 , O, S, -C(O)-, -S(O)- or -S(O) 2 -;
  • R 9 is H, C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, NR 9a R 9b , C(O)NR 9a R 9b , S(O) 2 R 9c , C(O)CH 2 CN, C(O)COOH, C(O)(3 to 8 membered heterocyclyl), C(O)OR 9d , C(O)CH(CH 3 )OR 9d or C(O)CH 2 OR 9d , wherein the C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally substituted with one or more R g ;
  • R 10 is H, C 1-6 alkyl, deuterated C 1-6 alkyl or 3 to 8 membered cycloalkyl, wherein the C 1-6 alkyl and 3 to 8 membered cycloalkyl are optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, amino and 3 to 8 membered cycloalkyl;
  • R 9 and R 10 may optionally form a 4- to 8-membered heterocyclic group together with the nitrogen atom to which they are attached, and the 4- to 8-membered heterocyclic group may optionally be substituted by one or more R g ;
  • R g1 is C 1-6 alkyl or C 1-6 alkoxy
  • Rg2 is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;
  • R g3 and R g4 are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;
  • R 4 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclyl, NR 4a R 4b , C(O)NR 4a R 4b , C(O)OR 4c , S(O) 2 R 4d , NR 4a C(O)R 4e or NR 4a C(O)OR 4c , wherein the C 1-6 alkyl, C 1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, 3 to 8-membered cycloalkyl and 3 to 8-member
  • R 5 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclyl, NR 5a R 5b , C(O)NR 5a R 5b , C(O)OR 5c , S(O) 2 R 5d , NR 5a C(O)R 5e or NR 5a C(O)OR 5c , wherein the C 1-6 alkyl, C 1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, 3 to 8-membered cycloalkyl and 3 to 8-member
  • R6 is H, C1-6 alkyl, C1-6 haloalkyl or 3 to 8 membered cycloalkyl
  • G is CR 5 , R 4 and R 5 together with the carbon atom to which they are attached form a 5- to 8-membered cycloalkyl group, a 5- to 8-membered heterocyclic group, a benzene group, alkyl or 5 to 6 membered heteroaryl, wherein the 5 to 8 membered cycloalkyl, 5 to 8 membered heterocyclyl, phenyl and 5 to 6 membered heteroaryl are optionally substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, cyano, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl;
  • G is CR 5 , R 5 and R 6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 5- to 8-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, oxo , hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , cyano , 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl;
  • R7 is H, D, halogen, C1-6 alkyl or C1-6 haloalkyl
  • Each R 8 is the same or different and is independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, hydroxy, cyano or 3 to 8 membered cycloalkyl;
  • R 4a , R 4b , R 5a , R 5b , R 9a , R 9b and R 9d are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • R 4c and R 5c are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • R 4d , R 5d and R 9c are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • R 4e and R 5e are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • n 1 or 2;
  • n and m are not both 2;
  • k 0, 1, or 2;
  • p 0, 1, 2, 3, 4, 5 or 6;
  • q 0, 1, 2, 3, or 4;
  • t 0, 1, 2, 3, 4, or 5;
  • heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 8-membered heterocyclic group, the 5- to 10-membered heteroaryl group and the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4.
  • G is CR 5 or N;
  • R 1 is LR 9 ;
  • L is a chemical bond, NR 10 , O, S, -C(O)-, -S(O)- or -S(O) 2 -;
  • R 9 is H, C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl, 5 to 10 membered heteroaryl, NR 9a R 9b , C(O)NR 9a R 9b , S(O) 2 R 9c , C(O)OR 9d or C(O)CH 2 OR 9d , wherein the C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl are each independently optionally substituted with one or more R g ;
  • R 10 is H or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, amino and 3 to 8 membered cycloalkyl;
  • R 9 and R 10 may optionally form a 4- to 8-membered heterocyclic group together with the nitrogen atom to which they are attached, and the 4- to 8-membered heterocyclic group may optionally be substituted by one or more R g ;
  • R g1 is C 1-6 alkyl or C 1-6 alkoxy
  • Rg2 is C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;
  • R g3 and R g4 are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl or 3- to 8-membered cycloalkyl;
  • R 4 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclyl, NR 4a R 4b , C(O)NR 4a R 4b , C(O)OR 4c , S(O) 2 R 4d , NR 4a C(O)R 4e or NR 4a C(O)OR 4c , wherein the C 1-6 alkyl, C 1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, 3 to 8-membered cycloalkyl and 3 to 8-member
  • R 5 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, hydroxy, cyano, amino, 3 to 8-membered cycloalkyl, 3 to 8-membered heterocyclyl, NR 5a R 5b , C(O)NR 5a R 5b , C(O)OR 5c , S(O) 2 R 5d , NR 5a C(O)R 5e or NR 5a C(O)OR 5c , wherein the C 1-6 alkyl, C 1-6 alkoxy, 3 to 8-membered cycloalkyl and 3 to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, 3 to 8-membered cycloalkyl and 3 to 8-member
  • R6 is H, C1-6 alkyl, C1-6 haloalkyl or 3 to 8 membered cycloalkyl
  • G is CR 5 , R 4 and R 5 together with the carbon atom to which they are attached form a 5- to 8-membered cycloalkyl, a 5- to 8-membered heterocyclyl, a phenyl or a 5- to 6-membered heteroaryl, wherein the 5- to 8-membered cycloalkyl, the 5- to 8-membered heterocyclyl, the phenyl and the 5- to 6-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, cyano, a 3- to 8-membered cycloalkyl and a 3- to 8-membered heterocyclyl;
  • G is CR 5 , R 5 and R 6 together with the atoms to which they are attached form a 5- to 8-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 5- to 8-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, oxo , hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , cyano , 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl;
  • R7 is H, D, halogen, C1-6 alkyl or C1-6 haloalkyl
  • Each R 8 is the same or different and is independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl , C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, hydroxy, cyano or 3 to 8 membered cycloalkyl;
  • R 4a , R 4b , R 5a , R 5b , R 9a , R 9b and R 9d are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • R 4c and R 5c are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • R 4d , R 5d and R 9c are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • R 4e and R 5e are the same or different and are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • n 1 or 2;
  • n and m are not both 2;
  • k 0, 1, or 2;
  • p 0, 1, 2, 3, 4, 5 or 6;
  • q 0, 1, 2, 3, or 4;
  • t 0, 1, 2, 3, 4, or 5;
  • heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 8-membered heterocyclic group, the 5- to 10-membered heteroaryl group or the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of heteroatoms is independently 1, 2, 3 or 4.
  • R 9 is C(O)CH 2 CN, C(O)COOH, C(O)(3- to 8-membered heterocyclyl) or C(O)CH(CH 3 )OR 9d ;
  • R 10 is a deuterated C 1-6 alkyl group or a 3- to 8-membered cycloalkyl group, wherein the 3- to 8-membered cycloalkyl group is optionally substituted with one or more substituents selected from halogen , hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy , cyano, amino and 3- to 8-membered cycloalkyl group.
  • the C 1-6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl or isopropyl.
  • the 3- to 8-membered cycloalkyl is a 3- to 6-membered cycloalkyl, such as cyclopropyl, cyclobutyl or cyclopentyl, and also such as cyclobutyl.
  • the heteroatom in the 3- to 8-membered heterocyclic group is N, O or S, such as N; the number of the heteroatoms can be 1, 2 or 3, such as 1.
  • the 3- to 8-membered heterocyclic group is a 3- to 6-membered heterocyclic group, such as azetidinyl Pyrrolidin piperidinyl or piperazinyl.
  • the 3- to 8-membered heterocyclic group is a 3- to 6-membered heterocyclic group, such as imidazolidinyl
  • the heteroatom in the 5- to 10-membered heteroaryl group is N, O or S, such as N; the number of the heteroatoms can be 1, 2 or 3, such as 2.
  • the 5- to 10-membered heteroaryl group is a 5- to 6-membered heteroaryl group or an 8- to 10-membered fused heteroaryl group; the 5- to 6-membered heteroaryl group may be a pyrrolyl group, a pyrazolyl group or an imidazolyl group, for example
  • R9 and R10 together with the nitrogen atom to which they are connected form a 4- to 8-membered heterocyclic group, wherein the heteroatom in the 4- to 8-membered heterocyclic group is N, O or S, such as N; and the number of the heteroatoms may be 1, 2 or 3, such as 1.
  • R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group is a 4- to 6-membered heterocyclic group, such as azetidinyl or pyrrolidin
  • the C 1-6 hydroxyalkyl group is independently a C 1-4 hydroxyalkyl group, such as -CH 2 CH 2 OH.
  • G is CR 5 ; R 5 is as defined in formula (I).
  • G is N.
  • the compound represented by formula (I) is a compound represented by formula (II),
  • R4 is H, halogen, C1-6 alkyl, hydroxyl, cyano, amino or 3 to 8 membered cycloalkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; the 3 to 8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl and cyano;
  • R5 is H, halogen, C1-6 alkyl, hydroxyl, cyano, amino or 3-8 membered cycloalkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3-8 membered cycloalkyl and 3-8 membered heterocyclic group; the 3-8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl and cyano;
  • R6 is H or C1-6 alkyl
  • R4 and R5 may optionally form together with the carbon atom to which they are attached a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclyl, a phenyl or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered cycloalkyl, the 5- to 6-membered heterocyclyl, the phenyl and the 5- to 6-membered heteroaryl are optionally substituted with one or more substituents selected from halogen, hydroxyl, C1-6 alkyl and cyano;
  • R 8A and R 8B are the same or different and are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 hydroxyalkyl;
  • R 1 , R 2 , R 3 , R 7 , n, m, p, q and k are as defined in formula (I).
  • the compound represented by formula (II) or a pharmaceutically acceptable salt thereof wherein R4 is H, halogen, C1-6 alkyl, C1-6 alkoxy , hydroxyl , cyano, amino or 3 to 8 membered cycloalkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; the 3 to 8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl and cyano;
  • R 5 is H, halogen, C 1-6 alkyl, hydroxyl, cyano, amino, C(O)NH 2 or 3 to 8 membered cycloalkyl, wherein the C 1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl; the 3 to 8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl and cyano.
  • the compound represented by formula (I) is a compound represented by formula (II-1) or formula (II-2),
  • R1 , R2 , R3 , R4 , R5 , R6 , R7 , R8A , R8B , n, m, p, q and k are as defined in formula (II).
  • R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl , cyano or 3-8 membered cycloalkyl
  • R5 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, cyano or 3-8 membered cycloalkyl.
  • R 4 is H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano or 3-8 membered cycloalkyl
  • R 5 is H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C(O)NH 2 , cyano or 3-8 membered cycloalkyl.
  • R 4 is H, -CH 3 , -CH 2 CH 3 , -OCH 3 , -CF 3 ,
  • R6 is H.
  • G is CR 5 ; R 5 and R 6 together with the atoms to which they are connected form a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from halogen, oxo, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , cyano , 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclic group.
  • the compound represented by formula (I) is a compound represented by formula (III), formula (IV) or formula (V),
  • R4 is H, halogen, C1-6 alkyl, hydroxyl, cyano, amino or 3 to 8 membered cycloalkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkoxy, C1-6 haloalkoxy, cyano, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclic group; the 3 to 8 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl and cyano;
  • R 11 is H, C 1-6 alkyl or 3 to 8 membered cycloalkyl
  • R 12 and R 13 are the same or different and are each independently H, halogen, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl;
  • R 8A and R 8B are the same or different and are each independently H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or C 1-6 hydroxyalkyl;
  • R 1 , R 2 , R 3 , R 7 , n, m, p, q and k are as defined in formula (I).
  • the compound represented by formula (I) is a compound represented by formula (III-1), formula (IV-1) or formula (V-1),
  • R1 , R2 , R3 , R4, R7 , R8A , R8B , R11 , R12 , R13 , n, m, p, q and k are as defined in formula (III), formula (IV) or formula (V).
  • the compound represented by formula (I) is a compound represented by formula (III-2), formula (IV-2) or formula (V-2),
  • R1 , R2 , R3 , R4, R7 , R8A , R8B , R11 , R12 , R13 , n, m, p, q and k are as defined in formula (III), formula (IV) or formula (V).
  • R4 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, cyano or 3 to 8 membered cycloalkyl.
  • R4 is H.
  • R 11 is a C 1-6 alkyl group, preferably a methyl group.
  • R12 is H, halogen, C1-6 alkyl, C1-6 haloalkyl or cyano
  • R13 is H, halogen or C1-6 alkyl.
  • n is 1, m is 1, and k is 0, 1 or 2; or, n is 1, m is 2, and k is 0, 1 or 2; or, n is 2, m is 1, and k is 0, 1 or 2.
  • n is 1
  • m is 1
  • k is 0, 1 or 2.
  • n is 1, m is 2, and k is 0, 1 or 2.
  • n is 2
  • m is 1
  • k is 0, 1 or 2.
  • the compounds of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts are disclosed herein.
  • R 1 , R 2 , R 3 , p and q are as defined in formula (I).
  • R 1 is NR 9 R 10 , OR 9 or C(O)NR 9a R 9b ;
  • R 9 is H, C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl or C(O)CH 2 OR 9d , wherein the C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally substituted with one or more R g ;
  • R 9d is H or C 1-6 alkyl;
  • R 9a is H or C 1-6 alkyl;
  • R 9b is H, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 hydroxyalky
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group is optionally substituted by one or more R g ;
  • Each Rg is the same or different and is independently halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, cyano, carboxyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkoxy, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are independently optionally substituted by one or more substituents selected from halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, oxo, cyano, amino, carboxyl and 3- to 8-membered cycloalkyl.
  • R 1 is NR 9 R 10 , OR 9 or C(O)NR 9a R 9b ;
  • R 9 is H, C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl, C(O)CH 2 CN, C(O)COOH, C(O)(3 to 8 membered heterocyclyl), C(O)CH(CH 3 )OR 9d or C(O)CH 2 OR 9d , wherein the C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally substituted with one or more R g ; R 9d is H or C R 9a
  • R9 and R10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group is optionally substituted by a or multiple R g ;
  • Each Rg is the same or different and is independently halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, cyano, carboxyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkoxy, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are independently optionally substituted by one or more substituents selected from halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, oxo, cyano, amino, carboxyl and 3- to 8-membered cycloalkyl.
  • R1 is
  • R1 is
  • R1 is
  • R2 and R3 are the same or different and are each independently H, halogen or C1-6 alkyl.
  • R2 and R3 are the same or different and are each independently H.
  • the compounds of formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), and formula (V-2) or their pharmaceutically acceptable salts are disclosed herein. for
  • R 1 is NR 9 R 10 , OR 9 or C(O)NR 9a R 9b ;
  • R 9 is H, C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 to 6 membered heteroaryl or C(O)CH 2 OR 9d , wherein the C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally substituted by one or more R g ;
  • R 9d is H or C 1-6 alkyl;
  • R 9a is H or C 1-6 alkyl;
  • R 9b is H, C 1-6 alkyl, C 1-6 haloalkyl or C 1-6 hydroxyalkyl;
  • R 10 is H or C 1-6 alkyl;
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group is optionally substituted by one or more R g ;
  • Each Rg is the same or different and is independently halogen, hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, cyano, carboxyl, 3- to 8-membered cycloalkyl or 3- to 8-membered heterocyclyl, wherein the C1-6 alkyl, C1-6 alkoxy, 3- to 8-membered cycloalkyl and 3- to 8-membered heterocyclyl are independently optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, oxo, cyano, amino, carboxyl and 3- to 8-membered cycloalkyl;
  • R2 and R3 are the same or different and are each independently H, halogen or C1-6 alkyl.
  • R7 is C1-6 alkyl or C1-6 haloalkyl.
  • R7 is a C1-6 alkyl group, preferably a methyl group.
  • each R 8 is the same or different and is independently H, halogen or C 1-6 alkyl.
  • R 8A and R 8B are the same or different and are each independently halogen, preferably chlorine.
  • R 1 is NR 9 R 10 or OR 9 ;
  • R 9 is H, C 1-6 alkyl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, C(O)CH 2 OR 9d , C(O)CH 2 CN or C(O)(3 to 8 membered heterocyclyl), wherein the C 1-6 alkyl, 3 to 8 membered cycloalkyl and 3 to 8 membered heterocyclyl are each independently optionally substituted by one or more R g ;
  • R 9d is H or C 1-6 alkyl;
  • R 10 is H or C 1-6 alkyl;
  • R 9 and R 10 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group is optionally substituted by one or more R g ;
  • Each Rg is the same or different and is independently halogen, hydroxyl, oxo, C1-6 alkyl, or carboxyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents selected from cyano and carboxyl;
  • R2 and R3 are the same or different and are each independently H;
  • R4 is H or C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by one or more substituents selected from halogen and hydroxy;
  • R 5 is halogen, C 1-6 alkyl or cyano, wherein the C 1-6 alkyl is optionally substituted by hydroxy;
  • R6 is H
  • R4 and R5 may optionally be taken together with the carbon atom to which they are attached to form a 5- to 6-membered cycloalkyl, a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl, wherein the 5- to 6-membered cycloalkyl, the 5- to 6-membered heterocyclyl and the 5- to 6-membered heteroaryl are optionally substituted with a C1-6 alkyl group;
  • G is CR 5 , R 5 and R 6 together with the atoms to which they are attached form a 5- to 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are optionally substituted with one or more substituents selected from oxo and C 1-6 alkyl;
  • R7 is C1-6 alkyl
  • R are the same or different and are each independently halogen
  • n 1;
  • n 1;
  • k 1 or 2;
  • p 1;
  • heteroatoms in the 3- to 8-membered heterocyclic group, the 4- to 8-membered heterocyclic group, the 5- to 6-membered heterocyclic group and the 5- to 6-membered heteroaryl group are independently one or more of N, O or S, and the number of the heteroatoms is independently 1, 2, 3 or 4.
  • exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table A below:
  • the exemplary specific compounds of the compound represented by formula (I) also include, but are not limited to, the structures in Table B below:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present disclosure also provides the use of compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, in the preparation of drugs for regulating CCR4.
  • the present disclosure also provides the use of compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, in the preparation of drugs for inhibiting CCR4.
  • the present disclosure also provides the use of compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing the same, in the preparation of drugs for preventing and/or treating CCR4-mediated diseases or conditions.
  • the present disclosure also provides formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), Use of a compound shown in formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for preventing and/or treating autoimmune diseases, inflammatory diseases and cancer; preferably, in the preparation of a medicament for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease.
  • the present disclosure also provides a method for inhibiting CCR4, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition containing the same.
  • the present disclosure also provides a method for preventing and/or treating a CCR4-mediated disease or condition, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), (II), (II-1), (II-2), (III), (III-1), (III-2), (IV), (IV-1), (IV-2), (V), (V-1), (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned isotope-labeled substance, or the aforementioned pharmaceutical composition comprising the same.
  • the present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases and cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the foregoing.
  • the present disclosure also provides a method for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or a compound shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a drug.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 modulator.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or the aforementioned pharmaceutical composition, for use as a CCR4 inhibitor.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and/or treating CCR4-mediated diseases or conditions.
  • the present disclosure also provides a compound shown in formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), or shown in Table A or Table B, or a pharmaceutical composition thereof
  • the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same, is used as a drug for preventing and/or treating autoimmune diseases, inflammatory diseases and cancer.
  • the present disclosure also provides a compound shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a drug for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease.
  • the CCR4-mediated disease is selected from the group consisting of an autoimmune disease, an inflammatory disease, and cancer.
  • the CCR4-mediated disease is selected from arthritis, psoriasis, systemic lupus erythematosus and inflammatory bowel disease.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotope-labeled substances thereof, based on the total weight of the composition.
  • the pharmaceutical composition contains 0.1-99.9% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), compounds shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotope-labeled substances thereof.
  • the pharmaceutical composition contains 0.5%-99.5% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof.
  • the pharmaceutical composition contains 1%-99% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (IV-1), formula (IV-2), formula (V), formula (V-1), formula (V-2), shown in Table A or Table B, or a pharmaceutically acceptable salt thereof, or an isotope-labeled substance thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of one or more pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of one or more pharmaceutically acceptable excipients.
  • the disclosed compounds can be administered in the form of a pharmaceutical composition.
  • These compositions can be prepared in a manner well known in the pharmaceutical field and can be administered by a variety of routes, depending on whether local or systemic treatment is required and the area to be treated. It can be administered topically (e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal), oral or parenteral.
  • topically e.g., transdermal, skin, eye and mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal
  • oral or parenteral e.g., by inhalation or insuff
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intraventricular administration. It can be administered parenterally in a single bolus form, or it can be administered, for example, by a continuous infusion pump.
  • the active ingredient is usually mixed with excipients and the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or dissolved in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaging. powder.
  • excipient refers to ingredients other than active ingredients, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • the pharmaceutically acceptable salts of the compounds described in the present disclosure may be inorganic salts or organic salts. If these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.
  • these compounds have a basic center, they can form acid addition salts; if these compounds have an acidic center, they can form base addition salts; if these compounds contain both an acidic center (e.g., a carboxyl group) and a basic center (e.g., an amino group), they can also form internal salts.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • cis and trans isomers for example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures and other mixtures, as well as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present disclosure.
  • the bond Indicates that the configuration is not specified. Indicates absolute or relative configuration. If there are chiral isomers in the chemical structure, the bond Can be or include both Two configurations. It can also express relative configuration. For example, when the substituents are located on two faces of cyclobutane, When the substituents are on the same side of the cyclobutane, express.
  • Tautomer refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also referred to as prototransfer tautomers
  • proton migration such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactimide isomerization. All tautomeric forms of all compounds in the present disclosure are within the scope of the present disclosure.
  • the name of the compound named in a single manner does not exclude any tautomer.
  • the present disclosure also includes some isotopically labeled compounds of the present disclosure that are identical to the structures described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H , 3H , 11C , 13C , 14C , 13N , 15N , 15O , 17O , 18O , 31P , 32P , 35S , 18F , 123I , 125I , and 36Cl , respectively. All isotopic composition changes of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have deuterium (i.e., at least 10% deuterium incorporation) at least 1000 times greater than the natural abundance of deuterium (which is 0.015%).
  • the natural abundance of the compound in the example may be at least 1000 times greater than deuterium, at least 2000 times greater than deuterium, at least 3000 times greater than deuterium, at least 4000 times greater than deuterium, at least 5000 times greater than deuterium, at least 6000 times greater than deuterium, or more.
  • Each available hydrogen atom connected to a carbon atom may be independently replaced by a deuterium atom.
  • deuterated starting materials may be used, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
  • the "therapeutically effective amount” of the present disclosure refers to the amount of active compound or drug that causes a biological or medical response in a tissue, system, animal, individual or human that is sought by researchers, veterinarians, physicians or other clinicians, and includes one or more of the following: (1) Prevention of disease: for example, prevention of disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed the disease pathology or symptoms. (2) Suppression of disease: for example, suppression of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., preventing further development of the pathology and/or symptoms).
  • Relief of disease for example, relief of disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (i.e., reversing the pathology and/or symptoms).
  • a "therapeutically effective amount” refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms that are, within the scope of reasonable medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems or complications, have a reasonable benefit/risk ratio, and are effective for the intended use.
  • the "patient” of the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms ( C1-6 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched chain isomers thereof, etc.
  • the alkyl group can be substituted or unsubstituted.
  • alkoxy refers to -O-(alkyl), wherein alkyl is defined as described herein.
  • the alkoxy group contains 1 to 12 (e.g., 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (C 1-12 alkoxy), and more preferably, the alkoxy group contains 1 to 6 carbon atoms (C 1-6 alkoxy).
  • Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups may be substituted or unsubstituted.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, fused, and bridged rings.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 members, in which each monocyclic ring in the system shares a carbon atom (called a spiro atom).
  • spiroalkyl refers to a cycloalkyl radical having one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan).
  • the cycloalkyl radical is divided into a single cycloalkyl radical, a double cycloalkyl radical or a multi-cycloalkyl radical, preferably a single cycloalkyl radical and a double cycloalkyl radical. It is more preferably 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan of single cycloalkyl radicals.
  • Non-limiting examples of cycloalkyl radicals include:
  • condensed cycloalkyl refers to 5 to 20 yuan, and each ring in the system shares a pair of adjacent carbon atoms with other rings in the system. All carbon polycyclic groups, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 yuan, more preferably 7 to 10 yuan (such as 7,8,9 or 10 yuan).
  • dicyclo, tricyclo, tetracycle or polycyclic condensed cycloalkyl can be divided, preferably dicyclo or tricyclo, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan and 6 yuan/6 yuan of dicycloalkyl.
  • condensed cycloalkyl include:
  • bridged cycloalkyl refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic.
  • bridged cycloalkyl include:
  • the cycloalkyl ring includes a cycloalkyl group (including monocyclic, spirocyclic, fused and bridged rings) as described herein fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferred The cycloalkyl group may be substituted or unsubstituted.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxo-substituted (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms being carbon.
  • the substituent contains 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11) ring atoms.
  • the invention relates to a heterocyclic group having 1 to 2 ring atoms, wherein 1 to 4 (e.g., 1, 2, 3, and 4) ring atoms are heteroatoms; more preferably, 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) ring atoms are heteroatoms; more preferably, 3 to 6 ring atoms are heteroatoms; and most preferably, 5 or 6 ring atoms are heteroatoms.
  • 1 to 4 e.g., 1, 2, 3, and 4
  • ring atoms are heteroatoms
  • 3 to 8 ring atoms e.g., 3, 4, 5, 6, 7, and 8
  • ring atoms are heteroatoms
  • 3 to 6 ring atoms are heteroatoms
  • most preferably, 5 or 6 ring atoms are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Polycyclic heterocyclic groups include spirocyclic, fused, and bridged heterocyclic groups.
  • spiro heterocyclic group refers to a polycyclic heterocyclic group of 5 to 20 yuan, in which one atom (called spiral atom) is shared between each monocyclic ring in the system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan).
  • the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. It is more preferably a 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral heterocyclic group.
  • spiral heterocyclic groups include:
  • fused heterocyclic radical refers to 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system.
  • the polycyclic heterocyclic group, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, and more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan).
  • the composition ring it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic radical, preferably a bicyclic or tricyclic, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan and 6 yuan/6 yuan bicyclic fused heterocyclic radical.
  • fused heterocyclic radicals include:
  • bridged heterocyclic group refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members).
  • bridged heterocyclic groups include:
  • the heterocyclyl ring includes a heterocyclyl as described herein (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • the heterocyclic group may be substituted or unsubstituted.
  • aryl refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated ⁇ electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • Aryl groups can be substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • yuan e.g., 5, 6, 7, 8, 9, or 10 yuan
  • 5 yuan or 6 yuan such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl as described herein fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • a heteroaryl group can be substituted or unsubstituted.
  • alkyl alkoxy
  • cycloalkyl heterocyclyl
  • aryl and “heteroaryl” and the like herein may be substituted or unsubstituted; when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more identical or different substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived from the parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", “divalent heterocyclic”, “heterocyclic”, “heteroaryl” and “heteroaryl". "Aryl”, "heteroarylene".
  • cycloalkyloxy refers to a cycloalkyl-O- group wherein cycloalkyl is as defined herein.
  • heterocyclyloxy refers to heterocyclyl-O- wherein heterocyclyl is as defined herein.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined herein.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined herein.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
  • halogen refers to F, Cl, Br or I.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O-, or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined herein.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.
  • a heterocycloalkyl group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive and progressive effect of the present invention is that the present invention provides a small molecule compound having a spiroheterocyclic substituted pyrimidine structure, which can be used as a CCR4 inhibitor, such as the compounds shown in Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (IV-1), Formula (IV-2), Formula (V), Formula (V-1), Formula (V-2), or those shown in Table A or Table B.
  • Such compounds or pharmaceutical compositions can be used to effectively treat or prevent CCR4-mediated diseases.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • Mass spectrometry was measured by Waters 2767 HPLC/Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC/Waters liquid chromatography-mass spectrometry.
  • the thin layer chromatography silica gel plate used is GF254 silica gel plate produced by Chenghua (Shanghai) Co., Ltd.
  • the specification of silica gel plate used in thin layer chromatography (TLC) is 0.2-0.25 mm, and the specification of thin layer chromatography separation and purification product is 0.4-0.5 mm.
  • Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1 liter.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.
  • reaction temperature is room temperature, ranging from 20°C to 30°C.
  • the chiral compounds separated can be distinguished by the order of retention time in the chiral chromatographic column. Therefore, the chiral compounds separated according to the retention time are distinguished by corresponding number suffixes such as P1 and P2. That is, suffix P1 corresponds to the chiral structure separated first, and suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it corresponds one to one with the compounds with number suffixes P1 and P2, but only indicates two forms of existence of the absolute configuration. The absolute configuration of the compounds with number suffixes P1 and P2 shall be based on the absolute configuration objectively corresponding to the specific retention time.
  • reaction solution was slowly poured into water (100 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • N, N-diisopropylethylamine 650 mg, 5.01 mmol
  • compound 1-6 222 mg, 1.66 mmol
  • the resulting reaction solution was stirred at room temperature for 3 hours.
  • the reaction was completed.
  • the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3).
  • the organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product.
  • methylmagnesium bromide (4.00mmol, 4mL, 1M) tetrahydrofuran solution was added dropwise to a solution of compound 7-3 (200mg, 0.39mmol) in anhydrous tetrahydrofuran (10mL). After the addition was complete, the cold bath was removed, the reaction solution was naturally warmed to room temperature and stirred overnight. The reaction was completed. Saturated aqueous ammonium chloride solution (20mL) was added to the reaction solution, and ethyl acetate was extracted (20mL x 3).
  • methylmagnesium bromide (2.00mmol, 2mL, 1M) tetrahydrofuran solution was added dropwise to a solution of compound 8-3 (190mg, 0.37mmol) in anhydrous tetrahydrofuran (10mL). After the addition was complete, the cold bath was removed, the reaction solution was naturally warmed to room temperature and stirred overnight. The reaction was completed. Saturated aqueous ammonium chloride solution (20mL) was added to the reaction solution, and ethyl acetate was extracted (20mL x 3).
  • Example 10 (10-P1, 10-P2, 10-P3 and 10-P4)
  • Reverse phase preparation column waters XB-C18 19x250mm, 10 ⁇ m;
  • the first group of compounds (one or two structures of 10-P1, 10-P2, 10-P3 and 10-P4):
  • the second group of compounds (one or two structures among 10-P1, 10-P2, 10-P3 and 10-P4):
  • Example 13 Compounds 13, 13-P1, 13-P2, 13-P3, 13-P4, 13R-P1, 13R-P2, 13S-P1 and 13S-P2)
  • Compound 13R was synthesized by replacing compound 13-1 in Example 13 with (R)-pyrrolidine-3-carboxylic acid, and 13R-P1 (retention time 1.333 minutes) and 13R-P2 (retention time 1.651 minutes) were obtained by SFC separation.
  • Example 13 The compound 13-1 in Example 13 was replaced with (S)-methylpyrrolidine-3-methyl ester to synthesize compound 13Z, which was separated by SFC to obtain to 13Z-P1 (retention time 1.671 minutes) and 13Z-P2 (retention time 2.221 minutes).
  • 13Z-P1 and 13Z-P2 were hydrolyzed with LiOH to obtain 13S-P1 and 13S-P2, respectively.
  • LiOH ⁇ H 2 O (1M, 3.2 mL) was added to a solution of 13Z-P1 (440 mg, 0.80 mmol) in MeOH (10 mL) and stirred at room temperature for 4 hours.
  • the pH of the reaction solution was adjusted to 6 with 2 mol/L dilute hydrochloric acid, and the reaction solution was concentrated and prepared by prep-HPLC (ACN/H 2 O (0.1% FA)) to obtain 13S-P1 (350 mg).
  • Lithium hydroxide (31 mg, 1.29 mmol) was added to a solution of 19-2 (130 mg, 0.24 mmol) in water (1 mL) and methanol (3 mL). After the addition was complete, the reaction was stirred at room temperature for 3 hours and then completed. The reaction solution was concentrated under reduced pressure, dissolved in methanol and filtered, and the filtrate was purified by high-performance liquid chromatography to obtain product 19 (80.66 mg).
  • Lithium hydroxide monohydrate 38 mg, 0.90 mmol was added to a mixed solution of water (1 mL) and methanol (3 mL) containing compound 42-1 (90 mg, 0.16 mmol). The reaction solution was stirred at room temperature for 3 hours, and the reaction was completed by TLC monitoring. After the reaction solution was concentrated under reduced pressure, the filtrate was purified by high-performance liquid chromatography to obtain compound 42 (42.88 mg).
  • Acetic acid (0.02 mL) was added to a methanol (5 mL) solution of compound 11-2 (70 mg, 0.16 mmol) and L-proline (36 mg, 0.31 mmol), stirred for 30 min, and sodium borohydride (49 mg, 1.30 mmol) was added to the reaction solution in batches. After the addition was completed, the reaction was stirred at room temperature for 16 hours, and the reaction was completed. Ethyl acetate (20 mL) and saturated sodium bicarbonate aqueous solution (30 mL) were added to the reaction solution, and the organic phase was separated and collected.
  • Example 46 The starting material 46-1 in Example 46 was replaced with the R-configured raw material 47-1, and the product 47 was finally obtained after five steps of reaction.
  • compound 19-1 (50 mg, 0.11 mmol) was dissolved in N, N-dimethylformamide (2 mL), and (S)-1-Boc-piperidine-2-carboxylic acid (50 mg, 0.22 mmol), N, N-diisopropylethylamine (43 mg, 0.33 mmol), HATU (84 mg, 0.22 mmol) were added thereto, and then stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reverse phase preparation to obtain compound 80-1 (36 mg).
  • HEK293-CCR4 cells were diluted to 1 ⁇ 10 6 cells/mL with culture medium (DMEM+10% FBS+300g/mL G418+BS 2g/mL+1% PS), and 20L/well was added to the 384-well cell plate after washing; after incubation at 37°C in an incubator with 5% CO 2 overnight, the cell culture medium was removed, and 20L of experimental buffer (20mM HEPES, 1 ⁇ HBSS, 0.5% BSA) and 20L of 2 ⁇ Fluo-4 detection reagent (Invitrogen, F10471, final concentration 4 ⁇ M, containing 2.5mM Probenecid) were added to each well in turn, Place in a 37°C incubator for 50 min, then stand at room temperature
  • the compound to be tested was prepared to a final concentration of 3M, 10 concentrations, 3-fold dilution, double wells, and a final DMSO concentration of 0.5%; 20L of experimental buffer was added to the cell culture plate after removing the culture medium, and then 20L of 2 ⁇ Fluo-4 detection reagent and 10L of compound were added, and the plate was incubated at 37°C for 50min, and then allowed to stand at room temperature for 10min, the FLIPR instrument was started, 10L of 6 ⁇ EC80 agonist working solution was transferred to the cell plate, and the reading was performed.
  • the inhibition rate of each compound was calculated according to the following formula:
  • RLU relative light absorbance, 1 to the maximum allowed reading
  • DMSO average fluorescence signal of DMSO group
  • LC average fluorescence signal of the highest antagonist concentration

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Abstract

La présente invention concerne un composé pyrimidine substitué par spiro-hétérocycle, son procédé de préparation et son utilisation. Plus particulièrement, l'invention concerne un composé pyrimidine substitué par spiro-hétérocycle tel que représenté dans la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, qui peut être utilisé pour préparer un médicament, en particulier pour préparer un médicament pour prévenir et/ou traiter une maladie ou une affection médiée par le facteur CCR4. Chaque groupe dans la formule (I) est tel que défini dans la description.
PCT/CN2023/134260 2022-11-28 2023-11-27 Composé pyrimidine substitué par spiro-hétérocycle, son procédé de préparation et son utilisation Ceased WO2024114561A1 (fr)

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WO2018134685A2 (fr) * 2017-01-17 2018-07-26 Liverpool School Of Tropical Medicine Composés
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
CN114450277A (zh) * 2019-09-30 2022-05-06 豪夫迈·罗氏有限公司 用于治疗和预防乙型肝炎病毒感染的经取代的嘧啶

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018134685A2 (fr) * 2017-01-17 2018-07-26 Liverpool School Of Tropical Medicine Composés
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
CN114450277A (zh) * 2019-09-30 2022-05-06 豪夫迈·罗氏有限公司 用于治疗和预防乙型肝炎病毒感染的经取代的嘧啶

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