WO2020151707A1 - Nouvel inhibiteur de cd73 à petites molécules, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Nouvel inhibiteur de cd73 à petites molécules, son procédé de préparation et son utilisation pharmaceutique Download PDF

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Publication number
WO2020151707A1
WO2020151707A1 PCT/CN2020/073526 CN2020073526W WO2020151707A1 WO 2020151707 A1 WO2020151707 A1 WO 2020151707A1 CN 2020073526 W CN2020073526 W CN 2020073526W WO 2020151707 A1 WO2020151707 A1 WO 2020151707A1
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group
general formula
alkyl
compound represented
pharmaceutically acceptable
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Chinese (zh)
Inventor
董平
李心
王浩蔚
刘健
庄凌航
张儒民
陶维康
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Priority to CN202080005990.1A priority Critical patent/CN112955444B/zh
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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • adenosine produces a wide range of physiological responses in the human body through its interaction with adenosine receptors (receptor subtypes: A1, A2A, A2B, and A3), including in the heart
  • adenosine receptors receptor subtypes: A1, A2A, A2B, and A3
  • the purpose of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, Prodrug, mixture form or its pharmaceutically acceptable salt:
  • Y is -O- or -S-;
  • W is selected from -O-, -S-, -N(R 10 )- and -C(R 11 )(R 12 )-;
  • G 1 and G 2 are the same or different, and are each independently selected from -N- or -C(R 13 )-;
  • L is an alkylene group, wherein the alkylene group is optionally further selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Substituted by one or more substituents in the aryl group and heteroaryl group;
  • R s , R t , R m and R n are the same or different, and are each independently selected from H, D, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl and amino;
  • R m and R n together form an oxo group
  • R 1 , R 2 , R 3 and R 4 are the same or different, and are each independently selected from hydroxyl, hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino , Azido and OR 14 ;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro and azido;
  • R 6 and R 7 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group, -C(R m )(R n )-OC(O)OR d , -C(R m )(R n )- OC(O)R d , -C(R m )(R n )C(O)OR d , cycloalkyl, heterocyclic, aryl and heteroaryl, wherein the alkyl group is optionally further selected Substituted by one or more substituents among cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d is selected from hydrogen atom, alkyl group and alkoxy group
  • R 9 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group , Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 10 is an alkyl group
  • R 13 is selected from hydrogen atom, halogen, alkyl, alkoxy, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • R 14 is selected from -C(O)R 15 , -C(O)OR 15 , -S(O) 2 R 15 and -P(O)(OR 6 )(OR 7 );
  • R 1 to R 9 , G 1 , G 2 , W, Y, Z, Q, L, M and n are as defined in the general formula (I).
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, wherein W is -O-.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, wherein said R 2 , R 4 and R 5 are hydrogen atoms.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, wherein R 1 and R 3 are the same or different, and are each independently selected from hydroxyl, hydrogen, halogen, alkyl, alkoxy, haloalkyl , Haloalkoxy and hydroxyalkyl, preferably hydroxy.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (III) or tautomers, mesosomes, racemates, enantiomers Conformers, diastereoisomers, prodrugs, mixture forms or their pharmaceutically acceptable salts:
  • R 6 to R 9 , M, Q, L and n are as defined in the general formula (I).
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixtures or pharmaceutically acceptable salts thereof, wherein said G 1 is -N-; G 2 is -CH-.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, wherein said R 6 and R 7 are the same or different, and are each independently selected from a hydrogen atom, an alkyl group or -C(R m )( R n )-OC(O)OR d ; R m , R n and R d are as defined in the general formula (I).
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, wherein said Q is -CH 2 -O-CH 2 -.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, wherein said L is -(CH 2 )s-; s is 1, 2 or 3.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, wherein M is NH.
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IV) or tautomers, mesosomes, racemates, enantiomers Conformers, diastereoisomers, prodrugs, mixture forms or their pharmaceutically acceptable salts:
  • R 8 , R 9 and n are as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers Forms, prodrugs, mixtures or pharmaceutically acceptable salts thereof which are compounds represented by the general formula (IV-1) or tautomers, mesoisomers, racemates, enantiomers Forms, diastereomers, prodrugs, mixture forms or their pharmaceutically acceptable salts:
  • R 8 and R 9 are as defined in the general formula (I).
  • the compound represented by the general formula (I) according to the present disclosure or its tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IV-2) or tautomers, mesosomes, racemates, and Enantiomers, diastereomers, prodrugs, mixture forms or their pharmaceutically acceptable salts:
  • R 16 and R 17 together with the connected nitrogen atom form a heterocyclic group, and the heterocyclic group is preferably a spiro heterocyclic group; wherein the heterocyclic group optionally contains 1 to 1 nitrogen atom. 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally further selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl Substituted by one or more substituents in the group, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 8 is as defined in the general formula (I).
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers In the form of a prodrug, a prodrug, a mixture or a pharmaceutically acceptable salt thereof, wherein said R 9 is selected from alkyl, cycloalkyl and heterocyclic group, wherein said alkyl, cycloalkyl and heterocyclic group are optionally One selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl Or more substituents, the cycloalkyl group and heterocyclic group include cycloalkyl and heterocyclic group condensed aryl and heteroaryl; preferably selected from C 1-6 alkyl, C 3-12 Cycloalkyl, 4- to 12-
  • the compound represented by the general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers In the form of a prodrug, a mixture, or a pharmaceutically acceptable salt thereof, wherein -(M) n -R 9 is selected from:
  • Typical compounds of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a compound represented by general formula (IA):
  • Y is -O- or -S-;
  • Z is O
  • R x is an alkyl group
  • W is selected from -O-, -S-, -N(R 10 )- and -C(R 11 )(R 12 )-;
  • M is selected from -NH-, -O- or -S-;
  • G 1 and G 2 are the same or different, and are each independently selected from -N- or -C(R 13 )-;
  • L is an alkylene group, wherein the alkylene group is optionally further selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Substituted by one or more substituents in the aryl group and heteroaryl group;
  • R s , R t , R m and R n are the same or different, and are each independently selected from H, D, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl and amino;
  • R m and R n together form an oxo group
  • R 2 and R 4 are the same or different, and are each independently selected from hydroxyl, hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano, amino, azido and OR 14 ;
  • R 5 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro and azido;
  • R 8 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group ;
  • R 9 is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, alkenyl group, alkynyl group , Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 10 is an alkyl group
  • R 11 and R 12 are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, and an alkenyl group;
  • R 13 is selected from hydrogen atom, halogen, alkyl, alkoxy, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • R 14 is selected from -C(O)R 15 , -C(O)OR 15 , -S(O) 2 R 15 and -P(O)(OR 6 )(OR 7 );
  • R 15 is selected from hydrogen atom, halogen, alkyl, haloalkyl, hydroxy and hydroxyalkyl;
  • n 0 or 1.
  • R x is an alkyl group
  • M is selected from -NH-, -O- or -S-;
  • G 1 and G 2 are the same or different, and are each independently selected from -N- or -C(R 13 )-;
  • L is an alkylene group, wherein the alkylene group is optionally further selected from alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, Substituted by one or more substituents in the aryl group and heteroaryl group;
  • R s , R t , R m and R n are the same or different, and are each independently selected from H, D, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl and amino;
  • R m and R n together form an oxo group
  • R 8 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl and heterocyclic group ;
  • R 9 is selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, alkenyl group and alkynyl group , Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro , Cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;
  • R 13 is selected from hydrogen atom, halogen, alkyl, alkoxy, hydroxyl, amino, nitro, cyano, cycloalkyl, heterocyclic, aryl and heteroaryl;
  • n 0 or 1.
  • Typical compounds of general formula (IA) of the present disclosure include but are not limited to:
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I), which comprises the following steps:
  • Z is -O-
  • R x is an alkyl group
  • R 6 and R 7 are hydrogen atoms
  • R 1 and R 3 are hydroxyl groups
  • R 2 , R 4 , R 5 , R 8 , R 9 , Q, L, Y, W, G 1 , G 2 , M and n are as defined in the general formula (I).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II), which includes the following steps:
  • Z is -O-
  • R x is an alkyl group
  • R 6 and R 7 are hydrogen atoms
  • R 1 and R 3 are hydroxyl groups
  • R 2 , R 4 , R 5 , R 8 , R 9 , Q, L, Y, W, G 1 , G 2 , M and n are as defined in the general formula (II).
  • Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III), which includes the following steps:
  • R x is an alkyl group
  • R 6 and R 7 are hydrogen atoms
  • R 8 , R 9 , Q, L, G 1 , G 2 , M and n are as defined in the general formula (III).
  • R 8 , R 9 and n are as defined in the general formula (IV).
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, prodrug, mixture form or The use of its pharmaceutically acceptable salt or a pharmaceutical composition containing it in the preparation of a medicament for inhibiting CD73.
  • the present disclosure further relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, prodrug, mixture form or Its pharmaceutically acceptable salt, or pharmaceutical composition containing it is prepared for the treatment of tumors, autoimmune diseases, immune system diseases, inflammatory diseases, nervous system diseases, neurodegenerative diseases and central nervous system diseases, depression, Use in medicines for Parkinson's disease, cerebral and cardiac ischemic diseases, sleep disorders or fibrosis; wherein the tumor is preferably selected from melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colorectal cancer , Lung cancer (such as non-small cell lung cancer or small cell lung cancer), kidney cancer, breast cancer, ovarian cancer, uterine cancer, endometriosis, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, Bone cancer, seminoma, testicular tumor, uterine cancer, head and
  • the present disclosure also relates to a method for inhibiting CD73, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, mesosomes, racemates, and enantiomers. Isomers, diastereomers, prodrugs, mixture forms or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound.
  • a suitable unit dose may be 0.1-1000 mg.
  • the substituents are independently optionally selected from halogen, alkyl, haloalkyl , Alkoxy, haloalkoxy, alkylthio, alkylamino, alkenyl, alkynyl, mercapto, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, One or more substituents among heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo groups are substituted.
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the heterocyclic ring includes the above heterocyclic groups (including monocyclic and polycyclic heterocyclic groups, such as spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups) fused to aryl, heteroaryl or cycloalkane
  • the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, 4H-1,2,3-triazolyl, 1H-tetrazole Group, 2H-tetrazolyl, 5H-tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl or pyrimidinyl
  • amino protecting group is to keep the amino group unchanged when other parts of the molecule react, and to protect the amino group with a group that is easy to remove.
  • Non-limiting examples include tert-butoxycarbonyl, acetyl, benzyl, allyl, 2,4-dimethoxybenzyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro.
  • the amino protecting group is preferably 2,4-dimethoxybenzyl.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • deuterated alkyl refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • R 1 and R 3 are hydroxyl groups
  • R 2 , R 4 , R 5 , R 8 , R 9 , Q, L, Y, W, G 1 , G 2 , M and n are as defined in the general formula (I).
  • Reagents for deprotection include but are not limited to trifluoroacetic acid, trimethylsilyl bromide, and hydrochloric acid.
  • R 6 and R 7 are hydrogen atoms
  • R 1 and R 3 are hydroxyl groups
  • R 2 , R 4 , R 5 , R 8 , R 9 , Q, L, Y, W, G 1 , G 2 , M and n are as defined in the general formula (II).
  • Reagents for deprotection include but are not limited to trifluoroacetic acid, trimethylsilyl bromide, and hydrochloric acid.
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • R x is an alkyl group
  • R 6 and R 7 are hydrogen atoms
  • R 8 , R 9 , Q, L, G 1 , G 2 , M and n are as defined in the general formula (III).
  • the above reaction is preferably carried out in a solvent.
  • the solvents used include but are not limited to: acetic acid, trifluoroacetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, tetrahydrofuran, methylene chloride, petroleum ether, ethyl acetate, n-hexane , Dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.
  • the preparation method of medicinal salt includes the following steps:
  • Reagents for deprotection include but are not limited to trifluoroacetic acid, trimethylsilyl bromide, and hydrochloric acid.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured with Bruker AVANCE-400 and 500 Ultrashield nuclear magnetometers, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). Labeled as tetramethylsilane (TMS).
  • the MS is measured with FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantageMAX) and Shimadzu LCMS-2020 liquid chromatography-mass spectrometer.
  • ESI FINNIGAN LCQAd
  • HPLC determination uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm column), Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm column) and Shimadzu OPTIONBOX-L high pressure liquid chromatography Instrument (Gimini 5um NX-C18 100x21.2mm chromatographic column).
  • CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).
  • the known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals, Shanghai Bi De Pharmaceutical Technology Co., Ltd. and other companies.
  • reaction can be carried out in an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the microwave reaction uses CEM Discover-S 908860 type microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC), the developing reagent used in the monitoring reaction, the eluent system of column chromatography and the developing reagent system of thin layer chromatography used to purify the compound include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: dichloromethane/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triacetate can also be added Adjust with alkaline or acidic reagents such as ethylamine and acetic acid.
  • TLC thin layer chromatography
  • N-Tetrabutylammonium fluoride (628 mg, 2.79 mmol) was added to a tetrahydrofuran (20.0 mL) solution of compound 1 g (1.00 g, 1.86 mmol), and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1h (610 mg, yield: 77%).
  • N-Tetrabutylammonium fluoride (95 mg, 0.42 mmol) was added to the tetrahydrofuran (3.0 mL) solution of compound 2d (160 mg, 0.28 mmol), and the reaction was stirred for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 2e (120 mg, yield: 94%).
  • N-Tetrabutylammonium fluoride (144 mg, 0.64 mmol) was added to the tetrahydrofuran (30.0 mL) solution of compound 3b (250 mg, 0.43 mmol), and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 3c (150 mg, yield: 75%).
  • N-Tetrabutylammonium fluoride (145 mg, 0.64 mmol) was added to the tetrahydrofuran (20.0 mL) solution of compound 4b (220 mg, 0.43 mmol), and the reaction was stirred for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 4c (60 mg, yield: 35%).
  • N-Tetrabutylammonium fluoride 600 mg, 2.66 mmol was added to the tetrahydrofuran (5.0 mL) solution of compound 5b (300 mg, 0.28 mmol), and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 5c (60 mg, yield: 25%).
  • N-Tetrabutylammonium fluoride (153 mg, 0.68 mmol) was added to the tetrahydrofuran (5.0 mL) solution of compound 6b (250 mg, 0.43 mmol), and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6c (180 mg, yield: 90%).
  • 2,3-Dihydro-1H-indene-1-carboxylic acid 7a (10.00g, 61.65mmol, finished) was dissolved in methanol solvent (200.0mL), concentrated sulfuric acid (3.0mL) was added dropwise, and heated to 60°C , Stir for 18 hours. The reaction solution was quenched by adding water (70 mL), extracted with ethyl acetate (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The title compound 7b (8.00 g, yield 73%) was obtained.
  • N-Tetrabutylammonium fluoride 150 mg, 0.666 mmol was added to the tetrahydrofuran (5.0 mL) solution of compound 7j (200 mg, 0.326 mmol), and the reaction was stirred for 2 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 7k (100 mg, yield: 61%).
  • Test Example 1 The in vitro inhibitory activity of the compound of the present disclosure on CD73 enzyme
  • CD73 enzyme is an extracellular-5'-nucleotidase, which converts extracellular nucleoside 5'monophosphate into nucleoside, with AMP or CMP as the preferred substrate.
  • recombinant human CD73 expressed from the Chinese Hamster Ovary cell line (R&D Systems) was used to convert cytidine monophosphate (CMP) into cytidine and phosphate.
  • CMP cytidine monophosphate
  • the CD73 enzyme was pre-incubated with the compound for 2 hours. Then the amount of phosphate is measured by a malachite green phosphate detection kit.
  • HEPES buffer Gibco, cat#15630-080
  • TECAN plate reader TECAN
  • the compound was first prepared into a 10 mM solution with DMSO, and then diluted 1:3 with DMSO for a total of 12 concentration points (the compounds with high inhibitory properties were diluted 1:3 with the highest concentration of 10 ⁇ M).
  • DMSO fetal sulfate
  • a 384-well plate combine 0.34 nM recombinant human 5'-nucleotidase (CD73) and the tested compound in a solution containing 20 mM HEPES buffer (pH 7.4), 137 mM NaCl, and 0.001% Tween 20. Incubate in assay buffer and pre-incubate at 37°C for 2 hours. The final reaction volume in each well is 12 ⁇ L.
  • the highest concentration of the compound is 125 ⁇ M and the DMSO concentration is 1.25%.
  • 3 ⁇ L of CMP dissolved in the assay buffer was added to each reaction well, and the final CMP concentration was 45 ⁇ M.
  • the reaction was incubated at 37°C for 15 minutes, and then 3 ⁇ L of malachite green reagent A was added to each reaction well.
  • the reaction plate is briefly rotated in the centrifuge for 30 seconds. After incubating for 20 minutes at room temperature, read the signal at OD 620 on a TECAN plate reader.
  • reaction containing CD73 enzyme, substrate CMP and DMSO (no compound) was used as a positive control for the assay, while a reaction containing substrate CMP and DMSO without CD73 enzyme was used as a negative control for the assay.
  • IC 50 values were calculated by plotting the logarithm of the compound concentration using GraphPad Prism program appropriate and in percent inhibition.
  • Table 1 The IC 50 value of in vitro inhibition of CD73 enzyme activity by the compounds of the present disclosure
  • the compound of the present disclosure has a significant inhibitory effect on CD73 enzyme activity in vitro.
  • Test Example 2 The inhibitory effect of the compound of the present disclosure on the membrane-bound CD73 enzyme activity on human melanoma A375 cells.
  • the membrane-bound CD73 enzyme activity on the surface of human melanoma A375 cells was used to convert cytidine-phosphate (CMP) into cytidine and phosphate in the presence of compound and CMP. Then the amount of phosphate is measured by a malachite green phosphate detection kit.
  • A375 cell line ATCC, Cat#CRL-1619
  • DMEM ATCC, Cat#, 30-2002
  • FBS Gibco, Cat#16-140-071
  • Penicillin-Streptomycin Gibco, Cat#15-140-122
  • HEPES Gibco, Cat#15630-080
  • KCl 2M Ambion, Cat#AM9640G
  • TECAN plate reader TECAN
  • A375 cells were cultured in DMEM medium containing 10% FBS and 1% penicillin-streptomycin. On the day before the assay, A375 cells were harvested with trypsin and counted. Cells were seeded into 96-well plates in 100 ⁇ L of medium (2500 cells/well). The next day, prepare an assay buffer containing 20 mM HEPES, 137 mM NaCl, 5.4 mM KCl, 1.3 mM CaCl 2 , 4.2 mM NaHCO 3 and 1 mg/mL glucose. Heat the buffer in a 37°C water bath. In the assay buffer containing 50 ⁇ M CMP, start with the highest concentration of 10 ⁇ M to prepare 3.16-fold serial dilutions of compounds, and make sure that each dilution contains the same amount of DMSO (0.1%).
  • NC is a negative control
  • PC is a positive control
  • IC 50 values were calculated by plotting the logarithm of the compound concentration using GraphPad Prism program appropriate and in percent inhibition.
  • Table 2 The IC 50 value of the compounds of the present disclosure on the inhibition of membrane-bound CD73 enzyme activity on human melanoma A375 cells
  • the compound of the present disclosure has a significant inhibitory effect on the CD73 enzyme activity in A375 cells.
  • Test Example 3 Mouse pharmacokinetic test of the compound of the present disclosure
  • mice Using mice as the test animal, the LC/MS/MS method was used to determine the drug concentration in plasma at different times after the mice were injected with the compound of Example 1 and gavage with the compound of Example 8. To study the pharmacokinetic behavior of the compound of the present disclosure in mice and evaluate its pharmacokinetic characteristics.
  • Example 2 Weigh the compound of Example 1, add 5% volume of DMSO and 5% Tween 80 (Shanghai Titan Technology Co., Ltd.) to dissolve, and then add 90% normal saline to prepare a colorless and clear solution of 0.1 mg/ml.
  • Example 8 Weigh the compound of Example 8, add 1.5% by volume of DMSO and 98.5% HBSS (Life Technologies) to prepare a 0.5 mg/ml white uniform suspension.
  • a group of C57 mice were fasted overnight and then injected into the administration Example 1.
  • the administration dose was 1 mg/kg, and the administration volume was 0.1 ml/10 g.
  • mice Another group of C57 mice were fasted overnight and then administered by gavage in Example 8.
  • the dosage was 10 mg/kg, and the dosage was 0.2 ml/10 g.
  • Example 1 The compound of Example 1 was administered to mice by injection, and 0.1ml of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after administration (3 animals at each time point), and placed In a heparinized test tube (source?), the plasma was separated after centrifugation at 3500 rpm for 10 minutes, and stored at -20°C.
  • mice were intragastrically administered the compound of Example 8, and 0.2ml of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours before and after administration (3 animals at each time point), Place it in a centrifuge tube pre-added with heparinized sodium (Chemical Reagent Co., Ltd. of Sinopharm Group), centrifuge at 3500 rpm for 10 minutes, separate the plasma, and store at -20°C.
  • Example 8 The concentration of Example 8 in mouse plasma was lower than the quantitative lower limit, but the product Example 1 was detected.
  • Example 8 is the prodrug of Example 1.

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Abstract

La présente invention concerne un nouvel inhibiteur de CD73 à petites molécules, une méthode de préparation de ce dernier, et une utilisation pharmaceutique de ce dernier. En particulier, la présente invention concerne un inhibiteur de CD73 à petites molécules, représenté par la formule générale (I), son procédé de préparation, une composition pharmaceutique contenant le dérivé, et son utilisation en tant qu'agent thérapeutique, en particulier dans la préparation d'un médicament pour le traitement de maladies et d'affections médiées par CD73. Les substituants de la formule générale (I) sont tels que définis dans la description.
PCT/CN2020/073526 2019-01-22 2020-01-21 Nouvel inhibiteur de cd73 à petites molécules, son procédé de préparation et son utilisation pharmaceutique Ceased WO2020151707A1 (fr)

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CN115884969A (zh) * 2020-09-01 2023-03-31 江苏恒瑞医药股份有限公司 稠合咪唑类衍生物、其制备方法及其在医药上的应用
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CN117466964A (zh) * 2022-07-21 2024-01-30 南京烁慧医药科技有限公司 双磷酸核苷类化合物及其制备方法
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CN115884969A (zh) * 2020-09-01 2023-03-31 江苏恒瑞医药股份有限公司 稠合咪唑类衍生物、其制备方法及其在医药上的应用
WO2023201267A1 (fr) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Polythérapie pour le traitement de cancers exprimant trop-2
CN117466964A (zh) * 2022-07-21 2024-01-30 南京烁慧医药科技有限公司 双磷酸核苷类化合物及其制备方法
WO2025137640A1 (fr) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Inhibiteurs azaspiro de wrn

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