WO2023202623A1 - Composé inhibiteur de polq et son utilisation - Google Patents

Composé inhibiteur de polq et son utilisation Download PDF

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Publication number
WO2023202623A1
WO2023202623A1 PCT/CN2023/089240 CN2023089240W WO2023202623A1 WO 2023202623 A1 WO2023202623 A1 WO 2023202623A1 CN 2023089240 W CN2023089240 W CN 2023089240W WO 2023202623 A1 WO2023202623 A1 WO 2023202623A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
compound
alkynyl
reaction solution
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PCT/CN2023/089240
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English (en)
Chinese (zh)
Inventor
李桢
唐锋
刘乐
刘璐
蒋蕾
周峰
李正涛
唐任宏
任晋生
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南京再明医药有限公司
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Publication of WO2023202623A1 publication Critical patent/WO2023202623A1/fr

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to a POLQ inhibitor compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and its use as a POLQ inhibitor in preventing or treating related diseases.
  • DNA double-strand break repair is critical for maintaining genome stability and cell survival.
  • HR homologous recombination
  • NHEJ non-homologous end joining
  • alt-MEJ non-traditional non-homologous end joining
  • MMEJ Microhomology-mediated end joining
  • Homologous recombination is a high-fidelity, accurate repair mechanism that can maintain genome stability and avoid inducing cancer.
  • Non-homologous end joining and microhomology-mediated end joining are error-prone repair pathways and can lead to mutations at repair sites.
  • DNA double-strand break repair defects can be exploited to develop targeted tumor therapies.
  • Tumor cells with impaired homologous recombination or nonhomologous end-joining repair will be more dependent on microhomology-mediated end-joining repair.
  • DNA polymerase ⁇ POLQ or POL ⁇
  • POLQ is a multifunctional enzyme composed of an N-terminal helicase domain (SF2HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & D.00e DNA Repair (2016), 44, 22-32 ).
  • the helicase domain mediates the removal of RPA proteins from single-stranded DNA and promotes annealing.
  • the polymerase domain can extend the ends of single-stranded DNA and fill gaps. The two domains work together to regulate microhomology-mediated ends. Functional during connection repair.
  • POLQ is critical for homologous recombination-deficient cells (e.g., synthetic lethality with FA/BRCA deficiency), and that POLQ is upregulated at protein levels in homologous recombination-deficient tumor cells (Ceccaldi et al. Nature (2015), 518(7538),258-262).
  • In vivo study results also show that POLQ is overexpressed in a series of ovarian, uterine and breast cancers with homologous recombination defects and poor prognosis (Higgins et al. Oncotarget (2010), 1, 175-184, Lemee et al.
  • POLQ is crucial for homologous recombination-deficient cells, and there is currently an unmet market need for the treatment of homologous recombination-deficient tumors.
  • Inhibiting the function of POLQ can inhibit microhomology-mediated end-joining repair of cells.
  • the development of inhibitors of POLQ function can provide a new strategy for targeted therapy of homologous recombination-deficient tumors.
  • the present disclosure relates to compounds of formula (I) or pharmaceutically acceptable salts thereof,
  • Y is selected from CH or N;
  • L is selected from -(CH 2 ) m -, -O-(CH 2 ) m -, -(CH 2 ) m -O- or C 3 -C 10 cycloalkylene;
  • n 1, 2, 3, 4, 5 or 6;
  • X is selected from C or N;
  • Ring A is selected from 5-10 membered heteroaryl, C 6 -C 14 aryl or 4-12 membered heterocyclyl, said 5-10 membered heteroaryl, C 6 -C 14 aryl or 4-12 membered Heterocyclyl is optionally substituted by R 1a ;
  • R 1 is selected from C 6 -C 14 aryl, 5-10 membered heteroaryl, 3-18 membered heterocyclyl or C 4 -C 10 cycloalkenyl, said C 6 -C 14 aryl, 5-10 One-membered heteroaryl, 3-18-membered heterocyclyl or C 4 -C 10 cycloalkenyl is optionally substituted by R 2a ;
  • R 2 is selected from C 6 -C 14 aryl, 5-10 membered heteroaryl, C 3 -C 10 cycloalkyl or 4-12 membered heterocyclyl, wherein the C 6 -C 14 aryl, 5- 10-membered heteroaryl, C 3 -C 10 cycloalkyl or 4-12 membered heterocyclyl is optionally substituted by R 3a ;
  • Each R 3a is independently selected from halogen, -NRR', hydroxyl, cyano, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, C 2 -C 10 Alkynyl, C 2 -C 10 alkenyl, 5-10 membered heteroaryl or 4-8 membered heterocyclyl, the C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10- cycloalkyl, C 2 -C 10 alkynyl, C 2 -C 10 alkenyl, 5-10 membered heteroaryl or 4-8 membered heterocyclyl is optionally substituted by R 3b ;
  • R and R' are independently selected from hydrogen, C 3 -C 10 cycloalkyl, C 1 -C 10 alkylcarbonyl, 4-8 membered heterocyclyl or C 1 -C 10 alkyl, the C 3 -C 10 cycloalkyl, C 1 -C 10 alkylcarbonyl, 4-8 membered heterocyclyl or C 1 -C 10 alkyl is optionally substituted by R 4b ;
  • Z is selected from CH2 .
  • Y is selected from CH.
  • Y is selected from N.
  • m is 1, 2, or 3.
  • m is 1 or 2.
  • m is 1.
  • n is 2.
  • L is selected from -(CH 2 ) m -, -O-(CH 2 ) m -, -(CH 2 ) m -O-, or C 3 -C 6 cycloalkylene.
  • L is selected from -(CH 2 ) 2 -, -OCH 2 -, -CH 2 O-, or
  • L is selected from -(CH 2 ) m -, -(CH 2 ) m -O-, or C 3 -C 10 cycloalkylene.
  • L is selected from -(CH 2 ) 2 -, -CH 2 O-, or
  • L is selected from -( CH2 ) m- .
  • L is selected from -( CH2 ) 2- .
  • L is selected from -( CH2 ) m -O-.
  • L is selected from -CH2O- .
  • L is selected from C 3 -C 10 cycloalkylene.
  • L is selected from C 3 -C 6 cycloalkylene.
  • L is selected from
  • L is selected from -O( CH2 ) m- .
  • L is selected from -OCH2- .
  • L is selected from -( CH2 ) m- or -O-( CH2 ) m- .
  • L is selected from -( CH2 ) 2- or -OCH2- .
  • X is selected from C.
  • X is selected from N.
  • Ring A is selected from 5-10 membered heteroaryl, C 6 -C 10 aryl, or 4-10 membered heterocyclyl, the 5-10 membered heteroaryl, C 6 -C 10 aryl group or 4-10 membered heterocyclyl group is optionally substituted by R 1a .
  • Ring A is selected from 5-6 membered heteroaryl or 9-membered heterocyclyl, which is optionally substituted with R 1a .
  • Ring A is selected from 6-membered heteroaryl or 9-membered heterocyclyl, which is optionally substituted with R 1a .
  • Ring A is selected from pyridyl, benzo[d][1,3]dioxolyl, imidazolyl, or pyrimidinyl, said pyridyl or benzo[d][1, 3] Dioxolyl, imidazolyl or pyrimidinyl is optionally substituted by R 1a .
  • Ring A is selected from pyridyl or benzo[d][1,3]dioxol. Pentenyl is optionally substituted by R 1a . In some embodiments, Ring A is selected from Where * indicates connection with R 1 .
  • Ring A is selected from Where * indicates connection with R 1 .
  • R 1a is selected from C 1 -C 6 alkyl, C 2 -C 6 alkynyl, cyano, or C 1 -C 6 alkoxy, said C 1 -C 6 alkyl, C 2 -C 6 alkynyl or C 1 -C 6 alkoxy is optionally substituted by R 1b .
  • R 1a is selected from C 1 -C 6 alkyl or C 2 -C 6 alkynyl, which is optionally substituted with R 1b .
  • R 1a is selected from C 1 -C 3 alkyl, C 2 -C 4 alkynyl, cyano, or C 1 -C 3 alkoxy.
  • R 1a is selected from C 1 -C 3 alkyl or C 2 -C 4 alkynyl.
  • R 1a is selected from methyl, ethynyl, cyano, or methoxy.
  • R 1a is selected from methyl or ethynyl. In some embodiments, Ring A is selected from Where * indicates connection with R 1 .
  • Ring A is selected from Where * indicates connection with R 1 .
  • Ring A is selected from 4-12 membered heterocyclyl, which is optionally substituted with R 1a .
  • Ring A is selected from 4-10 membered heterocyclyl, which is optionally substituted with R 1a .
  • Ring A is selected from 9-membered heterocyclyl, which is optionally substituted with R 1a .
  • Ring A is selected from benzo[d][1,3]dioxolyl optionally substituted by R 1a substitution.
  • Ring A is selected from
  • R 1a is selected from C 2 -C 10 alkynyl or C 2 -C 10 alkenyl, which is optionally substituted by R 1b .
  • R 1a is selected from C 2 -C 6 alkynyl, which is optionally substituted with R 1b .
  • R 1a is selected from C 2 -C 4 alkynyl.
  • R 1a is selected from ethynyl.
  • R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C 5 -C 7 cycloalkenyl, said C 6 -C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C 5 -C 7 cycloalkenyl are optionally substituted by R 2a .
  • R1 is selected from phenyl, C6 cycloalkenyl, or 6-membered heteroaryl, which phenyl, C6 cycloalkenyl, or 6-membered heteroaryl is optionally substituted with R2a .
  • R1 is selected from phenyl or C6 cycloalkenyl, which phenyl or C6 cycloalkenyl is optionally substituted with R2a .
  • R1 is selected from phenyl, cyclohexenyl, or pyridyl, which is optionally substituted with R2a .
  • R1 is selected from phenyl or cyclohexenyl, which is optionally substituted with R2a .
  • R1 is selected from
  • R1 is selected from
  • R 2a is selected from C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, cyano, halogen, or C 1 -C 6 alkyl, the C 1 -C 6 alkoxy group, C 2 -C 6 alkynyl group, C 2 -C 6 alkenyl group, C 3 -C 6 cycloalkyl group or C 1 -C 6 alkyl group Optionally substituted by R 2b .
  • R 2a is selected from C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, or C 3 -C 6 cycloalkyl, said C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl or C 3 -C 6 cycloalkyl is optionally substituted by R 2b .
  • R 2a is selected from C 1 -C 3 alkoxy, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl, cyano, halogen, or C 1 -C 3 alkyl.
  • R 2a is selected from C 1 -C 3 alkoxy, C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, or C 3 -C 6 cycloalkyl.
  • R 2a is selected from methoxy, ethynyl, vinyl, cyclopropyl, cyano, chloro, or methyl.
  • R 2a is selected from methoxy, ethynyl, vinyl, or cyclopropyl.
  • R 2a is selected from ethynyl, cyclopropyl, chloro, or methyl.
  • R1 is selected from
  • R1 is selected from
  • R 1 is selected from C 4 -C 10 cycloalkenyl, which is optionally substituted with R 2a .
  • R 1 is selected from C 5 -C 7 cycloalkenyl, which is optionally substituted with R 2a .
  • R1 is selected from C6 cycloalkenyl, which is optionally substituted with R2a .
  • R1 is selected from cyclohexenyl, which is optionally substituted with R2a .
  • R1 is selected from
  • R 2a is selected from C 2 -C 10 alkynyl, C 2 -C 10 alkenyl or C 3 -C 10 cycloalkyl, said C 2 -C 10 alkynyl, C 2 -C 10 Alkenyl or C 3 -C 10 cycloalkyl is optionally substituted by R 2b .
  • R 2a is selected from C 2 -C 6 alkynyl, C 2 -C 6 alkenyl or C 3 -C 6 cycloalkyl, said C 2 -C 6 alkynyl, C 2 -C 6 Alkenyl or C 3 -C 6 cycloalkyl is optionally substituted by R 2b .
  • R 2a is selected from C 2 -C 4 alkynyl, C 2 -C 4 alkenyl, or C 3 -C 6 cycloalkyl.
  • R 2a is selected from ethynyl, vinyl, or cyclopropyl.
  • R 2a is selected from C 2 -C 6 alkynyl, which is optionally substituted with R 2b .
  • R 2a is selected from C 2 -C 4 alkynyl.
  • R 2a is selected from ethynyl.
  • R1 is selected from
  • R 2 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl, or 4-10 membered heterocyclyl, said C 6 -C 10 Aryl, 5-10 membered heteroaryl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclyl are optionally substituted by R 3a .
  • R 2 is selected from C 6 -C 9 aryl, 9-membered heterocyclyl or 6-membered heteroaryl, said C 6 -C 9 aryl, 9-membered heterocyclyl or 6-membered heteroaryl The group is optionally substituted by R 3a .
  • R2 is selected from phenyl or 9-membered heterocyclyl, which is optionally substituted with R3a .
  • R is selected from phenyl, benzo[d][1,3]dioxolyl, pyridyl, or indanyl, said phenyl, benzo[d][1 ,3]dioxolyl, pyridyl or indanyl is optionally substituted by R 3a .
  • R is selected from phenyl or benzo[d][1,3]dioxolyl, Pentenyl is optionally substituted with R 3a .
  • R is selected from
  • R is selected from
  • R is selected from
  • R 3a is selected from halogen, C 2 -C 6 alkynyl, cyano, or C 1 -C 6 alkyl, the C 2 -C 6 alkynyl or C 1 -C 6 alkyl optionally Replaced by R 3b .
  • R 3a is selected from halogen, cyano, or C 2 -C 6 alkynyl, which is optionally substituted with R 3b .
  • R 3a is selected from fluoro, chlorine, ethynyl, cyano, or isopropyl, which isopropyl is optionally substituted with R 3b .
  • R 3a is selected from fluorine, chlorine, cyano, or ethynyl.
  • R 3b is selected from hydroxyl.
  • R 3a is selected from cyano.
  • R 3a is selected from halogen or C 2 -C 6 alkynyl, which is optionally substituted with R 3b .
  • R 3a is selected from fluorine, chlorine, bromine, iodine, or C 2 -C 4 alkynyl. In some embodiments, R 3a is selected from fluorine, chlorine, or ethynyl.
  • R is selected from
  • R is selected from
  • R is selected from
  • R is selected from
  • R2 is selected from 4-12 membered heterocyclyl or C9 aryl, which is optionally substituted with R3a .
  • R2 is selected from 9-membered heterocyclyl or C9 aryl, which is optionally substituted with R3a .
  • R2 is selected from benzo[d][1,3]dioxolyl or indanyl, said benzo[d][1,3]dioxol or indanyl optionally substituted by R 3a .
  • R is selected from
  • R2 is selected from 4-12 membered heterocyclyl, which is optionally substituted with R3a .
  • R2 is selected from 4-10 membered heterocyclyl, which is optionally substituted with R3a .
  • R2 is selected from 9-membered heterocyclyl, which is optionally substituted with R3a .
  • R2 is selected from benzo[d][1,3]dioxolyl optionally substituted by R 3a substitution.
  • R is selected from
  • R 3a is selected from C 2 -C 10 alkynyl or C 2 -C 10 alkenyl, which is optionally substituted by R 3b .
  • R 3a is selected from C 2 -C 6 alkynyl, which is optionally substituted with R 3b .
  • R 3a is selected from C 2 -C 4 alkynyl.
  • R 3a is selected from ethynyl.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of Formula (Ia) or a pharmaceutically acceptable salt thereof:
  • Q is selected from CH or N;
  • L, X, Y, ring A, R 2 and R 2a are as defined in formula (I).
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from a compound of formula (II) or a pharmaceutically acceptable salt thereof:
  • L, X, Y, ring A and R2 are as defined by formula (I).
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure is selected from the group consisting of compounds of formula (III) or a pharmaceutically acceptable salt thereof:
  • Y, L, X, ring A, R 1 and R 2 are as defined in formula (I).
  • the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.
  • the present disclosure provides a method for preventing or treating diseases mediated by DNA polymerase ⁇ in mammals, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable amount thereof to a mammal in need of such treatment, preferably a human. Acceptable salts, or pharmaceutical compositions thereof.
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating diseases mediated by DNA polymerase ⁇ .
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preventing or treating diseases mediated by DNA polymerase ⁇ .
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating diseases mediated by DNA polymerase ⁇ .
  • the DNA polymerase theta-mediated disease is a DNA polymerase theta overexpression disease.
  • the DNA polymerase theta-mediated disease is cancer.
  • the cancer is a cancer with reduced or deleted expression of the BRCA gene, deficiency of the BRCA gene, or reduced function of the BRCA protein.
  • the cancer is colorectal adenocarcinoma.
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating cancer.
  • X is located ortho to the ring atom in ring A to which Z is attached.
  • connection site such as a connection group
  • connection group Indicates that the N atom in the linking group is the linking site.
  • tautomer refers to a functional group isomer resulting from the rapid movement of an atom in a molecule between two positions.
  • Compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds can exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually yield a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form is dominant; in phenols, the enol form is dominant. This disclosure encompasses all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and therefore the compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S) )-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as enantiomers or diastereomers Enriched mixtures, all of the above isomers and mixtures thereof are within the definition of the compounds of the present disclosure. There may be additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms in substituents such as alkyl groups.
  • the compounds of the present disclosure containing asymmetric atoms can be isolated in an optically active pure form or in a racemic form.
  • the optically active pure form can be resolved from a racemic mixture or synthesized by using chiral starting materials or chiral reagents. .
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • the ethyl group is "optionally" substituted by halogen, which means that the ethyl group can be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), or polysubstituted. (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2, etc.) or completely substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3, etc.). It will be understood by those skilled in the art that any substitution or substitution pattern that is sterically impossible and/or cannot be synthesized will not be introduced for any group containing one or more substituents.
  • variable e.g, R a , R b
  • R a , R b its definition in each instance is independent. For example, if a group is replaced by 2 R b , there are separate options for each R b .
  • Cm - Cn refers to having an integer number of carbon atoms in the range of mn.
  • C 1 -C 10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula C n H 2n+1 , which alkyl group may be straight or branched.
  • C 1 -C 10 alkyl is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2- Methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-di Methylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 6 alkyl "can be understood to mean
  • C 1 -C 3 alkyl is understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl” or “C 1 -C 3 alkyl” and other ranges, and the “C 1 -C 6 alkyl” may further include “ C 1 -C 3 alkyl”.
  • alkoxy refers to a group produced by losing a hydrogen atom on a hydroxyl group of a straight-chain or branched alcohol, and can be understood as “alkyloxy” or “alkyl-O-”.
  • C 1 -C 10 alkoxy is understood to mean “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”; the term “C 1 -C 6 alkoxy” It can be understood as “C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy group” may include the ranges of "C 1 -C 6 alkoxy group” and "C 1 -C 3 alkoxy group”.
  • the "C 1 -C 6 alkoxy group”"C 1 -C 3 alkoxy” may further be included.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond.
  • C 2 -C 10 alkenyl is understood to mean a straight-chain or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C 2 -C 10 alkenyl” is preferably "C 2 -C 6 alkenyl", more preferably "C 2 -C 4 alkenyl", and even more preferably C 2 or C 3 alkenyl.
  • alkenyl group contains more than one double bond
  • the double bonds may be separated or conjugated to each other.
  • alkenyl group include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl , (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1 -Methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl wait.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond.
  • C 2 -C 10 alkynyl is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C 2 -C 10 alkynyl examples include, but are not limited to, ethynyl (-C ⁇ CH), prop-1-ynyl (-C ⁇ CCH 3 ), prop-2-ynyl (-CH 2 C ⁇ CH), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • C 2 -C 10 alkynyl is preferably "C 2 -C 6 alkynyl", more preferably "C 2 -C 4 alkynyl", and still more preferably C 2 or C 3 alkynyl.
  • cycloalkyl refers to a fully saturated carbocyclic ring that exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally 3 to 10 membered.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monocyclic, paracyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms.
  • cycloalkyl group examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2 .1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, etc.
  • C 3 -C 10 cycloalkyl may include “C 3 -C 6 cycloalkyl”, and the term “C 3 -C 6 cycloalkyl” is understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.
  • cycloalkyloxy is understood to mean “cycloalkyl-O-”.
  • cycloalkylene refers to a fully saturated divalent carbon ring that exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring.
  • C 3 -C 10 cycloalkylene refers to a fully saturated divalent carbon ring that exists in the form of a single ring, a double ring, a bridged ring or a spiro ring, and has 3 to 10 ring atoms. Specific examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, and the like.
  • cycloalkenyl refers to a non-aromatic carbon ring that is not fully saturated and exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring. Unless otherwise indicated, the carbocyclic ring is generally a 4 to 10 membered ring. Specific examples of the cycloalkenyl group include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, and the like.
  • 3-18 membered heterocyclyl refers to a heterocyclyl with a number of ring atoms of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 , and its ring atoms contain 1-5 heteroatoms or heteroatom groups independently selected from the above.
  • 4-12-membered heterocyclyl refers to a heterocyclyl with a number of ring atoms from 4 to 12, and its ring atoms contain 1-5 heteroatoms or heteroatom groups independently selected from the above.
  • 4-membered heterocyclyl refers to a heterocyclyl with a number of ring atoms of 4, 5, 6, 7, 8, 9 or 10, and its ring atoms contain 1 to 5 independently selected from the above.
  • specific examples of 4-membered heterocyclic groups include, but are not limited to, azetidinyl or oxetanyl
  • specific examples of 5-membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, Oxolenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydroxazolyl or 2,5-dihydro-1H-pyrrolyl
  • 6-membered heterocycle Specific examples of groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazin
  • the 8-membered heterocyclyl group include, but are not limited to, hexahydrocyclopenta[c]pyrrole-2(1H)-yl.
  • Specific examples of the 9-membered heterocyclyl group include, but are not limited to, benzo[d][1,3]dioxolyl.
  • Specific examples of the 10-membered heterocyclyl group include, but are not limited to, dihydroisoquinolyl.
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrole-2(1H)-yl; 5,6-membered bicyclic groups.
  • heterocyclic group may be a benzo-fused cyclic group of the above-mentioned 4-7 membered heterocyclic group.
  • specific examples include but are not limited to dihydroisoquinolinyl, benzo[d][1,3] Dioxolenyl etc.
  • “4-10-membered heterocyclyl” may include “5-10-membered heterocyclyl”, “4-7-membered heterocyclyl”, “5-6-membered heterocyclyl”, “6-8-membered heterocyclyl” , “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered "Heterocycloalkyl” and other scopes, "4-7 membered heterocyclyl” may further include “4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocyclyl” , “4-6 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl” and other ranges.
  • heterocyclyloxy is understood to mean “heterocyclyl-O-”.
  • heterocycloalkyl refers to a fully saturated cyclic group that exists in the form of a single ring, a branched ring, a bridged ring or a spiro ring, and the ring atoms of the ring contain 1-5 heteroatoms or heteroatom groups.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • Aryl groups can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • C 6 -C 14 aryl is understood to mean aryl groups having 6 to 14 carbon atoms.
  • a ring with 6 carbon atoms for example phenyl; or a ring with 9 carbon atoms (“C 9 aryl”), for example indanyl or indenyl; or a ring with 10 or a ring of 13 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl; or a ring of 13 carbon atoms (“C 13 aryl”), such as fluorenyl; or is a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms.
  • a ring with 6 carbon atoms (“C 6 aryl”), for example phenyl; or a ring with 9 carbon atoms (“C 9 aryl”), for example indanyl or indenyl; or a ring with 10
  • a ring of 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining ring atoms are C.
  • heteroaryl refers to an aromatic monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, and S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiazolyl Diazolyl, etc.
  • benzo derivatives such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole base, indazolyl, indolyl or isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, etc. and their benzo derivatives, such as quinolyl, quinazole Phyllinyl or isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • 9-10 membered heteroaryl refers to an aromatic ring system having 9 or 10 ring atoms, and includes Contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • 6-membered heteroaryl refers to an aromatic ring system having 6 ring atoms and containing 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • alkoxyacyl refers to -COO-alkyl.
  • C 1 -C 10 alkoxyacyl refers to -COO-C 1 -C 10 alkyl.
  • C 1 -C 6 alkoxyacyl refers to a -COO-C 1 -C 6 group.
  • C 1 -C 3 alkoxyacyl refers to -COO-C 1 -C 3 alkyl.
  • heterocyclylalkyl refers to -(alkylene)-heterocyclyl.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • amino refers to the -NH group .
  • terapéuticaally effective amount means (i) treating a particular disease, condition, or disorder, (ii) alleviating, ameliorating, or eliminating one or more symptoms of a particular disease, condition, or disorder, or (iii) delaying the symptoms described herein
  • the amount of a compound of the present disclosure that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without multiple toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refers to salts of pharmaceutically acceptable acids or bases, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.
  • composition refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds that are the same as those described herein, but in which one or more atoms are replaced by an atom having an atomic weight or mass number different from that typically found in nature.
  • isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution analyses. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present disclosure can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by following procedures similar to those disclosed in the Schemes and/or Examples below.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral administration.
  • the pharmaceutical composition of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.
  • the pharmaceutical composition is in an oral form.
  • the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, dragees, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or sugar-coated core.
  • suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the daily dosage is 0.1 mg/kg to 500 mg/kg body weight, preferably 0.5 mg/kg to 400 mg/kg body weight, more preferably 1 mg/kg to 200 mg/kg body weight as single or divided doses.
  • the compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by their combination with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present disclosure.
  • the ratios expressed for mixed solvents are volumetric mixing ratios.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the units of NMR shifts are 10 -6 (ppm).
  • the solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration when half of the maximum inhibitory effect is achieved. concentration.
  • the amount of acid or alkali in mobile phase A refers to the volume fraction, for example, “water (0.05% formic acid)” is the volume of formic acid is formic acid and water 0.05% of total volume.
  • B% represents the proportion of the volume of mobile phase B to the total volume of mobile phase A and mobile phase B during gradient elution.
  • B%: 50%-70% represents the proportion of the volume of mobile phase B to the total volume of mobile phase A and mobile phase B during gradient elution.
  • the ratio of the total volume of A and mobile phase B ranges from 50% to 70%.
  • Step 1 Synthesis of 5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazole-2-amine (intermediate 1-3)
  • Step 2 Synthesis of 3-(2-cyclopropylphenyl)pyridine-4-carboxylic acid methyl ester (intermediate 1-6)
  • Step 3 Synthesis of 3-(2-cyclopropylphenyl)pyridine-4-carboxylic acid (intermediate 1-7)
  • Step 4 N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-cyclopropylphenyl)pyridine-4- Synthesis of formamide (compound 1)
  • intermediate 1-7 (53.1 mg) and intermediate 1-3 (53.64 mg) were dissolved in N,N-dimethylformamide (1 mL), and HATU (126.57 mg) was added to the reaction solution. ), N,N-diisopropylethylamine (DIEA) (57.36 mg).
  • DIEA N,N-diisopropylethylamine
  • the reaction solution was stirred and reacted at 25°C for 16 hours.
  • the organic phase was concentrated under reduced pressure, and ethyl acetate (2 mL) and water (4 mL) were added.
  • the organic phase was washed with water (2 mL*3 times), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness.
  • Step 1 Synthesis of 3-(2-ethynylphenyl)pyridine-4-carboxylic acid methyl ester (intermediate 2-2)
  • intermediate 2-3 (30.4 mg) and intermediate 1-3 (32.92 mg) were dissolved in N,N-dimethylformamide (0.6 mL), and HATU (77.67 mg) was added to the reaction solution. mg), DIEA (35.20mg).
  • the reaction solution was stirred and reacted at 25°C for 16 hours.
  • the organic phase was concentrated under reduced pressure, ethyl acetate (1 mL) and water (2 mL) were added, the organic phase was washed with water (1 mL*3 times), and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness.
  • Step 1 Synthesis of 3-(2-methoxyphenyl)pyridine-4-carboxylic acid methyl ester (intermediate 3-1)
  • Step 2 Synthesis of 3-(2-methoxyphenyl)pyridine-4-carboxylic acid (intermediate 3-2)
  • Step 3 N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4- Synthesis of formamide (intermediate 3-3)
  • Step 4 5-((4-chlorobenzyl)oxy)-N-((3-(2-methoxyphenyl)pyridin-4-yl)methyl)-1,3,4-thiodi Synthesis of Azole-2-amine (Compound 3)
  • Step 2 Synthesis of 4-chloro-6-methylpyridine-3-carboxylic acid methyl ester (intermediate 4-3)
  • Step 3 Synthesis of 4-(2-ethynylphenyl)-6-methylpyridine-3-carboxylic acid methyl ester (intermediate 4-4)
  • Step 4 Synthesis of 4-(2-ethynylphenyl)-6-methylpyridine-3-carboxylic acid (intermediate 4-5)
  • Step 5 N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-4-(2-ethynylphenyl)-6-methyl Synthesis of pyridine-3-carboxamide (compound 4)
  • Step 1 Synthesis of 5-(4-chlorophenylethyl)-1,3,4-thiadiazole-2-amine (intermediate 5-3)
  • Step 2 N-(5-(4-chlorophenylethyl)-1,3,4-thiadiazol-2-yl)-3-(2-ethynylphenyl)pyridine-4-carboxamide (compound 5) synthesis
  • Step 1 N-(5-(4-chlorophenylethyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide ( Synthesis of compound 6)
  • Step 1 Synthesis of methyl 3-(2-vinylphenyl)pyridine-4-carboxylate (Intermediate 7-2)
  • Step 3 N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-3-(2-vinylphenyl)pyridine-4-methyl Synthesis of Amide (Compound 7)
  • Step 2 N-(5-(hydroxymethyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Intermediate 8 -Synthesis of 3)
  • reaction solution was purified by preparative liquid chromatography (YMC-Actus Triart C18 column 5um silica, 30mm diameter, 150mm length; water (containing 0.05wt% NH 4 HCO 3 ) and acetonitrile were mixed with decreasing polarity The solution was used as the eluent; acetonitrile gradient ratio 35%-75%, elution time 12 minutes) to obtain the title compound (380 mg).
  • Step 3 (5-(3-(2-methoxyphenyl)pyridine-4-carboxamide)-1,3,4-thiadiazol-2-yl)methylethanesulfonate (Intermediate 8 -4) synthesis
  • Step 4 N-(5-((4-chlorophenoxy)methyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4 -Synthesis of formamide (compound 8)
  • Step 1 Synthesis of 5-(3-(4-chlorophenyl)cyclobutyl)-1,3,4-thiadiazole-2-amine (intermediate 9-2)
  • Step 2 N-(5-(3-(4-chlorophenyl)cyclobutyl)-1,3,4-thiadiazol-2-yl)-3-(2-methoxyphenyl)pyridine -Synthesis of 4-carboxamide (compound 9)
  • reaction solution was purified by preparative liquid chromatography (YMC-Actus Triart C18 column 5um silica, 30mm diameter, 150mm length; water (containing 0.05wt% NH 4 HCO 3 ) and acetonitrile were mixed with decreasing polarity The solution was used as the eluent; acetonitrile gradient ratio 45%-85%, elution time 12 minutes) to obtain the title compound (12 mg).
  • Step 2 Synthesis of N-(5-((4-chlorobenzyl)oxy)thiazol-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (compound 10)
  • Step 1 Synthesis of 4-chloro-6-((trimethylsilyl)ethynyl)pyridine-3-carboxylic acid methyl ester (intermediate 11-2)
  • Step 2 Synthesis of 4-(2-methoxyphenyl)-6-(trimethylsilyl)ethynyl)pyridine-3-carboxylic acid methyl ester (intermediate 11-4)
  • Step 3 Synthesis of 6-ethynyl-4-(2-methoxyphenyl)pyridine-3-carboxylic acid (intermediate 11-5)
  • Step 4 N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-6-ethynyl-4-(2-methoxyphenyl )Synthesis of pyridine-3-carboxamide (compound 11)
  • Step 1 Synthesis of 6-(2-methoxyphenyl)benzo[d][1,3]dioxole-5-carboxylic acid methyl ester (intermediate 12-2)
  • Step 2 Synthesis of 6-(2-methoxyphenyl)benzo[d][1,3]dioxole-5-carboxylic acid (intermediate 12-3)
  • Step 1 Synthesis of 3-(cyclohex-1-en-1-yl)pyridine-4-carboxylic acid methyl ester (intermediate 13-2)
  • Step 2 Synthesis of 3-(cyclohex-1-en-1-yl)pyridine-4-carboxylic acid (intermediate 13-3)
  • Step 1 5-(benzo[d][1,3]dioxol-4-ylmethoxy)-1,3,4-thiadiazole-2-amine (intermediate 14-2 )Synthesis
  • Step 2 N-(5-(benzo[d][1,3]dioxol-4-ylmethoxy)-1,3,4-thiadiazol-2-yl)-3 Synthesis of -(2-methoxyphenyl)pyridine-4-carboxamide (compound 14)
  • Step 1 Synthesis of 5-((4-ethynylbenzyl)oxy)-1,3,4-thiadiazole-2-amine (intermediate 15-2)
  • Step 1 Synthesis of 4-chloro-6-methylpyridine-3-carboxylic acid methyl ester (intermediate 16-2)
  • Step 2 Synthesis of 4-(cyclohexen-1-yl)-6-methylpyridine-3-carboxylic acid methyl ester (intermediate 16-4)
  • Step 3 Synthesis of 4-(cyclohexen-1-yl)-6-methylpyridine-3-carboxylic acid (intermediate 16-5)
  • Step 1 5-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methoxy)-1,3,4-thiadiazole-2 -Synthesis of amine (intermediate 17-2)
  • Step 2 N-(5-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methoxy)-1,3,4-thiadi Synthesis of azole-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (compound 17)
  • Step 1 N-(5-(benzo[d][1,3]dioxol-4-ylmethoxy)-1,3,4-thiadiazol-2-yl)-3 Synthesis of -(2-cyclopropylphenyl)pyridine-4-carboxamide (compound 18)
  • Step 1 Synthesis of ethyl 6-cyano-4-(2-ethynylphenyl)nicotine ester (intermediate 21-2)
  • reaction solution was cooled to room temperature, slowly poured into water (50 mL), extracted with ethyl acetate (20 mL*3 times), the organic phases were combined, and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography ( 20g Fast silica gel column, gradient 0-30% ethyl acetate/petroleum ether, flow rate 30mL/min), the title compound (85mg) was obtained.
  • Step 2 Synthesis of 6-cyano-4-(2-ethynylphenyl)nicotine acid (intermediate 21-3)
  • reaction solution is directly purified by high performance liquid phase preparative chromatography (chromatographic column: Boston Prime C18 150*30mm*5um; mobile phase: [A: water (0.225% formic acid), B: acetonitrile]; B%: 55%-75% ,11min) to obtain the title compound (7mg).
  • Step 1 Synthesis of methyl 2-chloro-5-(2-ethynylphenyl)isonicotine ester (intermediate 22-2)
  • Step 2 Synthesis of methyl 2-cyano-5-(2-ethynylphenyl)isonicotine ester (intermediate 22-3)
  • Step 3 Synthesis of 2-cyano-5-(2-ethynylphenyl)isonicotine acid (intermediate 22-4)
  • Step 2 Synthesis of methyl 1-(2-ethynylphenyl)-1H-imidazole-5-carboxylate (intermediate 23-3)
  • Step 3 Synthesis of 1-(2-ethynylphenyl)-1H-imidazole-5-carboxylic acid (intermediate 23-4)
  • reaction solution was directly purified by high performance liquid chromatography (chromatographic column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 45%-65%, 11 minutes ) to obtain the title compound (12 mg).
  • Step 1 Synthesis of 5-(2-ethynylphenyl)pyrimidine-4-carboxylic acid methyl ester (intermediate 25-2)
  • the reaction solution was filtered, the filtrate was poured into water, ethyl acetate (30mL) was added, the aqueous phase was washed with ethyl acetate (30mL*2), the washed organic phase was dried with anhydrous sodium sulfate, and after filtration, the organic phase was The phase was concentrated to dryness under reduced pressure.
  • the residue was purified by flash silica gel column chromatography ( 12g Fast silica gel column, gradient 0-20% ethyl acetate/petroleum ether, flow rate, 60 mL/min), the title compound (210 mg) was obtained.
  • Step 3 N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-5-(2-ethynylphenyl)pyrimidine-4-methyl Amide (compound 25)
  • the residue was purified by preparative high performance liquid chromatography (Boston Green ODS C18 column 5um silica, 30mm diameter, 150mm length; water (containing 0.225% formic acid) and acetonitrile's reaction solution of decreasing polarity was used as the eluent ; Acetonitrile gradient ratio 50%-80%, elution time 12 minutes), the title compound (15.0 mg) was obtained.
  • Step 1 Synthesis of 5-(2-ethynylphenyl)-2-methoxyisonicotine methyl ester (intermediate 26-2)
  • Step 2 Synthesis of 5-(2-ethynylphenyl)-2-methoxyisonicotine acid (intermediate 26-3)
  • Step 3 N-(5-((4-chlorobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-5-(2-ethynylphenyl)-2-methoxy Isonicamide (compound 26)
  • reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Boston Green ODS C18 column 5um silica, 30mm diameter, 150mm length; the reaction solution with decreasing polarity of water (containing 0.225% formic acid) and acetonitrile was used as Eluent; acetonitrile gradient ratio 60%-80%, elution time 12 minutes) to obtain the title compound (18.0 mg).
  • Step 1 Synthesis of 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid methyl ester (intermediate 27-3)
  • Step 2 Synthesis of 4-(5-cyano-2-methoxyphenyl)-6-methylnicotinic acid (intermediate 27-4)
  • Step 3 Synthesis of 5-(4-bromophenylethyl)-1,3,4-thiadiazole-2-amine (intermediate 27-7)
  • Step 4 Synthesis of 4-(2-(5-amino-1,3,4-thiadiazol-2-yl)ethyl)benzonitrile (intermediate 27-5)
  • Step 5 4-(5-cyano-2-methoxyphenyl)-N-(5-(4-cyanophenylethyl)-1,3,4-thiadiazol-2-yl)-6 -Synthesis of methylnicotinamide (compound 27)
  • Step 1 Synthesis of 6-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)nicotinenitrile (intermediate 28-3)
  • reaction solution was purified by preparative high performance liquid chromatography (chromatographic column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 33%-53% ,11 minutes) to obtain the title compound (22.2 mg).
  • Step 1 Synthesis of 5-((5-chloropyridin-2-yl)methoxy)-1,3,4-thiadiazole-2-amine (intermediate 29-2)
  • reaction solution was purified by preparative high performance liquid chromatography (chromatographic column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 38%-58% , 11 minutes) to obtain the title compound (10.89 mg).
  • Step 3 Synthesis of 5-((2,3-dihydro-1H-indene 4-yl)methoxy)-1,3,4-thiadiazole-2-amine (intermediate 30-4)
  • Step 4 N-(5-((2,3-dihydro-1H-inden-4-yl)methoxy)-1,3,4-thiadiazol-2-yl)-3-(2- Synthesis of methoxyphenyl)isonicotinamide (compound 30)
  • intermediate 30-4 85 mg
  • intermediate 3-2 79 mg
  • HATU 132 mg
  • DIEA 89 mg
  • DMF 1 mL
  • the reaction solution was stirred at room temperature for 3 h.
  • the reaction was completed, it was filtered, and the filtrate was concentrated under reduced pressure to dryness.
  • the residue was purified by preparative high performance liquid chromatography (chromatographic column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: A: water (0.05% formic acid), B: acetonitrile; B%: 40%-80%, 10 minutes ) to obtain the title compound (30 mg).
  • Step 1 Synthesis of 2-methyl-4-(2-((trimethylsilyl)ethynyl)phenyl)pyrimidine-5-carboxylic acid ethyl ester (intermediate 31-3)
  • Step 2 Synthesis of 4-(2-ethynylphenyl)-2-methylpyrimidine-5-carboxylic acid (intermediate 31-4)
  • Step 3 N-(5-((4-cyanophenyl)methoxy)-1,3,4-thiadiazol-2-yl)-4-(2-ethynylphenyl)-2- Synthesis of methylpyrimidine-5-carboxamide (compound 31)
  • Step 1 Synthesis of 2-(2-bromo-4-chloro-phenyl)ethynyl tert-butyldimethylsilane (intermediate 32-2)
  • Step 2 Methyl 4-(2-(2-(tert-butyldimethylsilyl)ethynyl)-5-chlorophenyl)-6-methyl-pyridine-3-carboxylate (Intermediate 32 -Synthesis of 3)
  • intermediate 32-2 (0.95g), potassium acetate (0.85g), pinacol diborate (0.80g) and Pd(dppf)Cl 2 (0.21g) were dissolved in dioxane (10 mL), after addition, the temperature was raised to 70°C and stirred for 16 hours.
  • Step 3 Synthesis of 4-(5-chloro-2-ethynyl-phenyl)-6-methylpyridine-3-carboxylic acid (intermediate 32-4)
  • intermediate 32-3 (245 mg) and lithium hydroxide (184 mg) were dissolved in tetrahydrofuran (5 mL) and water (5 mL). After the addition was completed, the temperature was raised to 60°C and stirred for 16 h. Adjust the pH of the reaction solution to about 6 with 1M HCl solution, extract with ethyl acetate (30mL*2), combine the organic phases, wash twice with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, and filtrate under reduced pressure Concentrate to dryness to obtain the title compound (150 mg).
  • Step 4 4-(5-chloro-2-ethynyl-phenyl)-N-(5-((4-cyanobenzyl)oxy)-1,3,4-thiadiazol-2-yl Synthesis of )-6-methylpyridine-3-carboxamide (compound 32)
  • Step 1 Methyl 4-(2-((tert-butyldimethylsilyl)ethynyl)-5-cyclopropylphenyl)-6-methylpyridine-3-carboxylate (Intermediate 33- 1) synthesis
  • intermediate 32-3 (370mg), cyclopropylboronic acid pinacol ester (318mg), RuPhos Pd G3 (155mg), RuPhos (86mg) and potassium carbonate (383mg) were dissolved in dioxane (4 mL) and water (1 mL), after addition, raise the temperature to 70°C and stir for 2 hours.
  • Step 2 Synthesis of 4-(5-cyclopropyl-2-ethynylphenyl)-6-methylpyridine-3-carboxylic acid (intermediate 33-2)
  • the reaction solution was purified by high performance liquid chromatography [YMC-Actus Triart C18 column 5um silica, 30mm diameter, 150mm length; water (containing 0.05% NH 4 HCO 3 ) and acetonitrile's reaction solution with decreasing polarity was used as the eluent ; Acetonitrile gradient ratio 55%-80%, elution time 13 minutes] to obtain the title compound (9 mg).
  • Step 1 Synthesis of methyl 6-(((5-amino-1,3,4-thiadiazol-2-yl)oxy)methyl)nicotinate (intermediate 34-2)
  • reaction solution is slowly poured into water, ethyl acetate (30mL) is added, the organic phase is washed with water (30mL*2), the washed organic phase is dried with anhydrous sodium sulfate, and the organic phase is concentrated under reduced pressure to dryness, and the residue
  • the material was purified by flash silica gel column chromatography ( 12g Fast silica gel column, gradient 0 to 50% petroleum ether/ethyl acetate, flow rate 50 mL/min) to obtain the title compound (20.0 mg).
  • Step 3 4-(2-ethynylphenyl)-N-(5-((5-(2-hydroxypropan-2-yl)pyridin-2-yl)methoxy)-1,3,4- Synthesis of thiadiazol-2-yl)-6-methylnicotinamide (compound 34)
  • reaction solution was filtered and purified by preparative high performance liquid chromatography (Boston Green ODS C18 column 5um silica, 30mm diameter, 150mm length; a mixture of decreasing polarity of water (containing 0.225% formic acid) and acetonitrile was used as eluent solution; acetonitrile gradient ratio 20%-50%, elution time 14 minutes) to obtain the title compound (4 mg).
  • intermediate 27-5 (100 mg), intermediate 35-1 (121.02 mg, which can be synthesized according to the method reported in patent WO2022118210), N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (146.21 mg) , N-methylimidazole (106.96 mg) was dissolved in acetonitrile (10 mL). Under a nitrogen atmosphere, the reaction solution was stirred at 25°C for 3 h.
  • reaction solution was purified by preparative high performance liquid chromatography (chromatographic column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 35%-55% ,11min), the title compound (52.16mg) was obtained.
  • Step 1 Synthesis of 2',5'-dichloro-6-methyl-[4,4'-bipyridyl]-3-carboxylic acid methyl ester (intermediate 36-2)
  • Step 2 Synthesis of 5'-chloro-2',6-dimethyl-[4,4'-bipyridyl]-3-carboxylic acid methyl ester (intermediate 36-4)
  • Step 4 Synthesis of 5'-ethynyl-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (intermediate 36-7)
  • Step 5 N-(5-((4-cyanobenzyl)oxy)-1,3,4-thiadiazol-2-yl)-5'-ethynyl-2',6-dimethyl Synthesis of -[4,4'-bipyridyl]-3-carboxamide (compound 36)
  • reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Boston Prime C18 column 5um particle size, 30mm diameter, 150mm length; water (containing 0.225% formic acid) and acetonitrile's reaction solution with decreasing polarity was used as eluent solution; acetonitrile gradient ratio 18%-48%, elution time 8 minutes) to obtain the title compound (38 mg).
  • reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Boston Prime C18 column 5um particle size, 30mm diameter, 150mm length; water (containing 0.225% formic acid) and acetonitrile's reaction solution with decreasing polarity was used as eluent solution; acetonitrile gradient ratio 30%-60%, elution time 14 minutes) to obtain the title compound (24 mg).
  • N-terminal active peptide segment (M1-N899) of POLQ with ATPase activity is incubated with the compound, it reacts with the substrate dT50 under the action of ATP to generate ADP, which participates in the subsequent NADH oxidative coupling enzymatic reaction. Catalyzes the reaction of NADH to generate NAD + .
  • reaction buffer (20mM Tris HCl (pH 7.80), 80mM KCl, 10mM MgCl 2 , 1mM DTT, 0.01% w/v bovine serum albumin, 0.01% v/v Tween-20, 5% v/v Glycerol)
  • Dilute POLQ enzyme to 100 nM.
  • DMSO dimethyl sulfoxide
  • the concentration of each component in the reaction mixture solution is: 100 ⁇ M ATP, 300nM dT50, 300 ⁇ M NADH, 6mM PEP, 10U/mL Lactate dehydrogenase and 20U/mL pyruvate kinase.
  • Start the enzyme reaction by adding 20 ⁇ L/well of the reaction mixture solution.
  • the final concentration of the compound in the reaction system started from 10 ⁇ M, with 3-fold gradient dilution, the concentration range was from 10 ⁇ M to 0.0005 ⁇ M, and the final concentration of DMSO in the system was 0.2% v/v.
  • the 384-well plate was left to react at room temperature for 20 minutes, the OD value at 340 nm was read with an Envision microplate reader.
  • the experiment set up a blank group and a DMSO group.
  • the reaction system of the blank group was 0.2% v/v DMSO and reaction mixture solution.
  • the inhibition rate was considered to be 100% at this time;
  • the reaction system of the DMSO group was 0.2% v/v DMSO, POLQ(N) ( 100nM) and reaction mixture solution, the inhibition rate is considered to be 0 at this time.
  • Inhibition rate (%) (100-100*(OD max -OD compound )/(OD max -OD min ))%
  • OD max refers to the OD value of the well containing the reactant mixture and 0.2% v/v DMSO
  • OD compound refers to the OD value of the well containing the compound, enzyme and reactant mixture
  • OD min refers to the OD value of the well containing enzyme, reactant mixture and 0.2% v/v DMSO.
  • “++” indicates that the IC 50 range of the enzyme inhibitory activity of the compound to be tested is: 500 ⁇ IC 50 ⁇ 1000nM.
  • Test Example 2 Experiment on the inhibition of tumor cell proliferation by compounds
  • DLD-1 parental cells or DLD-1BRCA2(-/-) cells were diluted with RPMI 1640 medium containing 10% FBS and then added to a 96-well plate (90 ⁇ L/well). The number of cells was 600 cells/well respectively. Or 1200 pieces/well, place it in a 37°C, 5% CO2 incubator overnight. After diluting the test compound to different concentrations in dimethyl sulfoxide (DMSO), add Into a 96-well plate, the final concentration of the compound in the reaction system starts from 25 ⁇ M, and is diluted 4-fold. The concentration range of the compound is from 25 ⁇ M to 0.0004 ⁇ M, and the final concentration of DMSO is 0.25% v/v. After 7 days of incubation, add 50 ⁇ L/well CTG and incubate at room temperature for 10 minutes. Then use an Envision microplate reader to read the light signal value (Lum), and calculate the inhibition rate and half inhibitory concentration (IC 50 ).
  • DMSO dimethyl sul
  • the experiment set up blank wells and DMSO wells.
  • the blank wells were 100 ⁇ L of RPMI Medium 1640 medium containing 10% FBS. It was considered that the inhibitory rate of the compound on tumor cell growth at this time was 100%; the DMSO wells were added with 0.25% v/v in the cell wells. DMSO, it is believed that the inhibitory rate of the compound on tumor cell growth is 0 at this time.
  • Inhibition rate (%) 100*(Lum max -Lum compound )/(Lum max -Lum min )%
  • Lum max refers to the light signal value of the well containing cells and 0.25% v/v DMSO
  • Lum compound refers to the light signal value of the well containing the compound and cells
  • Lum min refers to the light signal value of the well containing culture medium and 0.25% v/v DMSO.
  • the growth inhibition of tumor cells by the compounds of the present disclosure was measured through the above test, and the measured IC 50 values are shown in Table 2 below.

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Abstract

La présente Invention concerne un composé inhibiteur de POLQ représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le contenant, et son utilisation dans la préparation d'un médicament destiné à la prévention ou au traitement de maladies médiées par POLQ.
PCT/CN2023/089240 2022-04-20 2023-04-19 Composé inhibiteur de polq et son utilisation WO2023202623A1 (fr)

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WO2024099336A1 (fr) * 2022-11-10 2024-05-16 Danatlas Pharmaceuticals Co., Ltd. Dérivés de thiadiazolyle, compositions et utilisations de ceux-ci
WO2024099337A1 (fr) * 2022-11-10 2024-05-16 Danatlas Pharmaceuticals Co., Ltd. Dérivés de thiadiazolyle, compositions et utilisations associées

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TW202237595A (zh) * 2020-12-02 2022-10-01 美商愛德亞生物科學公司 作為DNA聚合酶θ抑制劑之經取代噻二唑基衍生物
WO2022259204A1 (fr) * 2021-06-11 2022-12-15 Ideaya Biosciences, Inc. Composés thiadiazolyle liés à o utilisés en tant qu'inhibiteurs de l'adn polymérase thêta
WO2023050007A1 (fr) * 2021-09-29 2023-04-06 Repare Therapeutics Inc. Composés n-([(l,3,4-thiadiazolyle) ou (thiazolyle)]-5-substitués)carboxamide (substitué) et leur utilisation pour inhiber la polymérase thêta humaine
WO2023060573A1 (fr) * 2021-10-15 2023-04-20 Beijing Danatlas Pharmaceutical Co., Ltd. Nouveaux dérivés du type thiadiazolyle d'inhibiteurs de l'adn polymérase thêta
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WO2021028643A1 (fr) * 2019-08-09 2021-02-18 Artios Pharma Limited Composés hétérocycliques destinés à être utilisés dans le traitement du cancer
TW202237595A (zh) * 2020-12-02 2022-10-01 美商愛德亞生物科學公司 作為DNA聚合酶θ抑制劑之經取代噻二唑基衍生物
WO2022259204A1 (fr) * 2021-06-11 2022-12-15 Ideaya Biosciences, Inc. Composés thiadiazolyle liés à o utilisés en tant qu'inhibiteurs de l'adn polymérase thêta
WO2023050007A1 (fr) * 2021-09-29 2023-04-06 Repare Therapeutics Inc. Composés n-([(l,3,4-thiadiazolyle) ou (thiazolyle)]-5-substitués)carboxamide (substitué) et leur utilisation pour inhiber la polymérase thêta humaine
WO2023060573A1 (fr) * 2021-10-15 2023-04-20 Beijing Danatlas Pharmaceutical Co., Ltd. Nouveaux dérivés du type thiadiazolyle d'inhibiteurs de l'adn polymérase thêta
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024099336A1 (fr) * 2022-11-10 2024-05-16 Danatlas Pharmaceuticals Co., Ltd. Dérivés de thiadiazolyle, compositions et utilisations de ceux-ci
WO2024099337A1 (fr) * 2022-11-10 2024-05-16 Danatlas Pharmaceuticals Co., Ltd. Dérivés de thiadiazolyle, compositions et utilisations associées

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