WO2022095975A1 - Cd73抑制剂及其应用 - Google Patents
Cd73抑制剂及其应用 Download PDFInfo
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- WO2022095975A1 WO2022095975A1 PCT/CN2021/129079 CN2021129079W WO2022095975A1 WO 2022095975 A1 WO2022095975 A1 WO 2022095975A1 CN 2021129079 W CN2021129079 W CN 2021129079W WO 2022095975 A1 WO2022095975 A1 WO 2022095975A1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present disclosure belongs to the field of medicinal chemistry. Specifically, the present disclosure relates to CD73 inhibitors and applications thereof. More particularly, the present disclosure relates to a pyrimidinedione compound, a preparation method thereof, and use thereof in the preparation of medicines.
- CD73 also known as extracellular 5'-nucleotide hydrolase, is an exonuclease belonging to the metallophosphatase superfamily and is a peripheral glycoprotein whose major form is anchored by glycosylphosphatidylinositol (GPI) It is fixed on the plasma membrane with a molecular weight of 70KD and is encoded by the NT5E gene.
- GPI glycosylphosphatidylinositol
- CD73 is widely expressed on the cell surface of different tissues, including brain, lung, heart, spleen, lymph node, kidney, colon, vascular endothelium, and bone marrow; it is also expressed on various immune cells, including macrophages, neutrophils, myeloid suppression cells (MDSCs), dendritic cells (DCs), natural killer cells (NKs), and regulatory T cells (Tregs) (Soleimani A et al., Biochimie, 2020, 176:21-30.); a variety of tumor cells also have Highly expressed CD73, such as: melanoma, breast cancer, pancreatic cancer, ovarian cancer, colon cancer and prostate cancer, etc. (Gao Z et al., Biomed Res Int, 2014, 2014:460654.). CD73 is also present in a soluble form (sCD73) in biological fluids, including serum, and preserves holoenzyme activity.
- sCD73 soluble form
- CD73 mainly exerts physiological and pathological effects by hydrolyzing AMP (adenosine monophosphate) to produce extracellular adenosine (ADO).
- ADO is associated with four G protein-coupled receptors (GPCRs): A1 adenosine A2A adenosine receptor (A2AR), A2B adenosine receptor (A2BR) and A3 adenosine receptor (A3AR) play a role, of which A2AR plays a major role (Linden J et al., Annu.Rev.Immunol., 2019, 37:325-347.).
- GPCRs G protein-coupled receptors
- Adenosine receptors are not only expressed in tumor cells, but also expressed on the cell surface of immune cells and vascular endothelial cells infiltrated in the tumor microenvironment. After binding to the receptors, ADO produces a variety of immunosuppressive and tumor-promoting effects. .
- CD73 is closely related to tumor growth, angiogenesis and metastasis. Under normal physiological conditions, the extracellular ADO level is between 20 and 300 nM, but in the tumor microenvironment, the increase is maintained to the micromolar level (30-100 ⁇ M), and the high extracellular ADO concentration is mainly generated by CD73 hydrolysis of AMP affected. Studies have shown that soluble CD73 (sCD73) levels are increased in the plasma of cancer patients compared to healthy individuals (Klemens MR et al., Biochem. Biophys. Res. Commun., 1990, 172:1371-7..).
- CD73 is upregulated in pancreatic ductal carcinoma (PDAC) compared to normal pancreatic tissue and is associated with tumor size, metastasis and poor prognosis (Harvey Jerry B et al, Front Immunol, 2020, 11:508.).
- PDAC pancreatic ductal carcinoma
- ORIC-533 significantly reduced the ADO concentration in the tumor microenvironment while reducing tumor volume.
- CD73 inhibitors can block tumor growth by releasing immunosuppression, and can also be used in combination with other targeted therapies and/or immunotherapy and radiotherapy to increase the anti-tumor effect.
- CD73 levels were found to be upregulated in melanoma patients, whereas a distinct CD73-high-expressing macrophage population persisted in glioblastoma patients after anti-PD-1 treatment, and CD73 deficiency enhanced anti-PD-1 and anti-CTLA- 4.
- Efficacy in mouse glioblastoma model (Goswami S et al., Nat.Med., 2020, 26:39-46.); radiotherapy led to the destruction of some tumor cells, which released a large amount of intracellular ATP into the cells.
- CD73 inhibitor under the action of tumor cell surface or free CD73, it is converted into adenosine to produce immunosuppressive effect, which is considered to be one of the reasons for the poor prognosis of some patients after radiotherapy. Therefore, the combination of CD73 inhibitor and radiotherapy may produce synergy. effect (Wennerberg E et al. Cancer Immunol Res, 2020, 8:465-478.).
- CD73 inhibition may be a promising approach to treating tumors.
- the present disclosure aims to propose a novel CD73 inhibitor, which can be used to prepare a drug for the treatment of tumor-related diseases.
- the present disclosure proposes a compound, which is a compound represented by formula I, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug:
- R 1 is selected from wherein R a is independently selected from the following substituents: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heteroaryl Cycloalkyl, or, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; in the 5-8 membered heteroaryl, the heteroatom is selected from N, S, O and P One or more of the heteroatoms, the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the heteroatoms are The number is 1-3; in the 4-8-membered heterocycloalkenyl group, the heteroatom is selected from one or more of N, S, O and P, and the number of the heteroatom is 1-3;
- R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 1 -C 6 alkyl-O-, Unsubstituted or R b substituted C 1 -C 6 alkyl-S-, unsubstituted or R b substituted 5-8 membered aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, Unsubstituted or R b substituted 4-8 membered heterocycloalkyl, unsubstituted or R b substituted 4-8 membered heterocycloalkenyl, or, unsubstituted or R b substituted C 2 -C 6 alkene group; in C 1 -C 6 alkyl substituted by R b , in C 1 -C 6 alkyl -O- substituted by R b , in C 1 -C
- the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
- R 1 is selected from wherein R a is independently selected from the following substituents: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heteroaryl Cycloalkyl, or, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; in the 5-8 membered heteroaryl, the heteroatom is selected from N, S, O and P One or more of the heteroatoms, the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the heteroatoms are The number is 1-3; in the 4-8-membered heterocycloalkenyl group, the heteroatom is selected from one or more of N, S, O and P, and the number of the heteroatom is 1-3;
- R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 1 -C 6 alkyl-O-, Unsubstituted or R b substituted C 1 -C 6 alkyl-S-, unsubstituted or R b substituted 5-8 membered aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, Unsubstituted or R b substituted 4-8 membered heterocycloalkyl, unsubstituted or R b substituted 4-8 membered heterocycloalkenyl, or, unsubstituted or R b substituted C 2 -C 6 alkene group; in C 1 -C 6 alkyl substituted by R b , in C 1 -C 6 alkyl -O- substituted by R b , in C 1 -C
- the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
- R a is a C 1 -C 6 alkyl group
- the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
- the C 1 -C 6 alkyl is C 1 -C 4 alkane group, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
- R a is C 1 -C 6 alkyl substituted with 1-5 same or different halogens
- the halogen is F, Cl, Br or I, preferably F or Cl.
- R a is a C 1 -C 6 alkyl group substituted with 1-5 same or different halogens
- the number of halogen substitutions is 1, 2 or 3, preferably The ground is 3.
- R a is C 3 -C 6 cycloalkyl
- the C 3 -C 6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclopentyl Hexyl, preferably cyclopropyl.
- R a is a 5-8-membered aryl group
- the 5-8-membered aryl group is independently phenyl or naphthyl, preferably phenyl.
- R a is a 5-8-membered heteroaryl group
- the 5-8-membered heteroaryl group is independently pyrrole, pyrazole, triazole, furan, oxazole, thiophene , thiazole, pyridine, pyrazine or pyrimidine, preferably pyrazole, furan, thiophene or pyridine.
- R a is a 4-8 membered heterocycloalkyl
- the 4-8 membered heterocycloalkyl is independently azetidine, oxetane, tetrakis Hydropyrrolidinyl, tetrahydrofuranyl, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide, preferably azetidine or oxetane.
- R a is a 4-8 membered heterocyclenyl
- the 4-8 membered heterocyclenyl is independently dihydropyridyl, tetrahydropyridyl, tetrahydropyrimidine base, pyrroline, imidazoline, pyrazoline, dihydroimidazolyl, dihydropyrazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, dihydroisothiazolyl, Dihydrothienyl, dihydropyrrolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, dihydropyrazinyl, dihydropyrimidinyl or fluorodihydrofuranyl, preferably 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-
- R 2 is cyano
- the halogen is F, Cl, Br or I, preferably Cl.
- the C 1 -C 6 alkyl group when it is an unsubstituted or R b substituted C 1 -C 6 alkyl group, is a C 1 -C 4 alkyl group, preferably methyl , ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
- the C 1 -C 6 alkyl-O- is C 1 -C 4 alkyl-O-, preferably methyl-O-.
- the C 1 -C 6 alkyl-S- is C 1 -C 4Alkyl -S-, preferably methyl-S-.
- R 2 when R 2 is an unsubstituted or substituted 5-8-membered aryl group, the 5-8-membered aryl group is independently phenyl or naphthyl, preferably is phenyl.
- the 5-8-membered heteroaryl group is independently pyrrole, pyrazole, triazine azole, furan, oxazole, thiophene, thiazole, pyridine, pyrazine or pyrimidine, preferably pyrazole, furan, thiophene or pyridine.
- R 2 when R 2 is an unsubstituted or substituted 4-8-membered heterocycloalkyl group, the 4-8-membered heterocycloalkyl group is independently azetidine , oxetane, tetrahydropyrrolidinyl, tetrahydrofuranyl, hexahydropyran or tetrahydro-2H-thiopyran 1,1-dioxide, preferably azetidine or oxane Butane.
- R 2 is a 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b
- the 4-8-membered heterocycloalkenyl is independently a dihydropyridyl, Tetrahydropyridyl, tetrahydropyrimidinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, dihydroimidazolyl, dihydropyrazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazole base, dihydroisothiazolyl, dihydrothienyl, dihydropyrrolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, dihydropyrazinyl, dihydropyrimidinyl, or fluorobis Hydrofuranyl, preferably 1,2,3,4-tetrahydropyridyl, 1,2-
- R 2 is C 2 -C 6 alkenyl unsubstituted or substituted by R b
- the C 2 -C 6 alkenyl is vinyl, 1-propenyl, 2- A propenyl group, an allyl group, preferably a vinyl group or an allyl group.
- R 1 is selected from wherein R a is C 1 -C 6 alkyl unsubstituted or substituted with one or more halo, the same or different.
- R a is selected from C 1 -C 4 alkyl unsubstituted or substituted with 1-5 identical or different halogens.
- R a is selected from methyl, trifluoromethyl or difluoromethyl.
- R 2 is selected from hydrogen, halogen, cyano, unsubstituted or substituted C 1 -C 4 alkyl groups with R b , each of which is independently halogen.
- R 2 is selected from Cl or methyl.
- each of the R b is independently halogen, and the halogen is F, Cl or Br.
- R 1 is selected from
- R 2 is selected from hydrogen, halogen, cyano, unsubstituted or substituted C 1 -C 4 alkyl groups with R b , each of which is independently halogen.
- R 2 is Cl
- R 2 is selected from hydrogen, halogen, cyano, C 1 -C 4 alkyl unsubstituted or substituted by R b .
- the C 1 -C 4 alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
- R 2 is Cl
- R 1 is R 2 is selected from hydrogen, halogen, cyano, unsubstituted or C 1 -C 4 alkyl substituted by R b , C 1 -C 4 alkyl is selected from methyl, ethyl, preferably, R 2 is selected from Halogen, the halogen is F, Cl, Br or I, preferably Cl.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
- R1 is wherein R a is independently selected from the following substituents: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heteroaryl Cycloalkyl, or, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; in the 5-8 membered heteroaryl, the heteroatom is selected from N, S, O and P One or more of the heteroatoms, the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the heteroatoms are The number is 1-3; in the 4-8 membered heterocycloalkenyl group, the heteroatom is selected from one or more of N, S, O and P, and the number of the heteroatom is 1-3.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
- R1 is wherein R a is independently selected from the following substituents: hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl, 4-8 membered heteroaryl Cycloalkyl, or, C 1 -C 6 alkyl substituted by 1-5 identical or different halogens; in the 5-8 membered heteroaryl, the heteroatom is selected from N, S, O and P One or more of the heteroatoms, the number of heteroatoms is 1-3; in the 4-8 membered heterocycloalkyl, the heteroatoms are selected from one or more of N, S, O and P, and the heteroatoms are The number is 1-3; in the 4-8 membered heterocycloalkenyl group, the heteroatom is selected from one or more of N, S, O and P, and the number of the heteroatom is 1-3.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
- R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 1 -C 6 alkyl-O-, Unsubstituted or R b substituted C 1 -C 6 alkyl-S-, unsubstituted or R b substituted 5-8 membered aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, Unsubstituted or R b substituted 4-8 membered heterocycloalkyl, unsubstituted or R b substituted 4-8 membered heterocycloalkenyl, or, unsubstituted or R b substituted C 2 -C 6 alkene group; in C 1 -C 6 alkyl substituted by R b , in C 1 -C 6 alkyl -O- substituted by R b , in C 1 -C
- the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
- R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 1 -C 6 alkyl-O-, Unsubstituted or R b substituted C 1 -C 6 alkyl-S-, unsubstituted or R b substituted 5-8 membered aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, Unsubstituted or R b substituted 4-8 membered heterocycloalkyl, unsubstituted or R b substituted 4-8 membered heterocycloalkenyl, or, unsubstituted or R b substituted C 2 -C 6 alkene group; in C 1 -C 6 alkyl substituted by R b , in C 1 -C 6 alkyl -O- substituted by R b , in C 1 -C
- the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
- R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 1 -C 6 alkyl-O-, Unsubstituted or R b substituted C 1 -C 6 alkyl-S-, unsubstituted or R b substituted 5-8 membered aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, Unsubstituted or R b substituted 4-8 membered heterocycloalkyl, unsubstituted or R b substituted 4-8 membered heterocycloalkenyl, or, unsubstituted or R b substituted C 2 -C 6 alkene group; in C 1 -C 6 alkyl substituted by R b , in C 1 -C 6 alkyl -O- substituted by R b , in C 1 -C
- the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is:
- R 2 is selected from hydrogen, halogen, hydroxy, cyano, amino, unsubstituted or R b substituted C 1 -C 6 alkyl, unsubstituted or R b substituted C 1 -C 6 alkyl-O-, Unsubstituted or R b substituted C 1 -C 6 alkyl-S-, unsubstituted or R b substituted 5-8 membered aryl, unsubstituted or R b substituted 5-8 membered heteroaryl, Unsubstituted or R b substituted 4-8 membered heterocycloalkyl, unsubstituted or R b substituted 4-8 membered heterocycloalkenyl, or, unsubstituted or R b substituted C 2 -C 6 alkene group; in C 1 -C 6 alkyl substituted by R b , in C 1 -C 6 alkyl -O- substituted by R b , in C 1 -C
- the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the In the unsubstituted or 4-8 membered heterocycloalkyl substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3;
- the described In the 4-8-membered heterocycloalkenyl unsubstituted or substituted by R b the heteroatom is selected from one or more of N, S, O and P, and the number of heteroatoms is 1-3.
- the compound represented by formula I its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug is selected from any of the following compounds :
- the present disclosure proposes a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective dose of the above compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically Acceptable salts or prodrugs and pharmaceutically acceptable excipients.
- the pharmaceutical compositions of the present disclosure may include therapeutically effective doses of the above-mentioned compounds, tautomers, stereoisomers, hydrates, solvates, and pharmaceutically acceptable salts thereof
- prodrugs and pharmaceutically acceptable pharmaceutical carriers, diluents or excipients are mixed to prepare pharmaceutical preparations suitable for oral or parenteral administration.
- Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, and oral routes.
- the formulations can be administered by any route, eg, by infusion or bolus injection, by route of absorption through the epithelium or mucocutaneous (eg, oral mucosa or rectum, etc.). Administration can be systemic or local.
- formulations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions and the like.
- the formulations can be prepared by methods known in the art and include carriers, diluents or excipients conventionally used in the art of pharmaceutical formulations.
- the present disclosure proposes the above-mentioned compounds, or tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, with PD-1/PD-L1
- cancers include, for example, bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, neuroblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, ovarian cancer , pancreatic, prostate or kidney cancer.
- the present disclosure proposes that the above-mentioned compounds, tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs thereof, or the above-mentioned pharmaceutical compositions are prepared for use in Use in medicines for treating diseases related to CD73.
- the above-mentioned compounds or their tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs or the above-mentioned pharmaceutical compositions are prepared for the treatment of CD73-related diseases Use in a medicament useful in the treatment of cancer.
- cancers include, for example, bladder cancer, breast cancer, bile duct cancer, colorectal cancer, colon cancer, stomach cancer, gallbladder cancer, glioblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, Ovarian, pancreatic, prostate or kidney cancer.
- the present disclosure provides a method for treating a disease associated with CD73, the method comprising administering to a subject in need thereof the above-mentioned compound, its tautomer, stereoisomer, hydrated compounds, solvates, pharmaceutically acceptable salts or prodrugs and/or the above-mentioned pharmaceutical compositions.
- the CD73-related disease is cancer. These cancers include, for example, bladder cancer, breast cancer, bile duct cancer, rectal cancer, colon cancer, stomach cancer, gallbladder cancer, neuroblastoma, head and neck cancer, liver cancer, lung cancer, lymphoma, medulloblastoma, melanoma, ovarian cancer , pancreatic, prostate or kidney cancer. Terms and Definitions
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, organic acids and bases.
- salts are contemplated by the present disclosure. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used in the identification, characterization or purification of the compounds of the present disclosure.
- composition means a mixture of one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as a physiologically/pharmaceutically acceptable carrier and excipients.
- the purpose of a pharmaceutical composition is to facilitate the administration of a compound to an organism.
- excipient refers to a pharmaceutically acceptable inert ingredient.
- classes of the term “excipient” include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of a pharmaceutical formulation, ie make the formulation more suitable for direct compression by increasing flowability and/or stickiness.
- prodrug refers to a compound of the present disclosure that can be converted under physiological conditions or by solvolysis to a biologically active compound.
- the prodrugs of the present disclosure are prepared by modifying functional groups in the compounds, which modifications can be removed by conventional procedures or in vivo to yield the parent compounds.
- Prodrugs include compounds formed by connecting a hydroxyl group or amino group in the compounds of the present disclosure to any group. When the prodrugs of the compounds of the present disclosure are administered to mammalian individuals, the prodrugs are cleaved to form a free hydroxyl group, a free hydroxyl group, and a free group, respectively. the amino group.
- stereoisomer refers to isomers resulting from different arrangements of atoms in a molecule in space, and includes cis-trans isomers, enantiomers, diastereomers and conformers.
- the compounds of the present disclosure may exist as one of the possible isomers or as a mixture thereof, eg, as pure optical isomers, or as mixtures of isomers, eg, as racemic and non-isomeric isomers.
- the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule.
- the prefixes D and L or (+) and (–) are symbols used to designate the rotation of plane polarized light by the compound, where (–) or L indicates that the compound is levorotatory.
- the compounds described herein contain olefinic double bonds, unless otherwise specified, such double bonds include both E and Z geometric isomers. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl group may be in the cis- or trans- (cis- or trans-) configuration.
- Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques.
- Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include fractional recrystallization using chiral resolving acids, which are optically active salt-forming organic acids.
- Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids such as ⁇ - D and L forms of camphorsulfonic acid.
- resolving agents suitable for fractional crystallization methods include ⁇ -methyl-benzylamine in stereoisomerically pure form (eg, S and R forms or diastereomerically pure form), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc.
- Resolution of racemic mixtures can also be performed by elution on a chromatographic column packed with an optically active resolving agent (eg, dinitrobenzoylphenylglycine). It can be carried out by high performance liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).
- tautomer refers to an isomer of a functional group resulting from the rapid movement of an atom in two positions in a molecule.
- Compounds of the present disclosure may exhibit tautomerism.
- Tautomeric compounds can exist as two or more interconvertible species.
- Proton tautomers arise from the migration of covalently bonded hydrogen atoms between two atoms.
- Tautomers generally exist in equilibrium, and attempts to separate individual tautomers usually result in a mixture whose physicochemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule.
- the ketone form predominates; in phenols, the enol form predominates.
- the present disclosure includes all tautomeric forms of compounds.
- the compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
- compounds can be labeled with radioisotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
- an "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a nontoxic but sufficient amount of the drug or agent to achieve the desired effect.
- an "effective amount” of one active in a composition refers to the amount required to achieve the desired effect when used in combination with another active in the composition.
- the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
- active ingredient refers to a chemical entity that is effective in treating the target disorder, disease or condition.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
- Ketone substitution does not occur on aromatic groups.
- optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
- C 1 -C 6 alkyl is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
- the alkyl group is, for example, 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-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbut
- C 1 -C 6 alkyl-O- is to be understood as an alkyl group attached to the rest of the molecule through an oxygen atom, wherein "C 1 -C 6 alkyl” has the above definition. Such as methyl-O-, ethyl-O-.
- C 1 -C 6 alkyl-S- is to be understood as an alkyl group attached to the rest of the molecule through a sulfur atom, wherein "C 1 -C 6 alkyl” has the above definition. Such as methyl-S-, ethyl-S-.
- C 2 -C 6 alkenyl is to be understood as a straight or branched chain consisting only of carbon and hydrogen atoms, containing at least one double bond, having 2 to 6 carbon atoms and connected to the rest of the molecule by a single bond
- Chain hydrocarbon chain groups such as but not limited to vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-diene Base et al.
- C3 - C6cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 6 carbon atoms, including fused or bridged polycyclic ring systems. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
- 4-8 membered heterocyclyl or “4-8 membered heterocycloalkyl” is understood to mean a saturated, unsaturated or partially saturated monocyclic, bicyclic or tricyclic ring having 4 to 8 atoms, wherein 1, 2, 3, 4 or 5 ring atoms are selected from N, O and S, which may be attached through carbon or nitrogen unless otherwise specified, wherein the -CH2- group is optionally replaced by -C(O)- and wherein, unless otherwise stated to the contrary, a ring nitrogen atom or a ring sulfur atom is optionally oxidized to form an N-oxide or S-oxide or a ring nitrogen atom is optionally quaternized; wherein -NH in the ring is optionally substituted with acetyl, formyl, methyl or methanesulfonyl; and the ring is optionally substituted with one or more halogens.
- heterocyclyl group is bicyclic or tricyclic, at least one ring may optionally be a heteroaromatic ring or an aromatic ring, provided that at least one ring is non-heteroaromatic. If the heterocyclyl group is monocyclic, it must not be aromatic.
- heterocyclyl groups include, but are not limited to, piperidinyl, N-acetylpiperidinyl, N-methylpiperidinyl, N-formylpiperazinyl, N-methanesulfonylpiperazinyl, homopiperazinyl , piperazinyl, azetidinyl, oxetanyl, morpholinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, indoline, tetrahydropyranyl, dihydro -2H-pyranyl, tetrahydrofuranyl, tetrahydrothiopyranyl, tetrahydrothiopyran-1-oxide, tetrahydrothiopyran-1,1-dioxide, 1H-pyridin-2-one and 2,5 -Dioximidazolidinyl.
- 4-8 membered heterocycloalkenyl is to be understood as a non-aromatic monocyclic or polycyclic group containing 4 to 8 ring atoms, preferably 5 to 6 ring atoms, wherein the 4-8 membered heterocyclic group Cycloalkenyl contains 1 to 3 heteroatoms selected from N, O, S and P and contains at least one carbon-carbon double bond or carbon-nitrogen double bond.
- Aza, oxa or thia included in the group name means at least one nitrogen, oxygen or sulfur atom, respectively, as a ring atom.
- the nitrogen or sulfur atom of the 4-8 membered heterocycloalkenyl can optionally be oxidized to the corresponding N-oxide, S-oxide or S-dioxide.
- Preferred 4-8 membered heterocycloalkenyl groups include, but are not limited to, 1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3 ,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl , dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl and their oxides.
- 5-8 membered aryl is to be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 5-8 carbon atoms, especially a ring having 6 carbon atoms (" C 6 aryl”), such as phenyl; when the 5-8 membered aryl is substituted, it may be mono- or poly-substituted. Also, the substitution site is not limited, for example, it may be ortho-, para- or meta-substitution.
- 5-8 membered heteroaryl is to be understood as a monovalent radical having 5-8 ring atoms, especially 5 or 6 carbon atoms, and comprising 1-5 heteroatoms independently selected from N, O and S Monocyclic, bicyclic or tricyclic aromatic ring groups. Monovalent monocyclic, bicyclic or tricyclic aromatic ring groups of 1 to 3 heteroatoms independently selected from N, O and S are preferred and, in addition, may be benzofused in each case.
- heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl oxadiazolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.; group, carbazolyl group, acridine group, phenazinyl group, phenothiazinyl group, phenoxazinyl group and the like.
- halo or halogen is fluorine, chlorine, bromine and iodine.
- the description method "...independently” used in the present disclosure should be understood in a broad sense, meaning that the described individuals are independent of each other and may be independent of each other. are the same or different specific groups.
- the description mode "...independently” can either mean that in different groups, the specific options expressed in the same match do not affect each other, or it can mean that in the same group, the same symbols are used together. The specific options expressed between them do not affect each other.
- the present disclosure provides small-molecule CD73 inhibitors with novel structures, excellent pharmacokinetic properties, and good efficacy or druggability, which can be used to effectively treat CD73-related diseases and disorders.
- the compound of the present disclosure not only has a good inhibitory effect on recombinant human CD73 enzyme, but also has a strong inhibitory activity on CD73 enzyme bound on the surface of A375 cells, and can also significantly relieve AMP-induced inhibition of CD4 + T proliferation, with good in vitro efficacy.
- the compounds of the present disclosure have higher plasma free fractions and show more excellent druggability than the control compounds.
- the pharmacokinetic test results in mice and dogs show that the disclosed compounds exhibit excellent pharmacokinetic properties, especially Compound 3, Compound 4, Compound 9 and Compound 11. Compared with the positive control, the pharmacokinetics The chemical properties are significantly improved, and the medicinal properties are good.
- the compounds of the present disclosure can significantly inhibit the growth of CT-26 colorectal cancer and E.G7-OVA T-cell lymphoma when used alone or in combination with PD-1/L1 antibody.
- the combination of antibodies can significantly improve the effect of PD-1 antibody in inhibiting the growth of A375 melanoma. Compared with the positive compounds, the synergistic effect is more significant.
- the results of the in vivo efficacy test showed that the compound of the present disclosure in combination with the PD-1 antibody can significantly improve the inhibition of the growth of A375 melanoma by the PD-1 antibody. Compared with the positive compound, the compound 1 has better synergistic efficacy at the same dose.
- FIG. 1 is a graph of tumor volume changes measured at different times after administration according to an embodiment of the present disclosure.
- the structures of the compounds of the present disclosure were 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 for NMR measurement are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS).
- M molar concentration, such as 1M hydrochloric acid means 1mol/L hydrochloric acid solution
- IC 50 the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
- control compound 1 refers to the compound described in Test Example 1.
- control compound 2 refers to the compound described in Test Example 2.
- control compound 3 refers to the compound described in Test Example 3.
- the synthetic route of target compound 1 is as follows:
- the fifth step the synthesis of 3,6-dichloro-4-((1S,2S)-2-(fluoromethyl)cyclopropyl)pyridazine (1H)
- reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product.
- the synthetic route of target compound 2 is as follows:
- the first step Synthesis of trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid ethyl ester (2B)
- Ethyl trans-2-(trifluoromethyl)cyclopropane-1-carboxylate (5 g, 27.5 mmol) was dissolved in tetrahydrofuran (50 mL) and water (25 mL), and lithium hydroxide monohydrate (2.88 g, 68.6 mmol) was added in batches, and the temperature was raised to 80°C for 6 hours.
- the reaction system was spin-dried, water (50 mL) was added, and extracted with ethyl acetate (50 mL ⁇ 2).
- 2C Trans-2-(trifluoromethyl)cyclopropane-1-carboxylic acid
- the first step 5-(6-Chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)- Diketone (3) and 5-(6-Chloro-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H )-dione (4) preparation
- the separation method was (chromatographic column: DAICEL CHIRALPAK IG (250 mm ⁇ 30 mm, 10 ⁇ m); mobile phase: A: CO 2 , B: 0.05% diethylamine in ethanol; gradient: 50% B, time: 60 min; flow rate: 3 mL/min; column temperature: 35°C; column pressure: 100 Bar) to give 5-(6-chloro-5- ((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (3) (360.4 mg, 43.4% yield ) and 5-(6-chloro-5-((1R,2R)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (4) (332.5 mg, 39.9% yield).
- the synthetic route of target compound 3 is as follows:
- reaction system was diluted with water (100 mL), then extracted with ethyl acetate (100 mL ⁇ 2), the organic layers were combined, saturated aqueous sodium carbonate solution (100 mL) was added, and the mixture was stirred for 10 minutes.
- the fourth step the synthesis of 3,6-dichloro-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (3F)
- 3,6-Dichloropyridazine (450 mg, 3.02 mmol) and (1S,2S)-2-(trifluoromethyl)cyclopropanecarboxylic acid (465 mg, 3.02 mmol) were dissolved in water (15 mL) and concentrated Sulfuric acid (0.5 mL), warmed to 70°C under nitrogen protection. Then an aqueous solution of silver nitrate (257 mg, 1.51 mmol, 1.5 mL) was added rapidly, and then an aqueous solution of ammonium persulfate (2.07 g, 9.06 mmol, 5 mL) was slowly added dropwise, and the reaction was continued at 70° C. for 1 hour.
- the pH of the reaction solution was adjusted to about 9 with ammonia water, and then extracted with ethyl acetate (40 mL ⁇ 2). The organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product.
- the fifth step 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine ( 3H) synthesis
- 5-(6-chloro-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridine in Example 3 can be identified by matching Azin-3-yl)pyrimidine-2,4(1H,3H)-dione (compound 3), 5-(6-chloro-5-((1R,2R)-2-(trifluoromethyl)cyclopropane Absolute configuration of yl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione (compound 4).
- the fourth step Synthesis of 1-((1S,2S)-2-(3,6-dichloropyridazin-4-yl)cyclopropyl)ethan-1-one (5F)
- the pH of the reaction solution was adjusted to about 9 with ammonia water, and then extracted with ethyl acetate (50 mL ⁇ 2). The organic layers were combined, washed with saturated brine (25 mL), dried over sodium sulfate, and concentrated to obtain the crude product.
- Step 7 5-(6-Chloro-5-((1S,2S)-2-(2-hydroxypropan-2-yl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H Synthesis of ,3H)-dione (target compound 5)
- the synthetic route of target compound 6 is as follows:
- Step 3 5-(6-Chloro-5-((1S,2S)-2-(1-hydroxyethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H) - Synthesis of diketone (6)
- the synthetic route of target compound 7 is as follows:
- Step 2 5-(6-Methyl-5-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H) - Synthesis of diketone (7)
- 6-(2,4-Dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)pyridazine (150 mg, 441 ⁇ mol) was dissolved in an aqueous hydrochloric acid solution (1 M, 3 mL), and the temperature was raised to 50° C. to react for 12 hours. The reaction system was spin-dried to obtain the crude product, which was then separated by reversed-phase high performance liquid chromatography.
- the synthetic route of target compound 8 is as follows:
- Step 2 Synthesis of (1R,2R)-2-(hydroxymethyl)cyclopropane-1-carboxylate tert-butyl ester (8D)
- the fifth step the synthesis of 3,6-dichloro-4-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazine (8H)
- the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain the crude product.
- Step 7 5-(6-Chloro-5-((1R,2R)-2-(fluoromethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H,3H)-di Synthesis of ketone (target compound 8)
- benzyl bromide (120.4 g, 704.1 mmol) was dissolved in tetrahydrofuran (100 mL), and tetrabutylammonium iodide (18.6 g, 50.3 mmol) was added to the reaction solution, and the reaction was carried out at 25°C for 5 hours.
- reaction system was diluted with water (500 mL), then extracted with ethyl acetate (200 mL ⁇ 2), the organic layers were combined, saturated aqueous sodium carbonate solution (500 mL) was added, and the mixture was stirred for 10 minutes.
- the ninth step synthesis of 3,6-dichloro-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (9K)
- reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3). The organic phases were combined, washed with saturated brine (50 mL), dried over sodium sulfate, and concentrated to obtain the crude product.
- the eleventh step 5-(6-chloro-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2, Synthesis of 4(1H,3H)-diketone (9)
- the synthetic route of target compound 11 is as follows:
- (1S,2S)-2-(hydroxymethyl)cyclopropane-1-carboxylate tert-butyl ester (11A) (20 g, 116 mmol), potassium fluoride (27.0 g, 465 mmol), selective fluorine Reagent (61.6g, 174mmol) and silver trifluoromethanesulfonate (90g, 348mmol) were successively added to the reaction flask protected from light, and 2-fluoropyridine (33.8g, 348mmol) and trifluoromethyltrimethylsilane ( 49.5 g, 348 mmol) in ethyl acetate (600 mL) solution, and the reaction was continued for 18 h after the addition at room temperature.
- the third step Synthesis of 3,6-dichloro-4-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (11E)
- the reaction mixture was diluted with water (200 mL), then extracted with ethyl acetate (150 mL ⁇ 3), the organic layers were combined, dried over sodium sulfate, and concentrated to obtain the crude product.
- the crude product was separated by reversed-phase high performance liquid chromatography, and the separation method was as follows: chromatographic column: Phenomenex Luna C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.01%TFA)-ACN]; B%: 35%-65 %, 10min, to obtain light yellow oil 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-((trifluoromethoxy) Methyl)cyclopropyl)pyridazine (11G) (2 g, 27.7% yield).
- the fifth step 5-(6-chloro-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4( Synthesis of 1H,3H)-diketone (11)
- the synthetic route of target compound 12 is as follows:
- the reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (50 mL ⁇ 3), the organic layers were combined, dried over sodium sulfate, and concentrated to obtain the crude product.
- the crude product was separated by reversed-phase high performance liquid chromatography, and the separation method was as follows: chromatographic column: Phenomenex Luna C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.01% trifluoroacetic acid)-acetonitrile]; B%: 35% -65%, 10 min to give yellow solid 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(methoxymethyl)ring Propyl)pyridazine (12G) (35 mg, 20.2% yield).
- reaction solution was extracted with ethyl acetate (1500 mL ⁇ 2), the organic phases were combined, washed with saturated brine (2000 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the product, which was then washed with petroleum ether ( 500 mL) was beaten to give (R)-2-bromosuccinic acid (13B) (150 g, crude).
- benzyl bromide (17.0 g, 99.4 mmol) was dissolved in tetrahydrofuran (30 mL), and tetrabutylammonium iodide (2.62 g, 7.10 mmol) was added to the reaction solution, and the reaction was carried out at 25° C. for 5 hours.
- sodium hypochlorite solution (0.58 mL, 8%) and sodium chlorite (6.86 g, 75.9 mmol) were dissolved in water (75 mL) and slowly added dropwise to the reaction system at 0°C, followed by stirring at 25°C for 12 hours.
- the reaction system was diluted with water (200 mL), then extracted with ethyl acetate (300 mL ⁇ 2), the organic layers were combined, saturated aqueous sodium carbonate solution (200 mL) was added, and the mixture was stirred for 10 minutes.
- the ninth step synthesis of 3,6-dichloro-4-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazine (13K)
- Step 10 3-Chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2S)-2-(2,2,2-trifluoroethyl)ring Synthesis of propyl)pyridazine (13M)
- reaction mixture was diluted with water (20 mL), then extracted with ethyl acetate (50 mL ⁇ 2). The organic phases were combined, washed with saturated brine (100 mL), dried over sodium sulfate, and concentrated to obtain the crude product.
- the eleventh step 5-(6-chloro-5-((1R,2S)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2, Synthesis of 4(1H,3H)-diketone (13)
- the third step Synthesis of 3,6-dichloro-4-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazine (14E)
- the reaction mixture was diluted with water (100 mL), and then extracted with ethyl acetate (150 mL ⁇ 3). The organic layers were combined, dried over sodium sulfate, and concentrated to obtain the crude product.
- the crude product was separated by reversed-phase high performance liquid chromatography, and the separation method was as follows: chromatographic column: Phenomenex Luna C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water (0.01% trifluoroacetic acid)-acetonitrile]; B%: 35% -65%, 10min to give 3-chloro-6-(2,4-dimethoxypyrimidin-5-yl)-4-((1R,2R)-2-((trifluoromethoxy yl)methyl)cyclopropyl)pyridazine (14G) (60 mg, 3.4% yield).
- the fifth step 5-(6-chloro-5-((1R,2R)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4( Synthesis of 1H,3H)-diketone (14)
- Step 5 5-(6-Chloro-5-((1S,2S)-2-(ethoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4-di Ketone (target compound 16)
- Step 5 5-(6-Chloro-5-((1S,2S)-2-(isopropoxymethyl)cyclopropyl)pyridazin-3-yl)-1H-pyrimidine-2,4- Diketone (Target Compound 17)
- Step 6 3,6-Dichloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (18H)
- Step 7 3-Chloro-4-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl ) Pyridazine (18J)
- Step 8 5-(6-Chloro-5-((1S,2R)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H ,3H)-dione (18)
- Step 6 3,6-Dichloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazine (19H)
- Step 7 3-Chloro-4-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)-6-(2,4-dimethoxypyrimidin-5-yl ) pyridazine (19J)
- the reaction mixture was concentrated under reduced pressure to give crude product.
- Step 8 5-(6-Chloro-5-((1R,2S)-2-(2,2-difluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4(1H ,3H)-dione (19)
- the reaction mixture was diluted with water (100 mL), and then extracted with ethyl acetate (80 mL ⁇ 3). The organic layers were combined, dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was separated by reversed-phase high performance liquid chromatography.
- the separation method was as follows: chromatographic column: Phenomenex Luna C18 150 ⁇ 25 mm ⁇ 10 ⁇ m; mobile phase: [water (0.01% NH 3 .H 2 O)-acetonitrile]; B% : 35%-65%, 10min, to obtain light yellow solid 6-(2,4-dimethoxypyrimidin-5-yl)-4-((1S,2S)-2-(fluoromethyl)cyclopropyl )-3-methylpyridazine (20B) (1.6 g, 85.0% yield).
- Step 2 5-(5-((1S,2S)-2-(fluoromethyl)cyclopropyl)-6-methylpyridazin-3-yl)pyrimidine-2,4(1H,3H)- Diketone (Target Compound 20)
- the synthetic route of target compound 21 is as follows:
- the reaction mixture was diluted with water (50 mL), then extracted with ethyl acetate (50 mL ⁇ 3), the organic layers were combined, dried over sodium sulfate, and concentrated to obtain the crude product.
- the crude product was separated by reversed-phase high performance liquid chromatography.
- the separation method was: column: Phenomenex Luna C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: [water(0.01%NH 3 .H 2 O)-ACN]; B%: 35%-65%, 10min to give light yellow oil 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2S)-2-((tri Fluoromethoxy)methyl)cyclopropyl)pyridazine (21B) (0.8 g, 84.3% yield).
- Step 2 5-(6-Methyl-5-((1S,2S)-2-((trifluoromethoxy)methyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2,4 Synthesis of (1H,3H)-dione (target compound 21)
- the first step 6-(2,4-dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2R)-2-(2,2,2-trifluoroethyl) Cyclopropyl)pyridazine (22B)
- the second step 5-(6-methyl-5-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl)pyridazin-3-yl)pyrimidine-2, 4(1H,3H)-dione (target compound 22)
- 6-(2,4-Dimethoxypyrimidin-5-yl)-3-methyl-4-((1S,2R)-2-(2,2,2-trifluoroethyl)cyclopropyl ) pyridazine 400 mg, 853 umol
- tetrahydrofuran 2.00 mL
- hydrochloric acid 1 M, 10.0 mL
- Test Example 1 In vitro inhibitory activity of the compound on recombinant human CD73 enzyme
- test compound IC50 (nM) Control compound 1 12.47 Control compound 2 16.84 Control compound 3 27.03 1 4.59 2 23.21 3 11.62 4 58.42
- results of the in vitro enzyme test show that the compounds of the present disclosure have a good inhibitory effect on CD73 enzyme. Compared with the control compounds, some compounds show more excellent inhibitory effect on CD73 enzyme.
- Test Example 2 Inhibitory activity of compound on CD73 enzyme bound to human melanoma A375 cell surface
- A375 (ATCC; CRL-1619) cells were cultured in DMEM medium (Gibco; 11995-040) containing 10% FBS (Gibco; 10099-141C) and 1% P/S (Thermo; 10378016). When the cells are in good condition, trypsinize the cells, remove the supernatant by centrifugation, collect the cells, and then wash them with serum-free DMEM medium; resuspend and count in serum-free DMEM medium, according to 1 ⁇ 10 4 /well, 60 ⁇ L/ The wells were connected to a round-bottom 96-well plate, and a positive control (A375+AMP) and a negative control (only AMP) were set at the same time;
- the compound was diluted into a 5 ⁇ stock solution with a suitable concentration gradient with serum-free DMEM medium, added to the above-mentioned 96-well plate cells according to 20 ⁇ L/well, placed in an incubator, and pre-incubated for 30 min; AMP was prepared into a 5 ⁇ stock solution, and then the prepared AMP was added to the cells according to 20 ⁇ L/well, the final concentration was 200 ⁇ M, and incubated at 37 °C for 16 h; after the incubation, the 96-well plate was centrifuged at 1500 rpm for 3 min, and 50 ⁇ L/well of the supernatant was aspirated.
- the CD73 inhibition rate of different concentrations of compounds on A375 binding was calculated according to the following formula, with the compound concentration as the X-axis and the inhibition rate as the Y-axis, and the IC50 value of the compound's inhibition of A375 binding to CD73 was calculated by Prism software:
- test compound IC50 (nM) Control compound 1 247 Control compound 2 67.3 Control compound 3 162 1 30.7 3 26.8 4 134 7 54.9 9 5.56 11 39.8
- the experimental results show that the compounds of the present disclosure have strong inhibitory activity on the CD73 enzyme bound to the surface of A375 cells, and the inhibitory activity is significantly better than that of the positive compounds.
- HTDialysis HTD 96b
- HTDialysis HTD 96b
- DMSO dimethyl sulfoxide
- 380 ⁇ L of plasma was added to each well, and then 20 ⁇ L/well of working solution was added to the plasma and mixed well.
- the final compound concentration was 1 ⁇ M, and each well contained 0.2% DMSO.
- the 96-well plate was vortexed at 600 rpm for 10 minutes, centrifuged at 5594g for 15 minutes (Thermo Multifuge ⁇ 3R), and 50 ⁇ L of supernatant was transferred to a new 96-well plate , and the samples were mixed with 50 ⁇ L of ultrapure water for LC-MS/MS analysis.
- the results of the plasma protein binding rate test show that the compounds of the present disclosure have higher plasma free fractions, and show better druggability than the control compounds.
- Test Example 4 Activity of compound to relieve AMP-induced inhibition of human CD4 + T cell proliferation
- CD4 + T Primary Human CD4 + T was cultured in RPMI1640 (Shanghai Yuanpei Bio; L210KJ) medium containing 10% FBS (Gibco; 10099-141C) and 1% P/S (Thermo; 10378016). On the first day of the experiment, CD4 + T (Auscelles Biotechnology (Shanghai) Co., Ltd.; PB009-2F-C) cells were recovered, 3 ⁇ 10 4 /well, 50 ⁇ L/well, and plated in duplicate.
- a positive control group Human CD4 + T+IL-2+CD3/CD28 beads
- a negative control group Human CD4 + T+IL-2+CD3/CD28 beads+AMP
- dilute 4 ⁇ AMP Sigma; A1752-5G
- add AMP again, and add 20 ⁇ L/well to the above plate to make the final concentration 0.3 mM
- the cell proliferation was measured with CCK8 kit (DojinDO; CK04).
- the inhibition rate of AMP-induced CD4 + T cell proliferation inhibition under different compound concentrations was calculated according to the following formula, with the compound concentration as the X axis and the inhibition rate as the Y axis, and the EC of the compound to relieve the AMP-induced CD4 + T cell proliferation inhibition was calculated by the software Prism 50 value:
- Control compound 2 93.7 Control compound 3 341 1 71.9 3 111 4 1070 9 32.6 11 169
- the experimental results show that the compounds of the present disclosure can significantly relieve the AMP-induced inhibition of CD4 + T proliferation, and the activity is better than that of the positive compounds.
- mice Pharmacokinetic test in mice, using male ICR mice, 20-25 g, fasted overnight. Three mice were taken and administered by oral gavage (10 mg/kg). Blood was collected before administration, and at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration; another 3 mice were taken and administered intravenously (3 mg/kg) before administration, and Blood was collected at 15, 30 minutes and 1, 2, 4, 8, and 24 hours after administration. Blood samples were centrifuged at 6800g at 2-8°C for 6 minutes, and plasma was collected and stored at -80°C.
- mice pharmacokinetic test showed that the compounds of the present disclosure exhibited excellent pharmacokinetic properties, especially Compound 3, Compound 4, Compound 9 and Compound 11, and the pharmacokinetic properties were significantly improved compared with the positive control. .
- the results of the canine pharmacokinetic test show that the compounds of the present disclosure have comparable or better exposures than the control compounds, especially the exposures of 4 and compound 11 are much higher than those of the control compounds, showing excellent pharmacokinetic properties, Good medicinal properties.
- Test Example 6 In vivo efficacy test of A375 melanoma
- A375 cells in logarithmic growth phase were collected, incubated with Mitomycin C for 2 h, and then washed three times with PBS. After PBMC and A375 were co-cultured for 5 days, PBMC and freshly digested A375 cells were collected, and 5 ⁇ 10 5 PBMC and 4 ⁇ 10 6 A375 cells were inoculated into NCG mice according to 0.2 ml/mouse (containing 50% Matrigel) Right subcutaneous. After inoculation, mice were randomly divided into model group and administration group according to their body weight. The tumor size and animal body weight were measured and recorded before administration and during administration. effect.
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Abstract
Description
测试化合物 | IC 50(nM) |
对照化合物1 | 12.47 |
对照化合物2 | 16.84 |
对照化合物3 | 27.03 |
1 | 4.59 |
2 | 23.21 |
3 | 11.62 |
4 | 58.42 |
5 | 11.59 |
6 | 24.5 |
7 | 32.13 |
8 | 16.53 |
9 | 8.17 |
11 | 12.22 |
12 | 15.44 |
13 | 6871 |
14 | 3682 |
15 | 123.4 |
16 | 172.8 |
17 | 164.2 |
19 | 1248 |
20 | 9.55 |
测试化合物 | IC 50(nM) |
对照化合物1 | 247 |
对照化合物2 | 67.3 |
对照化合物3 | 162 |
1 | 30.7 |
3 | 26.8 |
4 | 134 |
7 | 54.9 |
9 | 5.56 |
11 | 39.8 |
18 | 17.6 |
测试化合物 | EC 50(nM) |
对照化合物2 | 93.7 |
对照化合物3 | 341 |
1 | 71.9 |
3 | 111 |
4 | 1070 |
9 | 32.6 |
11 | 169 |
Claims (24)
- 式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:其中,R 1选自 其中R a独立地选自下列取代基:氢、C 1-C 6烷基、C 3-C 6环烷基、5-8元芳基、5-8元杂芳基、4-8元杂环烷基、或、被1-5个相同或不同的卤素取代的C 1-C 6烷基;所述的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;R 2选自氢、卤素、羟基、氰基、氨基、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 1-C 6烷基-O-、未取代或被R b取代的C 1-C 6烷基-S-、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、未取代或被R b取代的4-8元杂环烯基、或、未取代或被R b取代的C 2-C 6烯基;被R b取代的C 1-C 6烷基中、被R b取代的C 1-C 6烷基-O-中、被R b取代的C 1-C 6烷基-S-中、被R b取代的5-8元芳基中、被R b取代的5-8元杂芳基中、被R b取代的4-8元杂环烷基中、被R b取代的4-8元杂环烯基中、或、被R b取代的C 2-C 6烯基中,所述的R b取代为一个或多个取代,所述的R b各自独立地选自下列取代基:卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基-O-;当取代基为多个时,所述的取代基相同或不同;所述的未取代或被R b取代的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个。
- 式I所示化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药:其中,R 1选自 其中R a独立地选自下列取代基:氢、C 1-C 6烷基、C 3-C 6环烷基、5-8元芳基、5-8元杂芳基、4-8元杂环烷基、或、被1-5个相同或不同的卤素取代的C 1-C 6烷基;所述的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原 子数为1-3个;所述的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;R 2选自氢、卤素、羟基、氰基、氨基、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 1-C 6烷基-O-、未取代或被R b取代的C 1-C 6烷基-S-、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、未取代或被R b取代的4-8元杂环烯基、或、未取代或被R b取代的C 2-C 6烯基;被R b取代的C 1-C 6烷基中、被R b取代的C 1-C 6烷基-O-中、被R b取代的C 1-C 6烷基-S-中、被R b取代的5-8元芳基中、被R b取代的5-8元杂芳基中、被R b取代的4-8元杂环烷基中、被R b取代的4-8元杂环烯基中、或、被R b取代的C 2-C 6烯基中,所述的R b取代为一个或多个取代,所述的R b各自独立地选自下列取代基:卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基-O-;当取代基为多个时,所述的取代基相同或不同;所述的未取代或被R b取代的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个。
- 根据权利要求1或权利要求2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,当R a为C 1-C 6烷基时,所述C 1-C 6烷基为C 1-C 4烷基,较佳地为甲基、乙基、正丙基、异丙基、正丁基或异丁基;和/或,当R a为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述C 1-C 6烷基为C 1-C 4烷基,较佳地为甲基、乙基、正丙基、异丙基、正丁基或异丁基;和/或,当R a为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素为F、Cl、Br或I,较佳地为F或Cl;和/或,当R a为被1-5个相同或不同的卤素取代的C 1-C 6烷基时,所述卤素取代的数量为1、2或3个,较佳地为3个;和/或,当R a为C 3-C 6环烷基时,所述的C 3-C 6环烷基独立地为环丙基、环丁基、环戊基或环己基,较佳地为环丙基;和/或,当R a为5-8元芳基时,所述的5-8元芳基独立地为苯基或萘基,较佳地为苯基;和/或,当R a为5-8元杂芳基时,所述的5-8元杂芳基独立地为吡咯、吡唑、三氮唑、呋喃、噁唑、噻吩、噻唑、吡啶、吡嗪或嘧啶,较佳地为吡唑、呋喃、噻吩或吡啶;和/或,当R a为4-8元杂环烷基时,所述的4-8元杂环烷基独立地为氮杂环丁烷、氧杂环丁烷、四氢吡咯烷基、四氢呋喃基、六氢吡喃或四氢-2H-硫吡喃1,1-二氧化物,较佳地为氮杂环丁烷或氧杂环丁烷;和/或,当R a为4-8元杂环烯基时,所述的4-8元杂环烯基独立地为二氢吡啶基、四氢吡啶基、四氢嘧啶基、吡咯啉基、咪唑啉基、吡唑啉基、二氢咪唑基、二氢吡唑基、二氢噁唑基、二氢噁二唑基、二氢噻唑基、二氢异噻唑基、二氢噻吩基、二氢吡咯基、3,4-二氢-2H-吡喃基、二氢呋喃基、二氢吡嗪基、二氢嘧啶基或氟代二氢呋喃基,较佳地为1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、3,4-二氢-2H-吡喃基或二氢呋喃基。
- 根据权利要求1或权利要求2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R 2为氰基;和/或,当R 2为卤素时,所述卤素为F、Cl、Br或者I,较佳地为Cl;和/或,当R 2为未取代或被R b取代的C 1-C 6烷基时,所述C 1-C 6烷基为C 1-C 4烷基,较佳地为甲基、乙基、正丙基、异丙基、正丁基或异丁基;和/或,当R 2为未取代或被R b取代的C 1-C 6烷基-O-时,所述C 1-C 6烷基-O-为C 1-C 4烷基-O-,较佳地为甲基-O-;和/或,当R 2为未取代或被R b取代的C 1-C 6烷基-S-时,所述C 1-C 6烷基-S-为C 1-C 4烷基-S-,较佳地为甲基-S-;和/或,当R 2为未取代或被R b取代的5-8元芳基时,所述的5-8元芳基独立地为苯基或萘基,较佳地为苯基;和/或,当R 2为未取代或被R b取代的5-8元杂芳基时,所述的5-8元杂芳基独立地为吡咯,吡唑、三氮唑、呋喃、噁唑、噻吩、噻唑、吡啶、吡嗪或嘧啶,较佳地为吡唑、呋喃、噻吩或吡啶;和/或,当R 2为未取代或被R b取代的4-8元杂环烷基时,所述的4-8元杂环烷基独立地为氮杂环丁烷、氧杂环丁烷、四氢吡咯烷基、四氢呋喃基、六氢吡喃或四氢-2H-硫吡喃1,1-二氧化物,较佳地为氮杂环丁烷或氧杂环丁烷;和/或,当R 2为未取代或被R b取代的4-8元杂环烯基时,所述的4-8元杂环烯基独立地为二氢吡啶基、四氢吡啶基、四氢嘧啶基、吡咯啉基、咪唑啉基、吡唑啉基、二氢咪唑基、二氢吡唑基、二氢噁唑基、二氢噁二唑基、二氢噻唑基、二氢异噻唑基、二氢噻吩基、二氢吡咯基、3,4-二氢-2H-吡喃基、二氢呋喃基、二氢吡嗪基、二氢嘧啶基或氟代二氢呋喃基,较佳地为1,2,3,4-四氢吡啶基、1,2-二氢吡啶基、1,4-二氢吡啶基、1,2,3,6-四氢吡啶基、3,4-二氢-2H-吡喃基或二氢呋喃基;和/或,当R 2为未取代或被R b取代的C 2-C 6烯基时,所述C 2-C 6烯基为乙烯基、1-丙烯基、2-丙烯基、烯丙基,较佳地为乙烯基或烯丙基。
- 根据权利要求6所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R a选自未取代或被1-5个相同或不同的卤素取代的C 1-C 4烷基,R 2选自氢、卤素、氰基、未取代或被R b取代的C 1-C 4烷基,所述R b各自独立地为卤素。
- 根据权利要求8所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,R 2选自氢、卤素、氰基、未取代或被R b取代的C 1-C 4烷基,所述R b各自独立地为卤素。
- 根据权利要求1或权利要求2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,所述化合物结构式为R 2选自氢、卤素、羟基、氰基、氨基、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 1-C 6烷基-O-、未取代或被R b取代的C 1-C 6烷基-S-、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、未取代或被R b取代的4-8元杂环烯基、或、未取代或被R b取代的C 2-C 6烯基;被R b取代的C 1-C 6烷基中、被R b取代的C 1-C 6烷基-O-中、被R b取代的C 1-C 6烷基-S-中、被R b取代的5-8元芳基中、被R b取代的5-8元杂芳基中、被R b取代的4-8元杂环烷基中、被R b取代的4-8元杂环烯基中、或、被R b取代的C 2-C 6烯基中,所述的R b取代为一个或多个取代,所述的R b各自独立地选自下列取代基:卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基-O-;当取代基为多个时,所述的取代基相同或不同;所述的未取代或被R b取代的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个。
- 根据权利要求1或权利要求2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,所述化合物结构式为R 2选自氢、卤素、羟基、氰基、氨基、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 1-C 6烷基-O-、未取代或被R b取代的C 1-C 6烷基-S-、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、未取代或被R b取代的4-8元杂环烯基、或、未取代或被R b取代的C 2-C 6烯基;被R b取代的C 1-C 6烷基中、被R b取代的C 1-C 6烷基-O-中、被R b取代的C 1-C 6烷基-S-中、被R b取代的5-8元芳基中、被R b取代的5-8元杂芳基中、被R b取代的4-8元杂环烷基中、被R b取代的4-8元杂环烯基中、或、被R b取代的C 2-C 6烯基中,所述的R b取代为一个或多个取代,所述的R b各自独立地选自下列取代基:卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基-O-;当取代基为多个时,所述的取代基相同或不同;所述的未取代或被R b取代的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个。
- 根据权利要求1或权利要求2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,所述化合物结构式为R 2选自氢、卤素、羟基、氰基、氨基、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 1-C 6烷基-O-、未取代或被R b取代的C 1-C 6烷基-S-、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、未取代或被R b取代的4-8元杂环烯基、或、未取代或被R b取代的C 2-C 6烯基;被R b取代的C 1-C 6烷基中、被R b取代的C 1-C 6烷基-O-中、被R b取代的C 1-C 6烷基-S-中、被R b取代的5-8元芳基中、被R b取代的5-8元杂芳基中、被R b取代的4-8元杂环烷基中、被R b取代的4-8元杂环烯基中、或、被R b取代的C 2-C 6烯基中,所述的R b取代为一个或多个取代,所述的R b各自独立地选自下列取代基:卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基-O-;当取代基为多个时,所述的取代基相同或不同;所述的未取代或被R b取代的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个。
- 根据权利要求1或权利要求2所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其特征在于,所述化合物结构式为R 2选自氢、卤素、羟基、氰基、氨基、未取代或被R b取代的C 1-C 6烷基、未取代或被R b取代的C 1-C 6烷基-O-、未取代或被R b取代的C 1-C 6烷基-S-、未取代或被R b取代的5-8元芳基、未取代或被R b取代的5-8元杂芳基、未取代或被R b取代的4-8元杂环烷基、未取代或被R b取代的4-8元杂环烯基、或、未取代或被R b取代的C 2-C 6烯基;被R b取代的C 1-C 6烷基中、被R b取代的C 1-C 6烷基-O-中、被R b取代的C 1-C 6烷基-S-中、被R b取代的5-8元芳基中、被R b取代的5-8元杂芳基中、被R b取代的4-8元杂环烷基中、被R b取代的4-8元杂环烯基中、或、被R b取代的C 2-C 6烯基中,所述的R b取代为一个或多个取代,所述的R b各自独立地选自下列取代基:卤素、羟基、氰基、氨基、C 1-C 6烷基、C 3-C 6环烷基、C 1-C 6烷基-O-;当取代基为多个时,所述的取代基相同或不同;所述的未取代或被R b取代的5-8元杂芳基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烷基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个;所述的未取代或被R b取代的4-8元杂环烯基中,杂原子选自N、S、O和P中的一种或多种,杂原子数为1-3个。
- 一种药物组合物,其特征在于,其包含如权利要求1-16中任一项所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,和药学上可接受的赋形剂。
- 根据权利要求1-16中任一项所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药与PD-1/PD-L1/CTLA-4抗体或者PD-1/PD-L1/CTLA-4抑制剂联用在制备用于治疗与CD73相关疾病药物中的用途。
- 根据权利要求1-16中任一项所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药、或如权利要求17所述的药物组合物在制备用于治疗与CD73相关疾病药物中的用途。
- 根据权利要求18或19所述的用途,其特征在于,所述CD73相关疾病为癌症。
- 根据权利要求20所述的用途,其特征在于,所述癌症为膀胱癌、乳腺癌、胆管癌、直肠癌、结肠癌、胃癌、胆囊癌、神经胶母细胞瘤、头颈癌、肝癌、肺癌、淋巴瘤、神经管母细胞瘤、黑色素瘤、卵巢癌、胰腺癌、前列腺癌或者肾癌。
- 一种治疗与CD73相关疾病的方法,其特征在于,所述方法包括向有需要的受试者施用权利要求1-16中任一项所述的如式I所示的化合物、其互变异构体、立体异构体、水合物、溶剂化物、药学上可接受的盐或前药和/或权利要求17所述的药物组合物。
- 根据权利要求22所述的方法,其特征在于,所述CD73相关疾病为癌症。
- 根据权利要求23所述的方法,其特征在于,所述癌症为膀胱癌、乳腺癌、胆管癌、直肠癌、结肠癌、胃癌、胆囊癌、神经胶母细胞瘤、头颈癌、肝癌、肺癌、淋巴瘤、神经管母细胞瘤、黑色素瘤、卵巢癌、胰腺癌、前列腺癌或者肾癌。
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