CN111868058B - FGFR inhibitor, preparation method and pharmaceutical application thereof - Google Patents

FGFR inhibitor, preparation method and pharmaceutical application thereof Download PDF

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CN111868058B
CN111868058B CN201980019954.8A CN201980019954A CN111868058B CN 111868058 B CN111868058 B CN 111868058B CN 201980019954 A CN201980019954 A CN 201980019954A CN 111868058 B CN111868058 B CN 111868058B
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cancer
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CN111868058A (en
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邓海兵
应海燕
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Provided are FGFR inhibitors having the structure of formula (I), a preparation method thereof and pharmaceutical applications thereof, wherein each substituent is defined in the specification and the claims. The series of compounds can be widely applied to preparing medicines for treating tumors, cancers, myeloproliferative diseases, bone or cartilage cell disorders and hypophosphatemia, and are expected to be developed into new generation FGFR inhibitor medicines.

Description

FGFR inhibitor, preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to an FGFR inhibitor, a preparation method and application thereof in pharmacy.
Technical Field
Fibroblast Growth Factor Receptor (FGFR) is a tyrosine kinase receptor that binds to fibroblast growth factor ligands. There are 4 FGFR receptors currently found to bind ligands and are closely related in a variety of physiological processes including tissue differentiation, angiogenesis, wound healing, and metabolic regulation. When the ligand binds, the receptor dimerizes and phosphorylates, stimulating activation of protein kinase activity, and recruiting many intracellular protein binding. These protein interactions can aid in the activation of a range of intracellular signaling pathways, including Ras-MAPK, AKT-PI3K, and phosphatase C, signaling pathways important for cell growth, proliferation, and survival.
Aberrant activation of this signaling pathway, such as overexpression of FGF ligands or activation mutations through FGFR, can lead to tumor growth, progression and resistance to traditional cancer therapies. In human tumors, changes in genes that can bring about ligand-independent receptor activation, including gene amplification, chromosomal translocation, and body mutation, etc., have been described. While DNA sequencing of thousands of tumor samples in large batches has revealed that a component of the FGFR signaling pathway is a gene with high frequency mutations in human cancers. Somatic mutations such as FGFR1 have been found in gliomas and lung cancers, FGFR2 mutations are more common in stomach and endometrial cancers, FGFR3 mutations are found in bladder cancers as well as multiple myeloma, and FGFG4 mutations are found in primary rhabdomyosarcoma.
FGF/FGFR-associated tumor types include, but are not limited to, cancers (e.g., bladder, breast, cervical, colon, endometrial, gastric, head and neck, kidney, liver, lung, ovarian, prostate); hematological malignancies (such as multiple myeloma, chronic lymphomas, adult T-cell leukemias, acute myelogenous leukemias, non-hodgkin's lymphomas, myeloproliferative neoplasms and fahrenheit macroglobulinemia) and other neoplasms (such as glioblastomas, melanomas and rhabdomyosarcomas). In addition to its role in tumors, FGFR activation has also been found to be associated with skeletal and chondrocyte lesions, such as hypoplasia and craniosynostosis.
Although some FGFR inhibitors have entered clinical and preclinical research and development, they are often not selective enough and have inhibitory effects on other kinases such as c-kit and PDGFRa, thus bringing about a concern that a certain therapeutic window is not large enough. Therefore, the development of inhibitors targeting FGFR selectivity would be of great interest in the clinical treatment of diseases with increased FGF or FGFR activity.
Disclosure of Invention
The object of the present invention is to provide an FGFR inhibitor.
The present invention provides in a first aspect a compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000293895180000031
wherein X is selected from C (R 7 ) Or N;
R 1 selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl or 5-)10 membered heteroaryl, said groups optionally being further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2);
R 2 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2);
R 3 、R 4 each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl or 5-to 10-membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2);
R 5 、R 6 each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 The above groups are optionally furtherIs/are selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2);
R 7 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2);
each R 8 Selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 11 R 12 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, carbonyl, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 11 R 12 Is substituted by a substituent of (2);
each R 9 Selected from hydrogen, deuterium, C 1-10 Alkyl, C 2-10 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl or 5-to 10-membered heteroaryl, optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, carbonyl, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 11 R 12 Is substituted by a substituent of (2);
each R 10 Selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl, C 1-10 Alkoxy, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered hetero epoxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 11 R 12 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy or-NR 11 R 12 Is substituted by a substituent of (2);
each R 11 、R 12 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkoxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, monoalkylamino, dialkylamino or C 1-10 Alkanoyl, said radicals optionally being further substituted with one or more radicals selected from deuterium, halogen, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 Substituted alkanoyl;
alternatively, R 11 、R 12 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclic group or a 4-10 membered heteroaryl group, said groups optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 1-10 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-10 membered heterocyclyl, 3-10 membered heterocyclyloxy, C 5-10 Aryl, C 5-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, monoalkylamino, dialkylamino or C 1-10 Substituted alkanoyl;
each r is independently 0, 1 or 2.
Preferably, the compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof, wherein X is selected from C (R 7 ) Or N; r is R 7 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 Substituent of (2)Substituted; r is R 8 、R 9 、R 10 、R 11 、R 12 R is as described above.
As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof, X is selected from C (R 7 ) Or N; r is R 7 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, allyl, ethynyl, C 3-6 Cycloalkyl, oxetanyl, azetidinyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, methoxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetamido; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
As a still further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from C (R 7 ) Or N; r is R 7 Selected from hydrogen, deuterium, fluorine, chlorine, cyano, nitro, azido, methyl, ethyl, isopropyl, allyl, ethynyl, cyclopropyl, cyclopropylmethyl, oxetanyl, azetidinyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, sulfamoyl, methoxy, ethoxy, isopropoxy, methoxyethyl, ethoxyethyl, hydroxymethyl, hydroxyethyl, cyanomethyl, trifluoromethyl, tridentate methyl, difluoromethyl, dideuteromethyl, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxymethyl, amino, dimethylamino, aminomethyl, aminocarbonyl, dimethylaminocarbonyl or acetamido.
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 5 、R 6 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2); r is R 8 、R 9 、R 10 、R 11 、R 12 R is as described above.
As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 5 、R 6 Each independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, nitro, azido, C 1-4 Alkyl, allyl, ethynyl, C 3-6 Cycloalkyl, oxetanyl, azetidinyl, phenyl, diazole, triazole, methanesulfonyl, isopropylsulfonyl, aminosulfonyl, hydroxy, methyOxy, ethoxy, isopropoxy, methoxycarbonyl, ethoxycarbonyl, acetyl, acetoxy, acetoxymethyl, amino, dimethylamino, aminocarbonyl, dimethylaminocarbonyl or acetamido; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 3 、R 4 Each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, nitro, azido, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroepoxy, C 5-8 Aryl, C 5-8 Aryloxy, 5-8 membered heteroaryl or 5-8 membered heteroaryloxy, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2); r is R 8 、R 9 、R 10 、R 11 、R 12 R is as described above.
As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 3 、R 4 Each independently selected from hydrogen,Deuterium, halogen, hydroxy, cyano, nitro, azido, C 1-4 Alkyl, C 1-4 Alkoxy, allyl, C 3-6 Cycloalkyl, C 3-6 A cycloalkoxy group, a 3-6 membered heterocyclic oxy group, a phenyl group, a diazole or a triazole; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, phenyl, methoxy, ethoxy, hydroxy or amino.
As a further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 2 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 Optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2); r is R 8 、R 9 、R 10 、R 11 、R 12 R is as described above.
As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 2 Selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C 0-4 -O-R 9 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 or-C 0-4 -NR 11 R 12 Substituted by one or more substituents selected from deuterium, halogen, optionally further substituted by one or more substituents selected from deuterium, halogen、C 1-4 Alkyl, trifluoromethyl, difluoromethyl, tridentate, dideutomethyl, cyclopropyl, =o, hydroxy, methoxy, ethoxy, isopropoxy or a carboxyl group; r is R 8 、R 9 、R 10 、R 11 、R 12 R is as described above.
As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (II):
Figure GPA0000293895180000081
wherein R is 2 Selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -C 0-4 -O-R 9 or-C 0-4 -NR 11 R 12 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -S (O) r R 8 、-O-R 9 、-C(O)OR 9 or-NR 11 R 12 Substituted by one or more substituents selected from deuterium, halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, =o, hydroxy, methoxy, ethoxy, isopropoxy, or a carboxyl group;
R 3 、R 4 each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, and C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 A cycloalkoxy group, a 3-6 membered heterocyclic group or a 3-6 membered heterocyclic oxy group; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;
R 5 、R 6 each independently of the otherIs selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, hydroxy, methoxy, ethoxy or isopropoxy; the above groups are optionally further substituted with one or more substituents selected from deuterium, fluorine, chlorine, cyano, methyl, ethyl, cyclopropyl, methoxy, ethoxy, hydroxy or amino;
R 1 、R 8 、R 9 、R 11 、R 12 r is as defined for the compounds of formula (I).
As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl or 5-8 membered heteroaryl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 Optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, halo substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -S(O) r R 8 、-C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 、-C 0-4 -C(O)R 10 、-C 0-4 -O-C(O)R 10 、-C 0-4 -NR 11 R 12 、-C 0-4 -C(＝NR 11 )R 10 、-C 0-4 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-4 -C(O)NR 11 R 12 or-C 0-4 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2); r is R 8 、R 9 、R 10 、R 11 、R 12 R is as described above.
As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl or 5-8 membered heteroaryl, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -C 0-4 -O-R 9 、-C 0-4 -C(O)OR 9 or-C 0-4 -NR 11 R 12 Substituted by one or more substituents selected from deuterium, halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, =o, hydroxy, methoxy, ethoxy, isopropoxy, or a carboxyl group; r is R 9 、R 10 、R 11 、R 12 As previously described.
As a further preferred embodiment, the compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, has the structure of formula (III):
Figure GPA0000293895180000091
wherein R is 1 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, halogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-8 membered heteroaryl, =o, -O-R 9 、-C(O)OR 9 or-NR 11 R 12 Substituted by one or more substituents selected from deuterium, halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, =o, hydroxy, methoxy, ethoxy, isopropoxy, or a carboxyl group;
R 2 selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -O-R 9 or-NR 11 R 12 The above groups are optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, =o, -O-R 9 、-C(O)OR 9 or-NR 11 R 12 Substituted by one or more substituents selected from deuterium, halogen, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, =o, hydroxy, methoxy, ethoxy, isopropoxy, or a carboxyl group;
R 9 、R 11 、R 12 as defined for the compounds of formula (I).
As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, said groups optionally being further substituted by one or more groups selected from deuterium, fluoro, chloro, methyl, ethyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, =o, hydroxy, methoxy, ethoxy, carboxy, amino, dimethylamino or diethylamino optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideuteromethyl, tridecylmethyl, cyclopropyl, =Substituents for O, hydroxy, methoxy, ethoxy, isopropoxy or carboxyl;
R 2 selected from 3-8 membered heterocyclyl, 5-6 membered heteroaryl or-NR 11 R 12 The above groups are optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, =o, hydroxy, methoxy, ethoxy, isopropoxy, carboxy, amino, dimethylamino or diethylamino optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideutomethyl, trideemethyl, cyclopropyl, =o, hydroxy, methoxy, ethoxy, isopropoxy or carboxy;
R 11 、R 12 Each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 5-6 Aryl or 5-6 membered heteroaryl, optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, hydroxy, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroepoxy, C 5-6 Aryl, C 5-6 Aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino, diethylamino or C 1-4 Substituted alkanoyl;
alternatively, R 11 、R 12 Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, which is optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, hydroxy, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heteroepoxy, C 5-6 Aryl, C 5-6 Aryloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy, amino, dimethylamino, diethylamino or C 1-4 The substituent of the alkanoyl group is substituted.
As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof 1 Selected from hydrogen, deuterium, C 1-4 Alkyl or 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, cyclopropyl, 3-6 membered heterocyclyl, phenyl, amino, dimethylamino or diethylamino, optionally further substituted with one or more substituents selected from deuterium, methyl, ethyl, difluoromethyl, trifluoromethyl, dideutomethyl, trideemethyl or cyclopropyl;
R 2 selected from diazolyl, triazolyl or-NR 11 R 12 The above groups are optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, =o, hydroxy, methoxy, ethoxy, isopropoxy or carboxy optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, methyl, ethyl, difluoromethyl, trifluoromethyl, dideutomethyl, trideemethyl or cyclopropyl;
R 11 、R 12 each independently selected from hydrogen, deuterium, C 1-4 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, hydroxy, C 1-4 Alkyl, difluoromethyl, trifluoromethyl, dideugenol, tridecylmethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, 3-8 membered heterocyclyl, phenyl, diazole, triazole, amino, dimethylamino, diethylamino or C 1-4 Substituted alkanoyl;
R 11 、R 12 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, which is optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, hydroxy, C 1-4 Alkyl, difluoromethyl, trifluoromethyl, dideutomethyl, tridecylmethyl, methoxy, ethoxy, isopropoxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered hetero-epoxyPhenyl, diazolyl, triazolyl, amino, dimethylamino, diethylamino or C 1-4 Substituted alkanoyl;
the heterocyclic groups each independently optionally contain 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.
As a most preferred embodiment, the compound of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, include, but are not limited to, the following:
Figure GPA0000293895180000101
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Figure GPA0000293895180000111
in a second aspect, the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof as described hereinbefore, comprising the steps of:
Figure GPA0000293895180000121
therein, X, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 As defined for the compounds of formula (I).
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as hereinbefore described, a stereoisomer, prodrug or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
In a fourth aspect, the present invention provides the use of a compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof as hereinbefore described in the manufacture of a medicament for the treatment of a tumour or cancer.
Preferably, the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myelogenous leukemia, hodgkin's lymphoma or non-hodgkin's lymphoma, fahrenheit macroglobulinemia, hairy-like lymphoma, cellular lymphoma, burkitt's lymphoma, glioblastoma, melanoma, or rhabdomyosarcoma.
In a fifth aspect, the present invention provides the use of a compound of formula (I), a stereoisomer, a prodrug thereof or a pharmaceutically acceptable salt thereof as hereinbefore described in the manufacture of a medicament for the treatment of a myeloproliferative disorder, a bone or chondrocyte disorder, and hypophosphatemia.
Preferably, the myeloproliferative disorder is selected from the group consisting of polycythemia, essential thrombocythemia, and essential myelofibrosis; the bone or cartilage cell disorder is selected from dysplasia, chondrodysplasia, dwarfism, lethal Teratosis (TD), aperture's syndrome, crouzon's syndrome, jackson-Weiss syndrome, beare-Stevenson skin return syndrome, pfeiffer syndrome or craniofacial atrophy syndrome; the hypophosphatemia is selected from X-linked low phosphorus rickets, autosomal recessive low phosphorus rickets, autosomal dominant low phosphorus rickets or tumor-induced ovarian malacia.
In a sixth aspect, the present invention provides a compound of formula (I), a stereoisomer, a prodrug thereof, or a pharmaceutically acceptable salt thereof, as described previously, for use as an FGFR inhibitor.
Detailed Description
The inventor of the application has studied extensively and intensively, and developed an FGFR inhibitor with a structure shown in a formula (I), a preparation method and pharmaceutical application thereof for the first time, wherein each substituent is defined in the specification and the claims. The serial compounds of the invention can be widely applied to the preparation of medicaments for treating tumors, cancers, myeloproliferative diseases, bone or cartilage cell disorders and hypophosphatemia, and are expected to be developed into new generation FGFR inhibitor medicaments. On this basis, the present invention has been completed.
Detailed description: unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a straight or branched saturated aliphatic hydrocarbon group, e.g., "C 1-10 Alkyl "refers to straight chain alkyl groups and branched alkyl groups comprising from 1 to 10 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like.
The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, e.g., "C 3-10 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 10 carbon atoms, and is divided into monocyclic cycloalkyl groups, polycyclic cycloalkyl groups, wherein:
monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to a polycyclic group having one carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as single-, double-, or multiple-spirocycloalkyl groups according to the number of common spiro atoms between rings, and include, but are not limited to:
Figure GPA0000293895180000131
"fused ring alkyl" refers to an all-carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system. The number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups including, but not limited to:
Figure GPA0000293895180000141
"bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms that are not directly attached, and which may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Bridged cycloalkyl groups, which may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic depending on the number of constituent rings, include, but are not limited to:
Figure GPA0000293895180000142
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is a heteroatom of integers 0, 1, 2), but excluding the ring moieties of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. For example, "5-10 membered heterocyclic group" means a cyclic group containing 5 to 10 ring atoms, and "3-10 membered heterocyclic group" means a cyclic group containing 3 to 10 ring atoms.
Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) between which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. The spiroheterocyclyl groups are classified as single spiroheterocyclyl groups, double spiroheterocyclyl groups or multiple spiroheterocyclyl groups according to the number of common spiro atoms between rings. Spiroheterocyclyl groups include, but are not limited to:
Figure GPA0000293895180000143
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Figure GPA0000293895180000151
"fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more (preferably 1, 2, 3 or 4) of which may contain one or more (preferably 1, 2 or 3) double bonds, but none of which has a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, they may be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclylalkyl groups, including but not limited to:
Figure GPA0000293895180000152
"bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more (preferably1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S (O) r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, bridged heterocyclyl groups that may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic include, but are not limited to:
Figure GPA0000293895180000153
the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, including but not limited to:
Figure GPA0000293895180000154
Figure GPA0000293895180000161
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The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., rings bearing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, e.g., "C 5-10 Aryl "refers to an all-carbon aryl group containing 5-10 carbons and" 5-10 membered aryl "refers to an all-carbon aryl group containing 5-10 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:
Figure GPA0000293895180000162
aryl groups may be substituted or unsubstituted and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S (O) r (where r is an integer of 0, 1, 2), e.g., 5-8 membered heteroaryl refers to a heteroaromatic system containing 5-8 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, including but not limited to:
Figure GPA0000293895180000171
heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., C 2-10 Alkenyl refers to straight or branched alkenyl groups containing 2 to 10 carbons. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.
Alkenyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido、C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, e.g., C 2-10 Alkynyl refers to straight or branched chain alkynyl groups containing 2 to 10 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.
Alkynyl groups may be substituted or unsubstituted and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"alkoxy" means-O- (alkyl) wherein alkyl is as defined above, e.g., "C 1-10 Alkoxy "refers to an alkyl oxy group containing 1 to 10 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"Cycloalkoxy" means and-O- (unsubstituted cycloalkyl) wherein the cycloalkyl is as defined above, e.g., "C 3-10 Cycloalkoxy "refers to a cycloalkyloxy group having 3-10 carbons including, but not limited to, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
The cycloalkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"3-10 membered heteroepoxy" means and-O- (unsubstituted 3-10 membered heterocyclyl) wherein 3-10 membered heterocyclyl is as defined above, 3-10 membered heterocyclyloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
“C 5-10 Aryloxy "means and-O- (unsubstituted C) 5-10 Aryl), wherein C 5-10 Aryl is as defined above, C 5-10 Aryloxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl groupHalogen substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
"5-10 membered heteroaryloxy" means and-O- (unsubstituted 5-10 membered heteroaryl), wherein the definition of 5-10 membered heteroaryl is as defined above, and 5-10 membered heteroaryloxy may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups selected independently from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, halo substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, =o, -C 0-8 -S(O) r R 8 、-C 0-8 -O-R 9 、-C 0-8 -C(O)OR 9 、-C 0-8 -C(O)R 10 、-C 0-8 -O-C(O)R 10 、-C 0-8 -NR 11 R 12 、-C 0-8 -C(＝NR 11 )R 10 、-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 、-C 0-8 -C(O)NR 11 R 12 or-C 0-8 -N(R 11 )-C(O)R 10 Is substituted by a substituent of (2).
“C 1-8 Alkanoyl "means C 1-8 The monovalent radicals remaining after removal of the hydroxyl groups from the alkyl acid are also generally denoted as "C 0-7 C (O) - ", e.g.," C 1 -C (O) - "refers to acetyl; "C 2 -C(O)-”Refers to propionyl; "C 3 -C (O) - "refers to butyryl or isobutyryl.
“-C 0-8 -S(O) r R 8 "finger-S (O) r R 8 Wherein the sulfur atom is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -O-R 9 "means-O-R 9 Wherein the oxygen atom is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -C(O)OR 9 "means-C (O) OR 9 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -C(O)R 10 "means-C (O) R 10 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -O-C(O)R 10 "means-O-C (O) R 10 Wherein the oxygen atom is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -NR 11 R 12 "refer to-NR 11 R 12 Wherein nitrogen atoms are attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -C(＝NR 11 )R 10 "refer to-C (=NR) 11 )R 10 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -N(R 11 )-C(＝NR 12 )R 10 "means-N (R) 11 )-C(＝NR 12 )R 10 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 Determination of alkyl groupsAs defined above.
“-C 0-8 -C(O)NR 11 R 12 "means-C (O) NR 11 R 12 Wherein the carbonyl group is attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
“-C 0-8 -N(R 12 )-C(O)R 11 "means-N (R) 12 )-C(O)R 11 Wherein nitrogen atoms are attached to C 0-8 On alkyl groups, where C 0 Alkyl means a bond, C 1-8 The definition of alkyl is as described above.
"halogen substituted C 1-10 Alkyl "refers to a 1-10 carbon alkyl group with hydrogen on the alkyl optionally substituted with fluorine, chlorine, bromine, iodine atoms, including but not limited to difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.
"halogen substituted C 1-10 Alkoxy "the hydrogen on the alkyl is optionally substituted with fluorine, chlorine, bromine, iodine atoms, 1-10 carbon alkoxy groups. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
"halogen" means fluorine, chlorine, bromine or iodine.
"MeOH" refers to methanol. "DMF" refers to N, N-dimethylformamide. "DCE" means 1, 2-dichloroethane. "THF" refers to tetrahydrofuran. "PE" refers to petroleum ether. "EA/EtOAc" refers to ethyl acetate. "DCM" refers to dichloromethane. "LiOH" refers to lithium hydroxide. "NaOH" means sodium hydroxide. "NaNO 2 "means sodium nitrite. "CuI" refers to copper iodide. Na (A) 2 SO 4 Refers to sodium sulfate. "" HOAc "means acetic acid. "NH 4 Oac "refers to ammonium acetate. "Et 3 N "refers to triethylamine. "NH 4 Cl "refers to ammonium chloride. "TFA" refers to trifluoroacetic acid. "m-CPBA" refers to m-chloroperoxybenzoic acid. "Pd (PPh) 3 ) 4 "means tetrakis (triphenylphosphine) palladium. "Pd (PPh) 3 ) 2 Cl 2 "" means "ditriphenylphosphine palladium dichloride".
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms in the group are replaced, independently of one another, by a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., olefins).
By "pharmaceutically acceptable salts" is meant in the present invention pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which salts may be prepared by methods known in the art.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
The LC-MS measurement was performed by using an Agilent 6120 mass spectrometer. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being dry solvent and the reaction temperature being in degrees celsius (°c) without specific description.
1. Preparation of intermediates
1. Preparation of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine
Figure GPA0000293895180000201
The first step: synthesis of 2, 4-difluoro-3-iodo-1, 5-dimethoxy benzene
Figure GPA0000293895180000202
The compound 2, 6-difluoro-3, 5-dimethoxyaniline (27.0 g,143 mmol) was added to 6.0M hydrochloric acid solution (240 mL) and NaNO was slowly added dropwise with cooling in an ice water bath 2 Aqueous solution (10.35 g,150mmol,30mL of water). After the 25 minute drop was complete, the reaction was continued for 15 minutes to give an orange suspension, which was added to an aqueous KI solution (94.9 g,570mmol,150mL of water). The reaction was allowed to warm to room temperature with stirring for 30 minutes to precipitate a solid. Filtering and washing to obtain a crude product. The crude product was added to MeOH (60 mL) and stirred at room temperature for 30 min. Filtering and drying to obtain 2, 4-difluoro-3-iodine-1, 5-Dimethoxybenzene (29.3 g, yield: 68%). 1 H NMR(400MHz，DMSO-d 6 )δ6.69(t，J＝8.0Hz，1H)，3.88(s，6H)。
And a second step of: synthesis of (2, 6-difluoro-3, 5-dimethoxyphenylacetylene) methyltrimethylsilane
Figure GPA0000293895180000211
2, 4-difluoro-3-iodo-1, 5-dimethoxybenzene (25.8 g,86.0 mmol), trimethylsilylacetylene (36.5 mL,258 mmol) CuI (817 mg,4.3 mmol) and triethylamine (35.8 mL,258 mmol) were added to DMF (250 mL). The gas is evacuated, nitrogen is used for protection, and then Pd (PPh) is added 3 ) 2 Cl 2 (3.15 g,4.3 mmol). The reaction was carried out at 50℃for 2 hours. The reaction is completed, saturated NH is added 4 The aqueous Cl solution was quenched and extracted 3 more times with dichloromethane. The organic phases were combined, na 2 SO 4 And (5) drying. Filtration and concentration gave a crude product (27.0 g) which was used directly in the next reaction. 1 H NMR(400MHz，CDCl 3 )δ6.61(t，J＝8.0Hz，1H)，3.86(s，6H)，0.28(s，9H)。
And a third step of: synthesis of 3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene
Figure GPA0000293895180000212
(2, 6-difluoro-3, 5-dimethoxyphenylacetylene) methyltrimethylsilane (27.0 g, crude) was added to THF/MeOH (200/200 mL) followed by aqueous NaOH (8.6 mL,8.6mmol, 1.0N). Stirring at room temperature for 15 minutes. The reaction is completed, saturated NH is added 4 The aqueous Cl solution was quenched and extracted 3 times with dichloromethane. The organic phases were combined, anhydrous Na 2 SO 4 And (5) drying. Filtration, concentration, and slurrying of crude product with MeOH (50 mL) at room temperature. Filtration gave 3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene (15.0 g,2 steps yield: 88%). 1 H NMR(400MHz，CDCl 3 )δ6.66(t，J＝8.0Hz，1H)，3.88(s，6H)，3.52(s，1H)。
Fourth step: synthesis of methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate
Figure GPA0000293895180000213
3-ethynyl-2, 4-difluoro-1, 5-dimethoxybenzene (10.0 g,50.5 mmol) and 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester (13.0 g,49.5 mmol) were dissolved in DMF (100 mL) and CuI (479 mg,2.52 mmol), pd (PPh) were added 3 ) 4 (2.91 g,2.52 mmol) Et 3 N (35.0 mL,252.5 mmol), nitrogen blanket. The reaction was carried out at 100℃for 1.5 hours. The reaction is completed, cooled to room temperature, and saturated NH is added 4 The aqueous Cl solution was quenched and extracted 3 times with dichloromethane. The organic phases were combined, anhydrous Na 2 SO 4 Drying, filtering and concentrating. The crude product was isolated by column chromatography over silica gel (PE: EA: dcm=10:2:1) to give methyl 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylate (15.4 g, yield: 82%). 1 H NMR(400MHz，CDCl 3 )δ8.82(s，1H)，6.69(t，J＝8.0Hz，1H)，4.03(s，3H)，3.90(s，6H)，2.63(s，3H).
Fifth step: synthesis of 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid
Figure GPA0000293895180000221
5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid methyl ester (30.0 g,78.9 mmol) was dissolved in THF (300 mL) and LiOH/H was added 2 O (236.8 mL,236.8mmol, 1M). The reaction was stirred at room temperature for 2 hours. After completion of the reaction, THF was removed by concentration, and the mixture was acidified to pH of about 3 with dilute hydrochloric acid to precipitate a solid. Filtration, washing with water and drying gave 5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (28.5 g, yield: 99%). 1 H NMR(400MHz，DMSO-d 6 )δ8.98(s，1H)，7.15(t，J＝8.0Hz，1H)，3.90(s，6H)，2.59(s，3H)。
Sixth step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d ] pyrimidin-8-one
Figure GPA0000293895180000222
5- ((2, 6-difluoro-3, 5-dimethoxyphenyl) ethynyl) -2- (methylthio) pyrimidine-4-carboxylic acid (2.5 g,6.83 mmol) was dissolved in DCE (50 mL) and TFA (0.5 mL) and copper acetate (62 mg,0.34 mmol) were added. Reflux with heat and react overnight. The reaction was complete, concentrated, slurried with additional MeOH (50 mL) and stirred at room temperature for 30 minutes. The solid was filtered and washed with MeOH (10 mL) and dried to give 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d ] ]Pyrimidin-8-one (2.0 g, yield: 80%). 1 H NMR(400MHz，DMSO-d 6 )δ9.23(s，1H)，7.22(t，J＝8.4Hz，1H)，7.17(s，1H)，3.93(s，6H)，2.63(s，3H).
Seventh step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8 (7H) -one
Figure GPA0000293895180000223
6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) -8H-pyrano [3,4-d]Pyrimidin-8-one (4.5 g,12.3 mmol) was dissolved in HOAc (45 mL) to which NH was added 4 OAc (9.4 g,123 mmol), reaction was stirred overnight at 120 ℃. Cooling at room temperature, adding appropriate amount of water (30 mL), stirring, suction filtering, washing the filter cake with water (20 mL), and drying to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3, 4-d)]Pyrimidin-8 (7H) -one (4.22 g, yield: 94%). 1 H NMR(400MHz，DMSO-d 6 )δ12.28(s，1H)，9.24(s，1H)，7.17(t，J＝8.4Hz，1H)，6.76(s，1H)，3.92(s，6H)，2.63(s，3H).
Eighth step: synthesis of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine
Figure GPA0000293895180000224
6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ]]Pyrimidin-8 (7H) -one (1 g,2.74 mmol) was dissolved in DCE (80 mL), heated to 90℃and then phenylphosphonic dichloride (3.0 mL,21.92 mmol) was added, heated and stirred for 16H, cooled, pH adjusted to neutral with sodium bicarbonate under ice bath, DCM extraction, silica gel column chromatography (DCM/EtOAc=0-10%)) to give 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] ]Pyrimidine (930 mg, 88% yield). 1 H NMR(400MHz，CDCl 3 )δ9.25(s，1H)，7.78(t，J＝1.2Hz，1H)，6.75(t，J＝8.0Hz，1H)，3.93(s，6H)，2.77(s，3H)。MS m/z(ESI)：384[M+H] + 。
2. Preparation of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine
Figure GPA0000293895180000231
8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (930 mg,2.42 mmol) was dissolved in DCM (50 mL), m-CPBA (1.23 g,6.05 mmol) was added and stirred at room temperature for 2 hours. The reaction was completed, quenched with sodium thiosulfate, extracted with DCM and separated by silica gel column chromatography (DCM/etoac=0-35%) to give 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ]]Pyrimidine (800 mg, 79% yield). 1 H NMR(400MHz，CDCl 3 )δ9.76(s，1H)，8.03(t，J＝1.2Hz，1H)，6.80(t，J＝8.0Hz，1H)，3.95(s，6H)，3.58(s，3H)。MS m/z(ESI)：416[M+H] + 。
2. Preparation of the Compounds of examples
Example 1 1 preparation of- (2- ((4- (diethylamino) butyl) amino) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol
Figure GPA0000293895180000232
The first step: synthesis of 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol
Figure GPA0000293895180000233
In 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (300 mg,0.782 mmol) and 3-methyl-3-acridine hydrochloride (290 mg,2.345 mmol) in acetonitrile (6 mL) was added N, N-diisopropylethylamine (0.605 mg,4.692 mmol). The reaction solution was placed in a sealed tube and stirred at 95℃for 18 hours. After cooling, ethyl acetate (50 mL) was added to dilute, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography separation [ eluent: (dichloromethane: ethyl acetate=0 to 40%) ]To obtain 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3, 4-d)]Pyrimidin-8-yl) -3-methylazetidin-3-ol (328 mg, yield: 96%). MS m/z (ESI): 435.4[ M+H ]] +
And a second step of: synthesis of 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol
Figure GPA0000293895180000241
In 1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ]]To a solution of pyrimidin-8-yl) -3-methylazetidin-3-ol (328 mg,0.755 mmol) in dichloromethane (8 mL) was added m-chloroperoxybenzoic acid (390 mg,2.265 mmol) in one portion. The reaction solution was stirred at room temperature for 20 hours. The reaction solution was washed with a saturated sodium sulfite solution and a sodium bicarbonate solution in this order, and finally with a saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a column chromatography fraction [ eluent: (dichloromethane: ethyl acetate=0 to 80%)]Obtaining 1- (6- (2, 6-di)Fluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]Pyrimidin-8-yl) -3-methylazetidin-3-ol (151 mg, yield: 42%). MS m/z (ESI): 467.4[ M+H ]] + 。
And a third step of: synthesis of 1- (2- ((4- (diethylamino) butyl) amino) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d ] pyrimidin-8-yl) -3-methylazetidin-3-ol
Figure GPA0000293895180000242
1- (6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3, 4-d)]Pyrimidin-8-yl) -3-methylazetidin-3-ol (14 mg,0.03 mmol) and N 1 ，N 1 Diethyl butane-1, 4-diamine (13 mg,0.09 mmol) was dissolved in acetonitrile (0.5 mL). The reaction solution was placed in a sealed tube and stirred at 80℃for 3 hours. The reaction solution was directly concentrated and subjected to reversed phase column chromatography separation [ mobile phase: (acetonitrile: water (0.1% formic acid) =5 to 35%)]Aqueous lyophilization gives 1- (2- ((4- (diethylamino) butyl) amino) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3, 4-d)]Pyrimidin-8-yl) -3-methylazetidin-3-ol (9 mg, 53% yield). MS m/z (ESI): 531.6[ M+H ]] + 。
1 H NMR(400MHz，CDCl 3 )δ8.82(s，1H)，8.53(s，1H，HCO 2 H)，6.87(s，1H)，6.66(t，J＝7.9Hz，1H)，5.67(s，1H)，4.43(s，4H)，3.91(s，6H)，3.52(s，2H)，3.10-3.00(m，6H)，2.12-1.64(m，4H)，1.57(s，3H)，1.25(t，J＝7.3Hz，6H).
Example 2N 1 - (8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d ]]Preparation of pyrimidin-2-yl) -N4, N4-diethylbutane-1, 4-diamine
Figure GPA0000293895180000251
The first step: synthesis of 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ] pyrimidine
Figure GPA0000293895180000252
In 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (600 mg,1.407 mmol) and azetidine hydrochloride (399mg, 4.221 mmol) in acetonitrile (12 mL) was added N, N-diisopropylethylamine (1.09 g,8.442 mmol). The reaction solution was placed in a sealed tube and stirred at 95℃for 16 hours. After cooling, ethyl acetate (50 mL) was added to dilute, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, followed by column chromatography separation [ eluent: (dichloromethane: ethyl acetate=0 to 15%) ]To give 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d ]]Pyrimidine (483 mg, yield: 84.9%). MS m/z (ESI): 405.4[ M+H ]] + .
And a second step of: synthesis of 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine
Figure GPA0000293895180000253
In 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]To a solution of pyrimidine (4813 mg,1.194 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (515 mg,2.986 mmol) in one portion. The reaction solution was stirred at room temperature for 24 hours. The reaction solution was washed with a saturated sodium sulfite solution and a sodium bicarbonate solution in this order, and finally with a saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a column chromatography fraction [ eluent: (dichloromethane: methanol=0 to 5%)]To give 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d ]]Pyrimidine (214 mg, yield: 41%). MS m/z (ESI): 437.4[ M+H ]] + .
And a third step of: n (N) 1 - (8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d ]]Synthesis of pyrimidin-2-yl) -N4, N4-diethylbutane-1, 4-diamine
Figure GPA0000293895180000254
In 8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]Pyrimidine (40 mg,0.091 mmol) and N 1 ，N 1 To a solution of diethyl butane-1, 4-diamine (39.6 mg,0.275 mmol) in acetonitrile (2 mL) was added N, N-diisopropylethylamine (35.5 mg,0.275 mmol). The reaction solution was placed in a sealed tube and stirred at 110℃for 18 hours. After cooling, ethyl acetate (20 mL) was added thereto, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and then concentrated with C 18 Reverse phase column separation [ mobile phase: (acetonitrile: water (0.1% formic acid) =10 to 30%)]And freeze-drying to obtain N 1 - (8- (azetidin-1-yl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) pyrido [3,4-d ]]Pyrimidin-2-yl) -N4, N4-diethylbutane-1, 4-diamine (25 mg, yield: 54%). MS m/z (ESI): 501.6[ M+H ]] + .
1 H NMR(400MHz，CDCl 3 )δ8.84(s，1H)，8.61(s，1H，HCOOH)，6.88(s，1H)，6.66(t，J＝7.9Hz，1H)，5.81(br s，1H)，4.60-4.30(m，4H)，3.91(s，6H)，3.53(t，J＝6.4Hz，2H)，2.98(q，J＝7.3Hz，4H)，2.90(t，J＝8.0Hz，2H)，2.40(p，J＝7.5Hz，2H)，1.87-1.75(m，2H)，1.76-1.67(m，2H)，1.23(t，J＝7.2Hz，6H).
Examples 3 to 21 were prepared by the synthetic methods of examples 1 or 2:
Figure GPA0000293895180000261
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Figure GPA0000293895180000271
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Figure GPA0000293895180000281
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Figure GPA0000293895180000291
example 22N 8 - (cyclopropylmethyl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N 2 - (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Preparation of pyrimidine-2, 8-diamines
Figure GPA0000293895180000292
The first step: synthesis of 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ] pyrimidin-2-amine
Figure GPA0000293895180000293
In 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -2- (methylsulfonyl) pyrido [3,4-d]To a solution of pyrimidine (400 mg, 0.962mmol) and 4-methyl-1-piperazineethylamine (344 mg,2.405 mmol) in dichloromethane (10 mL) was added N, N-diisopropylethylamine (372 mg,2.886 mmol). The reaction solution was stirred at 50℃under reflux for 2 hours. After cooling, the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ]]Pyrimidin-2-amines. MS m/z (ESI): 479.6[ M+H ]] + .
And a second step of: n (N) 8 - (cyclopropylmethyl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N 2 - (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Synthesis of pyrimidine-2, 8-diamine
Figure GPA0000293895180000301
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In 8-chloro-6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Pyrimidine-2-amines (4)To a solution of 0mg,0.084 mmol) and cyclopropylmethylamine (30 mg,0.418 mmol) in tert-butanol (2 mL) was added N, N-diisopropylethylamine (32.5 mg,0.275 mmol). The reaction solution was placed in a sealed tube and stirred at 115℃for 18 hours. After concentration, ethyl acetate (20 mL) was added thereto for dilution, and the mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and then separated with a preparation plate [ developing agent: (dichloromethane: methanol (5% ammonia) =10:1) ]Obtaining N 8 - (cyclopropylmethyl) -6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -N 2 - (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d]Pyrimidine-2, 8-diamine (17.7 mg, yield: 51%). MS m/z (ESI): 514.6[ M+H ]] + .
1 H NMR(400MHz，CDCl 3 )δ8.86(s，1H)，6.88(s，1H)，6.66(t，J＝7.9Hz，1H)，6.56-6.50(m，1H)，5.88(s，1H)，3.91(s，6H)，3.64(dd，J＝11.1，5.2Hz，2H)，3.44(dd，J＝7.0，5.5Hz，2H)，3.04-2.50(m，10H)，2.42(s，3H)，0.88(t，J＝6.9Hz，1H)，0.58-0.49(m，2H)，0.35-0.26(m，2H).
Example 23 was prepared by the synthetic method of example 22:
Figure GPA0000293895180000302
EXAMPLE 24 preparation of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ] pyrimidin-2-amine
Figure GPA0000293895180000303
The first step: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrido [3,4-d ] pyrimidine
Figure GPA0000293895180000311
8-chloro-6- (2, 6-difluoro)-3, 5-dimethoxyphenyl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (200 mg,0.52 mmol), (1-methyl-1H-pyrazol-4-yl) boronic acid (131 mg,1.04 mmol), potassium phosphate (221 mg,1.04 mmol), XPhos-Pd-G2 (41 mg,0.052 mmol) were dissolved in tetrahydrofuran (10 mL) and water (3 mL), replaced with nitrogen three times, and the reaction was stirred at 45℃overnight. Cooled, diluted with ethyl acetate (100 mL), washed once with water (20 mL x 2) and saturated brine (20 mL x 2), dried over sodium sulphate, filtered and concentrated then chromatographed on silica gel column (eluent: PE/ea=3/1) to give 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrido [3, 4-d) ]Pyrimidine (230 mg, 100% yield). MS m/z (ESI): 430.4[ M+H ]] + .
And a second step of: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfonyl) pyrido [3,4-d ] pyrimidine
Figure GPA0000293895180000312
6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylthio) pyrido [3,4-d]Pyrimidine (230 mg,0.54 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (282 mg,1.38 mmol) was added and stirred overnight at room temperature. Quenching by adding sodium thiosulfate, regulating the saturated sodium bicarbonate to be alkaline, extracting by using dichloromethane, washing by using the saturated sodium bicarbonate and saline solution at one time, and concentrating to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -2- (methylsulfonyl) pyrido [3,4-d]Crude pyrimidine (300 mg) was used directly in the next step. MS m/z (ESI): 462.4[ M+H ]] + 。
And a third step of: synthesis of 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ] pyrimidin-2-amine
Figure GPA0000293895180000313
6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl)-1H-pyrazol-4-yl) -2- (methylsulfonyl) pyrido [3,4-d]Crude pyrimidine (100 mg,0.18 mmol), 2- (4-methylpiperazin-1-yl) ethan-1-amine (51 mg,0.36 mmol), DIPEA (70 mg,0.54 mmol) was dissolved in 20mL acetonitrile and the reaction was stirred overnight at 110 ℃ using a tube sealer. Direct concentration, reverse phase column chromatography separation (eluent: 30% water/acetonitrile, 5% formic acid added), aqueous phase lyophilization to obtain 6- (2, 6-difluoro-3, 5-dimethoxyphenyl) -8- (1-methyl-1H-pyrazol-4-yl) -N- (2- (4-methylpiperazin-1-yl) ethyl) pyrido [3,4-d ]Pyrimidin-2-amine (70 mg, 72% yield). MS m/z (ESI): 525.6[ M+H ]] + .
1 H NMR(400MHz，Methanol-d 4 )δ9.19(s，1H)，8.60(s，2H)，8.48(s，2H，HCOOH)，7.65(s，1H)，6.99(t，J＝8.1Hz，1H)，4.01(s，3H)，3.95(s，6H)，3.78(t，J＝6.4Hz，2H)，3.27-3.08(m，8H)，2.91-2.86(m，2H)，2.80(s，3H).
Biological test evaluation
1. In vitro biochemical kinase assay of FGFR 1-3
The invention adopts a Caliper Assay to measure the property of the compound on the inhibition activity of FGFR1, FGFR2 and FGFR 3. The specific experimental process is as follows:
1. the kinase reaction carried out by the invention is carried out in 384-well plates, and the kinase reaction is incubated for a certain time at 28 ℃ in a reaction system of 50mM HEPES,pH7.5,0.0015%Brij-35 and a basic kinase buffer solution by using a certain concentration of kinase (Carna) and a certain concentration of ATP and 1 mu M peptide FAM-P22 (GL Biochem, cat. No. 112393); for FGFR1, the enzyme concentration was 0.25nm, atp concentration was 382 μm, and the reaction time was 20 minutes; for FGFR2, the enzyme concentration was 2.5nm, atp concentration was 1 μm, and the reaction time was 40 minutes; for FGFR3, the enzyme concentration was 8nM, the ATP concentration was 4.7. Mu.M, and the reaction time was 30 minutes
2. Stop solution (100mM HEPES,pH7.5,0.2%Caliper coating reagent, 50mM EDTA and 0.015% Brij 35) was added to stop the reaction;
3. transfer the well plate with terminated kinase reaction to a Caliper for reading;
4. phosphorylated and non-phosphorylated peptides were separated using the Caliper microfluidic migration shift technique, and analytes were transferred by constant buffer flow through the chip, and substrate peptide migration was monitored by its labeled fluorescent signal. Kinase activity was calculated using the formed phosphopeptide.
5. Determination of IC by non-linear regression analysis of percent inhibition at different compound concentrations 50 Values. The enzymatic activities of the compounds of the specific examples are shown in Table 1.
2. Cell proliferation assay (Cell Titer Glo (CTG) assay)
The present invention evaluates compounds for inhibition of cell proliferation dependent on FGFR signaling pathways by viability assays using CTG reagent (Promega, #g7573). Cell lines representing different tumor types, such as H1581 lung cancer cells (with amplification of FGFR1 gene) or Snu-16 stomach cancer cells (with amplification of FGFR2 gene) from Nanjac are selected as follows:
1. 90ul of cells were inoculated into a tissue culture medium treated 96-well plate (Costar # 3904), cultured overnight in a 5% carbon dioxide incubator at 37℃followed by the addition of 10. Mu.L of medium containing a 10-fold final concentration of the compound dilution.
2. Dose effect was evaluated by serial dilutions of the test compounds, starting at concentrations of 10 μm or less.
3. Cells were incubated at 37℃with 5% CO 2 After incubation for 3 days, 50 μl CTG was added and readings were made using Envision (Pelkin Elmer) to quantify cellular ATP levels the percentage inhibition of cell proliferation/survival by the compound could be assessed by comparing cellular ATP levels after different concentrations of inhibitor compared to cellular ATP levels of the DMSO control
4. Determination of compound concentration (IC) resulting in half maximal growth inhibition using four-parameter curve fitting in Graphpad Prism 50 ). The cell activities of the compounds of the specific examples are shown in Table 1.
TABLE 1 enzymatic and cellular Activity assay results
Figure GPA0000293895180000321
/>
Figure GPA0000293895180000331
From the enzymatic activity data of the compounds in specific examples, the compounds in the series of the invention have strong inhibition effect on the kinase activities of FGFR1, FGFR2 and FGFR 3. From the cell activity data of the compounds in specific examples, the series of compounds provided by the invention have a strong inhibition effect on the proliferation activity of H1581 lung cancer cells and/or Snu stomach cancer cells which are highly expressed by FGFR1, FGFR2 and FGFR 3.
All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims (10)

1. A compound of formula (iii), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0004179390820000011
wherein, the liquid crystal display device comprises a liquid crystal display device,
R 1 selected from hydrogen, C 1-4 Alkyl or 3-6 membered heterocyclic groups, the above C 1-4 An alkyl group or a 3-6 membered heterocyclic group optionally further substituted with one or more substituents selected from deuterium, methyl, ethyl, 3-6 membered heterocyclic group, phenyl, dimethylamino or diethylamino, said groups optionally being further substituted with one or more substituents selected from methyl, difluoromethyl, trifluoromethyl, dideutomethyl or trideemethyl;
R 2 Selected from diazolyl, triazolyl or-NR 11 R 12 The above groups are optionally further substituted with one or more groups selected from deuterium or C 1-4 Substituted by substituents of alkyl radicals, the radicals being optionally further substituted by one moreSubstituted with one or more substituents selected from deuterium, methyl, ethyl, difluoromethyl, trifluoromethyl, dideutomethyl or trideemethyl;
R 11 、R 12 each independently selected from hydrogen or C 1-4 Alkyl, wherein C 1-4 The alkyl group is optionally further substituted with one or more substituents selected from deuterium or cyclopropyl;
or R is 11 、R 12 Together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group, which is optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, hydroxy, C 1-4 Substituents of alkyl, methoxy, ethoxy or isopropoxy;
the heterocyclic groups each independently comprise 1 or 2 heteroatoms selected from nitrogen atoms or oxygen atoms.
2. The compound of formula (iii), stereoisomer thereof or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0004179390820000012
/>
Figure FDA0004179390820000021
3. a process for the preparation of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1 comprising the steps of:
Figure FDA0004179390820000031
or alternatively, the process may be performed,
Figure FDA0004179390820000032
wherein R is 1 、R 2 The method of claim 1.
4. A pharmaceutical composition comprising a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 and a pharmaceutically acceptable carrier.
5. Use of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 in the manufacture of a medicament for the treatment of a tumour or cancer.
6. The use according to claim 5, wherein the tumor or cancer is selected from bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, esophageal cancer, gall bladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, B-cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, hairy-like lymphoma, burkitt's lymphoma, glioblastoma, melanoma or rhabdomyosarcoma.
7. The use according to claim 5, wherein the tumor or cancer is selected from the group consisting of: adult T-cell leukemia, acute myelogenous leukemia, fahrenheit macroglobulinemia, and cellular lymphomas.
8. Use of a compound of formula (iii), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 in the manufacture of a medicament for the treatment of a myeloproliferative disease, a bone or chondrocyte disorder or hypophosphatemia.
9. The use according to claim 8, wherein the myeloproliferative disease is selected from erythrocytosis, primary thrombocytosis or primary myelofibrosis;
the bone or cartilage cell disorder is selected from dysplasia, dwarfism, lethal teratopathy, atur syndrome, kluyzong syndrome, jackson-Wei Sizeng syndrome, bel-stevenson skin stria syndrome, fevere syndrome or craniofacial atrophy syndrome;
the hypophosphatemia is selected from X-linked low phosphorus rickets, autosomal recessive low phosphorus rickets, autosomal dominant low phosphorus rickets or tumor-induced ovarian malacia.
10. The use according to claim 8, wherein the bone or chondrocyte disorder is cartilage dysplasia.
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