WO2024032647A1 - Procédé de préparation d'un composé hétérocyclique contenant de l'azote en tant qu'inhibiteur de la protéase 1 spécifique de l'ubiquitine, ainsi que application et utilisation de celui-ci - Google Patents

Procédé de préparation d'un composé hétérocyclique contenant de l'azote en tant qu'inhibiteur de la protéase 1 spécifique de l'ubiquitine, ainsi que application et utilisation de celui-ci Download PDF

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WO2024032647A1
WO2024032647A1 PCT/CN2023/111923 CN2023111923W WO2024032647A1 WO 2024032647 A1 WO2024032647 A1 WO 2024032647A1 CN 2023111923 W CN2023111923 W CN 2023111923W WO 2024032647 A1 WO2024032647 A1 WO 2024032647A1
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alkyl
cycloalkyl
compound
membered heterocyclyl
group
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PCT/CN2023/111923
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English (en)
Chinese (zh)
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别平彦
万正勇
彭建彪
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上海济煜医药科技有限公司
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Publication of WO2024032647A1 publication Critical patent/WO2024032647A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a preparation method, application and use of a nitrogen-containing heterocyclic compound as a ubiquitin-specific protease 1 inhibitor.
  • Ubiquitination is a reversible process involving the deubiquitinating enzyme (DUB) family, which regulates various cellular processes by deconjugating ubiquitin from substrates.
  • DUBs are encoded by approximately 100 human genes and are divided into 6 families, the largest of which is the ubiquitin-specific protease (USP) with more than 50 members.
  • USP ubiquitin-specific protease
  • DUBs and their substrate proteins are commonly dysregulated in cancer, supporting the hypothesis that targeting specific DUB family members may contribute to tumor growth, survival, differentiation, and maintenance by enhancing ubiquitination and subsequent degradation of oncogenic substrates and the tumor microenvironment. The activity of other key proteins involved leads to anti-tumor activity.
  • USP1 is a cysteine isopeptidase of the USP subfamily of DUB.
  • Full-length human USP1 consists of 785 amino acids, including the catalytic triad consisting of Cys90, His593 and Asp751.
  • USP1 deubiquitinates various cellular targets involved in different processes related to cancer. For example, USP1 deubiquitinates PCNA (proliferating cell nuclear antigen), a key protein in translesion synthesis (TLS), and FANCD2 (Fanconi anemia complementation group D2), a key protein in the Fanconi anemia (FA) pathway. ). Therefore, inhibition of USP1 with small molecule inhibitors has the potential to become a therapeutic approach for the treatment of cancer and other conditions. For the above reasons, there is a considerable unmet need for potent small molecule inhibitors of USP1.
  • PCNA proliferating cell nuclear antigen
  • TLS translesion synthesis
  • FANCD2 Feanconi anemia complementation group D2
  • the present invention provides the compound represented by formula (I), its optical isomer or its pharmaceutically acceptable salt,
  • X 1 is selected from N and CR 1X ;
  • X 2 is selected from N and CR 2X ;
  • X 3 is selected from N and CR 3X ;
  • X 4 is selected from N and CR 4X ;
  • R 1 , R 1X , R 2X , R 3X , and R 4X are each independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2- 6 alkynyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne base, C 1-6 heteroalkyl, C 3-6 cycloalkyl or -OC 3-6 cycloalkyl optionally substituted by 1, 2 or 3 OH, NH 2 , F, Cl, Br, I, CN, NO 2 , COOH substitution;
  • R 2 is selected from phenyl, naphthyl and 5-6-membered heteroaryl, and the phenyl, naphthyl or 5-6-membered heteroaryl is optionally substituted by 1, 2 or 3 R';
  • R 3 and R 4 are each independently selected from H, OH, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hetero alkyl and C 3-6 cycloalkyl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl or C 3-6 cycloalkyl is optionally replaced by 1 , 2 or 3 OH, NH 2 , F, Cl, Br, I, CN, NO 2 , COOH substitution;
  • X 5 , X 6 , X 7 , and X 8 are each independently selected from N and CR X ;
  • R _ _ _ _ _ _ _ 6 cycloalkyl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl or C 3-6 cycloalkyl is optionally replaced by 1, 2 or 3 OH, NH 2 , F, Cl, Br, I, CN, NO 2 and COOH substitutions;
  • the two optional substituents on R 5 together with the carbon atoms to which they are connected form a C 3-6 cycloalkyl group, a 3-9 membered heterocyclyl group, a C 6-14 aryl group or a 5-6 1-membered heteroaryl
  • the C 3-6 cycloalkyl, 3-9-membered heterocyclyl, C 6-14 aryl or 5-6-membered heteroaryl is optionally substituted by 1, 2 or 3 OH, NH 2 , halogen, CN, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl or -OC 3-6 cycloalkyl substitution;
  • R a and R b are each independently selected from H, D, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hetero Alkyl, C 3-9 cycloalkyl, OC 3-9 cycloalkyl, C 6-14 aryl, 5-9 membered heteroaryl , 3-9 membered heterocyclyl, -O-3-9 membered hetero Ring group, -OC 6-14 aryl and -O-5-9 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hetero Alkyl, C 3-9 cycloalkyl, OC 3-9 cycloalkyl, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, -O-3-9 membered hetero Ring group, -OC 6-14 aryl group and -O-5-9 membered heteroaryl group
  • the structure of the compound represented by formula (I), its optical isomer or its pharmaceutically acceptable salt is as follows:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from N or C(R');
  • the structure of the compound represented by formula (I), its optical isomer or its pharmaceutically acceptable salt is as follows,
  • the structure of the compound represented by formula (I), its optical isomer or its pharmaceutically acceptable salt is as follows:
  • R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H , R 5I , R 5J , R 5K , R 5L , R 5M , R 5N and R 5O are selected independently.
  • R a and R b are each independently selected from H, D, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hetero Alkyl, C 3-9 cycloalkyl, OC 3-9 cycloalkyl, C 6-14 aryl, 5-9 membered heteroaryl , 3-9 membered heterocyclyl, -3-9 membered heterocyclyl , -OC 6-14 aryl and -O-5-9 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl , C 3-9 cycloalkyl, OC 3-9 cycloalkyl, C 6-14 aryl, 5- 9-membered heteroaryl, 3-9-membered heterocyclyl, -O-3-9-membered heterocyclyl, -OC 6-14- aryl and -O-5-9-member
  • the structural unit Selected from The remaining variables are as defined in the present invention.
  • the structural unit Selected from The remaining variables are as defined in the present invention.
  • R 1 , R 1X , R 2X , R 3X , and R 4X are each independently selected from H, OH, CN , F, Cl, Br, I, C 1-3 alkyl , C 1 -3 alkoxy, C 1-3 alkylthio, C 1-3 alkylamino, C 2-3 alkenyl, C 2-3 alkynyl, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl base, the C 1-3 alkyl group, C 1-3 alkoxy group, C 1-3 alkylthio group, C 1-3 alkylamino group, C 2-3 alkenyl group, C 2-3 alkynyl group, C 3 -6 cycloalkyl or -OC 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 OH, NH 2 , F, Cl, Br, I, CN, NO 2 and COOH, and the remaining variables are as defined in the present invention. definition.
  • R 1 , R 1X , R 2X , R 3X , and R 4X are each independently selected from H, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl, The remaining variables are as defined in the present invention.
  • R 2 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolyl and pyrazolyl, said phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolyl or pyrazole
  • the radicals are optionally substituted by 1, 2, 3 or 4 R', and the remaining variables are as defined in the present invention.
  • R' is each independently selected from H, CN, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -OCD 3 , -OCHF 2 , -OCH 3 , -SCH 3 ,
  • the remaining variables are as defined in the present invention.
  • R 2 is selected from The remaining variables are as defined in the present invention.
  • R 2A , R 2B , R 2C , R 2D , R 2E , R 2F , R 2G , R 2H, R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O is each independently selected from H, CN, methyl, ethyl, -OCH 3 , -OCH 2 CH 3 , -OCD 3 , -OCHF 2 , -OCH 3 , -SCH 3 , The remaining variables are as defined in the present invention.
  • R 3 and R 4 are each independently selected from H, OH, CN, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 1- 3 alkylthio, C 1-3 alkylamino, C 2-3 alkenyl, C 2-3 alkynyl and C 3-6 cycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy , C 1-3 alkylthio, C 1-3 alkylamino, C 2-3 alkenyl, C 2-3 alkynyl or C 3-6 cycloalkyl optionally substituted by 1, 2 or 3 OH, NH 2 , F, Cl, Br, I, CN, NO 2 or COOH are substituted, and the remaining variables are as defined in the present invention.
  • R 3 and R 4 are each independently selected from H, D, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl, and the remaining variables are as defined in the present invention .
  • R a and R b are each independently selected from H, D, CN, F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hetero Alkyl, C 3-9 cycloalkyl, OC 3-9 cycloalkyl, C 6-14 aryl, 5-9 membered heteroaryl , 3-9 membered heterocyclyl, -O-3-9 membered hetero Ring group, -OC 6-14 aryl and -O-5-9 membered heteroaryl, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hetero Alkyl, C 3-9 cycloalkyl, OC 3-9 cycloalkyl, C 6-14 aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, -O-3-9 membered hetero Ring group, -OC 6-14 aryl group and -O-5-9 membered heteroaryl group
  • R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H, R 5I , R 5J , R 5K , R 5L , R 5M , R 5N , R 5O is each independently selected from H, D, CN, F, Cl, Br, I, OCH 3 , OCH 2 CH 3 , CF 3 , CHF 2 , CD 3 , methyl, ethyl, The remaining variables are as defined in the present invention.
  • R5 is selected from The remaining variables are as defined in the present invention.
  • the present invention also provides compounds of the following formula, their optical isomers or their pharmaceutically acceptable salts, which are selected from:
  • the present invention also proposes the use of the aforementioned compound, its optical isomer or its pharmaceutically acceptable salt in the preparation of drugs for the treatment of diseases related to USP1 activity or expression level.
  • the above-mentioned USP1 activity or expression level-related diseases are selected from cancer-related diseases and the like.
  • the above-mentioned cancer-related diseases are selected from bone cancer, brain cancer, soft tissue cancer, kidney cancer, bladder cancer, skin cancer, lung cancer, colon cancer, nervous system cancer, head and neck cancer, pancreatic cancer, and ovarian cancer. , breast cancer, uterine cancer, cervical cancer, etc.
  • the above-mentioned bone cancer is selected from osteosarcoma, chondrosarcoma, etc.
  • the above-mentioned brain cancer is selected from the group consisting of glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, etc.
  • the above-mentioned soft tissue cancer is selected from rhabdoid sarcoma and the like.
  • the above-mentioned skin cancer is selected from melanoma, etc.
  • the above-mentioned lung cancer is selected from non-small cell lung cancer, etc.
  • the phrase "at least one" when used in reference to a list of one or more elements shall be understood to mean at least one element selected from any one or more elements in the list of elements, but not necessarily including At least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements.
  • This definition also allows that elements other than those specifically identified within the stated list of elements referred to by the phrase "at least one" may optionally be present, whether related or unrelated to those specifically identified elements.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, Similar acids such as suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also includes amino acids such as arginine etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • “Pharmaceutically acceptable carrier” means non-toxic solid, semi-solid or liquid fillers, diluents, encapsulating materials, formulation aids or vehicles commonly used in the art with therapeutic agents, which together constitute “drug composition” to administer to a subject.
  • a pharmaceutically acceptable carrier is non-toxic to the recipient at the doses and concentrations employed and is compatible with the other ingredients of the formulation.
  • the pharmaceutically acceptable carrier is suitable for the formulation used.
  • the present disclosure provides a method for inhibiting the USP1 protein, which method includes contacting the USP1 protein or a composition comprising the USP1 protein with one or more compounds of the present disclosure.
  • the present disclosure generally relates to a method for treating a disease, disorder or disorder in an animal suffering from, or at risk of suffering from, a condition responsive to inhibition of a USP1 protein, said method comprising administering to said animal An effective amount of one or more compounds of the present disclosure is administered.
  • the present disclosure further relates to a method of inhibiting USP1 protein in an animal in need thereof, comprising administering to said animal a therapeutically effective amount of at least one compound of the present disclosure.
  • USP1 and ubiquitin-specific protease 1 refer to any native polypeptide or polynucleotide encoding USP1.
  • USP1 encompasses "full-length” unprocessed USP1 polypeptide as well as any form of USP1 resulting from intracellular processing (eg, removal of the signal peptide).
  • the term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allelic variants.
  • USP1 polypeptides described herein can be derived from a variety of sources, such as isolated from human tissue types or from another source, or produced by recombinant or synthetic methods.
  • Human USP1 sequences are known and include, for example, the sequence (including isoforms) publicly available as UniProt No. 094782.
  • the term "human USP1 protein” refers to a USP1 protein comprising the amino acid sequence set forth in SEQ ID NO: 1 in U.S. Provisional Patent Application No. 62/857,986, filed June 6, 2019.
  • USP1 is a deubiquitinating enzyme that acts as part of a complex with UAF1.
  • the "deubiquitinase activity" of USP1 includes its ability to deubiquitinate as part of the USP1-UAF1 complex.
  • the term "specifically binds" to a protein or a domain of a protein is a term well known in the art, as are methods of determining the specific binding achieved.
  • a molecule is said to react or associate with a particular protein or domain of a protein more frequently, faster, for longer duration, and/or with higher affinity than it would with an alternative protein or domain.
  • Molecules exhibit "specific binding” or "preferential binding”. It will be appreciated that a molecule that specifically or preferentially binds to a first protein or domain may or may not specifically or preferentially bind to a second protein or domain.
  • “specific binding” or “preferential binding” does not necessarily require (but may include) exclusive binding.
  • references to union mean preferential union.
  • a USP1 inhibitor that specifically binds to USP1, UAF1, and/or the USP1-UAF1 complex may not bind to other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (USP46-UAF1), or may bind less than USP1 binds with low affinity to other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (eg, USP46-UAF1).
  • cancer refers to or describe a physiological disorder of a population of cells in a mammal characterized by unregulated cell growth.
  • the term encompasses both solid cancers and hematological/lymphoid cancers.
  • cancers include, but are not limited to, cancers with defects in DNA damage repair pathways.
  • Other examples of cancer include, but are not limited to, ovarian cancer, breast cancer (including triple-negative breast cancer), non-small cell lung cancer (NSCLC), and osteosarcoma.
  • Cancers can be BRCA1 or BRCA2 wild-type.
  • the cancer can also be BRCA1 or BRCA2 mutated.
  • the cancer may also be a PARP inhibitor-resistant or refractory cancer, or a PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.
  • C 1-6 alkylcarbonyl refers to a C 1-6 alkyl group attached to the rest of the molecule through a carbonyl group.
  • the "-" may be omitted.
  • the dashed line indicates the point of attachment of the group to the rest of the molecule.
  • the dotted line represents a single bond or its absence, which also means represents a single key or double bond
  • substituted or “substituted by” means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and variants of hydrogen, as long as the valence state of the particular atom is normal and The substituted compound is stable.
  • substituent which may include deuterium and variants of hydrogen, as long as the valence state of the particular atom is normal and The substituted compound is stable.
  • optionally substituted or “optionally substituted” refers to a group that may or may not be substituted, unless otherwise specified, and the type and number of substituents are chemically achievable. The basis can be arbitrary.
  • any variable e.g., R
  • its definition in each instance is independent.
  • R e.g., R
  • a group is substituted by 1, 2 or 3 R', then said group may optionally be substituted by 1 or 2 or 3 R', and in each case R' All have independent options.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings.
  • the carbon atom is attached to the substituted group.
  • the middle connecting group L is -CH 2 O-.
  • -CH 2 O- can be formed by connecting phenyl and cyclopentyl in the same direction as the reading order from left to right. It can also be composed by connecting phenyl and cyclopentyl in the opposite direction to the reading order from left to right.
  • halogen means fluorine, chlorine, bromine, iodine.
  • deuterium also known as heavy hydrogen and hydrogen-2, is a stable isotope of hydrogen.
  • the element symbol is generally D or 2H .
  • the number of atoms on a ring is usually defined as the number of ring members.
  • a "3-6 membered ring” refers to a “ring” with 3-6 atoms arranged around it.
  • C 1-6 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it can Is it monovalent (such as CH 3 ), bivalent (-CH 2 -) or polyvalent (such as ).
  • Examples of C 1-6 alkyl groups include, but are not limited to, CH 3 , wait.
  • C 1-4 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl groups, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 - ) or multiple prices (such as times ).
  • Examples of C 1-4 alkyl groups include, but are not limited to, CH 3 , wait.
  • C 2-6 alkenyl is used to mean a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond. Can be located anywhere on the group.
  • the C 2-6 alkenyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 2-6 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.
  • C 2-3 alkenyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, carbon-carbon double bond Can be located anywhere on the group.
  • the C 2-3 alkenyl group includes C 3 and C 2 alkenyl groups; the C 2-3 alkenyl group can be monovalent, divalent or multivalent. Examples of C 2-3 alkenyl groups include, but are not limited to wait.
  • C 2-6 alkynyl is used to mean a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, carbon-carbon triple bond Can be located anywhere on the group. It can be monovalent, bivalent or polyvalent.
  • the C 2-6 alkynyl group includes C 2- 3. C 2-4 , C 2-5 , C 3-4 , C 3-5 , C 3-6, C 4-5 , C 4-6 , C 5-6 , C 6 , C 5 , C 4 , C 3 and C 2 alkynyl. Examples of C 2-6 alkynyl groups include, but are not limited to wait.
  • C 2-3 alkynyl is used to mean a straight-chain or branched hydrocarbon group composed of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond. Can be located anywhere on the group. It can be monovalent, bivalent or polyvalent.
  • the C 2-3 alkynyl group includes C 3 and C 2 alkynyl groups. Examples of C 2-3 alkynyl groups include, but are not limited to wait.
  • oxo refers to an oxygen atom that is double bonded to a carbon atom or another element, including to the nitrogen of the pyridine ring, to form pyridine N-oxide.
  • oxo 5-6 membered heteroaryl includes, but is not limited to
  • heteroalkyl by itself or in combination with another term refers to a stable linear or branched alkyl group or a combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
  • the heteroatoms are selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl group is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl group is C 1-3 heteroalkyl.
  • Heteroatoms or groups of heteroatoms can be located at any internal position of a heteroalkyl group, including where the alkyl group is attached to the rest of the molecule, but the term "alkoxy" is a conventional expression meaning attachment to the rest of the molecule through an oxygen atom of those alkyl groups.
  • C 1-6 alkoxy means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy oxygen group, s-butoxy group and t-butoxy group), pentyloxy group (including n-pentyloxy group, isopentyloxy group and neopentyloxy group), hexyloxy group, etc.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkoxy groups, etc.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino means those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino group wait.
  • C 1-6 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH(CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 , etc.
  • C 1-3 alkylamino means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylamino groups, etc.
  • Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 ) 2 etc.
  • C 1-6 alkylthio means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through a sulfur atom.
  • the C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkane Sulfur group etc.
  • Examples of C 1-6 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , and the like.
  • C 1-3 alkylthio means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkylthio groups, etc.
  • Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, and the C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule.
  • the 3-9-membered heterocyclic group includes 3-8-membered, 3-7-membered, 3-6-membered, 3-5-membered, 3-4-membered, 4-5-membered, 4-6-membered, 4-7-membered, 4-8 yuan, 4-9 yuan, 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 6-7 yuan, 6-8 yuan, 6-9 yuan, 7-8 yuan, 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered and 9-membered heterocyclic groups, etc.
  • 3-9 membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), methyl Phylyl group (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, iso
  • the term "5-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which Two ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings.
  • the heteroatom may occupy the attachment position of the heterocyclyl to the rest of the molecule.
  • the 5-6 membered heterocyclyl group includes 5-membered and 6-membered heterocyclyl groups, etc.
  • Examples of 5-6 membered heterocyclyl groups include, but are not limited to, 1,3-dioxolane, Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl, etc.), methyl Phylyl group (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxaziny
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” may be used interchangeably in the present invention
  • the term “5-6 membered heteroaryl” means 5 to 6 ring atoms. It consists of a monocyclic group with a conjugated ⁇ electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl).
  • azolyl group, etc. imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyrid
  • C 6-14 aryl by itself or in combination with other terms means a monocyclic or bicyclic aromatic ring system having six to fourteen carbon atoms, respectively.
  • Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthrenyl, onionyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl.
  • the aryl group can be selected from phenyl or theanyl.
  • the aryl group can be phenyl.
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , also include any range from n to n+m, for example, C1-12 includes C1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; similarly, n yuan to n The +m member indicates that the number of atoms in the ring is n to n+m.
  • a 3-12 membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring.
  • 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and so on.
  • acyl such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as
  • hydroxyl protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB),
  • the compounds of formula (I) may contain one or more chiral centers and thus two or more stereoisomers exist. Accordingly, the compounds of the invention may exist in the form of individual stereoisomers (e.g. enantiomers, diastereomers) and mixtures in any proportions, e.g. racemates, and, where appropriate, Can exist in the form of its tautomers and geometric isomers.
  • individual stereoisomers e.g. enantiomers, diastereomers
  • mixtures e.g. racemates
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of protection of the present invention.
  • stereoisomer refers to compounds that have the same chemical constitution but differ in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers and conformational isomers.
  • enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • diastereomer refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography such as HPLC.
  • the prefixes d and l or (+) and (-) are used to indicate the sign of a compound's rotation of plane-polarized light, where (-) or l indicates that the compound is levorotatory.
  • Compounds with the prefix (+) or d are dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of each other.
  • Specific stereoisomers may also be called enantiomers, and mixtures of such isomers are often called enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in chemical reactions or methods without stereoselectivity or stereospecificity.
  • the terms “racemic mixture” and “racemate” refer to two enantiomers that are not optically active. Equimolar mixture of conformations.
  • the racemic mixture can be used in its own form or separated into the individual isomers. By resolution, stereochemically pure compounds can be obtained or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger N.L. and Eliel E.L., "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Chiral forms of individual isomers can be prepared from chiral precursors.
  • the mixture can be prepared by combining individual enantiomers with chiral acids (e.g., 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.)
  • chiral acids e.g., 10-camphorsulfonic acid, camphoric acid, alpha-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.
  • Chemical separation of the mixture to obtain the individual isomers is accomplished by forming diastereomeric salts, fractionally crystallizing said salts, and then freeing one or both of the separated bases, optionally repeating this process, thereby One or both isomers are obtained substantially free of the other isomer, i.e.
  • the racemate can be covalently linked to the chiral compound (auxiliary) to give the diastereomers.
  • tautomer or “tautomeric form” means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called proton transfer tautomers
  • proton transfer tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. Transformation of all isotopic compositions of the compounds of the invention,
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the compounds disclosed in the present invention may have one or more chiral centers, and each chiral center independently has an R configuration or an S configuration.
  • the chiral centers of some of the compounds disclosed in the present invention are marked *R, *S, R*, or S*, which means that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chirality
  • the center is a chiral center with a single configuration.
  • the compound is an enantiomeric monomer with a single configuration, a diastereoisomer monomer with a single configuration, or a diastereomer with a single configuration of the chiral center. Mixture of isomers (for example: other chiral center configurations are not resolved).
  • this type of compound can be determined according to its corresponding chromatography column conditions (such as chromatography column model, chromatography column packing) , column size, mobile phase, etc.) to confirm the corresponding retention time ( RT ).
  • the raw materials used in the present invention are all commercially available unless otherwise specified.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using a Bruker ASCEND TM -400 nuclear magnetic instrument. The measurement solvents were deuterated sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was tetramethylsilane. (TMS)
  • MS was measured using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography mass spectrometers.
  • HPLC was measured using Shimadzu HPLC-2010C high-pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5 ⁇ m column)
  • the thin layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.2mm.
  • the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm. .
  • High-performance liquid phase preparation uses Waters2767, Waters2545, and Innovation Hengtong LC3000 preparative chromatographs.
  • Chiral preparative column chromatography uses Shimadzu LC20-AP and THARSFC PREP80.
  • the pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.
  • Microwave reaction uses Biotage initiator+ type microwave reactor.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 liter.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.
  • reaction temperature is room temperature, and the temperature range is 20°C-30°C.
  • reaction solution was added to water and extracted with ethyl acetate.
  • organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue was passed through silica gel Compound 2-2 (700 mg, yield: 40%, yellow solid) was obtained through column purification.
  • compound 6-2 75 mg, 205.95 ⁇ mol was added with 1-(1-methylethyl)-2-[4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboran-2-yl)methyl]phenyl]-4-trifluoromethylimidazole (81.19mg, 205.95 ⁇ mol), potassium phosphate (87.43mg, 411.89 ⁇ mol), 1,1'-bisdi Phenylphosphine ferrocene palladium dichloride (15.07 mg, 20.59 ⁇ mol) was dissolved in toluene (5 mL)/water (1 mL). Replace nitrogen three times. The reaction was carried out at 90°C for 2 hours.
  • compound 6-2 (10.44g, 28.67mmol) was added with 5-methyl-1-[4-[(4,4,5,5-tetramethyl-1,3,2-dioxa Boran-2-yl)methyl]phenyl]-3-trifluoromethylpyrazole (21.0g, 57.35mmol), sodium tert-butoxide (8.26g, 86.02mmol), [1,1′-bis( Di-tert-butylphosphino)ferrocene]dichloropalladium (II) (4.67 g, 7.17 mmol) was dissolved in toluene (500 mL)/water (50 mL). Replace nitrogen three times. The reaction was carried out at 100°C for 2 hours.
  • compound 41-1 (7g, 35mmol) and compound 2-1 (2.71g, 17mmol) were added to 1,4-dioxane/water (70/14mL), and potassium phosphate (7.54, 35mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (1.69g, 3.55mmol) and methanesulfonic acid (2-dicyclohexylphosphine-2',4', 6'-Tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.50g, 1.77mmol), reaction solution Stir at 100°C for 16 hours, add the reaction solution to water, and extract with ethyl acetate.
  • LCMS detects that the raw material reaction is complete and the target product is generated.
  • reaction solution was concentrated and added to water (80mL), extracted with ethyl acetate (100mL*3), the organic phases were combined, washed with water (100mL), washed with saturated brine (100mL), dried and concentrated over anhydrous sodium sulfate. Afterwards, the crude product of compound 54-2 (7.8g, crude product, yellow oil) was obtained.
  • Step 8 Synthesis of Compound 61
  • reaction solution was stirred at 100°C for 16 hours.
  • the reaction solution was added to water and extracted with ethyl acetate.
  • the organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated.
  • the residue was purified through liquid phase preparation to obtain compound 61 (96.91 mg, yield: 34%).
  • compound 66-2 200 mg, 880.03 ⁇ mol
  • Raney nickel 51.65 mg, 880.03 ⁇ mol
  • the reaction solution was directly filtered and spin-dried to obtain compound 66-3 (200 mg, crude product, yellow oil).
  • compound 68-3 40 mg, 140.18 ⁇ mol
  • compound 24-8 48.15 mg, 154.20 ⁇ mol
  • dichloromethane 5 mL
  • 2-(7-azabenzotriazole) was added Azole)-N,N,N',N'-tetramethylurea hexafluorophosphate (79.95mg, 210.27 ⁇ mol) and N,N-diisopropylethylamine (90.59mg, 700.91 ⁇ mol) at 20°C Reaction time is 16 hours.
  • references for the preparation method of reference compound KSQ-4279 (Example 143, WO2020132269A1)
  • Ubiquitin Rhodamine 110 reaction substrate Use reaction buffer (50mM HEPES [pH 7.8], 0.5mM EDTA, 1mM DTT, 0.1mg/ml BSA and 0.01% Tween-20) to prepare a final concentration of 150nM Ubiquitin Rhodamine 110 (R&D ,E-555-050) substrate mixture.
  • reaction buffer 50mM HEPES [pH 7.8], 0.5mM EDTA, 1mM DTT, 0.1mg/ml BSA and 0.01% Tween-20
  • Compound preparation Dissolve the compounds to be tested in DMSO, and the final concentration of DMSO used is 1%. The compounds were prepared with DMSO into different concentrations. Multiple wells were set up for each concentration and 3-fold gradient dilution was performed, resulting in a total of 11 concentrations. Corresponding vehicle controls were also set up. After dilution, dilute the compound 25-fold with reaction buffer.
  • USP1/UAF1 deubiquitination reaction Add 5 ⁇ L 4x USP1/UAF1 complex solution and 5uL 4x compound to each well of the assay plate and incubate for 15 minutes, then add 10 ⁇ L 2x Ubiquitin Rhodamine 110 reaction substrate to start the reaction. Centrifuge, seal the plate, and incubate at 37°C for 30 minutes.
  • the compound of the present invention has excellent in vitro activity and can inhibit the deubiquitination activity of USP1/UAF1 on Ubiquitin Rhodamine 110.
  • Example 10 Using ICR mice as test animals, Example 10, Example 11 and KSQ-4279 were administered orally, and the LC-MS/MS method was used to measure the drug concentrations in plasma at different times to study the effects of the compounds of the present invention and the compounds of the comparative example on small Pharmacokinetic characteristics in mice.
  • Example 10 add an appropriate amount of 5% DMSO+10% Solutol+85% Saline, vortex and ultrasonicate to prepare a 1 mg/mL clear solution.
  • Example 11 add an appropriate amount of 5% DMSO+10% Solutol+85% Saline, vortex and ultrasonicate to prepare a 1 mg/mL clear solution.
  • KSQ-4279 add an appropriate amount of 5% DMSO+10% Solutol+85% Saline, vortex and sonicate to prepare a 1 mg/mL clear solution.
  • Each compound to be tested was administered to ICR mice in the intravenous group and gavage group (3 mice in each group) after fasting overnight (IV, dosage 1 mg/kg, volume 5 mL/kg; PO, administration Dosage 10mg/kg, administration volume 10mL/kg), take food 4 hours after administration.
  • LC-MS/MS was used to determine the content of the test compound in the plasma of mice after intravenous and intragastric administration.
  • Example 10 The pharmacokinetic parameters of Example 10, Example 11 and KSQ-4279 of the present invention are shown in Table 2.

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Abstract

La présente invention concerne un composé hétérocyclique contenant de l'azote en tant qu'inhibiteur de la protéase 1 spécifique de l'ubiquitine, un procédé de préparation de celui-ci et son utilisation. En particulier, la présente invention concerne un composé représenté par la formule (I) ou un isomère optique ou un sel pharmaceutiquement acceptable de celui-ci, et son utilisation en tant qu'inhibiteur de la protéase 1 spécifique de l'ubiquitine.
PCT/CN2023/111923 2022-08-09 2023-08-09 Procédé de préparation d'un composé hétérocyclique contenant de l'azote en tant qu'inhibiteur de la protéase 1 spécifique de l'ubiquitine, ainsi que application et utilisation de celui-ci WO2024032647A1 (fr)

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CN113164485A (zh) * 2018-12-20 2021-07-23 Ksq治疗公司 被取代的吡唑并嘧啶和被取代的嘌呤以及其作为泛素特异性加工蛋白酶1(usp1)抑制剂的用途
WO2022216820A1 (fr) * 2021-04-07 2022-10-13 Forma Therapeutics, Inc. Inhibition de la protéase 1 spécifique de l'ubiquitine (usp1)
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