WO2022122044A1 - 作为gls1抑制剂的杂环化合物 - Google Patents
作为gls1抑制剂的杂环化合物 Download PDFInfo
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- WO2022122044A1 WO2022122044A1 PCT/CN2021/137567 CN2021137567W WO2022122044A1 WO 2022122044 A1 WO2022122044 A1 WO 2022122044A1 CN 2021137567 W CN2021137567 W CN 2021137567W WO 2022122044 A1 WO2022122044 A1 WO 2022122044A1
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- alkyl
- compound
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- haloalkoxy
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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 relates to the field of medicinal chemistry; in particular, the present invention relates to a new class of derivatives containing tricyclic heteroaryl groups, their synthesis methods and their use as a GLS1 inhibitor in the preparation of medicines for the treatment of tumors and other related diseases applications in .
- Glutamine the most abundant amino acid in the human body, plays a crucial role in the growth and development of tumor cells. As a result, many tumor cells have been described as "addicted to glutamine".
- glutaminase In the process of glutamine metabolism, one of the important enzymes is glutaminase, which is located in the inner membrane of mitochondria in cells and can catalyze the reaction of glutamine to glutamate. Under the action of hydrogenase, it is converted into ⁇ -ketoglutarate, which enters the tricarboxylic acid cycle in the form of a substrate, and provides a metabolic intermediate for the macromolecular synthesis of tumor cells.
- the glutaminase in the human body can be divided into two types from the genetic coding, one is called kidney-type glutaminase (GLS or GLS1); the other is called liver-type (liver-type) glutaminase. Aminamidase (GLS2).
- GLS1 is abundantly expressed in various parts of the body such as kidney, brain, intestine, liver, lymphocytes, and importantly, is often highly expressed in tumor cells. Although these two types are highly similar in amino acid sequence, they come from different related genes, have different protein structure and dynamic characteristics, thus perform different functions, and involve different regulatory mechanisms.
- GLS1 activity or expression are selected from the group consisting of B cell lymphoma, monocytic leukemia, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, Lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, stomach cancer, multiple Various solid tumors and hematological tumors such as myeloma, allergic asthma, myelofibrosis, rheumatoid arthritis, polycythemia splenomegaly, hypereosinophilic syndrome, essential thrombocytopenia, systemic giant cell disease and other diseases.
- the purpose of the present invention is to provide a new class of GLS1 inhibitors.
- the first aspect of the present invention provides a compound of the following formula (II), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof. :
- R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl , C 1-6 haloalkyl, C 1-4 haloalkoxy, C 2-6 alkenyl, C 2-6 haloalkenyl , C 2-6 alkynyl, C 2-6 haloalkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl;
- R is selected from the group consisting of: C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 1-4 haloalkoxy, C 2-4 Alkynyl, C 1-4 haloalkoxy, C 1-4 haloalkenyl, C 1-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 alkoxy, 3-8 membered Cycloalkyl, 3-8 membered halocycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkyl-O-, 3-8 membered halocycloalkyl-O-, 3-8 membered Halocycloalkyl-NR i -, C 1-4 haloalkyl 3-8 membered cycloalkyl-O-, C 1-4 haloalkyl 3-8 membered cycloalkyl-NR i
- R is selected from C 2-6 alkenyl, 3-8 membered cycloalkyl, 3-8 membered halocycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkyl- O-, C 1-4 haloalkoxy 3-8-membered cycloalkyl-O-, or 3-8-membered halocycloalkyl-O-, R 2 is selected from C 2-6 haloalkenyl, C 2-6 alkynyl, or C 2-6 haloalkynyl;
- R k is selected from hydrogen, halogen, or C 1-4 alkyl.
- formula (II) is formula (III):
- R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, 3-8 membered cycloalkyl;
- R 2 is selected from the group consisting of C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl.
- formula (II) is formula (IV):
- R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl;
- Y is selected from chemical bond, O, S, or NR i ; wherein, R i is selected from hydrogen or C 1-4 alkyl;
- U is selected from N or CR m ; wherein, R m is selected from hydrogen, halogen, or C 1-4 alkyl;
- R f and R g are each independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1 -4 alkyl, hydroxy C 1-4 alkyl, C 1-4 haloalkoxy, or C 1-4 haloalkoxy C 1-4 alkyl;
- Each R n is independently selected from hydrogen, halogen, or C 1-4 alkyl
- R k is selected from hydrogen, halogen, or C 1-4 alkyl
- c and d are each independently selected from 1, 2, 3, 4, 5, or 6;
- e is selected from 0, 1, 2, 3, or 4.
- formula (II) is formula (V):
- R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, 3-8 membered cycloalkyl;
- R f and R g are each independently selected from the group consisting of hydrogen, deuterium, fluoro, C 1-4 alkyl;
- R k is selected from hydrogen, halogen, or C 1-4 alkyl
- c and d are each independently selected from 1, 2, or 3.
- formula (II) is formula (VI):
- R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, 3-8 membered cycloalkyl.
- formula (II) is formula (VII):
- R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkynyl, 3-8 membered cycloalkyl;
- R x is selected from the group consisting of C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl;
- f and g are each independently selected from 0, 1, 2, 3, or 4; provided that f and g cannot be 0 at the same time.
- fragment in formula (II) choose from the following structures:
- the compound of formula (II) is selected from the following group:
- the second aspect of the present invention provides a compound of the following structure, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof:
- the third aspect of the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising, as an active ingredient, the compound described in the first aspect or the second aspect of the present invention, or an optical isomer thereof, which is pharmaceutically Acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
- the third aspect of the present invention provides a compound according to the first aspect of the present invention, or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, or a solvate thereof.
- the use of it is used to prepare a pharmaceutical composition for treating diseases or conditions mediated by GLS1 activity or expression level.
- the diseases and conditions mediated by GLS1 activity or expression are selected from the group consisting of B-cell lymphoma, monocytic leukemia, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell Lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, Skin cancer, lymphoma, gastric cancer, multiple myeloma and other solid tumors and hematological tumors, as well as allergic asthma, myelofibrosis, rheumatoid arthritis, polycythemia splenomegaly, eosinophilic leukemia syndrome, primary Thrombocytopenia, systemic giant cell disease and other diseases.
- the inventors After long-term and in-depth research, the inventors have unexpectedly discovered a class of GLS1 inhibitors containing tricyclic aryl compounds with novel structures, as well as their preparation methods and applications.
- the compounds of the present invention can be applied to the treatment of various diseases related to the activity of the kinases. Based on the above findings, the inventors have completed the present invention.
- each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
- alkyl refers to a straight chain (ie, unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight and branched chain groups .
- a carbon number limitation eg, C 1-10
- C 1-8 alkyl refers to an alkyl group containing 1-8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or similar groups.
- alkenyl refers to a straight or branched, carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number limitation (eg, C2-8 ), it means that the alkenyl group contains 2-8 carbon atoms.
- C 2-8 alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or the like group.
- alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
- the alkynyl group can be straight or branched, or a combination thereof.
- a carbon number limitation eg, C 2-8 alkynyl
- C 2-8 alkynyl refers to straight or branched chain alkynyl groups having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
- cycloalkyl refers to a monocyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having saturated or partially saturated .
- a cycloalkyl group is preceded by a carbon number limitation (eg C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
- C 3-8 cycloalkyl refers to saturated or partially unsaturated monocyclic or bicycloalkyl having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclo pentyl, cycloheptyl, or similar groups.
- “Spirocycloalkyl” refers to a bicyclic or polycyclic group in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more double bonds, but none of the rings have fully conjugated pi electrons system.
- “Fused cycloalkyl” refers to an all-carbobicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more bicyclic bonds, but none of the rings have a fully conjugated pi electron system.
- “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system .
- the atoms contained in the cycloalkyl group are all carbon atoms.
- the following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.
- Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, such as phenyl and naphthyl.
- the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be in a conjugated pi-electron system on the carbon atom of the ring.
- Aryl groups can be substituted or unsubstituted.
- Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group containing one to more heteroatoms A polycyclic group formed by condensing nitrogen, oxygen and sulfur) with an aryl group, and the attachment site is located on the aryl group. Heteroaryl groups can be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.
- Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
- monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
- Polycyclic heterocyclyl refers to heterocyclyl including spiro, fused and bridged rings.
- “Spirocyclic heterocyclyl” refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (called a spiro atom) with other rings in the system, wherein one or more ring atoms are selected from nitrogen, oxygen or sulfur, the remaining ring atoms are carbon.
- “Fused-ring heterocyclyl” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but no A ring has a fully conjugated pi electron system and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
- “Bridged heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system , and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If both saturated and aromatic rings are present in the heterocyclyl group (for example, the saturated and aromatic rings are fused together), the point of attachment to the parent must be on the saturated ring. Note: When the point of attachment to the parent is on an aromatic ring, it is called a heteroaryl group, not a heterocyclyl group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.
- halogen refers to F, Cl, Br, and I.
- substituted refers to the replacement of one or more hydrogen atoms on a specified group with a specified substituent. Particular substituents are those described correspondingly in the preceding paragraphs, or the substituents appearing in the various examples. Unless otherwise specified, an optionally substituted group may have at any substitutable position of the group a substituent selected from a specified group, which may be the same or different at each position.
- a cyclic substituent such as a heterocyclyl
- substituents contemplated by the present invention are those that are stable or chemically achievable.
- the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group.
- a pharmaceutically acceptable salt refers to a salt suitable for contact with the tissue of a subject (eg, a human) without undue side effects.
- a pharmaceutically acceptable salt of a compound of the present invention includes a salt of a compound of the present invention that has an acidic group (eg, potassium, sodium, magnesium, calcium) or has a basic salts of compounds of the invention (eg, sulfates, hydrochlorides, phosphates, nitrates, carbonates).
- the present invention provides a class of compounds of formula (II), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrated Use of substances, pharmaceutically acceptable carriers or excipients for inhibiting GLS1.
- the compounds of the present invention are useful as a GLS1 inhibitor.
- the expression or activity of various protein kinases mentioned above are significantly increased. These overexpressed and/or abnormal levels of protein kinase activity are directly related to the occurrence and development of tumors.
- the compounds of the present invention are single and/or dual inhibitors of these protein kinases. Diseases can be prevented, alleviated or cured by modulating the activity of these protein kinases.
- Indicated diseases include B cell lymphoma, monocytic leukemia, liver cancer, rectal cancer, bladder cancer, throat cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glial Plasma cell tumor, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma and other solid tumors and blood tumors and allergies Asthma, myelofibrosis, rheumatoid arthritis, polycythemia splenomegaly, eosinophilic leukocytosis syndrome, essential thrombocytopenia, systemic giant cell disease and other diseases.
- Compounds of the present invention can be combined with biological agents such as PD-1 inhibitors (eg and ) as a combination drug in the treatment of various cancers and related diseases.
- biological agents such as PD-1 inhibitors (eg and ) as a combination drug in the treatment of various cancers and related diseases.
- compositions may be combined with pharmaceutically acceptable excipients or The carriers are formulated together and the resulting compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
- the compositions may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions. Sterile powder, etc.
- the pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin (increase), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and high molecular polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic) and lubricants such as magnesium stearate, glycerin and talc.
- disintegrants such as starch, croscarmellose sodium, complex silicates and high molecular polyethylene glycol
- granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic
- lubricants such as magnesium stearate, glycerin and talc.
- the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, powders.
- the amount of a compound or pharmaceutical composition of the present invention administered to a patient is not fixed, but is usually administered in a pharmaceutically effective amount. Meanwhile, the amount of the compound actually administered can be determined by the physician according to the actual situation, including the condition to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, and the like.
- the dosage of a compound of the present invention will depend upon the particular use of the treatment, the mode of administration, the patient's condition, and the judgment of the physician.
- the ratio or concentration of a compound of the present invention in a pharmaceutical composition depends on a variety of factors, including dosage, physicochemical properties, route of administration, and the like.
- compositions and methods of administration are provided.
- the compound of the present invention Since the compound of the present invention has excellent inhibitory activity against a series of protein kinases, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are
- the pharmaceutical composition of the main active ingredient can be used for the treatment, prevention and alleviation of diseases related to the activity or expression of GLS1.
- the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
- the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
- the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose.
- the "one dose” is a capsule or tablet.
- “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gelling substances which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity. "Compatibility” as used herein means that the components of the composition can be admixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
- Examples of pharmaceutically acceptable carrier moieties include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
- cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
- gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate
- the mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
- Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
- the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
- Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
- liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
- inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylform
- compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
- Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
- compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
- Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
- Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
- the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
- the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
- a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
- the administration dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
- the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
- GLS1 inhibitor A novel structure of GLS1 inhibitor is provided, as well as preparation and application thereof.
- the inhibitor can inhibit the activity of the above-mentioned protein kinase at a very low concentration.
- a pharmaceutical composition for treating diseases related to GLS1 activity is provided.
- a GLS1 inhibitor with good oral absorption is provided.
- compound 5b (1.24 g, 3.62 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), triisopropylsilylacetylene (659.4 mg, 3.62 mmol), Pd(PPh 3 ) 2 Cl 2 were added successively (254.1 mg, 0.362 mmol), cuprous iodide (69 mg, 0.362 mmol) and diisopropylethylamine (5 mL). The reaction mixture was stirred at 25°C overnight.
- reaction solution was cooled to room temperature, it was diluted with ethyl acetate (50 mL), cooled to 0° C., and quenched with saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue gave compound 7e as a yellow liquid (285 mg), which was used directly in the next step.
- compound 9b-cis (410 mg, 1.52 mmol), X-Phos (109 mg, 0.228 mmol) and Pd 2 (dba) 3 (139 mg, 0.152 mmol) were dissolved in tetrahydrofuran (5 mL) and bubbled with nitrogen flow Soak and deoxygenate for 5 minutes.
- the freshly prepared ethyl acetate zinc bromide reagent (9.1 mL, 4.55 mmol) was then added, and the oxygen was deoxygenated by bubbling a stream of nitrogen for 10 minutes. The mixture was heated to 55°C and stirred for 1 hour.
- reaction solution was cooled to room temperature, it was diluted with ethyl acetate (50 mL), cooled to 0° C., and quenched with saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to obtain yellow liquid compound 9c-cis (189 mg, 42%).
- reaction solution was cooled to room temperature, it was diluted with ethyl acetate (50 mL), cooled to 0° C., and quenched with saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a yellow liquid crude compound 11c (1.5 g). used directly in the next reaction.
- compound 12g (18mg, 0.07mmol) was dissolved in anhydrous dioxane (3mL), 4b (54.58mg, 0.084mmol), allyl palladium (II) (1.3mg, 0.003 mmol), XantPhos (8.1 mg, 0.014 mmol), Cs2CO3 ( 45.6 mg, 0.14 mmol). The reaction mixture was stirred at 80°C overnight.
- reaction solution was cooled to room temperature, quenched by adding saturated aqueous ammonium chloride solution, extracted with water (20 mL) and ethyl acetate (3 ⁇ 10 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. , the filtrate was concentrated under reduced pressure to obtain the crude product.
- the glutamine oxidase/Amplex Red coupling method was used to measure the activity of glutaminase GLS1, and the inhibitory ability of the compounds to GLS1 activity was detected.
- L-glutamic acid can be oxidized to ⁇ -ketoglutarate, NH 3 and H 2 O 2 by glutamate oxidase.
- Amplex Red reagent can react with the generated H 2 O 2 in a stoichiometric ratio of 1:1 to form a highly fluorescent resorufin, which can be detected by the assay.
- the fluorescence intensity of Lufin reflects the rate of enzyme-catalyzed reaction and the activity of the enzyme.
- the ability of compounds to inhibit cellular GLS1 activity was assessed using A549 intracellular glutaminase and coupled assays to measure cellular glutamate consumption.
- the specific method is as follows: inoculate cells in a 96-well plate at a density of 3-5 ⁇ 10 3 A549 cells/well, add solutions of compounds to be tested at different concentrations, and incubate at 37° C. for 24 hours.
- the supernatant was discarded, washed 1-2 times with PBS, and 20 ⁇ L of cell lysate (the composition was 10 mM Tris pH7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1 mM NaF, 20 mM Na 4 P 2 O 7 , 2mM Na3VO4 , 1 % Triton X-100, 10% glycerol, 0.1% SDS and 0.5% deoxycholate), lysed for 30 minutes on ice.
- the cell lysate was collected into a 1.5 ml centrifuge tube and centrifuged at 12,000 rpm for 10 minutes.
- CCK-8 assay Cell proliferation and the inhibitory effect of compounds on cell growth were detected by CCK-8 assay.
- the basic principle is that the CCK-8 reagent contains WST-8, which is a water-soluble tetrazolium salt with the chemical name of 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl) Phenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazole monosodium salt.
- WST-8 is a water-soluble tetrazolium salt with the chemical name of 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl) Phenyl)-5-(2,4-disulfonic acid benzene)-2H-tetrazole monosodium salt.
- This reagent can be reduced to a water-soluble yellow formazan product (Formazan) by NAD + produced in cells in the presence of an electron-coupling reagent. The more living cells,
- absorbance values can be measured by colorimetry and the proportion of viable cells can be calculated.
- the specific method is as follows: A549 cells were inoculated into 96-well plates at a cell density of 3-5 ⁇ 10 3 cells/well, the cells were cultured for 24 hours and then added with drugs, added with different concentrations of test compound solutions, and incubated at 37°C for 48 hours. After incubation, add 10 ⁇ L of CCK-8 solution to each well and continue to incubate in the incubator for 3-4 hours. Take out the culture plate and put it in the microplate reader, measure the absorbance value at the wavelength of 450nm, set the blank control group at the same time, analyze the original data and calculate the IC 50 value.
- H2122 cells with good growth status were selected and digested with trypsin. Add fresh medium, mix well, and centrifuge at 800 rpm for 3 minutes. The cells were seeded in 96-well plates at a seeding density of 2000 cells per well, and cultured overnight in a 37°C incubator. The next day, the culture plate was taken out, and the compound was diluted in four-fold gradient, treated with administration, and then placed in a 37°C incubator for 72 hours.
- test results of representative compounds on the proliferation inhibitory activity of non-small cell lung cancer H2122 cells are listed in Table 2.
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Abstract
本发明提供了作为GLS1抑制剂的杂环化合物,具体地,本发明提供了一种如下式(II)所示结构的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物。上述的化合物具有GLS1抑制活性,可以作为GLS1相关的疾病或病症的治疗剂。
Description
本发明涉及药物化学领域;具体地说,本发明涉及一类新型含有三环杂芳基的衍生物,其合成方法及其作为一种GLS1抑制剂在制备药物用于治疗肿瘤等相关多种疾病中的应用。
肿瘤细胞的快速生长不仅需要能量,也需要核酸、脂肪酸和蛋白质进行新细胞的生成。谷氨酰胺作为人体中最丰富的氨基酸,在肿瘤细胞的生长和发展过程中起到了至关重要的作用。因此,许多肿瘤细胞被描述为“沉溺于谷氨酰胺”(addicted to glutamine)的细胞。
在谷氨酰胺新陈代谢的过程中,其中一个重要的酶是谷氨酰胺酶,它位于细胞中线粒体的内膜,可以催化由谷氨酰胺生成谷氨酸的反应,谷氨酸在谷氨酸脱氢酶的作用下转变为α-酮戊二酸,以底物的形式进入三羧酸循环,为肿瘤细胞的大分子合成提供新陈代谢的中间体。人体中的谷氨酰胺酶从基因编码上可以分为两种类型,一种叫肾脏型(kidney-type)谷氨酰胺酶(GLS或GLS1);另一种叫做肝脏型(liver-type)谷氨酰胺酶(GLS2)。GLS1在身体的各个部分比如:肾脏、大脑、肠、肝脏、淋巴细胞都有丰富的表达,重要的是经常在肿瘤细胞中高表达。这两种类型虽然在氨基酸的序列上高度相似,但它们来自不同的相关基因,具有不同的蛋白结构和动力学特征,从而行使不同的功能,并且涉及的调节机制也不同。
细胞的恶性转化伴随着核酸和蛋白质合成的显著增加。对快速增长的肿瘤细胞来说蛋白质的高速合成,需要不断提供必需和非必需的氨基酸,谷氨酰胺作为人体中最丰富的氨基酸,为这一巨大的需求提供了保证。谷氨酰胺代谢在细胞内的线粒体中进行,因此谷氨酰胺必须通过细胞膜从细胞外运到细胞质中,再从细胞质中通过线粒体膜运到线粒体内。研究表明,肿瘤细胞通过细胞膜运输谷氨酰胺远比正常细胞快。在艾氏腹水(Ehrlich ascites)癌细胞上的研究,也证明了该癌细胞线粒体膜上存在的一种特殊的谷氨酰胺运输系统可以比正常细胞更快的速度把谷氨酰胺运入线粒体。因为谷氨酰胺酶的活性是依赖于无机磷的浓度,而肿瘤细胞线粒体中无机磷浓度高,所以其谷氨酰胺酶活性高。事实上科学研究证明谷氨酰胺酶的高活性和肿瘤细胞的快速生长紧密相关。用谷氨酰胺酶的反义mRNA去转染艾氏腹水癌细胞,不但它们的生长受到抑制而且形态也发生了变化。用反义mRNA转染的癌细胞,接种到小鼠体内,这样的癌细胞完全失去了产生肿瘤的能力,这样的小鼠和健康动物完全一样。这些科学发现充分说明了谷氨酰胺酶的活性与癌症发生和发展紧密相关,谷氨酰胺酶已成为抗癌疗法中受到人们极大关注的目的基因。
GLS1活性或表达量介导的疾病和病症选自下组:B细胞淋巴瘤、单核细胞白血病、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓瘤等多种实体瘤和血液瘤以及过敏性哮喘、骨髓纤维化、类风湿性关节炎、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病等疾病。
因此,开发一种有效的谷氨酰胺酶的抑制剂,特别是肾脏型谷氨酰胺酶的抑制剂,变 得重要而紧迫。
发明内容
本发明的目的是提供一类新型的GLS1抑制剂。
本发明的第一方面,提供了一种如下式(II)所示结构的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物:
“*”表示手性中心,可为R型或S型;
R
2选自下组:氢、氘、卤素、C
1-6烷基、C
1-6卤代烷基、C
1-4卤代烷氧基、C
2-6烯基、C
2-
6卤代烯基、C
2-6炔基、C
2-6卤代炔基、3-8元环烷基、3-8元杂环基;
R
3选自下组:C
2-6烯基、C
2-6卤代烯基、C
2-6炔基、C
2-6卤代炔基、C
1-4卤代烷氧基C
2-4炔基、C
1-4卤代烷氧基、C
1-4卤代烯氧基、C
1-4卤代炔氧基、C
1-4卤代烷氧基C
1-4烷氧基、3-8元环烷基、3-8元卤代环烷基、3-8元杂环基、3-8元环烷基-O-、3-8元卤代环烷基-O-、3-8元卤代环烷基-NR
i-、C
1-4卤代烷基3-8元环烷基-O-、C
1-4卤代烷基3-8元环烷基-NR
i-、C
1-4卤代烷氧基3-8元环烷基-O-、C
1-4卤代烷氧基3-8元环烷基-NR
i-、C
1-4卤代烷氧基C
1-4烷基3-8元环烷基-O-、C
1-4卤代烷氧基C
1-4烷基3-8元环烷基-NR
i-、C
1-4卤代烷氧基C
1-4烷氧基3-8元环烷基-O-、CyC=R
5、-O-CyC=R
5、-S-CyC=R
5、或-NR
i-CyC=R
5;其中,所述的CyC为饱和的3-8元环烷基,或饱和的4-8元杂环基,且所述的R
5选自下组:O、CR
fR
g,其中,R
f和R
g各自独立地选自下组:氢、氘、卤素、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基、C
1-4烷氧基C
1-4烷基、羟基C
1-4烷基、C
1-4卤代烷氧基、C
1-4卤代烷氧基C
1-4烷基;R
i选自氢或C
1-4烷基;所述的CyC可任选地被一到多个R
n取代;其中,R
n选自氢、卤素、或C
1-4烷基;
前提条件是,当R
3选自C
2-6烯基、3-8元环烷基、3-8元卤代环烷基、3-8元杂环基、3-8元环烷基-O-、C
1-4卤代烷氧基3-8元环烷基-O-、或3-8元卤代环烷基-O-时,R
2选自C
2-6卤代烯基、C
2-6炔基、或C
2-6卤代炔基;
R
k选自氢、卤素、或C
1-4烷基。
在另一优选例中,式(II)为式(III):
R
2选自下组:C
1-6烷基、C
1-6卤代烷基、C
2-6炔基、3-8元环烷基;
R
3选自下组:C
2-6炔基、C
2-6卤代炔基、C
1-4卤代烷氧基C
2-4炔基、3-8元卤代环烷基-NR
i-、C
1-4卤代烷氧基C
1-4烷氧基、C
1-4卤代烷基3-8元环烷基-O-、C
1-4卤代烷氧基C
1-4烷基 3-8元环烷基-O-、C
1-4卤代烷氧基C
1-4烷氧基3-8元环烷基-O-、CyC=R
5、-O-CyC=R
5、-S-CyC=R
5、或-NR
i-CyC=R
5;其中,所述的CyC为饱和的3-8元环烷基,或饱和的4-8元杂环基,且所述的R
5选自下组:O、CR
fR
g,其中,R
f和R
g各自独立地选自下组:氢、氘、卤素、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基、C
1-4烷氧基C
1-4烷基、羟基C
1-4烷基、C
1-4卤代烷氧基、C
1-4卤代烷氧基C
1-4烷基;R
i选自氢或C
1-4烷基;所述的CyC可任选地被一到多个R
n取代;其中,R
n选自氢、卤素、或C
1-4烷基。
在另一优选例中,R
2选自下组:C
2-6卤代烯基、C
2-6炔基、C
2-6卤代炔基。
在另一优选例中,R
3选自下组:C
2-6炔基、C
2-6卤代炔基、C
1-4卤代烷氧基C
2-4炔基、C
1-4卤代烷氧基C
1-4烷氧基、C
1-4卤代烷基3-8元环烷基-O-、C
1-4卤代烷氧基C
1-4烷基3-8元环烷基-O-、C
1-4卤代烷氧基C
1-4烷氧基3-8元环烷基-O-、CyC=R
5、或-O-CyC=R
5;其中,所述的CyC为饱和的3-8元环烷基,或饱和的4-8元杂环基,且所述的R
5选自下组:O、CR
fR
g,其中,R
f和R
g各自独立地选自下组:氢、氘、卤素、C
1-4烷基、C
1-4卤代烷基;所述的CyC可任选地被一到多个R
n取代;其中,R
n选自氢、卤素、或C
1-4烷基。
在另一优选例中,式(II)为式(IV):
“*”表示手性中心;
R
2选自下组:氢、氘、卤素、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6卤代烯基、C
2-6炔基、C
2-6卤代炔基、3-8元环烷基、3-8元杂环基;
Y选自化学键、O、S、或NR
i;其中,R
i自选自氢或C
1-4烷基;
U选自N或CR
m;其中,R
m选自选自氢、卤素、或C
1-4烷基;
R
f和R
g各自独立地选自下组:氢、氘、卤素、C
1-4烷基、C
1-4卤代烷基、C
1-4烷氧基、C
1-4烷氧基C
1-4烷基、羟基C
1-4烷基、C
1-4卤代烷氧基、或C
1-4卤代烷氧基C
1-4烷基;
各个R
n各自独立地选自氢、卤素、或C
1-4烷基;
R
k选自氢、卤素、或C
1-4烷基;
c和d各自独立地选自1、2、3、4、5、或6;
e选自0、1、2、3、或4。
在另一优选例中,式(II)为式(V):
“*”表示手性中心;
R
2选自下组:氢、氘、卤素、C
1-6烷基、C
1-6卤代烷基、C
2-6烯基、C
2-6卤代烯基、C
2-6炔基、C
2-6卤代炔基、3-8元环烷基;
R
f和R
g各自独立地选自下组:氢、氘、氟、C
1-4烷基;
R
k选自氢、卤素、或C
1-4烷基;
c和d各自独立地选自1、2、或3。
在另一优选例中,式(II)为式(VI):
R
2选自下组:C
1-6烷基、C
1-6卤代烷基、C
2-6炔基、3-8元环烷基。
在另一优选例中,式(II)为式(VII):
R
2选自下组:C
1-6烷基、C
1-6卤代烷基、C
2-6炔基、3-8元环烷基;
R
x选自下组:C
1-4卤代烷基、C
1-4卤代烷氧基C
1-4烷基、C
2-4烯基、C
2-4炔基;
“*”表示手性中心。
在另一优选例中,所述的式(II)化合物选自下组:
本发明的第二方面,提供了一种如下式所示结构的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物:
本发明的第三方面,提供了一种药物组合物,所述的药物组合物包括作为活性成分的如本发明第一方面或第二方面所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,和药学上可接受的载体。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物的用途,其用于制备治疗GLS1活性或表达量介导的疾病或病症的药物组合物。
在另一优选例中,所述的GLS1活性或表达量介导的疾病和病症选自下组:B细胞淋巴 瘤、单核细胞白血病、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓瘤等多种实体瘤和血液瘤以及过敏性哮喘、骨髓纤维化、类风湿性关节炎、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病等疾病。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
本发明人经过长期而深入的研究,意外地发现了一类结构新颖的含有三环芳基化合物的GLS1抑制剂,以及它们的制备方法和应用。本发明化合物可以应用于与所述激酶的活性相关的各种疾病的治疗。基于上述发现,发明人完成了本发明。
术语
除特别说明之处,本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处,本发明的所有化合物之中,各手性碳原子(手性中心)可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,在单独或作为其他取代基一部分时,术语“烷基”指只含碳原子的直链(即,无支链)或支链饱和烃基,或直链和支链组合的基团。当烷基前具有碳原子数限定(如C
1-10)时,指所述的烷基含有1-10个碳原子。例如,C
1-8烷基指含有1-8个碳原子的烷基,包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“烯基”是指直链或支链,具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C
2-8)时,指所述的烯基含有2-8个碳原子。例如,C
2-8烯基指含有2-8个碳原子烯基,包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的,或其组合。当炔基前具有碳原子数限定(如C
2-8炔基)时,指所述的炔基含有2-8个碳原子。例如,术语“C
2-8炔基”指具有2-8个碳原子的直链或支链炔基,包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用,在单独或作为其他取代基一部分时,术语“环烷基”指具有饱和的或部分饱和的单元环,二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C
3-10)时,指所述的环烷基含有3-10个碳原子。在一些优选实施例中,术语“C
3-8环烷基”指具有3-8个碳原子的饱和或部分不饱和的单环或二环烷基,包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。所述 环烷基所含原子全部为碳原子。如下是环烷基的一些例子,本发明并不仅局限下述的环烷基。
除非有相反陈述,否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子,本发明并不仅局限下述的芳基。
“杂芳基”指包含一个到多个杂原子(任选自氮、氧和硫)的具有芳香性的单环或多环基团,或者包含杂环基(含一个到多个杂原子任选自氮、氧和硫)与芳基稠合形成的多环基团,且连接位点位于芳基上。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子,本发明并不仅局限下述的杂芳基。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指系统中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。“稠环杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基 团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,而且其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团,这些可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,而且其中一个或多个环原子选自氮、氧或硫,其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起),连接到母体的点一定是在饱和的环上。注:当连接到母体的点在芳环上时,称为杂芳基,不称为杂环基。如下是杂环基的一些例子,本发明并不仅局限下述的杂环基。
如本文所用,在单独或作为其他取代基一部分时,术语“卤素”指F、Cl、Br和I。
如本文所用,术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。环状取代基,例如杂环基,可以与另一个环相连,例如环烷基,从而形成螺二环系,即两个环具有一个共用碳原子。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):C
1-8烷基、C
2-8烯基、C
2-8炔基、C
3-8环烷基、3-至12-元杂环基,芳基、杂芳基、卤素、羟基、羧基(-COOH)、C
1-8醛基、C
2-10酰基、C
2-10酯基、氨基。
为了方便以及符合常规理解,术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点,而不包括那些化学上不能实现的取代。
如本文所用,除非特别说明,术语“药学上可接受的盐”指适合与对象(例如,人)的组织接触,而不会产生不适度的副作用的盐。在一些实施例中,本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如,钾盐,钠盐,镁盐,钙盐)或具有碱性基团的本发明的化合物的盐(例如,硫酸盐,盐酸盐,磷酸盐,硝酸盐,碳酸盐)。
用途:
本发明提供了一类式(II)的化合物,或它们的氘代衍生物、它们的盐、异构体(对映异构体或非对映异构体,如果存在的情况下)、水合物、可药用载体或赋形剂用于抑制GLS1的用途。
本发明化合物可用作一种GLS1抑制剂。
在癌症病人体内,上述所提到的各种蛋白激酶的表达或活性都明显增高。这些过度表达和/或异常的蛋白激酶活性水平与肿瘤的发生发展直接关联。本发明化合物是这些蛋白激酶的单一和/或双重抑制剂。通过调节这些蛋白激酶活性得到预防、缓解或治愈疾病。所指疾病包括B细胞淋巴瘤、单核细胞白血病、肝癌、直肠癌、膀胱癌、咽 喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓瘤等多种实体瘤和血液瘤以及过敏性哮喘、骨髓纤维化、类风湿性关节炎、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病等疾病。
从某种角度上说,双重蛋白激酶抑制剂同时干扰两种不同的激酶,所产生的抗肿瘤效果往往具有叠加性,因此具有更有效治疗各种癌症的潜力。
可将本发明化合物及其氘代衍生物,以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起,得到的组合物可在体内给予哺乳动物,例如男人、妇女和动物,用于治疗病症、症状和疾病。组合物可以是:片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液。无菌粉末等。一些实施例中,药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇),造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中,所述药物组合物是适于口服的剂型,包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定,通常按药用有效量给药。同时,实际给予的化合物的量可由医师根据实际情况决定,包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素,包括剂量、理化性质、给药途径等。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。
药物组合物和施用方法
由于本发明化合物具有优异的对一系列蛋白激酶的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与GLS1活性或表达量相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选5~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
1.提供了一种如式II所示的化合物。
2.提供了一种结构新颖的GLS1抑制剂,及其制备和应用,所述的抑制剂在极低浓度下即可抑制上述蛋白激酶的活性。
3.提供了一类治疗与GLS1活性相关疾病的药物组合物。
4.提供了一种口服吸收良好的的GLS1抑制剂。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
实施例1:化合物1的制备
化合物1a(465mg,4.39mmol)和碳酸钠(558mg,5.27mmol)溶于乙腈(15mL)中,70℃下搅拌1小时。随后再向反应液中缓慢加入化合物1b(983mg,4.39mmol)的乙腈(5mL)稀释液。反应混合液在70℃下搅拌过夜。TLC监测反应完毕。待反应混合物冷却后减压浓缩,将所得粗品溶于二氯甲烷后再经二氯甲烷萃取(3x20mL)。合并的有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=15:1)得到无色油状化合物1c(448mg,收率48%)。
1H NMR(500MHz,CDCl
3)δ5.09-4.91(m,1H),3.25(d,J=5.5Hz,2H),2.83-2.76(m,4H),2.46-2.36(m,2H),2.00(t,J=2.6Hz,1H),1.45(s,9H)。
室温下将化合物1d(319mg,2.11mmol)溶于甲基叔丁基醚(15mL)中,再分别依次加入化合物1c(448mg,2.11mmol)和二异丙基乙基胺(1.09g,8.44mmol)。反应混合液在室温下搅拌过夜。TLC监测反应完毕后,反应混合物减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1)得到红色固体化合物1e(335mg,收率49%)。
1H NMR(500MHz,CDCl
3)δ4.75(s,1H),4.00-3.90(m,4H),3.46(d,J=5.9Hz,2H),2.66-2.60(m,2H),2.00(s,1H),1.39(s,9H)。
化合物1e(335mg,1.03mmol)和4-二甲氨基吡啶(25mg,0.21mmol)的四氢呋喃(8mL)混合液在60℃下搅拌2天。TLC监测反应完毕后,反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1)得到棕色固体化合物1f(297mg,收率97%)。
1H NMR(500MHz,CDCl
3)δ6.89(s,1H),4.97(s,1H),3.71(t,J=8.1Hz,2H),3.60(t,J=5.9Hz,2H),3.47-3.38(m,2H),3.09-2.99(m,2H),1.37(s,9H)。MS m/z 299.3[M+H]
+。
室温下向甲醇(15mL)中加入化合物1f(235mg,0.79mmol)和钯碳催化剂(10%,80mg),该反应混合物在室温和1大气压的氢气氛围下搅拌1小时。TLC监测反应完成。反应混合物经过硅藻土过滤,滤液经减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1)得到粗品棕色固体化合物1g(222mg)直接用于下一步反应。MS m/z 265.3[M+H]
+。
将化合物1g(222mg,0.84mmol)溶于1,4-二氧六环(4mL)中,再加入HCl二氧六环溶液(4M,1mL),反应混合物在室温下搅拌过夜。TLC监测反应完毕。反应混合物减压浓缩。将所得混合物溶于水中,经饱和碳酸氢钠溶液中和,二氯甲烷萃取 (3x10mL)。合并的有机相再经饱和食盐水洗涤,无水硫酸钠干燥,过滤后减压浓缩。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=6:1,2%氨水)得到黄色固体化合物1h(122mg,两步收率94%)。MS m/z 165.2[M+H]
+。
化合物1h(20mg,0.12mmol)和化合物1i(22mg,0.12mmol)溶于乙腈(6mL)中,再加入二异丙基乙基胺(24mg,0.18mmol),反应混合物在80℃下搅拌2小时。TLC监测反应完毕。待反应混合物冷却至室温后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=10:1,2%氨水)得到黄色油状化合物1j(20mg,收率62%)。MS m/z 264.4[M+H]
+。
化合物1j(20mg,0.07mmol),化合物1k(13mg,0.07mmol),1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(59mg,0.11mmol)和二异丙基乙基胺(15mg,0.11mmol)的N,N-二甲基甲酰胺(2mL)混合液在室温下搅拌4小时。TLC监测反应完毕后,反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=15:1,2%氨水)得到白色固体化合物1(9mg,收率29%)。
1H NMR(500MHz,CD
3OD)δ8.16(d,J=4.5Hz,1H),7.49-7.43(m,2H),7.41-7.33(m,3H),7.06(d,J=4.5Hz,1H),4.90(s,1H),3.70-3.62(m,6H),3.42(s,3H),3.06(t,J=7.6Hz,2H)。MS m/z 412.5[M+H]
+。
实施例2:化合物2的制备
将化合物1f(60mg,0.20mmol)溶于甲醇(4mL)中,再加入HCl二氧六环溶液(4M,1mL),反应混合物在40℃下搅拌2小时。TLC监测反应完毕。向反应混合物中加入适量氨水调节PH至碱性,再将该混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1,2%氨水)得到粗品黄色油状化合物2a(50mg)直接用于下一步反应。MS m/z 199.2[M+H]
+。
化合物2a(50mg,0.25mmol)和化合物1i(45mg,0.25mmol)溶于乙腈(3mL)中,再加入二异丙基乙基胺(49mg,0.38mmol),反应混合物在80℃下搅拌2小时。TLC监测反应完毕。待反应混合物冷却至室温后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1,2%氨水)得到灰白色固体化合物2b(58mg,两步收率97%)。MS m/z 298.4[M+H]
+。
化合物2b(58mg,0.19mmol),化合物1k(32mg,0.19mmol),1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(152mg,0.29mmol)和二异丙基乙基胺(38mg,0.29mmol)的N,N-二甲基甲酰胺(2mL)混合液在室温下搅拌1小时。TLC监测反应完毕后,反应混合物减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=25:1,2%氨水)得到白色固体化合物2(38mg,收率44%)。
1H NMR(500MHz,CD
3OD)δ7.50-7.42(m,2H),7.40-7.32(m,3H),7.05(s,1H),4.89(s,1H),3.72(t,J=8.1Hz,2H),3.67-3.56(m,4H),3.41(s,3H),3.05(t,J=8.1Hz,2H)。MS m/z 446.4[M+H]
+。
实施例3:化合物3的制备
将化合物3a(3.0g,16.12mmol)溶于THF(50mL)中,冷却至-78℃。于氮气氛围下,加入LDA(2M in THF,16mL)。反应混合物在-78℃下搅拌0.5小时,再加入碳酸二甲酯(1.45g,16.12mmol),搅拌5min后,转至室温搅拌2小时。TLC检测反应完毕。将反应液在冰浴下以饱和氯化铵水溶液(100mL)猝灭,再用乙酸乙酯萃取(3x 100mL)。合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩。所得粗品再经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1)得到类白色固体化合物3b(1.50g,38%)。MS m/z 244.2,246.2[M+H]
+。
将化合物3b(1.50g,6.15mmol)溶于DMF(20mL)中,再加入化合物三乙基硅基乙炔(862mg,6.15mmol),Pd(PPh
3)
2Cl
2(431mg,0.61mmol),碘化亚铜(234mg,1.23mmol)及DIPEA(2.38g,18.45mmol)。反应混合物于氮气氛围下90℃加热搅拌2小时。TLC检测反应完毕。将反应混合物经硅藻土过滤,滤液减压浓缩,经硅胶柱层析纯化(石油醚:乙酸乙酯=5:1)得化合物3c(1.20g,64%)。MS m/z 304.5[M+H]
+。
将化合物3c(1.20g,3.95mmol)溶于甲醇(20mL)中,再加入氨甲醇溶液(7M,20mL),室温搅拌24h。TLC检测反应完毕。将反应液减压浓缩,经硅胶柱层析(二氯甲烷:甲醇=20:1)纯化得化合物3d(612mg,89%)。
1H NMR(500MHz,CDCl
3)δ7.39(s,1H),7.21(s,1H),7.19(s,1H),5.44(s,1H),3.75(s,2H),3.32(s,1H),2.59(s,3H)。MS m/z 175.2[M+H]
+。
将碘化亚铜(44mg,0.23mmol),碳酸钾(317mg,2.30mmol),菲罗啉(83mg,0.46mmol),3,3-二甲基-1-(三氟甲基)-1,2-苯并碘氧杂戊环(568mg,1.72mmol)在氮气氛围下溶于无水二氯甲烷(20mL)中。再缓慢滴加化合物3d(200mg,1.15mmol)的二氯甲烷(20mL)溶液,滴毕,室温搅拌2小时。LCMS监测反应完毕。将反应液减压浓缩,粗品经硅胶柱层析(二氯甲烷:甲醇=20:1)纯化得化合物3e(85mg,31%)。MS m/z 243.2[M+H]
+。
将化合物3f(15mg,0.04mmol,根据专利CN201580037629报道方法制备),化合物3e(13mg,0.06mmol),铜粉(3mg,0.05mmol),碳酸钾(11mg,0.08mmol),N,N'-二甲基乙二胺(4mg,0.05mmol)溶于甲苯(5mL)中。反应混合物 于氮气氛围下135℃加热搅拌1小时。TLC检测反应完毕。将反应混合物冷却至室温,倒入冰水中,再用乙酸乙酯萃取(3x 20mL)。合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩。所得粗品再经制备型薄层板纯化(二氯甲烷:甲醇=20:1)得到类白色固体化合物3(2mg,10%)。
1H NMR(500MHz,CDCl
3)δ10.75(s,1H),8.39(d,J=9.1Hz,1H),8.16(d,J=0.9Hz,1H),7.32(d,J=9.1Hz,1H),7.28(s,1H),7.25(s,1H),7.13-7.10(m,1H),5.01-4.87(m,1H),4.75-4.65(m,1H),4.64-4.54(m,1H),3.92(s,2H),3.16-3.05(m,2H),3.01(d,J=5.0Hz,3H),2.70(s,3H),2.29-2.19(m,1H),2.15-2.06(m,1H)。MS m/z 519.4[M+H]
+。
实施例4:化合物4的制备
将化合物3d(54mg,0.29mmol),2-碘-1,1,1-三氟乙烷(240mg,1.14mmol),Pd
2(dba)
3(27mg,0.03mmol),三乙烯二胺(128mg,1.14mmol),双(2-二苯基磷苯基)醚(65mg,0.12mmol)溶于甲苯(5mL)中。反应混合物于氮气氛围下80℃加热搅拌4小时。LCMS检测反应完毕。将反应混合物冷却至室温,经硅藻土过滤,滤液减压蒸馏,所得粗品经硅胶柱层析纯化(乙酸乙酯)得化合物4a(40mg,52%)。
1H NMR(500MHz,CDCl
3)δ7.41(s,1H),7.20(s,1H),7.17(s,1H),5.39(s,1H),3.76(s,2H),3.31(q,J=9.4Hz,2H),2.60(s,3H)。MS m/z 257.3[M+H]
+。
将化合物4a(30mg,0.12mmol),化合物4b(50mg,0.08mmol,根据专利CN201580037629报道方法制备),碘化亚铜(15mg,0.08mmol),磷酸钾(33mg,0.16mmol),N,N'-二甲基乙二胺(14mg,0.16mmol)溶于甲苯(3mL)中。氮气氛围下135℃加热搅拌1小时。TLC检测反应完毕。将反应混合物冷却至室温,倒入冰水中,再用乙酸乙酯萃取(3x 20mL)。合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩。所得粗品再经制备型薄层板纯化(二氯甲烷:甲醇=20:1)得到类白色固体化合物4c(15mg,25%)。MS m/z 776.8[M+H]
+。
将化合物4c(18mg,0.02mmol)溶于二氯甲烷(5mL)中,再加入盐酸二氧六 环(4M,1mL)。反应液于50℃加热搅拌4小时。LCMS监测反应完毕。将反应液减压浓缩得化合物4d粗品(10mg)直接用于下一步反应。MS m/z 520.4[M+H]
+。
将化合物4d(10mg,0.02mmol)溶于DMF(2mL)中,再加入甲胺盐酸盐(3mg,0.04mmol),二异丙基乙胺(8mg,0.06mmol),HATU(12mg,0.03mmol)。将反应混合物于室温下搅拌1小时。LCMS监测反应完毕。将反应混合物倒入冰水中,再用二氯甲烷萃取(3x 20mL)。合并的有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩。所得粗品再经制备型薄层板纯化(二氯甲烷:甲醇=20:1)得到黄色固体化合物4(2mg,19%)。
1H NMR(500MHz,CDCl
3)δ11.01(s,1H),8.39(d,J=9.1Hz,1H),8.16(d,J=0.7Hz,1H),7.31(d,J=9.2Hz,1H),7.16(s,1H),7.13(s,1H),7.12-7.09(m,1H),5.02-4.87(m,1H),4.75-4.65(m,1H),4.63-4.54(m,1H),3.88(s,2H),3.33-3.26(m,2H),3.15-3.06(m,2H),3.01(d,J=5.0Hz,3H),2.65(s,3H),2.31-2.20(m,1H),2.14-2.06(m,1H)。MS m/z 533.5[M+H]
+。
实施例5:化合物5的制备
将氢化钠(186mg,4.47mmol)溶于四氢呋喃(15mL)中,在0℃下分批加入3,3-二氟环丁醇(483mg,4.47mmol),并在0℃下搅拌0.25小时,随后再向反应液中加入化合物5a(1g,3.57mmol)。反应混合液在25℃下搅拌4小时。TLC监测反应完毕。往反应瓶中加入冰水(20mL),乙酸乙酯萃取(3x 10mL),合并的有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=20:1)得到白色固体化合物5b(1.24g,100%)。
1H NMR(500MHz,CDCl
3)δ6.89(s,2H),4.71–4.64(m,1H),3.20–3.11(m, 2H),2.84–2.73(m,2H).
在氮气氛围下,将化合物5b(1.24g,3.62mmol)溶于无水四氢呋喃(20mL)中,依次加入三异丙基硅基乙炔(659.4mg,3.62mmol),Pd(PPh
3)
2Cl
2(254.1mg,0.362mmol),碘化亚铜(69mg,0.362mmol)和二异丙基乙胺(5mL)。反应混合液在25℃下搅拌过夜。TLC监测反应完毕,加入水(30mL)和乙酸乙酯(20mL*3)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=30:1-20:1)得到白色固体化合物5c(1.1g,68%)。
1H NMR(500MHz,CDCl
3)δ6.86(d,J=2.0Hz,1H),6.84(d,J=2.0Hz,1H),4.73–4.65(m,1H),3.19–3.09(m,2H),2.83–2.71(m,2H),1.19–1.06(m,21H).
在氮气氛围下,化合物5c(1.1g,2.47mmol)溶于无水四氢呋喃(5mL)中,依次加入溴化锌基乙酸乙酯(15mL,7.43mmol),Pd
2(dba)
3(142mg,0.247mmol),Xphos(117.57mg,0.247mmol)。反应混合液在55℃下搅拌2小时。TLC监测反应完毕,待反应混合物冷却后,加入饱和氯化铵水溶液(10mL)和水(10mL),用乙酸乙酯(3x10mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=20:1-10:1)得到黄色固体化合物5d(946mg,85%)。
1H NMR(500MHz,CDCl
3)δ6.81(d,J=2.5Hz,1H),6.72(d,J=2.5Hz,1H),4.76–4.64(m,1H),4.18(q,J=7.0Hz,2H),3.80(s,2H),3.17–3.06(m,2H),2.83–2.71(m,2H),1.27(t,J=7.0Hz,3H),1.19–1.10(m,21H).
将化合物5d(946mg,2.09mmol)溶于氨甲醇溶液(7M,10mL)中,85℃搅拌2小时。TLC检测反应完毕。反应液冷却至室温。减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=100:1-25:1)得到黄色固体化合物5e(720mg,81.5%)。
1H NMR(500MHz,CDCl
3)δ6.81(d,J=2.0Hz,1H),6.70(d,J=2.0Hz,1H),5.98(brs,1H),4.75–4.66(m,1H),3.68(s,2H),3.19–3.07(m,2H),2.82–2.70(m,2H),1.18–1.10(m,21H).
在氮气氛围下将化合物5e(84mg,0.2mmol)溶于无水二氧六环(5mL)中,依次加入化合物4b(194mg,0.3mmol),烯丙基二氯化钯(Ⅱ)(8mg,0.02mmol),Xantphos(34.8mg,0.06mmol),碳酸铯(130mg,0.4mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入二氯甲烷(5ml),过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=2:1)。得到黄色固体化合物5f(60mg,32%)。
1H NMR(500MHz,CDCl
3)δ10.27(s,1H),8.43(d,J=9.5Hz,1H),8.04(d,J=1.5Hz,1H),7.87(d,J=9.5Hz,1H),6.82(d,J=2.5Hz,1H),6.71(d,J=2.5Hz,1H),5.18–5.02(m,1H),4.80–4.60(m,3H),3.90(s,2H),3.22–3.09(m,3H),2.83–2.72(m,2H),2.56–2.46(m,1H),1.59(s,9H),1.45(s,9H),1.41(s,9H),1.17–1.13(m,21H).
将化合物5f(50mg,0.0675mmol)溶于三氟乙酸(5mL)中,在50℃下搅拌1小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得到粗品,用无水四氢呋喃(3x10mL)带掉剩余的三氟乙酸。减压旋干得到黄色固体化合物5g(35mg,100%),直接用于下一步反应。
将化合物5g(35mg,0.0675mmol)溶于四氢呋喃(5mL)中,依次加入二异丙基乙胺(131mg,1.01mmol),HATU(128mg,0.3375mmol),甲胺盐酸盐(23mg,0.3375mmol)。反应混合液在25℃下搅拌1小时。TLC监测反应完毕。减压除 去溶剂,用二氯甲烷(20mL)稀释,水洗(3x20mL),有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经薄层制备板层析分离纯化(二氯甲烷:甲醇=15:1)得到白色固体化合物5h(15mg,32%)。
1H NMR(500MHz,CDCl
3)δ9.98(s,1H),8.34(d,J=9.0Hz,1H),8.16(d,J=1.0Hz,1H),7.30(d,J=9.0Hz,1H),7.12(q,J=5.0Hz,1H),6.83(d,J=2.0Hz,1H),6.73(d,J=2.0Hz,1H),5.02–4.87(m,1H),4.75–4.65(m,2H),4.64–4.54(m,1H),3.90(s,2H),3.18–3.04(m,4H),3.01(d,J=5.0Hz,3H),2.83–2.72(m,2H),2.28–2.15(m,1H),2.13–2.01(m,1H),1.18–1.12(m,21H).
将化合物5h(15mg,0.021mmol)溶于四氢呋喃(2.4mL)中,加入四丁基氟化铵(1M,0.6mL)。反应混合液在25℃下搅拌0.25小时,TLC监测反应完毕。用二氯甲烷(20mL)稀释,水洗(3x20mL),有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经薄层制备板层析分离纯化(二氯甲烷:甲醇=15:1)得到白色固体化合物5(8mg,70%)。
1H NMR(500MHz,CDCl
3)δ10.15(s,1H),8.37(d,J=9.0Hz,1H),8.16(s,1H),7.31(d,J=9.0Hz,1H),7.11(q,J=5.0Hz,1H),6.86(d,J=2.0Hz,1H),6.76(d,J=2.0Hz,1H),5.01–4.86(m,1H),4.75–4.65(m,2H),4.63–4.54(m,1H),3.89(s,2H),3.22(s,1H),3.20–3.03(m,4H),3.01(d,J=5.0Hz,3H),2.84–2.73(m,2H),2.31–2.17(m,1H),2.14–2.03(m,1H)。MS m/z 543.13[M+H]
+。
实施例6:化合物6的制备
将6a(2.00g,10.0mmol)溶于DMF(17ml)中,在-40℃下分批加入二氟甲基(2-吡啶基)砜(1.62g,8.36mmol)叔丁醇钾(1.69g,15.05mmol)的20mlDMF溶液并在-40℃下搅拌0.25小时,随后再向反应液中加入饱和氯化铵5ml,3M盐酸13ml。反应混合液缓慢升到室温。TLC监测反应完毕。往反应瓶中加入冰水(100mL),甲叔醚(3x30mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1)得到白色固体化合物6b(1.76g,90%)。
将6b(1.757g,7.53mmol)溶于3M HCl/EA中,在25℃下搅拌2小时,TLC监测反应完毕。过滤,DCM清洗滤渣,烘干得到白色固体化合物6c(0.986g,77%)。
在氮气氛围下,将化合物6c(2.04g,12mmol)溶于无水DMF(20mL)中,0℃下分批加入钠氢(4.0g,100mmol),反应混合液在25℃下搅拌10min。加入2,6-二甲基-4-硝基吡啶(2.82g,10mmol)室温反应过夜,TLC监测反应无进展,加入水(50mL)和甲叔醚(3x20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=10:1)得到白色固体化合物6d(0.98g,26%)。
在氮气氛围下,化合物6d(257mg,0.70mmol)溶于无水四氢呋喃(5mL)中,-78℃加正丁基锂(0.5,0.768mmol)反应混合液在-78℃下搅拌0.5小时。加入碘甲烷(298mg,2.10mmol),反应混合液在-78℃下搅拌2小时。TLC监测反应完毕,加入饱和氯化铵水溶液(5mL)和水(5mL),乙酸乙酯(3x5mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(石油醚:乙酸乙酯=5:1)得到黄色液体化合物6e(135mg,67%)。
1H NMR(500MHz,CDCl
3)δ6.66(d,1H),6.46(d,1H),3.40(m,4H),2.41(s,3H),2.27(m,4H),
在氮气氛围下,化合物6e(325mg,1.07mmol)溶于无水四氢呋喃(5mL)中,依次加入溴化锌基乙酸乙酯(6.5mL,3.22mmol),Pd
2(dba)
3(61.64mg,0.11mmol),Xphos(51.03mg,0.11mmol)。反应混合液在55℃下搅拌2小时。TLC监测反应完毕,待反应混合物冷却后,加入饱和氯化铵水溶液(10mL)和水(10mL),乙酸乙酯(3x10mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品6f(530mg)。直接用于下一步。
将化合物6f(333mg,1.07mmol)溶于氨甲醇溶液(7M,10mL)中,85℃搅拌2小时。TLC检测反应完毕。反应液冷却至室温。减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=100:1-25:1)得到黄色固体化合物6g(97mg,两步收率32%)。
在氮气氛围下将化合物6g(42mg,0.15mmol)溶于无水二氧六环(3mL)中,依次加入化合物4b(146mg,0.225mmol),烯丙基二氯化钯(Ⅱ)(6mg,0.015mmol),Xantphos(26mg,0.045mmol),碳酸铯(98mg,0.3mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入二氯甲烷(5mL),过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=25:1)。得到黄色固体化合物6h(35mg,30%)。
1H NMR(500MHz,CDCl
3)δ8.49(d,1H),8.08(s,1H),7.88(d,1H),6.48(dd,2H),5.06-5.19(m,1H),4.70(m,2H),3.79(s,2H),3.44(m,4H),3.25(dd,1H),2.58(dd,1H),2.56(s,3H),2.28(m,4H),1.46(s,9H),1.42(s,9H),1.46(s,9H),1.26(s,9H),
将化合物6h(35mg,0.044mmol)溶于三氟乙酸(5mL)中,在50℃下搅拌1小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得到粗品,用无水四氢呋喃(3x10mL)带三氟乙酸。减压旋干得到黄色固体化合物6i(25mg,100%)。
将化合物6i(25mg,0.044mmol)溶于四氢呋喃(2mL)中,依次加入二异丙基乙胺(131mg,1.01mmol),HATU(128mg,0.3375mmol),甲胺盐酸盐(23mg,0.3375mmol)。反应混合液在25℃下搅拌1小时。TLC监测反应完毕。减压整除四氢呋喃,用二氯甲烷(20mL)稀释,水洗(3x20mL),有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品薄层层析分离纯化(二氯甲烷:甲醇=15:1)得到白色固体化合物6(5mg,20%)。
1H NMR(500MHz,CDCl
3)δ11.54(s,1H),8.35(d,J=9.1Hz,1H),8.17(d,J=1.3Hz 1H),7.29(d,J=9.1Hz,1H),7.12(q,J=5.3Hz,1H),6.53(s,1H),6.47(d,J=2.4Hz,2H),5.01-4.85(m,1H),4.74-4.54(m,2H),3.78(s,2H),3.50-3.46(m,4H),3.15-3.06(m,2H),3.03(d,J=5.0Hz 3H),2.55(s,3H),2.32-2.28(m,4H),2.20-2.16(m,2H)。MS m/z 585.5[M+H]
+。
实施例7:化合物7的制备
在氮气氛围和-50℃下,向t-BuOK(1.68g,15.0mmol)的无水DMF(15mL)溶液中滴加化合物7a(1.76g,10.0mmol)和二氟甲基(2-吡啶基)砜(1.61g,8.33mmol)的DMF(5mL)溶液,混合物于-45℃搅拌30分钟。滴加饱和氯化铵(15mL)和3M盐酸(15mL),后缓慢升至室温,并反应3h,用水(60mL)和MTBE(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚:乙酸乙酯=5:1)得到无色液体化合物7b,423mg,收率20%。
1H NMR(500MHz,CDCl
3)δ7.38-7.29(m,5H),4.44(s,2H),4.16(m,1H),2.91(m,2H),2.68(m,2H)。
在氮气氛围和-78℃下,将化合物7b(423mg,2.01mmol)溶于DCM(10mL)中,然后加入BBr
3(4mL,4.02mmol),于-78℃搅拌30分钟。用饱和碳酸氢钠溶液(5mL)淬灭。水相用DCM萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析纯化得到黄色液体化合物7c(198mg,82%)。
在氮气氛围和冰浴0℃下,向氢化钠(96mg,2.40mmol)的无水四氢呋喃(10mL)混悬溶液中滴加化合物7c(198mg,1.65mmol)的无水四氢呋喃(5mL)溶液,混合物 0℃搅拌30分钟。滴加2-溴-6-甲基-4硝基吡啶(434mg,2.00mmol)的无水四氢呋喃(5mL)溶液,混合物升至25℃搅拌过夜。用水(100mL)淬灭反应,用乙酸乙酯(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚:乙酸乙酯=10:1)得到淡黄色液体化合物7d,418mg,收率87%。
1H NMR(500MHz,CDCl
3),δ6.71(d,1H),6.53(d,1H),4.78(m,1H),3.20(m,2H),2.85(m,2H),2.47(s,3H)。
在氮气氛围下,将化合物7d(400mg,1.38mmol),X-Phos(66mg,0.138mmol)和Pd
2(dba)
3(127mg,0.138mmol)溶于四氢呋喃(5mL)中,用氮气流鼓泡除氧5分钟。然后加入现制备的乙酸乙酯溴化锌试剂(8.3mL,4.15mmol),再用氮气流鼓泡除氧10分钟,混合物加热至55℃搅拌1小时。待反应液冷却至室温,用乙酸乙酯(50mL)稀释,冷却至0℃,用饱和氯化铵溶液(50mL)淬灭。水相用乙酸乙酯萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物得到黄色液体化合物7e(285mg),直接用于下一步。
将化合物7e(270mg,0.908mmol)溶于7M氨甲醇溶液(8mL)中,密封反应管,加热至80℃搅拌2h。浓缩反应液,残留物用柱层析分离纯化(二氯甲烷:甲醇=15:1)得到白色固体化合物7f(177mg,两步收率48%)。
1H NMR(500MHz,CDCl
3)δ7.50(bs,1H),6.52(d,J=2.0Hz,1H),6.48(d,J=2.0Hz,1H),5.65(bs,1H),4.80(m,1H)3.62(s,2H),3.18(m,2H),2.85(m,2H),2.48(s,3H)。
在氮气氛围下化合物7f(77mg,0.29mmol)溶于无水二氧六环(3mL)中,依次加入4b(223mg,0.34mmol),烯丙基二氯化钯(Ⅱ)(5.3mg,0.0057mmol),XantPhos(33mg,0.057mmol),Cs
2CO
3(187mg,0.57mmol)反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入二氯甲烷(5mL),过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=35:1)。得到黄色固体化合物7g(78mg,收率34%)。MS m/z 788.7[M+H]
+。
将化合物7g(78mg,0.099mmol)溶在TFA(3mL)中,50℃搅拌1.5小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得到粗品,用无水四氢呋喃(3x10mL)带出TFA。减压旋干得到7h(59mg,收率100%)。MS m/z 532.4[M+H]
+。
将化合物7h(59mg,0.1mmol)溶在THF(3mL)中,依次加入DIPEA(129mg,1.0mmol),HATU(190mg,0.5mmol),甲胺盐酸盐(35mg,0.5mmol)。反应混合液在25℃下搅拌1小时。TLC监测反应完毕。减压浓缩,用二氯甲烷(3x20mL)和水(20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品用反向柱层析分离纯化,冷冻干燥后得到化合物7(0.82mg,收率2%)。
1H NMR(500MHz,DMSO-d
6)δ11.30(s,1H),8.52(s,1H),8.47(d,J=4.7Hz,1H),8.23(d,J=9.2Hz,1H),7.60(d,J=9.2Hz,1H),6.72(d,J=2.1Hz,1H),6.66(d,J=2.1Hz,1H),5.12-4.97(m,1H),4.97-4.89(m,1H),4.78-4.70(m,2H),3.95(m,2H),3.86(s,2H),3.20(m,2H),3.03(m,2H),2.76(d,J=4.7Hz,3H),2.38(s,3H),2.00-(m,2H)。MS m/z 545.6[M+H]+。
实施例8:化合物8的制备
氮气氛围和冰浴0℃下,向NaH(186mg,4.64mmol)的无水四氢呋喃(10mL)混悬溶液中滴加化合物2,2,2-三氟乙醇(446mg,4.46mmol)的无水四氢呋喃(5mL)溶液,混合物于0℃搅拌30分钟。滴加2,6-二溴-4-硝基吡啶(1.00g,3.57mmol)的无水四氢呋喃(5mL)溶液,混合物升至25℃搅拌过夜。用水(100mL)淬灭反应,用乙酸乙酯(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚:乙酸乙酯=10:1)得到黄色固体化合物8b(986mg,83%)
在氮气氛围下,将化合物8b(800mg,2.388mmol)溶于无水四氢呋喃(5mL)中,依次加入Pd(PPh
3)
2Cl
2(167.8mg,0.238mmol),CuI(45.5mg,0.238mmol),DIPEA(925.87mg,164mmol),最后加入三异丙基硅基乙炔(480mg,2.63mmol)。混合物在室温下搅拌16小时,反应结束后,过滤,用THF(3x5mL)洗涤滤饼,收集滤液,减压浓缩得到粗品。柱层析纯化(PE:EA=20:1)得到白色固体化合物8c(735mg,70%)。
1H NMR(500MHz,CDCl
3)δ7.00(m,2H),4.40(m,2H),1.13(s,18H),1.12(s,3H)
在氮气氛围下,将化合物8c(735mg,1.68mmol),XPhos(80mg,0.168mmol)和Pd
2(dba)
3(96.6mg,0.168mmol)溶于四氢呋喃(5mL)中,用氮气流鼓泡除氧5分钟。然后加入现做的乙酸乙酯溴化锌试剂(10.1mL,5.04mmol),再用氮气流鼓泡除氧10分钟,混合物加热至55℃搅拌2小时。待反应液冷却至室温,用乙酸乙酯(50mL)稀释,冷却至0℃,用饱和氯化铵溶液(50mL)淬灭。水相用乙酸乙酯萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析纯化(PE:EA=20:1-10:1)得到黄色液体化合物8d(590mg,82%)。
1H NMR(500MHz,CDCl
3),δ6.94(d,1H),6.87(d,1H),4.39(q,2H),4.17(q,2H),3.83(s,2H),1.27(t,3H),1.14(s,18H),1.13(s,3H).
将化合物8d(590mg,1.3mmol)溶于7M氨甲醇溶液(8mL)中,密封反应管,加热 至80℃搅拌过夜。浓缩反应液,残留物用柱层析分离纯化(二氯甲烷:甲醇=20:1)得到黄色固体化合物,用石油醚(5mL)打浆后得到8e(316mg,55%).
1H NMR(500MHz,CDCl
3),δ7.20(s,1H),6.95(d,1H),6.83(d,1H),5.65(s,1H),4.41(q,2H),3.70(s,2H),1.14(s,18H),1.13(s,3H).
在氮气氛围下,化合物8e(100mg,0.24mmol)溶于无水二氧六环(5mL)中,依次加入4b(466mg,0.48mmol),烯丙基二氯化钯(Ⅱ)(10mg,0.024mmol),XantPhos(41.65mg,0.072mmol),Cs
2CO
3(160mg,0.48mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入二氯甲烷(5mL),过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=15:1)。得到黄色固体化合物8f(200mg,收率89%)。
将化合物8f(200mg,0.215mmol)溶在TFA(3mL)中,50℃搅拌1小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得到粗品,用无水四氢呋喃(3x10mL)带出TFA。减压旋干得到8g(131mg,收率90%)
将化合物8g(131mg,0.1935mmol)溶在THF(3mL)中,依次加入DIPEA(375.12mg,2.9mmol),HATU(367.88mg,0.9675mmol),甲胺盐酸盐(67mg,0.97mmol)。反应混合液在25℃下搅拌1小时。TLC监测反应完毕。减压旋干THF,用二氯甲烷(3x20mL)和水(20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品薄层层析分离纯化(二氯甲烷:甲醇=15:1)得到8h(48mg,收率36%)。
将化合物8h(48mg,0.069mmol)溶在THF(5mL)中,加入TBAF/THF(1M,0.4mL)。反应混合液在25℃下搅拌0.25小时,TLC监测反应完毕。用二氯甲烷(10mL)和水(3x10mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品经PTLC分离纯化(二氯甲烷:甲醇=17:1),冷冻干燥后得到化合物8(2.75mg,收率8%)。
1H NMR(500MHz,DMSO-d
6)δ11.33(s,1H),8.53(s,1H),8.50(d,J=4.5Hz,1H),8.21(d,J=9.2Hz,1H),7.61(d,J=9.2Hz,1H),7.25(d,J=1.8Hz,1H),7.17(d,J=1.8Hz,1H),5.12-4.96(m,1H),4.95(m,2H),4.85-4.69(m,2H),4.37(s,1H),3.95(s,2H),3.02(m,2H),2.76(d,J=4.6Hz,3H),2.00(m,2H)。MS m/z 535.07[M+H]
+。
实施例9:化合物9的制备
在氮气氛围和冰浴0℃下,向氢化钠(104mg,2.60mmol)的无水四氢呋喃(10mL) 混悬溶液中滴加化合物3-(二氟甲基)环丁-1-醇(293mg,2.40mmol)的无水四氢呋喃(5mL)溶液,混合物在0℃下搅拌30分钟,滴加9a(434mg,2.00mmol)的无水四氢呋喃(5mL)溶液,混合物升至25℃搅拌过夜。用水(100mL)淬灭反应,用乙酸乙酯(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚:乙酸乙酯=10:1)得到两个立体异构体化合物,9b-cis:9b-trans(4:1),其中主要产物为顺式异构体9b-cis,416mg,收率71%。
1H NMR(500MHz,CDCl
3)δ6.71(d,1H),6.53(d,1H),5.80(t,1H),4.64(m,1H),2.62(m,2H),2.46(s,3H),2.47(m,1H),2.23(m,2H)。9b-trans,110mg,收率19%。
1H NMR(500MHz,CDCl
3)δ6.69(d,1H),6.51(d,1H),5.93(t,1H),4.77(m,1H),2.80(m,1H),2.62(m,2H),2.47(s,3H),2.38(m,2H)。
氮气氛围下,将化合物9b-cis(410mg,1.52mmol),X-Phos(109mg,0.228mmol)和Pd
2(dba)
3(139mg,0.152mmol)溶于四氢呋喃(5mL)中,用氮气流鼓泡除氧5分钟。然后加入现制备的乙酸乙酯溴化锌试剂(9.1mL,4.55mmol),再用氮气流鼓泡除氧10分钟,混合物加热至55℃搅拌1小时。待反应液冷却至室温,用乙酸乙酯(50mL)稀释,冷却至0℃,用饱和氯化铵溶液(50mL)淬灭。水相用乙酸乙酯萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析纯化得到黄色液体化合物9c-cis(189mg,42%)。
将化合物9c-cis(180mg,0.60mmol)溶于7M氨甲醇溶液(8mL)中,密封反应管,加热至80℃搅拌2h。浓缩反应液,残留物用柱层析分离纯化(二氯甲烷:甲醇=15:1)得到白色固体化合物9d-cis(98mg,60%).
1H NMR(500MHz,CDCl
3)δ7.51(s,1H),6.50(m,1H),6.48(d,1H),5.80(m,1H),5.42(s,1H),4.65(m,1H),3.63(s,2H),2.61(m,2H),2.48(s,3H),2.46(m,1H),2.22(m,2H)。
在氮气氛围下化合物9d-cis(38mg,0.14mmol)溶于无水二氧六环(3mL)中,依次加入4b(183mg,0.282mmol),烯丙基二氯化钯(Ⅱ)(3mg,0.0071mmol),XantPhos(16.3mg,0.028mmol),Cs
2CO
3(92mg,0.282mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入二氯甲烷(5mL),过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=35:1)。得到黄色固体化合物9e-cis(41mg,收率37%)。
将化合物9e-cis(41mg,0.052mmol)溶在TFA(3mL)中,50℃搅拌1.5小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得到粗品,用无水四氢呋喃(3x10mL)带走TFA。减压旋干得到9f-cis(35mg,收率100%)。
将化合物9f-cis(27mg,0.0519mmol)溶在THF(3mL)中,依次加入DIPEA(67.1mg,0.519mmol),HATU(98.67mg,0.259mmol),甲胺盐酸盐(18mg,0.259mmol)。反应混合液在25℃下搅拌1小时。TLC监测反应完毕。减压旋走THF,用二氯甲烷(3x20mL)和水(20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品用反向柱分离纯化,冷冻干燥后得到9(11.5mg,收率40%)。
1H NMR(500MHz,DMSO-d
6)δ11.31(s,1H),8.51(s,1H),8.46(d,J=4.7Hz,1H),8.21(d,J=9.2Hz,1H),7.60(d,J=9.2Hz,1H),6.73(d,J=2.1Hz 1H),6.66(d,J=2.1Hz 1H),6.10(td,J=57.2Hz,J=4.1Hz,1H),5.11-4.95(m,1H),4.81(m,1H),4.78-4.70(m,2H),3.86(s,2H),3.35(m,2H),3.03(m,2H),2.76(d,J=4.7Hz,3H),2.60(m,2H),2.48(m,1H),2.38(s,3H),2.00(m,2H)。MS m/z 547.29[M+H]
+。
实施例10:化合物10的制备
在氮气氛围下,化合物3,3-二氟环丁胺(107mg,1.00mmol)溶于无水二氧六环(5mL)中,依次加入Pd
2(dba)
3(92mg,0.1mmol),10a(366mg,1.5mmol),XantPhos(116mg,0.2mmol),Cs
2CO
3(651mg,2mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入饱和氯化铵水溶液淬灭,再用水(20mL)和THF(3x10mL)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1)。得到黄色固体化合物10b(109mg,收率40%)。
1H NMR(500MHz,CDCl
3)δ6.28(d,1H),6.18(d,1H),4.55(s,1H),3.89(m,1H),3.71(m,5H),3.07(m,2H),2.46(m,2H),2.42(s,3H).
将化合物10b(364mg,1.34mmol)溶于7M氨甲醇溶液(5mL)中,密封反应管,加热至53℃搅拌过夜。浓缩反应液,残留物用柱层析分离纯化(二氯甲烷:甲醇=20:1)得到黄色固体化合物,用石油醚(10mL)打浆后得到白色固体化合物10c(230mg,67%).
1H NMR(500MHz,CDCl
3)δ7.65(s,1H),6.21(d,1H),6.16(d,1H),5.36(s,1H),4.41(m,1H),3.89(m,1H),3.56(s,2H),3.08(m,2H),2.46(m,2H),2.42(s,3H)。
在氮气氛围下化合物10c(60mg,0.235mmol)溶于无水二氧六环(5mL)中,依次加入4b(306mg,0.48mmol),烯丙基二氯化钯(Ⅱ)(4.3mg,0.0116mmol),XantPhos(26.9mg,0.047mmol),Cs
2CO
3(153mg,0.47mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入饱和氯化铵水溶液淬灭,再用水(20mL)和二氯甲烷(3x10mL)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=15:1-10:1)。得到黄色固体化合物10d(100mg,收率55%)。
将化合物10d(100mg,0.129mmol)溶在TFA(2mL)中,50℃搅拌1小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得到粗品,用无水四氢呋喃(3x10mL)带出TFA。减压浓缩得到10e(68mg,收率100%)。
将化合物10e(68mg,0.129mmol)溶在THF(5mL)中,依次加入DIPEA(166.7mg,1.29mmol),HATU(245.25mg,0.645mmol),甲胺盐酸盐(45mg,0.645mmol)。反应混合液在25℃下搅拌2小时。TLC监测反应完毕,用二氯甲烷(3x20mL)和水(20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后 滤液减压浓缩得到粗品。该粗品用反向柱分离纯化,冷冻干燥后得到化合物10(4.5mg,收率7%)。
1H NMR(500MHz,DMSO-d
6)δ11.44(s,1H),8.52(s,1H),8.49(q,J=4.7Hz,1H),8.24(d,J=9.15Hz,1H),7.61(d,J=9.15Hz,1H),6.38(s,1H),6.27(s,1H)5.10-4.96(m,1H),4.85-4.70(m,2H),3.87-3.79(m,1H),3.73(s,2H),3.13-2.96(m,5H),2.76(d,J=4.7Hz,3H),2.47-2.42(m,1H),2.29(s,3H),2.18-2.07(m,1H),2.05-1.94(m,2H).MS m/z 532.04[M+H]
+。
实施例11:化合物11的制备
将2-苄氧基乙醇(3.60g,23.65mmol),(溴二氟甲基)三甲基硅烷(9.60g,47.30mmol),醋酸钾(9.28g,94.60mmol)悬浮于DCM(20mL)以及水(20mL)的混和溶液中,在25℃下搅拌过夜。用水(100mL)和DCM(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚:乙酸乙酯=10:1)得到黄色液体化合物,1-苄氧基2-二氟甲氧基乙烷,3.02g,收率63%。
1H NMR(500MHz,CDCl
3)δ7.35(m,4H),7.30(m,1H),6.28(t,1H),4.58(s,2H),4.02(t,2H),3.68(t,2H)。
在氢气氛围下,将化合物1-苄氧基2-二氟甲氧基乙烷(3.02g,14.94mmol),Pd(1.0g),溶于四氢呋喃(70mL)甲醇(30mL)中,反应16h,过滤,浓缩。得到黄色液体化合物2-二氟甲氧基乙醇(1.60g,90%)。
1H NMR(500MHz,CDCl
3)δ6.28(t,1H),3.98(t,2H),3.83(t,2H)。
在氮气氛围和冰浴0℃下,向氢化钠(260mg,6.50mmol)的无水四氢呋喃(10mL)混悬溶液中滴加化合物2-二氟甲氧基乙醇(672mg,6.00mmol)的无水四氢呋喃(5mL)溶液,混合物0℃搅拌30分钟。滴加11a(1.09g,5.00mmol)的无水四氢呋喃(5mL)溶液,混合物升至25℃搅拌过夜。用水(100mL)淬灭反应,用乙酸乙酯(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚:乙酸乙酯=8:1)得到黄色液体化合物11b,1.326g,收率92%。
1H NMR(500MHz,CDCl
3)δ6.85(d,1H),6.65(d,1H),6.29(t,1H),4.20(s,4H),2.48(s,3H)。
在氮气氛围下,将化合物11b(1.15g,3.97mmol),X-Phos(283mg,0.596mmol)和Pd
2(dba)
3(364mg,0.397mmol)溶于四氢呋喃(5mL)中,用氮气流鼓泡除氧5分钟。然后加入锌试剂(30ml,11.93mmol),再用氮气流鼓泡除氧10分钟,混合物加热至 55℃搅拌45min。待反应液冷却至室温,用乙酸乙酯(50mL)稀释,冷却至0℃,用饱和氯化铵溶液(50mL)淬灭。水相用乙酸乙酯萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩得到黄色液体粗品化合物11c(1.5g)。直接用于下一步反应。
将化合物11c(70mg,0.242mmol)溶于7M氨甲醇溶液(8mL)中,密封反应管,加热至80℃搅拌2h,浓缩反应液,残留物用柱层析分离纯化(二氯甲烷:甲醇=15:1)得到白色固体化合物11d(42mg)。
1H NMR(500MHz,CDCl
3)δ7.47(s,1H),6.64(d,1H),6.61(d,1H),6.29(t,1H),5.59(q,1H),4.20(s,4H),3.64(s,2H),3.49(s,3H)。
在氮气氛围下化合物11d(48mg,0.185mmol)溶于无水二氧六环(3mL)中,依次加入4b(240mg,0.37mmol),烯丙基二氯化钯(Ⅱ)(3.4mg,0.009mmol),XantPhos(21.4mg,0.037mmol),Cs
2CO
3(121mg,0.37mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入二氯甲烷(15mL),过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=25:1)。得到黄色固体化合物11e(46mg,收率32%)。
将化合物11e(45mg,0.052mmol)溶在TFA(3mL)中,于50℃搅拌1.5小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得到粗品,用无水四氢呋喃(3x10mL)带出TFA。减压旋干得到11f(31mg,收率100%)。
将化合物11f(31mg,0.059mmol)溶解在THF(3mL)中,依次加入DIPEA(70mg,0.59mmol),HATU(112mg,0.295mmol),甲胺盐酸盐(21mg,0.295mmol)。反应混合液在25℃下搅拌1小时。TLC监测反应完毕。减压浓缩,用二氯甲烷(3x20mL)和水(20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品用反向柱分离纯化,冷冻干燥后得到11(4.86mg,两步收率17%)。
1H NMR(500MHz,DMSO-d
6)δ11.31(s,1H),8.52(s,1H),8.47(d,J=4.6Hz,1H),8.28(s,0.5H),8.22(d,J=9.1Hz,1H),7.60(d,J=9.1Hz,1H),6.84(s,1H),6.79(s,1H),6.74(t,J=75.6Hz,0.5H),5.10-4.95(m,1H),4.85-4.70(m,2H),4.43(m,1H),4.28(m,1H),4.25(m,1H),4.17(m,1H),3.88(s,2H),3.02(m,2H)2.76(d,J=5.25Hz,3H),2.39(s,3H),2.06(m,2H)。MS m/z=537.6[M+H]
+
实施例12:化合物12的制备
氮气氛围和冰浴0℃下,向NaH(111mg,2.77mmol)的无水四氢呋喃(5mL)混悬溶液中滴加化合物1-羟基环丙烷羧酸甲酯(322mg,2.77mmol)的无水四氢呋喃(5mL)溶液,混合物升至室温搅拌30分钟。然后冷却至0℃,滴加2-溴-6-甲基-4-硝基吡啶(500mg,2.31mmol)的无水四氢呋喃(5mL)溶液,混合物升至25℃搅拌过夜。用水(100mL)淬灭反应,用乙酸乙酯(3x50mL)萃取,合并有机相,有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用柱层析分离纯化(石油醚:乙酸乙酯=6:1)得到黄色固体化合物12b(255mg,39%)。
1H NMR(500MHz,CDCl
3)δ6.85(d,J=1.9Hz,1H),6.64(d,J=1.9Hz,1H),3.75(s,3H),2.48(s,3H),1.68–1.64(m,2H),1.36–1.32(m,2H)。
将化合物12b(255mg,0.89mmol)溶于无水四氢呋喃(5mL)中,在氮气氛围和冰浴0℃下,慢慢滴加DIBAL-H(1M,2.2mL,2.2mmol)正己烷溶液,混合物在室温下搅拌1小时。冷却至0℃,加入0.5M酒石酸钾钠水溶液(3mL)淬灭,用乙酸乙酯(50mL)稀释,并在室温下搅拌15分钟。过滤,用乙酸乙酯洗固体,滤液用饱和食盐水洗。有机相用无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层硅胶板分离纯化(石油醚:乙酸乙酯=2:1),得到白色固体化合物12c(210mg,92%)。
1H NMR(500MHz,CDCl
3)δ6.98(d,J=1.8Hz,1H),6.73(d,J=1.8Hz,1H),3.86(s,2H),2.46(s,3H),1.09–1.05(m,2H),1.01–0.97(m,2H)。
在氮气氛围和干冰浴-60℃下,向草酰氯(0.13mL,1.56mmol)的无水二氯甲烷(5mL)溶液中滴加二甲基亚砜(0.65mL)的无水二氯甲烷(0.5mL)溶液。搅拌5分钟后,加入化合物12c(200mg,0.78mmol)的无水二氯甲烷(2mL)溶液,继续搅拌15分钟。然后加入三乙胺(0.54ml,3.89mmol),混合物缓慢升至室温,搅拌1小时。用二氯甲烷(50mL)稀释有机相用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层硅胶板分离纯化(石油醚:乙酸乙酯=2:1)得到黄色油状液体化合物12d(151mg,76%)。
1H NMR(500MHz,CDCl
3)δ9.39(s,1H),6.84(d,J=2.0Hz,1H),6.65(d,J=2.0Hz,1H),2.48(s,3H),1.69(dd,J=8.8,5.5Hz,2H),1.51(dd,J=8.8,5.5Hz,2H)。
将化合物12d(220mg,0.86mmol)溶于二氯甲烷(2ml)中,冰盐浴冷却至-10℃,加入BAST(667mg,3.02mmol)。混合物在0℃下搅拌1小时,然后升至室温搅拌2小时。加入二氯甲烷(50mL)稀释反应液,用饱和碳酸氢钠水溶液洗,再用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用用制备薄层硅胶板分离纯化(石油醚:乙酸乙酯=3:1)得到白色固体化合物12e(198mg,收率83%,50%纯度)。
1H NMR(500MHz,CDCl
3)δ6.99(d,J=1.8Hz,1H),6.75(d,J=1.8Hz,1H),6.04(t,J=56.1Hz,1H),2.48(s,3H),1.32–1.28(m,2H),1.17–1.12(m,2H)。
锌试剂的制备:在氮气氛围下,向锌粉(516mg,8.08mmol)的四氢呋喃(2mL)混悬液中加入TMSCl(44mg,0.4mmol),混合物在室温下搅拌15分钟。然后加入溴乙酸乙酯(664mg,4.0mmol)的四氢呋喃(6mL)溶液,混合物在30℃下搅拌30分钟。最后得到浅绿色的锌试剂为约0.5M的四氢呋喃溶液,使用时用滤头过滤直接用于下一步反应。
将化合物12e(313mg,1.13mmol),XPhos(28mg,0.06mmol)和Pd
2(dba)
3(26mg,0.03mmol)溶于四氢呋喃(5mL)中,用氮气流鼓泡除氧5分钟。然后加入上述得到的锌试剂(6.8mL,3.39mmol),再用氮气流鼓泡除氧10分钟,混合物加热至50℃搅拌2 小时。待反应液冷却至室温,用乙酸乙酯(50mL)稀释,冷却至0℃,用饱和氯化铵溶液(50mL)淬灭。水相用乙酸乙酯萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩。残留物用制备薄层硅胶板分离纯化(二氯甲烷:甲醇=20:1)得到黄色液体化合物12f(240mg,收率75%,50%纯度)。
1H NMR(500MHz,CDCl
3)δ6.79(s,1H),6.71(s,1H),6.08(t,J=56.3Hz,1H),4.18(q,J=7.1Hz,2H),3.75(s,2H),2.49(s,3H),1.29–1.24(m,5H),1.16–1.10(m,2H)。
将化合物12f(85mg,0.3mmol)溶于7M氨甲醇溶液(5mL)中,密封反应管,加热至60℃搅拌过夜。浓缩反应液,残留物用制备薄层硅胶板分离纯化(二氯甲烷:甲醇=15:1)得到黄色固体化合物12g(43mg,收率56%,66%纯度)。
1H NMR(500MHz,CDCl
3)δ7.49(brs,1H),6.74(d,J=1.9Hz,1H),6.73(d,J=1.9Hz,1H),6.05(t,J=56.2Hz,1H),5.41(brs,1H),3.65(s,2H),2.51(s,3H),1.31–1.27(m,2H),1.16–1.11(m,2H)。
在氮气氛围下化合物12g(18mg,0.07mmol)溶于无水二氧六环(3mL)中,依次加入4b(54.58mg,0.084mmol),烯丙基二氯化钯(Ⅱ)(1.3mg,0.003mmol),XantPhos(8.1mg,0.014mmol),Cs
2CO
3(45.6mg,0.14mmol)。反应混合液在80℃下搅拌过夜。TLC监测反应完毕,反应液冷却至室温,加入饱和氯化铵水溶液淬灭,再用水(20mL)和乙酸乙酯(3x10mL)萃取,合并有机相,用饱和食盐水洗,无水硫酸钠干燥,过滤,滤液减压浓缩得到粗品。该粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇=20:1)。得到黄色固体化合物12h(25mg,收率36%)。
将化合物12h(50mg,0.0645mmol)溶在TFA(3mL)中,50℃搅拌2小时,TLC监测反应完毕,反应液冷却至室温,减压浓缩得品,用无水四氢呋喃(3x10mL)带出TFA。减压浓缩得到12i(30mg,收率100%)。
将化合物12i(30mg,0.0645mmol)溶在THF(5mL)中,依次加入DIPEA(84mg,0.645mmol),HATU(122.6mg,0.3225mmol),甲胺盐酸盐(23mg,0.3225mmol)。反应混合液在25℃下搅拌2小时。TLC监测反应完毕。,用二氯甲烷(3x20mL)和水(20mL)萃取,有机相经饱和食盐水洗涤,无水硫酸钠干燥,过滤后滤液减压浓缩得到粗品。该粗品用反向柱分离纯化,冷冻干燥后得到化合物12(2.2mg,收率7%)。
1H NMR(500MHz,DMSO-d
6)δ11.32(s,1H),8.53(s,1H),8.50(q,J=4.7Hz,1H),8.23(d,J=9.1Hz,1H),7.61(d,J=9.1Hz,1H),6.92(d,J=1.9Hz,1H),6.86(d,J=1.8Hz,1H),6.23(t,J=54.5Hz,1H),5.11-4.96(m,1H),4.86-4.70(m,2H),3.89(s,2H),3.04(m,2H),2.77(d,J=4.7Hz,3H),2.41(s,3H),2.00(m,2H),1.27(m,2H),1.16(m,2H)。MS m/z 533.05[M+H]
+。
实施例13:生物活性测试
1.GLS1酶活性测试
采用谷氨酰胺氧化酶/Amplex Red偶联法测定谷氨酰胺酶GLS1活性,并检测化合物对GLS1活性的抑制能力。L-谷氨酸可经谷氨酸氧化酶氧化为α-酮戊二酸、NH
3及H
2O
2。当体系中存在辣根过氧化物酶(HRP)时,Amplex Red试剂可与生成的H
2O
2以1:1的化学定量比反应,形成高荧光的试卤灵(resorufin),通过检测试卤灵的荧光强度来反映酶催化反应速率及酶的活性。利用A549细胞内谷氨酰胺酶并耦合分析测定细胞谷氨酸消耗量,评估化合物抑制细胞GLS1活性的能力。具体方法如下:以3~5×10
3A549细胞/孔的密度接种细胞于96孔板中,加入不同浓度的待测化合物溶液,37℃孵育24小时。孵育完成后,弃上清,PBS洗涤1-2次,加入20μL的细胞裂解液 (成分为10mM Tris pH7.4、l00mM NaCl、1mM EDTA、1mM EGTA、1mM NaF、20mM Na
4P
2O
7、2mM Na
3VO
4、1%Triton X-100、10%甘油、0.1%SDS和0.5%脱氧胆酸盐),冰上裂解30分钟。将细胞裂解液收集至1.5ml离心管中,12000rpm离心10分钟。离心后取上清4μL细胞裂解液转移到384孔板,加入35μL检测液(含27.5μm Amplex Red、0.1375U/ml辣根过氧化物酶、0.044U/mL谷氨酸氧化酶、100mM Tris pH7.5)。避光室温孵育30分钟后,孔板在荧光酶标仪上535/590nm波长处读取荧光值,分析原始数据并计算IC
50值。代表性化合物的GLS1酶活性测试结果列于表1.
2.GLS1细胞活性测试
采用CCK-8法检测细胞增殖及化合物对细胞生长的抑制作用。基本原理为CCK-8试剂中含有WST-8,是一种水溶性的四唑盐,化学名为2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺酸苯)-2H-四唑单钠盐。该试剂可在电子耦合试剂存在的情况下,可被细胞中产生的NAD
+还原成为水溶性的黄色甲瓒产物(Formazan)。活细胞越多,产生的Formazan就越多,颜色也会越深。最后可通过比色法测量吸光度值并计算活细胞比例。具体方法如下:以3~5×10
3个/孔细胞密度将A549细胞接种于96孔板中,细胞培养24小时后加药,加入不同浓度的待测化合物溶液,37℃孵育48小时。孵育完成后,向每孔中加入10μL CCK-8溶液,继续在培养箱中孵育3-4小时。取出培养板放入酶标仪中,450nm波长处测定吸光度值,同时设定空白对照组等,分析原始数据并计算IC
50值。
代表性化合物的GLS1细胞活性测试结果列于表1.
表1.GLS1酶和GLS1细胞抑制活性
阳性对照化合物IPN-60090
(根据专利CN201580037629报道方法制备而得)
从表1数据可见,本专利发明的代表性化合物(如化合物4,7,8,9,11和12) 对GLS1酶和细胞活性的抑制都明显优于阳性对照化合物IPN-60090。
3.对非小细胞肺癌H2122细胞增殖的抑制活性测试
选择生长状态良好的H2122细胞,用胰酶消化。加入新鲜的培养基,充分混合均匀后,800rpm离心3分钟。按照每孔2000个细胞的种板密度接种于96孔板中,37℃培养箱中培养过夜。第二天,取出培养板,将化合物按照四倍的梯度稀释,给药处理,再放入37℃培养箱中培养72小时。
将细胞培养板放置室温中平衡30分钟;每孔加入100μL CellTiter Glo检测试剂,在振板机上混匀2分钟,诱导细胞裂解;将96孔板在室温中放置10分钟,使其发光信号稳定;粘贴白色的底膜于培养板底部,使用Enspire检测化学发光值。各化合物的IC50值用XLFit软件的非线性回归方法分析。
代表性化合物对非小细胞肺癌H2122细胞增殖抑制活性测试结果列于表2.
表2.对非小细胞肺癌H2122细胞增殖的抑制
化合物 | IC 50(nM) |
IPN-60090 | 160.5 |
7 | 75 |
9 | 58.5 |
12 | 72 |
从表2数据可见,本专利发明的代表性化合物(如化合物7,9,12)对非小细胞肺癌H2122细胞增殖的抑制活性优于阳性对照化合物IPN-60090。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (13)
- 一种如下式(II)所示结构的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物:“*”表示手性中心,可为R型或S型;R 2选自下组:氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、C 1-4卤代烷氧基、C 2-6烯基、C 2- 6卤代烯基、C 2-6炔基、C 2-6卤代炔基、3-8元环烷基、3-8元杂环基;R 3选自下组:C 2-6烯基、C 2-6卤代烯基、C 2-6炔基、C 2-6卤代炔基、C 1-4卤代烷氧基C 2-4炔基、C 1-4卤代烷氧基、C 1-4卤代烯氧基、C 1-4卤代炔氧基、C 1-4卤代烷氧基C 1-4烷氧基、3-8元环烷基、3-8元卤代环烷基、3-8元杂环基、3-8元环烷基-O-、3-8元卤代环烷基-O-、3-8元卤代环烷基-NR i-、C 1-4卤代烷基3-8元环烷基-O-、C 1-4卤代烷基3-8元环烷基-NR i-、C 1-4卤代烷氧基3-8元环烷基-O-、C 1-4卤代烷氧基3-8元环烷基-NR i-、C 1-4卤代烷氧基C 1-4烷基3-8元环烷基-O-、C 1-4卤代烷氧基C 1-4烷基3-8元环烷基-NR i-、C 1-4卤代烷氧基C 1-4烷氧基3-8元环烷基-O-、CyC=R 5、-O-CyC=R 5、-S-CyC=R 5、或-NR i-CyC=R 5;其中,所述的CyC为饱和的3-8元环烷基,或饱和的4-8元杂环基,且所述的R 5选自下组:O、CR fR g,其中,R f和R g各自独立地选自下组:氢、氘、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、羟基C 1-4烷基、C 1-4卤代烷氧基、C 1-4卤代烷氧基C 1-4烷基;R i选自氢或C 1-4烷基;所述的CyC可任选地被一到多个R n取代;其中,R n选自氢、卤素、或C 1-4烷基;前提条件是,当R 3选自C 2-6烯基、3-8元环烷基、3-8元卤代环烷基、3-8元杂环基、3-8元环烷基-O-、C 1-4卤代烷氧基3-8元环烷基-O-、或3-8元卤代环烷基-O-时,R 2选自C 2-6卤代烯基、C 2-6炔基、或C 2-6卤代炔基;R k选自氢、卤素、或C 1-4烷基。其中,各个上述的烷基、烯基、炔基、环烷基、和杂环基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代:卤素、C 1-4烷基、C 1-4卤代烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO 2、OR h、SR h、NR hR h、C(O)R e、C(O)OR h、C(O)NR hR h、NR hC(O)R e、或S(O) 2R e,前提条件是所形成的化学结构是稳定的和有意义的;其中,各个R h各自独立为氢、或C 1-4烷基,或两个R h与其连接的氮原子一起形成3-至-8元杂环基,此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子;各个R e各自独立地为选自下组的基团:氢、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 3-8环烷基、3-至8-元杂环基、芳基、或杂芳基;除非特别说明,所述的环烷基或碳环、杂环基或杂环包括单环、并环、螺环或桥环。
- 如权利要求1所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,其特征在于,式(II)为式(III):R 2选自下组:C 1-6烷基、C 1-6卤代烷基、C 2-6炔基、3-8元环烷基;R 3选自下组:C 2-6炔基、C 2-6卤代炔基、C 1-4卤代烷氧基C 2-4炔基、3-8元卤代环烷基-NR i-、C 1-4卤代烷氧基C 1-4烷氧基、C 1-4卤代烷基3-8元环烷基-O-、C 1-4卤代烷氧基C 1-4烷基3-8元环烷基-O-、C 1-4卤代烷氧基C 1-4烷氧基3-8元环烷基-O-、CyC=R 5、-O-CyC=R 5、-S-CyC=R 5、或-NR i-CyC=R 5;其中,所述的CyC为饱和的3-8元环烷基,或饱和的4-8元杂环基,且所述的R 5选自下组:O、CR fR g,其中,R f和R g各自独立地选自下组:氢、氘、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、羟基C 1-4烷基、C 1-4卤代烷氧基、C 1-4卤代烷氧基C 1-4烷基;R i选自氢或C 1-4烷基;所述的CyC可任选地被一到多个R n取代;其中,R n选自氢、卤素、或C 1-4烷基。
- 如权利要求1或2所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,其特征在于,R 2选自下组:C 2-6卤代烯基、C 2-6炔基、C 2-6卤代炔基。
- 如权利要求1或2所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,其特征在于,R 3选自下组:C 2-6炔基、C 2-6卤代炔基、C 1-4卤代烷氧基C 2-4炔基、C 1-4卤代烷氧基C 1-4烷氧基、C 1-4卤代烷基3-8元环烷基-O-、C 1-4卤代烷氧基C 1-4烷基3-8元环烷基-O-、C 1-4卤代烷氧基C 1-4烷氧基3-8元环烷基-O-、CyC=R 5、或-O-CyC=R 5;其中,所述的CyC为饱和的3-8元环烷基,或饱和的4-8元杂环基,且所述的R 5选自下组:O、CR fR g,其中,R f和R g各自独立地选自下组:氢、氘、卤素、C 1-4烷基、C 1-4卤代烷基;所述的CyC可任选地被一到多个R n取代;其中,R n选自氢、卤素、或C 1-4烷基。
- 如权利要求1所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,其特征在于,式(II)为式(IV):“*”表示手性中心;R 2选自下组:氢、氘、卤素、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6卤代烯基、C 2-6炔基、C 2-6卤代炔基、3-8元环烷基、3-8元杂环基;Y选自化学键、O、S、或NR i;其中,R i自选自氢或C 1-4烷基;U选自N或CR m;其中,R m选自选自氢、卤素、或C 1-4烷基;R f和R g各自独立地选自下组:氢、氘、卤素、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基、C 1-4烷氧基C 1-4烷基、羟基C 1-4烷基、C 1-4卤代烷氧基、或C 1-4卤代烷氧基C 1-4烷基;各个R n各自独立地选自氢、卤素、或C 1-4烷基;R k选自氢、卤素、或C 1-4烷基;c和d各自独立地选自1、2、3、4、5、或6;e选自0、1、2、3、或4。
- 一种药物组合物,其特征在于,所述的药物组合物包括作为活性成分的如权利要求1-11任一所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物,和药学上可接受的载体。
- 如权利要求1-11任一所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物的用途,其特征在于,用于制备治疗GLS1活性或表达量介导的疾病或病症的药物组合物;较佳地,所述的GLS1活性或表达量介导的疾病和病症选自下组:B细胞淋巴瘤、单核细胞白血病、肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓瘤等多种实体瘤和血液瘤以及过敏性哮喘、骨髓纤维化、类风湿性关节炎、脾大性红细胞增多、嗜酸性白细胞增多综合征、原发性血小板减少症、系统性巨细胞疾病等疾病。
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