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WO2024197429A1 - Heterocyclic compound serving as androgen receptor modulator and use of heterocyclic compound - Google Patents

Heterocyclic compound serving as androgen receptor modulator and use of heterocyclic compound Download PDF

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Publication number
WO2024197429A1
WO2024197429A1 PCT/CN2023/083548 CN2023083548W WO2024197429A1 WO 2024197429 A1 WO2024197429 A1 WO 2024197429A1 CN 2023083548 W CN2023083548 W CN 2023083548W WO 2024197429 A1 WO2024197429 A1 WO 2024197429A1
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Prior art keywords
compound
formula
pharmaceutically acceptable
ring
acceptable salt
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PCT/CN2023/083548
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French (fr)
Chinese (zh)
Inventor
秦冲
张思琪
张赛
金文聪
孟晓蕾
马梦君
葛玲
刘兆娟
Original Assignee
青岛普泰科生物医药科技有限公司
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Priority to PCT/CN2023/083548 priority Critical patent/WO2024197429A1/en
Publication of WO2024197429A1 publication Critical patent/WO2024197429A1/en

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to a compound represented by formula I, an optical isomer, an isotopic derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound and the use of the compound as an androgen receptor (AR) modulator.
  • AR androgen receptor
  • PC Prostate cancer
  • AR Androgen receptors
  • PC Androgen receptors
  • AR dimers After AR combines with its ligand androgen in vivo, it forms AR dimers, which are then phosphorylated and transferred from the cytoplasm to the nucleus, and then mediate the transcription and activation of various pathways in the nucleus.
  • AR regulates the dynamic balance between proliferation and apoptosis of prostate epithelial cells. This dynamic balance is broken in PC tissues, promoting the proliferation and survival of tumor cells, which is the main cause of prostate cancer. Because AR plays an important role in the development of PC, treating PC by inhibiting AR from entering the nucleus has gradually become a research hotspot, and a series of AR inhibitor drugs have been developed based on this.
  • AR inhibitors targeting AR have appeared one after another.
  • AR inhibitors are often divided into steroidal and non-steroidal, which differ in chemical structure, pharmacological action and safety. Steroidal AR inhibitors can reduce testosterone levels and bind to other hormone receptors, so they are prone to cross-reactions.
  • Non-steroidal AR inhibitors used as monotherapy tend to increase overall testosterone levels and And it is more specific to AR.
  • steroidal AR inhibitors were developed for the treatment of PC before nonsteroidal AR inhibitors, they were gradually replaced by nonsteroidal AR inhibitors due to their easy adverse reactions.
  • the present invention provides a class of AR modulators with a completely new structure, which can reduce the expression of AR, show obvious concentration dependence and time dependence on the degradation of AR, and have obvious activity in inhibiting the proliferation of prostate cancer cells.
  • the present invention provides a compound represented by formula I, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof,
  • Ring A, Ring B, Ring C, Ring D, and Ring E are each independently selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, or C 5-10 heteroaryl, which is optionally substituted with 0, 1, 2, 3, 4, or 5 R 2 ;
  • L is selected from -L 4 -L 3 -L 2 -L 1 -L 0 - or -CO-NH-(CH 2 ) p -CO-R 0 -, provided that when L is selected from -CO-NH-(CH 2 ) p -CO-R 0 -, one or more methylene groups therein are optionally substituted by 1, 2 or 3 O atoms;
  • L 1 , L 3 , and L 5 are each independently selected from a single bond, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O, S, NH, -CO-, -SO-, -SO 2 -, -C 1-6 alkyl-O-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-6 alkyl-O- is optionally substituted by 1, 2 or 3 R 3 ;
  • L 0 , L 2 , L 4 are each independently selected from a single bond, a C 3-8 cycloalkyl group, a C 3-8 heterocycloalkyl group, a C 6-10 aryl group or a C 5-10 heteroaryl group, wherein the C 3-8 cycloalkyl group, the C 3-8 heterocycloalkyl group, the C 6-10 aryl group or the C 5-10 heteroaryl group is optionally substituted by 1 to 4 R 4 groups;
  • R 0 is selected from -NH-, piperidinyl, cyclohexyl or piperazinyl;
  • R 1 is selected from H, OH, halogen, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino;
  • R 2 , R 3 , R 4 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , CN, nitro, carboxyl, C 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , carboxyl, C 3-6 cycloalkyl are optionally substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , CN, nitro, carboxyl; preferably, R 2 is independently selected from one or more halogen (most preferably fluorine or chlorine),
  • n is selected from 0, 1, 2 or 3
  • p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • R 1 is selected from H, C 1-6 alkyl
  • L 1 and L 3 are independently selected from a single bond or a C 1-6 alkyl group
  • L 5 is selected from a single bond, O, S, NH, -CO-, -SO- or -SO 2 -;
  • L 0 , L 2 , and L 4 are each independently selected from C 5-6 cycloalkyl, C 5-6 heterocycloalkyl, C 6-10 aryl, or C 5-10 heteroaryl;
  • Ring A, Ring B, and Ring E are each independently selected from optionally substituted phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, quinolyl, isoquinolyl, or quinoxalinyl;
  • Ring C is selected from optionally substituted C 6-10 aryl or C 5-10 heteroaryl
  • Ring D is selected from optionally substituted C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
  • L 0 , L 2 , and L 4 are each independently selected from a single bond, a C 5-6 cycloalkyl group, or a C 5-6 heterocycloalkyl group;
  • Ring A, Ring B, and Ring E are each independently selected from an optionally substituted phenyl or pyridyl group;
  • Ring C is selected from optionally substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
  • Ring D is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl or tetrahydropyranyl;
  • L 0 , L 2 , L 4 are each independently selected from a single bond, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; Ring D is selected from optionally substituted cyclobutyl, cyclopentyl or cyclohexyl.
  • L is selected from the following linking groups, not specifically defined, wherein the two linking positions of the following linking groups are The positions can be arbitrarily selected for connection, for example, the left part of L in the structure of Formula I can be connected to the left or right side of the following connecting group, and correspondingly, the right part of L in the structure of Formula I can be connected to the right or left side of the following connecting group. It is particularly preferred that the left part of L in the structure of Formula I is connected to the left side of the following connecting group, and the right part of L in the structure of Formula I is connected to the right side of the following connecting group.
  • L is preferably:
  • the present invention also provides a compound shown in formula II, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure shown in formula II is as follows:
  • the present invention also provides a compound represented by formula III, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula III is as follows:
  • the present invention also provides a compound represented by formula IV, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula IV is as follows:
  • the present invention also provides a compound represented by formula V, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula V is as follows:
  • the present invention also provides a compound represented by formula VI, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula VI is as follows:
  • the present invention further provides a compound represented by formula VII, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula VII is as follows:
  • the compound of the present invention is selected from:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the Any compound, its optical isomer, isotopic derivative or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients or carriers.
  • the present invention also provides the use of the aforementioned compound, its optical isomer, isotope derivative or pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of androgen receptor modulators.
  • the present invention also provides the use of the aforementioned compound, its optical isomer, isotope derivative or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a drug for treating diseases associated with androgen receptor.
  • the disease described in some embodiments of the present invention is cancer, metabolic disorder, cardiovascular and cerebrovascular disease, hyperlipidemia or obesity.
  • the cancer is selected from prostate cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, squamous cell carcinoma, brain cancer, basal cell carcinoma, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, testicular cancer, pancreatic cancer, kidney cancer or gastric cancer; leukemia; benign and malignant lymphomas; melanoma; myeloproliferative diseases; sarcoma; thyroid cancer, astrocytoma; Hodgkin's disease, Wilman tumor or teratoma.
  • the above-mentioned benign and malignant lymphomas include Burkitt's lymphoma and non-Hodgkin's lymphoma; sarcomas include Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and Schwannoma.
  • sarcomas include Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myos
  • a dash ("-") not between two letters or symbols indicates the attachment point of a substituent, and the order of attachment is arbitrary. However, when the attachment point of a substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.
  • R2 When the R2 substituent on the benzene ring has no fixed structure, it means that R2 can be attached to any position, and R2 can be 0, 1, 2, 3, 4 or 5.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of the compounds of the invention, prepared from compounds having specific substituents discovered by the invention with relatively nontoxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or 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 a solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, etc.; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in the form of free acid or base are prepared by reacting with a stoichiometric amount of an appropriate base or acid.
  • the compounds of the present invention may exist in specific stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
  • the present invention also includes all suitable isotopic variants of the compounds of this invention.
  • the isotopic variant of the compounds of this invention is understood to be such a compound, wherein at least one atom in the compounds of this invention is replaced by another atom with the same atomic number but an atomic mass different from the atomic mass common or mainly present in nature.
  • isotopes that can be introduced into the compounds of this invention are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and iodine such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I.
  • isotopic variants of the compounds of the invention can be used, for example, to study the mechanism of action or distribution of the active substance in vivo; since they can be prepared and detected relatively easily, compounds labeled with 3 H- or 14 C-isotopes are particularly suitable for this.
  • isotopes e.g. deuterium
  • the introduction of isotopes can produce certain therapeutic advantages due to the higher metabolic stability of the compound, such as an increase in the half-life in vivo or a reduction in the effective dose required; such modifications of the compounds of the invention may therefore optionally also represent a preferred embodiment of the invention.
  • Isotopic variants of the compounds of the invention can be prepared by methods known to those skilled in the art, thereby, for example, by the specifications given in the following methods and embodiments, using the corresponding isotopic modifications of the individual reagents and/or starting compounds.
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • compounds may be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or C-14 (14C).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or “optionally” means that the event or situation described subsequently may but does not necessarily occur, and the description includes situations in which the event or situation occurs and situations in which the event or situation does not occur.
  • substituted or “substituted by" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • substituent which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • optionally substituted or “optionally substituted by" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.
  • any variable e.g., R
  • its definition is independent at each occurrence.
  • R e.g., R
  • the group may be optionally substituted with 1, 2, 3, 4 or 5 R, and each occurrence of R is an independent choice.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • substituents When the listed substituents do not specify through which atom they are bonded to the substituted group, such substituents may be bonded through any atom thereof.
  • a pyridyl substituent may be bonded to the substituted group through any carbon atom on the pyridine ring.
  • linking group L is -CH2O-
  • -CH2O- can be connected in the same direction as the reading order from left to right, or in the opposite direction to the reading order from right to left.
  • the combination of the linking group, substituent and/or its variants is allowed only when such combination will produce a stable compound.
  • the number of atoms in a ring is generally defined as the ring member number, for example, "3-6 membered ring” refers to a “ring” having 3-6 atoms arranged around it.
  • C 1-6 alkyl is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl 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, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom.
  • the C 1-6 alkoxy 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, 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, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl and the like.
  • cycloalkyl itself or in combination with other terms represents a cyclic form of an alkyl, alkenyl or alkynyl or mixture thereof.
  • the cycloalkyl may contain fused rings, but does not include fused aryl and heteroaryl, unless otherwise specified as unsubstituted, otherwise the cycloalkyl may be substituted.
  • cycloalkyl examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohexynyl, cyclohexadienyl, cyclopentadienyl, cyclopentenyl, cycloheptyl, norbornyl, etc. If the size of the ring is not specified, the cycloalkyl described herein contains 3-8 ring members or 3-6 ring members.
  • heterocycle or “heterocycloalkyl” or “heterocyclyl” by itself or in combination with other terms represents a cycloalkyl group containing at least one ring carbon atom and at least one ring heteroatom selected from O, N, P, Si and S, preferably selected from N, O and S, wherein the ring is non-aromatic but may contain unsaturation.
  • the nitrogen and sulfur atoms in the heterocyclic group may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the ring heteroatoms are selected from N, O and S.
  • the heterocyclic group described herein contains 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-5, 4-6, 4-7, 4-8, 5-10, 5-8 ring members, and at least one ring member is a heteroatom selected from N, O and S; usually no more than 3 of these heteroatoms are contained in the heterocyclic group, and usually no more than 2 of these heteroatoms are contained in a single ring of the heterocyclic group.
  • the heterocyclic group may be fused to other carbocyclic, heterocyclic or aryl rings.
  • the heterocyclic group can be connected to the rest of the molecule on the ring carbon or ring heteroatom, and the heterocyclic group can be substituted as described for the alkyl.
  • the heterocycle can include fused rings, but does not include the fused system containing the heteroaryl as a part of the fused ring system.
  • the example of the heterocyclic group includes but is not limited to 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, 1,2,3,4-tetrahydropyridyl, dihydroindole (indoline), tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothioph
  • aryl refers to an aromatic hydrocarbon group, which can be a single ring or multiple rings (e.g., 1-3 rings) with rings fused together.
  • An aryl group may contain fused rings, wherein one or more rings are optionally cycloalkyl, but do not include heterocyclic or heteroaromatic rings; a fused system containing at least one heteroaromatic ring is referred to as a heteroaryl group, and a phenyl ring fused to a heterocyclic ring is referred to herein as a heterocyclic group.
  • Aryl groups include fused ring systems in which a phenyl ring is fused to a cycloalkyl ring.
  • aryl groups include, but are not limited to, phenyl, 1-naphthyl, tetralin, dihydro-1H-indene, 2-naphthyl, tetralinyl, and the like.
  • heteroaryl refers to a group containing a single ring or two or three condensed rings, wherein at least one ring is an aromatic ring containing 1 to 4 heteroatoms selected from N, O and S as ring members (i.e., it contains at least one heteroaromatic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally substituted with a quaternary amine.
  • the heteroaryl group may be attached to the rest of the molecule through a ring carbon or a ring heteroatom, and if the group is bicyclic or tricyclic, it may be attached through any ring of the heteroaryl group.
  • the heteroaryl group may contain fused rings, one or more of which may be cycloalkyl or heterocycloalkyl or aryl, provided that at least one ring is a heteroaromatic ring.
  • Non-limiting examples of heteroaryl are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl,
  • Aryl and/or heteroaryl groups typically contain up to 4 substituents per ring (0-4), sometimes 0-3 or 0-2 substituents.
  • aryloxy and heteroaryloxy refer to aryl and heteroaryl groups, respectively, attached to the rest of the molecule through an oxygen linker (-O-).
  • halo or halogen itself or as part of other substituents refers to fluorine, chlorine, bromine or iodine atoms.
  • terms such as “haloalkyl” should include monohaloalkyl and perhaloalkyl.
  • halo (C 1 -C 4 ) alkyl should include but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.
  • perhalo refers to each group in which all available valence bonds are replaced by halogen.
  • perhaloalkyl includes -CCl 3 , -CF 3 , -CCl 2 CF 3 , etc.
  • perfluoroalkyl and perchloroalkyl are subgroups of perhaloalkyl in which all available valence bonds are replaced by fluorine and chlorine, respectively.
  • Non-limiting examples of perfluoroalkyl include -CF 3 and -CF 2 CF 3.
  • Non-limiting examples of perchloroalkyl include -CCl 3 and -CCl 2 CCl 3 .
  • Amino refers herein to the group -NH2 or -NRR', wherein R and R' are independently selected from hydrogen or alkyl (e.g. lower alkyl).
  • arylamino refers herein to the group -NRR', wherein R is aryl and R' is hydrogen, alkyl or aryl.
  • aralkylamino refers herein to the group -NRR', wherein R is aralkyl and R' is hydrogen, alkyl, aryl or aralkyl.
  • Substituted amino refers to an amino group wherein at least one of R and R' is not H, i.e. the amino group carries at least one substituent.
  • alkylamino refers to -alkyl-NRR', wherein R and R' are independently selected from hydrogen or alkyl (e.g. lower alkyl).
  • the chemical structure or chemical name should include all possible stereoisomers, conformers, rotational isomers and tautomers of the compound.
  • a compound containing a chiral carbon atom should include the (R) enantiomer and the (S) enantiomer and mixtures of enantiomers, including racemic mixtures;
  • a compound containing two chiral carbon atoms should include all enantiomers and diastereomers (including (R, R), (S, S), (R, S) and (R, S) isomers).
  • the present invention also includes the use of any or all stereochemical forms, enantiomers, diastereomers, conformers, rotamers, tautomers, solvates, hydrates, polymorphs, crystalline forms, amorphous forms, salts, pharmaceutically acceptable salts, metabolites, and prodrugs of the compounds.
  • the pharmaceutical composition of the present invention contains at least one compound according to any embodiment disclosed herein (including pharmaceutically acceptable salts of these compounds) mixed with at least one pharmaceutically acceptable excipient, carrier or diluent.
  • the pharmaceutical composition is a sterile composition, or a composition consisting mainly of or only of the above-mentioned compound and one or more pharmaceutically acceptable excipients, carriers and/or diluents.
  • the pharmaceutical composition comprises at least two pharmaceutically acceptable carriers and/or excipients described herein.
  • Certain compounds of the present invention may exist in non-solvated forms as well as solvated forms (i.e., solvates).
  • the compounds of the present invention may also include hydrated forms (i.e., hydrates).
  • solvates and hydrate forms are identical to non-solvated forms in terms of biological efficacy and are included within the scope of the present invention.
  • the present invention also includes all polymorphs, including crystalline and non-crystalline forms. Typically, for the intended use of the present invention, all physical forms are available and are intended to be included within the scope of the present invention.
  • therapeutically effective amount refers to an amount capable of producing the desired pharmacological and/or physiological effect.
  • the effect may be preventive, capable of completely or partially preventing a disease or its symptoms; and/or may be therapeutic, capable of partially or completely curing a disease and/or side effects associated with the disease.
  • a therapeutically effective amount of a compound of the invention generally includes any amount sufficient to inhibit Raf activity that can be detected by any of the assays described herein, by other CDK or CDK9 kinase activity assays known to those skilled in the art, or by detecting inhibition or alleviation of cancer symptoms.
  • compositions described herein comprise at least one pharmaceutically acceptable carrier or excipient; preferably, the composition comprises at least one carrier or excipient other than water or at least one carrier or excipient in addition to water.
  • compositions can be pharmaceutically acceptable carriers, adjuvants, or vehicles, which, as used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form.
  • the compounds of the present invention may have systemic and/or local effects.
  • they may be administered in a suitable manner, for example, by oral, parenteral, pulmonary, intranasal, sublingual, lingual, buccal, rectal, transdermal, transconjunctival or otic routes, or as implants or stents.
  • Suitable for oral administration are dosage forms which act according to the prior art, release the compound according to the invention quickly and/or with modification and contain the compound according to the invention in crystalline and/or amorphisized and/or dissolved form, such as tablets (uncoated or coated tablets, for example with an enteric coating or with a coating which delays dissolution or an insoluble coating which controls the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilisates, capsules (for example hard or soft capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
  • tablets uncoated or coated tablets, for example with an enteric coating or with a coating which delays dissolution or an insoluble coating which controls the release of the compound according to the invention
  • tablets which disintegrate rapidly in the mouth or films/wafers, films/lyophilisates
  • capsules for example hard or soft capsules
  • dragees dragee
  • Parenteral administration can be performed by bypassing an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal).
  • Suitable dosage forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
  • Dosage forms suitable for other routes of administration are, for example, inhalation forms (including powder inhalers, nebulizers), nasal drops, solutions and sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration; suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (milks), pastes, foams, dusting powders, implants or stents.
  • inhalation forms including powder inhalers, nebulizers
  • nasal drops solutions and sprays
  • tablets, films/wafers or capsules for lingual, sublingual or buccal administration
  • suppositories ear or eye preparations
  • vaginal capsules aqueous suspensions (lotions, shaking mixtures)
  • lipophilic suspensions ointments
  • creams e.
  • treatment refers to administering to an individual suffering from a disease or experiencing symptoms of the disease
  • One or more drug substances in particular compounds of formula (I) as described herein and/or pharmaceutically acceptable salts thereof, are used to cure, alleviate, mitigate, alter, treat, improve, ameliorate or affect the disease or the symptoms of the disease.
  • prevention refers to the administration of one or more drug substances, in particular compounds of formula (I) as described herein and/or pharmaceutically acceptable salts thereof, to an individual with a physique susceptible to the disease, to prevent the individual from suffering from the disease.
  • the terms “treating”, “contacting” and “reacting” refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction that produces the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture, which ultimately lead to the formation of the indicated and/or desired product.
  • the compounds defined in the present invention or their pharmaceutically acceptable salts, or pharmaceutically acceptable compositions containing them, are effective modulators of androgen receptors. It is expected that the compounds of the present invention are potentially useful agents in treating diseases or medical conditions mediated solely or in part by androgen receptors.
  • the compounds of the present invention may cause downregulation of androgen receptors and/or are selective agonists, partial agonists, antagonists or partial antagonists of androgen receptors.
  • the compounds according to the invention are preferably suitable for the treatment and/or prevention of androgen receptor-dependent diseases.
  • cancer and tumor diseases include in particular cancer and tumor diseases.
  • these diseases include in particular the following diseases, but are not limited to these diseases: breast cancer and breast tumors (breast cancer including ductal and lobular forms, as well as breast cancer in situ), respiratory tract tumors (small cell carcinoma and non-small cell carcinoma, bronchial carcinoma), brain tumors (e.g.
  • tumors of the brain stem and hypothalamus astrocytomas, ependymomas, glioblastomas, gliomas, medulloblastomas, meningiomas, and neuroectodermal and pineal tumors
  • tumors of the digestive organs esophageal cancer, gastric cancer, gallbladder cancer, small intestine cancer, colon cancer, rectal cancer and anal cancer
  • liver tumors including hepatocellular carcinoma, bile duct cancer and mixed hepatocellular bile duct cancer
  • tumors of the head and neck laryngeal cancer, tongue cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer and oral cancer, oral melanoma
  • skin tumors basal cell carcinoma, acanthosarcoma, squamous cell carcinoma, Kaposi sarcoma, malignant melanoma, non-melanoma skin cancer, Merkel cell skin cancer, mast cell tumors
  • the compounds of the invention can be administered to animals (e.g., humans) to treat a variety of conditions and disorders, including, but not limited to, maintaining muscle strength and function (e.g., in the elderly); reversing or preventing frailty or age-related functional decline ("ARFD") in the elderly (e.g., senile muscle atrophy); treating the catabolic side effects of glucocorticoids; preventing and/or treating loss of bone mass, density or growth (e.g., osteoporosis and osteopenia); treating chronic fatigue syndrome (CFS); chronic myalgia; treating acute fatigue syndrome and muscle loss following elective surgery (e.g., postoperative rehabilitation); accelerate wound healing; accelerate fracture repair (e.g., accelerate recovery of hip fracture patients); accelerate healing of complex fractures, such as distraction osteogenesis; joint replacement; prevent postoperative adhesion formation; accelerate tooth repair or growth; maintain sensory function (e.g., hearing, vision, smell, and taste); treatment of periodontal disease; treatment of post-fracture
  • ARFD
  • treatment of relative insufficiency of testosterone secretion treatment of hypothermia; treatment of congestive heart failure; treatment of dysregulation of fat metabolism (e.g., in patients receiving HIV or AIDS treatments such as protease inhibitors); treatment of muscle atrophy (e.g., due to physical inactivity, bed rest, or a weight-reduced state); treatment of musculoskeletal injuries (e.g., in the elderly); improvement of global lung function; treatment of sleep disorders; treatment of the catabolic state of chronic critical illness; age-related decreases in testosterone levels in men, male menopause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, decreased libido), urinary incontinence, male and female contraception, hair loss, and enhancement of bone and muscle performance/strength.
  • dysregulation of fat metabolism e.g., in patients receiving HIV or AIDS treatments such as protease inhibitors
  • treatment of muscle atrophy
  • androgen receptor-associated conditions include prostate cancer, benign prostatic hyperplasia and prostatic hypertrophy, acne (acne vulgaris), seborrheic dermatitis, hirsutism, male pattern baldness and male pattern hair loss, precocious puberty, polycystic ovary syndrome, paraphilia, virilization, etc.
  • the compounds of the invention may also be used to improve ovulation in farmed animals.
  • the compounds of the present invention can be used alone or, if necessary, in combination with one or more other pharmacologically effective substances, provided that this combination does not cause undesirable and unacceptable side effects.
  • suitable combination active substances 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, refametinib (BAY 86-9766, RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, leucovorin, capecitabine, carboplatin, carmofur, carmustine, catumaxomab
  • FIG1 is a graph showing the effect of the example compounds on the AR expression level of AR-positive human prostate cancer cells LNCaP;
  • FIG. 2 is a graph showing the results of the Example compounds inhibiting the proliferation of human prostate cancer cells LNCaP.
  • the raw material 1 (2.0 g, 9.26 mmol) was dissolved in dichloromethane (60 mL), and piperazine-1-carboxylic acid was added.
  • Tert-butyl ester (1.75 g, 9.4 mmol) and triethylamine (2 mL, 14.0 mmol).
  • the reaction mixture was stirred at room temperature for 6 h and extracted with water (100 mL ⁇ 3).
  • the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, it was recrystallized from ethanol to obtain 2.4 g of a light yellow solid with a yield of 80.60%.
  • UPLC-MS calculated for C 16 H 23 N 3 O 4 [M+H] + :321.38, found:321.92.
  • the raw material 16 (100 mg, 0.63 mmol) was dissolved in anhydrous tetrahydrofuran, and two drops of DMF and SOCl 2 (2 mL, 18 mmol) were added. The mixture was stirred at 70° C. for 4 h, and the solvent was evaporated to obtain a yellow viscous liquid.
  • the intermediate 21 (280 mg, 0.80 mmol) was dissolved in dichloromethane (20 mL), and a 4M hydrochloric acid/dioxane solution (2.0 mL) was added. The mixture was stirred at room temperature for 4 h. TLC showed that the reaction of the raw material was complete. The solvent was evaporated to obtain a yellow solid. UPLC-MS calculated for C 13 H 15 ClN 2 O[M+H] + :250.73, found:250.75.
  • the synthetic route was as in Example 1, except that the raw material was replaced by 6-chloropyridazine-3-carboxylic acid instead of 2-chloropyrimidine-5-carboxylic acid in Example 1, and 25 mg of SQA-703 white powder solid was obtained by preparative liquid phase.
  • UPLC-MS calculated for C 48 H 57 ClN 10 O 5 [M+H] + :889.50, found:889.50.
  • N-Boc- ⁇ -aminobutyric acid 55 mg, 0.27 mmol
  • HATU 158 mg, 0.42 mmol
  • DIPEA 0.24 mL, 1.38 mmol
  • Boc-beta-alanine (57 mg, 0.3 mmol), HATU (171 mg, 0.45 mmol) and DIPEA (0.26 mL, 1.5 mmol) were dissolved in anhydrous DMF, stirred and reacted for 15 min under argon protection, and a DMF solution of intermediate 63 (115 mg, 0.28 mmol) was added, and the reaction was stirred at room temperature overnight.
  • the synthesis of intermediate 66 can refer to the preparation method of intermediate 40 in Example 5;
  • Test Example 1 Evaluation of the effect of reducing androgen receptor (AR) expression
  • AR-positive human prostate cancer cells LNCaP were seeded in 6-well microplates (Corning) in RPMI 1640 containing 10% FBS (hereinafter referred to as evaluation medium) at a concentration of 3X 10 5 /well and cultured overnight.
  • the evaluation medium containing the example compound was added to the culture medium to a final concentration of 1 and 10 ⁇ mol/L, and cultured for 24 hours. After 24 hours of culture, the culture medium was removed, the cells were washed with PBS, and RIPA lysis buffer containing 1% Protease Inhibitor Cocktail was added.
  • the total protein extract was obtained, and the protein concentration in the extract was detected by the BCA method; SDS-PAGE was used for protein electrophoresis, and then the protein was transferred to a PVDF (MilliporeSigma IPVH00010) membrane by constant current electrophoresis at 200mA for 90min; the PVDF membrane was placed in 5% skim milk and blocked at room temperature for 1h; the immune reaction was carried out using Anti-Androgen Receptor antibody [EPR1535(2)] (HRP) (abcam) and anti-AR-V7 Speccific antibody (Cell Signaling); after washing the membrane, ECL luminescence was added The solution was exposed. The grayscale analysis of the bands was performed using the software Image J. The GAPDH protein band was simultaneously detected for each sample as an internal reference. The AR protein degradation rate of the example compound was calculated based on the grayscale of the protein band.
  • Test Example 2 Androgen-dependent prostate cancer cell proliferation inhibitory activity
  • Androgen receptor-positive human prostate cancer cells LNCaP were seeded in a transparent bottom 96-well microplate (Corning) in RPMI 1640 medium (hereinafter referred to as evaluation medium) containing 5% carbon adsorbed serum (CCS) at a concentration of 4 ⁇ 10 3 /well and cultured for 48 hours.
  • evaluation medium RPMI 1640 medium
  • CCS carbon adsorbed serum
  • Evaluation medium containing R1881 the final concentration of R1881 was 0.1 nmol/L
  • evaluation medium containing Example compounds or Comparative Example compounds Enzalutamide: Enzalutamide
  • the final concentrations of the Example or Comparative Example compounds were 1.53, 4.6, 13.8, 41.1, 123.4, 370.3, 1111, 3333 and 10000 nmol/L), and the number of viable cells was measured after 96 hours of culture.
  • the number of viable cells was measured using WST-1 (Roche).
  • the cell proliferation activity value of 0.1 nmol/L R1881 was set as 100%, and the cell proliferation activity of only the evaluation medium was set as 0%, and the 50% proliferation inhibition concentration ( IC50 value) was calculated based on the measured viable cell number using logistic regression.
  • the results of cell proliferation inhibition are shown in Table 2.
  • the example compounds showed different degrees of prostate cancer cell proliferation inhibition activity, among which SQA-710 showed excellent tumor cell proliferation inhibition activity, with the maximum half inhibition concentration (IC 50 ) of 36.0nmol/L (LNCaP cell line) and 30.2nmol/L (22RV1 cell line).
  • IC 50 the maximum half inhibition concentration of 36.0nmol/L
  • 22RV1 cell line the maximum half inhibition concentration
  • Enzalutamide was used as a positive control, and its IC 50 in LNCaP cell line was 52nmo1/L, while it was almost ineffective in 22RV1 cell line.
  • a mouse model was constructed using the human prostate cancer 22RV1 cell line (enzalutamide resistant), and the mouse strain was balb/c nude mice.
  • the solvent for the example compound was 20% PEG400+6% Cremophor EL+74% PBS, and the drug was administered by intraperitoneal injection.
  • the administration cycle was Qod4*weeks, and the dosage was 5mg/kg or 10mg/kg. After 16 days of administration, the tumor volume of the mice was measured, and the experimental results are shown in Figure 2.
  • Example compound H3 (10mg/kg), SQA-710 (5mg/kg and 10mg/kg), SQA-814 (5mg/kg) Compared with the Control group, it showed significant and comparable tumor proliferation inhibition ability, while the compound SQA-702, which was active at the cellular level, was not effective in the mouse model.
  • SQA-710 showed certain toxicity to mice regardless of whether it was administered at 5 mg/kg or 10 mg/kg, while SQA-814, when administered at 5 mg/kg, was able to ensure efficacy without significant effect on the weight of mice.
  • the compounds in the examples all have a certain effect of reducing the AR expression level of LNCap cells, among which SQA-710 has the best AR degradation activity, with a DC 50 of about 20nM, which can not only inhibit the growth of LNCap cells in a dose-dependent manner, but also significantly inhibit the growth of Enzalutamide-resistant 22RV1 tumor cells.
  • SQA-710 as a small molecule conjugate drug of AR antagonist and Hsp90 inhibitor, has a higher tumor inhibition activity than the effects of the two small molecules when used alone, which shows that this conjugate drug has a similar effect to a dual-target inhibitor and produces a synergistic effect.

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Abstract

The present invention relates to a novel heterocyclic compound and a use thereof. The structure of the compound is represented by formula I. The present invention also relates to an optical isomer, isotope derivative or pharmaceutically acceptable salt of the compound, or a pharmaceutical composition comprising the compound. The compound or the pharmaceutical composition is used as an androgen receptor (AR) modulator for treating related diseases, and can be used alone or in combination with other therapeutic agents.

Description

作为雄激素受体调节剂的杂环化合物及其应用Heterocyclic compounds as androgen receptor modulators and their use 技术领域Technical Field
本发明涉及式I所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，包含所述化合物的药物组合物以及所述化合物作为雄激素受体(AR)调节剂的应用。The present invention relates to a compound represented by formula I, an optical isomer, an isotopic derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound and the use of the compound as an androgen receptor (AR) modulator.
背景技术Background Art
前列腺癌(prostate cancer，PC)是男性泌尿生殖系统常见的恶性肿瘤之一，也是导致男性死亡的第二大病因。2016年，我国新发前列腺癌患者数量为12万，预计至2030年，这一数字将上升至23.7万人，新发患者数量的年复合增长率为5％。PC的治疗包括前列腺切除术、放射治疗和化学治疗。经过治疗后，部分患者会出现血PSA升高，尽管实施了复发性PC的新疗法，肿瘤细胞仍然频繁的出现转移，称为转移性去势抵抗性前列腺癌(mCRPC)；也有部分PC患者通过传统影像学检查未发现任何远处转移，被归类为非转移性去势抵抗性前列腺癌(nmCRPC)。随着PC发病率的日益提高，人们对其发病机制的研究也在逐步深入。Prostate cancer (PC) is one of the common malignant tumors of the male urogenital system and the second leading cause of death in men. In 2016, the number of new prostate cancer patients in my country was 120,000. It is estimated that by 2030, this number will rise to 237,000, with an annual compound growth rate of 5%. The treatment of PC includes prostatectomy, radiotherapy and chemotherapy. After treatment, some patients will have elevated blood PSA. Despite the implementation of new treatments for recurrent PC, tumor cells still frequently metastasize, which is called metastatic castration-resistant prostate cancer (mCRPC); some PC patients have no distant metastasis found through traditional imaging examinations and are classified as non-metastatic castration-resistant prostate cancer (nmCRPC). With the increasing incidence of PC, people's research on its pathogenesis is also gradually deepening.
雄激素受体(androgenreceptors,AR)是具有配体结合区、DNA结合区以及多个磷酸化位点的类固醇激素受体。AR在体内与配体雄激素合后，形成AR二聚体，进而磷酸化并从细胞质转移到细胞核，然后在细胞核内介导各种途径的转录和激活。正常成人前列腺内AR调控前列腺上皮细胞增殖与凋亡的动态平衡，在PC组织中这种动态平衡被打破，促进了肿瘤细胞的增殖和存活，这是前列腺癌发病的主要原因。由于AR在PC的发展过程中发挥着重要的作用，通过抑制AR进入细胞核来治疗PC逐渐成为研究热点，并以此为基础研发出一系列的AR抑制剂类药物。Androgen receptors (AR) are steroid hormone receptors with ligand binding regions, DNA binding regions, and multiple phosphorylation sites. After AR combines with its ligand androgen in vivo, it forms AR dimers, which are then phosphorylated and transferred from the cytoplasm to the nucleus, and then mediate the transcription and activation of various pathways in the nucleus. In normal adult prostates, AR regulates the dynamic balance between proliferation and apoptosis of prostate epithelial cells. This dynamic balance is broken in PC tissues, promoting the proliferation and survival of tumor cells, which is the main cause of prostate cancer. Because AR plays an important role in the development of PC, treating PC by inhibiting AR from entering the nucleus has gradually become a research hotspot, and a series of AR inhibitor drugs have been developed based on this.
雄激素受体信号通路在前列腺癌、乳腺癌、膀胱癌等的发生、发展中都起着重要作用，因此以AR为靶点的AR抑制剂相继出现。在PC的治疗中，AR抑制剂常被分为甾体和非甾体类，它们在化学结构、药理作用和安全性上各不相同。甾体类AR抑制剂可降低睾酮水平，并可与其他激素受体结合，因此易产生交叉反应。而用作单一疗法的非甾体类AR抑制剂更倾向于提高整体的睾酮水平，并 且对AR更具特异性。甾体类AR抑制剂虽先于非甾体AR抑制剂被开发用于PC的治疗，但由于其易产生不良反应而逐渐被非甾体类AR抑制剂所取代。Androgen receptor signaling pathway plays an important role in the occurrence and development of prostate cancer, breast cancer, bladder cancer, etc. Therefore, AR inhibitors targeting AR have appeared one after another. In the treatment of PC, AR inhibitors are often divided into steroidal and non-steroidal, which differ in chemical structure, pharmacological action and safety. Steroidal AR inhibitors can reduce testosterone levels and bind to other hormone receptors, so they are prone to cross-reactions. Non-steroidal AR inhibitors used as monotherapy tend to increase overall testosterone levels and And it is more specific to AR. Although steroidal AR inhibitors were developed for the treatment of PC before nonsteroidal AR inhibitors, they were gradually replaced by nonsteroidal AR inhibitors due to their easy adverse reactions.
近年来，随着对AR结构及其生物学功能更深一步的认识，研究人员正致力于开发更佳的AR类似物，新一代无激动剂活性的AR抑制剂被研究用于更有效地抑制AR。In recent years, with a deeper understanding of AR structure and its biological function, researchers are working to develop better AR analogs, and a new generation of AR inhibitors without agonist activity are being studied to more effectively inhibit AR.
本发明针对现有技术的不足，提供了一类全新结构的AR调节剂，其能够降低AR的表达，对AR的降解表现出明显的浓度依赖性和时间依赖性，具有明显的抑制前列腺癌细胞增殖的活性。In view of the deficiencies of the prior art, the present invention provides a class of AR modulators with a completely new structure, which can reduce the expression of AR, show obvious concentration dependence and time dependence on the degradation of AR, and have obvious activity in inhibiting the proliferation of prostate cancer cells.
发明内容Summary of the invention
本发明提供了式I所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，
The present invention provides a compound represented by formula I, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof,
其中，in,
环A、环B、环C、环D、环E分别独立地选自任选被0、1、2、3、4或5个R2取代的C3-8环烷基、C3-8杂环烷基、C6-10芳基或C5-10杂芳基；Ring A, Ring B, Ring C, Ring D, and Ring E are each independently selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, or C 5-10 heteroaryl, which is optionally substituted with 0, 1, 2, 3, 4, or 5 R 2 ;
L选自-L4-L3-L2-L1-L0-或-CO-NH-(CH2)p-CO-R0-，条件是当L选自-CO-NH-(CH2)p-CO-R0-时，其中的1个或多个亚甲基任选的被1、2或3个O原子取代；L is selected from -L 4 -L 3 -L 2 -L 1 -L 0 - or -CO-NH-(CH 2 ) p -CO-R 0 -, provided that when L is selected from -CO-NH-(CH 2 ) p -CO-R 0 -, one or more methylene groups therein are optionally substituted by 1, 2 or 3 O atoms;
L1、L3、L5分别独立地选自单键、C1-6烷基、C2-6烯基、C2-6炔基、O、S、NH、-CO-、-SO-、-SO2-、-C1-6烷基-O-，所述C1-6烷基、C2-6烯基、C2-6炔基、-C1-6烷基-O-任选被1、2或3个R3取代；L 1 , L 3 , and L 5 are each independently selected from a single bond, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O, S, NH, -CO-, -SO-, -SO 2 -, -C 1-6 alkyl-O-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-6 alkyl-O- is optionally substituted by 1, 2 or 3 R 3 ;
L0、L2、L4分别独立地选自单键、C3-8环烷基、C3-8杂环烷基、C6-10芳基或C5-10杂芳基，所述C3-8环烷基、C3-8杂环烷基、C6-10芳基或C5-10杂芳基任选被1-4个R4取代；L 0 , L 2 , L 4 are each independently selected from a single bond, a C 3-8 cycloalkyl group, a C 3-8 heterocycloalkyl group, a C 6-10 aryl group or a C 5-10 heteroaryl group, wherein the C 3-8 cycloalkyl group, the C 3-8 heterocycloalkyl group, the C 6-10 aryl group or the C 5-10 heteroaryl group is optionally substituted by 1 to 4 R 4 groups;
R0选自-NH-、哌啶基、环己基或哌嗪基； R 0 is selected from -NH-, piperidinyl, cyclohexyl or piperazinyl;
R1选自H、OH、卤素、NH2、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6烷氨基；R2、R3、R4分别独立地选自H、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、OH、NH2、CN、硝基、羧基、C3-6环烷基，所述的C1-6烷基、C1-6烷氧基、C1-6卤代烷基、OH、NH2、羧基、C3-6环烷基任选被1-3个选自卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、OH、NH2、CN、硝基、羧基的取代基取代；优选的，R2独立的选自一个或多个选自卤素(最优选为氟或氯)、氰基或三氟甲基。R 1 is selected from H, OH, halogen, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino; R 2 , R 3 , R 4 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , CN, nitro, carboxyl, C 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , carboxyl, C 3-6 cycloalkyl are optionally substituted with 1-3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , CN, nitro, carboxyl; preferably, R 2 is independently selected from one or more halogen (most preferably fluorine or chlorine), cyano or trifluoromethyl.
m选自0或1，n选自0、1、2或3，p选自0、1、2、3、4、5、6、7、8、9或10。m is selected from 0 or 1, n is selected from 0, 1, 2 or 3, and p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
优选的，R1选自H、C1-6烷基；Preferably, R 1 is selected from H, C 1-6 alkyl;
L1、L3独立地选自单键或C1-6烷基；L 1 and L 3 are independently selected from a single bond or a C 1-6 alkyl group;
L5选自单键、O、S、NH、-CO-、-SO-或-SO2-；L 5 is selected from a single bond, O, S, NH, -CO-, -SO- or -SO 2 -;
L0、L2、L4分别独立地选自C5-6环烷基、C5-6杂环烷基、C6-10芳基或C5-10杂芳基；L 0 , L 2 , and L 4 are each independently selected from C 5-6 cycloalkyl, C 5-6 heterocycloalkyl, C 6-10 aryl, or C 5-10 heteroaryl;
环A、环B、环E分别独立地选自任选取代的苯基、萘基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、哒嗪基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、苯并噁唑基、吲哚基、喹啉基、异喹啉基或喹喔啉基；Ring A, Ring B, and Ring E are each independently selected from optionally substituted phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, quinolyl, isoquinolyl, or quinoxalinyl;
环C选自任选取代的C6-10芳基或C5-10杂芳基；Ring C is selected from optionally substituted C 6-10 aryl or C 5-10 heteroaryl;
环D选自任选取代的C3-8环烷基或C3-8杂环烷基；Ring D is selected from optionally substituted C 3-8 cycloalkyl or C 3-8 heterocycloalkyl;
进一步优选的，More preferably,
L0、L2、L4分别独立地选自单键、C5-6环烷基或C5-6杂环烷基；L 0 , L 2 , and L 4 are each independently selected from a single bond, a C 5-6 cycloalkyl group, or a C 5-6 heterocycloalkyl group;
环A、环B、环E分别独立地选自任选取代的苯基或吡啶基；Ring A, Ring B, and Ring E are each independently selected from an optionally substituted phenyl or pyridyl group;
环C选自任选取代的苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基；Ring C is selected from optionally substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
环D选自任选取代的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、四氢呋喃基、四氢噻吩基或四氢吡喃基；Ring D is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl or tetrahydropyranyl;
更进一步优选的，More preferably,
L0、L2、L4分别独立地选自单键、环戊基、环己基、吡咯烷基、哌啶基、哌嗪基或吗啉基；环D选自任选取代的环丁基、环戊基或环己基。L 0 , L 2 , L 4 are each independently selected from a single bond, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; Ring D is selected from optionally substituted cyclobutyl, cyclopentyl or cyclohexyl.
优选的，L选自如下连接基团，没有特别定义，如下连接基团的两个连接位 置可以任意选择连接，例如式I结构中L左侧部分可以与如下连接基团的左侧或右侧连接，相应地，式I结构中L右侧部分可以与如下连接基团的右侧或左侧连接，特别优选的，式I结构中L左侧部分与如下连接基团的左侧连接，式I结构中L右侧部分与如下连接基团的右侧连接，L优选为：
Preferably, L is selected from the following linking groups, not specifically defined, wherein the two linking positions of the following linking groups are The positions can be arbitrarily selected for connection, for example, the left part of L in the structure of Formula I can be connected to the left or right side of the following connecting group, and correspondingly, the right part of L in the structure of Formula I can be connected to the right or left side of the following connecting group. It is particularly preferred that the left part of L in the structure of Formula I is connected to the left side of the following connecting group, and the right part of L in the structure of Formula I is connected to the right side of the following connecting group. L is preferably:
在本发明的另一方面，本发明还提供了式Ⅱ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，式Ⅱ所示的结构如下：
In another aspect of the present invention, the present invention also provides a compound shown in formula II, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure shown in formula II is as follows:
所述各基团的定义如上所述。The definitions of the above groups are as described above.
在本发明的另一方面，本发明还提供了式Ⅲ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，式Ⅲ所示的结构如下：
In another aspect of the present invention, the present invention also provides a compound represented by formula III, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula III is as follows:
式Ⅲ，所述各基团的定义如上所述。In formula III, the above-mentioned groups are as defined above.
在本发明的另一方面，本发明还提供了式Ⅳ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，式Ⅳ所示的结构如下：
In another aspect of the present invention, the present invention also provides a compound represented by formula IV, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula IV is as follows:
式Ⅳ，所述各基团的定义如上所述。In formula IV, the above-mentioned groups are as defined above.
在本发明的另一方面，本发明还提供了式Ⅴ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，式Ⅴ所示的结构如下：
In another aspect of the present invention, the present invention also provides a compound represented by formula V, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula V is as follows:
式Ⅴ，所述各基团的定义如上所述。In formula V, the groups are as defined above.
在本发明的另一方面，本发明还提供了式Ⅵ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，式Ⅵ所示的结构如下：
In another aspect of the present invention, the present invention also provides a compound represented by formula VI, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula VI is as follows:
式Ⅵ，所述各基团的定义如上所述。In formula VI, the above groups are as defined above.
在本发明的另一方面，本发明还提供了式Ⅶ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，式Ⅶ所示的结构如下：
In another aspect of the present invention, the present invention further provides a compound represented by formula VII, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and the structure represented by formula VII is as follows:
式Ⅶ，所述各基团的定义如上所述。In formula VII, the above groups are as defined above.
在本发明的另一方面，本发明所述的化合物选自：

In another aspect of the present invention, the compound of the present invention is selected from:

所述化合物的信息如下：








The information of the compound is as follows:








在本发明的再一方面，本发明还提供了一种药物组合物，其包含本发明所述 的任一化合物、其光学异构体、同位素衍生物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂或载体。In another aspect of the present invention, the present invention also provides a pharmaceutical composition comprising the Any compound, its optical isomer, isotopic derivative or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients or carriers.
在本发明的再一方面，本发明还提供了前面所述的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐或前面所述的药物组合物在制备雄激素受体调节剂中的用途。In yet another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomer, isotope derivative or pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of androgen receptor modulators.
在本发明的再一方面，本发明还提供了前面所述的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐或前面所述的药物组合物在制备治疗与雄激素受体相关的疾病的药物中的用途。In another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomer, isotope derivative or its pharmaceutically acceptable salt or the aforementioned pharmaceutical composition in the preparation of a drug for treating diseases associated with androgen receptor.
本发明的一些方案中所述的疾病为癌症、代谢紊乱性疾病、心脑血管疾病、高血脂或肥胖症。The disease described in some embodiments of the present invention is cancer, metabolic disorder, cardiovascular and cerebrovascular disease, hyperlipidemia or obesity.
本发明的一些方案中，癌症选自前列腺癌、乳腺癌、膀胱癌、卵巢癌、子宫颈癌、鳞状细胞癌、脑癌、基底细胞癌、结直肠癌、食管癌、头癌、肾癌、肝癌、肺癌、颈癌、睾丸癌、胰腺癌、肾癌或胃癌；白血病；良性和恶性淋巴瘤；黑色素瘤；骨髓增生性疾病；肉瘤；甲状腺癌、星形细胞瘤；霍奇金病、威尔曼瘤或畸胎癌。In some embodiments of the present invention, the cancer is selected from prostate cancer, breast cancer, bladder cancer, ovarian cancer, cervical cancer, squamous cell carcinoma, brain cancer, basal cell carcinoma, colorectal cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, testicular cancer, pancreatic cancer, kidney cancer or gastric cancer; leukemia; benign and malignant lymphomas; melanoma; myeloproliferative diseases; sarcoma; thyroid cancer, astrocytoma; Hodgkin's disease, Wilman tumor or teratoma.
本发明的一些方案中，上述良性和恶性淋巴瘤包括伯基特氏淋巴瘤和非霍奇金淋巴瘤；肉瘤包括尤因肉瘤、血管肉瘤、卡波西氏肉瘤、脂肪肉瘤、肌肉瘤、周围神经上皮瘤、滑膜肉瘤、神经胶质瘤、星形细胞瘤、少突神经胶质瘤、室管膜瘤、成胶质细胞瘤、神经母细胞瘤、神经节瘤、神经节神经胶质瘤、髓母细胞瘤、松果体细胞肿瘤、脑膜瘤、脑膜肉瘤、神经纤维瘤和许旺细胞瘤。In some embodiments of the present invention, the above-mentioned benign and malignant lymphomas include Burkitt's lymphoma and non-Hodgkin's lymphoma; sarcomas include Ewing's sarcoma, angiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma and Schwannoma.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered ambiguous or unclear without special definition, but should be understood according to the ordinary meaning.
不在两个字母或符号之间的短横(“-”)表示取代基的连接位点，其连接顺序是任意的。然而，当取代基的连接位点对本领域技术人员来说是显而易见的时候，例如，卤素取代基，“-”可以被省略。A dash ("-") not between two letters or symbols indicates the attachment point of a substituent, and the order of attachment is arbitrary. However, when the attachment point of a substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.
当苯环上的R2取代基没有固定结构时，其表示R2可以连接在苯环上的任一 位置，且R2可以为0、1、2、3、4或5个。When the R2 substituent on the benzene ring has no fixed structure, it means that R2 can be attached to any position, and R2 can be 0, 1, 2, 3, 4 or 5.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药效上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当化合物中含有相对碱性的官能团时，可以通过在溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药效上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、三氟乙酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to salts of the compounds of the invention, prepared from compounds having specific substituents discovered by the invention with relatively nontoxic acids or bases. When the compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, etc.; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.
本发明的药效上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in the form of free acid or base are prepared by reacting with a stoichiometric amount of an appropriate base or acid.
本发明的化合物可以存在特定的立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明要求保护的范围之内。 The compounds of the present invention may exist in specific stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.
本发明还包括本发明化合物的所有适合的同位素变体。在此情况下，本发明化合物的同位素变体应理解为这样的化合物，其中本发明化合物内的至少一个原子被具有相同原子序数但原子质量不同于自然界中常见的或主要存在的原子质量的另一个原子替代。可引入本发明化合物中的同位素实例为氢、碳、氮、氧、硫、氟、氯、溴及碘的同位素，诸如2H(氘)、3H(氚)、11C、13C、14C、13N、15N、15O、17O、18O、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、129I以及131I。本发明化合物的特定同位素变体(诸如特别是其中引入一个或多个放射性同位素的那些)可用于例如研究活性物质在体内的作用机制或分布；因为它们可相对容易地制备及检测，用3H-或14C-同位素标记的化合物尤其适合于此。此外，引入同位素(例如氘)可产生某些由于化合物更高的代谢稳定性而产生的治疗优势，诸如体内半衰期延长或所需的有效剂量减少；本发明化合物的所述修饰因此任选地还可代表本发明的优选实施方案。本发明化合物的同位素变体可通过本领域技术人员已知的方法制备，从而例如通过下述方法及实施方案中给定的规范，使用各个试剂和/或起始化合物的相应同位素修饰来制备。The present invention also includes all suitable isotopic variants of the compounds of this invention. In this case, the isotopic variant of the compounds of this invention is understood to be such a compound, wherein at least one atom in the compounds of this invention is replaced by another atom with the same atomic number but an atomic mass different from the atomic mass common or mainly present in nature. Examples of isotopes that can be introduced into the compounds of this invention are isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 I. Certain isotopic variants of the compounds of the invention (such as those in which one or more radioactive isotopes are introduced in particular) can be used, for example, to study the mechanism of action or distribution of the active substance in vivo; since they can be prepared and detected relatively easily, compounds labeled with 3 H- or 14 C-isotopes are particularly suitable for this. In addition, the introduction of isotopes (e.g. deuterium) can produce certain therapeutic advantages due to the higher metabolic stability of the compound, such as an increase in the half-life in vivo or a reduction in the effective dose required; such modifications of the compounds of the invention may therefore optionally also represent a preferred embodiment of the invention. Isotopic variants of the compounds of the invention can be prepared by methods known to those skilled in the art, thereby, for example, by the specifications given in the following methods and embodiments, using the corresponding isotopic modifications of the individual reagents and/or starting compounds.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, compounds may be labeled with radioactive isotopes, such as tritium (3H), iodine-125 (125I) or C-14 (14C). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention. "Optional" or "optionally" means that the event or situation described subsequently may but does not necessarily occur, and the description includes situations in which the event or situation occurs and situations in which the event or situation does not occur.
术语“被取代的”或“被…取代”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。术语“任选被取代的”或“任选被…取代”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" or "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被1、2、3、4或5个 R所取代，则所述基团可以任选地1、2、3、4或5个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition is independent at each occurrence. Thus, for example, if a group is represented by 1, 2, 3, 4, or 5 If the group is substituted with R, the group may be optionally substituted with 1, 2, 3, 4 or 5 R, and each occurrence of R is an independent choice. Also, combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
当其中一个变量选自单键时，表示其连接的两个基团直接相连。When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected.
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When the listed substituents do not specify through which atom they are bonded to the substituted group, such substituents may be bonded through any atom thereof. For example, a pyridyl substituent may be bonded to the substituted group through any carbon atom on the pyridine ring.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，连接基团L为-CH2O-，此时-CH2O-既可以按与从左往右的读取顺序相同的方向连接，也可以按照与从右往左的读取顺序相反的方向连接所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When the listed linking group does not specify its connection direction, its connection direction is arbitrary. For example, the linking group L is -CH2O-, then -CH2O- can be connected in the same direction as the reading order from left to right, or in the opposite direction to the reading order from right to left. The combination of the linking group, substituent and/or its variants is allowed only when such combination will produce a stable compound.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“3-6元环”是指环绕排列3-6个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.
除非另有规定，术语“C1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C1-6烷基包括C1-5、C1-4、C1-3、C1-2、C2-6、C2-4、C6和C5烷基等；其可以是一价(如CH3)、二价(-CH2-)或者多价。Unless otherwise specified, the term "C 1-6 alkyl" is used to represent a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl 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, etc.; it can be monovalent (such as CH 3 ), divalent (-CH 2 -) or polyvalent.
除非另有规定，术语“C1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C1-6烷氧基包括C1-4、C1-3、C1-2、C2-6、C2-4、C6、C5、C4和C3烷氧基等。C1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。Unless otherwise specified, the term "C 1-6 alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through an oxygen atom. The C 1-6 alkoxy 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, etc. Examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentyl and neopentyl), hexyl and the like.
术语“环烷基”自身或在其与其它术语的组合中代表烷基、链烯基或炔基或其混合物的环状形式。另外，环烷基可以包含稠合环，但不包括稠合的芳基和杂芳基，除非特别指明为未取代的，否则环烷基可以是取代的。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、1-环己烯基、3-环己烯基、环己炔基、环己炔基、环己二烯基、环戊二烯基、环戊烯基、环庚基、降冰片基等。如果没有指明环的大小，本文中所述环烷基含有3-8个环成员或3-6个环成员。 The term "cycloalkyl" itself or in combination with other terms represents a cyclic form of an alkyl, alkenyl or alkynyl or mixture thereof. In addition, the cycloalkyl may contain fused rings, but does not include fused aryl and heteroaryl, unless otherwise specified as unsubstituted, otherwise the cycloalkyl may be substituted. Examples of cycloalkyl include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cyclohexynyl, cyclohexadienyl, cyclopentadienyl, cyclopentenyl, cycloheptyl, norbornyl, etc. If the size of the ring is not specified, the cycloalkyl described herein contains 3-8 ring members or 3-6 ring members.
术语“杂环”或“杂环烷基”或“杂环基”自身或者在与其它术语的组合中代表含有至少一个环碳原子和至少一个环杂原子的环烷基，所述杂原子选自O、N、P、Si和S，优选选自N、O和S，其中所述环是非芳族的但是可以含有不饱和度。杂环基团中的氮和硫原子可以任选被氧化，氮杂原子可以任选被季铵化。在多个实施方案中，环杂原子选自N、O和S。如果没有另外说明，本文中所述杂环基团含有3-10、3-9、3-8、3-7、3-6、3-5、4-5、4-6、4-7、4-8、5-10、5-8个环成员，并且至少一个环成员为选自N、O和S的杂原子；通常在杂环基团中含有不多于3个这些杂原子，通常在杂环基团的单个环中含有不多于2个这些杂原子。杂环基团可以与其他碳环、杂环或芳基环稠合。杂环基团可以与分子的其余部分在环碳或环杂原子上相连，杂环基团可以如对烷基所述那样被取代。另外，杂环可以包含稠合环，但不包括含有作为稠合环系一部分的杂芳基的稠合系统。杂环基团的实例包括但不限于1-(1，2，5，6-四氢吡啶基)、1-哌啶基、2-哌啶基、3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、1，2，3，4-四氢吡啶基、二氢吲哚(吲哚啉)、四氢呋喃-3-基、四氢噻吩-2-基、四氢噻吩-3-基、1-哌嗪基、2-哌嗪基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。The term "heterocycle" or "heterocycloalkyl" or "heterocyclyl" by itself or in combination with other terms represents a cycloalkyl group containing at least one ring carbon atom and at least one ring heteroatom selected from O, N, P, Si and S, preferably selected from N, O and S, wherein the ring is non-aromatic but may contain unsaturation. The nitrogen and sulfur atoms in the heterocyclic group may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In various embodiments, the ring heteroatoms are selected from N, O and S. If not otherwise specified, the heterocyclic group described herein contains 3-10, 3-9, 3-8, 3-7, 3-6, 3-5, 4-5, 4-6, 4-7, 4-8, 5-10, 5-8 ring members, and at least one ring member is a heteroatom selected from N, O and S; usually no more than 3 of these heteroatoms are contained in the heterocyclic group, and usually no more than 2 of these heteroatoms are contained in a single ring of the heterocyclic group. The heterocyclic group may be fused to other carbocyclic, heterocyclic or aryl rings. The heterocyclic group can be connected to the rest of the molecule on the ring carbon or ring heteroatom, and the heterocyclic group can be substituted as described for the alkyl. In addition, the heterocycle can include fused rings, but does not include the fused system containing the heteroaryl as a part of the fused ring system. The example of the heterocyclic group includes but is not limited to 1-(1,2,5,6-tetrahydropyridyl), 1-piperidyl, 2-piperidyl, 3-piperidyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, 1,2,3,4-tetrahydropyridyl, dihydroindole (indoline), tetrahydrofuran-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl, 2-piperazinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including 1,2-oxazinyl, 1,2-thiazinyl, ...
除非另外说明，术语“芳基”是指芳族烃基，它可以是单环或环稠合到一起的多环(例如1-3个环)。芳基可以含有稠合环，其中一或多个环任选为环烷基，但不包括杂环或杂芳族环；含有至少一个杂芳族环的稠合系统被称为杂芳基，与杂环稠合的苯基环在本文中被称为杂环基团。芳基包括其中苯基环稠合于环烷基环的稠合的环系统。芳基的实例包括但不限于苯基、1-萘基、四氢化萘、二氢-1H-茚、2-萘基、四氢萘基等。Unless otherwise indicated, the term "aryl" refers to an aromatic hydrocarbon group, which can be a single ring or multiple rings (e.g., 1-3 rings) with rings fused together. An aryl group may contain fused rings, wherein one or more rings are optionally cycloalkyl, but do not include heterocyclic or heteroaromatic rings; a fused system containing at least one heteroaromatic ring is referred to as a heteroaryl group, and a phenyl ring fused to a heterocyclic ring is referred to herein as a heterocyclic group. Aryl groups include fused ring systems in which a phenyl ring is fused to a cycloalkyl ring. Examples of aryl groups include, but are not limited to, phenyl, 1-naphthyl, tetralin, dihydro-1H-indene, 2-naphthyl, tetralinyl, and the like.
本文中使用的术语“杂芳基”是指含有单环或者二或三个稠合环的基团，其中至少一个环为含有1-4个作为环成员的选自N、O和S的杂原子的芳族环(即它含有至少一个杂芳族环)，其中氮和硫原子任选被氧化，且氮原子任选被季胺 化。杂芳基可以通过环碳或环杂原子与分子的其余部分相连，并且如果该基团为双环或三环，它可以通过杂芳基的任何环相连。杂芳基可以含有稠合环，其中一或多个环任选为环烷基或杂环烷基或芳基，前提是至少一个环为杂芳族环。杂芳基的非限定性实例为1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。每一个上述芳基和杂芳基环系的取代基选自下述的可接受的取代基。The term "heteroaryl" as used herein refers to a group containing a single ring or two or three condensed rings, wherein at least one ring is an aromatic ring containing 1 to 4 heteroatoms selected from N, O and S as ring members (i.e., it contains at least one heteroaromatic ring), wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally substituted with a quaternary amine. The heteroaryl group may be attached to the rest of the molecule through a ring carbon or a ring heteroatom, and if the group is bicyclic or tricyclic, it may be attached through any ring of the heteroaryl group. The heteroaryl group may contain fused rings, one or more of which may be cycloalkyl or heterocycloalkyl or aryl, provided that at least one ring is a heteroaromatic ring. Non-limiting examples of heteroaryl are 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
芳基和/或杂芳基通常每个环含有至多4个取代基(0-4个)，有时含有0-3个或0-2个取代基。术语“芳基氧基”和“杂芳基氧基”分别是指通过氧连接基团(-O-)与分子其余部分相连的芳基和杂芳基。Aryl and/or heteroaryl groups typically contain up to 4 substituents per ring (0-4), sometimes 0-3 or 0-2 substituents. The terms "aryloxy" and "heteroaryloxy" refer to aryl and heteroaryl groups, respectively, attached to the rest of the molecule through an oxygen linker (-O-).
除非另外说明，术语“卤代”或“卤素”自身或者作为其它取代基的一部分是指氟、氯、溴或碘原子。另外，术语例如“卤代烷基”应当包括单卤代烷基和全卤代烷基。例如，术语“卤代(C1-C4)烷基”应当包括但不限于三氟甲基、2，2，2-三氟乙基、4-氯丁基、3-溴丙基等。前缀“全卤代”是指其中所有可用价键被卤素代替的各个基团。例如“全卤代烷基”包括-CCl3、-CF3、-CCl2CF3等。术语“全氟烷基”和“全氯烷基”为全卤代烷基的亚组，其中所有可用价键分别被氟和氯代替。全氟烷基的非限定性实例包括-CF3和-CF2CF3。全氯代烷基的非限定性实例包括-CCl3和-CCl2CCl3。Unless otherwise indicated, the term "halo" or "halogen" itself or as part of other substituents refers to fluorine, chlorine, bromine or iodine atoms. In addition, terms such as "haloalkyl" should include monohaloalkyl and perhaloalkyl. For example, the term "halo (C 1 -C 4 ) alkyl" should include but is not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc. The prefix "perhalo" refers to each group in which all available valence bonds are replaced by halogen. For example, "perhaloalkyl" includes -CCl 3 , -CF 3 , -CCl 2 CF 3 , etc. The terms "perfluoroalkyl" and "perchloroalkyl" are subgroups of perhaloalkyl in which all available valence bonds are replaced by fluorine and chlorine, respectively. Non-limiting examples of perfluoroalkyl include -CF 3 and -CF 2 CF 3. Non-limiting examples of perchloroalkyl include -CCl 3 and -CCl 2 CCl 3 .
“氨基”在本文中是指基团-NH2或-NRR′，其中R和R′相互独立选自氢或烷基(例如低级烷基)。术语“芳基氨基”在本文中是指基团-NRR′，其中R为芳基并且R′为氢、烷基或芳基。术语“芳烷基氨基”在本文中是指基团-NRR′，其中R为芳烷基并且R′为氢、烷基、芳基或芳烷基。“取代的氨基”是指氨基，其中至少一个R和R’不为H，即氨基携有至少一个取代基。术语烷基氨基是指-烷基-NRR′，其中R和R′各自独立地选自氢或烷基(例如低级烷基)。"Amino" refers herein to the group -NH2 or -NRR', wherein R and R' are independently selected from hydrogen or alkyl (e.g. lower alkyl). The term "arylamino" refers herein to the group -NRR', wherein R is aryl and R' is hydrogen, alkyl or aryl. The term "aralkylamino" refers herein to the group -NRR', wherein R is aralkyl and R' is hydrogen, alkyl, aryl or aralkyl. "Substituted amino" refers to an amino group wherein at least one of R and R' is not H, i.e. the amino group carries at least one substituent. The term alkylamino refers to -alkyl-NRR', wherein R and R' are independently selected from hydrogen or alkyl (e.g. lower alkyl).
除非在化学结构或化学名称中明确指明立体化学，否则所述化学结构或化 学名称应当包括所有可能存在的所述化合物的立体异构体、构象异构体、旋转异构体和互变异构体。例如，含有手性碳原子的化合物应当包括(R)对映异构体和(S)对映异构体以及对映异构体的混合物，包括外消旋混合物；含有两个手性碳的化合物应当包括所有的对映异构体和非对映异构体(包括(R，R)、(S，S)、(R，S)和(R，S)异构体)。Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the chemical structure or chemical name The chemical name should include all possible stereoisomers, conformers, rotational isomers and tautomers of the compound. For example, a compound containing a chiral carbon atom should include the (R) enantiomer and the (S) enantiomer and mixtures of enantiomers, including racemic mixtures; a compound containing two chiral carbon atoms should include all enantiomers and diastereomers (including (R, R), (S, S), (R, S) and (R, S) isomers).
在本文所述结构式的化合物的所有用途中，本发明也包括所述化合物的任何或所有立体化学形式、对映异构体、非对映异构体、构象异构体、旋转异构体、互变异构体、溶剂化物、水化物、多晶型、结晶型、非结晶型、盐、药学上可接受的盐、代谢物和前药的用途。In all uses of compounds of the formulae described herein, the present invention also includes the use of any or all stereochemical forms, enantiomers, diastereomers, conformers, rotamers, tautomers, solvates, hydrates, polymorphs, crystalline forms, amorphous forms, salts, pharmaceutically acceptable salts, metabolites, and prodrugs of the compounds.
本发明的药物组合物含有与至少一种药学上可接受的赋形剂、载体或稀释剂混合的至少一种根据本文公开的任何实施方案的化合物(包括这些化合物的药学上可接受的盐)。优选地，药物组合物为无菌组合物，或主要由或仅由上述化合物和一种或多种药学上可接受的赋形剂、载体和/或稀释剂组成的组合物。在一些实施方案中，药物组合物包含至少两种药学上可接受的本文所述的载体和/或赋形剂。The pharmaceutical composition of the present invention contains at least one compound according to any embodiment disclosed herein (including pharmaceutically acceptable salts of these compounds) mixed with at least one pharmaceutically acceptable excipient, carrier or diluent. Preferably, the pharmaceutical composition is a sterile composition, or a composition consisting mainly of or only of the above-mentioned compound and one or more pharmaceutically acceptable excipients, carriers and/or diluents. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable carriers and/or excipients described herein.
本发明的某些化合物可以以非溶剂化形式以及溶剂化形式(即溶剂化物)形式存在。本发明化合物也可以包括水合形式(即水合物)。通常，溶剂化物和水合物形式与非溶剂化物形式在生物学效能方面是相同的，均包含在本发明的范围内。本发明也包括所有的多晶型物，包括结晶和非结晶形式。通常，对于本发明所预期的用途而言，所有的物理形式均可用，它们意图也包含在本发明的范围内。Certain compounds of the present invention may exist in non-solvated forms as well as solvated forms (i.e., solvates). The compounds of the present invention may also include hydrated forms (i.e., hydrates). Typically, solvates and hydrate forms are identical to non-solvated forms in terms of biological efficacy and are included within the scope of the present invention. The present invention also includes all polymorphs, including crystalline and non-crystalline forms. Typically, for the intended use of the present invention, all physical forms are available and are intended to be included within the scope of the present invention.
本文中使用的“治疗有效量”是指能够产生希望的药理学和/或生理学作用的量。该作用可以是预防性的，能够完全或部分预防疾病或其症状；和/或可以是治疗性的，能够部分或完全治愈疾病和/或与疾病有关的副作用。本发明化合物的治疗有效量通常包括通过本文中所述任何实验、通过本领域技术人员已知的其它CDK或CDK9激酶活性测定法或者通过检测癌症症状的抑制或缓解可以检测到的足以使Raf活性受到抑制的任何量。As used herein, "therapeutically effective amount" refers to an amount capable of producing the desired pharmacological and/or physiological effect. The effect may be preventive, capable of completely or partially preventing a disease or its symptoms; and/or may be therapeutic, capable of partially or completely curing a disease and/or side effects associated with the disease. A therapeutically effective amount of a compound of the invention generally includes any amount sufficient to inhibit Raf activity that can be detected by any of the assays described herein, by other CDK or CDK9 kinase activity assays known to those skilled in the art, or by detecting inhibition or alleviation of cancer symptoms.
本文中使用的术语“药学上可接受的载体”及其同类物是指技术人员已知的辅助剂、粘合剂、稀释剂等，它们适合于施用于个体(例如哺乳动物或非哺乳 动物)。两种或多种载体的组合也涵盖在本发明中。本文所述的药学上可接受的载体和任何其它成分可以适用于特定的剂型的预期施用途径(例如口服、胃肠外)中。所述适用性是技术人员容易识别的，特别是根据本文中所提供的教导。本文所述的药用组合物包含至少一种药学上可接受的载体或赋形剂；优选所述组合物包含除水之外的至少一种载体或赋形剂或除了水之外还包含至少一种载体或赋形剂。The term "pharmaceutically acceptable carrier" and its equivalents used herein refer to adjuvants, binders, diluents, etc. known to technicians, which are suitable for administration to an individual (e.g., a mammal or non-lactating mammal) Animals). Combinations of two or more carriers are also encompassed by the present invention. The pharmaceutically acceptable carriers and any other ingredients described herein can be adapted for the intended route of administration (e.g., oral, parenteral) of a particular dosage form. Such adaptability is readily recognized by a skilled artisan, particularly in light of the teachings provided herein. The pharmaceutical compositions described herein comprise at least one pharmaceutically acceptable carrier or excipient; preferably, the composition comprises at least one carrier or excipient other than water or at least one carrier or excipient in addition to water.
药用辅料可以是药学上可接受的载体，辅剂，或赋形剂，这些像本发明所应用的，包括任何溶剂，稀释剂，或其他液体赋形剂，分散剂或悬浮剂，表面活性剂，等渗剂，增稠剂，乳化剂，防腐剂，固体粘合剂或润滑剂，等等，适合于特有的目标剂型。Pharmaceutical excipients can be pharmaceutically acceptable carriers, adjuvants, or vehicles, which, as used in the present invention, include any solvents, diluents, or other liquid excipients, dispersants or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., suitable for the specific target dosage form.
本发明的化合物可具有全身和/或局部作用。为此目的，它们可以以适合的方式施用，例如通过口服、胃肠外、肺部、鼻内、舌下、舌部、含服、直肠、经皮、透皮、经结膜或耳部途径，或作为植入物或支架。The compounds of the present invention may have systemic and/or local effects. For this purpose, they may be administered in a suitable manner, for example, by oral, parenteral, pulmonary, intranasal, sublingual, lingual, buccal, rectal, transdermal, transconjunctival or otic routes, or as implants or stents.
适于口服施用的是这样的剂型，其根据现有技术起作用，快速和/或调节释放本发明的化合物且含有结晶和/或非结晶(amorphisized)和/或溶解形式的本发明化合物，例如片剂(无包衣或包衣片剂，例如具有肠溶衣或有延迟溶解的包衣或不溶性包衣，这些包衣控制本发明化合物的释放)、在口腔中快速崩解的片剂、或膜/糯米纸囊剂(wafer)、膜/冻干物、胶囊(例如硬胶囊或软胶囊)、糖衣丸剂、颗粒剂、小丸剂、散剂、乳剂、混悬剂、气雾剂或溶液剂。Suitable for oral administration are dosage forms which act according to the prior art, release the compound according to the invention quickly and/or with modification and contain the compound according to the invention in crystalline and/or amorphisized and/or dissolved form, such as tablets (uncoated or coated tablets, for example with an enteric coating or with a coating which delays dissolution or an insoluble coating which controls the release of the compound according to the invention), tablets which disintegrate rapidly in the mouth, or films/wafers, films/lyophilisates, capsules (for example hard or soft capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
胃肠外施用可绕过吸收步骤(例如静脉内、动脉内、心内、椎管内或腰内)或包括吸收(例如肌肉内、皮下、皮内、经皮或腹膜内)而进行。适于胃肠外施用的剂型包括呈溶液剂、混悬剂、乳剂、冻干物或无菌粉末形式的注射和输注制剂。Parenteral administration can be performed by bypassing an absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Suitable dosage forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
适于其他施用途径的剂型为例如吸入剂型(包括粉末吸入器、喷雾器)、滴鼻剂、溶液剂及喷雾剂；用于舌部、舌下或含服施用的片剂、薄膜/糯米纸囊剂或胶囊；栓剂、耳部或眼部制剂、阴道胶囊、水性混悬剂(洗剂、振荡合剂(shaking mixture))、亲脂性混悬剂、软膏、乳膏、经皮治疗系统(例如贴剂)、乳制剂(milks)、糊剂、泡沫剂、扑粉、植入物或支架。Dosage forms suitable for other routes of administration are, for example, inhalation forms (including powder inhalers, nebulizers), nasal drops, solutions and sprays; tablets, films/wafers or capsules for lingual, sublingual or buccal administration; suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), emulsions (milks), pastes, foams, dusting powders, implants or stents.
本文所用的术语“治疗”指给患有疾病或者具有所述疾病的症状的个体施用 一种或多种药物物质、特别是本文所述的式(I)化合物和/或其药学上可接受的盐，用以治愈、缓解、减轻、改变、医治、改善、改进或影响所述疾病或者所述疾病的症状。本文所用的术语“预防”指给具有易患所述疾病的体质的个体施用一种或多种药物物质、特别是本文所述的式(I)化合物和/或其药学上可接受的盐，用以防止个体罹患该疾病。当涉及化学反应时，术语“处理”、“接触”和“反应”指在适当的条件下加入或混合两种或更多种试剂，以产生所示的和/或所需的产物。应当理解的是，产生所示的和/或所需的产物的反应可能不一定直接来自最初加入的两种试剂的组合，即，在混合物中可能存在生成的一个或多个中间体，这些中间体最终导致了所示的和/或所需的产物的形成。As used herein, the term "treatment" refers to administering to an individual suffering from a disease or experiencing symptoms of the disease One or more drug substances, in particular compounds of formula (I) as described herein and/or pharmaceutically acceptable salts thereof, are used to cure, alleviate, mitigate, alter, treat, improve, ameliorate or affect the disease or the symptoms of the disease. The term "prevention" as used herein refers to the administration of one or more drug substances, in particular compounds of formula (I) as described herein and/or pharmaceutically acceptable salts thereof, to an individual with a physique susceptible to the disease, to prevent the individual from suffering from the disease. When referring to a chemical reaction, the terms "treating", "contacting" and "reacting" refer to the addition or mixing of two or more reagents under appropriate conditions to produce the indicated and/or desired product. It should be understood that the reaction that produces the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, that is, there may be one or more intermediates generated in the mixture, which ultimately lead to the formation of the indicated and/or desired product.
本发明中定义的化合物或其可药用盐，或含有它们的可药用组合物，是雄激素受体的有效调节剂。预期本发明化合物在治疗由雄激素受体单独或部分介导的疾病或医学状况方面是可能有用的药剂。本发明化合物可引起雄激素受体的下调和/或是雄激素受体的选择性激动剂，部分激动剂，拮抗剂或部分拮抗剂。The compounds defined in the present invention or their pharmaceutically acceptable salts, or pharmaceutically acceptable compositions containing them, are effective modulators of androgen receptors. It is expected that the compounds of the present invention are potentially useful agents in treating diseases or medical conditions mediated solely or in part by androgen receptors. The compounds of the present invention may cause downregulation of androgen receptors and/or are selective agonists, partial agonists, antagonists or partial antagonists of androgen receptors.
本发明的化合物优选适于治疗和/或预防雄激素受体依赖性疾病。The compounds according to the invention are preferably suitable for the treatment and/or prevention of androgen receptor-dependent diseases.
可使用本发明的化合物治疗的疾病特别包括癌症及肿瘤疾病。在本发明的情形下，这些疾病特别包括以下疾病，但不限于这些疾病：乳腺癌和乳腺肿瘤(乳腺癌包括导管和小叶形式，以及原位乳腺癌)、呼吸道肿瘤(小细胞癌和非小细胞癌、支气管癌)、脑肿瘤(例如脑干和下视丘的肿瘤、星形细胞瘤、室管膜瘤、胶质母细胞瘤、神经胶质瘤、髓母细胞瘤、脑膜瘤以及神经外胚层和松果体肿瘤)，消化器官的肿瘤(食道癌、胃癌、胆囊癌、小肠癌、结肠癌、直肠癌及肛门癌)，肝肿瘤(包括肝细胞癌、胆管癌及混合型肝细胞胆管癌)、头部和颈部的肿瘤(喉癌、舌癌、鼻咽癌、口咽癌、唇癌及口腔癌、口腔黑色素瘤)，皮肤肿瘤(基底细胞癌、棘细胞癌、鳞状细胞癌、卡波西肉瘤、恶性黑色素瘤、非黑色素瘤样皮肤癌、梅克尔细胞皮肤癌、肥大细胞肿瘤)、支持和结缔组织的肿瘤(包括软组织肉瘤、骨肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、纤维肉瘤、血管肉瘤、平滑肌肉瘤、脂肉瘤、淋巴肉瘤及横纹肌肉瘤)、眼部的肿瘤(包括眼内黑色素瘤和视网膜母细胞瘤)、内分泌腺和外分泌腺的肿瘤(例如甲状腺和甲状旁腺的肿瘤、胰腺癌和唾液腺癌、腺癌)，泌尿道的肿瘤(膀胱肿瘤、阴茎肿瘤、肾肿瘤、肾盂肿瘤及输尿管肿瘤)及生殖器官的肿瘤(女性的子宫内膜癌、子宫 颈癌、卵巢癌、阴道癌、外阴癌和子宫癌以及男性的前列腺癌和睾丸癌)。其还包括呈实体形式及循环细胞形式的血液、淋巴系统及脊髓的增殖性疾病，诸如白血病、淋巴瘤及骨髓增殖性疾病，例如急性髓性白血病、急性淋巴母细胞性白血病、慢性淋巴细胞性白血病、慢性髓性白血病和毛细胞白血病，及AIDS相关淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、皮肤T细胞淋巴瘤、伯基特淋巴瘤及中枢神经系统中的淋巴瘤。Diseases that can be treated with the compounds of the invention include in particular cancer and tumor diseases. In the context of the present invention, these diseases include in particular the following diseases, but are not limited to these diseases: breast cancer and breast tumors (breast cancer including ductal and lobular forms, as well as breast cancer in situ), respiratory tract tumors (small cell carcinoma and non-small cell carcinoma, bronchial carcinoma), brain tumors (e.g. tumors of the brain stem and hypothalamus, astrocytomas, ependymomas, glioblastomas, gliomas, medulloblastomas, meningiomas, and neuroectodermal and pineal tumors), tumors of the digestive organs (esophageal cancer, gastric cancer, gallbladder cancer, small intestine cancer, colon cancer, rectal cancer and anal cancer), liver tumors (including hepatocellular carcinoma, bile duct cancer and mixed hepatocellular bile duct cancer), tumors of the head and neck (laryngeal cancer, tongue cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer and oral cancer, oral melanoma) , skin tumors (basal cell carcinoma, acanthosarcoma, squamous cell carcinoma, Kaposi sarcoma, malignant melanoma, non-melanoma skin cancer, Merkel cell skin cancer, mast cell tumors), tumors of supporting and connective tissue (including soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, fibrosarcoma, angiosarcoma, leiomyosarcoma, liposarcoma, lymphosarcoma and rhabdomyosarcoma), tumors of the eye (including intraocular melanoma and retinoblastoma), tumors of the endocrine and exocrine glands (such as tumors of the thyroid and parathyroid glands, pancreatic cancer and salivary gland cancer, adenocarcinoma), tumors of the urinary tract (bladder tumors, penis tumors, kidney tumors, renal pelvis tumors and ureteral tumors) and tumors of the reproductive organs (endometrial cancer, uterine cancer in women) It also includes proliferative diseases of the blood, lymphatic system and spinal cord in both solid and circulating cell forms, such as leukemias, lymphomas and myeloproliferative diseases, for example acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia and hairy cell leukemia, and AIDS-related lymphomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma and lymphomas in the central nervous system.
在另一实施方案中，本发明化合物能向动物(例如人)施用，用以治疗各种病症和障碍，包括(但不限于)保持肌肉强度和功能(例如，老年人中)；逆转或防止老年人中的虚弱或与年龄有关的机能衰退(“ARFD”)(例如老年性肌肉萎缩)；治疗糖皮质素的分解代谢副作用；防止和/或治疗骨质量、密度或生长减退(例如骨质疏松和骨质减少)；治疗慢性疲劳综合症(CFS)；慢性肌痛；治疗急性疲劳综合症和择期手术后的肌肉损失(例如，手术后康复)；加快伤口愈合；加快骨折修复(例如加快髋骨折患者的恢复)；加快复杂骨折的愈合，例如牵引成骨；关节替换；防止术后粘连形成；加快牙齿修复或生长；保持感觉功能(例如听觉、视觉、嗅觉和味觉)；牙周病的治疗；治疗骨折后消瘦和与慢性阻塞性肺病(COPD)、慢性肝病、艾滋病、失重状态、癌症恶病质、灼伤和创伤恢复、慢性分解代谢状态(例如昏迷)、饮食障碍(例如厌食症)和化疗有关的消瘦；治疗心肌病；治疗血小板减少；治疗与克罗恩病有关的生长延缓；治疗短肠综合症；治疗肠易激综合症；治疗炎性肠病；治疗克罗恩病和溃疡性结肠炎；治疗与移植有关的并发症；治疗生理性短小状态，包括生长激素缺陷儿童和与慢性疾病有关的短小状态；治疗肥胖和与肥胖有关的生长延缓；治疗厌食症(例如，与恶病质或老化有关的厌食症)；治疗皮质醇增多症和库欣综合症；佩吉氏病；治疗骨关节炎；诱发搏动性生长激素释放；治疗骨软骨发育不良；治疗抑郁、神经质、易激惹和紧张；治疗心理能量降低和低自尊感(例如积极性/自信降低)；改进认知功能(例如，治疗痴呆，包括阿尔茨海默病和短期记忆丧失)；治疗与肺机能不良和呼吸机依赖有关的分解代谢；治疗心机能不良(例如与血管病、心肌梗死、心脏肥大或充血性心力衰竭有关的心肌能不良)；降低血压；防止心室机能不良或防止再灌注事件；治疗慢性渗析的成年人；逆转或减慢老化的分解代谢状态；减缓或逆转创伤后的蛋白分解代谢响应(例如，逆转与手术、充血性心力衰竭、 心肌病、灼伤、癌症、COPD等有关的分解代谢状态)；减轻恶病质和由于慢性疾病例如癌症或艾滋病造成的蛋白质丢失；治疗高胰岛素血，包括成胰岛细胞增生；治疗免疫抑制患者；治疗与多发性硬化病或其它神经变性障碍有关的消瘦；促进髓鞘质修复；保持皮肤厚度；治疗代谢稳态和肾稳态(例如在虚弱的老年人中)；刺激成骨细胞；骨重建和软骨生长；调节食物摄入；治疗哺乳动物(例如人)有胰岛素抗性，包括非胰岛素依赖性糖尿病；治疗心脏的胰岛素抗性；改善睡眠质量和校正由于REM睡眠过度增加和REM潜伏期减小造成的老年化生长激素分泌相对不足；治疗低体温；治疗充血性心力衰竭；治疗脂肪代谢失调(例如在接受HIV或AIDS治疗例如蛋白酶抑制剂的患者中)；治疗肌萎缩(例如由于体力活动缺乏，卧床休息或减负重状态)；治疗肌肉骨骼损伤(例如在老年人中)；改善全面的肺功能；治疗睡眠障碍；治疗长期危重病态的分解代谢状态；男性中与年龄有关的睾酮水平降低，男性更年期，性腺功能衰退，男性激素替代治疗，男性和女性性功能障碍(例如，勃起功能障碍，性驱动降低，性满足降低，性欲减退)，尿失禁，男性和女性避孕，脱发以及增强骨和肌肉的性能/强度。In another embodiment, the compounds of the invention can be administered to animals (e.g., humans) to treat a variety of conditions and disorders, including, but not limited to, maintaining muscle strength and function (e.g., in the elderly); reversing or preventing frailty or age-related functional decline ("ARFD") in the elderly (e.g., senile muscle atrophy); treating the catabolic side effects of glucocorticoids; preventing and/or treating loss of bone mass, density or growth (e.g., osteoporosis and osteopenia); treating chronic fatigue syndrome (CFS); chronic myalgia; treating acute fatigue syndrome and muscle loss following elective surgery (e.g., postoperative rehabilitation); accelerate wound healing; accelerate fracture repair (e.g., accelerate recovery of hip fracture patients); accelerate healing of complex fractures, such as distraction osteogenesis; joint replacement; prevent postoperative adhesion formation; accelerate tooth repair or growth; maintain sensory function (e.g., hearing, vision, smell, and taste); treatment of periodontal disease; treatment of post-fracture wasting and wasting associated with chronic obstructive pulmonary disease (COPD), chronic liver disease, AIDS, weightlessness, cancer cachexia, burn and trauma recovery, chronic catabolic states (e.g., coma), eating disorders (e.g., anorexia), and chemotherapy; treatment of cardiomyopathy; treatment of thrombocytopenia; treatment of Growth retardation associated with Crohn's disease; treatment of short bowel syndrome; treatment of irritable bowel syndrome; treatment of inflammatory bowel disease; treatment of Crohn's disease and ulcerative colitis; treatment of complications associated with transplantation; treatment of physiological shortness, including shortness in children with growth hormone deficiency and shortness associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treatment of anorexia (e.g., anorexia associated with cachexia or aging); treatment of hypercortisolism and Cushing's syndrome; Paget's disease; treatment of osteoarthritis; induction of pulsatile growth hormone release; treatment of osteochondrodysplasia; treatment of depression, nervousness, irritability and tension; treatment of Treatment of decreased psychological energy and low self-esteem (e.g., decreased motivation/confidence); improvement of cognitive function (e.g., treatment of dementia, including Alzheimer's disease and short-term memory loss); treatment of catabolism associated with pulmonary dysfunction and ventilator dependence; treatment of cardiac dysfunction (e.g., myocardial dysfunction associated with vascular disease, myocardial infarction, cardiac hypertrophy, or congestive heart failure); lowering of blood pressure; prevention of ventricular dysfunction or prevention of reperfusion events; treatment of adults on chronic dialysis; reversal or slowing of the catabolic state of aging; slowing or reversal of the protein catabolic response following trauma (e.g., reversal of the protein catabolic response associated with surgery, congestive heart failure, The invention is intended to be used for the treatment of catabolic states associated with cardiomyopathy, burns, cancer, COPD, etc.); to reduce cachexia and protein loss due to chronic diseases such as cancer or AIDS; to treat hyperinsulinemia, including islet cell hyperplasia; to treat immunosuppressed patients; to treat wasting associated with multiple sclerosis or other neurodegenerative disorders; to promote myelin repair; to maintain skin thickness; to treat metabolic homeostasis and renal homeostasis (e.g., in frail elderly people); to stimulate osteoblasts; to remodel bone and cartilage; to regulate food intake; to treat mammals (e.g., humans) with insulin resistance, including non-insulin-dependent diabetes mellitus; to treat cardiac insulin resistance; to improve sleep quality and to correct aging-related growth stimuli due to excessive increases in REM sleep and decreased REM latency. treatment of relative insufficiency of testosterone secretion; treatment of hypothermia; treatment of congestive heart failure; treatment of dysregulation of fat metabolism (e.g., in patients receiving HIV or AIDS treatments such as protease inhibitors); treatment of muscle atrophy (e.g., due to physical inactivity, bed rest, or a weight-reduced state); treatment of musculoskeletal injuries (e.g., in the elderly); improvement of global lung function; treatment of sleep disorders; treatment of the catabolic state of chronic critical illness; age-related decreases in testosterone levels in men, male menopause, hypogonadism, male hormone replacement therapy, male and female sexual dysfunction (e.g., erectile dysfunction, decreased sexual drive, decreased sexual satisfaction, decreased libido), urinary incontinence, male and female contraception, hair loss, and enhancement of bone and muscle performance/strength.
在一项实施方案中，与雄激素受体有关的病症包括前列腺癌，良性前列腺增生和前列腺肥大，痤疮(寻常痤疮)，脂溢病，多毛症，雄性脱发和男性型脱发，性早熟，多囊性卵巢综合症，性倒错，男性化等。本发明化合物还可用于改善饲养动物的排卵。In one embodiment, androgen receptor-associated conditions include prostate cancer, benign prostatic hyperplasia and prostatic hypertrophy, acne (acne vulgaris), seborrheic dermatitis, hirsutism, male pattern baldness and male pattern hair loss, precocious puberty, polycystic ovary syndrome, paraphilia, virilization, etc. The compounds of the invention may also be used to improve ovulation in farmed animals.
本发明的化合物可单独使用，或若需要，与一种或多种其他药理学有效的物质组合使用，条件是此组合不引起不期望和不可接受的副作用。The compounds of the present invention can be used alone or, if necessary, in combination with one or more other pharmacologically effective substances, provided that this combination does not cause undesirable and unacceptable side effects.
可提及以下物质作为适合的组合活性物质的实例：131I-chTNT、阿巴瑞克、阿比特龙、阿柔比星、阿地白介素、阿仑珠单抗、阿利维A酸、六甲蜜胺、氨鲁米特、氨柔比星、安吖啶、阿那曲唑、arglabin、三氧化二砷、天冬酰胺酶、阿扎胞苷、巴利昔单抗、BAY 80-6946、BAY 1000394、refametinib(BAY 86-9766,RDEA 119)、贝洛替康、苯达莫司汀、贝伐珠单抗、贝沙罗汀、比卡鲁胺、比生群、博来霉素、硼替佐米、布舍瑞林、白消安、卡巴他赛、亚叶酸钙、左亚叶酸钙、卡培他滨、卡铂、卡莫氟、卡莫司汀、卡妥索单抗、塞来昔布、西莫白介素、西妥昔单抗、苯丁酸氮芥、氯地孕酮、氮芥、顺铂、克拉立滨、氯屈膦酸、氯法拉滨、crisantaspase、环磷酰胺、环丙特龙、阿糖胞苷、达卡巴 嗪、放线菌素D、达促红素α、达沙替尼、柔红霉素、地西他滨、地加瑞克、地尼白介素2、地舒单抗、地洛瑞林、二溴螺氯铵、多西他赛、去氧氟尿苷、多柔比星、多柔比星+雌酮、依库珠单抗、依屈洛单抗、依利醋铵、艾曲泊帕、内皮他丁、依诺他滨、表柔比星、环硫雄醇、促红素α、倍他依泊汀、艾铂、艾立布林、厄洛替尼、雌二醇、雌莫司汀、依托泊甙、依维莫司、依西美坦、法罗唑、非格司亭、氟达拉滨、氟尿嘧啶、氟他胺、福美坦、福莫司汀、氟维司群、硝酸镓、加尼瑞克、吉非替尼、吉西他滨、吉妥珠单抗、glutoxim、戈舍瑞林、二盐酸组胺、组氨瑞林、羟基脲、I-125种子(I-125seeds)、伊班膦酸、替伊莫单抗、伊达比星、异环磷酰胺、伊马替尼、咪喹莫德、英丙舒凡、干扰素α、干扰素β、干扰素γ、伊匹木单抗、伊立替康、伊沙匹隆、兰瑞肽、拉帕替尼、来那度胺、来格司亭、香菇多糖、来曲唑、亮丙瑞林、左旋咪唑、利舒脲、洛铂、洛莫司汀、氯尼达明、马索罗酚、甲羟孕酮、甲地孕酮、美法仑、美雄烷、巯嘌呤、甲氨蝶呤、甲氧沙林、甲氨基酮戊酸盐、甲睾酮、米法莫肽、米替福新、米立铂、二溴甘露醇、米托胍腙、二溴卫矛醇、丝裂霉素、米托坦、米托蒽醌、奈达铂、奈拉滨、尼洛替尼、尼鲁米特、尼妥珠单抗、尼莫司汀、尼曲吖啶、奥法木单抗、奥美拉唑、奥普瑞白介素、奥沙利铂、p53基因治疗、紫杉醇、帕利夫明、钯-103种子(palladium-103seed)、帕米磷酸、帕木单抗、帕唑帕尼、培门冬酶、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、培非司亭、培干扰素α-2b、培美曲塞、喷他佐辛、喷司他丁、培洛霉素、培磷酰胺、毕西巴尼、吡柔比星、普乐沙福、普卡霉素、聚氨葡糖、聚磷酸雌二醇、多糖-k、卟吩姆钠、普拉曲沙、泼尼莫司汀、丙卡巴肼、喹高莱、氯化镭-223、雷洛昔芬、雷替曲塞、雷莫司汀、雷佐生、瑞戈非尼、利塞膦酸、利妥昔单抗、罗米地新、罗米司亭、沙格司亭、sipuleucel-T、西佐喃、索布佐生、甘氨双唑钠、索拉非尼、链佐星、舒尼替尼、他拉泊芬、他米巴罗汀、他莫昔芬、他索纳明、替西白介素、替加氟、替加氟+吉美拉西+奥替拉西、替莫泊芬、替莫唑胺、坦罗莫司、替尼泊甙、睾酮、替曲膦、沙立度胺、塞替派、胸腺法新、硫鸟嘌呤、托珠单抗、托泊替康、托瑞米芬、托西莫单抗、曲贝替定、曲妥珠单抗、曲奥舒凡、维甲酸、曲洛司坦、曲普瑞林、曲磷胺、色氨酸、乌苯美司、戊柔比星、凡他尼布、伐普肽、vemurafenib、长春碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、伏林 司他、伏罗唑、钇-90玻璃微球、净司他丁、净司他丁酯、唑来膦酸、佐柔比星。The following may be mentioned as examples of suitable combination active substances: 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, hexamethylmelamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, refametinib (BAY 86-9766, RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, leucovorin, capecitabine, carboplatin, carmofur, carmustine, catumaxomab, celecoxib, simulleukin, cetuximab, chlorambucil, chlormadinol, nitrogen mustard, cisplatin, cladribine, clodronic acid, clofarabine, cristantaspase, cyclophosphamide, ciprofloxacin, cytarabine, dacarbazine azine, actinomycin D, daptomycin alfa, dasatinib, daunorubicin, decitabine, degarelix, denileukin-2, denosumab, deslorelin, spironium bromide, docetaxel, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, epirubicin, cyclothiocarb, erythropoietin alfa, beta-ectin Poetin, aplatin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, farozole, filgrastim, fludarabine, fluorouracil, flutamide, formestane, fotemustine, fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin, hydroxyurea, I -125 seeds (I-125seeds), ibandronic acid, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferon α, interferon β, interferon γ, ipilimumab, irinotecan, ixabepilone, lanreotide, lapatinib, lenalidomide, levofloxacin, lentinan, letrozole, leuprorelin, levamisole, lisuride, lobaplatin , lomustine, lonidamine, masoprofen, medroxyprogesterone, megestrol acetate, melphalan, melastrazine, mercaptopurine, methotrexate, methoxsalen, aminolevulinate, methyltestosterone, mifamortide, miltefosine, miriplatin, dibromomannitol, mitoguanidine, dibromodulanol, mitomycin, mitotane, mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide, nimotuzumab, nimosin tin, nitrilosin, ofatumumab, omeprazole, opreleukin, oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed, pamidronate, pantumumab, pazopanib, pegaspargase, PEG-beta-epoetin (methoxy PEG-beta-epoetin), pegfilgrastim, peginterferon α-2b, pemetrexed, pentazocine, pentostatin, pelocycin, perfosfamide, bixibanib, pirarubicin, plerixafor, plicamycin, polyglucosamine, polyestradiol phosphate, polysaccharide-k, porfimer sodium, pralatrexate, prednimustine, procarbazine, quinolone, radium-223 chloride, raloxifene, raltitrexed, ranimustine, razoxane, regorafenib, risedronic acid, rituximab, ro Midesin, romiplostim, sargramostim, sipuleucel-T, sizoran, sobuzosine, sodium glycosides, sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tasonamine, tesileukin, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide amine, thiotepa, thymalfasin, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trastuzumab, treosulfan, tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex, valrubicin, fentanyl, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vorin Vorozole, yttrium-90 glass microspheres, nestatin, nestatin butyl ester, zoledronic acid, and doxycycline.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。The compounds were named according to conventional nomenclature in the art or using software, and commercially available compounds were named according to the supplier's catalog name.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为实施例化合物对AR阳性人前列腺癌细胞LNCaP的AR表达量影响图；FIG1 is a graph showing the effect of the example compounds on the AR expression level of AR-positive human prostate cancer cells LNCaP;
图2为实施例化合物抑制人前列腺癌细胞LNCaP的细胞增殖抑制结果图。FIG. 2 is a graph showing the results of the Example compounds inhibiting the proliferation of human prostate cancer cells LNCaP.
具体实施方式DETAILED DESCRIPTION
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.
关键中间体12的制备
Preparation of key intermediate 12
将原料1(2.0g,9.26mmol)溶于二氯甲烷(60mL)中，加入哌嗪-1-甲酸 叔丁酯(1.75g,9.4mmol)和三乙胺(2mL,14.0mmol)。反应混合物在室温下搅拌6h，并用水(100mL×3)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥。除去溶剂后，用乙醇重结晶，得到浅黄色固体2.4g，收率80.60％。UPLC-MS calculated for C16H23N3O4[M+H]+:321.38,found:321.92.
The raw material 1 (2.0 g, 9.26 mmol) was dissolved in dichloromethane (60 mL), and piperazine-1-carboxylic acid was added. Tert-butyl ester (1.75 g, 9.4 mmol) and triethylamine (2 mL, 14.0 mmol). The reaction mixture was stirred at room temperature for 6 h and extracted with water (100 mL × 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After removing the solvent, it was recrystallized from ethanol to obtain 2.4 g of a light yellow solid with a yield of 80.60%. UPLC-MS calculated for C 16 H 23 N 3 O 4 [M+H] + :321.38, found:321.92.
将中间体2(1.5g,4.67mmol)和二水合氯化亚锡(5.27g,23.33mmol)置于乙酸乙酯(50mL)中并在室温下搅拌过夜。添加饱和碳酸氢钠水液(20mL)并剧烈搅拌1小时。通过过滤去除固体，乙酸乙酯和水萃取，有机相经无水硫酸镁干燥并浓缩得到黄色固体1.09g，收率80.15％。UPLC-MS calculated for C16H25N3O2[M+H]+:291.40,found:291.93.
Intermediate 2 (1.5 g, 4.67 mmol) and stannous chloride dihydrate (5.27 g, 23.33 mmol) were placed in ethyl acetate (50 mL) and stirred at room temperature overnight. Saturated sodium bicarbonate solution (20 mL) was added and stirred vigorously for 1 hour. The solid was removed by filtration, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous magnesium sulfate and concentrated to obtain 1.09 g of a yellow solid with a yield of 80.15%. UPLC-MS calculated for C 16 H 25 N 3 O 2 [M+H] + :291.40, found:291.93.
将氯甲酸苯酯(0.47mL,3.74mmol)溶于二氯甲烷中，在0℃下往溶液里缓慢滴加中间体3(1.09g,3.74mmol)的二氯甲烷溶液，一边加一边搅拌，滴加完毕后保持在0℃条件下继续反应30min。缓慢加入三乙胺(0.62mL,4.49mmol)的二氯甲烷溶液，反应过夜后加入水和二氯甲烷萃取，有机相加入无水硫酸镁干燥，蒸干溶剂后柱层析(V石油醚/V乙酸乙酯＝1/1)，得白色固体900mg，收率58.48％。UPLC-MS calculated for C23H29N3O4[M+H]+:411.50,found:412.06.
Dissolve phenyl chloroformate (0.47 mL, 3.74 mmol) in dichloromethane, slowly add dichloromethane solution of intermediate 3 (1.09 g, 3.74 mmol) to the solution at 0°C, stirring while adding, and continue to react at 0°C for 30 min after the addition is complete. Slowly add dichloromethane solution of triethylamine (0.62 mL, 4.49 mmol), react overnight, add water and dichloromethane to extract, add anhydrous magnesium sulfate to dry the organic phase, evaporate the solvent and column chromatography (V petroleum ether /V ethyl acetate = 1/1) to obtain 900 mg of white solid, with a yield of 58.48%. UPLC-MS calculated for C 23 H 29 N 3 O 4 [M+H] + :411.50, found:412.06.
将中间体4(230mg,0.59mmol)溶于1,4-二氧六环(10mL)，加入水合肼(2.95mmol)，100℃下反应4h，TLC检测原料反应完全，除去溶剂，冷却有固体析出，得中间体5粗品。
Intermediate 4 (230 mg, 0.59 mmol) was dissolved in 1,4-dioxane (10 mL), and hydrazine hydrate (2.95 mmol) was added. The mixture was reacted at 100°C for 4 h. TLC showed that the reaction of the raw material was complete. The solvent was removed and solid was precipitated upon cooling to obtain a crude intermediate 5.
0℃下将POCl3(1.53mL,16.43mmol)缓慢滴加到DMF(1.53mL)中，将(1.0g,6.57mmol)原料6溶于DMF(2.5mL)中，缓慢滴加至混合液中，移至室温反应1h，升至50℃反应1h，冷却至室温，加入14％的NaOH/水(3g/18mL)溶液，搅拌并升至75℃反应15min，冷却至室温，用稀盐酸将溶液酸化至pH＝2-3，搅拌1h左右，乙酸乙酯萃取，旋干有机相得红褐色粘稠液体。UPLC-MS calculated for C10H12O3[M+H]+:180.20,found:180.32.
At 0℃, POCl 3 (1.53mL, 16.43mmol) was slowly added dropwise to DMF (1.53mL). (1.0g, 6.57mmol) of raw material 6 was dissolved in DMF (2.5mL) and slowly added dropwise to the mixture. The mixture was moved to room temperature for reaction for 1h, heated to 50℃ for reaction for 1h, cooled to room temperature, 14% NaOH/water (3g/18mL) solution was added, stirred and heated to 75℃ for reaction for 15min, cooled to room temperature, acidified the solution to pH=2-3 with dilute hydrochloric acid, stirred for about 1h, extracted with ethyl acetate, and the organic phase was spin-dried to obtain a reddish brown viscous liquid. UPLC-MS calculated for C 10 H 12 O 3 [M+H] + :180.20, found:180.32.
将中间体7溶于乙腈(15mL)，加入K2CO3(7.26g,52.56mmol)和溴苄(1.95mL,16.43mmol)，回流反应1.5h，冷却至室温，蒸干溶剂，柱层析(V石油醚/V乙 酸乙酯＝20/1)分离，得淡黄色固体1.5g,两步收率63.34％。UPLC-MS calculated for C24H24O3[M+H]+:360.45,found:360.62.
Intermediate 7 was dissolved in acetonitrile (15 mL), K 2 CO 3 (7.26 g, 52.56 mmol) and benzyl bromide (1.95 mL, 16.43 mmol) were added, and the mixture was refluxed for 1.5 h, cooled to room temperature, and the solvent was evaporated to dryness. The mixture was separated by column chromatography (V petroleum ether /V ethyl acetate = 20/1) to obtain 1.5 g of a light yellow solid, with a two-step yield of 63.34%. UPLC-MS calculated for C 24 H 24 O 3 [M+H] + :360.45, found:360.62.
将中间体8(201mg,0.59mmol)溶于乙醇(5mL)中，加入冰醋酸(0.04mL)，室温搅拌下向溶液中缓缓加入中间体5(195mg,0.59mmol)，将反应移至80℃条件下反应1h。反应结束后柱层析(V二氯甲烷/V甲醇＝＝35/1)，得290mg白色固体，收率71.04％。UPLC-MS calculated for C41H49N5O5[M+H]+:691.87,found:692.10.
Intermediate 8 (201 mg, 0.59 mmol) was dissolved in ethanol (5 mL), glacial acetic acid (0.04 mL) was added, and intermediate 5 (195 mg, 0.59 mmol) was slowly added to the solution under stirring at room temperature, and the reaction was moved to 80°C for 1 h. After the reaction, column chromatography (V dichloromethane /V methanol == 35/1) was performed to obtain 290 mg of white solid, with a yield of 71.04%. UPLC-MS calculated for C 41 H 49 N 5 O 5 [M+H] + :691.87, found:692.10.
将中间体9(290mg,0.42mmol)加入乙醇(5mL)中，形成悬浊液，加入K3Fe(CN)6(414mg,1.26mmol)和NaOH(84mg,2.1mmol)，100℃下回流反应8h，TLC检测原料反应完全，过滤掉无机物残渣，蒸干溶剂后柱层析(V二氯甲烷/V甲醇＝＝35/1)纯化，得中间体284mg，收率98.02％。UPLC-MS calculated for C41H47N5O5[M+H]+:689.86,found:690.11.
Intermediate 9 (290 mg, 0.42 mmol) was added to ethanol (5 mL) to form a suspension, K 3 Fe(CN) 6 (414 mg, 1.26 mmol) and NaOH (84 mg, 2.1 mmol) were added, and the mixture was refluxed at 100°C for 8 h. TLC showed that the reaction of the raw material was complete, and the inorganic residue was filtered out. After the solvent was evaporated, column chromatography (V dichloromethane /V methanol ==35/1) was used for purification to obtain 284 mg of the intermediate with a yield of 98.02%. UPLC-MS calculated for C 41 H 47 N 5 O 5 [M+H] + :689.86, found:690.11.
将中间体10(280mg,0.45mmol)溶于二氯甲烷(20mL)中，加入4M的盐酸/二氧六环溶液(1.5mL)，室温搅拌反应2h。TLC检测原料反应完全后，蒸干溶剂，用乙酸乙酯和饱和碳酸氢钠溶液萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，蒸干有机相得中间体11粗品。
Intermediate 10 (280 mg, 0.45 mmol) was dissolved in dichloromethane (20 mL), and 4M hydrochloric acid/dioxane solution (1.5 mL) was added, and the mixture was stirred at room temperature for 2 h. After TLC detected that the reaction of the raw material was complete, the solvent was evaporated, and the mixture was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated to obtain the crude intermediate 11.
将上步中间体11溶于甲醇(20mL)中，加入适量Pd/C，H2环境下室温搅拌反应5h。TLC检测原料反应完全后，过滤，蒸干溶剂得黄色固体130mg，两步收率75.59％。UPLC-MS calculated for C22H27N5O3[M+H]+:409.49,found:410.13. The intermediate 11 in the previous step was dissolved in methanol (20 mL), and an appropriate amount of Pd/C was added . The mixture was stirred at room temperature under H2 for 5 h. After the reaction of the raw material was complete by TLC, the mixture was filtered and the solvent was evaporated to obtain 130 mg of a yellow solid. The yield of the two steps was 75.59%. UPLC -MS calculated for C22H27N5O3[M+H] + : 409.49, found : 410.13.
关键中间体63的制备
Preparation of key intermediate 63
合成路线及方法参照关键中间体12，原料由4-硝基溴化苄替换成N-Boc-4-硝基苯乙胺，UPLC-MS calculated for C18H20N4O3[M+H]+:341.39,found:341.52.实施例的制备：The synthetic route and method refer to the key intermediate 12, and the raw material is replaced by N-Boc-4-nitrophenylethylamine from 4-nitrobenzyl bromide. UPLC-MS calculated for C 18 H 20 N 4 O 3 [M+H] + :341.39, found:341.52. Preparation of Example:
实施例1：SQA-701的合成

Example 1: Synthesis of SQA-701

0℃下将NaH(60％)(50mg,1.23mmol)加入到溶有3-羟基-2,2,4,4-(四甲基)环丁基氨基甲酸叔丁酯(250mg,1.03mmol)的DMF(20mL)溶液中，搅拌反应20min。将原料13(161mg,1.03mmol)加入反应体系，升至室温反应4h，TLC检测原料反应完全，乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，旋干有机相后柱层析(V石油醚/V乙酸乙酯＝8/1)得白色固体320mg，收率82.00％。UPLC-MS calculated for C20H27ClN2O3[M+H]+:378.90,found:378.92.
At 0°C, NaH (60%) (50 mg, 1.23 mmol) was added to a DMF (20 mL) solution containing tert-butyl 3-hydroxy-2,2,4,4-(tetramethyl)cyclobutylcarbamate (250 mg, 1.03 mmol), and the mixture was stirred for 20 min. Raw material 13 (161 mg, 1.03 mmol) was added to the reaction system, and the mixture was heated to room temperature for 4 h. TLC detected that the reaction of the raw material was complete, and the mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried by spin drying and then column chromatography (V petroleum ether /V ethyl acetate = 8/1) was performed to obtain 320 mg of a white solid with a yield of 82.00%. UPLC-MS calculated for C 20 H 27 ClN 2 O 3 [M+H] + :378.90, found:378.92.
将中间体14(320mg,0.84mmol)溶于二氯甲烷(20mL)，加入4M的盐酸/二氧六环溶液(2.5mL)，室温搅拌反应4h，TLC检测原料反应完全，除去溶剂得黄色固体。UPLC-MS calculated for C15H19ClN2O[M+H]+:278.78,found:278.87.
Intermediate 14 (320 mg, 0.84 mmol) was dissolved in dichloromethane (20 mL), 4M hydrochloric acid/dioxane solution (2.5 mL) was added, and the mixture was stirred at room temperature for 4 h. TLC showed that the reaction of the raw material was complete, and the solvent was removed to obtain a yellow solid. UPLC-MS calculated for C 15 H 19 ClN 2 O[M+H] + :278.78, found:278.87.
将原料16(100mg,0.63mmol)溶于无水四氢呋喃中，加入两滴DMF和SOCl2(2mL,18mmol)，70℃搅拌反应4h，蒸干溶剂得黄色粘稠液体。
The raw material 16 (100 mg, 0.63 mmol) was dissolved in anhydrous tetrahydrofuran, and two drops of DMF and SOCl 2 (2 mL, 18 mmol) were added. The mixture was stirred at 70° C. for 4 h, and the solvent was evaporated to obtain a yellow viscous liquid.
将中间体15(75mg,0.24mmol)和DIPEA(0.12mL,0.71mmol)溶于无水 二氯甲烷(20mL)中，室温搅拌反应20min，加入中间体17(51mg,0.29mmol)，氩气保护下室温搅拌反应过夜，蒸干溶剂后柱层析(V石油醚/V乙酸乙酯＝8/1)得淡黄色固体100mg，收率99.37％。UPLC-MS calculated for C20H20Cl2N4O2[M+H]+:419.31,found:418.91.
Intermediate 15 (75 mg, 0.24 mmol) and DIPEA (0.12 mL, 0.71 mmol) were dissolved in anhydrous The mixture was stirred in dichloromethane (20 mL) at room temperature for 20 min, and intermediate 17 (51 mg, 0.29 mmol) was added. The mixture was stirred at room temperature overnight under argon protection. The solvent was evaporated and then column chromatography (V petroleum ether /V ethyl acetate = 8/1) was performed to obtain 100 mg of a light yellow solid with a yield of 99.37%. UPLC-MS calculated for C 20 H 20 Cl 2 N 4 O 2 [M+H] + :419.31, found:418.91.
将中间体18(100mg,0.24mmol)与4-羟甲基哌啶(33mg,0.29mmol)及DIPEA(0.08mL,0.48mmol)一起溶于二氯甲烷(20mL)中，室温搅拌反应过夜。TLC检测原料反应完全，蒸干溶剂后柱层析(V二氯甲烷/V甲醇＝25/1)得黄色固体100mg，收率83.66％。UPLC-MS calculated for C26H32ClN5O3[M+H]+:498.02,found:497.97.
Intermediate 18 (100 mg, 0.24 mmol) was dissolved in dichloromethane (20 mL) together with 4-hydroxymethylpiperidine (33 mg, 0.29 mmol) and DIPEA (0.08 mL, 0.48 mmol) and stirred at room temperature overnight. TLC showed that the reaction of the raw material was complete. After evaporating the solvent, column chromatography (V dichloromethane /V methanol = 25/1) was performed to obtain 100 mg of a yellow solid with a yield of 83.66%. UPLC-MS calculated for C 26 H 32 ClN 5 O 3 [M+H] + :498.02, found:497.97.
将中间体19(70mg,0.14mmol)溶于二氯甲烷(20mL)中，将DMP(102mg,0.24mmol)缓慢加入反应瓶中，室温搅拌反应2h。TLC检测原料反应完全，有机相依次用饱和碳酸氢钠、饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂后柱层析(V二氯甲烷/V甲醇＝50/1)得浅黄色固体60mg，收率86.05％。UPLC-MS calculated for C26H30ClN5O3[M+H]+:496.01,found:495.91.
Intermediate 19 (70 mg, 0.14 mmol) was dissolved in dichloromethane (20 mL), and DMP (102 mg, 0.24 mmol) was slowly added to the reaction flask, and the reaction was stirred at room temperature for 2 h. TLC detected that the raw material reaction was complete, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, and the solvent was evaporated and column chromatography (V dichloromethane /V methanol = 50/1) was performed to obtain 60 mg of light yellow solid, with a yield of 86.05%. UPLC-MS calculated for C 26 H 30 ClN 5 O 3 [M+H] + :496.01, found:495.91.
将中间体20(50mg,0.08mmol)与中间体12(40mg,0.08mmol)一起溶于DMF(6mL)中，滴加两滴冰乙酸，室温搅拌反应20min，加入NaBH(OAc)3(34mg,0.16mmol)，室温搅拌反应过夜。通过制备液相得到SQA-701白色粉 末状固体40mg,收率55.62％。UPLC-MS calculated for C48H57ClN10O5[M+H]+:889.50,found:889.62.Intermediate 20 (50 mg, 0.08 mmol) and intermediate 12 (40 mg, 0.08 mmol) were dissolved in DMF (6 mL), two drops of glacial acetic acid were added, stirred at room temperature for 20 min, NaBH(OAc) 3 (34 mg, 0.16 mmol) was added, and stirred at room temperature for overnight. SQA-701 white powder was obtained by preparing liquid phase 40 mg of solid powder, yield 55.62%. UPLC-MS calculated for C 48 H 57 ClN 10 O 5 [M+H] + :889.50, found:889.62.
实施例2：SQA-702的合成
Example 2: Synthesis of SQA-702
0℃下将NaH(60％)(50mg,1.23mmol)加入到溶有反-4-BOC-氨基环己醇(222mg,1.03mmol)的DMF(20mL)溶液中，搅拌反应20min。将原料13(161mg,1.03mmol)加入反应体系，升至室温反应4h，TLC检测原料反应完全，乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，旋干有机相后柱层析(V石油醚/V乙酸乙酯＝5/1)得白色固体280mg，收率77.48％。UPLC-MS calculated for C18H23ClN2O3[M+H]+:350.84,found:350.82.
At 0°C, NaH (60%) (50 mg, 1.23 mmol) was added to a DMF (20 mL) solution containing trans-4-BOC-aminocyclohexanol (222 mg, 1.03 mmol) and stirred for 20 min. Raw material 13 (161 mg, 1.03 mmol) was added to the reaction system and the mixture was heated to room temperature for 4 h. TLC detected that the reaction of the raw material was complete. The mixture was extracted with ethyl acetate and water. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was dried by spin drying and then column chromatography (V petroleum ether /V ethyl acetate = 5/1) was performed to obtain 280 mg of a white solid with a yield of 77.48%. UPLC-MS calculated for C 18 H 23 ClN 2 O 3 [M+H] + :350.84, found:350.82.
将中间体21(280mg,0.80mmol)溶于二氯甲烷(20mL)，加入4M的盐酸/二氧六环溶液(2.0mL)，室温搅拌反应4h，TLC检测原料反应完全，蒸干溶剂得黄色固体。UPLC-MS calculated for C13H15ClN2O[M+H]+:250.73,found:250.75.
The intermediate 21 (280 mg, 0.80 mmol) was dissolved in dichloromethane (20 mL), and a 4M hydrochloric acid/dioxane solution (2.0 mL) was added. The mixture was stirred at room temperature for 4 h. TLC showed that the reaction of the raw material was complete. The solvent was evaporated to obtain a yellow solid. UPLC-MS calculated for C 13 H 15 ClN 2 O[M+H] + :250.73, found:250.75.
将中间体22(50mg,0.17mmol)和DIPEA(0.09mL,0.52mmol)溶于无水二氯甲烷(20mL)中，室温搅拌反应20min，加入中间体17(36mg,0.21mmol)，氩气保护下室温搅拌反应过夜，蒸干溶剂后柱层析(V石油醚/V乙酸乙酯＝5/1)得淡黄色固体67mg，收率99.84％。UPLC-MS calculated for C18H16Cl2N4O2[M+H]+:391.25,found:390.79.
Intermediate 22 (50 mg, 0.17 mmol) and DIPEA (0.09 mL, 0.52 mmol) were dissolved in anhydrous dichloromethane (20 mL), stirred at room temperature for 20 min, and intermediate 17 (36 mg, 0.21 mmol) was added. Stirred at room temperature under argon protection overnight, and the solvent was evaporated and column chromatography (V petroleum ether /V ethyl acetate = 5/1) was performed to obtain 67 mg of a light yellow solid, with a yield of 99.84%. UPLC-MS calculated for C 18 H 16 Cl 2 N 4 O 2 [M+H] + :391.25, found:390.79.
将中间体23(67mg,0.17mmol)与4-羟甲基哌啶(23mg,0.21mmol)及DIPEA(0.06mL,0.34mmol)一起溶于二氯甲烷(20mL)中，室温搅拌反应过夜。TLC检测原料反应完全，蒸干溶剂后柱层析(V二氯甲烷/V甲醇＝25/1)得淡黄色粘稠液体75mg，收率93.87％。UPLC-MS calculated for C24H28ClN5O3[M+H]+:469.97,found:469.96.
Intermediate 23 (67 mg, 0.17 mmol) was dissolved in dichloromethane (20 mL) together with 4-hydroxymethylpiperidine (23 mg, 0.21 mmol) and DIPEA (0.06 mL, 0.34 mmol) and stirred at room temperature overnight. TLC showed that the reaction of the raw material was complete. After evaporating the solvent, column chromatography (V dichloromethane /V methanol = 25/1) was performed to obtain 75 mg of a light yellow viscous liquid with a yield of 93.87%. UPLC-MS calculated for C 24 H 28 ClN 5 O 3 [M+H] + :469.97, found:469.96.
将中间体24(75mg,0.15mmol)溶于二氯甲烷(20mL)中，将DMP(126mg,0.3mmol)缓慢加入反应瓶中，室温搅拌反应2h。TLC检测原料反应完全，有机相依次用饱和碳酸氢钠、饱和食盐水洗，无水硫酸钠干燥，蒸干溶剂后柱层析(V二氯甲烷/V甲醇＝50/1)得白色固体58mg，收率82.63％。UPLC-MS calculated for C24H26ClN5O3[M+H]+:467.95,found:467.90.
Intermediate 24 (75 mg, 0.15 mmol) was dissolved in dichloromethane (20 mL), and DMP (126 mg, 0.3 mmol) was slowly added to the reaction flask, and the reaction was stirred at room temperature for 2 h. TLC detected that the raw material reaction was complete, and the organic phase was washed with saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous sodium sulfate, and the solvent was evaporated and column chromatography (V dichloromethane /V methanol = 50/1) was performed to obtain 58 mg of white solid, with a yield of 82.63%. UPLC-MS calculated for C 24 H 26 ClN 5 O 3 [M+H] + :467.95, found:467.90.
将中间体25(52mg,0.11mmol)与中间体12(45mg,0.11mmol)一起溶于DMF(6mL)中，滴加两滴冰乙酸，室温搅拌反应20min，加入NaBH(OAc)3(46mg,0.22mmol)，室温搅拌反应过夜。通过制备液相得到SQA-702白色粉末状固体38mg,收率40.10％。UPLC-MS calculated for C46H53ClN10O5[M+H]+:861.45,found:861.50.Intermediate 25 (52 mg, 0.11 mmol) and intermediate 12 (45 mg, 0.11 mmol) were dissolved in DMF (6 mL), two drops of glacial acetic acid were added, and the mixture was stirred at room temperature for 20 min. NaBH(OAc) 3 (46 mg, 0.22 mmol) was added, and the mixture was stirred at room temperature overnight. 38 mg of SQA-702 was obtained as a white powder solid by preparative liquid phase, with a yield of 40.10%. UPLC-MS calculated for C 46 H 53 ClN 10 O 5 [M+H] + :861.45, found:861.50.
实施例3：SQA-703的合成
Example 3: Synthesis of SQA-703
合成路线参照实施例1，原料由实施例1中的2-氯嘧啶-5-羧酸替换为6-氯哒嗪-3-羧酸，通过制备液相得到SQA-703白色粉末状固体25mg。UPLC-MS calculated for C48H57ClN10O5[M+H]+:889.50,found:889.50.The synthetic route was as in Example 1, except that the raw material was replaced by 6-chloropyridazine-3-carboxylic acid instead of 2-chloropyrimidine-5-carboxylic acid in Example 1, and 25 mg of SQA-703 white powder solid was obtained by preparative liquid phase. UPLC-MS calculated for C 48 H 57 ClN 10 O 5 [M+H] + :889.50, found:889.50.
实施例4：SQA-704的合成
Example 4: Synthesis of SQA-704
合成路线参照实施例2，通过制备液相得到SQA-704白色粉末状固体65mg。UPLC-MS calculated for C47H54ClN9O5[M+H]+:861.47,found:861.64.The synthetic route was as in Example 2, and 65 mg of SQA-704 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 47 H 54 ClN 9 O 5 [M+H] + :861.47, found:861.64.
实施例5：SQA-705的合成

Example 5: Synthesis of SQA-705

将对苯二甲酸单甲酯(80mg,0.28mmol)、HATU(158mg,0.42mmol)和DIPEA(0.24mL,1.38mmol)溶于无水DMF中，氩气保护下搅拌反应15min，加入22(50mg,0.28mmol)的DMF溶液，室温搅拌反应过夜。加入水和乙酸乙酯萃取，有机相依次用饱和氯化铵、饱和碳酸氢钠和饱和食盐水洗，无水硫酸镁干燥，柱层析(V石油醚/V乙酸乙酯＝2/1)得固体77mg,收率67％。UPLC-MS calculated for C22H21ClN2O4[M+H]+:413.88,found:413.62.
Dissolve monomethyl terephthalate (80 mg, 0.28 mmol), HATU (158 mg, 0.42 mmol) and DIPEA (0.24 mL, 1.38 mmol) in anhydrous DMF, stir and react for 15 min under argon protection, add DMF solution of 22 (50 mg, 0.28 mmol), stir and react at room temperature overnight. Add water and ethyl acetate for extraction, wash the organic phase with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in turn, dry over anhydrous magnesium sulfate, and column chromatography (V petroleum ether /V ethyl acetate = 2/1) to obtain 77 mg of solid, with a yield of 67%. UPLC-MS calculated for C 22 H 21 ClN 2 O 4 [M+H] + :413.88, found:413.62.
将中间体40(70mg,0.17mmol)溶于四氢呋喃溶液中，加入氢氧化锂(72mg,1.7mmol)和少量水，室温搅拌反应过夜。TLC检测原料反应完全，蒸干有机相，加入水和乙酸乙酯萃取(有机相废弃)。水相用盐酸调pH至2-3，乙酸乙酯萃取三次，合并有机相后用饱和食盐水洗，无水硫酸镁干燥得中间体40粗品60mg。
Dissolve the intermediate 40 (70 mg, 0.17 mmol) in tetrahydrofuran solution, add lithium hydroxide (72 mg, 1.7 mmol) and a small amount of water, and stir at room temperature to react overnight. TLC detected that the raw material reacted completely, evaporated the organic phase, added water and ethyl acetate to extract (the organic phase was discarded). The aqueous phase was adjusted to pH 2-3 with hydrochloric acid, extracted with ethyl acetate three times, and the organic phases were combined and washed with saturated brine, and dried over anhydrous magnesium sulfate to obtain 60 mg of the crude intermediate 40.
将中间体40(60mg,0.15mmol)、HATU(86mg,0.22mmol)和DIPEA(0.13mL,0.75mmol)溶于无水DMF中，氩气保护下搅拌反应15min，加入4-哌啶甲醇(21mg,0.18mmol)的DMF溶液，室温搅拌反应过夜。加入饱和氯化铵淬灭反应，乙酸乙酯萃取，有机相依次用饱和氯化铵、饱和碳酸氢钠和饱和食盐水洗，无水硫酸镁干燥，柱层析(V二氯甲烷/V甲醇＝20/1)得白色固体57mg,收率76.6％。UPLC-MS calculated for C27H30ClN3O4[M+H]+:497.01,found:496.98.Intermediate 40 (60 mg, 0.15 mmol), HATU (86 mg, 0.22 mmol) and DIPEA (0.13 mL, 0.75 mmol) were dissolved in anhydrous DMF, stirred and reacted for 15 min under argon protection, and a DMF solution of 4-piperidinemethanol (21 mg, 0.18 mmol) was added, and the reaction was stirred at room temperature overnight. Saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in sequence, dried over anhydrous magnesium sulfate, and column chromatography (V dichloromethane /V methanol = 20/1) to obtain 57 mg of a white solid with a yield of 76.6%. UPLC-MS calculated for C 27 H 30 ClN 3 O 4 [M+H] + :497.01, found:496.98.
剩余合成方法参照实施例2，通过制备液相得到SQA-705白色粉末状固体47mg。UPLC-MS calculated for C49H55ClN8O6[M+H]+:888.49,found:888.24.The remaining synthesis method was similar to that of Example 2, and 47 mg of SQA-705 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 49 H 55 ClN 8 O 6 [M+H] + :888.49, found:888.24.
实施例6：SQA-706的合成
Example 6: Synthesis of SQA-706
合成路线参照实施例2，原料由实施例2中的2-氯-4-氟苯腈替换为2-三氟甲基-4-氟苯腈，通过制备液相得到SQA-706白色粉末状固体45mg。UPLC-MS  calculated for C47H53F3N10O5[M+H]+:896.01,found:895.88.The synthetic route was as in Example 2, except that the raw material was replaced by 2-trifluoromethyl-4-fluorobenzonitrile from 2-chloro-4-fluorobenzonitrile in Example 2, and 45 mg of SQA-706 white powder solid was obtained by preparative liquid phase. UPLC-MS calculated for C 47 H 53 F 3 N 10 O 5 [M+H] + :896.01,found:895.88.
实施例7：SQA-707的合成
Example 7: Synthesis of SQA-707
将N-Boc-γ-氨基丁酸(55mg,0.27mmol)、HATU(158mg,0.42mmol)和DIPEA(0.24mL,1.38mmol)溶于无水DMF中，氩气保护下搅拌反应15min，加入对中间体12(115mg,0.28mmol)的DMF溶液，室温搅拌反应过夜。加入水和乙酸乙酯萃取，有机相依次用饱和氯化铵、饱和碳酸氢钠和饱和食盐水洗，无水硫酸镁干燥，柱层析(V二氯甲烷/V甲醇＝15/1)得固体72mg,收率45.1％。UPLC-MS calculated for C31H42N6O6[M+H]+:595.72,found:595.54.
N-Boc-γ-aminobutyric acid (55 mg, 0.27 mmol), HATU (158 mg, 0.42 mmol) and DIPEA (0.24 mL, 1.38 mmol) were dissolved in anhydrous DMF, stirred and reacted for 15 min under argon protection, and a DMF solution of intermediate 12 (115 mg, 0.28 mmol) was added, and the reaction was stirred at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous magnesium sulfate, and column chromatography (V dichloromethane /V methanol = 15/1) to obtain 72 mg of solid, with a yield of 45.1%. UPLC-MS calculated for C 31 H 42 N 6 O 6 [M+H] + :595.72, found:595.54.
将中间体49(70mg,0.12mmol)溶于二氯甲烷(20mL)，加入4M的盐酸/二氧六环溶液(1.0mL)，室温搅拌反应4h，TLC检测原料反应完全，除去溶剂得中间体50粗品。
Intermediate 49 (70 mg, 0.12 mmol) was dissolved in dichloromethane (20 mL), and 4 M hydrochloric acid/dioxane solution (1.0 mL) was added. The mixture was stirred at room temperature for 4 h. TLC indicated that the reaction was complete. The solvent was removed to obtain a crude intermediate 50.
将中间体40(40mg,0.1mmol)、HATU(57mg,0.15mmol)和DIPEA(0.01mL,0.5mmol)溶于无水DMF中，氩气保护下搅拌反应15min，加入对中间体50(64mg,0.12mmol)的DMF溶液，室温搅拌反应过夜。加入水和乙酸乙酯萃取，有机相依次用饱和氯化铵、饱和碳酸氢钠和饱和食盐水洗，无水硫酸镁干燥，通过制备液相得到SQA-707灰白色粉末状固体35mg,收率39.9％。UPLC-MS calculated for C47H51ClN8O7[M+H]+:876.43,found:876.06.Intermediate 40 (40 mg, 0.1 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (0.01 mL, 0.5 mmol) were dissolved in anhydrous DMF, stirred and reacted for 15 min under argon protection, and a DMF solution of intermediate 50 (64 mg, 0.12 mmol) was added, and the reaction was stirred at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in turn, and dried over anhydrous magnesium sulfate. 35 mg of SQA-707 was obtained by preparative liquid phase, with a yield of 39.9%. UPLC-MS calculated for C 47 H 51 ClN 8 O 7 [M+H] + :876.43, found:876.06.
实施例8：SQA-708的合成

Example 8: Synthesis of SQA-708

合成路线参照实施例7，原料由实施例7中的N-Boc-γ-氨基丁酸替换为Boc-5-氨基戊酸，通过制备液相得到SQA-708白色粉末状固体58mg。UPLC-MS calculated for C48H53ClN8O7[M+H]+:890.46,found:890.28.The synthetic route was as in Example 7, the raw material was replaced by Boc-5-aminopentanoic acid instead of N-Boc-γ-aminobutyric acid in Example 7, and 58 mg of SQA-708 white powder solid was obtained by preparative liquid phase. UPLC-MS calculated for C 48 H 53 ClN 8 O 7 [M+H] + :890.46, found:890.28.
实施例9：SQA-709的合成
Example 9: Synthesis of SQA-709
合成路线参照实施例7，原料由实施例7中的N-Boc-γ-氨基丁酸替换为Boc-6-氨基己酸，通过制备液相得到SQA-709灰白色粉末状固体36mg。UPLC-MS calculated for C49H55ClN8O7[M+H]+:904.49,found:904.22.The synthetic route was as in Example 7, the raw material was replaced by Boc-6-aminocaproic acid from N-Boc-γ-aminobutyric acid in Example 7, and 36 mg of SQA-709 off-white powder solid was obtained by preparative liquid phase. UPLC-MS calculated for C 49 H 55 ClN 8 O 7 [M+H] + :904.49, found:904.22.
实施例10：SQA-710的合成
Example 10: Synthesis of SQA-710
合成步骤及处理方法参照实施例2，通过制备液相得到SQA-710灰白色粉末状固体26mg。UPLC-MS calculated for C52H64ClN11O5[M+H]+:959.62,found:960.02.The synthesis steps and treatment methods were similar to those in Example 2, and 26 mg of SQA-710 off-white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 52 H 64 ClN 11 O 5 [M+H] + :959.62, found:960.02.
实施例11：WCA-814的合成
Example 11: Synthesis of WCA-814
合成路线参照实施例2和3，通过制备液相得到WCA-814白色粉末状固体30mg。UPLC-MS calculated for C46H53ClN10O5[M+H]+:861.45,found:861.45. The synthetic route was as in Examples 2 and 3, and 30 mg of WCA-814 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 46 H 53 ClN 10 O 5 [M+H] + :861.45, found:861.45.
实施例12：XLA-721的合成
Example 12: Synthesis of XLA-721
将Boc-beta-丙氨酸(57mg,0.3mmol)、HATU(171mg,0.45mmol)和DIPEA(0.26mL,1.5mmol)溶于无水DMF中，氩气保护下搅拌反应15min，加入对中间体63(115mg,0.28mmol)的DMF溶液，室温搅拌反应过夜。加入水和乙酸乙酯萃取，有机相依次用饱和氯化铵、饱和碳酸氢钠和饱和食盐水洗，无水硫酸镁干燥，柱层析(V二氯甲烷/V甲醇＝15/1)得固体70mg,收率48.6％。UPLC-MS calculated for C26H33N5O6[M+H]+:512.59,found:512.62.
Boc-beta-alanine (57 mg, 0.3 mmol), HATU (171 mg, 0.45 mmol) and DIPEA (0.26 mL, 1.5 mmol) were dissolved in anhydrous DMF, stirred and reacted for 15 min under argon protection, and a DMF solution of intermediate 63 (115 mg, 0.28 mmol) was added, and the reaction was stirred at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in turn, dried over anhydrous magnesium sulfate, and column chromatography (V dichloromethane /V methanol = 15/1) to obtain 70 mg of solid, with a yield of 48.6%. UPLC-MS calculated for C 26 H 33 N 5 O 6 [M+H] + :512.59, found:512.62.
将中间体64(70mg,0.14mmol)溶于二氯甲烷(20mL)，加入4M的盐酸/二氧六环溶液(1.0mL)，室温搅拌反应4h，TLC检测原料反应完全，除去溶剂得中间体65粗品。
Intermediate 64 (70 mg, 0.14 mmol) was dissolved in dichloromethane (20 mL), and 4 M hydrochloric acid/dioxane solution (1.0 mL) was added. The mixture was stirred at room temperature for 4 h. TLC indicated that the reaction was complete. The solvent was removed to obtain a crude intermediate 65.
中间体66的合成可参照实施例5中中间体40的制备方法；The synthesis of intermediate 66 can refer to the preparation method of intermediate 40 in Example 5;
将中间体66(42mg,0.1mmol)、EDCI(39mg,0.2mmol)、HOAT(27mg,0.2mmol)和DIPEA(0.05mL,0.3mmol)溶于无水DMF中，氩气保护下搅拌反应10min，加入对中间体65(64mg,0.12mmol)的DMF溶液，室温搅拌反应过夜。加入水和乙酸乙酯萃取，有机相依次用饱和氯化铵、饱和碳酸氢钠和饱和食盐水洗，无水硫酸镁干燥，通过制备液相得到XLA-721白色粉末状固体51mg,收率62.1％。UPLC-MS calculated for C44H46ClN7O7[M+H]+:821.35,found:820.34.Intermediate 66 (42 mg, 0.1 mmol), EDCI (39 mg, 0.2 mmol), HOAT (27 mg, 0.2 mmol) and DIPEA (0.05 mL, 0.3 mmol) were dissolved in anhydrous DMF, stirred and reacted for 10 min under argon protection, and a DMF solution of intermediate 65 (64 mg, 0.12 mmol) was added, and the reaction was stirred at room temperature overnight. Water and ethyl acetate were added for extraction, and the organic phase was washed with saturated ammonium chloride, saturated sodium bicarbonate and saturated brine in turn, and dried over anhydrous magnesium sulfate. 51 mg of XLA-721 white powder solid was obtained by preparing liquid phase, with a yield of 62.1%. UPLC-MS calculated for C 44 H 46 ClN 7 O 7 [M+H] + :821.35, found:820.34.
实施例13：XLA-722的合成

Example 13: Synthesis of XLA-722

合成方法参照实施例12，通过制备液相得到XLA-722白色粉末状固体22mg。UPLC-MS calculated for C42H42ClN7O7[M+H]+:793.30,found:792.29.The synthesis method was similar to that of Example 12, and 22 mg of XLA-722 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 42 H 42 ClN 7 O 7 [M+H] + :793.30, found:792.29.
实施例14：XLA-723的合成
Example 14: Synthesis of XLA-723
合成方法参照实施例12，通过制备液相得到XLA-723白色粉末状固体36mg。UPLC-MS calculated for C43H44ClN7O7[M+H]+:807.33,found:806.32.The synthesis method was similar to that of Example 12, and 36 mg of XLA-723 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 43 H 44 ClN 7 O 7 [M+H] + :807.33, found:806.32.
实施例15：XLA-724的合成

Example 15: Synthesis of XLA-724

合成方法参照实施例12，通过制备液相得到XLA-724白色粉末状固体48mg。UPLC-MS calculated for C44H46ClN7O7[M+H]+:821.35,found:820.34.The synthesis method was similar to that of Example 12, and 48 mg of XLA-724 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 44 H 46 ClN 7 O 7 [M+H] + :821.35, found:820.34.
实施例16：XLA-725的合成
Example 16: Synthesis of XLA-725
合成方法参照实施例12，通过制备液相得到XLA-725白色粉末状固体39mg。UPLC-MS calculated for C45H48ClN7O7[M+H]+:835.38,found:834.37.The synthesis method was similar to that of Example 12, and 39 mg of XLA-725 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 45 H 48 ClN 7 O 7 [M+H] + :835.38, found:834.37.
实施例17：XLA-726的合成
Example 17: Synthesis of XLA-726
合成方法参照实施例12，通过制备液相得到XLA-726白色粉末状固体23mg。UPLC-MS calculated for C46H50ClN7O7[M+H]+:849.41,found:848.42.The synthesis method was similar to that of Example 12, and 23 mg of XLA-726 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 46 H 50 ClN 7 O 7 [M+H] + :849.41, found:848.42.
实施例18：XLA-727的合成
Example 18: Synthesis of XLA-727
合成方法参照实施例12，通过制备液相得到XLA-727白色粉末状固体42mg。UPLC-MS calculated for C47H52ClN7O7[M+H]+:863.44,found:863.46. The synthesis method was similar to that of Example 12, and 42 mg of XLA-727 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 47 H 52 ClN 7 O 7 [M+H] + :863.44, found:863.46.
实施例19：XLA-728的合成
Example 19: Synthesis of XLA-728
合成方法参照实施例12，通过制备液相得到XLA-728白色粉末状固体37mg。UPLC-MS calculated for C48H54ClN7O7[M+H]+:877.46,found:877.98.The synthesis method was similar to that of Example 12, and 37 mg of XLA-728 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 48 H 54 ClN 7 O 7 [M+H] + :877.46, found:877.98.
实施例20：XLA-729的合成
Example 20: Synthesis of XLA-729
合成方法参照实施例12，通过制备液相得到XLA-729白色粉末状固体40mg。UPLC-MS calculated for C49H56ClN7O7[M+H]+:891.49,found:891.26. The synthesis method was similar to that of Example 12, and 40 mg of XLA-729 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 49 H 56 ClN 7 O 7 [M+H] + :891.49, found:891.26.
实施例21：XLA-730的合成
Example 21: Synthesis of XLA-730
合成方法参照实施例12，通过制备液相得到XLA-730白色粉末状固体31mg。UPLC-MS calculated for C45H48ClN7O9[M+H]+:867.38,found:868.42.The synthesis method was similar to that of Example 12, and 31 mg of XLA-730 white powder solid was obtained by preparing the liquid phase. UPLC-MS calculated for C 45 H 48 ClN 7 O 9 [M+H] + :867.38, found:868.42.
生物评价试验Biological evaluation test
试验例1：雄激素受体(AR)表达量的降低作用的评价Test Example 1: Evaluation of the effect of reducing androgen receptor (AR) expression
将AR阳性人前列腺癌细胞LNCaP在含有10％FBS的RPMI 1640(以下记作评价培养基)中以达到3X 105/孔的量接种于6孔微孔培养板(Corning)，培养过夜。在该培养物中添加含有实施例化合物的评价培养基中，使得实施例化合物的终浓度达到1和10μmol/L,培养24小时。24小时培养后，除去培养基，利用PBS清洗细胞之后，添加含有1％Protease Inhibitor Cocktail的RIPA裂解液，经裂解、离心后获得总蛋白提取液，通过BCA法检测提取液中的蛋白浓度；采用SDS-PAGE进行蛋白电泳，之后200mA恒流电转90min将蛋白转印到PVDF(MilliporeSigma IPVH00010)膜上；将PVDF膜置于含有5％的脱脂奶中，室温封闭1h；分别使用Anti-Androgen Receptor抗体[EPR1535(2)](HRP)(abcam)和抗AR-V7 Speccific抗体(Cell Signaling)进行免疫反应；洗膜后滴加ECL发光 液，曝光。使用软件Image J对条带进行灰度分析。每个样品同时检测GAPDH蛋白条带作为内参。根据蛋白条带灰度计算实施例化合物AR蛋白降解率。AR-positive human prostate cancer cells LNCaP were seeded in 6-well microplates (Corning) in RPMI 1640 containing 10% FBS (hereinafter referred to as evaluation medium) at a concentration of 3X 10 5 /well and cultured overnight. The evaluation medium containing the example compound was added to the culture medium to a final concentration of 1 and 10 μmol/L, and cultured for 24 hours. After 24 hours of culture, the culture medium was removed, the cells were washed with PBS, and RIPA lysis buffer containing 1% Protease Inhibitor Cocktail was added. After lysis and centrifugation, the total protein extract was obtained, and the protein concentration in the extract was detected by the BCA method; SDS-PAGE was used for protein electrophoresis, and then the protein was transferred to a PVDF (MilliporeSigma IPVH00010) membrane by constant current electrophoresis at 200mA for 90min; the PVDF membrane was placed in 5% skim milk and blocked at room temperature for 1h; the immune reaction was carried out using Anti-Androgen Receptor antibody [EPR1535(2)] (HRP) (abcam) and anti-AR-V7 Speccific antibody (Cell Signaling); after washing the membrane, ECL luminescence was added The solution was exposed. The grayscale analysis of the bands was performed using the software Image J. The GAPDH protein band was simultaneously detected for each sample as an internal reference. The AR protein degradation rate of the example compound was calculated based on the grayscale of the protein band.
LNCaP细胞的结果示于图1和表1。AR表达降低作用为50％以上时表示为“降低”。在本发明化合物中，实施例化合物SQA-701、SQA-702、SQA-703、SQA-704、SQA-705、SQA-706、SQA-710、WCA-814均表现出一定的AR表达降低作用，且在后续实验中，化合物对AR的降解表现出明显的浓度依赖性和时间依赖性。The results of LNCaP cells are shown in Figure 1 and Table 1. When the AR expression reduction effect is 50% or more, it is expressed as "reduction". Among the compounds of the present invention, the example compounds SQA-701, SQA-702, SQA-703, SQA-704, SQA-705, SQA-706, SQA-710, and WCA-814 all showed a certain AR expression reduction effect, and in subsequent experiments, the compounds showed obvious concentration dependence and time dependence on AR degradation.
表1
Table 1
试验例2：雄激素依赖的前列腺癌细胞增殖抑制活性Test Example 2: Androgen-dependent prostate cancer cell proliferation inhibitory activity
将雄激素受体阳性的人前列腺癌细胞LNCaP在含有5％碳吸附血清(CCS)的RPMI 1640培养基(以下记作评价培养基)中以达到4×103/孔的量接种于透明底96孔微孔培养板(Corning)，培养48h。在该培养物中添加含有R1881的评价培养基(R1881的终浓度为0.1nmo1/L)和含有实施例化合物或比较例化合物(Enzalutamide:恩杂鲁胺)的评价培养基。(该实施例或比较例化合物的终浓度为1.53、4.6、13.8、41.1、123.4、370.3、1111、3333和10000nmo1/L)，培养96小时后，测定活细胞数。活细胞数使用WST-1(Roche)进行测定。将0.1nmol/L的R1881的细胞增殖活性值设为100％，将仅有评价培养基的细胞增殖活性设为 0％，根据测得的活细胞数利用logistic回归算出50％增殖抑制浓度(IC50值)。Androgen receptor-positive human prostate cancer cells LNCaP were seeded in a transparent bottom 96-well microplate (Corning) in RPMI 1640 medium (hereinafter referred to as evaluation medium) containing 5% carbon adsorbed serum (CCS) at a concentration of 4×10 3 /well and cultured for 48 hours. Evaluation medium containing R1881 (the final concentration of R1881 was 0.1 nmol/L) and evaluation medium containing Example compounds or Comparative Example compounds (Enzalutamide: Enzalutamide) were added to the culture. (The final concentrations of the Example or Comparative Example compounds were 1.53, 4.6, 13.8, 41.1, 123.4, 370.3, 1111, 3333 and 10000 nmol/L), and the number of viable cells was measured after 96 hours of culture. The number of viable cells was measured using WST-1 (Roche). The cell proliferation activity value of 0.1 nmol/L R1881 was set as 100%, and the cell proliferation activity of only the evaluation medium was set as 0%, and the 50% proliferation inhibition concentration ( IC50 value) was calculated based on the measured viable cell number using logistic regression.
细胞增殖抑制结果示于表2。实施例化合物表现出不同程度的前列腺癌细胞增殖抑制活性，其中SQA-710表现出优秀的肿瘤细胞增殖抑制活性，最大半数抑制浓度(IC50)分别为36.0nmol/L(LNCaP细胞系)和30.2nmol/L(22RV1细胞系)。Enzalutamide作为阳性对照，其在LNCaP细胞系中的IC50为52nmo1/L，而在22RV1细胞系中几乎无效。The results of cell proliferation inhibition are shown in Table 2. The example compounds showed different degrees of prostate cancer cell proliferation inhibition activity, among which SQA-710 showed excellent tumor cell proliferation inhibition activity, with the maximum half inhibition concentration (IC 50 ) of 36.0nmol/L (LNCaP cell line) and 30.2nmol/L (22RV1 cell line). Enzalutamide was used as a positive control, and its IC 50 in LNCaP cell line was 52nmo1/L, while it was almost ineffective in 22RV1 cell line.
表2
Table 2
试验例3：化合物在前列腺癌小鼠模型上的初步药效筛选Experimental Example 3: Preliminary efficacy screening of compounds in prostate cancer mouse model
以人前列腺癌22RV1细胞系(恩杂鲁胺耐药)构建小鼠模型，小鼠品系为balb/c nude mice。实施例化合物溶媒为20％PEG400+6％Cremophor EL+74％PBS，采取腹腔注射方式给药，给药周期为Qod4*weeks，给药剂量为5mg/kg或10mg/kg。在给药16天后，测量小鼠肿瘤体积，实验结果如图2所示。实施例化合物H3(10mg/kg)、SQA-710(5mg/kg及10mg/kg)、SQA-814(5mg/kg) 与Control组相比表现出明显的、效果相当的肿瘤增殖抑制能力，而在细胞水平具有活性的化合物SQA-702在小鼠模型上效果不佳。A mouse model was constructed using the human prostate cancer 22RV1 cell line (enzalutamide resistant), and the mouse strain was balb/c nude mice. The solvent for the example compound was 20% PEG400+6% Cremophor EL+74% PBS, and the drug was administered by intraperitoneal injection. The administration cycle was Qod4*weeks, and the dosage was 5mg/kg or 10mg/kg. After 16 days of administration, the tumor volume of the mice was measured, and the experimental results are shown in Figure 2. Example compound H3 (10mg/kg), SQA-710 (5mg/kg and 10mg/kg), SQA-814 (5mg/kg) Compared with the Control group, it showed significant and comparable tumor proliferation inhibition ability, while the compound SQA-702, which was active at the cellular level, was not effective in the mouse model.
此外，SQA-710无论以5mg/kg进行给药，还是以10mg/kg进行给药，对小鼠均表现出一定的毒性，而SQA-814在5mg/kg进行给药时，能够在保证药效的同时，对小鼠体重无明显影响。In addition, SQA-710 showed certain toxicity to mice regardless of whether it was administered at 5 mg/kg or 10 mg/kg, while SQA-814, when administered at 5 mg/kg, was able to ensure efficacy without significant effect on the weight of mice.
结论in conclusion
实施例化合物对LNCap细胞的AR表达量均有一定的降低作用，其中SQA-710的AR降解活性最优，其DC50约20nM，不仅可以剂量依赖性地抑制LNCap细胞生长，更对Enzalutamide耐药的22RV1肿瘤细胞生长有显著抑制。此外，SQA-710作为一种AR拮抗剂和Hsp90抑制剂的小分子偶联药物，其肿瘤抑制活性均高于两种小分子在单独应用时的作用，可见这种偶联药物发挥了类似双靶点抑制剂的效果而产生协同作用。The compounds in the examples all have a certain effect of reducing the AR expression level of LNCap cells, among which SQA-710 has the best AR degradation activity, with a DC 50 of about 20nM, which can not only inhibit the growth of LNCap cells in a dose-dependent manner, but also significantly inhibit the growth of Enzalutamide-resistant 22RV1 tumor cells. In addition, SQA-710, as a small molecule conjugate drug of AR antagonist and Hsp90 inhibitor, has a higher tumor inhibition activity than the effects of the two small molecules when used alone, which shows that this conjugate drug has a similar effect to a dual-target inhibitor and produces a synergistic effect.
在以22RV1构建的动物模型上对实施例化合物进行药效评价，发现SQA-814在具有和SQA-710相当抗肿瘤增殖活性的同时，还兼具更低的毒性，值得进行后续的进一步研究。The efficacy of the example compounds was evaluated in an animal model constructed with 22RV1, and it was found that SQA-814 had comparable anti-tumor proliferation activity to SQA-710, but also had lower toxicity, and was worthy of further study.
应当理解的是，本发明不限于上述本发明的特定实施方式，因为可以对特定实施方式进行变化，并且其仍然落入所附权利要求的范围内。 It should be understood that the present invention is not limited to the specific embodiments of the invention described above, as variations may be made thereto and still fall within the scope of the appended claims.

Claims (27)

  1. 式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，
    The compound represented by formula I, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof,
    其中，环A、环B、环C、环D、环E分别独立地选自任选被0、1、2、3、4或5个R2取代的C3-8环烷基、C3-8杂环烷基、C6-10芳基或C5-10杂芳基；wherein Ring A, Ring B, Ring C, Ring D, and Ring E are independently selected from C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6-10 aryl, or C 5-10 heteroaryl, which are optionally substituted with 0, 1, 2, 3, 4, or 5 R 2 ;
    L选自-L4-L3-L2-L1-L0-或-CO-NH-(CH2)p-CO-R0-，条件是当L选自-CO-NH-(CH2)p-CO-R0-时，其中的一个或多个亚甲基任选的被1、2或3个O原子取代；L is selected from -L 4 -L 3 -L 2 -L 1 -L 0 - or -CO-NH-(CH 2 ) p -CO-R 0 -, provided that when L is selected from -CO-NH-(CH 2 ) p -CO-R 0 -, one or more methylene groups therein are optionally substituted by 1, 2 or 3 O atoms;
    L1、L3、L5分别独立地选自单键、C1-6烷基、C2-6烯基、C2-6炔基、O、S、NH、-CO-、-SO-、-SO2-、-C1-6烷基-O-，所述C1-6烷基、C2-6烯基、C2-6炔基、-C1-6烷基-O-任选被1、2或3个R3取代；L 1 , L 3 , and L 5 are each independently selected from a single bond, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O, S, NH, -CO-, -SO-, -SO 2 -, -C 1-6 alkyl-O-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-6 alkyl-O- is optionally substituted by 1, 2 or 3 R 3 ;
    L0、L2、L4分别独立地选自单键、C3-8环烷基、C3-8杂环烷基、C6-10芳基或C5-10杂芳基，所述C3-8环烷基、C3-8杂环烷基、C6-10芳基或C5-10杂芳基任选被1-4个R4取代；L 0 , L 2 , L 4 are each independently selected from a single bond, a C 3-8 cycloalkyl group, a C 3-8 heterocycloalkyl group, a C 6-10 aryl group or a C 5-10 heteroaryl group, wherein the C 3-8 cycloalkyl group, the C 3-8 heterocycloalkyl group, the C 6-10 aryl group or the C 5-10 heteroaryl group is optionally substituted by 1 to 4 R 4 groups;
    R0选自-NH-、哌啶基、环己基或哌嗪基；R 0 is selected from -NH-, piperidinyl, cyclohexyl or piperazinyl;
    R1选自H、OH、卤素、NH2、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6烷氨基；R 1 is selected from H, OH, halogen, NH 2 , CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino;
    R2、R3、R4分别独立地选自H、卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、OH、NH2、CN、硝基、羧基、C3-6环烷基，所述的C1-6烷基、C1-6烷氧基、C1-6卤代烷基、OH、NH2、羧基、C3-6环烷基任选被1-3个选自卤素、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、OH、NH2、CN、硝基、羧基的取代基取代；R 2 , R 3 , and R 4 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , CN, nitro, carboxyl, and C 3-6 cycloalkyl, and the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , carboxyl, and C 3-6 cycloalkyl are optionally substituted with 1 to 3 substituents selected from halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, OH, NH 2 , CN, nitro, and carboxyl;
    m选自0或1，n选自0、1、2或3，p选自0、1、2、3、4、5、6、7、8、9或10。m is selected from 0 or 1, n is selected from 0, 1, 2 or 3, and p is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  2. 如权利要求1所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其 药学上可接受的盐，其中R1选自H、C1-6烷基。The compound represented by formula I as claimed in claim 1, its optical isomer, isotopic derivative or A pharmaceutically acceptable salt, wherein R 1 is selected from H, C 1-6 alkyl.
  3. 如权利要求1-2任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，L1、L3独立地选自单键或C1-6烷基。The compound represented by formula I as claimed in any one of claims 1 to 2, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein L 1 and L 3 are independently selected from a single bond or a C 1-6 alkyl group.
  4. 如权利要求1-3任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，L5选自单键、O、S、NH、-CO-、-SO-或-SO2-。The compound represented by formula I according to any one of claims 1 to 3, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein L 5 is selected from a single bond, O, S, NH, -CO-, -SO- or -SO 2 -.
  5. 如权利要求1-4任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，L0、L2、L4分别独立地选自单键、C5-6环烷基、C5-6杂环烷基、C6-10芳基或C5-10杂芳基。The compound of formula I according to any one of claims 1 to 4, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein L 0 , L 2 and L 4 are independently selected from a single bond, a C 5-6 cycloalkyl group, a C 5-6 heterocycloalkyl group, a C 6-10 aryl group or a C 5-10 heteroaryl group.
  6. 如权利要求1-5任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，L0、L2、L4分别独立地选自单键、C5-6环烷基或C5-6杂环烷基。The compound of formula I as claimed in any one of claims 1 to 5, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein L 0 , L 2 and L 4 are independently selected from a single bond, a C 5-6 cycloalkyl group or a C 5-6 heterocycloalkyl group.
  7. 如权利要求1-6任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，L0、L2、L4分别独立地选自单键、环戊基、环己基、吡咯烷基、哌啶基、哌嗪基或吗啉基。The compound of formula I according to any one of claims 1 to 6, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein L 0 , L 2 and L 4 are independently selected from a single bond, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.
  8. 如权利要求1-7任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，环A、环B、环E分别独立地选自任选取代的苯基、萘基、吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、哒嗪基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、苯并噁唑基、吲哚基、喹啉基、异喹啉基或喹喔啉基，所述取代基如上所述。The compound of formula I according to any one of claims 1 to 7, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein ring A, ring B and ring E are independently selected from optionally substituted phenyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, benzoxazolyl, indolyl, quinolyl, isoquinolyl or quinoxalinyl, and the substituents are as described above.
  9. 如权利要求8所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，环A、环B、环E分别独立地选自任选取代的苯基或吡啶基，所述取代基如上所述。The compound represented by formula I as claimed in claim 8, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein ring A, ring B and ring E are independently selected from optionally substituted phenyl or pyridyl, and the substituents are as described above.
  10. 如权利要求1-9任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，环C选自任选取代的C6-10芳基或C5-10杂芳基，所述取代基如上所述。The compound represented by formula I according to any one of claims 1 to 9, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein ring C is selected from an optionally substituted C 6-10 aryl or C 5-10 heteroaryl, and the substituent is as described above.
  11. 如权利要求10所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，环C选自任选取代的苯基、吡啶基、嘧啶基、吡嗪基或哒嗪基，所述取代基如上所述。The compound of formula I as claimed in claim 10, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein ring C is selected from optionally substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, and the substituents are as described above.
  12. 如权利要求1-11任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素 衍生物或其药学上可接受的盐，环D选自任选取代的C3-8环烷基或C3-8杂环烷基，所述取代基如上所述。The compound represented by formula I according to any one of claims 1 to 11, its optical isomers, isotopes The derivative or a pharmaceutically acceptable salt thereof, wherein ring D is selected from optionally substituted C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, and the substituents are as described above.
  13. 如权利要求12所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，环D选自任选取代的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氧杂环丁基、四氢呋喃基、四氢噻吩基或四氢吡喃基，所述取代基如上所述。The compound of formula I as claimed in claim 12, its optical isomers, isotopic derivatives or pharmaceutically acceptable salts thereof, wherein ring D is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl or tetrahydropyranyl, and the substituents are as described above.
  14. 如权利要求13所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，环D选自任选取代的环丁基、环戊基或环己基，所述取代基如上所述。The compound represented by formula I as claimed in claim 13, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein ring D is selected from an optionally substituted cyclobutyl, cyclopentyl or cyclohexyl, and the substituent is as described above.
  15. 如权利要求1-14任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，所述化合物具有如式Ⅱ所示的结构：
    The compound of formula I according to any one of claims 1 to 14, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula II:
  16. 如权利要求1-15任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，所述化合物具有如式Ⅲ所示的结构：
    The compound of formula I according to any one of claims 1 to 15, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula III:
  17. 如权利要求1-16任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，所述化合物具有如式Ⅳ所示的结构：

    The compound of formula I according to any one of claims 1 to 16, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula IV:

  18. 如权利要求1-17任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，所述化合物具有如式Ⅴ所示的结构：
    The compound of formula I according to any one of claims 1 to 17, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula V:
  19. 如权利要求1-17任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，所述化合物具有如式Ⅵ所示的结构：
    The compound of formula I according to any one of claims 1 to 17, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula VI:
  20. 如权利要求1-17任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，所述化合物具有如式Ⅶ所示的结构：
    The compound of formula I according to any one of claims 1 to 17, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound has a structure as shown in formula VII:
  21. 如权利要求1-17任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，其中L选自

    The compound of formula I according to any one of claims 1 to 17, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein L is selected from

  22. 如权利要求1-21任一项所述的式Ⅰ所示的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐，所述化合物选自：

    The compound of formula I according to any one of claims 1 to 21, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

  23. 一种药物组合物，其包含权利要求1-22任一项所述的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂或载体。A pharmaceutical composition comprising the compound according to any one of claims 1 to 22, its optical isomer, isotopic derivative or pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients or carriers.
  24. 权利要求1-22任一项所述的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐或权利要求23所述的药物组合物在制备雄激素受体调节剂中的用途。Use of the compound according to any one of claims 1 to 22, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the preparation of an androgen receptor modulator.
  25. 权利要求1-22任一项所述的化合物、其光学异构体、同位素衍生物或其药学上可接受的盐或权利要求23所述的药物组合物在制备治疗与雄激素受体相关的疾病的药物中的用途。Use of the compound according to any one of claims 1 to 22, its optical isomer, isotopic derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 in the preparation of a medicament for treating diseases associated with androgen receptor.
  26. 权利要求25所述的用途，其特征在于所述的疾病为癌症、代谢紊乱性疾病、心脑血管疾病、高血脂或肥胖症。The use according to claim 25 is characterized in that the disease is cancer, metabolic disorder, cardiovascular and cerebrovascular disease, hyperlipidemia or obesity.
  27. 权利要求26所述的用途，其特征在于所述的癌症为前列腺癌、乳腺癌或膀 胱癌。 The use according to claim 26, characterized in that the cancer is prostate cancer, breast cancer or bladder cancer Bladder cancer.
PCT/CN2023/083548 2023-03-24 2023-03-24 Heterocyclic compound serving as androgen receptor modulator and use of heterocyclic compound WO2024197429A1 (en)

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