CN114736203A - Heterocyclic compounds as BCL-2 inhibitors - Google Patents

Heterocyclic compounds as BCL-2 inhibitors Download PDF

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Publication number
CN114736203A
CN114736203A CN202110017291.5A CN202110017291A CN114736203A CN 114736203 A CN114736203 A CN 114736203A CN 202110017291 A CN202110017291 A CN 202110017291A CN 114736203 A CN114736203 A CN 114736203A
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optionally substituted
hydrogen
alkyl
compound
methyl
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孔祥龙
周超
郑之祥
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Nanjing Innocare Pharma Tech Co ltd
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Nanjing Innocare Pharma Tech Co ltd
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Priority to PCT/CN2022/070756 priority patent/WO2022148439A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Abstract

The invention provides a heterocyclic compound as a BCL-2 inhibitor shown in a formula (I), a pharmaceutical composition containing the heterocyclic compound and application of the heterocyclic compound in treating or preventing related diseases and dysfunctions mediated by BCL-2, such as tumors. The invention also relates to a method for preparing the heterocyclic compound.

Description

Heterocyclic compounds as BCL-2 inhibitors
Technical Field
The present invention relates to heterocyclic compounds, pharmaceutical compositions containing them and their use as B-cell lymphoma-2 (BCL-2) inhibitors. More particularly, the present invention provides novel heterocyclic compounds that are inhibitors of BCL-2, pharmaceutical compositions containing such heterocyclic compounds, and uses of such heterocyclic compounds to treat or prevent diseases and disorders mediated by BCL-2, such as tumors. The invention also relates to a method for preparing the heterocyclic compound.
Background
The BCL-2 protein family is one of the core regulatory mechanisms of apoptosis (also called programmed cell death), and can receive and transmit Intrinsic intracellular signals or external environmental stress signals such as nutritional or hypoxic stress, DNA damage, oncogene over-activation, endoplasmic reticulum stress, etc., and mainly plays a dominant role in the Intrinsic pathway of apoptosis (Intrinsic pathway). BCL-2 (B-cell lymphoma-2) protein was first discovered in 1986 and expressed by the BCL-2 gene. The BCL-2 gene is a protooncogene, and the protein expressed therefrom is called a BCL-2 family protein. The protein of 27 BCL-2 families in human bodies can be divided into 3 subclasses according to function and sequence analysis, the first subclass is antagonistic to apoptosis and comprises BCL-XL, BCL-2, BCL-W, MCL-1 and BFL-1 which are mainly positioned on mitochondria to protect the mitochondria from stress damage; the other two subclasses are those that promote apoptosis, one of which is the ultimate performer of mitochondrial damage, including BAX and BAK. The rest of the genes are classified in BH3 subclass, and can directly sense various cell adversity stress signals. The dynamic balance of interactions between proteins that antagonize and promote apoptosis determines the life and death of a cell. BCL-2 protein for antagonizing apoptosis is closely related to tumors, and abnormal over-expression of BCL-2 family protein exists in about 50 percent of tumors (such as leukemia, rectal cancer, prostate cancer and the like), wherein abnormal BCL-2 activity exists widely in blood tumors. Multiple signal pathways such as JAK-STAT, NFkB and UPS (ubiquitin-proteasome system) can cause over-expression of BCL-2 protein for antagonizing apoptosis.
The high expression of BCL-2 family antagonistic apoptosis protein is related to drug resistance of various tumors, for example, the overexpression of BCL-2 antagonistic apoptosis protein can make tumor cells escape apoptosis caused by antitumor drugs, thereby causing drug resistance. Studies have shown that inhibition of BCL-2 family proteins can inhibit tumor neovascularization and thus tumor metastasis (Benjamin, D.; Isaac, J).et al.J. Clin. oncol. 2008, 26(25), 4180). Therefore, the target inhibition of the BCL-2 family anti-apoptosis protein can inhibit the occurrence, development and drug resistance of tumors.
Although more than 20 small molecule inhibitors targeting the BCL-2 family have been reported, the next step is toIn clinical experiments, few cases of Obatoclax of Tiwa achieve partial response in only 1 of 26 treated Chronic Lymphocytic Leukemia (CLL), have strong neurotoxicity, and the development is terminated in 2013; navitoclax (ABT-263) developed by Alberwein, although showing a good response rate of 50% in phase I dose ramp-up experiments in patients with relapsed or refractory lymphoid malignancies, also shows very strong targeted toxicity to BCL-XL: such as platelet lowering and severe anemia. Venetocalax (ABT-199), developed by Erbery in combination with Roche, is a highly selective inhibitor of BCL-2 (Andrew, J.; Joel, D).et al.Nature Medicine, 2013, 19(2), 202, has greatly improved Objective Remission Rate (ORR) and complete remission rate (CR) by combined administration with Ibrutinib and the like in the treatment of relapsed/refractory Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), Multiple Myeloma (MM) and the like (Valentin, R.; Grablob, S).et al.Blood, 2018, 132(12),1248), but has the toxic and side effects of leukopenia and thrombopenia, anemia, diarrhea, dizziness, fatigue, susceptibility to infection and the like, and serious toxic and side effects also comprise pneumonia, anemia, high fever and the like. There is therefore a need to develop selective BCL-2 inhibitors with high activity and low toxic side effects.
Disclosure of Invention
The present invention relates to compounds of formula (I), isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts thereof,
Figure 451962DEST_PATH_IMAGE001
wherein:
X1selected from optionally substituted C3-C6 cycloalkyl or optionally substituted 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, wherein said optional substituents are selected from hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S; preferably, X1Selected from optionally substituted C5-C6 cycloalkyl or optionally substituted C5-C6 cycloalkyl containing 1 or 2 substituents selected fromN, O, S, wherein the optional substituent is selected from the group consisting of hydroxy, C1-C4 alkyl, C1-C4 alkoxy, 4 or 5 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from N, O, S; further preferably, X1Selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1, 4-dioxane, piperidinyl, morpholinyl, wherein the optional substituents are selected from hydroxy, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl; most preferably, X1Is selected from (1)r,4r) -1-hydroxy-1-methylcyclohexan-4-yl group, (ii)), (S) -1, 4-dioxan-2-yl group, ((iii))R) -1, 4-dioxane-2-yl, tetrahydropyran-4-yl, 1- (oxetan-3-yl) piperidin-4-yl, (ii) aS) -4- (oxetan-3-yl) morpholin-2-yl;
X2selected from 5-6 membered heterocycloalkylene containing 1 or 2 heteroatoms selected from N, O, S, wherein the heterocycloalkylene is optionally substituted with 1 or 2C 1-C4 alkyl groups or halogen; preferably, X2Selected from 6-membered heterocycloalkylene containing 2N atoms, wherein the heterocycloalkylene is optionally substituted with 1 or 2C 1-C4 alkyl; further preferably, X2Is selected from
Figure 431419DEST_PATH_IMAGE002
Wherein said piperazinyl is optionally substituted with 1C 1-C4 alkyl; still further preferably, X2Is selected from
Figure 211156DEST_PATH_IMAGE003
Wherein said piperazinyl is optionally substituted with 1 methyl group; most preferably, X2Is selected from
Figure 606365DEST_PATH_IMAGE004
、
Figure 420738DEST_PATH_IMAGE005
；
R0Selected from hydrogen, halogen; preferably, R0Selected from hydrogen, fluorine, chlorine; most preferably, R0Selected from hydrogen, fluorine;
R1、R2each independently selected from hydrogen, C1-C6 alkyl; preferably, R1、R2Each independently selected from hydrogen, C1-C4 alkyl; further preferably, R1、R2Each independently selected from hydrogen, methyl, ethyl; most preferably, R1、R2Each independently selected from hydrogen, methyl;
n is selected from 1 to 4; preferably, n is selected from 1,3 or 4.
Preferably, the present invention relates to a compound of formula (I), as described above, an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1selected from optionally substituted C5-C6 cycloalkyl or optionally substituted 5-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, wherein said optional substituents are selected from hydroxy, C1-C4 alkyl, C1-C4 alkoxy, 4 or 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S;
X2selected from 6-membered heterocycloalkylene containing 2N atoms, wherein the heterocycloalkylene is optionally substituted with 1 or 2C 1-C4 alkyl groups;
R0selected from hydrogen, halogen;
R1、R2each independently selected from hydrogen, C1-C6 alkyl;
n is selected from 1-4.
Further preferably, the present invention relates to a compound of formula (I), as described above, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1, 4-dioxane, piperidinyl, morpholinyl, wherein the optional substituents are selected from hydroxy, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl;
X2is selected from
Figure 806982DEST_PATH_IMAGE006
Wherein said piperazinyl is optionally substituted with 1C 1-C4 alkyl;
R0selected from hydrogen, halogen;
R1、R2each independently selected from hydrogen, C1-C4 alkyl;
n is selected from 1-4.
Still further preferably, the present invention relates to a compound of formula (I), an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof as described above, wherein:
X1selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1, 4-dioxane, piperidinyl, morpholinyl, wherein said optional substituents are selected from hydroxy, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl;
X2is selected from
Figure 74015DEST_PATH_IMAGE007
Wherein said piperazinyl is optionally substituted with 1C 1-C4 alkyl;
R0selected from hydrogen, fluorine, chlorine;
R1、R2each independently selected from hydrogen, C1-C4 alkyl;
n is selected from 1,3 or 4.
More preferably, the present invention relates to a compound of formula (I), as described above, an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1is selected from (1)r,4r) -1-hydroxy-1-methylcyclohexan-4-yl group, ((iii)), (ii)S) -1, 4-dioxan-2-yl group, ((iii))R) -1, 4-dioxan-2-yl, tetrahydropyran-4-yl, 1- (oxetan-3-yl) piperidin-4-yl, (iii) a salt thereofS) -4- (oxetan-3-yl) morpholin-2-yl;
X2is selected from
Figure 272915DEST_PATH_IMAGE008
Wherein said piperazinyl is optionally substituted with 1 methyl group;
R0selected from hydrogen, fluorine;
R1、R2each independently selected from hydrogen, methyl, ethyl;
n is selected from 1,3 or 4.
Still further preferably, the present invention relates to a compound of formula (I), an isomer, a prodrug, a solvate, a stable isotopic derivative or a pharmaceutically acceptable salt thereof as described above, wherein:
X1is selected from (1)r,4r) -1-hydroxy-1-methylcyclohexan-4-yl group, ((iii)), (ii)S) -1, 4-dioxan-2-yl group, ((iii))R) -1, 4-dioxan-2-yl, tetrahydropyran-4-yl, 1- (oxetan-3-yl) piperidin-4-yl, (iii) a salt thereofS) -4- (oxetan-3-yl) morpholin-2-yl;
X2is selected from
Figure 941794DEST_PATH_IMAGE009
、
Figure 935158DEST_PATH_IMAGE010
；
R0Selected from hydrogen, fluorine;
R1、R2each independently selected from hydrogen, methyl;
n is selected from 1,3 or 4.
Still further preferably, the present invention relates to a compound of formula (I), as described above, an isomer, prodrug, solvate, stable isotopic derivative thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure 751804DEST_PATH_IMAGE011
Figure 488816DEST_PATH_IMAGE012
Figure 12201DEST_PATH_IMAGE013
Figure 442046DEST_PATH_IMAGE014
the present invention also relates to the use of a compound of formula (I), an isomer, a prodrug, a solvate, a stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof according to any one of the embodiments of the present invention in the manufacture of a medicament for use as a BCL-2 inhibitor.
The present invention also relates to the use of a compound of formula (I) as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease associated with BCL-2 mediated disorders, such as a tumour selected from the group consisting of hematological malignancies including acute lymphatic leukaemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma.
The present invention further relates to a pharmaceutical composition comprising a compound of formula (I) as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients.
The invention also relates to the use of a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or prevention of a related disease mediated by BCL-2, such as a tumor selected from the group consisting of hematological malignancies, including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma.
The present invention also relates to a method of treating or preventing a related disorder mediated by BCL-2, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the embodiments of the present invention or its isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition according to the invention, said related disease, such as a tumor, selected from hematological malignancies including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma.
Another aspect of the present invention relates to a compound according to any one of the embodiments of the present invention, or an isomer, prodrug, solvate, stable isotope derivative or pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a related disease mediated by BCL-2, such as a tumor selected from the group consisting of hematological malignancies including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma.
Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents and excipients for use in the treatment or prevention of a related disease mediated by BCL-2, such as a tumor selected from the group consisting of hematological malignancies, including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma.
Another aspect of the present invention relates to a compound of formula (I) as described in any one of the embodiments of the present invention or an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, for use as a medicament for the treatment and/or prevention of a related disease mediated by BCL-2. The BCL-2 mediated associated disease, for example a tumor, selected from hematological malignancies including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma.
According to the present invention, the drug may be in any pharmaceutical dosage form including, but not limited to, tablets, capsules, solutions, lyophilized formulations, injections.
The pharmaceutical preparations of the present invention may be administered in dosage units containing a predetermined amount of the active ingredient per dosage unit. Such units may contain, for example, from 0.5 mg to 1g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 300 mg, of a compound of the invention, depending on the condition to be treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparations may be administered in dosage units containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or sub-dose, or corresponding fraction thereof, of the active ingredient as indicated above. In addition, pharmaceutical formulations of this type may be prepared using methods well known in the pharmaceutical art.
The pharmaceutical formulations of the invention may be adapted for administration by any desired suitable method, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared, for example, by combining the active ingredient with one or more excipients or one or more adjuvants using all methods known in the pharmaceutical art.
Preparation process
The invention also provides a method for preparing the compound.
Scheme 1
Figure 683671DEST_PATH_IMAGE015
R0And X1As defined above;
the first step is as follows:
dissolving a compound (I) in chlorosulfonic acid, reacting for 10-20 hours under oil bath heating (120-150 ℃), cooling to room temperature, quenching with ice water, extracting with ethyl acetate, drying and concentrating an organic phase to obtain a crude product, dissolving the crude product in anhydrous tetrahydrofuran, dropwise adding ammonia water at low temperature (-80 to-60 ℃), continuously stirring for 1-5 hours, and acidifying with an acid such as hydrochloric acid to obtain a compound (II);
the second step is that:
dissolving the compound (II) and corresponding amine in a solvent (such as acetonitrile), adding a base (such as triethylamine or diisopropylethylamine, and the like), and stirring for 10-20 hours at the temperature of 25-60 ℃ under the protection of inert gas (such as nitrogen or argon) to obtain a compound (III).
Scheme 2
Figure 21111DEST_PATH_IMAGE016
R1、R2And n is as defined above;
the first step is as follows:
adding phosphorus oxychloride dropwise into ice bath under the protection of nitrogenN,NAfter dropwise adding, stirring at room temperature for 30 minutes, cooling to 0 ℃, dropwise adding a dichloromethane solution of the compound (IV), and reacting at room temperature-60 ℃ for 10-24 hours to obtain a compound (V);
the second step is that:
adding a compound (V), p-chlorobenzoic acid, alkali such as potassium carbonate, a phase transfer catalyst such as tetra-n-butylammonium bromide and a catalyst such as palladium acetate into a solvent such as water under the protection of nitrogen, vacuumizing the system, replacing with nitrogen for three times, heating to 40-100 ℃, and reacting for 2-10 hours to obtain a compound (VI);
the third step:
dissolving the compound (VI) in a solvent such as tetrahydrofuran or methanol, adding a reducing agent such as sodium borohydride, and stirring at room temperature for 1-5 hours to obtain a compound (VII);
the fourth step:
dissolving the compound (VII) in a solvent such as dichloromethane, adding a chlorinated reagent such as thionyl chloride, and stirring at room temperature for 10-24 hours to obtain a compound (VIII).
Scheme 3
Figure 664582DEST_PATH_IMAGE017
R0、R1、R2N and X1As defined above; r3Selected from H or methyl;
the first step is as follows:
compound (IX) (IX)Synthetic reference:Journal of Organic Chemistry84(8), 4814-4829, 2019) and the corresponding piperazine or methylpiperazine (X) are dissolved in a solvent (e.g. dimethyl sulfoxide) and a base such as dimethyl sulfoxide is added at room temperatureN,N-diisopropylethylamine, stirred at a temperature of 50-100 ℃ for 12-24 hours to obtain a compound (XI);
the second step is that:
dissolving compound (XI) and compound (VIII) in a solvent such as acetonitrile, and adding a base such as acetonitrileN,NHeating diisopropylethylamine to 50-90 ℃, and stirring for 8-24 hours to obtain a compound (XII);
the third step:
dissolving the compound (XII) in a solvent such as water or ethanol, adding an alkali such as lithium hydroxide, heating to 50-90 ℃, stirring for 1-5 hours, and acidifying with an acid such as hydrochloric acid to obtain a compound (XIII);
the fourth step:
compound (XIII), compound (III), a condensing agent such as 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and a base such as 4-dimethylaminopyridine are dissolved in a solvent such as dichloromethane, and stirred at room temperature for 12 to 36 hours to obtain compound (XIV).
Detailed Description
Definition of
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings. Groups not specifically defined in the present invention have meanings commonly represented in the art, which are well known to those skilled in the art.
The expression "Cx-Cy" used in the present invention represents a range of the number of carbon atoms, wherein x and y are both integers, for example C3-C8 cycloalkyl represents cycloalkyl having 3-8 carbon atoms, C0-C2 alkyl represents alkyl having 0-2 carbon atoms, wherein C0 alkyl means a single chemical bond.
In the present invention, the term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms, for example, straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the various branched chain isomers thereof, and the like. Alkyl groups may be optionally substituted or unsubstituted.
In the present invention, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, or may be a 3,4, 5, 6-membered ring. Non-limiting examples of monocyclic ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted.
In the present invention, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10, 3 to 8 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S (O) m (wherein m is an integer from 0 to 2), but not including the ring moiety of-O-O-, -O-S-or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms of which 1 to 4 are heteroatoms, more preferably a heterocyclyl ring comprising 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, most preferably a 5-or 6-membered ring of which 1 to 4 are heteroatoms, more preferably 1 to 3 are heteroatoms, most preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, piperidinyl, 4-piperidinyl, piperazinyl, 1, 4-dioxanyl, morpholinyl, 2-morpholinyl, 4-morpholinyl, thiomorpholinyl, pyranyl, tetrahydropyranyl, 4-tetrahydropyranyl, homopiperazinyl, dioxanyl, 2-dioxanyl, tetrahydrofuranyl and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. The heterocyclic group may be optionally substituted or unsubstituted.
In the present invention, the term "heterocyclylene" refers to a substituted or unsubstituted heterocyclic group having a core of two terminal monovalent groups resulting from the removal of one hydrogen atom from each of the two terminal atoms; the heterocyclyl group has the meaning as described hereinbefore. Non-limiting examples of "heterocyclylene" include pyrrolidinylene, piperidinyl, piperazinyl, morpholinylene, and the like.
In the present invention, the term "halogen" refers to fluorine, chlorine, bromine or iodine.
In the present invention, "optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
In the present invention, "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable in combination with a carbon atom having an unsaturated (e.g., olefinic) bond.
Such substituents include, but are not limited to, the various groups described previously.
The compounds claimed in the present invention include not only the compounds themselves, but also isomers, prodrugs, solvates, stable isotopic derivatives of the compounds or pharmaceutically acceptable salts thereof.
The term "pharmaceutical composition" as used herein means a mixture containing one or more of the isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts thereof, of the compounds of the present invention and other chemical components. Other components such as pharmaceutically acceptable carriers, diluents and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
The term "comprising" as used in the specification includes "consisting of ….
The "room temperature" of the invention means 15-30 ℃.
The "stable isotope derivative" of the present invention includes: an isotopically substituted derivative in which any hydrogen atom in the formula (I) is substituted by 1 to 5 deuterium atoms, an isotopically substituted derivative in which any carbon atom in the formula (I) is substituted by 1 to 3 carbon 14 atoms, or an isotopically substituted derivative in which any oxygen atom in the formula (I) is substituted by 1 to 3 oxygen 18 atoms.
The "pharmaceutically acceptable salts" of the present invention are described in Berge,et al.as discussed in "pharmaceutical acceptable salts", j. pharm. sci., 66, 1-19(1977), and as would be apparent to a pharmaceutical chemist, said salts are substantially non-toxic and provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion, etc.
The pharmaceutically acceptable salts of the present invention can be synthesized by a general chemical method.
In general, salts can be prepared by reacting the free base or acid with an equivalent stoichiometric amount or an excess of the acid (inorganic or organic) or base in a suitable solvent or solvent composition.
The term "prodrug" as used herein means that a compound is metabolized in vivo to the original active compound. Prodrugs are typically inactive substances or less active than the active parent compound, but may provide convenient handling, administration, or improved metabolic performance.
The "isomer" of the present invention means a tautomer, meso form, racemate, enantiomer, diastereomer, mixture form, etc. of the compound of the formula (I) of the present invention. All such isomers, including stereoisomers, geometric isomers, are included in the present invention. The geometric isomers include cis-trans isomers.
As used herein, "solvate" refers to the association of one or more solvent molecules with a compound of the present invention or a salt thereof. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, ethyl acetate, acetic acid, and the like.
The present invention includes any polymorph as well as any hydrate or other solvate of the compound or salt thereof.
In the present invention, the term "patient" generally refers to a mammal, particularly a human.
In the present invention, the term "tumor" includes benign tumors and malignant tumors, such as cancers.
In the present invention, the term "cancer" includes various tumors mediated by BCL-2, including, but not limited to, hematological malignancies including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, prostate cancer, rectal cancer, pancreatic cancer, brain glioma.
In the present invention, the term "therapeutically effective amount" is meant to include an amount of a compound of the present invention effective to treat or prevent the associated diseases mediated by BCL-2.
Examples
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
The structure of all compounds of the invention can be identified by nuclear magnetic resonance (1H NMR) and/or mass spectrometric detection (MS).
1H NMR chemical shifts (. delta.) are reported as PPM (parts per million). NMR was performed by Bruker AVANCE III-400MHz spectrometer. Suitable solvents are selected from deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), deuterated dimethyl sulfoxide (DMSO-d 6 ) Etc., tetramethylsilane as an internal standard (TMS).
Low resolution Mass Spectrometry (MS) was determined by an Agilent 1260 HPLC/6120 mass spectrometer using an Agilent ZORBAX XDB-C18, 4.6X 50 mm, 3.5 μm.
Gradient elution conditions one: 0-1 minute: 95% solvent a1 and 5% solvent B1, 1-2 min: 5% solvent a1 and 95% solvent B1; 2.01-2.50 minutes: 95% solvent a1 and 5% solvent B1. The percentages are volume percentages of a solvent based on the total solvent volume. Solvent a 1: 0.01% aqueous formic acid; solvent B1: 0.01% formic acid in acetonitrile; the percentages are the volume percent of solute in solution.
The thin-layer silica gel plate is generally selected from HSGF254 or GF254 silica gel plate of tobacco yellow sea or Qingdao. The column chromatography generally uses 100-200 or 200-300 mesh silica gel of the yellow sea of the tobacco pipe as a carrier.
Preparative liquid chromatography (prep-HPLC) using Waters SQD2 mass spectrometry directed to a high pressure liquid chromatography separator, XBridge-C18; 30X 150 mm preparation column, 5 μm;
the method comprises the following steps: acetonitrile-water (0.2% formic acid) flow rate 25 mL/min; the second method comprises the following steps: acetonitrile-water (0.8% ammonium bicarbonate) flow rate 25 mL/min;
known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Acros Organics, Aldrich Chemical Company, Shao Yuan Chemical technology (Accela ChemBio Inc), Shanghai Bide medicine, Shanghai Aladdin chemistry, Shanghai Michelle chemistry, Bailinger chemistry, Annaige chemistry, and the like.
In the examples, the solvents used in the reaction were all anhydrous solvents unless otherwise specified. Wherein the anhydrous tetrahydrofuran is commercial tetrahydrofuran, sodium block is used as a water removing agent, benzophenone is used as an indicator, the solution is refluxed until the solution is blue-purple under the protection of argon, and the solution is distilled and collected and stored at room temperature under the protection of argon. Other anhydrous solvents are available from Annaiji chemistry and carbofuran chemistry. All the anhydrous solvents were transferred and used under argon unless otherwise specified.
In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the reaction temperature was room temperature and the temperature range was 15 ℃ to 30 ℃ unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate systems. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and an acidic or basic reagent may be added for adjustment.
Intermediate 1
3-fluoro-5-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) benzenesulfonamides
Figure 999749DEST_PATH_IMAGE018
First step of
3, 4-difluoro-5-nitrobenzenesulfonamide
1, 2-difluoro-3-nitrobenzene (10.00 g, 62.89 mmol) was dissolved in chlorosulfonic acid (21 mL) and heated to 150 ℃ with stirring at reflux for 10 hours. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture in an ice bath to adjust the pH to about 7. Extraction was performed with dichloromethane (100 mL. times.3), and the organic phase was washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product of 3, 4-difluoro-5-nitrobenzenesulfonyl chloride. Isopropanol (200 mL) and ammonia (5 mL, 37%) were added to a 1000 mL three-necked flask and stirred at-78 ℃ for 10 minutes. The crude product, 3, 4-difluoro-5-nitrobenzenesulfonyl chloride, was dissolved in isopropanol (30 mL), slowly added dropwise to the above mixture of isopropanol and aqueous ammonia at-78 deg.C, stirred at-78 deg.C for two hours after the addition was completed, and diluted hydrochloric acid (1N) was added to adjust the pH of the system to about 6. Then the reaction mixture is heated to room temperature, decompressed and concentrated to remove most of the isopropanol solvent, pure water is added into the isopropanol solvent, solid is separated out, and a solid crude product is obtained by filtration. The crude product was purified by slurrying with dichloromethane to give the desired product 3, 4-difluoro-5-nitrobenzenesulfonamide (4.90 g, yellow solid). Yield: 33 percent.
1H NMR (400 MHz, DMSO-d 6 ) δ 8.38-8.36 (m, 1H), 8.29-8.26 (m, 1H), 7.84 (s, 2H)。
Second step of
3-fluoro-5-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) benzenesulfonamides
The compound 3, 4-difluoro-5-nitrobenzenesulfonamide (1.55 g, 6.51 mmol) and (tetrahydro-2)H-pyran-4-yl-methylamine (0.89 g, 7.73 mmol),N,NDiisopropylethylamine (3.91 g, 30.31 mmol) and acetonitrile (20.0 mL). Stirred at 40 ℃ for 2 hours. The solvent was spun off, the mixture quenched with 50 mL of water and extracted with ethyl acetate (60 mL. times.2). The combined organic phases were washed with saturated brine (50 mL. times.3). Separating out organic phase, drying with anhydrous sodium sulfate, filtering to remove drying agent, and removing solvent under reduced pressure to obtain crude product. Column chromatography purification (petroleum ether/ethyl acetate = 1: 1) to obtain the target product 3-fluoro-5-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) benzenesulfonamide (1.66 g, yellow solid). Yield: 76 percent.
MS m/z (ESI): 334 [M + 1];
1H NMR (400 MHz, DMSO-d 6 ) δ 8.33-8.30 (m, 2H), 7.76-7.74 (m, 1H), 7.45 (s, 2H), 3.86-3.84 (m, 2H), 3.50-3.45 (m, 2H), 3.29-3.23 (m, 3H), 1.59-1.57 (m, 2H), 1.25-1.20 (m, 2H)。
Synthesis of intermediate 2 Steps reference is made to intermediate 1, where the second step is performed with (S) -1, 4-dioxacycloalkane-2-methylamine instead of (tetrahydro-2H-pyran-4-yl) methylamine.
Figure 728670DEST_PATH_IMAGE019
Intermediate 3
3-fluoro-5-nitro-4- (((1- (3-oxetanyl) piperidin-4-yl) methyl) amino) benzenesulfonamide
Figure 807485DEST_PATH_IMAGE020
First step of
4- (((2-fluoro-6-nitro-4-sulfamoylphenyl) amino) methyl) piperidine-1-carboxylic acid tert-butyl ester
The compound 3, 4-difluoro-5-nitrobenzenesulfonamide (0.30 g, 1.26 mmol) and 4- (aminomethyl) piperidine-1-carboxylic acid tert-butyl ester (0.28 g, 1.28 mmol),N,NDiisopropylethylamine (0.47 g, 3.63 mmol) and acetonitrile (8 mL) were mixed and stirred at 40 ℃ for 2 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL. times.2). The combined organic phases were washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, the filtrate was dried by spinning, and the residue was purified by column chromatography (petroleum ether/acetic acid = 3: 2) to give the target product tert-butyl 4- (((2-fluoro-6-nitro-4-sulfamoylphenyl) amino) methyl) piperidine-1-carboxylate (0.49 g, yellow solid). Yield: 89 percent.
MS m/z (ESI): 433 [M + 1];
1H NMR (400 MHz, CD3OD) δ 8.41-8.37 (m, 1H), 7.64-7.60 (m, 1H), 4.02-4.00 (m, 2H), 3.47-3.44 (m, 2H), 2.67-2.64 (m, 2H), 1.75-1.66 (m, 3H), 1.35 (s, 9H), 1.14-1.03 (m, 2H)。
Second step of
3-fluoro-5-nitro-4- ((piperidin-4-ylmethyl) amino) benzenesulfonamide
The compound, tert-butyl 4- (((2-fluoro-6-nitro-4-sulfamoylphenyl) amino) methyl) piperidine-1-carboxylate (0.49 g, 1.12 mmol) was mixed with trifluoroacetic acid (3 mL) and dichloromethane (9 mL), and stirred at room temperature for 0.5 hour. The solvent was dried by evaporation, the pH of the mixture was adjusted to neutral with triethylamine, and the solvent was dried again to give crude 3-fluoro-5-nitro-4- ((piperidin-4-ylmethyl) amino) benzenesulfonamide (0.35 g, as a yellow oil). This mixture was used in the next reaction without purification. MS M/z (ESI) 333 [ M + 1];
the third step
3-fluoro-5-nitro-4- (((1- (3-oxetanyl) piperidin-4-yl) methyl) amino) benzenesulfonamide
Compound 3-fluoro-5-nitro-4- ((piperidin-4-ylmethyl) amino) benzenesulfonamide (0.35 g, 1.05 mmol), and oxetanyl-3-one (0.23 g, 3.15 mmol), sodium cyanoborohydride (0.23 g, 5.23 mmol) and methanol (8 mL) were mixed and stirred at ordinary temperature for 1.5 hours. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL. times.2). The organic phases were combined and washed with saturated brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, dried by spinning, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 3: 1) to give the desired product 3-fluoro-5-nitro-4- (((1- (3-oxetanyl) piperidin-4-yl) methyl) amino) benzenesulfonamide (0.32 g, yellow solid). Yield: 78 percent.
MS m/z (ESI): 389 [M + 1];
1H NMR (400 MHz, CD3OD) δ 8.47-8.46 (m, 1H), 7.72-7.70 (m, 1H), 4.68-4.65 (m, 2H), 4.60-4.59 (m, 2H), 3.57-3.55 (m, 2H), 3.49-3.45 (m, 1H), 2.83-2.80 (m, 2H), 1.89-1.78 (m, 3H), 1.42-1.20 (m, 4H)。
Intermediate 4
(3aR,7aS) -5- (chloromethyl) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-indene
Figure 367779DEST_PATH_IMAGE021
First step of
(3aR,7aS) -6-chloro-3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-indene-5-carbaldehyde
Will be provided withN,NDimethylformamide (8.76 g, 0.12 mol) and dry dichloromethane (300 mL) were mixed, the ice bath was cooled to 0 deg.C, and phosphorus oxychloride (13.86 g, 0.09 mol) was slowly added dropwise. Stirring for 30 minutes at 0 ℃ after the dropwise addition is finished, then returning to room temperature and stirring for 3 hours, cooling the ice bath to 0 ℃, and slowly dropwise adding the compound (3 a)S,7aR) -7 a-methyloctahydro-5H-inden-5-one (synthetic reference: tetrahedron)n Letters, 35(1), 171-174; 1994) (9.00 g, 0.06 mol) and anhydrous dichloromethane (50 mL), and after completion of the dropwise addition, the mixture was returned to room temperature and stirred for 48 hours. The mixture was quenched with saturated ammonium chloride solution (300 mL), the organic phase was separated, desolventized under reduced pressure, and the residue was combined with the aqueous phase and extracted with methyl tert-butyl ether (150 mL. times.3). The combined organic phases were washed with saturated brine (150 mL. times.2), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and the filtrate was desolventized under reduced pressure to give the desired product ((3 a)R,7aS) -6-chloro-3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1HIndene-5-carboxaldehyde (10.30 g, yellow liquid), yield: 88 percent. MS m/z (ESI): 199& 201 [M + 1]；
Second step of
(3aR,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-indene-5-carboxaldehyde
Compound ((3 a)R,7aS) -6-chloro-3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1HIndene-5-carboxaldehyde (10.30 g, 0.05 mol), 4-chlorobenzeneboronic acid (7.80 g, 0.05 mol) and water (300 mL) were mixed, and palladium acetate (1.13 g, 5.00 mmol), potassium carbonate (20.70 g, 0.15 mol) and tetrabutylammonium bromide (16.10 g, 0.05 mol) were added under argon protection, and stirred at 50 ℃ for 6 hours under argon protection. This mixture was quenched with water (100 mL) and methyl tert-butyl ether (200 mL). The organic phase was separated and the aqueous phase was extracted with methyl tert-butyl ether (150 mL. times.2). The combined organic phases were washed with saturated brine (150 mL. times.2), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. The filtrate is decompressed and desolventized to obtain a crude product, and the crude product is purified by flash column chromatography (petroleum ether/ethyl acetate = 95: 5) to obtain a target product (3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1HIndene-5-carboxaldehyde (4.00 g, yellow liquid). Yield: 28 percent.
MS m/z (ESI): 275 & 277 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 7.44-7.30 (m, 2H), 7.20-7.02 (m, 2H), 2.72-2.33 (m, 3H), 2.11-1.74 (m, 4H), 1.72-1.22 (m, 4H), 1.02 (s, 3H)。
The third step
((3aR,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methanol
Reacting a compound (3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1HIndene-5-carboxaldehyde (1.00 g, 3.65 mmol) and tetrahydrofuran (40 mL) were combined, sodium borohydride (0.28 g, 7.30 mmol) was added, and the mixture was stirred at room temperature for 1 hour. This mixture was quenched with saturated ammonium chloride solution (60 mL) and dichloromethane (60 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (30 mL. times.3). The combined organic phases were washed with saturated brine (80 mL. times.2), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. Decompressing and desolventizing the filtrate to obtain a target product ((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methanol (0.95 g, light yellow liquid). Yield: 94 percent. MS m/z (ESI): 259& 261 [M - 17];
The fourth step
(3aR,7aS) -5- (chloromethyl) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-indene
Compound ((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methanol (0.95 g, 3.44 mmol), thionyl chloride (3.0 mL) and dichloromethane (30 mL) were mixed and stirred at room temperature for 1 hour. Decompression desolventizing to obtain the target product (3 a)R,7aS) -5- (chloromethyl) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1HIndene (1.01 g, light yellow liquid). And (5) crude product. MS m/z (ESI) 295, 297& 299 [M + 1]。
Synthesis of intermediate 5 reference is made to the synthesis step of intermediate 4, where the first step is with (3 a)R,7aS) -7 a-methyloctahydro-5HInden-5-one (synthetic reference: Tetrahedron Letters, 35(1), 171-S,7aR) -7 a-methyloctahydro-5H-inden-5-one.
Figure 139426DEST_PATH_IMAGE022
Intermediate 6
(1R,6S) -4- (chloromethyl) -3- (4-chlorophenyl) -1-methylbicyclo [4.1.0]Hept-3-enes
Figure 90065DEST_PATH_IMAGE023
First step of
(1S,6R) -4-chloro-6-methylbicyclo [4.1.0]Hept-3-ene-3-carbaldehyde
Will be driedN,NDimethylformamide (4.66 g, 63.83 mmol) was added to dry dichloromethane (160 mL), and phosphorus oxychloride (9.76 g, 63.83 mmol) was slowly added dropwise at room temperature and stirred for 3 hours. Will (1)R, 6R) -1-methylbicyclo [4.1.0]Heptan-3-one (3.96 g, 31.92 mmol) (synthetic reference: Tetrahedron Letters, 60(11), 785-788; 2019) was dissolved in dry dichloromethane (80 mL), and the solution was slowly dropped into the reaction mixture and stirred at room temperature overnight. TLC dot plate detection of reaction completion, slowly dropwise adding the reaction solution to ice-cold saturated aqueous ammonium chloride solution, separating the organic phase, extracting the aqueous phase with dichloromethane (200 mL. times.2), combining the organic phases, washing with saturated brine (200 mL. times.2), drying the organic phase with anhydrous sodium sulfate, filtering, removing the solvent from the filtrate under reduced pressure to obtain crude product (1)S,6R) -4-chloro-6-methylbicyclo [4.1.0]Hept-3-ene-3-carbaldehyde (4.25 g, pale yellow oil). Yield: 28 percent.
1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 2.9-2.69 (m, 3H), 2.47-2.40 (m, 1H), 1.15 (s, 3H), 1.02-0.97 (m, 1H), 0.43-0.40 (m, 1H), 0.33-0.31 (m, 1H)。
Second step of
(1R,6S) -4- (4-chlorophenyl) -6-methylbicyclo [4.1.0]Hept-3-ene-3-carbaldehyde
Will (1)S,6R) -4-chloro-6-methylbicyclo [4.1.0]Hept-3-ene-3-carbaldehyde (0.45 g, 2.68 mmol), p-chlorobenzoic acid (0.50 g, 3.20 mmol), tetrabutylammonium bromide (1.30 g, 4.00 mmol) were dissolved in water (10 mL), and potassium carbonate (1.10 g, 8.00 mmol) and palladium acetate (0.06 g, 0.27 mmol) were added. Stirring was carried out at 45 ℃ for 3 hours under nitrogen. Cooling to room temperature, extracting with ethyl acetate(30 mL. times.3), the combined organic phases were washed with saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1: 10) to obtain the objective product (1)R, 6S) -4- (4-chlorophenyl) -6-methylbicyclo [4.1.0]Hept-3-ene-3-carbaldehyde (0.23 g, yellow oil).
MS m/z (ESI)：247 & 249 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.47 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 2.95-2.90 (m, 1H), 2.80-2.66 (m, 2H), 2.50-2.42 (m, 1H), 1.18 (s, 3H), 1.08-1.03 (m, 1H), 0.43-0.36 (m, 2H)。
The third step
((1S,6R) -4- (4-chlorophenyl) -6-methylbicyclo [4.1.0]Hept-3-en-3-ylmethanol
Will (1)R,6S) -4- (4-chlorophenyl) -6-methylbicyclo [4.1.0]Hept-3-ene-3-carbaldehyde (3.24 g, 13.10 mmol) was added to tetrahydrofuran (50 mL) and methanol (10 mL), and sodium borohydride (0.71 g, 19.70 mmol) was added in portions at 0 ℃. Stirred at room temperature for 1 hour. Quenching with saturated ammonium chloride solution (100 mL), extracting with ethyl acetate (50 mL. times.3), combining the organic phases, washing with saturated brine (50 mL. times.2), drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate to give the crude product ((1)S,6R) -4- (4-chlorophenyl) -6-methylbicyclo [4.1.0]Hept-3-en-3-yl) methanol (3.43 g, yellow oil). MS m/z (ESI): 249& 251 [M + 1]。
The fourth step
(1R,6S) -4- (chloromethyl) -3- (4-chlorophenyl) -1-methylbicyclo [4.1.0]Hept-3-enes
Will ((1)S,6R) -4- (4-chlorophenyl) -6-methylbicyclo [4.1.0]Hept-3-en-3-yl) methanol (3.43 g, 13.10 mmol) was dissolved in dry dichloromethane (100 mL) and addedN,NDimethylformamide (48 mg, 0.66 mmol). Thionyl chloride (3.12 g, 26.2 mmol) was dissolved in dichloromethane (50 mL), and the solution was slowly added dropwise to the reaction solution while cooling on ice, followed by stirring at room temperature for 3 hours. Detecting the reaction by TLC silica gel plate, and reducing pressureRemoving solvent, dissolving the crude product in dichloromethane, addingN,N-diisopropylethylamine (5 mL), stirred for 10 min, rotary evaporated to concentrate to give crude product (1)R,6S) -4- (chloromethyl) -3- (4-chlorophenyl) -1-methylbicyclo [4.1.0]Hept-3-ene (3.50 g, yellow oil).
1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0, 2H), 3.86 (s, 2H), 2.62-2.60 (m, 1H), 2.56-2.49 (m, 2H), 2.42-2.40 (m, 1H), 1.13 (s, 3H), 1.00-0.96 (m, 1H), 0.49-0.47 (m, 1H), 0.34-0.32 (m, 1H)。
Synthesis of intermediate 7 reference was made to the synthesis of intermediate 6, where the first step was with (1)S,6S) -1-methylbicyclo [4.1.0]Heptan-3-one (synthetic reference: Tetrahedron Letters, 60(11), 785-788; 2019) instead of (1)R,6R) -1-methylbicyclo [4.1.0]Hept-3-one.
Figure 972570DEST_PATH_IMAGE024
Intermediate 8
(4aS,8aR) -6- (chloromethyl) -7- (4-chlorophenyl) -4 a-methyl-1, 2,3,4,4a,5,8,8 a-octahydronaphthalene
Figure 325054DEST_PATH_IMAGE025
First step of
(4aS,8aR) -4 a-methyloctahydro-1H-spiro [ naphthalene-2, 2' - [1,3 ]]Dioxolanes]
Compound (4 a)S,8aR) -4 a-methylhexahydro-1H-spiro [ naphthalene-2, 2' - [1,3 ]]Dioxolanes]-5(3H) -ketones (synthetic reference: organic Letters, 20(1), 130-, (133; 2018) (3.36 g, 15.00 mmol), hydrazine hydrate (10.00 g, 0.18 mmol) and potassium hydroxide (8.40 g, 0.15 mmol) were added to diethylene glycol (120 mL), and the mixture was stirred at 240 ℃ for 2 hours and then cooled to room temperature. The reaction mixture was diluted with water (500 mL), the mixture was extracted with ethyl acetate (150 mL. times.3), and the organic phases were combined and separately saturated with water (200 mL) and waterAnd brine (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (4 a)S,8aR) -4 a-methyloctahydro-1H-spiro [ naphthalene-2, 2' - [1,3 ]]Dioxolanes](2.90 g, colorless oil). Yield: 92 percent.
1H NMR (400 MHz, CDCl3) δ 3.95-3.91 (m, 4H), 1.75-1.62 (m, 5H), 1.53-1.45 (m, 5H), 1.44-1.33 (m, 5H), 0.99 (s, 3H)。
Second step of
(4aS,8aR) -4 a-methyloctahydronaphthalene-2- (1)H) Ketones
Reacting the compound (4 a)S,8aR) -4 a-methyloctahydro-1H-spiro [ naphthalene-2, 2' - [1,3 ]]Dioxolanes](2.90 g, 13.80 mmol) was dissolved in tetrahydrofuran (20 mL), concentrated hydrochloric acid (37%, 10 mL) was added, and after stirring at room temperature for 1 hour, water (100 mL) was added for dilution, and the tetrahydrofuran was removed by concentration. The aqueous phase was extracted with methyl tert-butyl ether (50 mL. times.3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (4 a)S,8aR) -4 a-methyloctahydronaphthalene-2- (1)H) Ketone (2.00 g, colorless oil). Yield: 87.2 percent. MS M/z (ESI) 167 [ M + 1]]；
The third step
(4aR,8aS) -3-chloro-8 a-methyl-1, 4,4a,5,6,7,8,8 a-octahydronaphthalene-2-carbaldehyde
Phosphorus oxychloride (5.50 g, 36.00 mmol) was added dropwise to the ice bath under nitrogen protectionN,NAfter dropwise addition of dimethylformamide (5.30 g, 72.00 mmol) in dichloromethane (50 mL), the mixture was warmed to room temperature and stirred for 0.5 hour. Cooled again to 0 ℃ and the compound (4 a) is added dropwiseS,8aR) -4 a-methyloctahydronaphthalene-2- (1)H) Ketone (2.00 g, 12.00 mmol) was stirred at room temperature overnight. 40% aqueous sodium acetate (20 mL) was added and stirred at room temperature for 0.5 hour. The organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL. times.2), the combined organic phases were washed with water (30 mL. times.2) and saturated brine (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the product (4 a) (product X2, 4K)R,8aS) -3-chloro-8 a-methyl-1,4,4a,5,6,7,8,8 a-octahydronaphthalene-2-carbaldehyde (2.30 g, yellow oil). Yield: and 90 percent. MS m/z (ESI) 213& 215 [M + 1]；
The fourth step
(4aR,8aS) -3- (4-chlorophenyl)-8 a-methyl-1, 4,4a,5,6,7,8,8 a-octahydronaphthalene-2-carbaldehyde
Will (4 a)R,8aS) -3-chloro-8 a-methyl-1, 4,4a,5,6,7,8,8 a-octahydronaphthalene-2-carbaldehyde (2.30 g, crude product, 10.80 mmol), p-chlorobenzeneboronic acid (2.00 g, 13.00 mmol), potassium carbonate (4.50 g, 32.40 mmol), tetra-n-butylammonium bromide (3.50 g, 10.80 mmol) and palladium acetate (0.49 g, 2.20 mmol) were added to water (60 mL), the system was evacuated three times with nitrogen, warmed to 50 ℃ and stirred for 4 hours. Cooling to room temperature, extracting the reaction solution with ethyl acetate (50 mL. times.2), combining the organic phases, washing with saturated brine (50 mL), separating the organic phase, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the residue with silica gel column (0-5% ethyl acetate/petroleum ether) to obtain (4 a)R,8aS) -3- (4-chlorophenyl)-8a-Methyl radical-1,4,4a,5,6,7,8,8a-Octahydronaphthalene-2-carbaldehyde (0.90 g, pale yellow oil). Yield: 33.1 percent.
MS m/z (ESI): 289 & 291 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 7.39-7.32 (m, 2H), 7.18-7.11 (m, 2H), 2.61-2.52 (m, 1H), 2.45-2.35 (m, 1H), 2.23-2.13 (m, 1H), 1.86-1.78 (m, 1H), 1.78-1.65 (m, 1H), 1.50-1.37 (m, 3H), 1.33-1.04 (m, 5H), 0.89 (s, 3H)。
The fifth step
(4aR,8aS) -3- (4-chlorophenyl)-8a-Methyl radical-1,4,4a,5,6,7,8,8a-Octahydronaphthalene-2-methanol
Will (4 a)R,8aS) -3- (4-chlorophenyl)-8a-Methyl radical-1,4,4a,5,6,7,8,8a-Octahydronaphthalene-2-carbaldehyde (0.90 g, 3.10 mmol) was dissolved in a tetrahydrofuran/methanol mixed solution (v/v = 10/1, 11 mL), and sodium borohydride (0.24 g, 6.20 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction was quenched by the addition of saturated ammonium chloride solution (30 mL). Acetic acid for reaction solutionExtraction with ethyl ester (30 mL. times.2), combined organic phases washed with saturated brine (30 mL), organic phases dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give (4 a)R,8aS) -3- (4-chlorophenyl)-8a-Methyl radical-1,4,4a,5,6,7,8,8a-Octahydronaphthalene-2-methanol (0.63 g, yellow oil). Yield: 69.5 percent. MS m/z (ESI) 273& 275 [M - 17]；
The sixth step
(4aS,8aR) -6- (chloromethyl) -7- (4-chlorophenyl) -4 a-methyl-1, 2,3,4,4a,5,8,8 a-octahydronaphthalene
Will (4 a)R,8aS) -3- (4-chlorophenyl)-8a-Methyl radical-1,4,4a,5,6,7,8,8a-Octahydronaphthalene-2-methanol (0.63 g, 2.17 mmol) was dissolved in dichloromethane (20 mL), and thionyl chloride (0.77 g, 6.51 mmol) was added and stirred at room temperature overnight. Concentrating the reaction solution under reduced pressure to obtain (4 a)S,8aR) -6- (chloromethyl) -7- (4-chlorophenyl) -4 a-methyl-1, 2,3,4,4a,5,8,8 a-octahydronaphthalene (0.67 g, yellow oil). And (5) crude product.
1H NMR (400 MHz, CDCl3) δ7.34-7.28 (m, 2H), 7.17-7.11 (m, 2H), 4.00-3.84 (m, 2H), 2.36-2.26 (m, 2H), 2.09-1.98 (m, 2H), 1.86-1.80 (m, 1H), 1.73-1.65 (m, 2H), 1.49-1.30 (m, 6H), 0.97 (s, 3H)。
Synthesis of intermediate 9 reference was made to the synthesis of intermediate 8, where the first step was with (4 a)R,8aS) -4 a-methylhexahydro-1H-spiro [ naphthalene-2, 2' - [1,3 ]]Dioxolanes]-5(3H) -ketones (synthetic reference: organic Letters, 20(1), 130-S,8aR) -4 a-methylhexahydro-1H-spiro [ naphthalene-2, 2' - [1,3 ]]Dioxolanes]-5(3H) -a ketone.
Figure 851892DEST_PATH_IMAGE026
Intermediate 11
5- (chloromethyl) -6- (4-chlorophenyl) -2,3,3a,4,7,7 a-hexahydro-1H-indene
Figure 289826DEST_PATH_IMAGE027
First step of
6-carbonyl octahydro-1H-indene-5-carboxylic acid methyl ester
The compound dimethyl carbonate (0.45 g, 5.00 mol) and tetrahydrofuran (10 mL) were mixed, sodium hydride (0.08 g, 2.00 mol, 60% dispersion in mineral oil) was added in portions under argon, and stirred at 50 ℃ for 5 minutes. Then octahydro-5 is addedH-inden-5-one (synthetic reference: Advanced Synthesis)&Catalysis, 360(20), 3924 (3929), 2018) (0.14 g, 1.00 mol), stirred at 70 ℃ for 2 hours. The mixture was quenched with water (25 mL) and ethyl acetate (25 mL), the organic phase separated and the aqueous phase extracted with ethyl acetate (25 mL. times.2). The combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, and performing decompression desolventizing on the filtrate to obtain a crude product. The crude product is purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 30: 1) to give the desired product 6-carbonyloctahydro-1H-indene-5-carboxylic acid methyl ester (0.07 g, yellow liquid). Yield: 37 percent.
1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 2.61-2.57 (m, 1H), 2.22-2.18 (m, 2H), 2.02-1.97 (m, 2H), 1.76-1.70 (m, 3H), 1.45-1.40 (m, 3H), 1.18-1.12 (m, 2H)。
Second step of
6- (((trifluoromethyl) sulfonyl) oxo) -2,3,3a,4,7,7 a-hexahydro-1-olH-indene-5-carboxylic acid methyl ester
Reacting the compound 6-carbonyl octahydro-1HMethyl (0.07 g, 0.37 mmol) indene-5-carboxylate, 1,1, 1-trifluoro-acetic acidN-phenyl-N- ((trifluoromethyl) sulfonyl) methanesulfonamide (0.21 g, 0.6 mmol), potassium carbonate (0.14 g, 1.0 mmol),N,N-dimethylformamide (3 mL) and tetrahydrofuran (3 mL) were combined and stirred at 45 ℃ for 15 hours under argon. After cooling to room temperature, the mixture was quenched with water (25 mL) and ethyl acetate (25 mL), the organic phase was separated and the aqueous phase was extracted with ethyl acetate (25 mL. times.2). The combined organic phases were washed with saturated brine (50 mL. times.2). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the desiccant, filtering to obtain filtrateDecompressing and desolventizing to obtain a crude product. The crude product was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate = 30: 1) to afford the desired product 6- (((trifluoromethyl) sulfonyl) oxo) -2,3,3a,4,7,7 a-hexahydro-1H-indene-5-carboxylic acid methyl ester (37 mg, yellow liquid). Yield: 57 percent. MS m/z (ESI): 329 [ M + 1]]；
The third step
6- (4-chlorophenyl) -2,3,3a,4,7,7 a-hexahydro-1-carboxylic acidH-indene-5-carboxylic acid methyl ester
The compound (6- (((trifluoromethyl) sulfonyl) oxo) -2,3,3a,4,7,7 a-hexahydro-1HMethyl indene-5-carboxylate (37 mg, 0.20 mmol), 4-chlorobenzeneboronic acid (50 mg, 0.30 mmol), ethylene glycol dimethyl ether (4 mL), and methanol (2 mL) were mixed, and tetrakis (triphenylphosphine) palladium (20 mg, 0.02 mmol), cesium fluoride (80 mg, 0.50 mmol) and reacted at 70 ℃ for 15 hours under argon protection were added under argon protection. Cooled to room temperature and the mixture quenched with water (25 mL) and ethyl acetate (25 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (25 mL. times.2). The combined organic phases were washed with saturated brine (50 mL. times.2). Drying with anhydrous sodium sulfate, filtering to remove the drying agent, desolventizing the filtrate under reduced pressure to obtain a crude product, and purifying the crude product with a silica gel column (petroleum ether/ethyl acetate = 30: 1) to obtain the target product 6- (4-chlorophenyl) -2,3,3a,4,7,7 a-hexahydro-1H-indene-5-carboxylic acid methyl ester (40 mg, yellow liquid). Yield: 65 percent.
MS m/z (ESI)：291 & 293 [M + 1]；
1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 3.45 (s, 3H), 2.89-2.85 (m, 1H), 2.41-2.38 (m, 1H), 2.27-2.23 (m, 1H), 2.16-2.12 (m, 1H), 2.00-1.96 (m, 2H), 1.73-1.68 (m, 3H), 1.47-1.39 (m, 3H)。
The fourth step
(6- (4-chlorophenyl) -2,3,3a,4,7,7 a-hexahydro-1-ylH-inden-5-yl) methanol
The compound 6- (4-chlorphenyl) -2,3,3a,4,7,7 a-hexahydro-1HMethyl-indene-5-carboxylate (40 mg, 0.17 mmol) and tetrahydrofuran (3 mL) were mixed and the temperature dropped to-15 ℃ in an ice salt bath and lithium aluminum hydride (10 mg, 0.30 mmol) was added slowly in portionsl), after the addition was completed, the temperature was naturally raised to room temperature, and the mixture was stirred for 3 hours. Quench with hydrochloric acid (1M, 0.30 mmol, 0.3 mL). The mixture was extracted with methylene chloride (25 mL. times.3), and the combined organic phases were washed with saturated brine (25 mL. times.3). Dried over anhydrous sodium sulfate and filtered to remove the drying agent. The filtrate is decompressed and desolventized to obtain the target product (6- (4-chlorphenyl) -2,3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methanol (40 mg, light yellow liquid), yield: 98 percent. MS m/z (ESI) 245& 247 [M - 17]。
The fifth step
5- (chloromethyl) -6- (4-chlorophenyl) -2,3,3a,4,7,7 a-hexahydro-1H-indene
The compound (6- (4-chlorphenyl) -2,3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methanol (40 mg, 0.13 mmol), thionyl chloride (0.1 mL) and dichloromethane (3 mL) were mixed and stirred at room temperature for 1 hour. Decompression desolventizing to obtain the target product 5- (chloromethyl) -6- (4-chlorphenyl) -2,3,3a,4,7,7 a-hexahydro-1HIndene (40 mg, light yellow liquid), crude. MS m/z (ESI): 281, 283& 285 [M + 1]。
Intermediate 12
(R)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (3-methylpiperazin-1-yl) benzoic acid methyl ester
Figure 772760DEST_PATH_IMAGE028
(R)-2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (3-methylpiperazin-1-yl) benzoic acid methyl ester
Compound 2- ((1)H-pyrrolo [2,3-b ] s]Pyridin-5-yl) oxo) -4-fluorobenzoic acid methyl ester (synthesis reference: journal of Organic Chemistry, 84(8), 4814-R) -2-methylpiperazine (3.00 g, 30.00 mmol),N,NDiisopropylethylamine (3.12 g, 24.18 mmol) and dimethyl sulfoxide (20 mL). Stirred at 60 ℃ for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (60 mL. times.2). The combined organic phases were washed with saturated brine (50 mL. times.3). The organic phase was dried over anhydrous sodium sulfate, andfiltering to remove the drying agent, and carrying out decompression and desolventizing to obtain a crude product. Column chromatography purification (dichloromethane/methanol = 90: 10) gives the desired product (R)-2-((1H-pyrrolo [2,3-b ] s]Pyridin-5-yl) oxo) -4- (3-methylpiperazin-1-yl) benzoic acid methyl ester (2.55 g, yellow solid). Yield: 70 percent.
MS m/z (ESI): 367 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.92 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.36-7.35 (m, 1H), 6.66-6.63 (m, 1H), 6.43 (d, J = 1.6 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 3.79 (s, 3H), 3.54-3.48 (m, 2H), 3.05-3.02 (m, 1H), 2.93-2.84 (m, 2H), 2.77-2.71 (m, 1H), 2.42-2.37 (m, 1H), 1.08 (d, J = 6.4 Hz, 3H)。
Example 1
2-((1HPyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
Figure 245330DEST_PATH_IMAGE029
First step of
2-((1H-pyrrolo [2,3-b ] s]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) benzoic acid methyl ester
Reacting a compound (3 a)R,7aS) -5- (chloromethyl) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-indene (intermediate 4) (1.01 g, 3.44 mmol), 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (piperazin-1-yl) benzoic acid methyl ester (synthesis reference: WO 2010138588A 2) (1.21 g, 3.44 mmol),N,Ndiisopropylethylamine (1.80 g, 13.76 mmol) and acetonitrile (30 mL) were mixed and stirred at 75 ℃ for 16 h. Cooling to room temperature, adding water (100 mL)Diluted, extracted with ethyl acetate (100 mL. times.2), and the combined organic phases were washed with saturated brine (100 mL). Drying the organic phase with anhydrous sodium sulfate, filtering to remove the drying agent, performing vacuum desolventizing on the filtrate to obtain a crude product, and purifying the crude product by flash column chromatography (petroleum ether/ethyl acetate = 1: 1) to obtain the target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) benzoic acid methyl ester (0.95 g, white solid). Yield: 45 percent.
MS m/z (ESI): 611 & 613 [M + 1];
1H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.39-7.33 (m, 1H), 7.25-7.21 (m, 2H), 6.99-6.90 (m, 2H), 6.60-6.58 (m, 1H), 6.45-6.43 (m, 1H), 6.27 (s, 1H), 3.78 (s, 3H), 3.24-3.02 (m, 4H), 2.90-2.65 (m, 2H), 2.45-1.88 (m, 6H), 1.83-1.50 (m, 6H), 1.46-1.19 (m, 3H), 1.00 (s, 3H)。
Second step of
(2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) benzoic acid
Will 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) benzoic acid methyl ester (0.95 g, 1.56 mmol), sodium hydroxide (0.30 g, 7.50 mmol), ethanol (20 mL) and water (1 mL) were mixed and stirred at 80 ℃ for 1 hour. The solution was desolventized under reduced pressure, and water (30 mL) and hydrochloric acid (1M, 15 mL) were added to the residue. The mixture was extracted with methylene chloride (30 mL. times.3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered to remove the drying agent. Decompression desolventizing to obtain a target product (2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) benzoic acid (0.90 gWhite solid), yield: 97 percent. MS m/z (ESI) 597& 599 [M + 1];
The third step
2-((1H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide
Will (2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) benzoic acid (0.50 g, 1.00 mmol), 3-nitro-4- (((tetrahydro-2)H-pyran-4-yl) methyl) amino) benzenesulfonamide (0.44 g, 1.40 mmol) (synthesis reference: WO 2018041248A 1), 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.38 g, 2.00 mmol), 4-dimethylaminopyridine (0.12 g, 1.00 mmol), triethylamine (0.20 g, 2.00 mmol) and dichloromethane (60 mL) were mixed and stirred at room temperature for 16 hours. Water (50 mL) was added for dilution, the organic phase was separated, the aqueous phase was extracted with dichloromethane (50 mL. times.2), and the combined organic phases were washed with saturated brine (50 mL). Drying with anhydrous sodium sulfate, filtering, removing solvent from the filtrate under reduced pressure to obtain crude product, and purifying the residue by flash column chromatography (dichloromethane/methanol = 97: 3) to obtain the target product 2- ((1)H-pyrrolo [2,3-b]Pyridin-5-yl) oxo) -4- (4- (((3 a)R,7aS) -6- (4-chlorophenyl) -3 a-methyl-2, 3,3a,4,7,7 a-hexahydro-1H-inden-5-yl) methyl) piperazin-1-yl) -N- ((3-nitro-4- (((tetrahydro-2))H-pyran-4-yl) methyl) amino) phenyl) sulfonyl) benzamide 1 (0.27 g, light yellow solid), yield: 30 percent.
MS m/z (ESI): 894 & 896 [M + 1];
1H NMR (400 MHz, CDCl3) δ 10.35-9.99 (m, 2H), 8.89 (s, 1H), 8.52 (s, 1H), 8.31-8.11 (m, 2H), 8.00-7.86 (m, 1H), 7.71 (s, 1H), 7.50 (s, 1H), 7.31-7.14 (m, 2H), 6.99-6.78 (m, 3H), 6.64-6.39 (m, 2H), 5.99 (s, 1H), 4.19-3.91 (m, 2H), 3.53-3.37 (m, 2H), 3.33-3.21 (m, 2H), 3.16-3.01 (m, 4H), 2.96-2.65 (m, 2H), 2.47-2.13 (m, 5H), 2.10-1.87 (m, 3H), 1.83-1.69 (m, 4H), 1.67-1.49 (m, 3H), 1.46-1.21 (m, 5H), 0.98 (s, 3H)。
Synthetic procedures for examples 2 to 31 reference was made to the procedure of example 1.
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Biological experiments
Assay for the inhibition of BCL-2 biological Activity
Evaluation of the Effect of the Compounds of the invention on the biological Activity of BCL-2 Using fluorescence polarization assay
The experimental methods are summarized as follows:
the effect of a compound on the biological activity of BCL-2 was assessed by examining the effect of the compound on the binding activity of BCL-2 and leukemia pro-apoptotic protein (BIM) using an affinity assay method based on the principle of fluorescence polarization. The reaction buffer contained the following components: PBS (pH 7.4, 3mM Na)2HPO4、155mM NaCl、1mM KH2PO4) 1mM DTT; the human recombinant Bcl-2 protein (the product number is 10195-H08E) is purchased from Beijing Yiqiao Shenzhou biotechnology limited and diluted to 5nM by reaction buffer; FITC-labeled BIM polypeptide was purchased from Nanjing King-Share Biotech, Inc. and diluted to 5nM in reaction buffer.
Compounds were dissolved in 100% DMSO diluted to 0.1, 1, 10 μ M, and then serially diluted 4-fold with DMSO to minimum concentrations of 0.0061, 0.061, 0.61nM, 50-fold each concentration point using reaction buffer.
To a black 384-well assay plate, 3. mu.L of the compound solution and 12. mu.L of BCL-2 solution were added, mixed well and incubated at room temperature for 15 minutes. Then, 15. mu.L of FITC-BIM solution was added, and the reaction mixture was incubated at room temperature for 30 minutes in the absence of light, and then immediately subjected to detection of fluorescence polarization on an Envision multifunctional microplate reader (Perkin Elmer) at 480nm as an excitation wavelength and 535nm as an emission wavelength. In this experiment, the BCL-2 protein was not added as a negative control (100% inhibition), and the BCL-2 protein but not the compound was added as a positive control (0% inhibition). The percent inhibition of BCL-2 affinity by a compound can be calculated using the following equation:
compound IC50Values were calculated from 8 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:
Y = Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))
wherein Y is the inhibition percentage, X is the logarithm value of the concentration of the compound to be detected, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.
Assay for the inhibition of the biological Activity of BCL-XL
Evaluation of the Effect of the Compounds of the invention on the biological Activity of BCL-XL Using fluorescence polarization assay
The experimental methods are summarized as follows:
an affinity assay method using fluorescence polarization principles assesses the effect of a compound on the biological activity of BCL-XL by detecting its effect on the binding activity of BCL-XL and BIM. The reaction buffer contained the following components: PBS (pH 7.4, 3mM Na)2HPO4、155mM NaCl、1mM KH2PO4) 1mM DTT; the humanized recombinant Bcl-XL protein (cargo number 10455-H08E) was purchased from Beijing Yiqian Shenzhou Biotechnology Co., Ltd and diluted to 10nM by reaction buffer; FITC-labeled BIM polypeptide was purchased from Nanjing King-Share Biotech, Inc. and diluted to 10nM in reaction buffer.
Compounds were dissolved in 100% DMSO diluted to 1 μ M and then serially diluted 4-fold with DMSO to a minimum concentration of 0.061nM, 50-fold each concentration point using reaction buffer.
To a black 384-well assay plate, 3. mu.L of the compound solution and 12. mu.L of BCL-XL solution were added, mixed well and incubated at room temperature for 15 minutes. Then, 15. mu.L of FITC-BIM solution was added, and the reaction mixture was incubated at room temperature for 30 minutes in the absence of light, and then immediately subjected to detection of fluorescence polarization on an Envision multifunctional microplate reader (Perkin Elmer) at 480nm as an excitation wavelength and 535nm as an emission wavelength. In this experiment, the BCL-XL protein was not added as a negative control (100% inhibition) and the BCL-XL protein but not the compound was added as a positive control (0% inhibition). The percent inhibition of BCL-XL affinity by a compound can be calculated using the following equation:
compound IC50Values were calculated from 8 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:
Y = Bottom+(Top-Bottom)/(1+10^((logIC50-X)*slope factor))
wherein Y is the inhibition percentage, X is the logarithm value of the concentration of the compound to be detected, Bottom is the maximum inhibition percentage, Top is the minimum inhibition percentage, and slope factor is the curve slope coefficient.
RS4 half the effective inhibitory concentration IC of 11 cells (acute lymphoblastic leukemia cells)50Measurement of (2)
The effect of the compounds of the invention on the proliferation of RS4;11 cells was evaluated using a luminescence cell viability assay.
The experimental methods are summarized as follows:
the cell proliferation of RS4, 11 was detected using CellTilter-glo (CTG) assay kit by detecting ATP, a key indicator of viable cell metabolism, using a unique, highly sensitive and stable luciferase that produces a luminescent signal proportional to the number of viable cells in the culture medium.
The CellTilter-Glo reagent (Promega, G7572) consists of CellTilter-Glo freeze-dried powder and CellTilter-Glo buffer solution, and the freeze-dried powder is dissolved in the buffer solution when in use.
RS4, 11 cell (ATCC, CRL-1873) cultureIn RPMI1640 complete medium (Thermofeisher, 72400-047) containing 10% FBS (GBICO, 10099-141) and 100 units/ml streptomycin mixed solution (Thermofeisher, 15140122), when the coverage of cells in the culture container reaches 80-90%, the cells were digested and blown off with 0.25% trypsin (containing EDTA) (Thermofeisher, Cat. 25200056) and planted in white 384-well plates (Thermofeisher, Cat. 164610), and then the 384-well plates were placed at 37 ℃ and 5% CO2Was cultured overnight in an incubator. Compounds were dissolved in 100% DMSO diluted to 5mM and then serially diluted 4-fold in DMSO to a minimum concentration of 0.061 μ M, each concentration point diluted 50-fold with FBS-free RPMI1640 medium. If the compound IC50The values are very low and the initial concentration of the compound can be reduced. After overnight, 3 μ L of the diluted compound was added to each well and mixed by gentle centrifugation, wherein the cell-free group served as negative control (100% inhibition) and the 0.2% DMSO group served as positive control (0% inhibition). The 384 well plate was placed at 37 ℃ in 5% CO2The incubation was continued in the incubator, after 48 hours the cells were allowed to equilibrate to room temperature, 15. mu.L of CTG reagent was added to each well, the plates were gently shaken for 3 minutes to ensure adequate cell lysis, allowed to stand for 10 minutes to stabilize the luminescence signal, and the luminescence signal was read using EnVision (Perkin Elmer).
The percentage of inhibition of RS4, 11 cell proliferation by the compound can be calculated by the following formula:
percent inhibition =100-
Compound IC50Values were calculated from 8 concentration points using XLfit (ID Business Solutions ltd., UK) software by the following formula:
Y = Bottom + (Top- Bottom)/(1+10^((LogIC50-X) * slope factor))
wherein Y is the percentage of inhibition, Bottom is the Bottom plate of the curve, Top is the Top plate of the curve, and X is the logarithm of the concentration of the compound to be measured.
The results of the in vitro BCL-2 and BCL-XL protein activity detection experiments are shown in Table 1 below, and the results of the cell experiments are shown in Table 2 below.
Table 1: BCL-2 and BCL-XL protein activity detection result
Compound numbering FP BCL-2 IC50 (nM) FP BCL-XL IC50 (nM)
1 6.14 >1000
2 9.13 >1000
3 2.62 >1000
4 4.01 >1000
5 2.46 >1000
6 3.53 >1000
7 1.7 >1000
8 12.15 >1000
9 8.25 >1000
10 14.51 >1000
11 7.37 >1000
12 7.14 >1000
13 3.28 >1000
14 7.03 >1000
15 3.49 >1000
16 2.9 >1000
17 5.39 >1000
18 17.68 >1000
19 9.22 >1000
20 15.04 >1000
21 19.53 >1000
22 7.14 >1000
23 2.11 >1000
24 4.99 >1000
25 10.13 >1000
26 0.58 >1000
27 0.85 >1000
28 3.99 >1000
29 2.89 >1000
30 1.5 >1000
31 1.2 >1000
Table 2: RS4, 11 cell activity test results
Compound number RS4;11 IC50 (nM)
1 19.5
3 9.0
5 4.75
6 10.77
7 2.8
8 83
9 29
10 30
11 41
12 37
13 12
14 19
15 37
16 11
17 15
23 14
24 16
25 37
26 4.5
27 16
28 5.8
29 6
30 26
31 13
Venetoclax 5.5
As can be seen from the experimental results, the compounds of the examples of the invention can effectively and selectively inhibit the activity of BCL-2, and have weak inhibition on BCL-XL. Can be used for treating various cancers caused by abnormal over-expression of BCL-2 family protein: especially including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma, etc. And avoids toxic side effects, such as platelet lowering, caused by BCL-XL inhibition. Part of the compounds can also effectively inhibit RS4 and 11 acute lymphocyte proliferation. Has strong inhibition effect on malignant hematological diseases such as acute lymphatic leukemia and the like.
It will be evident to those skilled in the art that the disclosure is not limited to the exemplary embodiments described above, and that it may be embodied in other specific forms without departing from the essential characteristics of the present disclosure. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than to the foregoing embodiments, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims (10)

1. A compound of formula (I), an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof,
Figure 236859DEST_PATH_IMAGE001
wherein:
X1selected from optionally substituted C3-C6 cycloalkyl or optionally substituted 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, wherein said optional substituents are selected from hydroxy, halogen, C1-C6 alkyl, C1-C6 alkoxy, 3-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S; preferably, X1Selected from optionally substituted C5-C6 cycloalkyl or optionally substituted 5-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, wherein said optional substituents are selected from hydroxy, C1-C4 alkyl, C1-C4 alkoxy, 4 or 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S; further preferably, X1Selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1, 4-dioxane, piperidinyl, morpholinyl, wherein said optional substituents are selected from hydroxy, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl; most preferably, X1Is selected from (1)r,4r) -1-hydroxy-1-methylcyclohexaneAlk-4-yl group, (S) -1, 4-dioxan-2-yl group, ((iii))R) -1, 4-dioxan-2-yl, tetrahydropyran-4-yl, 1- (oxetan-3-yl) piperidin-4-yl, (iii) a salt thereofS) -4- (oxetan-3-yl) morpholin-2-yl;
X2selected from 5-6 membered heterocycloalkylene containing 1 or 2 heteroatoms selected from N, O, S, wherein the heterocycloalkylene is optionally substituted with 1 or 2C 1-C4 alkyl groups or halogen; preferably, X2Selected from 6-membered heterocycloalkylene containing 2N atoms, wherein the heterocycloalkylene is optionally substituted with 1 or 2C 1-C4 alkyl groups; further preferably, X2Is selected from
Figure 622841DEST_PATH_IMAGE002
Wherein said piperazinyl is optionally substituted with 1C 1-C4 alkyl; still further preferably, X2Is selected from
Figure 402578DEST_PATH_IMAGE003
Wherein said piperazinyl is optionally substituted with 1 methyl group; most preferably, X2Is selected from
Figure 532208DEST_PATH_IMAGE004
、
Figure 346580DEST_PATH_IMAGE005
；
R0Selected from hydrogen, halogen; preferably, R0Selected from hydrogen, fluorine, chlorine; most preferably, R0Selected from hydrogen, fluorine;
R1、R2each independently selected from hydrogen, C1-C6 alkyl; preferably, R1、R2Each independently selected from hydrogen, C1-C4 alkyl; further preferably, R1、R2Each independently selected from hydrogen, methyl, ethyl; most preferably, R1、R2Each independently selected from hydrogen, methyl;
n is selected from 1-4; preferably, n is selected from 1,3 or 4.
2. A compound of formula (I) according to claim 1, an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1selected from optionally substituted C5-C6 cycloalkyl or optionally substituted 5-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S, wherein said optional substituents are selected from hydroxy, C1-C4 alkyl, C1-C4 alkoxy, 4 or 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from N, O, S;
X2selected from 6-membered heterocycloalkylene containing 2N atoms, wherein the heterocycloalkylene is optionally substituted with 1 or 2C 1-C4 alkyl groups;
R0selected from hydrogen, halogen;
R1、R2each independently selected from hydrogen, C1-C6 alkyl;
n is selected from 1-4.
3. A compound of formula (I) according to claim 1, an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1, 4-dioxane, piperidinyl, morpholinyl, wherein the optional substituents are selected from hydroxy, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl;
X2is selected from
Figure 169042DEST_PATH_IMAGE006
Wherein said piperazinyl is optionally substituted with 1C 1-C4 alkyl;
R0selected from hydrogen, halogen;
R1、R2each independently selected from hydrogen, C1-C4 alkyl;
n is selected from 1-4.
4. A compound of formula (I) according to claim 1, an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1selected from optionally substituted cyclohexyl or optionally substituted tetrahydropyranyl, 1, 4-dioxane, piperidinyl, morpholinyl, wherein said optional substituents are selected from hydroxy, C1-C4 alkyl, oxetanyl or tetrahydrofuranyl;
X2is selected from
Figure 406382DEST_PATH_IMAGE007
Wherein said piperazinyl is optionally substituted with 1C 1-C4 alkyl;
R0selected from hydrogen, fluorine, chlorine;
R1、R2each independently selected from hydrogen, C1-C4 alkyl;
n is selected from 1,3 or 4.
5. A compound of formula (I) according to claim 1, an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1is selected from (1)r,4r) -1-hydroxy-1-methylcyclohexan-4-yl group, ((iii)), (ii)S) -1, 4-dioxan-2-yl group, ((iii))R) -1, 4-dioxan-2-yl, tetrahydropyran-4-yl, 1- (oxetan-3-yl) piperidin-4-yl, (iii) a salt thereofS) -4- (oxetan-3-yl) morpholin-2-yl;
X2is selected from
Figure 605282DEST_PATH_IMAGE008
Wherein said piperazinyl is optionally substituted with 1 methyl group;
R0selected from hydrogen, fluorine;
R1、R2each independently selected from hydrogen, methyl, ethyl;
n is selected from 1,3 or 4.
6. A compound of formula (I) according to claim 1, an isomer, prodrug, solvate, stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein:
X1is selected from (1)r,4r) -1-hydroxy-1-methylcyclohexan-4-yl group, ((iii)), (ii)S) -1, 4-dioxan-2-yl group, ((iii))R) -1, 4-dioxan-2-yl, tetrahydropyran-4-yl, 1- (oxetan-3-yl) piperidin-4-yl, (iii) a salt thereofS) -4- (oxetan-3-yl) morpholin-2-yl;
X2is selected from
Figure 274161DEST_PATH_IMAGE009
、
Figure 939629DEST_PATH_IMAGE010
；
R0Selected from hydrogen, fluorine;
R1、R2each independently selected from hydrogen, methyl;
n is selected from 1,3 or 4.
7. A compound of formula (I) according to claim 1, an isomer, prodrug, solvate, stable isotopic derivative thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
Figure 693958DEST_PATH_IMAGE011
Figure 430970DEST_PATH_IMAGE012
Figure 423197DEST_PATH_IMAGE013
Figure 853041DEST_PATH_IMAGE014
。
8. use of a compound according to any one of claims 1-7, or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use as a BCL-2 inhibitor.
9. Use of a compound according to any one of claims 1-7, or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a BCL-2 mediated related disease, such as a tumor selected from the group consisting of hematological malignancies including acute lymphatic leukemia, lung cancer, breast cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, brain glioma.
10. A pharmaceutical composition comprising a compound according to any one of claims 1-7 or an isomer, prodrug, solvate, stable isotopic derivative or pharmaceutically acceptable salt thereof, optionally one or more other BCL-2 inhibitors, and one or more pharmaceutically acceptable carriers, diluents, and excipients.
CN202110017291.5A 2021-01-07 2021-01-07 Heterocyclic compounds as BCL-2 inhibitors Pending CN114736203A (en)

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