Substituted 7-azaindole-3-carboxylic acid-based mcl-1 protein inhibitors, methods of making and uses thereof

Abstract

The application discloses a substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor and a preparation method and application thereof, and the compound has a structure as shown in a general formula I. The compound has strong inhibitory activity on Mcl-1 protein, can prevent or treat related mammal diseases caused by abnormal expression of Mcl-1 protein, and the application also relates to a pharmaceutical use of a composition with the compound of the general formula I.

Description

Technical Field

[0001] This invention relates to a substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor, its preparation, pharmaceutical composition, and pharmaceutical uses, belonging to the field of pharmaceutical technology. Background Technology

[0002] Apoptosis, also known as programmed cell death (PCD), is a highly genetically regulated cell death process. It eliminates senescent or damaged cells in an organism, preventing abnormal cell growth and unlimited proliferation, and plays a crucial role in embryonic growth and cell homeostasis. Escape from apoptosis is a key marker of tumors and one of the main reasons for tumor resistance to chemotherapy, radiotherapy, and various anticancer drugs. Therefore, in recent decades, designing targeted apoptosis-related regulatory factors to restore normal apoptosis in tumor cells has become an important direction in anti-tumor research and development.

[0003] Studies have shown that the B-cell leukemia / lymphoma-2 (Bcl-2) protein family is a key regulator of apoptosis, playing a crucial role in the mitochondrial-mediated endogenous pathway. Based on different structures and functions, the Bcl-2 protein family is mainly divided into anti-apoptotic proteins (such as Bcl-2, Bcl-xL, Mcl-1), multi-domain pro-apoptotic proteins (such as Bax, Bak), and pro-apoptotic BH3-only proteins (such as Bad, Bid, Bmf). When cells receive death signals and undergo endogenous apoptosis, pro-apoptotic BH3-only proteins activate Bax and Bak, altering the permeability of the mitochondrial outer membrane, releasing pro-apoptotic factors such as cytochrome c into the cell, activating caspase, and triggering a series of cascade reactions, ultimately leading to apoptosis. Anti-apoptotic Bcl-2 proteins are highly expressed in various cancer cells and are closely related to tumor development, progression, and resistance to chemotherapy drugs. Therefore, developing small molecule inhibitors that antagonize the anti-apoptotic Bcl-2 protein is an important research strategy in the development of anti-tumor drugs.

[0004] Over the past few decades, anti-apoptotic Bcl-2 protein inhibitors have been a hot research topic, extensively studied by medicinal chemists worldwide. Notably, venetoclax (ABT-199), as the first selective Bcl-2 inhibitor, has been approved for marketing by the U.S. Food and Drug Administration (FDA). However, ABT-199 has poor binding affinity to Mcl-1, resulting in less than ideal efficacy in inducing apoptosis in certain Mcl-1-dependent hematologic malignancies and solid tumor cells. It often requires combination therapy with Mcl-1 inhibitors to effectively kill tumor cells. To address this clinical challenge, the search for novel small-molecule inhibitors targeting Mcl-1 has become a highly challenging and valuable research topic in the current field of cancer (especially malignant tumor) treatment. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor, and also provides a method for preparing this compound.

[0006] The present invention further provides pharmaceutical compositions of the compound and its pharmaceutical uses.

[0007] The technical solution of the present invention is as follows:

[0008] I. Substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitors

[0009] A substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor is a compound having the general formula I or a pharmaceutically acceptable salt thereof.

[0010]

[0011] In general formula I, R1 is an alkyl, aryl, or heteroaryl group; R1 is preferably an optionally substituted C1-C10 alkyl, C3-C10 cycloalkyl, C5-C15 aryl group, or a monoheterocyclic aryl group containing 5 or 6 ring atoms, or a diheterocyclic aryl group having 8 to 15 ring atoms, wherein the heterocyclic aryl group contains 1 to 4 heteroatoms, wherein the heteroatoms are independently selected from O, S, N, or oxidized S or N; the carbon atom or nitrogen atom is the linking point of the heterocyclic ring structure, maintaining a stable aromatic ring;

[0012] In general formula I, R2 is isopropyl or -A-R4;

[0013] Wherein, A is a CH2, NH, O, or S atom, preferably CH2; R4 is an optionally substituted aryl or heteroaryl; R4 is preferably an optionally substituted C5-C15 aryl, or a monoheterocyclic aryl containing 5 or 6 ring atoms, or a diheterocyclic aryl having 8 to 15 ring atoms, wherein the heterocyclic aryl contains 1 to 4 heteroatoms, wherein the heteroatoms are independently selected from O, S, N, or oxidized S or N; the carbon atom or nitrogen atom is the linking point of the heteroaryl ring structure, maintaining a stable aromatic ring;

[0014] In general formula I, R3 is an optionally substituted aryl or heteroaryl group; R3 is preferably an optionally substituted C5-C15 aryl group, a monoheterocyclic aryl group containing 5 or 6 ring atoms, or a diheterocyclic aryl group having 8 to 15 ring atoms, wherein the heterocyclic aryl group contains 1 to 4 heteroatoms, wherein the heteroatoms are independently selected from O, S, N or oxidized S or N; the carbon atom or nitrogen atom is the linking point of the heterocyclic ring structure, maintaining a stable aromatic ring;

[0015] The group or substituent is selected from hydroxyl, halogen, nitro, cyano, guanidinium, carboxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, arylalkoxy, heteroaryl containing 1-2 heteroatoms and having a ring number of 5-10, and 1-3 of the above groups or substituents are connected at any accessible position to produce a stable compound.

[0016] According to a preferred embodiment of the present invention, in general formula I,

[0017] R1 is an aromatic group Ar, -NH-R5, consisting of a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a morpholine group or piperazine group substituted with or without 1-2 hydroxyl groups, halogens, nitro groups, cyano groups, or a substituted group; Ar is a phenyl, naphthyl, pyridyl, pyridazinyl, pyrazinyl, indoleyl, quinazolinyl, purine, indoleyl, quinolinyl, pyrimidinyl, pyrroleyl, pyrazolyl, thiazolyl, benzo[b]thiazolyl, isoxazolyl, or oxadiazole. The following are aromatic groups: alkyl, isothiazolyl, tetrazolyl, imidazolyl, triazine, furanyl, benzofuranyl, and indolyl; R5 is a C1-C6 alkyl group substituted or unsubstituted with 1-2 hydroxyl, halogen, nitro, or cyano groups, and Ar is an aromatic group connected to a C1-C3 alkylene group; the substituents are hydroxyl, halogen, nitro, cyano, guanidinyl, carboxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C5-C10 aryl, or heteroaryl containing 1-2 heteroatoms and having a ring with 5-10 atoms;

[0018] R2 is isopropyl or -CH2-R4; R4 is 3-indolyl and phenyl, naphthyl, pyridinyl, pyridazinyl, pyrazinyl, indoleyl, quinazolinyl, purine, indolyl, quinolinyl, pyrimidinyl, pyrroleyl, pyrazolyl, thiazolyl, benzo[b]thiazolyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuranyl, and indolyl; the substituent is hydroxyl, halogen, nitro, cyano, guanidinyl, carboxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C5-C10 aryl, substituted arylalkoxy, or heteroaryl with 1-2 heteroatoms and a ring number of 5-10.

[0019] R3 is an aromatic group Ar, -NH-R5, linked to a morpholine group or piperazine group with 1-2 hydroxyl, halogen, nitro, or cyano substituents or without substitution; Ar is a phenyl, naphthyl, pyridinyl, pyridazinyl, pyrazinyl, indoleyl, quinazolinyl, purine, indoleyl, quinolinyl, pyrimidinyl, pyrroleyl, pyrazolyl, thiazolyl, benzo[b]thiazolyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazoleyl Azolyl, triazine, furanyl, benzofuranyl, and indoleyl; R4 is a C1-C6 alkyl group substituted or unsubstituted with 1-2 hydroxyl, halogen, nitro, or cyano substituents, and the above aromatic group Ar is linked to a C1-C3 alkylene group; the substituents are hydroxyl, halogen, nitro, cyano, guanidinyl, carboxyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, C3-C8 cycloalkyl, C5-C10 aryl, and heteroaryl groups containing 1-2 heteroatoms with a ring number of 5-10;

[0020] According to the present invention, more preferably, the compound of general formula I is one of the following:

[0021] (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(1-(4-nitrobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A1)

[0022] (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A2)

[0023] (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A3)

[0024] (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A4)

[0025] (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A5)

[0026] (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-((4-nitrophenyl)oxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A6)

[0027] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A7)

[0028] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A8)

[0029] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A9)

[0030] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A10)

[0031] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A11)

[0032] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A12)

[0033] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A13)

[0034] (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-((4-nitrophenyl)oxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A14)

[0035] (S)-1-(4-bromobenzyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A15)

[0036] (S)-1-(4-bromobenzyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A16)

[0037] (S)-N-(3-(4-(benzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1-(4-bromobenzyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A17)

[0038] (S)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(3-(4-bromobenzyl)-1-(4-methylbenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A18)

[0039] (S)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A19)

[0040] (S)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A20)

[0041] The preferred compounds listed above are numbered in parentheses to correspond to the reaction routes below and the compound structures in Table 1.

[0042] The terms and definitions used in this article have the following meanings:

[0043] "Aryl" refers to an aromatic hydrocarbon containing a ring system, such as phenyl or naphthyl, which is optionally fused with a cycloalkyl group, preferably having 5-7 ring atoms, more preferably 5-6 ring atoms. Preferred aryl groups contain 5-15 carbon atoms.

[0044] "Heteroaryl" is an aromatic heterocycle, which can be monocyclic or bicyclic. They contain one or more, preferably 1-4, more preferably 1-3, and even more preferably 1-2 heteroatoms, independently selected from O, S, and N. Heteroaryl includes oxidized S or N, such as sulfinyl, sulfonyl, and N oxides of tricyclic nitrogen. A carbon or nitrogen atom serves as a bonding point in the heteroaryl ring structure, thereby maintaining a stable aromatic ring. Examples of heteroaryl include, but are not limited to, pyridinyl, pyrazinyl, indene, benzo[b]thiophene, quinazolinyl, purinyl, indole, quinolinyl, pyrimidinyl, pyrroleyl, oxazolyl, thiazolyl, thiophene, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazole, triazinyl, furanyl, benzofuranyl, and indoleyl.

[0045] "Arylalkyl" refers to an aryl group linked by a C1-C6 alkylene group.

[0046] "Heteroarylene alkyl" refers to a heteroarylene group linked by a C1-C6 alkylene group.

[0047] "Aryl alkenyl" refers to an aryl group linked by a C2-C6 alkenyl group.

[0048] "Heteroarylene" refers to a heteroarylene group linked by a C2-C6 alkenyl group.

[0049] "Alkyl" refers, alone or in combination, to a group derived from an alkane containing 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms (unless otherwise specified). It is a straight-chain alkyl or branched alkyl group, and includes straight-chain or branched alkyl groups containing a cycloalkyl moiety or interrupted by a cycloalkyl moiety. The straight-chain or branched alkyl groups are linked at any available point to produce a stable compound. Examples include, but are not limited to, 4-(isopropyl)-cyclohexylethyl or 2-methyl-cyclopropylpentyl. In many embodiments, the alkyl group is a straight-chain or branched alkyl group containing 1 to 15 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 2 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and similar alkyl groups.

[0050] "alkylene" is a divalent alkane-derived carbon group that is straight-chain or branched, in which two hydrogen atoms are removed from the same or different carbon atoms. Examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, and -CH2CH(CH3)-.

[0051] "Alkenyl" refers, alone or in combination, as used herein, to a straight-chain or branched hydrocarbon containing 2 to 6, preferably 2 to 4, carbon atoms and 1 to 2, preferably a carbon-carbon double bond. Examples of alkenyl include, but are not limited to, vinyl, propenyl, isopropenyl, and butenyl.

[0052] "Cycloalkyl" is a substituted or unsubstituted, saturated or unsaturated cyclic group containing a carbon atom and / or one or more heteroatoms. The ring can be a monocyclic or fused ring, a bridged ring or a spirocyclic ring system. The number of ring atoms in each ring is 3 to 8, more preferably 3 to 6, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and similar groups.

[0053] "Alkoxy" indicates the -O-alkyl group.

[0054] "Halogen" alone or in combination refers to all halogens, namely chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).

[0055] "Pharmaceutically acceptable salt" refers to a salt form of a compound of general formula I that is both therapeutically effective and non-toxic. It can be an anionic salt formed by any acidic group (such as a carboxyl group) or a cationic salt formed by any basic group (such as an amino group). Many such salts are known in the art. These include cationic salts formed on any acidic group (such as a carboxyl group) or anionic salts formed on any basic group (such as an amino group). Many of these salts are known in the art, such as cationic salts including salts of alkali metals (such as sodium and potassium) and alkaline earth metals (such as magnesium and calcium), as well as organic salts (such as ammonium salts). Anionic salts can also be conveniently obtained by treating the basic form of I with appropriate acids, including inorganic acids such as sulfuric acid, nitric acid, and phosphoric acid; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, 2-hydroxy-1,2,3-triamnic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexylsulfinic acid, 2-hydroxybenzoic acid, and 4-amino-2-hydroxybenzoic acid. These salts are well known to those skilled in the art, who can prepare any salt provided by the knowledge in this field. Furthermore, those skilled in the art can choose one salt over another based on factors such as solubility, stability, and ease of preparation. The determination and optimization of these salts are within the experience of those skilled in the art.

[0056] As used herein, “stereoisomer” defines all possible stereoisomers of the compounds of the present invention or their physiological derivatives. Unless otherwise indicated, the chemical nomenclature of the compounds of the present invention includes mixtures of all possible stereochemical forms, comprising all diastereomers and enantiomers of the basic structural molecule, as well as a single isomer of the substantially pure compound of the present invention, i.e., containing less than 10%, preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other isomers. All stereoisomers of the peptide-like compounds of the present invention are clearly included within the scope of the present invention.

[0057] Compounds of general formula I may also exist in other protected forms or derivatives, which are obvious to those skilled in the art and should all be included within the scope of this invention.

[0058] The substituents described above can themselves be replaced by one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979). Preferred substituents include alkyl, alkenyl, alkoxy, hydroxy, oxy, nitro, amino, aminoalkyl (e.g., aminomethyl), cyano, halogen, carboxyl, carbonylalkoxy (e.g., carbonylethoxy), thio, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrroleyl), imino, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.

[0059] "Pharmaceutical composition" refers to a preparation containing a therapeutically significant amount of an active pharmaceutical agent, prepared in a form suitable for administration to a patient. Therefore, the preparation does not contain any one or more components in amounts that a reasonably prudent medical practitioner would find unsuitable for administration to a general population. In many cases, such pharmaceutical compositions are sterile preparations.

[0060] Room temperature refers to the ambient temperature during experimental operations, which should be controlled within the range of 10 to 30°C.

[0061] II. Preparation method of substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitors

[0062] A method for preparing substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitors includes the following steps: using 7-azaindole-3-carboxylic acid as a starting material, the carboxyl group is first protected by esterification under acidic conditions to obtain intermediate 1. Then, a nucleophilic substitution reaction is carried out with benzyl bromide with different substituents at the N-position of azaindole, followed by demethylation under alkaline conditions to generate key intermediates 2a-2e; furthermore, different substituted amino acids 3a-3e undergo amide condensation reactions with different substituted benzenesulfonamides to generate key intermediates 4a-4l; 4a-4l is deprotected by Boc at the amino group in saturated hydrogen chloride gas of ethyl acetate, and then undergoes amide condensation with intermediates 3a-3e in the presence of carbomonium salt condensing agents 2-(7-azobenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine to obtain target compounds A1-A20.

[0063] The synthesis route is as follows:

[0064]

[0065] Among them, the definitions of R1-R3 are the same as those described in general formula I above;

[0066] Reagents and conditions: a) Acetyl chloride, methanol, ice bath-reflux; b) i. Benzyl bromide with different substituents, potassium carbonate, dimethylformamide (DMF); ii. 1M NaOH solution, potassium carbonate, 1,4-dioxane, reflux; c) 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEA), dichloromethane, room temperature; d) i. Ethyl acetate solution saturated with hydrogen chloride, room temperature; ii. 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEA), dimethylformamide (DMF), room temperature.

[0067] The structural formulas of the target compounds in the synthetic route are shown in Table 1 below:

[0068]

[0069] Table 1 Structural formulas of the target compounds

[0070]

[0071] The specific steps for operating the compound will be described in detail in the embodiments.

[0072] Those skilled in the art can modify the above steps to improve the yield. They can determine the synthetic route based on basic knowledge in the field, such as selecting reactants, solvents, and temperatures. Yields can be improved by using various conventional protecting groups to avoid side reactions. These conventional protection methods can be found, for example, in T. Greene, *Protecting Groups in Organic Synthesis*.

[0073] III. Application of 7-azaindole-3-carboxylic acid-based Mcl-1 protein inhibitors

[0074] This invention also provides the application of this series of compounds in the preparation of drugs for the prevention or treatment of mammalian diseases caused by abnormal Mcl-1 protein expression. These mammalian diseases associated with abnormal Mcl-1 protein expression include cancer, neurodegenerative diseases, viral infections, inflammation, leukemia, malaria, and diabetes.

[0075] Furthermore, the present invention also includes a pharmaceutical composition suitable for oral administration to mammals, comprising any compound of general formula I above, and a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.

[0076] Furthermore, the present invention also includes a pharmaceutical composition suitable for parenteral administration to mammals, comprising any compound of general formulas I and II above, and a pharmaceutically acceptable carrier, optionally comprising one or more pharmaceutically acceptable excipients.

[0077] The in vitro bioactivity of the compound was evaluated by testing both enzyme activity inhibition and cellular activity.

[0078] In the in vitro enzyme inhibition experiment, the fluorescence polarization assay was used. In the specific measurement system, 5-FAM-labeled Bid-BH3 peptide was used as the fluorescent labeling molecule. This molecule can specifically bind to Mcl-1 protein, and its dissociation constant (Ki) is... d At around 30-60 nM, the two compounds produce a high polarization value after binding. If the target compound being tested can bind to the target protein, it will competitively inhibit the binding of Bid to that protein, leading to a decrease in polarization value. This allows us to obtain a dose-effect curve of the competitive binding of the target compound, and finally calculate the inhibition constant K. i .

[0079] The cellular activity of the compounds was tested using the CCK-8 assay. Human highly metastatic liver cancer cell lines HCCLM-3 and HeLa cells, and normal cell line L929 were seeded into 96-well plates, with culture medium containing different concentrations of the compounds added to each well. After incubation, the cells were stained with CCK-8 and incubated for a further period. The absorbance (OD) value of each well was measured at 450 nm using a microplate reader, and the cell growth inhibition rate was calculated to determine the activity of the compounds.

[0080] In vitro enzyme inhibition experiments showed that most of the compounds in this invention exhibited strong inhibitory activity against Mcl-1 protein. Among them, compounds A2, A3, A5, A7, A14, A15, and A16 showed activities comparable to the positive control drug UMI-77, while compounds A3, A5, and A14 showed higher inhibitory activity against Mcl-1 protein than UMI-77. Simultaneously, in in vitro anti-tumor cell proliferation assays, compounds A5 and A14 showed better inhibitory activity against the human highly metastatic hepatocellular carcinoma cell line HCCLM-3 than the positive control drug UMI-77, demonstrating significant development potential and the ability to guide the discovery of novel Mcl-1 protein inhibitors. Detailed Implementation

[0081] The present invention will be further described below with reference to embodiments, but is not limited thereto.

[0082] Example 1

[0083] Synthesis of 1-(4-bromobenzyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (2a). Intermediate 1 (1.76 g, 10 mmol) was added to DMF (40 mL) and dissolved by stirring at room temperature. Solid K₂CO₃ (4.14 g, 30 mmol) was added and the mixture was stirred at room temperature for 0.5 h. Then, p-bromobenzyl bromide (2.74 g, 11 mmol) was added and the mixture was stirred for another 2 h. 100 mL of 1 mol / L HCl solution was added, and the mixture was extracted with 150 mL of EtOAc. The organic layer was dried over anhydrous Na₂SO₄ for 0.5 h. The solid was collected by half-rotation and filtered to obtain 2.10 g of a pale yellow solid, which was dissolved in 30 mL of 1,4-dioxane and then 30 mL of 1 mol / L NaOH solution was added. The mixture was refluxed for 12 h and then cooled overnight. The solvent was evaporated, and the pH was adjusted to 2-3 by adding 1 mol / L hydrochloric acid solution. The mixture was filtered and dried to obtain a white solid 2a with a yield of 91% and an mp of 211-213℃. 1 H NMR (400MHz, DMSO-d6), δ12.36 (s, 1H), 8.40-8.33 (m, 3H), 7.53 (d, J = 8.4Hz, 2H), 7.30-7.26 (m, 3H), 5.52 (s, 2H).

[0084] Synthesis of (S)-tert-butyl(1-(3-nitro-4-chlorobenzenesulfonamide)-1-oxo-3-phenylprop-2-yl)carbamate (4a). N-Boc-L-phenylalanine (1.33 g, 5 mmol) was dissolved in 30 mL of anhydrous dichloromethane, followed by the sequential addition of DIEA (1.75 mL, 10 mmol) and HATU (2.29 g, 6 mmol). After stirring at room temperature for 30 min, 3-nitro-4-chlorobenzenesulfonamide (1.3 g, 1.1 mmol) was added. The mixture was stirred overnight at room temperature, and the solvent was evaporated to dryness. The mixture was then extracted twice with ethyl acetate, and the combined ethyl acetate layers were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and evaporation to dryness, the mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 7:1) to give 1.96 g of a white solid, 4a, in 81% yield, mp: 117-119 °C. 1 H NMR(500MHz, CDCl3), δ10.22(s,1H),8.45(s,1H),8.17-8.25(m,1H),7.72(d,J=8.5Hz,1H),7.20-7.19(m ,3H),7.03(d,J=4.5Hz,2H),5.16(s,1H),4.38(s,1H),3.04-3.00(m,1H),2.93-2.89(m,1H),1.38(s,9H).

[0085] Synthesis of (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(1-(4-nitrobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A1). A key intermediate, 4a (0.58 g, 1.2 mmol), was dissolved in 20 mL of ethyl acetate saturated with hydrogen chloride gas. After stirring overnight at room temperature, the solution was filtered and dried, and the hydrochloride intermediate was collected for later use. Another key intermediate, 2a (0.36 g, 1 mmol), was dissolved in 20 mL of anhydrous DMT and stirred at room temperature. Every 10 min, DIEA (0.61 mL, 3.5 mmol) and HATU (0.46 g, 1.2 mmol) were added sequentially. After stirring for 1 h, the reserved hydrochloride intermediate was added, and the mixture was stirred overnight at room temperature. The reaction solvent was evaporated to dryness, and then an appropriate amount of ethyl acetate was added and transferred to a separatory funnel. The mixture was washed twice with 1 mol / L hydrochloric acid solution and saturated saline solution, respectively. After drying with anhydrous sodium sulfate, the mixture was filtered and evaporated to dryness. The solution was then purified by column chromatography (petroleum ether:ethyl acetate = 1:2) to obtain 0.173 g of pale yellow solid Al, yield: 25%, mp: 145-147℃. 1 H NMR (400MHz, DMSO-d6), δ12.91 (s, 1H), 8.43 (d, J = 8.8Hz, 2H), 8.38-8.34 (m, 2H), 8.31-8.29(m,2H),8.17(d,J=9.2Hz,2H),7.67-7.63(m,4H),7.52(d,J=8.4Hz,2H) ,7.35(d,J=8.4Hz,2H),7.30(d,J=7.2Hz,2H),7.24-7.20(m,3H),7.18(t,J=7.2Hz ,1H),5.66-5.49(m,2H),4.71-4.65(m,1H),3.04-2.99(m,1H),2.87-2.82(m,1H). 13 C NMR (100MHz, DMSO-d6), δ172.24,164.17,150.67,147.56,144.87,144.22,138.93,138.72,137.68,137.63,132.90,131.7 7,130.07,129.70,129.61,129.33,128.84,128.59,127.45,126.97,124.87,119.09,117.96,108.47,55.24,47.48,36.51.

[0086] Example 2

[0087] Synthesis of (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A2). The intermediates and target compound were prepared as in Example 1. Yield: 31%, mp: 192-194 °C. 1 H NMR (400MHz, DMSO-d6), δ12.92 (s, 1H), 8.52 (d, J = 1.6Hz, 1H), 8.39-8.30 (m, 4 H),8.17(dd,J1=2.0Hz,J2=8.8Hz,1H),8.05(d,J=8.8Hz,1H),7.67-7.63(m,4 H),7.51(d,J=8.8Hz,2H),7.36(d,J=8.0Hz,2H),7.28-7.14(m,6H),5.66-5.5 0(m,2H),4.69-4.64(m,1H),3.05(dd,J1=5.2Hz,J2=13.6Hz,1H),2.91(m,1H). 13 C NMR (100MHz, DMSO-d6), δ172.25,164.24,147.62,147.55,144.22,139.48,138.95,138.72,137.68,137.48,133.50,132.88,132.79,13 1.83,131.20,130.08,129.60,129.34,128.87,128.60,128.56,127.47,126.95,125.46,119.11,118.00,108.39,55.22,47.50,36.43.

[0088] Example 3

[0089] Synthesis of (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A3). The intermediates and target compound were prepared as in Example 1. Yield: 22%, mp: 185-187 °C. 1H NMR (400MHz, DMSO-d6), δ12.89 (s, 1H), 8.43 (d, J = 8.8Hz, 2H), 8.32 (s, 4H), 8.17 ( d,J=8.4Hz,2H),7.63(s,4H),7.56(d,J=8.0Hz,2H),7.49(d,J=8.4Hz,2H),7.36(d ,J=7.2Hz,4H),7.21(d,J=8.0Hz,3H),6.85(d,J=8.0Hz,2H),5.65(dd,J1=15.2Hz ,J2=46.4Hz,2H),4.99(s,2H),4.64(s,1H),2.99-2.94(m,1H),2.83-2.77(m,1H). 13 C NMR (100MHz, DMSO-d6), δ172.32,164.12,157.26,150.62,147.53,144.22,138.92,138.71,137.70,137.01,132.87,131.76,130.68,130.2 0,130.05,129.89,129.66,129.33,128.85,128.60,127.46,124.85, 121.34,119.08,117.96,114.86,108.53,68.73,55.43,47.48,35.75.

[0090] Example 4

[0091] Synthesis of (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A4). The intermediates and target compound were prepared as in Example 1. Yield: 26%, mp: 167-168 °C. 1H NMR (400MHz, DMSO-d6), δ12.93(s,1H),8.56(s,1H),8.35-8.30(m,4H),8.18(d,J=8.4Hz, 1H),8.05(d,J=8.4Hz,1H),7.65(d,J=6.4Hz,4H),7.56(d,J=7.2Hz,2H),7.49(d,J=7.6Hz ,2H),7.37(d,J=8.4Hz,4H),7.25-7.19(m,3H),6.86(d,J=7.6Hz,2H),5.66(dd,J1=15.6H z,J2=43.2Hz,2H),5.00(s,2H),4.64-4.59(m,1H),2.99-2.96(m,1H),2.84-2.78(m,1H). 13 C NMR (100MHz, DMSO-d6), δ172.33,164.22,157.31,147.60,147.55,144.22 ,139.52,138.93,138.73,137.68,137.02,133.48,132.89,132.78,131.7 6,131.19,130.69,130.18,129.77,129.33,128.85,128.61,127.46,125. 49,121.34,119.12,118.00,114.86,108.47,68.77,55.54,47.52,35.67.

[0092] Example 5

[0093] Synthesis of (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A5). The intermediates and target compound were prepared as in Example 1. Yield: 21%, mp: 130-132 °C. 1H NMR(400MHz,DMSO-d6),δ12.83(s,1H),8.55(s,1H),8.36-8.32(m,4H),8.17(d,J =6.8Hz,1H),8.04(d,J=8.4Hz,1H),7.66-7.63(m,4H),7.49(d,J=8.4Hz,2H),7.41 -7.30(m,7H),7.25-7.18(m,3H),6.87(d,J=8.4Hz,2H),5.65(dd,J1=15.2Hz,J2=4 3.2Hz,2H),5.01(s,2H),4.64-4.59(m,1H),2.99-2.94(m,1H),2.84-2.78(m,1H). 13 C NMR(100MHz,DMSO-d6),δ172.41,164.21,157.50,147.60,147.54,144.22,13 9.51,138.93,138.71,137.70,137.53,133.48,132.87,132.78,131.80,131.1 6,130.66,130.09,129.61,129.33,128.86,128.84,128.60,128.24,128.13,127.47,125.50,119.11,118.01,114.81,108.44,69.55,55.56,47.49,35.66.

[0094] Example 6

[0095] Synthesis of (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-((4-nitrophenyl)oxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A6). The intermediates and target compound were prepared as in Example 1. Yield: 16%, mp: 157-159 °C. 1H NMR (400MHz, DMSO-d6), δ12.87 (s, 1H), 8.41 (d, J = 8.1Hz, 2H), 8.35-8.31 (m, 3H), 8.23(d,J=8.4Hz,3H),8.16(d,J=8.4Hz,2H),7.67-7.62(m,6H),7.49(d,J=8.4Hz ,2H),7.36(d,J=8.0Hz,2H),7.21(d,J=7.6Hz,3H),6.88(d,J=8.0Hz,2H),5.65-5 .49(m,2H),5.18(s,2H),4.65-4.60(m,1H)3.00-2.96(m,1H),2.89-2.69(m,1H). 13 C NMR (100MHz, DMSO-d6), δ172.64,164.06,157.01,150.44,147.53,147.39,145.50,144.19,138.91,138.71,137.68,132.87,131.71,130.7 6,130.30,130.03,129.59,129.31,128.84,128.60,127.44,124.72, 123.99,119.06,117.94,114.87,108.63,68.38,55.52,47.50,35.91.

[0096] Example 7

[0097] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A7). The intermediates and target compound were prepared as in Example 1. Yield: 22%, mp: 142-144 °C. 1H NMR (500MHz, DMSO-d6), δ8.50 (s, 1H), 8.35 (dd, J1=1.5Hz, J2=4.5Hz, 1H), 8.31 (d, J=6.0Hz, 2H), 8.1 3(d,J=6.5Hz,2H),7.99(d,J=8.0Hz,1H),7.61(d,J=8.5Hz,2H),7.55(d,J=8.0Hz,2H),7.51(d,J=8. 5Hz,2H),7.36(t,J=9.0Hz,4H),7.24-7.21(m,3H),7.14(s,2H),6.81(d,J=7.5Hz,2H),5.62-5.49(m ,2H),4.97(s,2H),4.55(s,1H),2.99-2.96(m,1H),2.82(dd,J1=9.5Hz,J2=13.5Hz,1H),2.32(s,3H). 13 C NMR (100MHz, DMSO-d6), δ172.93,164.20,157.23,147.50,147.41,144.17,140.01,137.30,137.17,136.92,136.83,133.25,132.77,131. 72,130.71,130.12,129.97,128.51,127.16,126.86,125.40,121.32 ,119.07,117.98,114.78,108.54,68.75,55.76,47.57,35.95,21.07.

[0098] Example 8

[0099] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A8). The intermediates and target compound were prepared as in Example 1. Yield: 21%, mp: 139-141 °C. 1H NMR (400MHz, DMSO-d6), δ12.86 (s, 1H), 8.42 (d, J = 8.8Hz, 2H), 8.35-8.31 ( m,4H),8.17(s,2H),7.61(d,J=8.0Hz,2H),7.55-7.49(m,4H),7.36-7.31(m ,4H),7.24-7.19(m,5H),6.85(d,J=8.4Hz,2H),5.63-5.48(m,2H),4.98(s ,2H),4.64(s,1H),2.96(d,J=10.0Hz,1H),2.82-2.76(m,1H),2.32(s,3H). 13 C NMR (100MHz, DMSO-d6), δ172.20,164.15,157.29,150.68,147.55,144.82,144.20,140.01,137.28,137.23,137.02,136.93,131.75,130. 68,130.20,129.97,129.68,128.52,127.21,126.91,124.88,121.33 ,119.09,117.95,114.88,108.47,68.75,55.41,47.51,35.71,21.12.

[0100] Example 9

[0101] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A9). The intermediates and target compound were prepared as in Example 1. Yield: 18%, mp: 132-134 °C. 1 H NMR (400MHz, DMSO-d6), δ12.88 (s, 1H), 8.43 (d, J = 8.8Hz, 2H), 8.35-8.32 (m, 4H ),8.17(d,J=8.8Hz,2H),7.61(dd,J1=8.0Hz,J2=36.8Hz,4H),7.41-7.30(m,7H ),7.24-7.18(m,5H),6.86(d,J=8.4Hz,2H),5.64-5.48(m,2H),5.00(s,2H),4. 64(s,1H),2.97(dd,J1=4.4Hz,J2=13.6Hz,1H),2.82-2.76(m,1H),2.32(s,3H). 13C NMR (100MHz, DMSO-d6), δ172.31,164.15,157.48,150.64,147.55,144.20,140.00,137.53,137.28,137.23,136.95,131.74,130.66,129. 97,129.67,128.83,128.52,128.23,128.12,127.21,126.91,124.85 ,119.10,117.95,114.83,108.49,69.55,55.46,47.51,35.74,21.12.

[0102] Example 10

[0103] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A10). The intermediates and target compound were prepared as in Example 1. Yield: 20%, mp: 161-163 °C. 1 H NMR (400MHz, DMSO-d6), δ12.95(s,1H),8.56(s,1H),8.36-8.33(m,4H),8.18(d,J=10.4H z,1H),8.04(d,J=8.8Hz,1H),7.62(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),7.42-7.30(m ,7H),7.24-7.19(m,5H),6.87(d,J=8.4Hz,2H),5.65(d,J=15.2Hz,1H),5.53(d,J=15.6H z,1H),5.01(s,2H),4.61(s,1H),2.99(d,J=17.6Hz,1H),2.85-2.79(m,1H),2.32(s,3H). 13C NMR (100MHz, DMSO-d6), δ172.41,164.23,157.51,147.61,147.55,144.20,140. 01,139.51,137.53,137.29,137.24,136.94,133.48,132.78,131.79,131.16,1 30.66,130.08,129.97,129.61,128.84,128.52,128.23,128.13,127.22,126.92,125.50,119.12,117.99,114.81,108.40,69.55,55.56,47.51,35.66,21.12.

[0104] Example 11

[0105] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A11). The intermediates and target compound were prepared as in Example 1. Yield: 19%, mp: 148-150 °C. 1 H NMR(400MHz, DMSO-d6), δ12.86(s,1H),8.54(s,1H),8.36-8.31(m,4H),8.17(d,J=10.4Hz,1H),8.03(d,J=8.4Hz,1H),7.62(d,J=8.0Hz,2H),7. 53(d,J=8.0Hz,2H),7.41-7.21(m,10H),5.65(dd,J1=15.2Hz,J2=51.6H z,2H),4.61(s,1H),3.06-3.01(m,1H),2.86-2.82(m,1H),2.33(s,3H). 13 C NMR (100MHz, DMSO-d6), δ172.65,164.12,147.55,147.52,144.19,140.01,137.29,137.24,136.93,133.27,132.75,131.8 8,131.74,131.38,129.97,128.53,127.21,126.92,125.40,120.16,119.09,117.98,108.48,55.25,47.52,36.07,21.12.

[0106] Example 12

[0107] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A12). The intermediates and target compound were prepared as in Example 1. Yield: 18%, mp: 134-136 °C. 1 H NMR(400MHz,DMSO-d6),δ12.83(s,1H),8.48(s,1H),8.35-8.31(m,3H),8.13( d,J=8.4Hz,2H),7.97(d,J=8.4Hz,1H),7.61(d,J=8.0Hz,2H),7.53(d,J=7.6Hz ,2H),7.37-7.33(m,4H),7.26-7.21(m,3H),7.18(d,J=8.0Hz,2H),5.63-5.48 (m,2H),4.61-4.56(m,1H),3.07-3.02(m,1H),2.86-2.83(m,1H),2.33(s,3H). 13 C NMR (100MHz, DMSO-d6), δ163.70,147.51,147.22,144.08,139.98,137.89,137.29,137.25,136.95,132.65,132.54,131.9 0,131.57,131.18,129.98,128.54,127.18,126.92,125.01,119.82,119.05,117.89,108.96,55.72,47.54,36.97,21.11.

[0108] Example 13

[0109] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A13). The intermediates and target compound were prepared as in Example 1. Yield: 22%, mp: 152-154 °C. 1H NMR (400MHz, DMSO-d6), δ12.88 (s, 1H), 8.52 (d, J = 2.0Hz, 1H), 8.35-8.29 ( m,4H),8.16-8.13(m,1H),8.04(d,J=8.8Hz,1H),7.61(d,J=8.4Hz,2H),7.5 3(d,J=8.0Hz,2H),7.34(d,J=8.4Hz,2H),7.26-7.13(m,8H),5.64-5.48(m, 2H),4.67-4.62(m,1H),3.04-3.00(m,1H),2.90-2.84(m,1H),2.33(s,3H). 13 C NMR (100MHz, DMSO-d6), δ163.85,162.77,147.55,147.34,144.08,139.98,138.21,137.28,136.98,132.81,132.70,131.6 3,129.97,129.63,128.54,128.40,127.20,126.93,126.65,125.14,119.07,117.87,108.89,55.80,47.51,37.29,21.12.

[0110] Example 14

[0111] Synthesis of (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-((4-nitrophenyl)oxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A14). The intermediates and target compound were prepared as in Example 1. Yield: 41%, mp: 181-183 °C. 1 H NMR (400MHz, DMSO-d6), δ12.89 (s, 1H), 8.43 (d, J = 8.8Hz, 2H), 8.36-8.30 (m, 4H), 8.23 ​​(d, J=8.8Hz,2H),8.18(d,J=8.8Hz,2H),7.67(d,J=8.4Hz,2H),7.61(d,J=8.0Hz,2H),7.52(d, J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),7.24-7.20(m,5H),6.89(d,J=8.4Hz,2H),5.64-5.49 (m,2H),5.18(s,2H),4.69-4.63(m,1H)3.01-2.97(m,1H),2.85-2.79(m,1H),2.32(s,3H).13 C NMR (100MHz, DMSO-d6), δ163.70,147.51,147.22,144.08,139.98,137.89,137.29,137.25,136.95,132.65,132.54,131.90,1 31.57,131.18,129.98,128.54,127.18,126.92,125.01,119.82,119.05,117.89,108.96,63.52,55.72,47.54,36.97,21.11.

[0112] Example 15

[0113] Synthesis of (S)-1-(4-bromobenzyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A15). The intermediates and target compound were prepared as in Example 1. Yield: 21%, mp: 130-132 °C. 1 H NMR(400MHz, DMSO-d6), δ12.88(s,1H),8.41(d,J=7.6Hz,2H),8.32-8.26(m,4H),8.16(s,2H),7.57(dd,J1=8.4Hz,J2=10.0Hz,4H),7.38(d,J=8 .0Hz,2H),7.21(d,J=8.4Hz,5H),6.84(d,J=6.8Hz,2H),5.57-5.43(m,2 H),4.99(s,2H),4.63(s,1H),2.99(d,J=14.0Hz,1H),2.82-2.76(m,1H). 13 C NMR(100MHz,DMSO-d6),δ164.02,157.24,147.45,144.20,137.52,137.07,132.06,131.77,130.67,1 30.19,130.13,129.61,124.76,121.29,119.05,117.97,114.86,108.70,68.74,55.50,47.22,35.86.

[0114] Example 16

[0115] Synthesis of (S)-1-(4-bromobenzyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A16). The intermediates and target compound were prepared as in Example 1. Yield: 30%, mp: 161-163 °C. 1 H NMR(400MHz, DMSO-d6), δ12.88(s,1H),8.52(d,J=4.0Hz,1H),8.33-8.27(m,3H),8.15(dd,J1 =2.0Hz, J2=8.4Hz,2H),8.01(d,J=8.4Hz,1H),7.57-7.53(m,4H),7.39(d,J=8.4Hz,2H),7.23 -7.20(m,3H),7.16(d,J=8.4Hz,2H),6.84(d,J=8.4Hz,2H),5.57(dd,J1=15.6Hz,J2=38.8Hz, 2H),5.01(s,2H),4.60-4.55(m,1H),3.00-2.96(m,1H),2.84(dd,J1=9.2Hz,J2=13.6Hz,1H). 13 C NMR (100MHz, DMSO-d6), δ163.99,157.22,147.46,144.18,137.53,137.07,133.21,132.75,132.06,131.77,131.6 5,130.68,130.19,130.14,130.05,125.36,121.29,119.07,117.99,114.80,108.73,68.74,55.69,47.23,35.97.

[0116] Example 17

[0117] Synthesis of (S)-N-(3-(4-(benzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1-(4-bromobenzyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A17). The intermediates and target compound were prepared as in Example 1. Yield: 21%, mp: 138-140 °C. 1H NMR (400MHz, DMSO-d6), δ12.85 (s, 1H), 8.42 (d, J = 8.4Hz, 2H), 8.33-8.28 (m, 2H) ,8.26(s,2H),8.15(d,J=8.8Hz,2H),7.55(d,J=8.4Hz,2H),7.42-7.35(m,3H),7. 32-7.30(m,2H),7.22-7.16(m,5H),6.85(d,J=8.4Hz,2H),5.57(dd,J1=15.2Hz, J2=41.2Hz,2H),5.01(s,2H),4.60(s,1H),2.97-2.92(m,1H),2.81-2.75(m,1H). 13 C NMR(100MHz,DMSO-d6),δ,172.22,164.12,157.48,150.67,147.45,144.84,144.23,137.55,137.52,132.06,131.68,130. 65,130.12,129.69,128.85,128.24,128.12,124.88,121.30,119.07,118.00,114.84,108.58,69.55,55.44,47.20,35.71.

[0118] Example 18

[0119] Synthesis of (S)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(3-(4-bromobenzyl)-1-(4-methylbenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A18). The intermediates and target compound were prepared as in Example 1. Yield: 22%, mp: 130-132 °C. 1 H NMR(400MHz, DMSO-d6), δ12.49(s,1H),8.35-8.32(m,3H),8.03(s,1H),7.76(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,4H),7.47-7.43(m,2H),7 .36-7.31(m,7H),7.24-7.21(m,1H),7.15(d,J=8.0Hz,2H),5.65(d,J=15.2Hz,1H),5.52(d,J=15.2Hz,1H),4.56(s,1H),3.05(d,J=10.0Hz 1H),2.85-2.79(m,1H),2.36(s,3H). 13C NMR (100MHz, DMSO-d6), δ163.70,147.52,144.12,140.16,140.06,137.77,137.32,131.92,131.62,131.24,129.9 5,129.39,128.53,127.96,127.76,127.48,127.12,119.86,118.98,117.91,108.94,55.24,47.51,36.68,21.46.

[0120] Example 19

[0121] Synthesis of (S)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A19). The intermediates and target compound were prepared as in Example 1. Yield: 38%, mp: 145-147 °C. 1 H NMR(400MHz, DMSO-d6), δ12.98(s,1H),8.48(s,1H),8.35-8.31(m,3H),8.12(d,J=8.0Hz,2H), 7.97(d,J=7.6Hz,1H),7.64-7.60(m,4H),7.56(d,J=8.4Hz,2H),7.45-7.42(m,2H),7.36(d,J=8 .4Hz,5H),7.24-7.21(m,1H),7.13(d,J=7.2Hz,2H),6.81(d,J=8.4Hz,2H),5.65(d,J=15.2Hz,1 H),5.53(d,J=15.2Hz,1H),4.98(s,2H),4.53(s,1H),3.01(d,J=9.6Hz,1H),2.83-2.77(m,1H). 13 C NMR (100MHz, DMSO-d6), δ163.87,157.11,147.50,147.34,144.13,140.14,140.06,137.30,137.03,132.89,132.71,131.75,130.69,1 30.19,130.01,129.38,128.53,127.96,127.48,127.10,125.21,121.31,119.06,117.93,114.70,108.81,68.69,55.93,47.52,36.32.

[0122] Example 20

[0123] Synthesis of (S)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (A20). The intermediates and target compound were prepared as in Example 1. Yield: 35%, mp: 130-132 °C. 1 H NMR (500MHz, DMSO-d6), δ12.90(s,1H),8.42(d,J=42.0Hz,5H),8.17(s,2H),7.63(d,J=37.5Hz,7H),7.44(d,J= 42.0Hz,7H),7.21(s,3H),6.85(s,2H),5.66-5.51(m,2H),4.99(s,2H),4.64(s,1H),2.95(s,1H),2.79(s,1H). 13 C NMR (100MHz, DMSO-d6), δ172.24,164.17,157.27,150.65,147.53,144.92,144.23,140.12,140.10,137.26,137.01,131.75,130.69,130.18,1 29.84,129.67,129.38,128.52,127.97,127.49,127.10,124.84,121.3 3,119.08,117.97,114.89,114.78,108.49,68.75,55.44,47.53,35.74.

[0124] Example 21

[0125] Activity evaluation of the target compound.

[0126] Experimental Example 1: Inhibition assay of the target compound on Mcl-1 protein (In vitro)

[0127] Experimental reagents:

[0128] Bid-BH3 peptide (5-FAM-QEDIIRNIARHLAQVGDSMDRSIPPG) with N-terminus fluorescently labeled with 5-FAM was dissolved in 1×PBS;

[0129] Test buffer: 1×PBS;

[0130] Correction solution: 1 nM fluorescein, 10 mM NaOH;

[0131] Experimental apparatus:

[0132] TECAN Genios Pro Multifunctional Microplate Reader.

[0133] Experimental steps:

[0134] (1) Add the target protein and the small molecule compound to be tested to the test buffer, mix well, and incubate at room temperature in the dark for 30 min. Then add the fluorescently labeled Bid BH3 peptide to make the total volume of each solution 200 μL, mix well, and incubate at room temperature in the dark for 20 min.

[0135] (2) Take 60 μL of the above solution and the calibration solution and transfer them to a black 384-well plate (three parallel groups). Immediately detect the fluorescence polarization on the microplate reader. Use 485 nm as the excitation wavelength and 535 nm as the emission wavelength. Set the fluorescence polarization value of the calibration solution to 20 mP.

[0136] (3) All compounds were initially screened at three typical concentrations (1 μM, 10 μM, and 50 μM). Each compound was measured in triplicate on the same plate, and the average polarization value was taken. The inhibition rate was calculated based on the polarization values ​​of the negative control, positive control, and the tested compound. The target protein concentration typically used in the assay was 300–500 nM. The fluorescently labeled peptide was 5-FAM-Bid-BH3, and the positive control compound was AT-101. If the test results showed that the compound had an inhibition rate greater than 50% at 50 μM, and its inhibition rate showed a clear dose-dependent relationship at the three tested concentrations, then the compound was considered to have specific binding to the target protein, and further accurate IC50 determination was required. 50 Numerical value.

[0137] (4) For compounds showing significant activity in the initial screening, complete binding curves were determined at seven different concentrations (1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 50 μM, 100 μM). Each compound was measured in triplicate on the same plate, and the polarization values ​​were averaged. Data were processed and plotted using GraphPad Prism software to obtain the IC50 values ​​of the compounds. 50 value.

[0138] (5) Based on the total protein concentration, total fluorescent peptide concentration, protein-peptide complex dissociation constant, and IC50 of the detected compound used in the measurement. 50 The competitive inhibition constant K of the detection compound was obtained using the calculation methods described in the following literature. i(Nikolovska-Coleska, Z.; et al. Development and optimization of abinding assay for the XIAP BIR3 domain using fluorescence polarization. Anal Biochem. 2004, 332, 261-273).

[0139] The experimental results are shown in Table 2.

[0140] Table 2. Results of in vitro inhibition of Mcl-1 protein by the target compound.

[0141]

[0142] a The values ​​in the table are the average of the results of three trials.

[0143] As shown in the table, most compounds exhibited sub-micromolar inhibitory activity against Mcl-1. When R1 was 4-chlorobiphenyl or 4-methylbiphenyl, and the sulfonamide moiety was 4-chloro-3-nitrobenzenesulfonamide or 4-nitrobenzenesulfonamide, the compounds showed better inhibitory activity against Mcl-1 protein, such as compounds A2, A3, A5, A7, and A14. Among these, compounds A3, A5, and A14 showed inhibitory activity against Mcl-1 comparable to the positive control drug UMI-77. Furthermore, compounds A3, A5, and A14 exhibited higher inhibitory activity than the positive control drug, which is of great significance for further developing Mcl-1 protein inhibitors with higher activity and for preparing drugs to prevent and treat related mammalian diseases caused by abnormal Mcl-1 protein expression.

[0144] Experimental Example 2. Assay on the inhibitory activity of the target compound on cell proliferation (In vitro)

[0145] Three compounds with good enzyme activity were selected for in vitro assays to inhibit cancer cell proliferation. The results are shown in Table 3.

[0146] Terminology Explanation:

[0147] Liver cancer cell line HCCLM-3, cervical cancer cell line HeLa, and normal cell line L929.

[0148] IC 50 : Half-maximal inhibitory concentration.

[0149] Material:

[0150] HCCLM-3, HeLa, L929, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfonylbenzene)-2H-tetrazole monosodium salt CCK-8, 10% fetal bovine serum, 96-well plate

[0151] method:

[0152] Cell lines were cultured using standard methods. Logarithmic growth phase cells were used in all experiments.

[0153] Cell growth assay (CCK-8 assay): Adjust cell suspension to 5 × 10⁻⁶. 4 / mL (adjust suspension cells to 10) 5 Cells were seeded into 96-well plates at 100 μL / well, 2000-5000 cells / well. After 4 h of seeding, 100 μL of culture medium containing different concentrations of the compound was added to each well, with three replicates for each concentration. Wells without cells were used as blanks for reading, and wells with cells but without the compound were used as compound blanks. UMI-77 was used as a positive control for the compound. The plates were incubated at 37℃ and 5% CO2 for 48 h. Then, 10 μL of CCK-8 staining solution was added to each well, and incubation continued. After 2 h, the plates were shaken at constant temperature for 5-10 min. The absorbance (OD) value of each well was measured at 450 nm using a microplate reader. The cell growth inhibition rate was calculated using the following formula:

[0154]

[0155] Table 3. Results of antitumor cell proliferation experiments of compounds A3, A5, and A14

[0156]

[0157] a The values ​​in the table are the averages of three trials, and the values ​​after "±" represent the standard deviation.

[0158] In vitro antiproliferative activity experiments were conducted on three compounds with good enzyme activity against HCCLM-3 and HeLa tumor cells, as well as normal L929 cells. The test data showed that the three target compounds inhibited the growth of both HCCLM-3 and HeLa tumor cells, especially HCCLM-3 cells. Simultaneously, the three compounds exhibited growth inhibition comparable to the positive control in normal L929 cells. Among them, compounds A5 and A14 showed superior inhibitory activity against all three HCCLM-3 tumor cell types compared to the positive control UMI-77, indicating that substituted 7-azaindole Mcl-1 protein inhibitors have good development prospects and warrant further in-depth activity studies to develop more active compounds for the preparation of drugs for the prevention and treatment of mammalian diseases caused by abnormal Mcl-1 protein expression.

Claims

1. A substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor, a compound having the general formula I or a pharmaceutically acceptable salt thereof: In general formula I, R1 is an aromatic group Ar linked to a morpholine group or piperazine group that is substituted with 1-2 hydroxyl, halogen, or nitro groups or is unsubstituted; Ar is phenyl, naphthyl, or indole. R2 is isopropyl or -A-R4; where A It is CH2, NH, O or S, and R4 is a phenyl group containing 1-2 substituents or without substituents. The substituents are hydroxyl, halogen, nitro, cyano, guanidinyl or carboxyl. R3 is an aromatic group Ar linked to 1-2 substituted hydroxyl, halogen, nitro, or unsubstituted morpholine or piperazine groups; Ar is selected from phenyl, naphthyl, or indole; and is one of the following compounds: (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(1-(4-nitrobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-chloro-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-((4-nitrophenyl)oxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-(benzyloxy)phenyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-bromobenzyl)-1-(3-nitro-4-chlorobenzenesulfonyl)-1-oxo-3-phenylpropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-((4'-methyl-[1,1'-biphenyl]-4-yl)methyl)-N-(3-(4-((4-nitrophenyl)oxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxophenyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-(4-bromobenzyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-(4-bromobenzyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide; (S)-1-([1,1'-biphenyl]-4-ylmethyl)-N-(3-(4-(4-bromobenzyloxy)phenyl)-1-(4-chloro-3-nitrobenzenesulfonyl)-1-oxopropyl-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamide.

2. The method for preparing the substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor according to claim 1, comprising the following steps: Step 1: Using 7-azaindole-3-carboxylic acid as a raw material, a carboxylic acid esterification reaction is first carried out to protect the carboxyl group and generate intermediate 1; Step 2: A nucleophilic substitution reaction is carried out at the N position of intermediate 1 with benzyl bromide of different substituents, and then the methyl ester is removed under basic conditions to generate the key intermediates 2a-2e; Step 3: The amino acids 3a-3e protected by Boc with different substitutions undergo amide condensation reaction with benzenesulfonamides with different substitutions to generate intermediates 4a-4l; Step 4: The intermediates 4a-4l are first deprotected from Boc in ethyl acetate saturated with hydrogen chloride gas, and then undergo amide condensation with intermediates 2a-2e using a mixed caronium salt condensing agent O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate and N,N-diisopropylethylamine to obtain the target compounds A1-A20, which are substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitors.

3. The method for preparing the substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor according to claim 2, characterized in that: In step one, condition a uses acetyl chloride and methanol, and the temperature is set to react under reflux conditions, first using an ice bath and then heating.

4. The method for preparing the substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor according to claim 2, characterized in that: In step two, condition b involves reacting benzyl bromide with different substituents, potassium carbonate, and DMF at room temperature; then, 1M NaOH solution and 1,4-dioxane are used, and the mixture is heated under reflux.

5. The method for preparing the substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor according to claim 2, characterized in that: Step 3, condition c, uses O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, and dichloromethane, reacting at room temperature.

6. The method for preparing the substituted 7-azaindole-3-carboxylic acid Mcl-1 protein inhibitor according to claim 2, characterized in that: In step four, condition d involves reacting with an ethyl acetate solution saturated with hydrogen chloride at room temperature; followed by reacting with O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, and DMF at room temperature.

7. A pharmaceutical composition suitable for oral administration to mammals, comprising the Mcl-1 protein inhibitor of claim 1 and one or more pharmaceutically acceptable carriers or excipients.

8. A pharmaceutical composition suitable for parenteral administration to mammals, comprising the Mcl-1 protein inhibitor of claim 1 and one or more pharmaceutically acceptable carriers or excipients.

Images