CN116554057B - Compounds for reducing Erythropoietin (EPO) production and uses thereof - Google Patents
Compounds for reducing Erythropoietin (EPO) production and uses thereof Download PDFInfo
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- CN116554057B CN116554057B CN202310508673.7A CN202310508673A CN116554057B CN 116554057 B CN116554057 B CN 116554057B CN 202310508673 A CN202310508673 A CN 202310508673A CN 116554057 B CN116554057 B CN 116554057B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 83
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- 102000003951 Erythropoietin Human genes 0.000 title abstract description 40
- 108090000394 Erythropoietin Proteins 0.000 title abstract description 40
- 229940105423 erythropoietin Drugs 0.000 title abstract description 40
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
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- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 2
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
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- 208000010667 Carcinoma of liver and intrahepatic biliary tract Diseases 0.000 claims 1
- 206010073069 Hepatic cancer Diseases 0.000 claims 1
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- C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
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Abstract
The present application relates to compounds that reduce the production of Erythropoietin (EPO) and uses thereof. Specifically, the application discloses a compound shown as a formula (I) or pharmaceutically acceptable salt thereof. The application also relates to the medical application of the compound.
Description
Technical Field
The present application provides a novel class of compounds having pharmaceutical activity which are useful for reducing the production of Erythropoietin (EPO). The application also relates to compositions comprising said compounds and the use of said compounds and said compositions in the manufacture of a medicament for the treatment of diseases or conditions associated with EPO.
Background
Under normal physiological conditions, EPO (erythropoietin) is produced by peritubular interstitial cells in response to local tissue hypoxia, whereas in renal cell carcinoma, EPO is produced in tumor cells. Statistics show that two thirds of patients with renal cell carcinoma have elevated EPO compared to normal levels, while 8% of them exhibit polycythemia (polycythemia) (Reviews in literature 2002,4 (4), 163-170). In these patients, elevated serum erythrocyte concentrations are thought to be mediated by EPO. While polycythemia vera is prone to venous thrombosis, hemorrhage and vascular nervous system problems resulting in stroke and heart disease; if the treatment is lacking, the patient may be life threatening. Existing treatments include chronic phlebotomy, hydroxyurea and other cytopenia therapies, intravenous injection of radioactive phosphorus, busulfan, and JAK inhibitors such as ruxolitinib (ruxolitinib) and the like (journal of Chinese hematology Chin. J. Hematol.2022, vol 43, 537-541).
In addition, EPO levels are generally elevated in renal cell carcinoma, and thus EPO can be used as a potential tumor marker. The absence of EPO expression in clear kidney cell cancers is a separate predictor of negative impact on survival; that is, patients with Kidney Cancer with high EPO have better survival (Kidney Cancer 2017,1 (2), 143-149). Of course, the use of EPO as a possible marker for the treatment of clear kidney cell carcinoma patients also requires intensive research to understand the role of EPO in tumor biology. Patients with renal cell carcinoma having higher EPO levels may be more sensitive to the level of EPO, and thus lowering EPO levels is a potential and effective method of treating polycythemia and renal cell carcinoma.
Accordingly, it is desirable to develop an EPO inhibitor that can significantly reduce EPO levels, thereby achieving use in the treatment of various diseases such as polycythemia, renal cell carcinoma, other cancers, and the like.
Disclosure of Invention
The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof,
wherein ring A is selected from C5-C6 cycloalkyl or C5-C6 cycloalkenyl, said C5-C6 cycloalkyl or C5-C6 cycloalkenyl optionally substituted with 1, 2, 3 or 4R;
Ring B is selected from C5-C6 aryl or C5-C10 benzoheteroaryl, said C5-C6 aryl or C5-C10 benzoheteroaryl being optionally substituted with 1, 2 or 3R, and said C5-C10 benzoheteroaryl optionally containing 1 or 2N heteroatoms;
R 1 、R 2 、R 3 、R 4 each independently selected from hydrogen or halogen;
R 5 selected from hydrogen, halogen or hydroxy, preferably halogen or hydroxy; and is also provided with
R is each independently selected from hydrogen, halogen, C1-C3 alkyl or cyano, or two of R together with the carbon atom to which they are directly attached form an cycloalkenyl group.
In some embodiments according to the invention, the compound is represented by formula (II),
wherein ring B is selected from C5-C6 aryl or C5-C10 benzoheteroaryl;
R 1 、R 2 、R 3 、R 4 、R 6 and R is 7 Each independently selected from hydrogen or halogen, preferably R 1 ,R 2 ,R 3 ,R 4 Is H or F;
R 5 f or OH;
R 8 、R 9 each independently selected from hydrogen, halogen or C1-C3 alkyl, preferably R 8 ,R 9 H, F or methyl, or R 8 And R is 9 Together with the carbon atom to which it is directly attached, forms an cycloalkenyl group.
Preferably, the compound of formula (II) may be a compound represented by formula (II-1) or (II-2),
wherein R is 1 -R 9 As defined above;
R 10 、R 11 、R 12 each independently selected from hydrogen, halogen or cyano, preferably R 10 、R 11 、R 12 H, F or CN; and is also provided with
X, Y, Z are each independently C or N.
In some embodiments according to the application, the compound is represented by formula (III),
wherein C is F C 2 Is that
R 1 -R 7 As defined above; and is also provided with
R 10 、R 11 、R 12 Each independently selected from hydrogen, halogen or cyano, preferably R 10 、R 11 、R 12 H, F or CN.
The compounds of the present application may exist in the form of pharmaceutically acceptable salts thereof.
The term "pharmaceutically acceptable" means that the corresponding compound, carrier or molecule is suitable for administration to a human. Preferably, the term refers to use with mammals, preferably humans, as certified by regulatory authorities such as any national regulatory agency of CFDA (china), EMEA (europe), FDA (united states), etc.
The pharmaceutically acceptable salts include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexylamine sulfonate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2- (4-hydroxybenzyl) benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, napthalate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine and zinc salts. Semi-salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts:Properties, selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
As used herein, the term "substituted" means that one or more (preferably 1 to 4, more preferably 1 to 3) hydrogen atoms in the ring are independently replaced by a corresponding number of substituents.
As used herein, the term "independently" means that when the number of substituents exceeds one, the substituents may be the same or different.
As used herein, the term "optional" or "optionally" means that the event described may or may not occur. For example, a group "optionally substituted" means: the group may be unsubstituted or substituted.
The term "halogen" means-F, -Cl, -Br, or-I.
As used herein, the term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chains. In some embodiments of the present invention, in some embodiments,the alkyl group has 1 to 3, or 1 to 2, or 1 carbon atoms. For example, the term "C 1-3 Alkyl "refers to a straight or branched chain radical having 1 to 3 carbon atoms. The term "C 1-3 Alkyl "includes the term" C "in its definition 1-2 Alkyl "," C 1 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and the like. The alkyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents, preferably unsubstituted.
As used herein, the term "cycloalkenyl" refers to aliphatic hydrocarbons having at least one carbon-carbon double bond that are present outside the ring, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, the cycloalkenyl group has 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms, or 2-3 carbon atoms. For example, the term "exocyclic C 2-8 Alkenyl "refers to a straight or branched unsaturated radical (having at least one carbon-carbon double bond) having 2 to 8 carbon atoms present outside the ring. Alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-methyl-2-propenyl, butenyl, pentenyl, 3-hexenyl, and the like. The alkenyl group may be optionally substituted with one or more (e.g., 1 to 5) suitable substituents. As an exemplary illustration, in some preferred embodiments according to the present invention, the cycloalkenyl group may have the structure
As used herein, the term "C 5-6 Cycloalkyl "refers to cycloalkyl groups having 5 to 6 ring-forming carbon atoms. The cycloalkyl is a monocyclic ring. Examples of cycloalkyl groups are, for example, cyclopentyl and cyclohexyl. Cycloalkyl groups may be optionally substituted with one or more suitable substituents.
As used herein, the term "C 5-6 Cycloalkenyl "refers to cyclic hydrocarbons having 5-6 ring-forming carbon atoms and having at least one cycloalkenyl group. The cycloalkenyl group is a monocyclic ring. Examples of cycloalkenyl groups are, for example, cyclopentenyl and cyclohexenyl. Ring(s)Alkenyl groups may be optionally substituted with one or more suitable substituents.
As used herein, the term "C 5-6 Aryl "refers to an aryl group having an aromatic ring containing 5 to 6 carbon atoms, such as phenyl.
As used herein, the term "C 5-10 Benzoheteroaryl "refers to a hydrocarbon group having a benzene ring containing 5 to 10 carbon atoms fused to a heteroaromatic ring. Examples of benzoheteroaryl groups are, for example, benzopyrrole, benzopyrazole or benzimidazole.
In this context, a range of numbers relating to the number of substituents, the number of carbon atoms, and the number of ring atoms represents a list of all integers within the range, and the range is merely a simplified representation. For example: "C 5-6 "means 5 (C) 5 ) Or 6 (C) 6 ) A carbon atom; "C 5-10 "means 5 (C) 5 ) 6 (C) 6 ) 7 (C) 7 ) 8 (C) 8 ) 9 (C) 9 ) Or 10 carbon atoms (C) 10 ). Accordingly, a range of numbers relating to the number of substituents, the number of carbon atoms, the number of ring atoms also encompasses any one of its subranges, and each subrange is also considered disclosed herein.
In some embodiments, the compounds of the application are selected from:
cis-3-fluoro-5- (2, 4-trifluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
Cis-2-fluoro-4- (2, 4-trifluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
Cis-5- (2, 4-trifluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) isophthalonitrile
Cis-3-fluoro-5- (2, 2a, 4-tetrafluoro-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
3- (2, 2-difluoro-2 a-hydroxy-4-methylene-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) -5-fluorobenzonitrile
3- (2, 2-difluoro-2 a-hydroxy-4-methyl-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) -5-fluorobenzonitrile
3- (1, 1-difluoro-8 a-hydroxy-1, 2,8 a-tetrahydroacenaphthylen-4-yl) -5-fluorobenzonitrile
3- (1, 1-difluoro-8 a-hydroxy-1, 2,6,7,8 a-hexahydroacenaphthylen-4-yl) -5-fluorobenzonitrile
3-fluoro-5- (2, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
3-fluoro-5- (1, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
Trans-3-fluoro-5- (1, 2,3, 4-hexafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
Cis-3-fluoro-5- (1, 2,3, 4-hexafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
3-fluoro-5- (1,2,2,4,4-pentafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile
2, 4-tetrafluoro-6- (5-fluoro-1H-indazol-1-yl) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol
1- (2, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) -1H-indazole-6-carbonitrile
2, 4-tetrafluoro-6- (5-fluoro-1H-indol-1-yl) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol
2, 4-tetrafluoro-6- (6-fluoro-1H-indol-1-yl) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol
6- (1H-benzo [ d ] imidazol-1-yl) -2, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol
The compounds of the general formula (II) or (III) according to the invention can be synthesized by a number of methods familiar to the person skilled in the art. The following are given only a few exemplary synthetic methods, which are well known to those skilled in the art and can be variously modified. If desired, conventional techniques (including but not limited to filtration, distillation, crystallization, or column chromatography, among others) may be used to isolate and purify the starting materials, intermediates, and end products in the reaction. In addition, the various specific examples herein also illustrate methods of synthesizing the compounds of the present invention.
The compound is mainly synthesized by adopting the following technical scheme.
Scheme one: general synthesis of compounds having formula (II-1):
suzuki coupling reaction of the compound II-a with arylboronic acid or arylboronic acid pinacol ester II-B to give a compound of formula (II-1) in which R is B (OH) 2 Or BPin, the Pd catalyst used may be Pd (dppf) Cl 2 Or Pd (PPh) 3 ) 4 The base may be Na 2 CO 3 ,K 2 CO 3 Or Cs 2 CO 3 。
Scheme II: general synthesis of compounds having formula (II-2):
buchwald coupling of the compounds II-a with the heterocyclic compounds II-c gives the compounds of the formula (II-2), the Pd catalyst used being Pd (OAc) 2 Or Pd (or) 2 (dba) 3 The base may be K 2 CO 3 ,K 3 PO 4 Or t-BuOK, the phosphine ligand may be BINAP, XPhos, t-BuXPhos or Me 4 t-BuXPhos。
Scheme III: general synthesis of compounds having formula (iii):
suzuki coupling of a compound III-a with an arylboronic acid or arylboronic acid pinacol ester III-B to give a compound of formula (III) in which R is B (OH) 2 Or BPin, the Pd catalyst used may be Pd (dppf) Cl 2 Or Pd (PPh) 3 ) 4 The base may be Na 2 CO 3 ,K 2 CO 3 Or Cs 2 CO 3 。
The compounds of the application can inhibit EPO levels. For example, the compounds of the application may be used to selectively inhibit the activity of EPO in a cell or in an individual or patient in need of such inhibition by administering to the cell, individual or patient an inhibiting amount of a compound of the application.
In some embodiments, the compounds of the present application have excellent inhibitory activity against EPO.
In a second aspect, the present application provides a pharmaceutical composition comprising a compound of the application as described above, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, adjuvants or excipients.
The pharmaceutical compositions of the present application may be prepared in a manner well known in the pharmaceutical arts and may be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the site to be treated. Administration may be topical (including ophthalmic and to mucous membranes, including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), ocular, oral or parenteral. Methods for ocular delivery may include topical administration (eye drops), subconjunctival, periocular or intravitreal injection or introduction through balloon catheters or ophthalmic inserts surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial (e.g., intrathecal or intraventricular) administration. Parenteral administration may be in the form of a single bolus dose or may be by, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
If a solid carrier is used, the formulation may be in the form of a tablet, placed in a hard gel capsule in the form of a powder or granules, or in the form of a lozenge or troche. The solid carrier may include conventional excipients such as binders, fillers, tableting lubricants, disintegrants, wetting agents, and the like. The tablets may be film coated if desired by conventional techniques. If a liquid carrier is used, the formulation may be in the form of a syrup, emulsion, paste, soft gel capsule, sterile carrier for injection, aqueous or non-aqueous liquid suspension, or may be a dry product that is reconstituted with water or other suitable carrier prior to use. The liquid formulation may contain conventional additives such as suspending agents, emulsifying agents, wetting agents, non-aqueous vehicles (including edible oils), preserving agents, and flavoring and/or coloring agents. For parenteral administration, the carrier typically comprises at least mostly sterile water, but saline solutions, dextrose solutions, or the like can also be employed. Injectable suspensions may also be employed in which case conventional suspending agents may be employed. Conventional preservatives, buffering agents and the like may also be added to the parenteral dosage form. The pharmaceutical compositions are prepared by conventional techniques suitable for the desired formulations comprising the appropriate amount of the active ingredient (i.e., the compounds of the present application).
Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate).
These compositions may also contain various excipients, for example, preservatives, wetting agents, emulsifiers and dispersants. Inhibition of the action of microorganisms can be ensured by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, and the like). Isotonic agents, for example, sugars, sodium chloride, and the like may also be included. Absorption of the injectable pharmaceutical dosage form may be prolonged by the use of agents which delay absorption (e.g., aluminum monostearate and gelatin).
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) (e.g., sodium citrate or dicalcium phosphate), which may further include: (a) Fillers or admixtures (e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) Binders (e.g., carboxymethyl cellulose, alginates, gels, polyvinyl pyrrolidone, sucrose, and gum arabic); (c) humectants (e.g., glycerol); (d) Disintegrants (e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) a solution retarder (e.g., paraffin); (f) an absorption enhancer (e.g., a quaternary ammonium compound); (I) Wetting agents (e.g., cetyl alcohol and glycerol monostearate); (h) Adsorbents (e.g., kaolin and bentonite) and (i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate) or mixtures thereof.
Solid compositions of a similar type may also be used as fillers in soft-filled and hard-filled gel capsules using, for example, lactose and high molecular weight polyethylene glycols and the like as excipients.
Solid dosage forms (e.g., tablets, dragees, capsules, pills, and granules) may be prepared with coatings and shells (e.g., enteric coatings and others known in the art). They may contain opacifiers, they may also be compositions which release the active compound or compounds in a delayed manner in a certain part of the intestinal tract. Examples of useful embedding compositions are polymeric substances and waxes. The active component may also be in microencapsulated form, if appropriate with one or more of the abovementioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, dispersions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizing agents and emulsifiers (e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethyl formamide), oils (in particular, cottonseed, groundnut, corn, olive, castor, sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include, for example, wetting agents, emulsifying and suspending agents, flavoring agents, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Topical dosage forms of the compounds of the present application include ointments, powders, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any required preservatives, buffers or propellants. Ophthalmic formulations, eye ointments, powders and solutions are also included within the scope of the present application.
The amount of a compound of the present application in a pharmaceutical composition and dosage form may be suitably determined by one skilled in the art as desired, for example, the compound of the present application may be present in a therapeutically effective amount in a pharmaceutical composition or dosage form.
The present application also provides a method of treating a disease or disorder associated with EPO comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above. Wherein the patient is preferably a mammal, more preferably a human patient. Wherein the route of administration may be oral, topical (including but not limited to topical, spray, etc.), parenteral (including subcutaneous, intramuscular, cortical, and intravenous) administration, bronchial administration, nasal administration, etc.
In some embodiments, the EPO-associated disease or disorder is polycythemia, renal cell carcinoma, and other cancers.
Exemplary other cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, head and neck cancer (e.g., cancer of the larynx, laryngopharynx, nasopharynx, oropharynx, lips, and oral cavity), liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer, and non-small cell lung cancer, small cell cancer, and non-small cell cancer, bronchogenic carcinoma, pleural-pulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gall bladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, kaposi sarcoma, merkel cell skin cancer), brain cancer (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).
In some preferred embodiments, the EPO-associated disease or disorder is polycythemia.
In some preferred embodiments, the EPO-associated disease or disorder is renal cell carcinoma.
The application is further illustrated and described below in connection with specific embodiments.
Examples
The examples set forth herein below are for illustrative purposes only and are not intended to limit the scope of the claimed application in any way.
Unless otherwise stated, all reactants were obtained from commercial sources. The instruments and equipment used in the synthesis experiments and the product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.
Example 1: preparation of cis-3-fluoro-5- (2, 4-trifluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 1)
The synthetic route is as follows:
step a: preparation of intermediate 5, 7-dibromo-N- (3-methoxypropyl) -2, 3-dihydro-1H-indene-1-imine (1-1)
5, 7-dibromo-1-indenone (4.0 g,13.79 mmol), 3-methoxypropylamine (6.1 g,68.95 mmol) and trifluoroacetic acid (319.2 mg,2.8 mmol) were dissolved in toluene (50.0 mL), and the water separator was heated under reflux for 6h. LCMS showed complete reaction, cooled to room temperature and the reaction concentrated to give crude product 1-1 which was taken directly to the next step.
Step b: preparation of intermediate 5, 7-dibromo-2, 2-difluoro-2, 3-dihydro-1H-inden-1-one (1-2)
Intermediate 1-1 was dissolved in anhydrous acetonitrile (30.0 mL), anhydrous sodium sulfate (5.9 g,41.37 mmol) and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (Selectfluor) (14.7 g,41.37 mmol) were added, and stirred overnight at 80 ℃. After TLC showed completion of the reaction, it was cooled to room temperature, 6M HCl (5.0 mL) was added and stirred for 1h. Water was added thereto, extraction was performed with ethyl acetate, saturated brine was washed with water, dried over anhydrous sodium sulfate, filtered, dried by spinning, and the product 1-2 (1.9 g) was obtained by column chromatography.
1 H NMR(500MHz,Acetonitrile-d 3 )δ7.93(1H),7.77(1H),3.59(2H).
Step c: preparation of intermediate 1-allyl-5, 7-dibromo-2, 2-difluoro-2, 3-dihydro-1H-inden-1-ol (1-3)
Intermediate 1-2 (800.0 mg,2.45 mmol) was dissolved in anhydrous tetrahydrofuran (15.0 mL), and indium powder (562.6 mg,4.9 mmol) and (1S, 2R) -2-amino-1, 2-diphenylethanol (1.0 g,4.9 mmol) were added and replaced with nitrogen. Pyridine (387.6 mg,4.9 mmol) and allyl bromide (592.8 mg,4.9 mmol) were added dropwise in this order and stirred at room temperature for 2h. After completion of the TLC monitoring reaction, water quenching, ethyl acetate extraction, saturated brine washing, drying over anhydrous sodium sulfate, filtration, spin-drying and column chromatography were added to obtain the product 1-3 (950.0 mg).
1 H NMR(500MHz,DMSO-d 6 )δ7.73(1H),7.52(1H),6.16(1H),5.63–5.53(1H),4.95(1H),4.92(1H),3.43–3.34(1H),3.27(1H),2.82–2.76(1H),2.65(1H).
Step d: preparation of intermediate 6-bromo-2, 2-difluoro-4-methylene-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (1-4) and intermediate 7-bromo-2, 2-difluoro-1, 2-acenaphthene-2 a (3H) -ol (1-5)
Intermediate 1-3 (860.0 mg,2.35 mmol) was dissolved in anhydrous N, N-dimethylformamide (30.0 mL), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (174.2 mg,0.24 mmol) and potassium acetate (706.6 mg,7.2 mmol) were added, replaced with nitrogen, and stirred at 100℃for 2h. After completion of the TLC monitoring reaction, water, ethyl acetate extraction, saturated brine, dried over anhydrous sodium sulfate, filtration, spin-drying, column chromatography gave the products 1-4 (200.0 mg) and 1-5 (242.0 mg).
1-4: 1 H NMR(500MHz,DMSO-d 6 )δ7.65(1H),7.38(1H),6.21(1H),5.70(1H),5.30(1H),3.93(1H),3.33(1H),3.01(1H),2.73(1H).
1-5: 1 H NMR(500MHz,DMSO-d 6 )δ7.41(1H),7.36(1H),6.58(1H),6.12(1H),5.67(1H),3.61(1H),3.25(1H),2.58(2H).
Step e: preparation of intermediate 6-bromo-2, 2-difluoro-2 a-hydroxy-1, 2a, 3-tetrahydro-4H-cyclopenta [ cd ] inden-4-one (1-6)
Intermediate 1-4 (200.0 mg,0.70 mmol) was dissolved in dichloromethane (5.0 mL), acetonitrile (5.0 mL) and water (1.0 mL), cooled to 0deg.C, ruthenium trichloride (14.5 mg,0.070 mmol) was added, and sodium periodate (755.7 mg,3.5 mmol) was added in portions, maintaining stirring at 0deg.C for 0.5h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave the product 1-6 (140.0 mg).
ESI-MS m/z:333[M-H+HO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ7.84(1H),7.72(1H),6.69(1H),3.99(1H),3.41(1H),3.08(1H),2.73(1H).
Step f: preparation of the intermediate trans-6-bromo-2, 2-difluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] indene-2 a, 4-diol (1-7)
Intermediate 1-6 (140.0 mg,0.48 mmol) was dissolved in methanol (8.0 mL), cooled to 0deg.C, sodium borohydride (27.2 mg,0.72 mmol) was slowly added and stirred for 0.5h at 0deg.C. After completion of the TLC monitoring reaction, water quenching, ethyl acetate extraction, saturated brine washing, drying over anhydrous sodium sulfate, filtration, spin-drying and column chromatography were carried out to obtain the product 1-7 (134.0 mg).
ESI-MS m/z:335[M-H+HO 2 H] - 。
Step g: preparation of the intermediate cis-6-bromo-2, 4-trifluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (1-8)
Intermediate 1-7 (110.0 mg,0.38 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), purged with nitrogen, cooled to-78 ℃, and diethylaminosulfur trifluoride (61.5 mg,0.38 mmol) was slowly added dropwise, and stirred for 1h at-78 ℃. After completion of the reaction by LCMS, the reaction mixture was quenched by addition of saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried by spin-on, and separated by column chromatography to give product 1-8 (74.5 mg).
1 H NMR(500MHz,DMSO-d 6 )δ7.65(1H),7.55(1H),6.41(1H),5.99(1H),3.99(1H),3.35(1H),2.58(1H),2.31(1H).
Step h: preparation of cis-3-fluoro-5- (2, 4-trifluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 1)
Intermediate 1-8 (40.0 mg,0.14 mmol), 3-cyano-5-fluorobenzeneboronic acid (46.2 mg,0.28 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (5.1 mg, 0.0070 mmol), sodium carbonate (29.7 mg,0.28 mmol) were dissolved in 1, 4-dioxane (3.0 mL) and water (0.3 mL), replaced with nitrogen, and stirred at 100℃for 2h. After completion of the reaction, TLC was followed by addition of water, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation of the target compound 1 (35.7 mg) was isolated from the plate.
ESI-MS m/z:378[M-H+HCO 2 H] - ; 1 H NMR(500MHz,Acetonitrile-d 3 )δ7.83(1H),7.69(1H),7.65(1H),7.57(1H),7.55–7.52(2H),6.01(1H),4.28(1H),4.07(1H),3.39(1H),2.73(1H),2.45–2.38(1H)。
Example 2: preparation of cis-2-fluoro-5- (2, 4-trifluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 2)
The synthetic route is as follows:
intermediate 1-8 (30.0 mg,0.1 mmol), 3-cyano-4-fluorobenzeneboronic acid (33.0 mg,0.2 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (3.7 mg,0.005 mmol), sodium carbonate (21.2 mg,0.2 mmol) were dissolved in 1, 4-dioxane (3.0 mL) and water (0.3 mL), replaced with nitrogen, and stirred at 100℃for 2h. After completion of the reaction, TLC was followed by addition of water, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation of target compound 2 (15.3 mg) was isolated from the plate.
ESI-MS m/z:378[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.25(1H),8.07(1H),7.74(1H),7.64(1H),7.63(1H),6.40(1H),6.04(1H),4.05(1H),3.40–3.34(1H),2.62(1H),2.36(1H)。
Example 3: preparation of cis-5- (2, 4-trifluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) isophthalonitrile (Compound 3)
The synthetic route is as follows:
intermediate 1-8 (16.0 mg,0.06 mmol), 3, 5-dicyanophenylboronic acid pinacol ester (30.5 mg,0.12 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (2.2 mg, 0.003mmol), sodium carbonate (12.7 mg,0.12 mmol) were dissolved in 1, 4-dioxane (2.0 mL) and water (0.2 mL), replaced with nitrogen, and stirred at 100℃for 2h. After completion of the reaction, TLC was followed by addition of water, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation of the target compound 3 (7.4 mg) was isolated from the plate.
ESI-MS m/z:385[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.52(2H),8.47(1H),7.87(1H),7.76(1H),6.44(1H),6.04(1H),4.06(1H),3.37(1H),2.63(1H),2.37(1H)。
Example 4: preparation of cis-3-fluoro-5- (2, 2a, 4-tetrafluoro-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 4)
The synthetic route is as follows:
step a: preparation of the intermediate cis-6-bromo-2, 2-difluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-4-yl-4-nitrobenzoate (4-1)
Intermediate 1-7 (150.0 mg,0.52 mmol), 4-nitrobenzoic acid (173.8 mg,1.04 mmol), triphenylphosphine (272.8 mg,1.04 mmol) was dissolved in anhydrous tetrahydrofuran (8.0 mL), displaced with nitrogen, cooled to 0deg.C, diethyl azodicarboxylate (181.1 mg,1.04 mmol) was added and reacted overnight at room temperature. After TLC showed completion of the reaction, water was added thereto, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave product 4-1 (192.0 mg).
ESI-MS m/z:484[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.38(2H),8.23(2H),7.61(1H),7.55(1H),6.47(1H),6.26(1H),4.07–3.95(1H),3.39(1H),2.76(1H),2.38(1H).
Step b: preparation of the intermediate cis-6-bromo-2, 2-difluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] indene-2 a, 4-diol (4-2)
Intermediate 4-1 (192.0 mg,0.44 mmol) was dissolved in tetrahydrofuran (5.0 mL) and water (0.5 mL), lithium hydroxide (21.1 mg,0.88 mmol) was added, and stirred at room temperature for 2h. After TLC showed completion of the reaction, water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin to give product 4-2 (133.0 mg).
Step c: preparation of the intermediate cis-6-bromo-2, 2a, 4-tetrafluoro-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] indene (4-3)
Intermediate 4-2 (133.0 mg,0.44 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), cooled to-78℃and diethylaminosulfur trifluoride (212.8 mg,1.32 mmol) was added and stirred at-78℃for 3h. After completion of the reaction by TLC, the reaction solution was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by spin to give product 4-3 (133.0 mg).
Step d: preparation of cis-3-fluoro-5- (2, 2a, 4-tetrafluoro-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 4)
Intermediate 4-3 (133.0 mg,0.44 mmol), 3-cyano-5-fluorobenzeneboronic acid (145.1 mg,0.88 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (16.1 mg,0.022 mmol), sodium carbonate (93.3 mg,0.88 mmol) were dissolved in dioxane (5.0 mL) and water (0.5 mL), replaced with nitrogen, and stirred at 100℃for 2h. After completion of the reaction, TLC was followed by extraction with water, ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, followed by column chromatography to give the title compound 4 (72.0 mg).
1 H NMR(500MHz,DMSO-d 6 )δ8.11(1H),8.02–7.98(1H),7.91(1H),7.81(2H),7.02–6.84(1H),4.13(1H),3.60(1H),3.21(1H),2.61–2.51(1H).
Example 5: preparation of 3- (2, 2-difluoro-2 a-hydroxy-4-methylene-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) -5-fluorobenzonitrile (Compound 5)
The synthetic route is as follows:
Intermediate 1-4 (70.0 mg,0.24 mmol), 3-cyano-5-fluorobenzeneboronic acid (79.2 mg,0.48 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (8.8 mg,0.012 mmol), sodium carbonate (50.9 mg,0.48 mmol) were dissolved in 1, 4-dioxane (7.0 mL) and water (0.7 mL), replaced with nitrogen and stirred at 100℃for 2h. After completion of the reaction, TLC was followed by extraction with water, ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation plate separation gave the objective compound 5 (65.1 mg).
ESI-MS m/z:371[M-H+HCO 2 H]-; 1 H NMR(500MHz,DMSO-d 6 )δ8.07(1H),7.96(1H),7.86(1H),7.82(1H),7.57(1H),6.22(1H),5.73(1H),5.32(1H),4.06–3.94(1H),3.06(1H),2.79(1H)。
Example 6: preparation of 3- (2, 2-difluoro-2 a-hydroxy-4-methyl-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) -5-fluorobenzonitrile (Compound 6)
The synthetic route is as follows:
compound 5 (15.0 mg,0.046 mmol) was dissolved in methanol (3.0 mL), 10% palladium on carbon (1.5 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1h. After completion of LCMS monitoring reaction, filtration, spin-drying, preparative plate isolation of the target compound 6 (2.6 mg).
ESI-MS m/z:374[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.03(1H),7.91(1H),7.83(1H),7.49(1H),7.46(1H),6.03(1H),4.03–3.89(2H),2.34(1H),1.90(1H)。
Example 7: preparation of 3- (1, 1-difluoro-8 a-hydroxy-1, 2,8 a-tetrahydroacenaphthylen-4-yl) -5-fluorobenzonitrile (Compound 7)
The synthetic route is as follows:
intermediate 1-5 (30 mg,0.1 mmol), 3-cyano-5-fluorobenzeneboronic acid (33.0 mg,0.2 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (3.7 mg,0.005 mmol), sodium carbonate (21.2 mg,0.2 mmol) were dissolved in 1, 4-dioxane (3.0 mL) and water (0.3 mL), replaced with nitrogen, and stirred at 100℃for 2h. After completion of the reaction, TLC was followed by addition of water, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation of the target compound 7 (30.9 mg) was isolated from the plate.
ESI-MS m/z:371[M-H+HCO 2 H] - ; 1 H NMR(500MHz,Acetonitrile-d 3 )δ7.86–7.84(1H),7.72–7.67(1H),7.53–7.50(1H),7.47(1H),7.40(1H),6.68–6.65(1H),6.18–6.13(1H),3.68(1H),3.62(1H),3.32(1H),2.79(1H),2.63(1H)。
Example 8: preparation of 3- (1, 1-difluoro-8 a-hydroxy-1, 2,6,7,8 a-acenaphthylen-4-yl) -5-fluorobenzonitrile (Compound 8)
The synthetic route is as follows:
compound 7 (10.0 mg,0.031 mmol) was dissolved in methanol (3.0 mL), 10% palladium on carbon (1.0 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 1h. After completion of LCMS monitoring reaction, filtration, spin-drying, and preparative plate isolation of the title compound 8 (11.0 mg).
ESI-MS m/z:374[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.03(1H),7.91(1H),7.83(1H),7.53(1H),7.47(1H),5.70(1H),3.68(1H),3.17(1H),2.88(1H),2.68–2.59(1H),2.23–2.12(1H),1.91(2H),1.70–1.62(1H)。
Example 9: preparation of 3-fluoro-5- (2, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 9)
The synthetic route is as follows:
step a: preparation of intermediate 3- (2, 2-difluoro-2 a-hydroxy-4-oxo-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) -5-fluorobenzonitrile (9-1)
Intermediate 1-6 (100 mg,0.35 mmol), 3-cyano-5-fluorobenzeneboronic acid (115.5 mg,0.70 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (13.2 mg,0.018 mmol), sodium carbonate (74.2 mg,0.70 mmol) were dissolved in 1, 4-dioxane (5 mL) and water (0.5 mL), replaced with nitrogen and stirred at 100 ℃ for 2h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave the product 9-1 (122.3 mg).
ESI-MS m/z:374[M-H+HCO 2 H] - 。
Step b: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -2, 2-difluoro-4-oxo-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (9-2)
Intermediate 9-1 (120 mg,0.36 mmol) was dissolved in anhydrous dichloromethane (10 mL), 4-dimethylaminopyridine (4.4 mg,0.036 mmol) and triethylamine (91.1 mg,0.9 mmol) were added, cooled to 0deg.C, acetic anhydride (73.5 mg,0.72 mmol) was added and the reaction was resumed at room temperature for 2h. After the completion of the reaction, TLC was followed by extraction with water, ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying and column chromatography to give the product 9-2 (120 mg).
Step c: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -2, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (9-3)
Intermediate 9-2 (20.0 mg,0.05 mmol) was dissolved in anhydrous dichloromethane (0.1 mL), diethylaminosulfur trifluoride (241.8 mg,1.5 mmol) was added, and the mixture was stirred at 80℃for 5h. After completion of the reaction by TLC, the reaction solution was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the product 9-3 (21.4 mg) was isolated by preparative plate.
1 H NMR(500MHz,DMSO-d 6 )δ8.15(1H),8.04(1H),8.01(1H),7.95(1H),7.92(1H),4.13(1H),3.56(1H),3.47(1H),3.11(1H).
Step d: preparation of 3-fluoro-5- (2, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 9)
Intermediate 9-3 (18.0 mg,0.05 mmol) was dissolved in tetrahydrofuran (3 mL) and water (0.3 mL), lithium hydroxide (3.6 mg,0.15 mmol) was added, and stirred at room temperature for 2h. After completion of the reaction, TLC was followed by addition of water, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation of target compound 9 (17.0 mg) was isolated from the plate.
ESI-MS m/z:396[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.12(1H),8.03–7.99(1H),7.91–7.86(3H),6.74(1H),4.01(1H),3.39(1H),2.89–2.77(2H)。
Example 10: preparation of 3-fluoro-5- (1, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 10)
The synthetic route is as follows:
step a: preparation of intermediate 2,4, 6-tribromobenzaldehyde (10-1)
1,3, 5-tribromobenzene (100.0 g,317.7 mmol) was dissolved in anhydrous tetrahydrofuran (1.0L), replaced with nitrogen, cooled to-78℃and lithium diisopropylamide (190.0 mL,381.2 mmol) was added dropwise, stirred for 0.5h, anhydrous N, N-dimethylformamide (27.9 g,381.2 mmol) was added dropwise, and stirred for 2h at-78 ℃. After completion of the TLC monitoring reaction, saturated ammonium chloride was added to quench, extraction was performed with ethyl acetate, saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried to give crude product 10-1 (109.8 g).
Step b: preparation of intermediate 1- (2, 4, 6-tribromophenyl) but-3-en-1-ol (10-2)
Intermediate 10-1 (109.8 g,317.7 mmol) was dissolved in anhydrous tetrahydrofuran (1.0L), purged with nitrogen, cooled to 0℃and allylmagnesium bromide (476.6 mL,476.6 mmol) was added dropwise and stirred at 0℃for 2h. After completion of the TLC monitoring reaction, saturated ammonium chloride was added to quench, extraction was performed with ethyl acetate, saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and column-chromatographed to give product 10-2 (69.0 g).
Step c: preparation of intermediate 5, 7-dibromo-3-methylene-2, 3-dihydro-1H-inden-1-ol (10-3)
Intermediate 10-2 (69.0 g,179.3 mmol), ditriphenylphosphine palladium dichloride (6.3 g,9.0 mmol) and potassium acetate (52.8 g,537.9 mmol) were dissolved in acetonitrile (700.0 mL), replaced with nitrogen and stirred at 80℃for 4h. After completion of the TLC monitoring reaction, ethyl acetate was added for dilution, celite was used for filtration, and the filtrate was dried by spin-drying and separated by column chromatography to give the product 10-3 (19.0 g).
Step d: preparation of intermediate 5, 7-dibromo-3-methylene-2, 3-dihydro-1H-inden-1-one (10-4)
Intermediate 10-3 (14.0 g,46.1 mmol) was dissolved in anhydrous dichloromethane (200.0 mL), cooled to 0deg.C, and dess-Martin oxidant (39.1 g,92.2 mmol) was added and stirred for 3h at 0deg.C. After completion of the TLC monitoring reaction, celite was filtered, dichloromethane was used for washing, the filtrate was dried by spin-drying and the crude product 10-4 (14.0 g) was isolated by column chromatography.
Step e: preparation of intermediate 1-allyl-5, 7-dibromo-3-methylene-2, 3-dihydro-1H-inden-1-ol (10-5)
Intermediate 10-4 (14.0 g,46.1 mmol), indium powder (10.6 g,92.2 mmol) and (1S, 2R) -2-amino-1, 2-diphenylethanol (19.7 g,92.2 mmol) were dissolved in anhydrous tetrahydrofuran (150.0 mL), replaced with nitrogen, pyridine (7.3 g,92.2 mmol) and allyl bromide (11.1 g,92.2 mmol) were added and stirred at room temperature for 2h. After completion of the TLC monitoring reaction, water was added and stirred for 1 hour, extraction was performed with ethyl acetate, saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying and column chromatography were performed to obtain the product 10-5 (6.8 g).
Step f: preparation of intermediate 6-bromo-1, 4-dimethylene-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (10-6)
Intermediate 10-5 (6.8 g,19.8 mmol), bis triphenylphosphine palladium dichloride (0.7 g,1.0 mmol) and potassium acetate (5.8 g,59.4 mmol) were dissolved in acetonitrile (70.0 mL), replaced with nitrogen and stirred at 80℃for 4h. After completion of the TLC monitoring reaction, ethyl acetate was added for dilution, celite was used for filtration, and the filtrate was dried by spin-drying and separated by column chromatography to give the product 10-6 (2.3 g).
Step g: preparation of intermediate 3-fluoro-5- (2 a-hydroxy-1, 4-dimethylene-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (10-7)
Intermediate 10-6 (300.0 mg,1.14 mmol), 3-cyano-5-fluorobenzeneboronic acid (376.0 mg,2.28 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (41.7 mg,0.057 mmol), sodium carbonate (241.7 mg,2.28 mmol) were dissolved in 1, 4-dioxane (8.0 mL) and water (2.0 mL), replaced with nitrogen, and stirred at 100℃for 2h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave the product 10-7 (278.0 mg).
Step h: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -1, 4-dimethylene-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (10-8)
Intermediate 10-7 (278.0 mg,0.92 mmol), 4-dimethylaminopyridine (11.2 mg,0.092 mmol), triethylamine (232.7 mg,2.3 mmol) were dissolved in anhydrous dichloromethane (5.0 mL), cooled to 0deg.C, acetic anhydride (187.8 mg,1.84 mmol) was added dropwise and stirred at 0deg.C for 5h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave product 10-8 (233.0 mg).
Step i: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -1, 4-dioxo-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (10-9)
Intermediate 10-8 (233.0 mg,0.67 mmol) was dissolved in dichloromethane (5.0 mL), acetonitrile (5.0 mL) and water (1.0 mL), ruthenium trichloride (13.9 mg,0.067 mmol) was added, cooled to 0deg.C, sodium periodate (723.3 mg,3.35 mmol) was added, and stirred at 0deg.C for 3h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave the product 10-9 (140.0 mg).
Step j: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -1, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (10-10)
Intermediate 10-9 (80.0 mg,0.23 mmol) was dissolved in anhydrous dichloromethane (1.0 mL), diethylaminosulfur trifluoride (3.0 g,18.4 mmol) was added, and the mixture was stirred at 80℃for 10h. After completion of the reaction by TLC, the reaction solution was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the product 10-10 (34.0 mg) was isolated by preparative plate.
Step k: preparation of 3-fluoro-5- (1, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 10)
Intermediate 10-10 (34.0 mg,0.086 mmol) was dissolved in tetrahydrofuran (2.0 mL) and water (0.5 mL), lithium hydroxide (4.1 mg,0.17 mmol) was added, and stirred at room temperature for 2h. After completion of the reaction, TLC was followed by addition of water, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation of the target compound 10 (20.0 mg) was isolated from the plate.
ESI-MS m/z:396[M-H+HCO 2 H]-; 1 H NMR(500MHz,DMSO-d 6 )δ8.21(1H),8.13(2H),8.09(1H),7.92–7.89(1H),6.18(1H),3.00–2.86(4H)。
Example 11: preparation of trans-3-fluoro-5- (1, 2,3, 4-hexafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (compound 11) and cis-3-fluoro-5- (1, 2,3, 4-hexafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (compound 12)
The synthetic route is as follows:
step a: preparation of intermediate 6-bromo-2 a-hydroxy-2 a, 3-dihydro-1H-cyclopenta [ cd ] indene-1, 4 (2H) -dione (11-1)
Intermediate 10-6 (3.3 g,12.5 mmol) was dissolved in dichloromethane (30.0 mL), acetonitrile (30.0 mL) and water (30.0 mL), ruthenium trichloride (269.6 mg,1.3 mmol) was added, cooled to 0deg.C, sodium periodate (21.6 g,100.0 mmol) was added, and stirred at 0deg.C for 1h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave the product 11-1 (2.1 g).
Step b: preparation of intermediate 6-bromo-1, 4-bis ((3-methoxypropyl) imino) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (11-2)
Intermediate 11-1 (1.0 g,3.7 mmol), 3-methoxypropylamine (2.6 g,29.6 mmol) and trifluoroacetic acid (79.8 mg,0.7 mmol) were dissolved in toluene (35.0 mL) and heated to reflux with a water separator for 3h. After completion of the TLC monitoring, the solvent was spun-dried to give the crude product 11-2.
ESI-MS m/z:409[M+H] + 。
Step c: preparation of intermediate 6-bromo-2, 3-tetrafluoro-2 a-hydroxy-2 a, 3-dihydro-1H-cyclopenta [ cd ] indene-1, 4 (2H) -dione (11-3)
Intermediate 11-2 (3.7 mmol), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroboric acid) salt (13.1 g,37.0 mmol) and anhydrous sodium sulfate (4.2 g,29.6 mmol) were dissolved in anhydrous acetonitrile (30.0 mL), replaced with nitrogen, and stirred at 80℃for 8h. After completion of the TLC monitoring reaction, concentrated hydrochloric acid (3.0 mL) was added at room temperature, stirred for 0.5h, extracted with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried by spin-on, and separated by column chromatography to give the product 11-3 (465.0 mg).
Step d: preparation of intermediate 6-bromo-2, 3-tetrafluoro-1, 4-dioxo-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl benzoate (11-4)
Intermediate 11-3 (250.0 mg,0.74 mmol), triethylamine (303.6 mg,3.0 mmol) were dissolved in anhydrous dichloromethane (10.0 mL), cooled to 0deg.C, benzoyl chloride (267.1 mg,1.9 mmol) was added, and stirred for 2h at 0deg.C. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave the product 11-4 (354.0 mg).
Step e: preparation of intermediate 6-bromo-2, 3-tetrafluoro-1, 4-dihydroxy-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl benzoate (11-5)
Intermediate 11-4 (354.0 mg,0.74 mmol) was dissolved in methanol (10.0 mL), cooled to 0deg.C, sodium borohydride (42.0 mg,1.11 mmol) was added, and stirred at 0deg.C for 3h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave the product 11-5 (208.0 mg).
ESI-MS m/z:491[M-H+HCO 2 H] - ; 1 H NMR(500MHz,Acetonitrile-d 3 )δ8.03(1H),8.02(1H),7.71–7.67(1H),7.56–7.51(4H),5.96–5.90(2H),4.48(2H).
Step f: preparation of the intermediate cis-6-bromo-1, 2, 3-pentafluoro-4-hydroxy-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl benzoate (11-6) and the intermediate trans-6-bromo-1, 2, 3-pentafluoro-4-hydroxy-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl benzoate (11-7)
Intermediate 11-5 (137.0 g,0.31 mmol) was dissolved in anhydrous dichloromethane (5.0 mL), diethylaminosulfur trifluoride (499.7 mg,3.1 mmol) was added, and stirred at 40℃for 1.5h. After completion of the reaction by TLC, the reaction liquid was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the products 11-6 (30.0 mg) and 11-7 (15.0 mg) were isolated by preparative plate.
Step g: preparation of the intermediate trans-6-bromo-1, 2,3, 4-hexafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl benzoate (11-8)
Intermediate 11-6 (30.0 mg,0.067 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), diethylaminosulfur trifluoride (108.0 mg,0.67 mmol) was added, and the mixture was stirred at 80℃for 2h. After completion of the reaction by TLC, the reaction solution was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the product 11-8 (17.0 mg) was isolated by preparative plate.
Step h: preparation of the intermediate trans-6- (3-cyano-5-fluorophenyl) -1,2,3, 4-hexafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl benzoate (11-9)
Intermediate 11-8 (17.0 mg,0.038 mmol), 3-cyano-5-fluorobenzeneboronic acid (12.5 mg,0.076 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (1.4 mg,0.0019 mmol), sodium carbonate (8.1 mg,0.076 mmol) were dissolved in 1, 4-dioxane (1.0 mL) and water (0.1 mL), replaced with nitrogen, and stirred at 100℃for 2h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and the product 11-9 (16.1 mg) was isolated from the preparative plate.
Step i: preparation of trans-3-fluoro-5- (1, 2,3, 4-hexafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 11)
Intermediate 11-9 (16.1 mg,0.033 mmol) was dissolved in methanol (3.0 mL), 4M sodium hydroxide solution (0.08 mL,0.33 mmol) was added, and stirred at room temperature for 1.5h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and then target compound 11 (1.8 mg) was obtained by preparative liquid phase separation.
ESI-MS m/z:432[M-H+HCO 2 H] - ; 1 H NMR(500MHz,Acetonitrile-d 3 )δ8.12(2H),7.89(1H),7.74(1H),7.61(1H),6.01–5.98(1H),5.91–5.87(1H),5.41(1H)。
Step j: preparation of the intermediate cis-6-bromo-1, 2,3, 4-hexafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl benzoate (11-10)
Intermediate 11-7 (15.0 mg,0.033 mmol) was dissolved in anhydrous dichloromethane (1.0 mL), diethylaminosulfur trifluoride (53.2 mg,0.33 mmol) was added, and stirred at 80℃for 2h. After completion of the reaction by TLC, the reaction solution was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the product 11-10 (15.0 mg) was isolated by preparative plate.
Step k: preparation of cis-3-fluoro-5- (1, 2,3, 4-hexafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 12)
Intermediate 11-10 (15.0 mg,0.033 mmol), 3-cyano-5-fluorobenzeneboronic acid (10.9 mg,0.066 mmol), 1-bis (diphenylphosphine) dicyclopentadienyl iron palladium dichloride (1.2 mg,0.0017 mmol), sodium carbonate (7.0 mg,0.066 mmol) were dissolved in 1, 4-dioxane (1.0 mL) and water (0.1 mL), replaced with nitrogen, and stirred at 100 ℃ for 2h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and the objective compound 12 (25.2 mg) was obtained by preparative plate separation.
ESI-MS m/z:432[M-H+HCO 2 H] - ; 1 H NMR(500MHz,Acetonitrile-d 3 )δ7.91(1H),7.82(1H),7.79(1H),7.78–7.75(1H),7.61(1H),6.69(1H),5.92(1H),4.74(1H)。
Example 12: preparation of 3-fluoro-5- (1,2,2,4,4-pentafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 13)
The synthetic route is as follows:
step a: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -2, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (13-1)
Intermediate 9-2 (100.0 mg,0.27 mmol) was dissolved in anhydrous dichloromethane (0.5 mL), diethylaminosulfur trifluoride (1.3 g,8.1 mmol) was added, and the mixture was stirred at 80℃for 5h. After completion of the reaction by TLC, the reaction liquid was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried by spin-drying, and separated by column chromatography to give the product 13-1 (89.7 mg).
Step b: preparation of intermediate 1-bromo-6- (3-cyano-5-fluorophenyl) -2, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (13-2)
Intermediate 13-1 (60 mg,0.15 mmol), N-bromosuccinimide (101.5 mg,0.75 mmol), azobisisobutyronitrile (24.6 mg,0.15 mmol) was dissolved in carbon tetrachloride (3.0 mL), displaced with nitrogen and stirred at 80℃for 48h. After completion of the TLC monitoring reaction, extraction with methylene chloride, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and plate separation gave the product 13-2 (48.0 mg).
1 H NMR(500MHz,DMSO-d 6 )δ8.22–8.20(2H),8.18(1H),8.09(1H),7.95(1H),6.02(1H),3.53(1H),3.18(1H),2.14(3H).
Step c: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -2, 4-tetrafluoro-1-hydroxy-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (13-3)
Intermediate 13-2 (40 mg,0.085 mmol) sodium periodate (36.7 mg,0.17 mmol) was dissolved in anhydrous N, N-dimethylformamide (2.0 mL) and stirred at 150℃for 48h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and the product 13-3 (10.0 mg) was isolated from the preparative plate.
Step d: preparation of intermediate 6- (3-cyano-5-fluorophenyl) -1,2,2,4,4-pentafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (13-4)
Intermediate 13-3 (8.0 mg,0.02 mmol) was dissolved in anhydrous dichloromethane (1.0 mL), cooled to-78 ℃, diethylaminosulfur trifluoride (6.4 mg,0.04 mmol) was added, and stirred at-78℃for 1h. After completion of the reaction by TLC, the reaction solution was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin-drying, and the product 13-4 (6.9 mg) was isolated by preparative plate.
Step e: preparation of 3-fluoro-5- (1,2,2,4,4-pentafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) benzonitrile (Compound 13)
Intermediate 13-4 (6.9 mg,0.017 mmol) was dissolved in tetrahydrofuran (2 mL) and water (0.5 mL), lithium hydroxide (0.8 mg,0.034 mmol) was added and stirred at room temperature for 2h. After completion of the reaction, TLC was followed by addition of water, extraction with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and preparation of the target compound 13 (4.0 mg) was isolated from the plate.
ESI-MS m/z:414[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.18(1H),8.10–8.05(2H),7.95–7.92(2H),6.96(1H),5.95(1H),3.27–3.08(2H)。
Example 13: preparation of 2, 4-tetrafluoro-6- (5-fluoro-1H-indazol-1-yl) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (Compound 14)
The synthetic route is as follows:
step a: preparation of intermediate 6-bromo-2, 2-difluoro-4-methylene-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (14-1)
Intermediate 1-4 (8.3 g,28.91 mmol) was dissolved in anhydrous dichloromethane (80.0 mL), 4-dimethylaminopyridine (0.3 g,2.89 mmol) and triethylamine (7.3 g,72.28 mmol) were added, cooled to 0deg.C, acetic anhydride (5.9 g,57.82 mmol) was added dropwise and stirred at room temperature for 12h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave product 14-1 (8.6 g).
Step b: preparation of intermediate 6-bromo-2, 2-difluoro-4-oxo-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (14-2)
Intermediate 14-1 (2.0 g,6.08 mmol) and ruthenium trichloride (126.5 mg,0.61 mmol) were dissolved in dichloromethane (10.0 mL), acetonitrile (10.0 mL) and water (10.0 mL), cooled to 0deg.C, sodium periodate (6.6 g,30.40 mmol) was added and stirred for 1h at 0deg.C. After completion of the TLC monitoring reaction, water was added, extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and separated by column chromatography to give the product 14-2 (1.4 g).
Step c: preparation of intermediate 6-bromo-2, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-yl acetate (14-3)
Intermediate 14-2 (1.4 g,4.23 mmol) was dissolved in anhydrous dichloromethane (1.0 mL), diethylaminosulfur trifluoride (27.3 g,169.20 mmol) was added, and the mixture was stirred at 80℃for 10h. After completion of the reaction by TLC, the reaction solution was quenched into saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, dried by spin-drying, and separated by column chromatography to give 14-3 (930.0 mg).
Step d: preparation of intermediate 6-bromo-2, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (14-4)
Intermediate 14-3 (557.0 mg,1.58 mmol) was dissolved in tetrahydrofuran (10.0 mL) and water (2.0 mL), lithium hydroxide (113.5 mg,4.74 mmol) was added, and stirred at room temperature overnight. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration, spin-drying, and column chromatography gave product 14-4 (393.0 mg).
ESI-MS m/z:355[M-H+HCO 2 H] - 。
Step e: preparation of 2, 4-tetrafluoro-6- (5-fluoro-1H-indazol-1-yl) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (Compound 14)
Intermediate 14-4 (80.0 mg,0.26 mmol), 5-fluoroindazole (53.1 mg,0.39 mmol), tris (dibenzylideneacetone) dipalladium (23.8 mg,0.026 mmol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (22.1 mg,0.052 mmol) and potassium tert-butoxide (58.3 mg,0.52 mmol) were dissolved in toluene (5.0 mL), displaced with nitrogen and stirred at 120℃for 2h. After completion of the TLC monitoring reaction, water was added thereto, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and column chromatography was performed to obtain the target compound 14 (40.0 mg).
ESI-MS m/z:408[M+H+MeCN] + ; 1 H NMR(500MHz,DMSO-d 6 )δ8.42(1H),7.91–7.87(2H),7.81(1H),7.71(1H),7.42(1H),6.78(1H),4.04(1H),3.48(1H),2.95–2.80(2H)。
Example 14: preparation of 1- (2, 4-tetrafluoro-2 a-hydroxy-2, 2a,3, 4-tetrahydro-1H-cyclopenta [ cd ] inden-6-yl) -1H-indazole-6-carbonitrile (Compound 15)
The synthetic route is as follows:
intermediate 14-4 (50.0 mg,0.16 mmol), 6-cyanoindazole (34.4 mg,0.24 mmol), tris (dibenzylideneacetone) dipalladium (14.7 mg,0.016 mmol), 2-di-tert-butylphosphino-2 ',4',6' -triisopropylbiphenyl (13.6 mg,0.032 mmol) and potassium tert-butoxide (35.9 mg,0.32 mmol) were dissolved in toluene (3.0 mL), replaced with nitrogen and stirred at 120℃for 5h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and the title compound 15 (35.0 mg) was obtained by preparative plate separation.
ESI-MS m/z:418[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ8.61(1H),8.51(1H),8.12(1H),7.94(1H),7.88(1H),7.65(1H),6.79(1H),4.05(1H),3.50(1H),2.95–2.81(2H)。
Example 15: preparation of 2, 4-tetrafluoro-6- (5-fluoro-1H-indol-1-yl) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (Compound 16)
The synthetic route is as follows:
intermediate 14-4 (50.0 mg,0.16 mmol), 5-fluoroindazole (32.4 mg,0.24 mmol), tris (dibenzylideneacetone) dipalladium (23.8 mg,0.016 mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (24.8 mg,0.052 mmol) and potassium tert-butoxide (58.3 mg,0.52 mmol) were dissolved in toluene (3.0 mL), purged with nitrogen, and stirred at 120℃for 3h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and then target compound 16 (15.0 mg) was obtained by preparative liquid phase separation.
ESI-MS m/z:410[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ7.80(1H),7.70(1H),7.67(1H),7.53(1H),7.44(1H),7.06(1H),6.76(1H),6.72(1H),4.03(1H),3.45(1H),2.95–2.79(2H)。
Example 16: preparation of 2, 4-tetrafluoro-6- (6-fluoro-1H-indol-1-yl) -1,2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (Compound 17)
The synthetic route is as follows:
intermediate 14-4 (20.0 mg,0.064 mmol), 6-fluoroindole (13.0 mg,0.096 mmol), tris (dibenzylideneacetone) dipalladium (5.9 mg,0.0064 mmol), 2-dicyclohexylphosphorus-2 ',4',6' -triisopropylbiphenyl (6.2 mg,0.013 mmol) and potassium tert-butoxide (14.6 mg,0.13 mmol) were dissolved in toluene (1.0 mL), displaced with nitrogen and stirred at 100deg.C for 2h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and then target compound 17 (3.0 mg) was obtained by preparative liquid phase separation.
ESI-MS m/z:410[M-H+HCO 2 H] - ; 1 H NMR(500MHz,DMSO-d 6 )δ7.73(1H),7.71(1H),7.69–7.65(2H),7.33(1H),7.05–7.00(1H),6.76(1H),6.75–6.74(1H),4.03(1H),3.46(1H),2.94–2.80(2H)。
Example 17: preparation of 6- (1H-benzo [ d ] imidazol-1-yl) -2, 4-tetrafluoro-1, 2,3, 4-tetrahydro-2 aH-cyclopenta [ cd ] inden-2 a-ol (Compound 18)
The synthetic route is as follows:
intermediate 14-4 (55.0 mg,0.18 mmol), benzimidazole (31.9 mg,0.27 mmol), tris (dibenzylideneacetone) dipalladium (16.5 mg,0.018 mmol), 2-di-tert-butylphosphorus-3, 4,5, 6-tetramethyl-2 ',4',6' -triisopropylbiphenyl (17.3 mg,0.036 mmol) and tripotassium phosphate (76.4 mg,0.36 mmol) were dissolved in toluene (5.0 mL), replaced with nitrogen and stirred at 120℃for 2h. After completion of the TLC monitoring reaction, water was added, extraction was performed with ethyl acetate, washing with saturated brine, drying over anhydrous sodium sulfate, filtration and spin-drying, and the title compound 18 (24.2 mg) was obtained by preparative plate separation.
ESI-MS m/z:393[M-H+HCO 2 H]-; 1 H NMR(500MHz,DMSO-d 6 )δ8.54(1H),7.76–7.70(3H),7.56–7.54(1H),7.27(2H),6.74(1H),3.99(1H),3.41(1H),2.89–2.74(2H)。
Biological assay
Detection of EPO inhibition Rate of Compounds Using Hep3B cells
At 5X 10 4 Hep3B cells (cell bank of China academy of sciences, TCHu 106) were plated per mL at 37℃with 5% of IICarbon oxide incubator (Thermo Scientific BB, 150) overnight. The following day the cells were starved for 6 hours by changing the medium to one containing 0.5% FBS (Vivacell C04001-500), after which (6 ' -hydroxy-3 ' - (4-methoxyphenyl) -8' -oxo-8'H-spiro [ cyclopentane-1, 5' -indolizine) was added]After the plates were kept in a 37℃incubator with 5% carbon dioxide for 24 hours, a DMSO solution of the test compound was added to give final concentrations of 30000nM,7500nM,1875nM,469nM, 29nM,7.3nM,1.8nM,0.5nM and 0nM, respectively, and the reaction was continued for 48 hours, and cell supernatants were collected for EPO ELISA detection, and the detection was performed according to the ELISA kit (Shanghai Co., ltd., D711311-0096) protocol, and the values were read at a wavelength of 450nm (microplate reader, thermo Scientific (Multiskan Go), 511191200). Compound inhibition rate calculation formula: compound inhibition ratio = 1-100% > (dosing well EPO value-blank well EPO value)/(Control well EPO value-blank well EPO value). Calculating IC by linear fitting of inhibition rate 50 Values. Wherein Control hole: the concentration of the compound to be tested is 0nM and the final concentration is 30. Mu.M (6 ' -hydroxy-3 ' - (4-methoxyphenyl) -8' -oxo-8'H-spiro [ cyclopentane-1, 5' -indolizine)]-7' -carbonyl) or the like in DMSO for 72h to give a cell-containing well with an EPO content of 100%; blank holes: cell-containing wells without any compound added.
IC of some embodiments 50 The data are provided in Table 1, wherein A represents IC 50 Less than or equal to 1 mu M, B represents 1 mu M<IC 50 C represents IC and is less than or equal to 5 mu M 50 >5μM。
TABLE 1
Examples numbering | IC 50 (μM) | Examples numbering | IC 50 (μM) |
Example 1 | B | Example 10 | C |
Example 2 | B | Example 11 | B |
Example 3 | B | Example 12 | C |
Example 4 | A | Example 13 | C |
Example 5 | B | Example 14 | B |
Example 6 | C | Example 15 | C |
Example 7 | C | Example 16 | C |
Example 8 | A | Example 17 | C |
Example 9 | B | Example 18 | C |
The compounds of the examples tested showed excellent inhibitory activity against EPO.
While particular embodiments of the invention have been illustrated and described, it is not intended that these embodiments illustrate and describe all possible forms of the invention. Rather, the words used in the specification are words of description rather than limitation. It will be apparent to those skilled in the art that various other changes and modifications can be made without departing from the general scope of the disclosure. Accordingly, it is intended in the appended claims to cover all such changes and modifications that are within the scope of this invention.
Claims (16)
1. A compound of formula (I):
wherein,
ring A is selected from C5-C6 cycloalkyl or C5-C6 cycloalkenyl, said C5-C6 cycloalkyl or C5-C6 cycloalkenyl being optionally substituted with 1, 2, 3 or 4R,
ring B is selected from C5-C6 aryl or C5-C10 benzoheteroaryl, said C5-C6 aryl or C5-C10 benzoheteroaryl being optionally substituted with 1, 2 or 3R, and said C5-C10 benzoheteroaryl optionally containing 1 or 2N heteroatoms,
R 1 、R 2 、R 3 、R 4 each independently selected from the group consisting of hydrogen and halogen,
R 5 selected from the group consisting of hydrogen, halogen or hydroxy,
r are each independently selected from hydrogen, halogen, C1-C3 alkyl, or cyano, or two of R together with the carbon atom to which they are directly attached form an cycloalkenyl group, or
Pharmaceutically acceptable salts thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 5 Is halogen or hydroxy.
3. The compound, or pharmaceutically acceptable salt, according to claim 1, wherein the compound is of formula (II),
wherein the ring B, R 1 、R 2 、R 3 、R 4 And R is 5 As defined above;
R 6 and R is 7 Each independently selected from hydrogen or halogen;
R 8 、R 9 independently selected from hydrogen, halogen or C1-C3 alkyl, or R 8 And R is 9 Together with the carbon atom to which it is directly attached, forms an cycloalkenyl group.
4. A compound, or pharmaceutically acceptable salt, according to claim 3, wherein R 1 、R 2 、R 3 、R 4 Each independently is H or F.
5. A compound, or pharmaceutically acceptable salt, according to claim 3, wherein R 5 F or OH.
6. A compound, or pharmaceutically acceptable salt, according to claim 3, wherein R 6 、R 7 Each independently is H, F or methyl.
7. A compound, or pharmaceutically acceptable salt, according to claim 3, wherein R 8 、R 9 Each independently is H, F or methyl, or R 8 And R is 9 Together with the carbon atom to which it is directly attached, forms an exocyclic vinyl group.
8. The compound, or pharmaceutically acceptable salt, according to any one of claims 1-7, wherein the compound is represented by formula (II-1) or formula (II-2),
wherein R is 1 -R 9 As defined above;
R 10 、R 11 、R 12 each independently selected from hydrogen, halogen or cyano; and is also provided with
X, Y, Z are each independently C or N.
9. The compound, or pharmaceutically acceptable salt, according to claim 8, wherein R 10 、R 11 、R 12 H, F or CN.
10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (III),
Wherein,is->
R 1 -R 5 As defined above; and is also provided with
R 6 And R is 7 Each independently selected from hydrogen or halogen;
R 10 、R 11 、R 12 each independently selected from hydrogen, halogen or cyano.
11. The compound, or pharmaceutically acceptable salt, according to claim 10, wherein R 6 、R 7 Each independently H.
12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein R 10 、R 11 、R 12 Each independently H, F or CN.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of,
14. a pharmaceutical composition comprising a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, adjuvants or excipients.
15. Use of a compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, in the manufacture of a medicament for the treatment of a disease or disorder associated with EPO.
16. The use of claim 15, wherein the EPO-associated diseases and conditions are selected from the group consisting of: polycythemia, renal cell carcinoma, bladder carcinoma, breast carcinoma, cervical carcinoma, colorectal carcinoma, small intestine carcinoma, colon carcinoma, rectal carcinoma, anal carcinoma, endometrial carcinoma, head and neck carcinoma, liver carcinoma, lung carcinoma, ovarian carcinoma, prostate carcinoma, testicular carcinoma, uterine carcinoma, esophageal carcinoma, gallbladder carcinoma, pancreatic carcinoma, thyroid carcinoma, parathyroid carcinoma, skin carcinoma, and brain carcinoma.
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