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HK1260481A1 - Macrocyclic mcl1 inhibitors for treating cancer - Google Patents

Macrocyclic mcl1 inhibitors for treating cancer Download PDF

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Publication number
HK1260481A1
HK1260481A1 HK19120306.6A HK19120306A HK1260481A1 HK 1260481 A1 HK1260481 A1 HK 1260481A1 HK 19120306 A HK19120306 A HK 19120306A HK 1260481 A1 HK1260481 A1 HK 1260481A1
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HK
Hong Kong
Prior art keywords
chloro
methyl
tetramethyl
dithia
oxa
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HK19120306.6A
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Chinese (zh)
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HK1260481B (en
Inventor
Alexander Hird
Matthew Alan BELMONTE
Wenzhan YANG
John Paul SECRIST
Daniel William ROBBINS
Steven Lee KAZMIRSKI
Dedong Wu
Bo Peng
Jeffrey Johannes
Michelle Laurae LAMB
Qing Ye
Xiaolan Zheng
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Astrazeneca Ab
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Publication of HK1260481A1 publication Critical patent/HK1260481A1/en
Publication of HK1260481B publication Critical patent/HK1260481B/en

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Description

Macrocyclic MCL-1 inhibitors for the treatment of cancer
Background
Myeloid leukemia 1(Mcl-1) is an important anti-apoptotic member of the BCL-2 family of proteins and a major regulator of cell survival. Amplification of the MCL1 gene and/or overexpression of the MCL-1 protein has been observed in a variety of cancer types and is often involved in tumor development. Indeed, MCL1 is one of the most commonly amplified genes in human cancers. In many malignancies, Mcl-1 is a key survival factor and has been shown to mediate resistance to a variety of anticancer agents.
Mcl-1 promotes cell survival by binding to pro-apoptotic proteins such as Bim, Noxa, Bak and Bax and neutralizing their death-inducing activity. Inhibition of Mcl-1 thereby releases these pro-apoptotic proteins, often resulting in the induction of apoptosis in tumor cells that are dependent on Mcl-1 for survival. Thus, therapeutically targeting Mcl-1, alone or in combination with other therapies, is a promising strategy to treat numerous malignancies and overcome drug resistance in many human cancers.
SUMMARY
In one embodiment, disclosed is 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1(37) 4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula I)
In one embodiment, disclosed is (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula II)
Or a pharmaceutically acceptable salt thereof.
In one embodiment, disclosed is a compound that is (S)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020, 24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula III)
Or a pharmaceutically acceptable salt thereof.
In one embodiment, disclosed is a solid form (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula II), or a pharmaceutically acceptable salt thereof.
In one embodiment, disclosed is a pharmaceutical composition comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
In one embodiment, disclosed is a method of treating cancer comprising administering to a subject in need thereof a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In one embodiment, disclosed is a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating cancer.
In one embodiment, disclosed is the use of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
In one embodiment, disclosed is a pharmaceutical composition comprising a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, for use in treating cancer.
Brief description of the drawings
FIG. 1 illustrates form A (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Powder X-ray diffraction pattern of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate.
FIG. 2 illustrates form A (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) traces of trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate.
FIG. 3 illustrates form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Powder X-ray diffraction pattern of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
FIG. 4 illustrates form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) traces of trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
FIG. 5 illustrates form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Powder X-ray diffraction pattern of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
FIG. 6 illustrates form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) traces of trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
FIG. 7 illustrates form E (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Powder X-ray diffraction pattern of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
FIG. 8 illustrates form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazaHeptyl ring [27.7.1.14,7.011,15.016,21.020,24.030,35]Powder X-ray diffraction pattern of octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate.
FIG. 9 illustrates form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) traces of octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate.
FIG. 10 illustrates (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Powder X-ray diffraction pattern of the sodium salt of trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
FIG. 11 illustrates (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) traces of the sodium salt of trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
FIG. 12 illustrates (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Powder X-ray diffraction pattern of meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate.
FIG. 13 illustrates (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) traces of the meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate salt.
FIG. 14 illustrates the dose-dependent antitumor activity of example 2 in MOLP-8 tumor-bearing mice.
FIG. 15 illustrates the anti-tumor activity of example 2 in combination with bortezomib in NCI-H929 tumor-bearing mice.
FIG. 16 illustrates tumor regression induced by example 2 in MV-4-11 tumor-bearing mice.
Detailed Description
Compound (I)
In one embodiment, disclosed is 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula I)
Or a pharmaceutically acceptable salt thereof. In some aspects, disclosed are 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid. In some aspects, disclosed are 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]A pharmaceutically acceptable salt of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
In some embodiments, disclosed is (R)a) -17-chloro-5, 13,14, 22-tetramethylenetetramethylRadical-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula II)
Or a pharmaceutically acceptable salt thereof. In some aspects disclosed is (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid. In some aspects disclosed is (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]A pharmaceutically acceptable salt of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
In some embodiments, disclosed is (S)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula III)
Or a pharmaceutically acceptable salt thereof. In some aspects, disclosed is (S)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid. In some aspects, disclosed is (S)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]A pharmaceutically acceptable salt of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
The language "pharmaceutically acceptable salts" includes acid addition salts or base salts that retain the biological effectiveness and properties of the compounds of formulas (I), (II), and (III), and are typically not biologically or otherwise undesirable acid addition salts or base salts. In many cases, compounds of formula (I), (II) and (III) are capable of forming acid and/or base salts due to the presence of basic and/or carboxyl groups or groups similar thereto. In one embodiment, the pharmaceutically acceptable salt comprises a quaternary ammonium salt.
Pharmaceutically acceptable acid addition salts may be formed using inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, choline theophyllinate, citrate, edisylate (ethanedisulphonate), fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate, palmoate, phosphate/hydrogen phosphate/dihydrogen phosphate, dihydrogenphosphate, dihydrogensulfonate, Polygalacturonate, propionate, stearate, succinate, salicylate, sulfate/bisulfate, tartrate, tosylate, and trifluoroacetate. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonia as well as salts of ammonium and metals from columns I through XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include isopropylamine, benzathine, choline salt (cholinate), diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. In some aspects, the pharmaceutically acceptable salt of the compound of formula (I), (II), or (III) is a sodium salt. In some aspects, the pharmaceutically acceptable salt of the compound of formula (I), (II), or (III) is a meglumine salt.
Pharmaceutically acceptable salts of compounds of formula (I), (II) or (III) may be synthesized from basic or acidic moieties by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na)+、Ca2+、Mg2+Or K+Hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Typically, such reactions are carried out in water or in an organic solvent or in a mixture of the two. Generally, where feasible, it is desirable to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile. Additional lists of suitable salts can be found in, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mach publishing company (Mack publishing company), Iston, Pa. (1985); bergege (Berge), etcHuman, "journal of pharmaceutical science (j.pharm.sci.), 1977, 66, 1-19; and "handbook of pharmaceutically acceptable salts" of Stahl (Stahl) and wermute (Wermuth): properties, Selection and use (Handbook of pharmaceutical Salts: Properties, Selection, and use) "(Wiley-VCH Press, Weinheim (Weinheim), Germany, 2002).
Any formula given herein is also intended to represent unlabeled forms of the compounds of formula (I), (II), or (III) as well as isotopically labeled forms. Isotopically-labeled compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by the same element but with a different number of atoms by mass. Examples of isotopes that can be incorporated into compounds of formulae (I), (II) and (III) and salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、35S and125I. the compounds of formula (I), (II), (III) may include various isotopically labeled compounds in which a radioisotope, e.g., one in which a radioisotope is present3H、11H、14C、35S and36and (4) Cl. Isotopically-labelled compounds of formulae (I), (II) and (III) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using appropriate isotopically-labelled reagents in place of the non-labelled reagents previously employed.
The compounds of formulae (I), (II) and (III) may have different isomeric forms. The language "optical isomers" and "stereoisomers" refers to any of the various stereoisomeric configurations that may exist for a given compound of formulae (I), (II), and (III). In particular, due to limited rotation around the biaryl bond, the compounds of formula (I), (II) or (III) possess axial chirality and may therefore exist as mixtures of enantiomers/atropisomers with an enantiomeric excess of about 0% with>Between 98% e.e. When the compounds are in the form of pure enantiomers,can be passed through RaOr SaThe stereochemistry at each chiral center is specified. Such nomenclature may also be used for mixtures enriched in one enantiomer. Further description of atropisomerism and axial chirality and configurational ordering rules can be found in Elel (Eliel), E.L. and Wilen (Wilen), S.H. 'Stereochemistry of Organic Compounds' ('Stereochemistry of Organic Compounds') John Willi-Chi corporation (John Wiley and Sons, Inc.) 1994. Resolved compounds, whose absolute configuration is unknown, can be assigned (+) or (-) depending on the direction (dextro-or laevorotary) in which they rotate plane-polarized light at the wavelength of the sodium D line. The disclosure is intended to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)a) -and (S)a) Isomers may be prepared using chiral synthons, chiral reagents or chiral catalysts, or resolved using conventional techniques well known in the art, such as chiral HPLC.
Also disclosed are intermediates 1-25 and salts thereof in the examples.
Solid forms
In some embodiments, disclosed are solid forms of the compounds of formulas (I), (II), and (III), or pharmaceutically acceptable salts thereof. The term "solid form" includes polymorphs, crystalline salts, solvates, hydrates and amorphous forms of the compounds of formula (I), (II) and (II). The term "polymorph" includes crystalline materials having the same chemical composition but different molecular packing. The language "crystalline salt" includes crystal structures having the same chemical material but incorporating acid or base addition salts within the molecular packing of the crystal structure. The term "solvate" includes a crystal structure having the same chemical material but incorporating solvent molecules within the molecular packing of the crystal structure. The term "hydrate" includes a crystal structure having the same chemical material but incorporating water molecules within the molecular packing of the crystal structure. The language "amorphous form" includes compounds having the same molecular material, but not having the same molecular order of the crystal structure (e.g., polymorph, crystalline salt, solvate, or hydrate) of the molecular material.
It is generally known that solid materials can be characterized using conventional techniques such as X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of these solid materials can be determined by Karl Fischer analysis (Karl Fischer analysis).
The solid forms described herein provide XRPD patterns that are substantially the same as the XRPD patterns shown in the figures, and have a wide variety of 2-theta (2 theta) values as shown in the tables included herein. Those skilled in the art will appreciate that XRPD patterns or diffraction patterns may be obtained with one or more measurement errors depending on the measurement conditions (e.g., the equipment or machine used). Similarly, it is generally known that the intensity in an XRPD pattern can fluctuate as a result of preferred orientation depending on the measurement conditions or sample preparation. Those skilled in the art of XRPD will further appreciate that the relative intensities of peaks may also be affected by particles, for example, in excess of 30 μm in size and of non-uniform aspect ratio. It is understood by those of ordinary skill in the art that the position of the reflection can be affected by the exact height at which the sample is located in the diffractometer and the zero point correction of the diffractometer. The surface planarity of the sample may also have a subtle effect.
As a result of these considerations, the Diffraction pattern data presented should not be considered as absolute values (Jenkins R and sindel r.l. (Snyder, r.l.) 'Introduction to X-Ray powder Diffraction method' ('introductions to X-Ray powder Diffraction'), wilford willey & Sons 1996, bon C.W. (Bunn, C.W.) (1948), Chemical Crystallography (Chemical Crystallography), London clarithron de edition (clarendon press, London); kluge H.P. (Klug, H.P.) and Alexander L.E. (Alexander, L.E.) (1974), X-Ray Diffraction program (X-Ray Diffraction). It should also be understood that the solid forms embodied herein are not limited to those providing XRPD patterns identical to those shown in the figures, and that any solid form providing XRPD patterns substantially identical to those shown in the figures falls within the scope of the corresponding embodiments. Those skilled in the art of XRPD can judge substantial consistency of XRPD patterns. Typically, the measurement error in diffraction angles in XRPD is about 2 θ (± 0.2 °), and the degree of such measurement error should be taken into account when considering the X-ray powder diffraction patterns in these figures and when reading the data contained in the tables included herein.
It will also be understood by those skilled in the art that the value or range of values observed in the DSC thermogram for a particular compound will show variation between different purity batches. Thus, while the range may be small for one compound, the range may be quite large for other compounds. Typically, the measurement error of the diffraction angle in a DSC thermal event is about plus or minus 5 ℃, and the extent of such measurement error should be taken into account when considering the DSC data contained therein. TGA thermograms show similar variations so that one skilled in the art recognizes that these measurement errors should be taken into account when judging the essential identity of the TGA thermograms.
In some embodiments, disclosed are solid forms (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid, or a pharmaceutically acceptable salt thereof.
In some embodiments, disclosed are amorphous forms (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid, or a pharmaceutically acceptable salt thereof.
Form A
In some embodiments, disclosed are formsA(Ra) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak at about 7.0 ° expressed in 2 Θ (± 0.2 °).
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak at about 8.4 ° expressed in 2 Θ (± 0.2 °).
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak at about 12.5 ° expressed in 2 Θ (± 0.2 °).
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrateHaving an XRPD pattern comprising at least one peak at about 7.0 ° and 8.4 ° expressed as 2 Θ (± 0.2 °).
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak at about 7.0 ° and 12.5 ° expressed as 2 θ (± 0.2 °).
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak at about 8.4 ° and 12.5 ° expressed as 2 θ (± 0.2 °).
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak at about 7.0 °, 8.4 ° and 12.5 ° expressed in 2 θ (± 0.2 °).
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from about 5.4 °,7.0 °, 8.4 °, 10.7 °, 12.5 °,13.1 °, 14.4 °, 15.1 °, 15.6 °, 17.1 ° and 18.2 °.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern comprising at least one peak expressed in 2 Θ (± 0.2 °) selected from the peaks listed in table 2.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has an XRPD pattern substantially similar to that of fig. 1.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has a DSC thermogram comprising an endotherm with an onset of desolvation at about 121 ℃ and a peak at about 152 ℃.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has a DSC thermogram comprising an endotherm that begins to melt/decompose at about 181 ℃ and peaks at about 194 ℃.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-29-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has a DSC profile substantially similar to that of figure 2.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has a TGA thermogram exhibiting a mass loss of about 4.0% after heating from about 25 ℃ to about 160 ℃.
In some embodiments, form a (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate has a TGA profile substantially similar to that of figure 2.
Form B
In some embodiments, disclosed is form B (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Methanol trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid solvate
Form C
In some embodiments, disclosed is form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the group consisting of about 5.1 °,6.8 °,8.1 °, 10.1 °, 12.0 °, 14.1 °, 14.8 °, 15.3 °, 16.5 ° and 17.2 °.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the peaks listed in table 3.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern substantially similar to that of fig. 3.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a DSC thermogram including an endotherm with an onset of desolvation at about 123 ℃ and a peak at about 140 ℃.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentaazahept-eRing [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a DSC thermogram including an endotherm with a melting/decomposition onset at about 185 ℃ and a peak at about 196 ℃.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a DSC profile substantially similar to that of figure 4.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a TGA thermogram exhibiting a mass loss of about 6.4% after heating from about 25 ℃ to about 160 ℃.
In some embodiments, form C (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a TGA profile substantially similar to that of figure 4.
Form D
In some embodiments, disclosed is form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
In some casesIn the examples, form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the group consisting of about 5.7 °, 8.0 °, 11.7 °, 13.4 °, 14.7 °, 16.5 °, 18.5 °, 19.5 ° and 21.9 °.
In some embodiments, form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the peaks listed in table 4.
In some embodiments, form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern substantially similar to that of fig. 5.
In some embodiments, form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a DSC thermogram including an endotherm with an onset of melting at about 156 ℃ and a peak at about 175 ℃.
In some embodiments, form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a DSC profile substantially similar to that of figure 6.
In some embodiments, form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a TGA thermogram exhibiting a mass loss of about 3.6% after heating from about 25 ℃ to about 170 ℃.
In some embodiments, form D (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has a TGA profile substantially similar to that of figure 6.
Form E
In some embodiments, disclosed is form E (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid.
In some embodiments, form E (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the group consisting of about 8.3 °, 10.2 °, 11.6 °, 12.6 °, 13.9 °, 14.9 °, 16.0 °, 16.5 °, 17.5 ° and 18.6 °.
In some implementationsIn examples, form E (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the peaks listed in table 5.
In some embodiments, form E (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid has an XRPD pattern substantially similar to that of fig. 7.
Form F
In some embodiments, disclosed is form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate.
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak at about 7.9 ° expressed in 2 θ (± 0.2 °).
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tenTriene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak at about 11.9 ° expressed as 2 Θ (± 0.2 °).
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak at about 17.0 ° expressed as 2 θ (± 0.2 °).
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak at about 7.9 ° and 11.9 ° expressed as 2 θ (± 0.2 °).
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak at about 7.9 ° and 17.0 ° expressed as 2 θ (± 0.2 °).
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak at about 11.9 ° and 17.0 ° expressed as 2 θ (± 0.2 °).
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak at about 7.9 °, 11.9 ° and 17.0 ° expressed as 2 θ (± 0.2 °).
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from about 5.4 °, 7.9 °, 10.6 °, 11.9 °, 12.9 °, 14.3 °, 14.9 °, 15.7 °, 17.0 ° and 18.9 °.
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the peaks listed in table 6.
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has an XRPD pattern substantially similar to that of figure 8.
In some embodiments, form F (R)a) 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2,9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has a DSC thermogram comprising an endotherm with an onset of desolvation at about 40 ℃ and a peak at about 67 ℃.
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has a DSC thermogram comprising an endotherm that begins to melt/decompose at about 185 ℃ and peaks at about 195 ℃.
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has a DSC profile substantially similar to figure 9.
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The octadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid pentahydrate has a TGA thermogram exhibiting a mass loss of about 4.3% after heating from about 25 ℃ to about 100 ℃.
In some embodiments, form F (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-2The 3-carboxylic acid pentahydrate has a TGA profile substantially similar to that of figure 9.
Sodium salt
In some embodiments, disclosed is (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °), selected from about 10.7 °, 11.5 °, 13.4 °, 15.3 °, 16.3 °, 18.0 °, 18.6 °, 19.2 °, 19.9 ° and 23.2 °.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the peaks listed in table 7.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has an XRPD pattern substantially similar to that of fig. 10.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5,6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has a DSC thermogram comprising a broad desolvation onset endotherm at about 100 ℃ to about 200 ℃. In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016 ,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has a DSC thermogram comprising an endotherm with an onset of melting/decomposition at about 239 ℃ and a peak at about 246 ℃.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has a DSC profile substantially similar to figure 11.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has a TGA thermogram exhibiting a mass loss of about 4.0% after heating from about 25 ℃ to about 175 ℃.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid sodium salt has a TGA profile substantially similar to that of figure 11.
Meglumine salt
In some embodiments, disclosed is (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid meglumine salt.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid meglumine salt has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from about 6.3 °,7.6 °, 8.5 °, 9.2 °, 11.8 °, 12.9 °, 14.3 °, 15.7 ° and 18.2 °.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate salt has an XRPD pattern comprising at least one peak expressed in 2 θ (± 0.2 °) selected from the peaks listed in table 8.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate salt has an XRPD pattern substantially similar to that of figure 12.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate salt has a DSC thermogram including an endotherm with an onset of desolvation at about 69 ℃ and a peak at about 88 ℃. In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14, 7.011,15.016,21.020,24.030,35]The meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate salt has a DSC thermogram comprising an endotherm that begins to melt/decompose at about 102 ℃ and peaks at about 104 ℃.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid meglumine salt has a DSC profile substantially similar to that of FIG. 13.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate salt has a TGA thermogram exhibiting a mass loss of about 10.6% after heating from about 25 ℃ to about 150 ℃.
In some embodiments, (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]The meglumine trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate salt has a TGA profile substantially similar to that of figure 13.
Pharmaceutical composition
In some embodiments, disclosed are pharmaceutical compositions comprising compounds of formulas (I), (II), and (III), and a pharmaceutically acceptable excipient, carrier, or diluent.
The language "pharmaceutically acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, as determined by one of ordinary skill in the art.
The compositions disclosed may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as finely divided powders or liquid aerosols), for administration by insufflation (e.g., as finely divided powders), or for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular or intramuscular administration or as suppositories for rectal administration).
The compositions disclosed may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, a composition intended for oral use may comprise, for example, one or more coloring, sweetening, flavoring and/or preservative agents.
Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents, such as corn starch or alginic acid; binders, such as starch; lubricants, such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl or propyl paraben; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to modify their breakdown in the gastrointestinal tract and subsequent absorption of the active ingredient or to use conventional coatings and procedures well known in the art to improve their stability and/or appearance.
The composition for oral use may be in the form of: hard capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or soft capsules wherein the active ingredient is mixed with water or an oil (e.g., peanut oil, liquid paraffin, or olive oil).
Aqueous suspensions typically contain the active ingredient in the form of a fine powder or in the form of nano-or micronized particles, in combination with one or more suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of alkylene oxides with fatty acids (e.g. polyoxyethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g. heptadecaethyleneoxycetanol), or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol (e.g. polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g. polyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives, such as ethyl or propyl parabens; antioxidants, such as ascorbic acid; a colorant; a flavoring agent; and/or a sweetening agent, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient in conjunction with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
These pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin, or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums (e.g. acacia or tragacanth), naturally-occurring phosphatides (e.g. soya bean, lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. These emulsions may also contain sweetening, flavoring and preservative agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, a preservative, a flavouring and/or a colouring agent.
The pharmaceutical compositions may also be in the form of sterile injectable aqueous or oleaginous suspensions, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol.
Compositions for administration by inhalation may be in the form of conventional pressurised aerosols arranged to dispense the active ingredient as, or as, aerosols or liquid droplets comprising finely divided solids. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered amount of the active ingredient.
For further information on the formulations, the reader is referred to the Comprehensive Medicinal Chemistry database (Comprehensive Medicinal Chemistry) of Pegman Press 1990 (Corwin Hansch; ed.part 5, Chapter 25.2).
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For further information on the route of administration and the administration protocol, the reader is referred to the integrated pharmaceutical chemistry database of Pegmann Press 1990 (Kowinhamshire; eds.), Vol 5, Chapter 25.3.
The compounds of formulae (I), (II) and (III) may be administered once, twice, three times a day or according to the medically necessary number of times within a 24 hour period. In some embodiments, the compounds of formulae (I), (II), and (III) may be administered daily, once weekly, twice weekly, 3 times weekly, 4 times weekly, 5 times weekly, or 6 times weekly. One skilled in the art will be readily able to determine the amount of each individual dose based on the subject. In some embodiments, the compounds of formulae (I), (II), and (III) are administered in one dosage form. In some embodiments, the compounds of formulae (I), (II), and (III) are administered in multiple dosage forms.
Application method
In one aspect, disclosed is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating cancer.
In one aspect, disclosed is the use of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
In one aspect, disclosed are pharmaceutical compositions comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating cancer.
The term "cancer" includes, but is not limited to, hematological malignancies, such as acute myelogenous leukemia, multiple myeloma, mantle cell lymphoma, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, burkitt's lymphoma, follicular lymphoma, and solid tumors, such as non-small cell lung cancer (NSCLC), Small Cell Lung Cancer (SCLC), breast cancer, neuroblastoma, prostate cancer, melanoma, pancreatic cancer, uterine cancer, endometrial cancer, and colon cancer.
In one aspect, disclosed is a method for treating multiple myeloma in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating multiple myeloma.
In one aspect, disclosed is the use of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating multiple myeloma.
In one aspect, disclosed are pharmaceutical compositions comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for treating multiple myeloma.
In one aspect, disclosed is a method for treating acute myeloid leukemia in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in treating acute myeloid leukemia.
In one aspect, disclosed is the use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of acute myeloid leukemia.
In one aspect, disclosed are pharmaceutical compositions comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for treating acute myeloid leukemia.
In one aspect, disclosed is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in combination with an anti-cancer agent, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with an anti-cancer agent, or a pharmaceutically acceptable salt thereof, for use in treating cancer.
In one aspect, disclosed is the use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with an anti-cancer agent, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
In one aspect, disclosed are pharmaceutical compositions comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with an anti-cancer agent, or a pharmaceutically acceptable salt thereof, for use in treating cancer.
The language "in combination with … …" includes the sequential, separate or simultaneous administration of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, and an anti-cancer agent, or a pharmaceutically acceptable salt thereof. In some aspects, the compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, or a pharmaceutically acceptable salt thereof, are administered in the same formulation (e.g., in a fixed dose formulation). In some embodiments, the compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and the anti-cancer agent, or a pharmaceutically acceptable salt thereof, are administered in separate formulations and at substantially the same time, sequentially, or separately.
The language "anti-cancer agent" includes, but is not limited to, radiation, alkylating agents, angiogenesis inhibitors, antibodies, antibody-drug conjugates, anti-metabolites, anti-mitotic agents, anti-proliferative agents, anti-viral agents, aurora kinase inhibitors, other cell death activators (e.g., inhibitors of Bcl-2, Bcl-xL, Bcl-w, Bfl-1), activators of the death receptor pathway (e.g., FAS or TRAIL agonists), Bcr-Abl kinase inhibitors, BET (bromodomain protein) inhibitors, BiTE (bispecific T cell engager) antibodies, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs (double variable domain antibodies), leukemia virus oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, anti-cancer agents, anti-mitotic agents, anti-proliferative agents, EGFR inhibitors, Heat Shock Protein (HSP) inhibitors, Histone Deacetylase (HDAC) inhibitors, hormone therapy, immunological drugs, Inhibitors of Apoptotic Proteins (IAP), intercalating antibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, mammalian target of rapamycin (mTOR) inhibitors, microRNAs, inhibitors of mitogen-activated extracellular signal-regulated kinase (MEK), BRAF inhibitors, multivalent binding proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum chemotherapeutic agents, polo-like kinase (Plk) inhibitors, phosphoinositide-3 kinase inhibitors, protein body inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, etinoids/deltatoids plant alkaloids, small inhibitory ribonucleic acids (siRNA), topoisomerase inhibitors, And ubiquitin ligase inhibitors. Disclosed herein are combinations of any compound of formula (I), (II) or (III) with an anti-cancer agent.
Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brontalicin, busulfan, cisplatin, carboplatin, carboquone, carmustine (BCNU), chlorambucil, carmustine, and mixtures thereof,(lamotrigine, VNP 40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), macsfamide (mafosfamide), melphalan, dibromomannitol, dibromodulcitol, nimustine, nitrogen oxides of mustard, nitrosoureas, oxaliplatin, ramustine, temozolomide, thiotepa, flutolanil, flutol,(bendamustine), trooshan, rofessifamide, and the like.
Angiogenesis inhibitors include endothelial-specific receptors, (Tie-layer-2) inhibitors ((Tie-2) inhibitors), Epidermal Growth Factor Receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloprotein-2 (MMP-2) inhibitors, matrix metalloprotein-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs, vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors, ALK inhibitors, and the like.
The antimetabolite comprises(disodium pemetrexed, LY 231514, MTA), 5-azacitidine,(Capecitabine), carmofur,(cladribine), clofarabine, cytarabine octadecyl phosphate, arabinosidecytosine, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR (5-ethynyl-1- β -D-ribofuranosylimidazole-4-carboxamide), enocitabine, ethynylcytidine, fludarabine, 5-fluorouracil alone or in combination with folinic acid, and pharmaceutically acceptable salts thereof,(gemcitabine), hydroxyurea,(melphalan), mercaptopurine, 6-mercaptopurine nucleosides, methotrexate, mycophenolic acid, nelarabine, nolatrexed, octadecyl phosphate (ocfosfate), pyritrexol (pellitrexol), pentostatin, pemetrexed (pemetrexed), raltitrexed, ribavirin, triamcinolone (triapine), trimetrexate, S-1, tiazofurin (tiazofurin), tegafur, TS-1, vidarabine, UFT, and the like.
Bcl-2 protein inhibitors include ABT-199, AT-101((-) gossypol),(G3139 or Olimersen (antisense oligonucleotide targeting Bcl-2)), IPI-194, IPI-565, ABT-737, ABT-263, GX-070 (obacarax), and the like.
The Btk inhibitors include ibrutinib and acarabtinib (acalaburtinib), etc.
Bromodomain protein inhibitors include I-BET762, OTX-015, CPI-203, LY294002, and the like. CDK inhibitors include BMI-1040, BMS-032, BMS-387, CVT-2584, flavopiridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-nuclear inhibitor (roscovitine)), ZK-304709, and the like.
The EGFR inhibitor comprises EGFR antibody, ABX-EGF, anti-EGFR immunoliposome, EGF-vaccine, EMD-7200,(cetuximab), HR3. IgA antibody,(gefitinib)(erlotinib or OSI-774), TP-38, EGFR fusion protein,(lapatinib), TAGRISSO (AZD9291), and the like.
ALK inhibitors include crizotinib, ceritinib, and the like.
ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),(trastuzumab),(lapatinib),(2C4, pertuzumab), TAK-165, GW-572016 (ionofarnib), GW-282974, EKB-569, PI-166, dHER2(HER2 vaccine), APC-8024(HE-2 vaccine), anti-HER/2 neu bispecific antibody, B7.HER2IgG3, AS HER2 bifunctional bispecific antibody, mAB AR-209, mAB 2B-1, and the like.
Antibody drug conjugates include anti-CD 22-MC-MMAF, anti-CD 22-MC-MMAE, anti-CD 22-MCC-DM1, CR-011-vcMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35, SGN-75, and the like.
Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520; CENPE inhibitors, such as GSK923295A and the like.
MEK inhibitors include trametinib (GSK1120212), bimatinib (MEK162), sematinib (AZD6244), cobitinib (XL518), ARRY-142886, ARRY-438162, PD-325901, PD-98059, and the like.
BRAF inhibitors include sorafenib, vemurafenib, dabrafenib, GDC-0879, LGX818, and the like.
The platinum chemotherapeutic agent comprises cisplatin,(oxaliplatin), eptaplatin, lobaplatin, nedaplatin,(carboplatin), satraplatin, picoplatin, and the like.
VEGFR inhibitors include AVASTIN (bevacizumab), ABT-869, AEE-788, ANGIOZYMETM(ribozymes (Ribozyme Pharmaceuticals, Border, Colo.) and Kailon (Elmerrville, Calif.), Asertinib (AG-13736), AZD-2171, CP-547,632, IM-862, UGEN (Pegatantin) which inhibit angiogenesis,(sorafenib, BAY43-9006), pazopanib (GW-786034), vartananib (PTK-787, ZK-222584),(sunitinib SU-11248), Abbericept (VEGF-trap), ZACTIMATM(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806(mAb-806), an antibody specific for ErbB3, an antibody specific for BSG2, an antibody specific for DLL4, an antibody specific for C-met, and the like.
The antitumor antibiotics include the intercalating antibiotics aclarubicin, actinomycin D, amrubicin, anamycin, doxorubicin, adriamycin,(bleomycin), daunorubicin, and,Or(Liposomal doxorubicin), elsamitrucin, epirubicin, glarbuiin,(idarubicin), mitomycin C, nemorubicin, neocarzinostatin, pelomycin, pirarubicin, rebeccamycin, stimamer, streptozocin, and,(valrubicin), sitagliptin, and the like.
Inhibitors of DNA repair mechanisms, such as CHK kinase; inhibitors of DNA-dependent protein kinases; inhibitors of poly (ADP-ribose) polymerase (PARP inhibitors) including ABT-888 (veliparib), Olaparib, KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231, and the like; and Hsp90 inhibitors such as tanespimycin (tanespimacin) and retastatin (retaspimycin).
Proteasome inhibitors include(bortezomib), KYPROLIS (carfilzomib), NINLARO (ixazomib), MG132, NPI-0052, PR-171, and the like.
interferons include interferon α, interferon α -2a, interferon α -2b, interferon β, interferon gamma-1 a, interferon β, interferon α -2b, interferon β, and the like,(interferon gamma-1 b) or interferon gamma-n 1, combinations thereof, and the like. Other agents include(IFN- α), BAM-002 (oxidized glutathione),(tasolining),(tositumomab),(alemtuzumab), dacarbazine (decarbazine), dinibedipine, epratuzumab,(Legiostatin), lentinan, leukocyte α interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine, mitumomab, Moraxetin, MYLOTARGTM(Jimumab ozomicin),(filgrastim), OncoVAC-CL,(agovozumab), pembrolizumab (pemtumumab) (Y-muHMFG1),(sipuleucel) -T), sargrastim, xizopyran, a teichosine interleukin, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable,(BCG), ubenimex,(immunotherapeutic agent, Lorus drug), Z-100 (Maruyama's Specific Substance (SSM)), WF-10 (tetrachlorodecaoxide (TCDO)),(s),(aldesleukin)(thymalfasin),(daclizumab),(90Y-ibritumomab) and the like.
The pyrimidine analogs include cytarabine (ara C or arabinoside C), cytosine arabinoside, doxifluridine, and,(fludarabine), 5-FU (5-fluorouracil), floxuridine,(gemcitabine),(Raltitrexed), TROXATYLTM(triacetyluridine oleylsaxabine), and the like.
The antimitotic agent comprises barbiturates, epothilone D (KOS-862), N- (2- ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, and mixtures thereof,(docetaxel), PNU100940(109881), patupulon, XRP-9881 (larotaxel), vinflunine, ZK-EPO (synthetic epothilone), and the like.
In addition, compounds of formula (I), (II) and (III) can be combined with other chemotherapeutic agents, such as ABRAXANETM(ABI-007), ABT-100 (farnesyltransferase inhibitors),(Ad5CMV-p53 vaccine),Or(lovastatin),(poly I: poly C12U, synthetic RNA),(Exishulin),(pamidronic acid), arglabin (arglabin), L-asparaginase, actame (1-methyl-3, 17-dione-androsta-1, 4-diene),(tazarotene), AVE-8062 (combretastatin derivative) BEC2 (mitomomab), cachectin or cachexin (tumor necrosis factor), compactin (canvaxin) (vaccine),(cancer vaccine),(simoulukin),(histamine dihydrochloride),(human papilloma virus vaccines),(C：(cyclophosphamide); h:(doxorubicin); o: vincristineP: prednisone), CYPATTM(cyproterone acetate), combretastatin A4P, DAB (389) EGF (catalytic and transport domains of diphtheria toxin fused to human epidermal growth factor via His-Ala linker) or TransMID-107RTM(diphtheria toxin), dacarbazine, dactinomycin, 5, 6-dimethylxanthone-4-acetic acid (DMXAA), eniluracil, EVIZONTM(squalamine lactate),(T4N5 liposome lotion), discodermolide, DX-8951f (irinotecan mesylate), enzastaurin, EPO906 (epothilone B)(tetravalent human papilloma virus (types 6,11, 16, 18) recombinant vaccines)GMK (ganglioside conjugate vaccine),(prostate cancer vaccine), halofuginone, histrelin, hydroxyurea, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cinterdekinbestudoxox), IL-13-Pseudomonas exotoxin, interferon α, interferon gamma, JUNOVANTMOr MEPACTTM(mivakutide), clofenanib, 5, 10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine),(AE-941)、(trimethyoglul),(pentostatin),(ribonucleases),(melanoma vaccine therapy),(IL-2 vaccine), ORATHECINTM(rubitecan),(antibody cell drugs),Monoclonal antibody (mouse monoclonal antibody), paclitaxel, PANDIMEXTM(aglycone saponin obtained from Ginseng radix containing 20(S) protopanaxadiol (aPPD) and 20(S) protopanaxatriol (aPPT)), panitumumab,VF (cancer vaccine under study), pemetrexed, PEG interferon, phenytol, procarbazine, remamastat,(Cartesian) to,(lenalidomide), RSR13 (efaxil),LA (lanreotide),(Avermectin A), staurosporine (Astrosporine), Talospitabine (PT100),(bexarotene),(DHA-taxol),(canfosfamide, TLK286), temilize,(temozolomide), timifene, thalidomide,(STN-KLH), thymitaq (2-amino-3, 4-dihydro-6-methyl-4-oxo-5- (4-pyridylthio) quinazoline dihydrochloride), TNFaradETM(adenovirus vector: DNA vector containing the gene for tumor necrosis factor α),Or(bosentan), tretinoin (all-trans tretinoin), tetrandrine,(arsenic trioxide),UKRAIN (an alkaloid derivative derived from a larger celandine plant), vitaxin (an anti- α V β 3 antibody),(motesafen gadolinium) XINLAYTM(atrasentan), XYOTAXTM(Polyglutamic acid taxol),(Tribetidine), ZD-6126,(dexrazoxane),(zoledronic acid), zorubicin, and the like.
In one aspect, disclosed is a method for treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
In one aspect, disclosed is the use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer.
In one aspect, disclosed are pharmaceutical compositions comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
In one aspect, disclosed is a method for treating multiple myeloma in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof, for use in treating multiple myeloma.
In one aspect, disclosed is the use of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of multiple myeloma.
In one aspect, disclosed are pharmaceutical compositions comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in combination with bortezomib, or a pharmaceutically acceptable salt thereof, for use in treating multiple myeloma.
In one aspect, disclosed is a method for inhibiting Mcl-1 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof.
In one aspect, disclosed are compounds of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in inhibiting Mcl-1.
In one aspect, disclosed is the use of a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting Mcl-1.
In one aspect, disclosed are pharmaceutical compositions comprising a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for use in inhibiting Mcl-1.
The term "Mcl-1" refers to an anti-apoptotic member of the myeloid leukemia 1, BCL-2 family of proteins.
The language "effective amount" includes the amount of a compound of formula (I), (II), or (III) that will elicit the following biological or medical response in a subject, e.g., reduce or inhibit the activity of an enzyme or protein associated with Mcl-1 or cancer; ameliorating the symptoms of cancer; or slow or delay the progression of cancer. In some embodiments, the language "effective amount" includes an amount of a compound of formula (I), (II), or (III) that is effective to at least partially reduce, inhibit, and/or ameliorate cancer or inhibit Mcl-1, and/or reduce or inhibit growth of a tumor or proliferation of cancerous cells in a subject when administered to the subject.
The term "subject" includes warm-blooded mammals, e.g., primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, e.g., a human. In some embodiments, the subject has cancer. In some embodiments, the subject is in need of treatment (e.g., the subject will benefit from biological or medical treatment).
The language "inhibit" ("inhibit", "inhibition", or "inhibiting") includes a decrease in the baseline activity of a biological activity or process. In some embodiments, a compound of formula (I), (II), or (III) inhibits Mcl-1.
The language "treating" and "treatment" includes reducing or inhibiting an enzyme or protein activity associated with Mcl-1 or cancer in a subject, ameliorating one or more symptoms of cancer in a subject, or slowing or delaying the progression of cancer in a subject. The language "treating" also includes reducing or inhibiting the growth of a tumor or the proliferation of cancerous cells in a subject.
Examples of the invention
Aspects of the disclosure may be further defined by reference to the following non-limiting examples that detail the preparation of certain compounds and intermediates of the disclosure and methods for using the compounds of the disclosure. It will be apparent to those of ordinary skill in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure.
Unless otherwise stated:
(i) unless otherwise stated, the synthesis is carried out at ambient temperature (i.e. in the range of 17 ℃ to 25 ℃) and under an atmosphere of an inert gas such as nitrogen;
(ii) evaporation by rotary evaporation or under reduced pressure using a Genevac apparatus or Biotage v10 evaporator;
(iii) in an automated Teledyne IscoRf or Teledyne IscoUse of preloaded RediSep Rf GoldTMSilica gel column (20-40 μm, spherical particles), GraceResolvTMBarrel (Silica) or silica cartridge (40-63 μm) for silica gel chromatography.
(iv) Chiral preparative chromatography was performed via Watts (Waters) preparative 100 SFC-MS instrument with MS-and UV-initiated collection or via TharMultiGram III SFC instrument with UV collection.
(v) Chiral analytical chromatography was performed on Watts X5SFC-MS with UV detection or Watts UPC2SFC-MS with UV and ELSD detection.
(vi) The yield (when present) does not have to be the maximum obtainable;
(vii) typically, the structure of the final-product of formula I is confirmed by NMR chromatography; NMR chemical shift values were measured on the delta scale using solvent residual peaks as internal standards [ proton nuclear magnetic resonance spectroscopy was determined using a bruke advanced (bruker avance)500(500MHz), bruke advanced 400(400MHz), bruke advanced 300(300MHz), or bruke DRX (300MHz) instrument ]; unless otherwise stated, measurements were made at ambient temperature; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublets; dt, doublet triplet; bs, wide signal; ABq, AB multiplet.
(viii) Typically, the end-product of formula I is also characterized by mass spectrometry after liquid chromatography (UPLC); waters UPLC (column temperature 40 ℃, UV 220-300nm or 190-400nm, mass spectrum ESI with positive/negative conversion) equipped with waters SQ mass spectrometer was used for 1.50min (total run time with equilibration back to starting conditions etc. 1.70min) at 1mL/min flow rate using a solvent system of 97% a + 3% B to 3% a + 97% B, where a is 0.1% formic acid or 0.05% trifluoroacetic acid in water (for acid work) or 0.1% ammonium hydroxide in water (for base work) and B is acetonitrile. The column used for the acid analysis was Watts Acquity HSS T3(1.8 μm, 2.1X 50mm) and the column used for the base analysis was Watts Acquity BEH C18(1.7 μm, 2.1X 50 mm). Alternatively, UPLC is performed as follows: a waters UPLC equipped with a waters SQ mass spectrometer (column temperature 30 ℃, UV 210-400nm, mass spectrum ESI with positive/negative conversion) was used for 1.5min at a flow rate of 1mL/min (total run time with equilibration back to starting conditions: 2min) with a solvent gradient of 2% to 98% B, where a ═ 0.1% formic acid in water and B ═ 0.1% formic acid in acetonitrile (for acid work) or a ═ 0.1% ammonium hydroxide in water and B ═ acetonitrile (for base work). The column used for acid analysis was Watts Acquity HSS T3(1.8 μm, 2.1X 30mm), the column used for base analysis was Watts Acquity BEH C18(1.7 μm, 2.1X 30 mm); unless otherwise stated, the reporter molecule ion corresponds to [ M + H ] +; unless otherwise stated, for molecules with multiple isotopic patterns (Br, Cl, etc.), the reported value is the one obtained with the highest intensity.
(x) Intermediate purity was assessed by thin layer chromatography, mass spectrometry, LCMS, UPLC/MS, HPLC and/or NMR analysis;
(xi) The following abbreviations have been used:
ACN acetonitrile
aq. aqueous phase
conc. concentrated
DCM dichloromethane
Di-tert-BPF 1, 1' -bis (di-tert-butylphosphino) ferrocene
DMAP 4-dimethylaminopyridine
DMF N, N-dimethylformamide
DSC differential scanning calorimetry
DTBAD di-tert-butyldiazene-1, 2-dicarboxylate
enantiomeric excess of e.e
equiv. equivalent
ES electrospray mode
HPLC high performance liquid chromatography
Inj. injection
IPA isopropyl alcohol
LAH lithium aluminum hydride
LCMS liquid chromatography mass spectrometry
MS mass spectrometry
Sodium NaHMDS hexamethyldisilazane
NBS N-bromosuccinimide
NMR nuclear magnetic resonance
PE Petroleum Ether
PMB 4-methoxybenzyl
RBF round flask
RT Room temperature/ambient temperature
sat, saturated
SFC supercritical fluid chromatography
TBAF tetrabutylammonium fluoride
TBDPS tert-butyl diphenyl silicon base
TBDPSCl tert-butyl chlorodiphenylsilane
TFA trifluoroacetic acid
TGA thermogravimetric analysis
THF tetrahydrofuran
Tol. toluene
UPLC ultra-performance liquid chromatography
wt%
XRPD powder X-ray diffraction
Intermediate 1: methyl 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1H-indole-2-carboxylate
2-bromo-3-chloroaniline (600g, 2.91mol) and concentrated aqueous HCl in water (1500mL) (1500mL, 49.4mol) were placed in a 4-neck RBF. The mixture was stirred overnight to give a solution. Adding NaNO dropwise at 0-5 deg.C under stirring2(212g, 3.07mol) in water (720 mL). After 1.5h, a solution of KOAc (4020g, 40.9mol) in water (6000mL) and methyl 2-oxocyclopentane-1-carboxylate (420g, 2.95mol) was added dropwise with stirring at 0-5 ℃. The resulting solution was stirred at 0-5 ℃ for 0.5h, then at room temperature for 2 h. The solution was then extracted with 2 × 10L of DCM. The combined organic phases were washed with 1 × 5L of brine. Subjecting the solution to anhydrous Na2SO4Dried and concentrated to give methyl 1- ((2-bromo-3-chlorophenyl) diazenyl) -2-oxocyclopentane-1-carboxylate (1070g, 100%, 97 wt%).
A solution of concentrated sulfuric acid (1000mL, 18.8mol) in methanol (10000mL) and methyl 1- ((2-bromo-3-chlorophenyl) diazenyl) -2-oxocyclopentane-1-carboxylate (1400g, 3.89mol) was placed in a 4-neck RBF. The resulting solution was stirred in an oil bath for 2h at 70 ℃. The reaction mixture was cooled to 20 ℃ with a water/ice bath. The solid was collected by filtration. The solid was washed with 2 × 1L of MeOH and then dried in an oven under reduced pressure to give (E/Z) -dimethyl 2- (2- (2-bromo-3-chlorophenyl) hydrazono) adipate (1200g, 79%).
A solution of concentrated sulfuric acid (2L, 37.5mol) in methanol (10L) and (E/Z) -dimethyl 2- (2- (2-bromo-3-chlorophenyl) hydrazono) adipate (1200g, 2.96mol, 1.00 eq) was placed in a 4-neck RBF. The resulting solution was stirred in an oil bath for 72h at 80 ℃. The reaction mixture was cooled to 20 ℃ with a water/ice bath. The solid was collected by filtration, washed with 1L of MeOH and then air dried. The solid was then suspended in 2250mL of MeOH with stirring at 50 ℃ for 30 min. After cooling to 20 ℃, the solid was collected by filtration and washed with 500mL of MeOH and then air dried to give methyl 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1H-indole-2-carboxylate (intermediate 1, 930g, 84%); m/z (ES +), [ M + H +]+＝374。1HNMR (400MHz, chloroform-d) delta 2.68(t,2H),3.37(t,2H),3.64(s,3H),3.98(s,3H),7.25(d,1H),7.62(d,1H),8.83(s, 1H).
Intermediate 2: (4-bromo-1, 5-dimethyl-1H-pyrazol-3-yl) methanol
NBS (47.4g, 266mmol) was added portionwise to a solution of (1, 5-dimethyl-1H-pyrazol-3-yl) methanol (32.0g, 253mmol) in DCM (500mL) at 0 deg.C over 30 min. The resulting mixture was stirred at 25 ℃ for 1 h. The reaction mixture was diluted with DCM (200mL) and washed with water (250mL) and brine (150mL) in that order. Subjecting the organic layer to Na2SO4Dried, filtered and concentrated to provide a residue which was washed with PE/EtOAc (1:1) (10mL) to provide (4-bromo-1, 5-dimethyl-1H-pyrazol-3-yl) methanol (intermediate 2, 48.0g, 92%) which was used without further purification; m/z (ES +), [ M + H +]+＝205。1HNMR (300MHz, chloroform-d) delta 2.08(s,1H),2.26(s,3H),3.79(s,3H),4.63(s, 2H).
Intermediate 3: 4-bromo-3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazole
DMF (112mL) was added to (4-bromo-1, 5-dimethyl-1H-pyrazol-3-yl) methanol (intermediate 2, 3.74g, 18.3mmol) and the solution was cooled to 0 ℃. NaH (0.840g, 21.0mmol) (60% in oil) was added. The mixture was stirred at 0 ℃ for 10min, allowed to warm to room temperature and stirred for 20min to give a white suspension. 1- (chloromethyl) -4-methoxybenzene (2.72mL, 20.1mmol) and KI (0.303g, 1.83mmol) were added and the mixture was stirred for 1h and concentrated to dryness. Water (50mL) was added and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic phases are passed over Na2SO4Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give 4-bromo-3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazole (intermediate 3, 5.69g, 96%); m/z (ES +), [ M + H +]+＝325。1HNMR (400MHz, chloroform-d) delta 2.26(s,3H),3.80(s,3H),3.81(s,3H),4.47(s,2H),4.53(s,2H),6.85(d,2H),7.33(d, 2H).
Intermediate 4: 3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole
THF (83mL) was added to 4-bromo-3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazole (intermediate 3, 3.02g, 9.29mmol) and the resulting clear solution was cooled to-78 ℃. Butyllithium (6.96mL, 11.1mmol) (1.6M in hexanes) was added under Ar at-78 ℃. The mixture was stirred at-78 ℃ for 50 min. 2-Isopropoxy-4, 4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (2.65mL, 13.0mmol) was added. The acetone/dry ice bath was removed. The mixture was slowly warmed to room temperature and stirred for 4 h. Concentrating the mixture toDry and add EtOAc (200 mL). The resulting suspension was filtered through a pad of celite, washing with EtOAc (50 mL). The filtrate was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane/EtOAc) to give 3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (intermediate 4, 2.76g, 80%); m/z (ES +), [ M + H +]+＝373。1HNMR (400MHz, chloroform-d) delta 1.28(s,12H),2.40(s,3H),3.76(s,3H),3.80(s,3H),4.57(s,2H),4.61(s,2H),6.86(d,2H),7.33(d, 2H).
Intermediate 5: 1- ((tert-butyldiphenylsilyl) oxy) propan-2-one
1-hydroxypropan-2-one (34.9mL, 463mmol) was dissolved in anhydrous DMF (150mL) under Ar. Imidazole (34.1g, 501mmol) and DMAP (2.37g, 19.3mmol) were added and the solution was cooled to 0 ℃. TBDPSCl (100mL, 386mmol) was added slowly. The mixture was stirred at 0 ℃ for 15min and then at room temperature under Ar for 18 h. Water (1L) was added and the aqueous phase was extracted with hexane (4x 200 mL). The combined organic phases were washed with brine, over Na2SO4Dried, filtered and concentrated to give 1- ((tert-butyldiphenylsilyl) oxy) propan-2-one (intermediate 5, 120g, 100%). This material was used without further purification; m/z (ES +), [ M +18 +]+＝330。1H NMR (400MHz, chloroform-d) Δ 1.12(s,9H),2.20(s,3H),4.17(s,2H),7.36-7.49(m,6H),7.62-7.70(m, 4H).
Intermediate 6: ethyl 5- ((tert-butyldiphenylsilyl) oxy) -2-hydroxy-4-oxopent-2-enoate
THF (1.50L) was added to potassium tert-butoxide (69.0g, 570mmol) and the solution was cooled to 0 ℃. Slowly addingDiethyl oxalate (78.1g, 570mmol) was added, maintaining the temperature below 0 ℃. The solution was stirred at 0 ℃ for 30 min. 1- ((tert-butyldiphenylsilyl) oxy) propan-2-one (intermediate 5, 150g, 480mmol) was added slowly, maintaining the temperature below 0 ℃. The reaction mixture was stirred at 0 ℃ for 1h, and then EtOAc (300mL) was added. The resulting mixture was acidified with 1NHCl to pH 2 to 3. The layers were separated and the aqueous phase was extracted with EtOAc (4 × 300 mL). The combined organic phases were washed with brine, over Na2SO4Dried, filtered and concentrated to dryness to give ethyl 5- ((tert-butyldiphenylsilyl) oxy) -2-hydroxy-4-oxopent-2-enoate (intermediate 6, 160g, 80%) M/z (ES-), [ M-H-), (II-O-methyl-L-amino-phenyl-ethyl-2-enoate)]-＝411。1H NMR (400MHz, chloroform-d) Δ 1.13(s,9H),1.39(t,3H),4.31(s,2H),4.39(q,2H),6.88(s,1H)7.39-7.44(m,6H),7.65-7.68(m, 4H).
Intermediate 7: ethyl 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1H-pyrazole-3-carboxylate
Ethyl 5- ((tert-butyldiphenylsilyl) oxy) -2-hydroxy-4-oxopent-2-enoate (intermediate 6, 350g, 848mmol) was dissolved in ethanol (80.5 mL). The solution was cooled to 0 ℃ and hydrazine monohydrate (53.2g, 848mmol, 80 wt%) was added at 0 ℃. The mixture was stirred at 80 ℃ for 2 h. After completion, the mixture was cooled to 60 ℃, and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (161mL) and saturated NH4Cl (64.6 mL). The aqueous layer was extracted with EtOAc (2 × 64.6 ml). The combined organic layers were passed over Na2SO4Dried, filtered and evaporated to give the crude product. The crude product was purified by flash silica gel chromatography (0 to 20% EtOAc in PE) to give ethyl 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1H-pyrazole-3-carboxylate (intermediate 7, 176g, 60%); m/z (ES-), [ M-H [ ]]-＝407。1H NMR (400MHz, DMSO), (reported as a mixture of tautomers) delta 1.00(s,9H),1.28(t,3H),4.28(q,2H),4.73(d,2H),6.54(s,1HMainly comprising),6.71(s,1HOf secondary importance),7.42-7.50(m,6H),7.62-7.65(m.4H),13.48(s,1HMainly comprising)13.81(s,1HOf secondary importance)。
Intermediate 8: ethyl 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazole-3-carboxylate
Ethyl 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1H-pyrazole-3-carboxylate (intermediate 7, 175g, 428mmol) was dissolved in anhydrous THF (1750 mL). The solution was cooled to 0 ℃ and NaHMDS (238mL, 476mmol, 2M in THF) was added at 0 ℃. The resulting mixture was stirred at 0 ℃ for 10min, then at room temperature for 30 min. Methyl iodide (91.0g, 642mmol) was added and the mixture was stirred for 2 h. After completion of the reaction, the mixture was concentrated to dryness. EtOAc (3500mL) is added and the resulting solution is taken up with saturated aqueous NH4Cl solution (1750 mL). The aqueous phase was extracted with EtOAc (2 × 3500 mL). The combined organic phases are passed over Na2SO4Dried, filtered and evaporated to give ethyl 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazole-3-carboxylate (intermediate 8, 160g, 88%), M/z (ES +), [ M + H + ] -1H-pyrazole-3-carboxylate]+＝423。1H NMR (300MHz, chloroform-d) Δ 1.05(s,9H),1.41(t,3H),3.95(s,3H),4.42(q,2H),4.68(s,2H),6.56(s,1H),7.37-7.50(m,6H),7.61-7.69(m, 4H).
Intermediate 9: (5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methanol
THF (800mL) was added to ethyl 5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazole-3-carboxylate (intermediate 8, 160g, 378mmol) to give an orange solution. Cooling the solution to0 ℃ and LAH (189mL, 47.3mmol) (2.0M in THF) was added dropwise, keeping the temperature below 0 ℃. The resulting mixture was stirred at 0 ℃ for 1 h. The mixture was diluted with diethyl ether (1600mL) and water (14.4mL) was added dropwise below 0 ℃, followed by 15% aqueous NaOH solution (14.4mL) and water (43 mL). The resulting mixture was stirred at room temperature for 10 min. Adding anhydrous Na2SO4And the suspension was stirred for 15 min. The material was filtered through a pad of celite and washed with diethyl ether. The filtrate was concentrated to obtain (5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methanol (intermediate 9, 140g, 97%); m/z (ES +), [ M + H +]+＝381。1HNMR (300MHz, chloroform-d) delta 1.06(s,9H),3.85(s,3H),4.62(s,2H),4.64(s,2H),6.02(s,1H),7.35-7.53(m,6H),7.62-7.72(m, 4H).
Intermediate 10: 5- (((tert-butyldiphenylsilyl) oxy) methyl) -3- (chloromethyl) -1-methyl-1H-pyrazole
(5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methanol (intermediate 9, 380g, 998mmol) was dissolved in DCM (4560 mL). The solution was cooled to 0 ℃ and thionyl chloride (87.4mL, 1200mmol) was added very slowly at 0 ℃. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. In another flask, a saturated aqueous sodium bicarbonate solution (6330mL) was cooled to 0 ℃. The reaction mixture was slowly added to the sodium bicarbonate solution with stirring. The biphasic mixture was stirred until it stopped bubbling. The phases were separated. The organic phase was washed with brine, over anhydrous Na2SO4Dried, filtered and concentrated to give 5- (((tert-butyldiphenylsilyl) oxy) methyl) -3- (chloromethyl) -1-methyl-1H-pyrazole (intermediate 10, 392g, 98%) M/z (ES +), [ M + H + ]]+＝399。
1H NMR (400MHz, chloroform-d) delta 1.05(s,9H),3.83(s,3H),4.55(s,2H),4.64(s,2H),6.05(s,1H),7.34-7.49(m,6H),7.59-7.7(m,4H)。
Intermediate 11: s- ((5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thioacetate
5- (((tert-butyldiphenylsilyl) oxy) methyl) -3- (chloromethyl) -1-methyl-1H-pyrazole (intermediate 10, 390g, 977mmol) was dissolved in acetonitrile (4130 mL). Potassium thioacetate (233g, 1950mmol) and sodium iodide (149g, 9.42mmol) were added. The reaction mixture was stirred for 12 h. After completion of the reaction, the mixture was filtered through a celite bed and washed with dichloromethane. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (0 to 20% EtOAc in hexanes) to give S- ((5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thioacetate (intermediate 11, 309g, 72%) M/z (ES +), [ M + H + ]]+＝439。1HNMR (400MHz, chloroform-d) delta 1.04(s,9H),2.34(s,3H),3.80(s,3H),4.08(s,2H),4.60(s,2H),5.92(s,1H),7.35-7.5(m,6H),7.58-7.69(m, 4H).
Intermediate 12: 3- (Acetylthio) naphthalen-1-yl acetate
Under nitrogen at 20 ℃ under2(38.7g, 152mmol) was added in one portion to sodium 4-hydroxynaphthalene-2-sulfonate (75.0g, 305mmol), Ph3P (320g, 1220mmol) and 18-crown-6 (24.2g, 91.4mmol) in toluene (750 mL). The resulting mixture was stirred at 100 ℃ for 17 h. 1, 4-dioxane (150mL) and water (75mL) were added and the mixture was stirred at 100 ℃ for a further 1 h. Adding Na2SO4. The solids were removed by filtration and the filtrate was partially concentrated in vacuo to provide 3-mercaptonaphthalen-1-ol (360g, 14 wt% in toluene)). The product was used without further purification; m/z (ES)-)，[M-H]-＝175。
Ac was added under nitrogen at 0 ℃ over a period of 10min2O (162mL, 1720mmol) was added dropwise to DMAP (3.49g, 28.6mmol), 3-mercaptonaphthalen-1-ol (360g, 286mmol, 14 wt% in toluene), and Et3N (80mL, 572mmol) in DCM (1000 mL). The resulting mixture was stirred at 0 ℃ for 30 min. The reaction mixture was diluted with DCM (200mL) and washed successively with water (4 × 750mL) and saturated brine (500 mL). Subjecting the organic layer to Na2SO4Dried, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (PE/EtOAc) to give 3- (acetylthio) naphthalen-1-yl acetate (intermediate 12, 40.0g, 50%, over 2 steps); m/z (ES +), [ M + H +]+＝261。1HNMR (400MHz, chloroform-d) delta 2.48(s,3H),2.49(s,3H),7.34(d,1H),7.55-7.62(m,2H),7.88-7.92(m, 3H).
Intermediate 13: methyl 6-chloro-3- (3-methoxy-3-oxopropyl) -7- (3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylate
3- ((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (intermediate 4, 18.6g, 50.1mmol) was dissolved in a mixture of 1, 4-dioxane and water (4:1, 100 mL). Addition of Cs2CO3(26.1g, 80.1mmol), methyl 7-bromo-6-chloro-3- (3-methoxy-3-oxopropyl) -1H-indole-2-carboxylate (intermediate 1, 15.0g, 40.0mmol) and dichloro [1, 1' -bis (di-tert-butylphosphino) ferrocene]Palladium (II) (0.783g, 1.20mmol) followed by the addition of additional dioxane and water (300mL, 4: 1). The mixture is degassed and treated with N2And filling three times. The resulting brown clear mixture was placed in an oil bath preheated to 100 ℃. The mixture was stirred at 100 ℃ for 3 h. The mixture was cooled to room temperature and concentrated to 100 deg.CAnd (mL). EtOAc (200mL) and water (100mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases are passed over Na2SO4Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give methyl 6-chloro-3- (3-methoxy-3-oxopropyl) -7- (3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylate (intermediate 13, 20.0g, 92%); m/z (ES +), [ M + H +]+＝540。1H NMR (400MHz, chloroform-d) Δ 2.11(s,3H),2.73(t,2H),3.39-3.50(m,2H),3.68(s,3H),3.75(s,3H),3.78(s,3H),3.91(s,3H),4.14(d,1H),4.33-4.40(m,3H),6.76(d,2H),7.01(d,2H),7.25(d,1H),7.64(d,1H),9.17(s, 1H).
Intermediate 14: methyl 6-chloro-3- (3-methoxy-3-oxopropyl) -7- (3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -1-methyl-1H-indole-2-carboxylate
Methyl 6-chloro-3- (3-methoxy-3-oxopropyl) -7- (3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -1H-indole-2-carboxylate (intermediate 13, 22.2g, 37.2mmol, 90.5 wt%) was dissolved in anhydrous DMF (100 mL). Addition of Cs2CO3(18.2g, 55.8 mmol). The mixture was stirred for 20min and MeI (4.65mL, 74.4mmol) was added. The mixture was stirred for 2.5 h. Water (300mL) was added and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic phases were concentrated to dryness. The residue was dissolved in EtOAc (300mL) and the resulting solution was washed with water (3 × 50mL) to further remove DMF. Passing the organic phase over Na2SO4Dried, filtered and evaporated to dryness to give methyl 6-chloro-3- (3-methoxy-3-oxopropyl) -7- (3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -1-methyl-1H-indole-2-carboxylate (intermediate 14, 22.1g, 100%, 93.1 wt%), which was used without further purification; m/z (ES +), [ M + H +]+＝554。1H NMR (400MHz, chloroform-d) delta 2.06(s,3H),2.67(t,2H),3.29-3.41(m,2H),3.49(s,3H),3.67(s,3H),3.75(s,3H),3.89(s,3H),3.90(s,3H),4.25-4.36(m,4H),6.67(d,2H),6.86(d,2H),7.23(d,1H),7.62(d,1H)。
intermediate 15: methyl 6-chloro-7- (3- (hydroxymethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate
Methyl 6-chloro-3- (3-methoxy-3-oxopropyl) -7- (3- (((4-methoxybenzyl) oxy) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -1-methyl-1H-indole-2-carboxylate (intermediate 14, 22.1g, 37.3mmol) was dissolved in DCM (56mL) at 0 ℃ and TFA (28.7mL, 373mmol) was added. The ice bath was removed and the mixture was stirred at room temperature for 1.5 h. Water (200mL) was added. The organic phase was successively treated with water (3X 75mL) and saturated aqueous NaHCO3Washed (2 × 50mL) and the aqueous phase extracted with DCM (100 mL). The organic phases were combined and 2mL of MeOH and Et were added3N (2 mL). The mixture was stirred for 30min and concentrated to dryness. Water (50mL) was added and the aqueous phase was extracted with DCM (3 × 100 mL). Passing the organic phase over Na2SO4Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/EtOA then 10% MeOH in DCM) to give methyl 6-chloro-7- (3- (hydroxymethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 15, 13.7g, 85%); m/z (ES +), [ M + H +]+＝434。1H NMR (400MHz, chloroform-d) Δ 2.07(s,3H),2.67(t,2H),3.34(t,2H),3.54(s,3H),3.69(s,3H),3.92(s,3H),3.93(s,3H),4.48(ABq,2H),7.24(d,1H),7.65(d, 1H).
Intermediate 16: methyl 6-chloro-7- (3- (chloromethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate
Methyl 6-chloro-7- (3- (hydroxymethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 15, 13.0g, 29.9mmol) was dissolved in DCM (150mL) under Ar. The solution was cooled to 0 ℃ and thionyl chloride (2.62mL, 35.9mmol) was added. The ice bath was removed and the mixture was stirred at room temperature for 30min, then concentrated. DCM (50mL) was added and the resulting solution was successively washed with saturated aqueous NaHCO3Washed with brine and then Na2SO4Dried, filtered and concentrated to give methyl 6-chloro-7- (3- (chloromethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 16, 13.6g, 100%), which was used without purification; m/z (ES +), [ M + H +]+＝452。1HNMR (300MHz, chloroform-d) delta 2.06(s,3H),2.68(t,2H),3.58(t,2H),3.56(s,3H),3.68(s,3H),3.92(s,3H),3.93(s,3H),4.45(ABq,2H),7.26(d,1H),7.66(d, 1H).
Intermediate 17: methyl 6-chloro-7- (3- (iodomethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate
Methyl 6-chloro-7- (3- (chloromethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 16, 13.5g, 29.9mmol) was dissolved in acetonitrile (100mL), and sodium iodide (7.86g, 52.4mmol) was added. The mixture was stirred at 80 ℃ for 2.5 h. After cooling to room temperature, the mixture was filtered through a pad of celite and concentrated. Water (100mL) and EtOAc (100mL) were added, the layers were separated, and the aqueous phase was extracted with EtOAc (2 × 100 mL). The combined organics were passed over Na2SO4Dried, filtered and concentrated to give methyl 6-chloro-7- (3- (iodomethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 17, 15.7g, 96%); m/z (ES +), [ M + H +]+＝544。
1H NMR (400MHz, chloroform-d) Δ 2.06(s,3H),2.69(t,2H),3.37(t,2H),3.59(s,3H),3.68(s,3H),3.89(s,3H),3.94(s,3H),4.22(ABq,2H),7.27(d,1H),7.68(d, 1H).
Intermediate 18: methyl 7- (3- ((((5- ((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methylthio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -6-chloro-3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate
Methyl 6-chloro-7- (3- (iodomethyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 17, 7.60g, 13.9mmol) was dissolved in MeOH (30mL) and THF (15mL) to give a suspension. Addition of K2CO3(1.93g, 13.9 mmol). The mixture is degassed and treated with N2And (6) filling. S- ((5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thioacetate (intermediate 11, 6.74g, 15.4mmol) in degassed MeOH (15mL) was added dropwise over 5 min. After addition of the thioacetate solution, the mixture was degassed again and then stirred for 2 h. The mixture was concentrated to dryness and EtOAc (100mL) was added. The organic phase is washed with water and Na2SO4Dried and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give methyl 7- (3- (((((5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -6-chloro-3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 18, 7.10g, 63%); m/z (ES +), [ M + H +]+＝812。1HNMR (400MHz, chloroform-d) delta 1.04(s,9H),2.04(s,3H),2.65(t,2H),3.32(t,2H),3.52-3.57(m,5H),3.61(s,2H),3.68(s,3H),3.79(s,3H),3.89(s,3H),3.91(s,3H),4.58(s,2H),5.93(s,1H),7.22(d,1H),7.35-7.49(m,6H),7.58(d,1H),7.61-7.71(m, 4H).
Intermediate 19: methyl 6-chloro-7- (3- ((((5- (hydroxymethyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate
Methyl 7- (3- ((((5- (((tert-butyldiphenylsilyl) oxy) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -6-chloro-3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 18, 13.9g, 17.1mmol) was dissolved in THF (40mL) and TBAF (17.1mL, 17.1mmol) (1M in THF) was added. The mixture was stirred for 1h and then concentrated. EtOAc (200mL) was added and the organic phase was washed successively with water and brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give methyl 6-chloro-7- (3- ((((5- (hydroxymethyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 19, 8.40g, 86%); m/z (ES +), [ M + H +]+＝574。1HNMR (400MHz, chloroform-d) delta 2.05(s,3H),2.68(dd,2H),3.35(dd,2H),3.52-3.59(m,7H),3.67(s,3H),3.78(s,3H),3.88(s,3H),3.93(s,3H),4.56(s,2H),5.95(s,1H),7.24(d,1H),7.64(d, 1H).
Intermediate 20: methyl 6-chloro-7- (3- ((((5- (chloromethyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate
Methyl 6-chloro-7- (3- (((((5- (hydroxymethyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-Oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 19, 8.70g, 15.2mmol) was dissolved in anhydrous DCM (100 mL). The mixture was cooled to 0 ℃. Thionyl chloride (1.33mL, 18.2mmol) was added. The ice bath was removed. The mixture was stirred at room temperature for 30min, and then concentrated. Water (50mL) was added. The resulting solution was sequentially washed with water and saturated aqueous NaHCO3Washed with brine and then Na2SO4Dried, filtered and concentrated to give methyl 6-chloro-7- (3- (((((5- (chloromethyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 20, 9.00g, 100%) which was used without purification; m/z (ES +), [ M + H +]+＝592。1H NMR (400MHz, chloroform-d) Δ 2.05(s,3H),2.65-2.68(m,2H),3.31-3.41(m,2H),3.52-3.59(m,7H),3.68(s,3H),3.79(s,3H),3.89(s,3H),3.93(s,3H),4.49(s,2H),6.07(s,1H),7.25(d,1H)7.63(d, 1H).
Intermediate 21: methyl 6-chloro-7- (3- (((((5- (((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate
Will K2CO3(5.15g, 37.3mmol) was added to a mixture of methyl 6-chloro-7- (3- ((((5- (chloromethyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 20, 9.20g, 15.5mmol) and 3- (acetylthio) naphthalen-1-ylacetate (intermediate 12, 4.45g, 17.1mmol) in MeOH (120 mL). The resulting mixture was stirred for 1 h. The reaction mixture was evaporated to dryness. The residue was redissolved in EtOAc (150 mL). The resulting solution was washed with water (2X 100mL) and brine (100mL) in that order. Subjecting the organic layer to Na2SO4Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0-10% MeOH in DCM) to yieldMethyl 6-chloro-7- (3- (((((5- (((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 21, 7.42g, 65.3%); m/z (ES +), [ M + H +]+＝732。1HNMR (300MHz, chloroform-d) delta 2.09(s,3H),2.62-2.74(m,2H),3.31-3.66(m,12H),3.70(s,3H),3.94-3.96(m,8H),6.07(s,1H),6.65(d,1H)7.24(d,1H),7.43-7.56(m,2H),7.59-7.71(m,2H),7.71-7.80(m,1H),8.19-8.30(m, 1H).
Intermediate 22: methyl 6-chloro-7- (3- (((((5- (((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-hydroxypropyl) -1-methyl-1H-indole-2-carboxylate
Methyl 6-chloro-7- (3- ((((5- (((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-methoxy-3-oxopropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 21, 5.00g, 6.83mmol) was dissolved in THF (20mL) under Ar. The resulting solution was cooled to 0 ℃ and borane tetrahydrofuran complex (37.6mL, 37.6mmol) (1M in THF) was added. The ice bath was removed and the mixture was stirred at room temperature for 5.5 h. The reaction mixture was concentrated and cooled to 0 ℃, followed by addition of MeOH (20mL) and 6NHCl (40mL) (exothermic). The resulting solution was stirred at 0 ℃ for 10min, then at room temperature for 20 min. The volume of the mixture was reduced to 1/3 under reduced pressure. Water (200mL) was added and the aqueous phase was extracted with 10% MeOH in DCM (9 × 50 mL). The combined organic phases were successively treated with saturated aqueous NaHCO3(50mL) and brine, over Na2SO4Dried, filtered and concentrated. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give racemic methyl 6-chloro-7- (3- (((((5- (((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-one-Yl) -3- (3-hydroxypropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 22, 4.05g, 84%); m/z (ES +), [ M + H +]+＝704。1H NMR (400MHz, chloroform-d) Δ 1.93-2.03(m,2H),2.10(s,3H),3.18(t,2H),3.41-3.64(m,10H),3.68(t,2H),3.91-3.98(m,8H),6.05(s,1H),6.64(d,1H),7.25(d,1H)7.43-7.58(m,2H),7.61-7.68(m,2H),7.72-7.81(m,1H),8.26(d, 1H).
Intermediate 23: methyl 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazacyclohepta [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid ester
Triphenylphosphine (1.58g, 6.02mmol) was dissolved in toluene (30mL) and a solution of di-tert-butyldiazene-1, 2-dicarboxylate (1.39g, 6.02mmol) and methyl 6-chloro-7- (3- (((((5- (((4-hydroxynaphthalen-2-yl) thio) methyl) -1-methyl-1H-pyrazol-3-yl) methyl) thio) methyl) -1, 5-dimethyl-1H-pyrazol-4-yl) -3- (3-hydroxypropyl) -1-methyl-1H-indole-2-carboxylate (intermediate 22, 2.12g, 3.01mmol) in toluene (27.6mL) and THF (2.50mL) was added via an addition funnel over 1H. After addition, the mixture was stirred for 1 h. The reaction mixture was diluted with EtOAc (50mL) and MeOH (5mL), and then washed successively with water, 2N HCl, and brine, over Na2SO4Dried, filtered and concentrated. To the resulting residue was added MeOH (10 mL). The mixture was sonicated for 5min to give a white suspension. The solid was collected, washed with MeOH (6mL) and dried to give the first crop (1.34g, 64%). The mother liquor was concentrated and the residue was purified by silica gel column chromatography (hexanes/EtOAc) to give a second crop of product. The methyl 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazacyclohepta [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20The total amount of 23,29,31,33, 35-tridecene-23-carboxylic acid ester (intermediate 23) was 1.40g (68%); m/z (ES +), [ M + H +]+＝686。1HNMR (400MHz, chloroform-d) delta 2.05(s,3H),2.22-2.25(m,1H),2.38-2.51(m,1H),2.68(d,1H),3.09(d1H),3.21-3.32(m,2H),3.45-3.56(m,2H),3.63-3.73(m,4H),3.75-3.84(m,4H),3.84-3.96(m,8H),4.92(s,1H),6.25(d,1H),6.95(d,1H),7.50-7.59(m,4H),7.70-7.81(m,1H),8.22-8.38(m, 1H).
Intermediate 24 and intermediate 25: (R)a) - (+) -methyl 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazacycloheptane [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Tristearyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate and (S)a) - (-) -methyl 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4, 7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid ester
Intermediate 23(4.70g, 6.85mmol) was subjected to chiral SFC (Chiralpak)Column, 21 × 250mm, 5 μm, temperature 40 ℃, 45:55i-PrOH: CO2UV detection @220nm, loading 150mg/inj, concentration 60mg/mL, dilution MeOH/DCM, flow rate 60mL/min, outlet pressure 100 bar).
Intermediate 24, first eluting (R)a) The (+) -isomer (1.87g, 37%,>98％e.e.)：m/z(ES+)，[M+H]+＝686。1HNMR (400MHz, chloroform-d) delta 2.05(s,3H),2.22-2.25(m,1H),2.38-2.51(m,1H),2.67(d,1H),3.09(d,1H), 3.19-3.32(m,2H),3.45-3.56(m,2H),3.63-3.73(m,4H),3.75-3.84(m,4H),3.84-3.96(m,8H),4.92(s,1H),6.25(d,1H),6.95(d,1H),7.44-7.59(m,4H),7.70-7.81(m,1H),8.22-8.38(m,1H)。
Checking ee purity after purification:
the chiral analysis method comprises the following steps: SFC:column, 4.6 × 100mm, 5 μm, temperature 40 ℃, 35:65i-PrOH: CO2UV detection at 220nm, flow rate 5.0mL/min, outlet pressure 125 bar. The retention time is 1.63min,>98％ee，[α]D+64°(c＝0.1，MeOH)
intermediate 25, second eluting (S)a) - (-) -isomer: (1.40g, 28%,>98％e.e.)：m/z(ES+)，[M+H]+＝686。1HNMR (400MHz, chloroform-d) delta 2.05(s,3H),2.22-2.25(m,1H),2.38-2.51(m,1H),2.67(d,1H),3.09(d,1H), 3.19-3.32(m,2H),3.45-3.56(m,2H),3.63-3.73(m,4H),3.75-3.84(m,4H),3.84-3.96(m,8H),4.92(s,1H),6.25(d,1H),6.95(d,1H),7.44-7.59(m,4H),7.70-7.81(m,1H),8.22-8.38(m, 1H).
Checking ee purity after purification:
such as a chiral analysis method for intermediate 24. The retention time is 3.77min,>98％ee，[α]D-64°(c＝0.1，MeOH)
example 1: 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid
MeOH (48mL) and THF (48mL) were added to methyl 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13,22 pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate (intermediate 23, 1.25g, 1.78mmol) to give a suspension. LiOH (0.556g, 23.2mmol) and water (12mL) were added and the suspension was degassed and filled with Ar. The mixture was stirred at 80 ℃ for 2.5 h. After cooling to room temperature, 2N HCl (20mL) was added and the mixture was concentrated to dryness. Water (50mL) was added to the residue to give a white suspension. The white solid was collected by filtration and washed with water (2 × 10 mL). This solid was redissolved in 10% MeOH (150mL) in DCM over Na2SO4Dried, filtered and concentrated to dryness to give 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (example 1, 1.05g, 88%); m/z (ES +), [ M + H +]+＝672。1HNMR(400MHz,DMSO-d6)δ1.97(s,3H),2.20-2.30(m,1H),2.35-2.50(m,1H),2.90(d,1H),3.07-3.19(m,3H),3.40-3.47(m,2H),3.50(s,3H),3.71(s,3H),3.76(s,3H),3.86(dd,1H),4.07-4.15(m,1H),4.27(s,2H),4.76(s,1H),6.67(s,1H),7.14(d,1H),7.39(s,1H),7.45-7.52(m,2H),7.71(d,1H),7.87(d,1H),8.10(d,1H),13.32(br.s.,1H)。
Example 2: (R)a) - (+) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazacycloheptane [27.7.1.1 [ ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid
Will (R)a) - (+) -methyl 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazacycloheptane [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Thirty-eight carbons 1(37),4(38),6,11,1416,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid ester (intermediate 24, 1.87g, 2.51mmol) was dissolved in MeOH (8.35mL), THF (8.35mL), and water (8.35 mL). LiOH (0.90g, 37.6mmol) was added. The mixture was stirred for 4 h. The mixture was concentrated to dryness. 2N HCl (25mL) was added. The aqueous phase was extracted with 5% MeOH in DCM (4 × 30 mL). The combined organic phases were washed with brine, over Na2SO4Dried, filtered and concentrated. MeOH (20mL) was added to the residue to give a clear solution. This clear solution was concentrated to give a white solid which was dried under vacuum to give (R)a) - (+) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazacycloheptane [27.7.1.1 [ ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (example 2, 1.55g, 92%,>98％e.e.)；m/z(ES+)，[M+H]+＝672。1HNMR(400MHz,DMSO-d6)δ1.97(s,3H),2.20-2.30(m,1H),2.35-2.50(m,1H),2.90(d,1H),3.07-3.19(m,3H),3.40-3.47(m,2H),3.50(s,3H),3.71(s,3H),3.76(s,3H),3.86(dd,1H),4.07-4.15(m,1H),4.26(s,2H),4.75(s,1H),6.67(s,1H),7.14(d,1H),7.38(s,1H),7.45-7.52(m,2H),7.71(d,1H),7.87(d,1H),8.10(d,1H),13.32(br.s.1H)。
checking ee purity after purification:
the chiral analysis method comprises the following steps: SFC: chiralpakColumn, 4.6 × 250mm, 5 μm, temperature 40 ℃, 40:60MeOH: CO2UV detection at 220nm at a flow rate of 2.8mL/min, an outlet pressure of 100 bar and a retention time of 7.33min,>98％e.e.，[α]D+87°(c＝0.042，MeOH)
example 3: (S)a) - (-) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tenTriene-23-carboxylic acid
Starting from (S)a) - (-) -methyl 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl 1(37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylate (intermediate 25, 1.40g, 2.04mmol), the same procedure as given for example 2 is carried out to obtain (S)a) - (-) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (example 3, 1.25g, 91%,>98％e.e.)；m/z(ES+)，[M+H]+＝672。1HNMR(400MHz,DMSO-d6)δ1.97(s,3H),2.20-2.30(m,1H),2.35-2.50(m,1H),2.90(d,1H),3.07-3.19(m,3H),3.40-3.47(m,2H),3.50(s,3H),3.71(s,3H),3.76(s,3H),3.86(dd,1H),4.07-4.15(m,1H),4.27(s,2H),4.76(s,1H),6.67(s,1H),7.14(d,1H),7.38(s,1H),7.45-7.52(m,2H),7.71(d,1H),7.87(d,1H),8.10(d,1H),13.32(br.s.,1H)。
checking ee purity after purification:
as for the chiral analysis method of example 2: the retention time is 9.36min,>98％e.e.，[α]D-92°(c＝0.048)
example 4: in vitro Activity of examples 1,2 and 3
Caspase activity assay
This is a cellular assay used to measure induction of apoptosis in MOLP-8 (multiple myeloma), KMS-12-BM (multiple myeloma), MV-4-11 (acute myelogenous leukemia), and NCI-H23 (non-small cell lung cancer) cells after 6H of treatment. On the first day, 3000 (MOLP-8, KMS-12-BM, MV-4-1) cells were added1) Or 1250(NCI-H23) cells/well in 384-well white microplate in 50. mu.L growth medium (IMDM + 10% FBS +2mM L-Glu for MV-4-11, and RPMI-1640+ 10% FBS +2mM L-Glu for all other cell lines) and incubated overnight (37 ℃, 5% C0)280% RH). On the next day, the cells were treated with Mcl-1 inhibitor using ECHO acoustic liquid processor (10 point half-log serial dilution, 31.5 μm maximum concentration, 0.3% final DMSO concentration). Incubation (37 ℃, 5% C0)280% RH)6h, 25. mu.L of caspase-Glo 3/7 reagent (Promega) was added to each well and the plates were incubated at room temperature for 30min in the absence of light. Luminescence was recorded using an Infinite M200 microplate reader (Tecan) with 100ms integration time. EC was calculated using GeneData analysis software50The value is obtained.
TABLE 1 results from in vitro caspase activity assays
Example 5: in solid form (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid
X-ray powder diffraction (XRPD) analysis
XRPD analysis was performed using a Bruker D4 diffractometer, commercially available from Bruker AXS Inc. (Bruker AXS IncTM) (Madison, Wis.). The XRPD spectroscopy is performed by mounting a sample of material (about 20mg) for analysis on a single silicon crystal wafer holder (e.g., a bruke's silicon zero background X-ray diffraction sample holder) and by means of microscopyThe mirror mount spreads the sample into a thin layer. The sample was rotated at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays having a wavelength of 1.5406 angstroms (i.e., about 1.54 angstroms) generated by a copper long thin focusing tube operating at 40kV and 40 mA. The sample was exposed for 1 second per 2-theta increment of 0.02 deg. (continuous scan mode) in the range of 2-theta from 2 deg. to 40 deg. in theta-theta mode. The run time was 31 minutes and 41 seconds.
XRPD 2 θ values can vary over a reasonable range, for example, within a range of ± 0.2 °, and XRPD intensities can vary when substantially the same crystal form is measured for a variety of reasons, including for example, a preferred orientation. The principle of XRPD is described in publications such as, for example, gekazoo (Giacovazzo), c. et al (1995) basic principles of crystals (Fundamentals of Crystallography), oxford university press; jenkins (Jenkins), r. and snenide (Snyder), r.l. (1996) introduction of X-ray powder diffraction (introductiontto X-raypowder diffraction), John Wiley & Sons, new york; and kruge (Klug), h.p. and Alexander (Alexander), L.E. (1974) X-ray diffraction program (X-ray diffraction procedures), john william father, new york.
DSC analysis
For samples prepared according to standard methods, the samples available from TA were usedQ SERIES of (N.Y. Ka-Si, Delaware)TMDSC analysis was performed with a Q1000DSC calorimeter. Samples (approximately 2mg) were weighed into aluminum sample pans and transferred to the DSC. The instrument was purged with nitrogen at 50mL/min and data between about 22 ℃ and 300 ℃ was collected using a dynamic heating rate of about 10 ℃/min. Using standard software for thermal data, e.g. from TAWas analyzed at v.4.5A, general.
Weight distribution of heatAnalysis (TGA)
For samples prepared according to standard methods, a commercially available TA instrument was usedQ SERIES available (N.Y., T.C.)TMTGA was performed by Q5000 thermogravimetric analyzer. The sample (approximately 5mg) was placed in an aluminum sample pan and transferred into a TGA furnace. The instrument was purged with nitrogen at 50mL/min and data between 25 ℃ and 300 ℃ was collected using a dynamic heating rate of 10 ℃/min. Using standard software for thermal data, e.g. from TAWas analyzed at v.4.5A, general.
aForm A (R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentan 4,7 11,15 16,21 20,24 30,35Aza-heptylic [27.7.1.1.0.0.0.0 ] rings]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18, preparation of 20,23,29,31,33, 35-tridecene-23-carboxylic acid monohydrate
The method comprises the following steps:mixing 10mg of (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid is dissolved in 1.0mL of MeOH and 5 drops of water. The resulting solution was evaporated to dryness at ambient conditions. The resulting white powder was identified as form a.
The method 2 comprises the following steps:mixing 10mg of (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid form C (or form F) is suspended in 0.2mL of water. The resulting slurry was stirred for 2 days. The obtained solid is identifiedDefined as form a.
The method 3 comprises the following steps:adding (R) in an amount of 1.5ga) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (form F) was added to the vessel, and 4.5mL of MeOH and 0.5mL of H were added2O (9:1) to obtain a suspension. The resulting slurry was stirred overnight and the slurry was evaporated to dryness. XRPD showed conversion of form F to form a.
Form a (method 3) was analyzed by XRPD and the results are tabulated below (table 2) and shown in figure 1.
TABLE 2 XRPD peaks for form A
Form a (method 3) was analyzed by thermal techniques. DSC analysis indicated that form a had an endothermic event with desolvation starting at about 121 ℃ and peaking at about 158 ℃, followed by an endothermic event with melting/decomposition starting at about 181 ℃ and peaking at about 194 ℃. TGA indicates that form a exhibits a mass loss of about 4.0% after heating from about 25 ℃ to about 160 ℃. A representative DSC/TGA thermogram for form a is shown in figure 2.
From MeOH/H2Slow evaporation of O (1:1 volume ratio) gave single crystals of form a. Single crystal structural analysis demonstrated that form a was the monohydrate form. Crystallographic data: space group monoclinic system P2(1), unit cell size:
β＝90.23(2)°，
aform B (R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentan 4,7 11,15 16,21 20,24 30,35Aza-heptylic [27.7.1.1.0.0.0.0 ] rings]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18, preparation of 20,23,29,31,33, 35-tridecene-23-carboxylic acid
From (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Obtained in the slow evaporation of a solution of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid and meglumine in a 1:1 molar ratio in MeOH (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14 ,7.011,15.016,21.020,24.030,35]A single crystal of form B of trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid. When crystals appeared from the solution, the crystals were collected manually. Single crystal structural analysis demonstrated that form B was a monomethanolsolvate of the free acid. Crystallographic data: space group orthorhombic system P2(1)2(1)2(1), unit cell size:
aform C (R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentan 4,7 11,15 16,21 20,24 30,35Aza-heptylic [27.7.1.1.0.0.0.0 ] rings]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18, preparation of 20,23,29,31,33, 35-tridecene-23-carboxylic acid
The method comprises the following steps:300mg of amorphous form (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid is taken up in EtOH (3mL) and heated to dissolution. After cooling to room temperature, the solution was stirred overnight, at which time a solid had precipitated out. This solid was collected by filtration and dried to give form C (266mg, 81%).
The method 2 comprises the following steps:10mg of amorphous form (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid is suspended in 0.2mL of EtOH. The resulting slurry was stirred for 1 day. Form C was obtained after evaporation of the slurry at ambient conditions. Form C (method 1) was analyzed by XRPD and the results are tabulated below (table 3) and shown in fig. 3.
TABLE 3 XRPD peaks for form C
Form C (method 1) was analyzed by thermal techniques. DSC analysis indicated that form C had an endothermic event with desolvation starting at about 123 ℃ and a peak at about 140 ℃, followed by an endothermic event with melting/decomposition starting at about 185 ℃ and a peak at about 196 ℃. TGA indicates that form C exhibits a mass loss of about 6.4% after heating from about 25 ℃ to about 160 ℃. A representative DSC/TGA thermogram for form C is shown in figure 4.
aForm D (R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentan 4,7 11,15 16,21 20,24 30,35Aza-heptylic [27.7.1.1.0.0.0.0 ] rings]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18, preparation of 20,23,29,31,33, 35-tridecene-23-carboxylic acid
The method comprises the following steps:10mg of amorphous form (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid is suspended in 0.2mL of EtOAc. The resulting slurry was stirred for 1 day and a partially crystalline material was obtained. The external temperature of the vial was heated to 100 ℃, and the resulting slurry was stirred for 15 minutes. After cooling to ambient temperature, the slurry was stirred for 3 days and form D was identified.
The method 2 comprises the following steps:10mg of amorphous form (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid is dissolved in 0.2mL of hot acetone, and after the clear solution is cooled to room temperature, a white solid precipitates. The resulting suspension was stirred for 3 days. Form D was identified.
Form D (method 2) was analyzed by XRPD and the results are tabulated below (table 4) and shown in fig. 5.
TABLE 4 XRPD peaks for form D
Form D (method 2) was analyzed by thermal techniques. DSC analysis indicated that form D had a melting endothermic event that started at about 156 ℃ and peaked at about 175 ℃. TGA indicates that form D exhibits a mass loss of about 3.6% after heating from about 25 ℃ to about 170 ℃. A representative DSC/TGA thermogram for form D is shown in figure 6.
aForm E (R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentan 4,7 11,15 16,21 20,24 30,35Aza-heptylic [27.7.1.1.0.0.0.0 ] rings]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18, preparation of 20,23,29,31,33, 35-tridecene-23-carboxylic acid
5mg of (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadeca-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid was dissolved in 0.5mL of hot IPA/H2O (3:1), and crystals are obtained after cooling of the solution. The solution was slowly evaporated to dryness. Form E was identified.
Form E was analyzed by XRPD and the results are tabulated below (table 5) and shown in fig. 7.
TABLE 5 XRPD peaks for form E
aForm F (R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentan 4,7 11,15 16,21 20,24 30,35Aza-heptylic [27.7.1.1.0.0.0.0 ] rings]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18, 20,23,29,31,33, 35-tridecen-2-enePreparation of 3-formic acid pentahydrate
5mg of (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid is dissolved in 1.0mL of EtOH/H2O (3:1), and the resulting solution was slowly evaporated under a hood. The resulting crystalline material was identified as form F.
Form F was analyzed by XRPD and the results are tabulated below (table 6) and shown in fig. 8.
TABLE 6 XRPD peaks for form F
Form F was analyzed by thermal techniques. DSC analysis indicated that form F had an endothermic event with desolvation starting at about 40 ℃ and reaching a peak at about 67 ℃, followed by an endothermic event with melting/decomposition starting at about 185 ℃ and reaching a peak at about 195 ℃. TGA indicates that form F exhibits a mass loss of about 4.3% after heating from about 25 ℃ to about 100 ℃. A representative DSC/TGA thermogram for form F is shown in figure 9.
Mixing 10mg of (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid is dissolved in 1.0mL of acetone/H2O (4:1) and the resulting solution was slowly evaporated to dryness to yield form F. Analysis of the single crystal structure showed it to be in the pentahydrate form. Crystallographic data: space(s)Group triclinic P1, unit cell size:α is 96.298(15) °, β is 91.987(13) °, γ is 91.604(14) °, and
a(R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentaazahept-e 4,7 11,15 16,21 20,24 30,35Ring [27.7.1.1.0.0.0.0]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23, preparation of sodium 29,31,33, 35-tridecene-23-carboxylate
135mg of (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid form C (0.2mmol) is suspended in 5mL MeOH, and 200. mu.L of 1.0N NaOH aqueous solution is added to the suspension. The slurry was stirred until the solids dissolved. The clear solution was evaporated and the resulting solid was slurried with EtOAc for 3 days. The slurry was evaporated to dryness to obtain a crystalline material.
The crystals were analyzed by XRPD and the results are tabulated below (table 7) and shown in fig. 10.
TABLE 7 XRPD peaks for the sodium salt
The sodium salt was analyzed by thermal techniques. DSC analysis indicated that the sodium salt had a broad endothermic event with desolvation from about 100 ℃ to about 200 ℃, followed by a melting endothermic event that started at about 239 ℃ and peaked at about 246 ℃. TGA indicated that the sodium salt exhibited a mass loss of about 4.0% after heating from about 25 ℃ to about 175 ℃. A representative DSC/TGA thermogram of the sodium salt is shown in FIG. 11.
a(R) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentaazahept-e 4,7 11,15 16,21 20,24 30,35Ring [27.7.1.1.0.0.0.0]Thirty-eight carbon-1 (37),4(38),6,11,14,16,18,20,23, preparation of meglumine 29,31,33, 35-tridecene-23-carboxylate salt
135mg of (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (0.2mmol) is suspended in 2mL of MeOH, and 4mL of a 0.05M solution of meglumine in MeOH is added. The slurry was stirred overnight and then evaporated to dryness. About 2mL of EtOAc was added to produce a slurry, and the slurry was stirred for 3 days. The slurry was evaporated to dryness to obtain a crystalline material.
The meglumine salt was analyzed by XRPD and the results are tabulated below (table 8) and shown in fig. 12.
TABLE 8 XRPD peaks for meglumine salt
The meglumine salt was analyzed by thermal techniques. DSC analysis indicated that the meglumine salt had a broad endothermic event with desolvation starting at about 69 ℃ and peaking at about 88 ℃, followed by an endothermic event with desolvation starting at about 102 ℃ and peaking at about 104 ℃. TGA indicates that the meglumine salt exhibits a mass loss of about 10.6% after heating from about 25 ℃ to about 150 ℃. A representative DSC/TGA thermogram of this meglumine salt is shown in figure 13.
Example 6: single agents and combined activities of example 2 in vivo in a human multiple myeloma tumor model
The method comprises the following steps:example 2 was formulated in 30% 2-hydroxypropyl- β -cyclodextrin (HPBCD) (pH 9) and administered intravenously (iv) in a volume of 5ml/kg 5x 106MOLP-8 tumor cells or 107NCI-H929 tumor cells were injected subcutaneously into the right flank of C.B-17SCID female mice in a volume of 0.1 mL. Tumor volume (measured by caliper) was calculated using the following formula: length (mm) x width (mm)2/0.52. For efficacy studies, mice were randomized based on tumor volume and growth inhibition was assessed by comparing the difference in tumor volume between control and treatment groups. When the mean tumor size reached about 160mm for MOLP-83And for NCI-H929, up to about 230mm3Administration is started.
As a result:example 2 dose-dependent antitumor activity was induced in MOLP-8 tumor-bearing mice (FIG. 14). Single iv administration of example 2 at 10 or 30mg/kg resulted in significant antitumor activity of 52% and 92% Tumor Growth Inhibition (TGI), respectively. Of 13 of 14 mice measured 10 days post-dose, a single iv administration of example 2 at 60 or 100mg/kg induced complete tumor regression.
Example 2 also demonstrates the combined benefit of bortezomib with a proteasome inhibitor in NCI-H929 tumor-bearing mice (fig. 15). Administration of example 2 at 30mg/kg every other week in combination with 1mg/kg weekly bortezomib resulted in tumor regression, whereas no significant antitumor activity was observed with either agent alone.
Example 7: single agent activity in vivo in a human acute myeloid leukemia tumor model.
The method comprises the following steps:example 2 was formulated in 30% 2-hydroxypropyl- β -cyclodextrin (HPBCD) (pH 9) and administered in a single intravenous (iv) administration in a volume of 5ml/kg 106MV-4-11 tumor cells were injected subcutaneously in the right flank of C.B-17SCID female mice in a volume of 0.1 mL. Tumor volume (measured by calipers), animal body weight and tumor condition were recorded twice weekly during the study. Tumor volume (measured by caliper) was calculated using the following formula: length (mm) x width (mm)2/0.52. For efficacy studies, mice were randomized based on tumor volume and growth inhibition was assessed by comparing the difference in tumor volume between control and treatment groups. When the tumor size reaches about 230mm3Administration is started.
As a result:in mice bearing subcutaneous MV-4-11 tumors, treatment with example 2 resulted in significant antitumor activity. Mice receiving a single dose of 100mg/kg example 2 experienced 100% tumor regression (figure 16). The response was durable, with 4 of 6 mice remaining tumor-free 16 days after treatment. Mice receiving iv administration of 30mg/kg example 2 once a week also experienced tumor regression (approximately 73% on day 6), with 1 of 6 mice remaining tumor-free 16 days after treatment initiation.
Example 8: in vitro binding potency of examples 1,2 and 3
Biochemical binding TR-FRET assay for measuring protein complex disruption
The ability of a compound to disrupt the interaction between recombinant human Mcl-1 and a labeled BIM peptide probe was assessed using a TR-FRET assay.
The assay was constructed such that GST-labeled Mcl-1 protein was incubated with europium-labeled anti-GST antibody and a halite fluorescence (HyLite Fluor) 647-labeled peptide corresponding to BH3 domain of BIM. Obey 10-point, half-log10Dilution protocol was at 100. mu.M or 10. mu.MInitial evaluation of Compound IC50The value is obtained. Specifically, the human Mcl-1 enzyme from Mcl-1(E171-G327) was cloned into an overexpression vector, expressed as an N-terminal GST-tagged fusion protein in e.coli, and subsequently purified via glutathione sepharose affinity and size exclusion chromatography. The assay was performed in 384-well LV plates (Greiner catalog No. 784075) and run in the presence and absence of the compound of interest. mu.L of assay mixture per well contained 10mM Tris (pH7.4), 1.0mM DTT, 0.005% Tween-20, 150mM NaCl, 10% DMSO, and 1.5nM GST Mcl-1, 0.5nM LanthaScreen Eu-labeled GST antibody (Invitrogen catalog number PV5594), 4.0nM Hallite fluorescence (HyLite Fluor) 647-labeled BIM peptide [ C (Hilyte647C2 maleimide) -WIAQELRRIGDEFN (SEQ ID NO:1)]. The reaction was incubated at 24 ℃ for 90min and then read on a Tecan M1000 spectrofluorometer with excitation at 340nm and 612nm&Emission at 665 nm. Subsequently, the ratio of fluorescence emission intensity at 665nm to 612nm was calculated for each reaction, and the dose-response to ratio of test compound concentration was fitted to a selection fitting model that would provide the best fit quality using automated parameters to derive the IC for each test compound50The value is obtained. Table 9 provides the results from the TR-FRET Mcl1 binding assay.
Ratio calculation 665nm emission 612 10000 emission
Inhibition [% 100- [ (test ratio-min (compound control))/(max (DMSO control) -min (compound control)) ]
TABLE 9
Note that: the caspase activity of example 3 (compound III) as reported in table 1 and the FRET activity of example 3 (compound III) as reported in table 9 are highly dependent on the purity of the enantiomers, since most of the activity derives from RaEnantiomers (example 2, Compound)II) residual impurities. Thus, samples with lower enantiomeric purity exhibited increased potency in these assays. The data shown are geometric averages of multiple measurements from samples of different enantiomeric purity.
Sequence listing
<110> AstraZeneca pharmaceutical Co., Ltd (AstraZeneca AB)
<120> MCL-1 inhibitors and methods of use thereof
<130>200407-WO-PCT
<150>US 62/326156
<151>2016-04-22
<160>1
<170> PatentIn version 3.5
<210>1
<211>15
<212>PRT
<213> Artificial sequence
<220>
<223> HyLite Fluor 647-labeled BIM peptide
<220>
<221> features not yet classified
<222>(1)..(1)
<223> Hilyte647C2 Maleimide
<400>1
Cys Trp Ile Ala Gln Glu Leu Arg Arg Ile Gly Asp Glu Phe Asn
1 5 10 15

Claims (16)

1. A compound which is 17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.1 ]4,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula I)
Or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1.
3. A pharmaceutically acceptable salt of the compound of claim 1.
4. The compound of claim 1, wherein the compound of formula I has the structure: (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14, 7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula II)
Or a pharmaceutically acceptable salt thereof.
5. The compound of claim 4.
6. A pharmaceutically acceptable salt of the compound of claim 4.
7. The compound of claim 1, wherein the compound of formula I has the structure: (S)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14, 7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula III)
Or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7.
9. A pharmaceutically acceptable salt of the compound of claim 7.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, in crystalline form.
11. In solid form (R)a) -17-chloro-5, 13,14, 22-tetramethyl-28-oxa-2, 9-dithia-5, 6,12,13, 22-pentazepine [27.7.1.14,7.011,15.016,21.020,24.030,35]Trioctadecyl-1 (37),4(38),6,11,14,16,18,20,23,29,31,33, 35-tridecene-23-carboxylic acid (formula II)
Or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent.
13. A method of treating cancer, comprising administering to a subject in need thereof a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof.
14. A compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
15. Use of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.
16. A pharmaceutical composition comprising a compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.
HK19120306.6A 2016-04-22 2017-04-21 用于治疗癌症的大环mcl-1 抑制剂 HK1260481B (en)

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