Salts and solid forms of sonlotoclax intermediates

Abstract

The method for making sonlotoclax disclosed in the document is not suitable for scale-up because the intermediate, methyl 4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin-1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoate (compound 2), is obtained as an oil or liquid with low chemical purity. Therefore, new methods for making sonlotoclax are desirable. Disclosed herein are salt and solid forms of sonlotoclax intermediates, as well as processes for their preparation.

Description

[Technical Field]

[0001] Disclosed herein are salt and solid forms of sonlotoclax intermediates, as well as methods for making sonlotoclax. [Background technology]

[0002] International Publication No. WO2019 / 210828 discloses a series of Bcl-2 inhibitors, specifically 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide (hereinafter referred to as sonlotoclax). [ka] The method for preparing sonlotoclax disclosed in the document is not suitable for scale-up because the intermediate, methyl 4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin-1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoate (compound 2), is obtained as an oil or liquid with low chemical purity. Therefore, new methods for preparing sonlotoclax are desirable. [ka] [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2019 / 210828 Summary of the Invention [Means for solving the problem]

[0004] Provided herein are salts of Compound 2, as well as crystalline and amorphous forms thereof. Also provided herein are methods of making salts of Compound 2, as well as crystalline and amorphous forms thereof. Also provided herein are methods of making sonlotoclax using salts of Compound 2, as well as crystalline and amorphous forms thereof. [Brief explanation of the drawings]

[0005] [Figure 1A] 1 shows the XRPD pattern of Oxalate Type A. [Figure 1B] 1 shows the TGA / DSC curves of oxalate type A. [Figure 1C] 1 shows the NMR spectrum of oxalate type A. [Figure 2A] 1 shows the XRPD pattern of Oxalate Type B. [Figure 2B] 1 shows the TGA / DSC curves of oxalate type B. [Figure 2C] 1 shows the NMR spectrum of oxalate type B. [Figure 3A] 1 shows the XRPD pattern of oxalate Type C. [Figure 3B] 1 shows the TGA / DSC curves of oxalate Type C. [Figure 3C] 1 shows the NMR spectrum of oxalate type C. [Figure 4A] 1 shows the XRPD pattern of oxalate Type D. [Figure 4B] 1 shows the TGA / DSC curves of oxalate type D. [Figure 4C] 1 shows the NMR spectrum of oxalate type D. DETAILED DESCRIPTION OF THE INVENTION

[0006] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0007] As used herein, the term "solvate" refers to a crystalline form of Compound 2 that includes a solvent.

[0008] As used herein, the terms "crystal form" or "crystalline form" refer to a solid form that is crystalline. In certain embodiments, a crystalline form of a substance may be substantially free of amorphous forms and / or other crystalline forms. In certain embodiments, a crystalline form of a substance may contain less than about 1%, less than about 2%, less than about 3%, less than about 4%, less than about 5%, less than about 6%, less than about 7%, less than about 8%, less than about 9%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 35%, less than about 40%, less than about 45%, or less than about 50% by weight of one or more amorphous forms and / or other crystalline forms. In certain embodiments, a crystalline form of a substance may be physically and / or chemically pure. In certain embodiments, the crystalline form of the substance is about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0009] As used herein, unless otherwise specified, the terms "amorphous" or "amorphous form" mean that the substance, component, or product in question is substantially not crystalline as determined by X-ray diffraction. Specifically, the term "amorphous form" refers to a disordered solid form, i.e., a solid form lacking long-range crystalline order. In certain embodiments, an amorphous form of a substance may be substantially free of other amorphous and / or crystalline forms. In certain embodiments, an amorphous form of a substance may contain, on a weight basis, less than about 1 wt%, less than about 2 wt%, less than about 3 wt%, less than about 4 wt%, less than about 5 wt%, less than about 10 wt%, less than about 15 wt%, less than about 20 wt%, less than about 25 wt%, less than about 30 wt%, less than about 35 wt%, less than about 40 wt%, less than about 45 wt%, or less than about 50 wt% of one or more other amorphous and / or crystalline forms. In certain embodiments, the amorphous form of the substance can be physically and / or chemically pure, ie, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, or about 90% physically and / or chemically pure.

[0010] As used herein, the term "about" when used in reference to XRPD peak positions refers to the inherent variability of the peaks depending on the calibration of the instrument, the process used to prepare the crystalline forms of the present disclosure, changes in the crystalline form over time, and the type of instrument used for the analysis. The variability of the instrument used for the XRPD analysis was about ±0.2 degrees 2θ.

[0011] As used herein, the term "about" when used in reference to the onset of a DSC endothermic peak refers to the inherent variability of the peak depending on the calibration of the instrument, the process used to prepare the samples of the present disclosure, and the type of instrument used for the analysis. The variability of the instrument used for the DSC analysis was about ±1°C.

[0012] The term "about," as used herein other than as defined above, indicates that a number (e.g., temperature, pH, volume, etc.) may vary within ±10%, preferably ±5%, unless otherwise indicated.

[0013] An experimental measurement, result, or observation (e.g., an XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve) is "substantially in agreement" with another XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve if one of ordinary skill in the art would consider the XRPD pattern to correspond to the same single crystalline form of the same compound. Thus, an XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermal curve that substantially conforms to one or more of the figures provided herein may be identical or, more likely, slightly different. For example, an XRPD pattern that differs slightly from one or more of the figures may not necessarily exhibit every line of the diffraction pattern presented herein and / or may exhibit slight variations in the appearance or intensity of lines, or shifts in the position of lines. Such differences typically result from differences in the conditions under which the data was obtained or the purity of the samples used to obtain the data. One of ordinary skill in the art can determine whether a sample of a crystalline compound is in the same or a different form than those disclosed herein by comparing the XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermocurve of the sample to the corresponding XRPD pattern, DSC thermogram, NMR spectrum, DVS isotherm, or TGA thermocurve disclosed herein.

[0014] Surprisingly, the salt of Compound 2, preferably the oxalate salt of Compound 2, and even more preferably the oxalate salt of Compound 2, is a solid with very low viscosity and excellent stability. The crystalline forms of the oxalate salt of Compound 2, particularly Form B of the oxalate salt, can be obtained with very good purity without further purification, making them suitable for large-scale industrial processes. The particle size of Form B is 1-50 μm, preferably 1-30 μm, more preferably 5-20 μm, and even more preferably 5-10 μm. Such particle sizes can be easily and quickly obtained by filtration.

[0015] Aspect 1. A salt of formula (I): [ka] wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentianic acid, niacin, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; n is about 0.5 to about 3; Preferably, n is 0.5 to 2, more preferably, n is 0.5 to 1.5, and even more preferably, n is 1, and in certain embodiments, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, or 3.0.

[0016] Aspect 2. The salt of aspect 1, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and / or nitric acid.

[0017] Aspect 3. The salt of Aspect 1, wherein the acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid, preferably, the acid is selected from oxalic acid.

[0018] Aspect 4. The salt is of formula (II): [ka] In the formula, n is about 0.5 to about 3; Preferably, n is 0.5 to 2, more preferably, n is 0.5 to 1.5, even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0, and even more preferably, n is 1.0; Even more preferably, the salt according to aspect 1, wherein the salt is the oxalate salt of formula (III). [ka]

[0019] Embodiment 5. A crystalline form of the compound of formula IV, [ka] wherein [acid] is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentianic acid, niacin, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; [Solvent] is selected from H2O or an organic solvent; n is a number between about 0.5 and about 3; The above crystalline form, wherein m is a number of about 0.0 to about 5.0.

[0020] Aspect 6. The acid is selected from the group consisting of inorganic acids selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and / or nitric acid, or organic acids selected from fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentianic acid, niacin, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; Preferably, the acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; More preferably, the crystalline form according to aspect 5, wherein the acid is selected from oxalic acid.

[0021] Aspect 7. n is about 0.5 to about 3; Preferably, n is 0.5 to 2, more preferably, n is 0.5 to 1.5, even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0, and even more preferably, n is 1.0.

[0022] Aspect 8. The crystalline form of any one of aspects 5-7, wherein the [solvent] is selected from MeOH, EtOH, i-PrOH, n-PrOH, n-BuOH, t-BuOH, DCM, CPME, toluene, acetone, butanone, pentanone, HO, MeCN, THF, ether, propyl ether, n-heptane, hexane, 1,4-dioxane, or EtOAc.

[0023] Aspect 9: m is a number between about 0.0 and about 3.0, preferably between about 0.0 and about 2.0, more preferably between 0.1±0.1, 0.5±0.1, 1.0±0.2, 1.5±0.2, and 2.0±0.2, and even more preferably between 0 and 0.2, 0.95 and 1.05, 1.05 and 1.15, 1.45 and 1.55, or 1.90 and 2.10. and more preferably, m is 0.98 to 1.02, 1.08 to 1.12, or 1.48 to 1.52, 1.95 to 2.15, and even more preferably, m is 0, 0.1, 0.2, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0.

[0024] Embodiment 10. A crystalline form of the oxalate salt of Compound 2, comprising: (a) 2θ angle values: 3.89±0.2, 7.69±0.2, 10.55±0.2, 10.84±0.2, 11.21±0.2, 11.68±0.2, 12.31±0.2, 13.02±0.2, 13.83±0.2, 14.69±0.2, 15.36±0.2, 15.58±0.2, 16.60±0.2 , 17.58±0.2, 18.39±0.2, 18.98±0.2, 19.32±0.2, 19.81±0.2, 20.37±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.09±0.2, 23.48±0.2, 24.15±0.2, 24.76 crystalline form A, characterized by a powder X-ray diffraction pattern comprising 3, 4, 5, 6, 7, 8, 9, or more diffraction peaks independently selected from the group consisting of 25.44±0.2, 25.66±0.2, 26.18±0.2, 26.67±0.2, 27.00±0.2, 28.11±0.2, 28.71±0.2, 29.09±0.2, 29.55±0.2, 29.91±0.2, 31.52±0.2, 32.18±0.2, 32.80±0.2, 34.49±0.2, 34.97±0.2, 36.66±0.2, 38.52±0.2, 39.32±0.2, and 39.71±0.2; or (b) 2θ angle values: 4.05±0.2, 8.00±0.2, 10.79±0.2, 11.23±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 12.95±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2 , 17.14±0.2, 17.76±0.2, 18.41±0.2, 19.38±0.2, 20.08±0.2, 20.50±0.2, 21.04±0.2, 21.66±0.2, 22.08±0.2, 22.52±0.2, 23.34±0.2, 23.72±0.2, 24.09 crystalline form B, characterized by a powder X-ray diffraction pattern comprising 3, 4, 5, 6, 7, 8, 9, or more diffraction peaks independently selected from the group consisting of 24.82±0.2, 25.31±0.2, 25.66±0.2, 26.02±0.2, 27.21±0.2, 27.78±0.2, 28.21±0.2, 28.53±0.2, 29.01±0.2, 31.06±0.2, 31.45±0.2, 32.28±0.2, 33.02±0.2, 34.67±0.2, 35.30±0.2, 36.02±0.2, and 38.00±0.2; or (c) The values ​​of 2θ angles are 3.80±0.2, 4.01±0.2, 8.00±0.2, 10.42±0.2, 11.31±0.2, 11.55±0.2, 12.02±0.2, 12.94±0.2, 13.91±0.2, 14.13±0.2, 14.61±0.2, 16.04±0.2, 16.93±0.2, 17.76±0.2, 18.06±0.2. .43±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 22.34±0.2, 22.62±0.2, 23.16±0.2, 23.55±0.2, 23.76±0.2, 24.18±0.2, 24.86±0.2, 25.39±0.2, 2 5.65±0.2, 26.04±0.2, 26.46±0.2, 26.96±0.2, 27.53±0.2, 28.03±0.2, 28.47±0.2, 29.02±0.2, 29.47±0.2, 29.70±0.2, 30.16±0.2, 30.98±0.2, 31.36±0.2, 31.87±0.2, 32.53±0.2 , 33.38±0.2, 34.41±0.2, 35.63±0.2, 35.91±0.2, 36.59±0.2, 38.15±0.2, and 38.66±0.2, or (d) The values ​​of 2θ angles were 4.06±0.2, 8.03±0.2, 10.51±0.2, 10.84±0.2, 11.60±0.2, 12.06±0.2, 12.85±0.2, 14.04±0.2, 14.67±0.2, 16.08±0.2, 16.98±0.2, 17.36±0.2, and 17.80± 0.2, 18.36±0.2, 18.68±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.20±0.2, 21.66±0.2, 21.97±0.2, 22.38±0.2, 23.31±0.2, 23.80±0.2, 24.14±0.2 , 24.31±0.2, 24.93±0.2, 25.52±0.2, 26.77±0.2, 27.28±0.2, 27.48±0.2, 28.33±0.2, 28.75±0.2, 29.59±0.2, 30.10±0.2, 30.81±0.2, 31.20±0.2, 32.16±0.2, 32.61±0.2, 33.36±0.2, 36.05±0.2, 38.64±0.2, and 39.25±0.2, wherein the crystalline form is crystalline form D.

[0025] Embodiment 11. A crystalline form of the oxalate salt of Compound 2, comprising: (a) Diffraction peaks with 2θ angle values ​​of 11.68±0.2, 15.36±0.2, and 21.61±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 21.05±0.2, and 21.61±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, and 23.48±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 23.48±0.2, and 25.44±0.2; Even more preferably, crystalline form A, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with values ​​of 2-theta angles of 7.69±0.2, 10.55±0.2, 11.68±0.2, 11.21±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.48±0.2, and 25.44±0.2; or (b) diffraction peaks with 2θ angle values ​​of 11.80±0.2, 12.02±0.2, and 16.03±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 8.00±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, and 20.50±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 20.50±0.2, 23.72±0.2, and 26.02±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, and 26.02±0.2; Even more preferably, crystalline form B, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with values ​​of 2-theta angles of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, 26.02±0.2, and 28.21±0.2; or (c) diffraction peaks with 2θ angle values ​​of 10.42±0.2, 12.94±0.2, and 20.29±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 10.42±0.2, 12.94±0.2, 16.04±0.2, 18.91±0.2, 19.91±0.2, and 20.29±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, and 24.18±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.87±0.2, 23.16±0.2, and 24.18±0.2; Even more preferably, crystalline form C, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with values ​​of 2-theta angles of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.43±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 23.16±0.2, 24.18±0.2, and 28.47±0.2; or (d) diffraction peaks with 2θ angle values ​​of 10.51±0.2, 20.20±0.2, and 20.46±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 10.51±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, and 20.20±0.2, 20.46±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 10.51±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 20.20±0.2, 20.46±0.2, 21.66±0.2, and 23.80±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 10.51±0.2, 10.84±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.66±0.2, and 23.80±0.2; Even more preferably, the crystalline form is crystalline form D, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with values ​​of 2-theta angles of 10.51±0.2, 10.84±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 18.36±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.20±0.2, 21.66±0.2, 22.38±0.2, and 23.80±0.2.

[0026] Embodiment 12. A crystalline form of the oxalate salt of Compound 2, characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in a figure selected from the group consisting of Figure 1A, Figure 2A, Figure 3A, and Figure 4A.

[0027] Embodiment 13. A method for preparing a crystalline form of the oxalate salt of Compound 2, comprising: Step (1) dissolving the oxalate salt according to embodiment 4 in EtOH and slowly evaporating the resulting solution to obtain said crystalline form; or Step (2) dissolving the oxalate salt according to embodiment 4 in DCM and slowly evaporating the resulting solution to obtain said crystalline form; or step (3) suspending the oxalate salt of embodiment 4 in CPME and stirring the resulting mixture to obtain said crystalline form; or step (4) suspending the oxalate salt of embodiment 4 in toluene and stirring the mixture to obtain said crystalline form; Preferably, the oxalate salt according to embodiment 4 is in amorphous form.

[0028] Embodiment 14. The duration of step (1) is 0 to 10 days, preferably 0 to 7 days, more preferably 2 to 4 days, and even more preferably 1, 2, 3, 4, or 5 days; The duration of step (2) is 0 to 10 days, preferably 0 to 7 days, more preferably 2 to 4 days, and even more preferably 1, 2, 3, 4, or 5 days; The duration of step (3) is 0 to 10 days, preferably 0 to 7 days, more preferably 2 to 4 days, and even more preferably 1, 2, 3, 4, 5, 6, or 7 days; 14. The method for preparing a crystalline form according to embodiment 13, wherein the duration of step (4) is 0 to 10 days, preferably 0 to 7 days, more preferably 2 to 4 days, and even more preferably 1, 2, 3, 4, 5, 6, or 7 days.

[0029] Aspect 15. In step (1), the oxalate / EtOH (mg / ml) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, and even more preferably 30:1; In step (2), the oxalate / DCM (mg / ml) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, and even more preferably 30:1; In step (3), the oxalate / CPME (mg / ml) ratio is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, and even more preferably 60:1; 15. The method for preparing a crystalline form according to any one of aspects 13 to 14, wherein the oxalate / toluene (mg / ml) in step (4) is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, and even more preferably 60:1. Aspect 16. A method for preparing a crystalline form of the oxalate salt of Compound 2, wherein the temperature in step (1) is 0 to 50°C, preferably 10 to 40°C, more preferably 20 to 30°C, even more preferably 20 to 25°C or room temperature; the temperature in step (2) is 0 to 50°C, preferably 10 to 40°C, more preferably 20 to 30°C, even more preferably 20 to 25°C or room temperature; the temperature in step (3) is 0 to 50°C, preferably 10 to 40°C, more preferably 20 to 30°C, even more preferably 20 to 25°C or room temperature; The method, wherein the temperature in step (4) is 10 to 110°C, preferably 30 to 100°C, more preferably 60 to 90°C, and even more preferably 80°C or room temperature.

[0030] Embodiment 17. A method for preparing a crystalline form according to embodiments 13-16, wherein the starting material is amorphous, selected from types A, B, C, D, and preferably amorphous.

[0031] Embodiment 18. The method further comprises: Step (5) involves dissolving the free base of compound 3 in a solvent and then adding oxalic acid to obtain the oxalate salt, wherein compound 3 is [ka] and Preferably, the solvent in step (5) is methyl tert-butyl ether; More preferably, the oxalic acid is added by using a solution of methyl tert-butyl ether; Even more preferably, the method for preparing a crystalline form according to any one of embodiments 13 to 17, wherein step (5) is carried out at room temperature or between 20°C and 30°C.

[0032] Aspect 19. The crystalline form according to any one of Aspects 5 to 12, or the salt according to any one of Aspects 1 to 4, is used as an intermediate for sonlotoclax.

[0033] Aspect 20. As used herein, sonlotoclax [ka] or a salt thereof, comprising reacting a salt of formula (I) with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

[0034] In one embodiment of aspect 20, the reaction is carried out in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP).

[0035] Aspect 21. As used herein, sonlotoclax [ka] or a salt thereof, comprising reacting a salt of formula (I) with an acid or base to form (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid [ka] or a salt thereof.

[0036] In one embodiment of aspect 21, the acid is HCl or the base is NaOH.

[0037] Aspect 22. Provided herein is a method of making sonlotoclax, comprising the step of: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid [ka] or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

[0038] In one embodiment of aspect 22, the reaction is carried out in the presence of EDCI and DMAP.

[0039] In one embodiment of aspect 23, provided herein is a method for preparing a pharmaceutical composition comprising sonlotoclax, comprising mixing sonlotoclax with a pharmaceutically acceptable excipient, wherein the sonlotoclax is prepared according to a method provided herein.

[0040] Numbered embodiments:

[0041] Embodiment 1. A salt of formula (I): [ka] wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentianic acid, niacin, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; The salt wherein n is about 0.5 to about 3.

[0042] Embodiment 2. The salt of embodiment 1, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and / or nitric acid.

[0043] Embodiment 3. The salt of embodiment 1, wherein the acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid, preferably, the acid is selected from oxalic acid.

[0044] Embodiment 4. The salt is of formula (II): [ka] In the formula, n is about 0.5 to about 3; Preferably, n is 0.5 to 2, more preferably, n is 0.5 to 1.5, even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0, and even more preferably, n is 1.0; Even more preferably, the salt according to embodiment 1, wherein said salt is the oxalate salt of formula (III). [ka]

[0045] Embodiment 5. A crystalline form of a salt of formula IV, [ka] wherein [acid] is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentianic acid, niacin, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; [Solvent] is selected from H2O or an organic solvent; n is a number between about 0.5 and about 3; The above crystalline form, wherein m is a number of about 0.0 to about 5.0.

[0046] Embodiment 6. The acid is selected from the group consisting of inorganic acids selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and / or nitric acid, or organic acids selected from fumaric acid, tartaric acid (L-tartaric acid or D-tartaric acid), lauric acid, stearic acid, gentianic acid, niacin, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; Preferably, the acid is selected from tartaric acid (L-tartaric acid or D-tartaric acid), malic acid, citric acid, p-toluenesulfonic acid, D-DTTA, maleic acid, and / or oxalic acid; More preferably, the crystalline form of embodiment 5, wherein the acid is selected from oxalic acid.

[0047] In embodiment 7, n is about 0.5 to about 3; Preferably, n is 0.5 to 2, more preferably, n is 0.5 to 1.5, even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0, and even more preferably, n is 1.0. The crystalline form of any one of embodiments 5 to 6, wherein n is 0.5 to 2, more preferably, n is 0.5 to 1.5, even more preferably, n is 0.5, 1.0±0.1, 1.5±0.1, 2.0±0.1, 2.5±0.1, 3.0, and even more preferably, n is 1.0.

[0048] Embodiment 8. The crystalline form of any one of embodiments 5-7, wherein the solvent is selected from MeOH, EtOH, i-PrOH, n-PrOH, n-BuOH, t-BuOH, DCM, CPME, toluene, acetone, butanone, pentanone, HO, MeCN, THF, ether, propyl ether, n-heptane, hexane, 1,4-dioxane, or EtOAc.

[0049] Embodiment 9: m is a number of about 0.0 to about 3.0, preferably about 0.0 to about 2.0, more preferably a number selected from the group consisting of 0.1±0.1, 0.5±0.1, 1.0±0.2, 1.5±0.2, and 2.0±0.2, and even more preferably, m is a number selected from the group consisting of 0 to 0.2, 0.95 to 1.05, 1.05 to 1.15, 1.45 to 1.55, or 1.90 to 2.10. and more preferably, m is 0.98 to 1.02, 1.08 to 1.12, or 1.48 to 1.52, 1.95 to 2.15, and even more preferably, m is 0, 0.1, 0.2, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, or 7.0.

[0050] Embodiment 10. (a) 2θ angle values ​​are 3.89±0.2, 7.69±0.2, 10.55±0.2, 10.84±0.2, 11.21±0.2, 11.68±0.2, 12.31±0.2, 13.02±0.2, 13.83±0.2, 14.69±0.2, 15.36±0.2, 15.58±0.2, 16.60±0.2, 17.58±0.2, 18.39±0.2, 18.98±0.2, 19.32±0.2, 19.81±0.2, 20.37±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.09±0.2, 23.48±0.2, 24.15±0.2, 24.76±0.2. 2, 25.44±0.2, 25.66±0.2, 26.18±0.2, 26.67±0.2, 27.00±0.2, 28.11±0.2, 28.71±0.2, 29.09±0.2, 29.55±0.2, 29.91±0.2, 31.52±0.2, 32.18±0.2, 32.80±0.2, 34.49±0.2, 34.97±0.2, 36.66±0.2, 38.52±0.2, 39.32±0.2, and 39.71±0.2; or (b) The values ​​of 2θ angles are 4.05±0.2, 8.00±0.2, 10.79±0.2, 11.23±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 12.95±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2, 17.14±0.2, 17.76±0.2, 18.41±0.2, 19.38±0.2, 20.08±0.2, 20.50±0.2, 21.04±0.2, 21.66±0.2, 22.08±0.2, 22.52±0.2, 23.34±0.2, 23.72±0.2, 24.09±0.2. crystalline Form B of the Oxalate Salt, characterized by an X-ray powder diffraction pattern comprising 3, 4, 5, 6, 7, 8, 9, or more diffraction peaks independently selected from the group consisting of 2, 24.82±0.2, 25.31±0.2, 25.66±0.2, 26.02±0.2, 27.21±0.2, 27.78±0.2, 28.21±0.2, 28.53±0.2, 29.01±0.2, 31.06±0.2, 31.45±0.2, 32.28±0.2, 33.02±0.2, 34.67±0.2, 35.30±0.2, 36.02±0.2, and 38.00±0.2; or (c) 2θ angle values ​​are 3.80±0.2, 4.01±0.2, 8.00±0.2, 10.42±0.2, 11.31±0.2, 11.55±0.2, 12.02±0.2, 12.94±0.2, 13.91±0.2, 14.13±0.2, 14.61±0.2, 16.04±0.2, 16.93±0.2, 17.76±0.2, 18.4 3±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 22.34±0.2, 22.62±0.2, 23.16±0.2, 23.55±0.2, 23.76±0.2, 24.18±0.2, 24.86±0.2, 25.39±0.2, 25.6 5±0.2, 26.04±0.2, 26.46±0.2, 26.96±0.2, 27.53±0.2, 28.03±0.2, 28.47±0.2, 29.02±0.2, 29.47±0.2, 29.70±0.2, 30.16±0.2, 30.98±0.2, 31.36±0.2, 31.87±0.2, 32.53±0.2, 33.3 crystalline Form C of the Oxalate Salt, characterized by an X-ray powder diffraction pattern comprising 3, 4, 5, 6, 7, 8, 9, or more diffraction peaks independently selected from the group consisting of: 34.8±0.2, 34.41±0.2, 35.63±0.2, 35.91±0.2, 36.59±0.2, 38.15±0.2, and 38.66±0.2; or (d) The values ​​of 2θ angles were 4.06±0.2, 8.03±0.2, 10.51±0.2, 10.84±0.2, 11.60±0.2, 12.06±0.2, 12.85±0.2, 14.04±0.2, 14.67±0.2, 16.08±0.2, 16.98±0.2, 17.36±0.2, 17.80±0.2, 1 8.36±0.2, 18.68±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.20±0.2, 21.66±0.2, 21.97±0.2, 22.38±0.2, 23.31±0.2, 23.80±0.2, 24.14±0.2, 24.31±0.2, 10. The crystalline form of any one of embodiments 5-9, which is crystalline form D of the Oxalate Salt, characterized by an X-ray powder diffraction pattern comprising 3, 4, 5, 6, 7, 8, 9, or more diffraction peaks independently selected from the group consisting of 24.93±0.2, 25.52±0.2, 26.77±0.2, 27.28±0.2, 27.48±0.2, 28.33±0.2, 28.75±0.2, 29.59±0.2, 30.10±0.2, 30.81±0.2, 31.20±0.2, 32.16±0.2, 32.61±0.2, 33.36±0.2, 36.05±0.2, 38.64±0.2, and 39.25±0.2.

[0051] Embodiment 11. (a) Diffraction peaks with 2θ angle values ​​of 11.68±0.2, 15.36±0.2, and 21.61±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 21.05±0.2, and 21.61±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, and 23.48±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 10.55±0.2, 11.68±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 23.48±0.2, and 25.44±0.2; Even more preferably, crystalline Form A of the Oxalate Salt, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with 2-theta angle values ​​of 7.69±0.2, 10.55±0.2, 11.68±0.2, 11.21±0.2, 12.31±0.2, 15.36±0.2, 15.58±0.2, 18.39±0.2, 19.81±0.2, 21.05±0.2, 21.61±0.2, 21.91±0.2, 22.49±0.2, 23.48±0.2, and 25.44±0.2; or (b) diffraction peaks with 2θ angle values ​​of 11.80±0.2, 12.02±0.2, and 16.03±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 8.00±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, and 20.50±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 20.50±0.2, 23.72±0.2, and 26.02±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, and 26.02±0.2; Even more preferably, crystalline Form B of the Oxalate Salt, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with 2-theta angle values ​​of 8.00±0.2, 10.79±0.2, 11.80±0.2, 12.02±0.2, 12.45±0.2, 13.92±0.2, 15.55±0.2, 16.03±0.2, 16.83±0.2, 20.08±0.2, 20.50±0.2, 23.72±0.2, 24.09±0.2, 26.02±0.2, and 28.21±0.2; or (c) diffraction peaks with 2θ angle values ​​of 10.42±0.2, 12.94±0.2, and 20.29±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 10.42±0.2, 12.94±0.2, 16.04±0.2, 18.91±0.2, 19.91±0.2, and 20.29±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, and 24.18±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.87±0.2, 23.16±0.2, and 24.18±0.2; Even more preferably, crystalline Form C of the Oxalate Salt, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with 2-theta angle values ​​of 10.42±0.2, 12.02±0.2, 12.94±0.2, 16.04±0.2, 16.93±0.2, 18.43±0.2, 18.91±0.2, 19.91±0.2, 20.29±0.2, 20.96±0.2, 21.53±0.2, 21.87±0.2, 23.16±0.2, 24.18±0.2, and 28.47±0.2; or (d) diffraction peaks with 2θ angle values ​​of 10.51±0.2, 20.20±0.2, and 20.46±0.2; Preferably, diffraction peaks with 2θ angle values ​​of 10.51±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, and 20.20±0.2, 20.46±0.2; More preferably, diffraction peaks having 2θ angle values ​​of 10.51±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 20.20±0.2, 20.46±0.2, 21.66±0.2, and 23.80±0.2; Even more preferably, diffraction peaks with 2θ angle values ​​of 10.51±0.2, 10.84±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.66±0.2, and 23.80±0.2; Even more preferably, the crystalline form according to any one of embodiments 5 to 10 is crystalline form D of the Oxalate Salt, characterized by an X-ray powder diffraction pattern comprising diffraction peaks with values ​​of 2-theta angles of 10.51±0.2, 10.84±0.2, 12.06±0.2, 12.85±0.2, 16.08±0.2, 16.98±0.2, 18.36±0.2, 19.15±0.2, 19.85±0.2, 20.20±0.2, 20.46±0.2, 21.20±0.2, 21.66±0.2, 22.38±0.2, and 23.80±0.2.

[0052] Embodiment 12. The crystalline form of any one of embodiments 5-11, characterized by a powder X-ray diffraction pattern substantially selected from the group consisting of Figure 1A, Figure 2A, Figure 3A, and Figure 4A.

[0053] Embodiment 13. A method for preparing the crystalline form of any one of embodiments 5 to 12, comprising: Step (1) dissolving the oxalate salt of embodiment 4 in EtOH and slowly evaporating the resulting solution to obtain said crystalline form; or Step (2) dissolving the oxalate salt according to embodiment 4 in DCM and slowly evaporating the resulting solution to obtain said crystalline form; or Step (3) suspending the oxalate salt of embodiment 4 in CPME and stirring the resulting mixture to obtain said crystalline form; or Step (4) suspending the oxalate salt of embodiment 4 in toluene and stirring the mixture to obtain the crystalline form.

[0054] Embodiment 14. The time in step (1) is 0 to 10 days, preferably 0 to 7 days, more preferably 2 to 4 days, and even more preferably 1, 2, 3, 4, or 5 days; The duration of step (2) is 0 to 10 days, preferably 0 to 7 days, more preferably 2 to 4 days, and even more preferably 1, 2, 3, 4, or 5 days; The duration of step (3) is 0 to 10 days, preferably 0 to 7 days, more preferably 2 to 4 days, and even more preferably 1, 2, 3, 4, 5, 6, or 7 days; The method for preparing a crystalline form according to embodiment 13, wherein the duration of step (4) is 0-10 days, preferably 0-7 days, more preferably 2-4 days, and even more preferably 1, 2, 3, 4, 5, 6, or 7 days.

[0055] Embodiment 15. In step (1), the oxalate / EtOH (mg / ml) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, and even more preferably 30:1; In step (2), the oxalate / DCM (mg / ml) is 1:1 to 100:1, preferably 1:1 to 50:1, more preferably 20:1 to 40:1, and even more preferably 30:1; In step (3), the oxalate / CPME (mg / ml) ratio is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, and even more preferably 60:1; 15. The method for preparing a crystalline form according to embodiments 13-14, wherein the oxalate / toluene (mg / ml) in step (4) is 1:1 to 100:1, preferably 20:1 to 80:1, more preferably 40:1 to 70:1, and even more preferably 60:1.

[0056] Embodiment 16. The temperature in step (1) is 0 to 50°C, preferably 10 to 40°C, more preferably 20 to 30°C, even more preferably 20 to 25°C or room temperature; the temperature in step (2) is 0 to 50°C, preferably 10 to 40°C, more preferably 20 to 30°C, even more preferably 20 to 25°C or room temperature; the temperature in step (3) is 0 to 50°C, preferably 10 to 40°C, more preferably 20 to 30°C, even more preferably 20 to 25°C or room temperature; 16. The method for preparing the crystalline form of embodiments 13-15, wherein the temperature in step (4) is 10-110°C, preferably 30-100°C, more preferably 60-90°C, even more preferably 80°C or room temperature.

[0057] Embodiment 17. A process for the preparation of a crystalline form according to embodiments 13-16, wherein the starting material is amorphous, selected from types A, B, C, D, preferably amorphous.

[0058] Embodiment 18. A method for preparing the crystalline form of any of embodiments 13-17, further comprising: Step (5): Dissolving the free base of compound 3 in a solvent, and then adding oxalic acid to obtain the oxalate salt, [ka] and Preferably, the solvent in step (5) is methyl tert-butyl ether; More preferably, the oxalic acid is added by using a solution of methyl tert-butyl ether; Even more preferably, the temperature in step (5) is room temperature or 20°C to 30°C.

[0059] Embodiment 19. A process for the crystalline form of any one of embodiments 5-12 or the salt of any one of embodiments 1-4, wherein the crystalline form or the salt is used as an intermediate in the preparation of 2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-N-((4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(2-((S)-2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzamide. [Example]

[0060] [Table 5-1] [Table 5-2]

[0061] Equipment and parameters

[0062] For XRPD analysis, a PANalytical Empyrean and X'Pert3 powder X-ray diffractometer were used to characterize the physical forms obtained in this disclosure unless otherwise indicated. The XRPD parameters used are listed below. [Table 6]

[0063] For XRPD analysis, a Bruker D8 advanced X-ray powder diffractometer or equivalent was also used to characterize Form A and Form U. The XRPD parameters used are listed below. [Table 7]

[0064] The physical forms obtained in this disclosure were characterized using TGA and DSC unless otherwise specified. TGA data was collected using a TA Instruments TA Q500 / Q5000 TGA, and DSC was performed using a TA Instruments TA Q200 / Q2000 DSC. Details of the parameters used are provided below. [Table 8]

[0065] Several instruments were also used to test the TGA and DGA analysis of Forms A and U, with TGA data collected using a NETZSCH TG 209 F1 instrument and DSC performed using a TA Q20 or TA DSC 250 instrument. The parameters used are detailed below. [Table 9]

[0066] The DVS of the form obtained in this disclosure was measured using an SMS (Surface Measurement Systems) DVS Intrinsic without any special instructions (Method A). The relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters for the DVS test are as follows: [Table 10]

[0067] The DVS of Forms A and U was also measured by DVS Intrinsic (Method B) on an SMS (Surface Measurement Systems). The relative humidity at 25°C was calibrated against the deliquescence points of LiCl, Mg(NO3)2, and KCl. The parameters for the DVS test are as follows: [Table 11]

[0068] Single crystal X-ray diffraction data were collected at 120 K using a Rigaku XtaLAB Synergy R (Cu K radiation, 1.54184 Å) diffractometer. The instrument parameters are as follows: [Table 12]

[0069] The following examples are intended to further illustrate certain embodiments of the present disclosure, but are not intended to limit the scope of the disclosure.

[0070] Seven acids and seven organic solvents were used for the salt formation of compound 2 (see Table 1).

[0071] In one example, compound 2 (1.0 g, 1.73 mmol) and oxalic acid (0.16 g, 1.73 mmol) in MTBE (10 mL) solution were added dropwise. The reaction mixture was stirred for approximately 6 hours and filtered to yield a wet cake of methyl 4-(2-{(2S)-2-[2-(propan-2-yl)phenyl]pyrrolidin-1-yl}-7-azaspiro[3.5]nonan-7-yl)-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoate oxalate (compound 3). This solid has low water absorption and poor electrostatic capacity, making it difficult to adsorb to objects.

[0072] Other salts of compound 2 were prepared using the same procedure as that described for compound 3, but using other acids. The following amounts of the other acids were used: D-(-)-tartaric acid (0.26 g, 1.73 mmol), p-toluenesulfonic acid (0.3 g, 1.73 mmol), D-DTTA (0.67 g, 1.73 mmol), citric acid (0.33 g, 1.73 mmol), malic acid (0.23 g, 1.73 mmol), and maleic acid (0.20 g, 1.73 mmol). Other organic solvents were used in 10 mL volumes. The corresponding physical forms of the salts of compound 2 are shown in Table 1. The results indicate that when the acid used for salt formation is oxalic acid or D-DTTA, the resulting salts are in solid form in certain organic solvents. Considering the simplification of the process, D-DTTA / MTBE and oxalic acid / MTBE are preferred salt-forming systems. However, D-DTTA (MW 386.35 g / mol) may generate more waste in the reaction than oxalic acid (MW 90.03 g / mol).

[0073] [Table 1]

[0074] Synthesis of compound 3 [ka]

[0075] The free base of 3 (21 g) was dissolved in methyl tert-butyl ether (110 g). The temperature was adjusted to 20-30°C, and then a solution of oxalic acid (3.33 g) in methyl tert-butyl ether (110 g) was added within 2 hours. The solution was stirred at 20-30°C for 16 hours. The resulting solid was filtered and washed with methyl tert-butyl ether (20 g). The filtered solid was dried at a temperature below 45°C for 20-28 hours to obtain an amorphous solid.

[0076] Example 1A: Preparation of Compound 3 Form A (Form A)

[0077] The crystalline form A of Compound 3 sample was obtained by slow evaporation of a solution of the amorphous form of Compound 3 in EtOH at room temperature.

[0078] Procedure: 30 mg of amorphous solid Compound 3 was weighed into a 3 mL glass vial, and 1 mL of EtOH was added to obtain a clear solution. The solution was allowed to evaporate at room temperature for 3 days to induce precipitation, yielding crystalline Form A.

[0079] The resulting Form A was characterized using powder X-ray diffraction (XRPD) patterns (performed on a Bruker D8 advanced powder X-ray diffractometer), which showed that Form A is a crystalline form (see Figure 1A). The characteristic peaks and peak intensity percentages obtained from the XRPD analysis are shown in Table 1A.

[0080] [Table 1A-1] [Table 1A-2]

[0081] The TGA results showed a weight loss of 2.7% between 100 and 150 °C and a weight loss of 14% between 160 and 250 °C. The DSC results showed three endothermic peaks at 51 °C, 114 °C, and 192 °C (onset temperatures), respectively (Figure 1B). 1 Approximately 0.27% EtOH was observed in the H NMR spectrum ( Figure 1C ).

[0082] Example 2A: Preparation of Compound 3 Form B (Form B)

[0083] The crystalline form B of compound 3 sample was obtained by slow evaporation of a solution of amorphous form of compound 3 in DCM at room temperature.

[0084] Procedure: 30 mg of amorphous solid Compound 3 was weighed into a 3 mL glass vial, and 1 mL of DCM was added to obtain a clear solution. The solution was allowed to evaporate at room temperature to induce precipitation, yielding crystalline Form B.

[0085] The resulting Form B was characterized using an XRPD pattern, which showed that Form B was crystalline (see Figure 2A). The characteristic peaks and peak intensity percentages obtained from the XRPD analysis are shown in Table 2A.

[0086] [Table 2A-1] [Table 2A-2]

[0087] The TGA results showed a weight loss of 0.9% between 100 and 150 °C and a weight loss of 8.6% between 170 and 250 °C. The DSC results showed three endothermic peaks at 53 °C, 124 °C, and 192 °C (onset temperatures), respectively (Figure 2B). 1 Approximately 3% DCM was observed in the 1 H NMR spectrum (Figure 2C).

[0088] Example 3A: Preparation of Compound 3 Form C (Form C)

[0089] The crystalline form C of Compound 3 sample was obtained by slurrying the amorphous form of Compound 3 in CPME at room temperature.

[0090] Procedure: 30 mg of amorphous solid Compound 3 was weighed into a 3 mL glass vial, and 0.5 mL of CPME was added to obtain a suspension. The mixture was magnetically stirred at 800 RPM for 4 days at room temperature to obtain crystalline Form C.

[0091] The resulting Form C was characterized using an XRPD pattern, which showed that Form C was crystalline (see Figure 3A). The characteristic peaks and peak intensity percentages obtained from the XRPD analysis are shown in Table 3A.

[0092] [Table 3A-1] [Table 3A-2]

[0093] TGA results showed a weight loss of 4.1% from 95 to 150 °C and a weight loss of 14.8% from 150 to 250 °C. DSC results showed two endothermic peaks at 131 °C and 194 °C (onset temperatures), respectively (Figure 3B). 1 Approximately 5.9% CPME was observed in the H NMR spectrum ( Figure 3 C).

[0094] Example 4A: Preparation of Compound 3 Form D (Form D)

[0095] The crystalline form D of Compound 3 sample was obtained by slurrying the amorphous form of Compound 3 in toluene at 80°C.

[0096] Procedure: 30 mg of amorphous solid Compound 3 was weighed into a 3 mL glass vial, and 0.5 mL of toluene was added to obtain a suspension. The mixture was magnetically stirred at 800 RPM for 4 days at 80°C to obtain crystalline Form D.

[0097] The resulting Form D was characterized using an XRPD pattern, which showed that Form D was crystalline (see Figure 4A). The characteristic peaks and peak intensity percentages obtained from the XRPD analysis are shown in Table 4A.

[0098] [Table 4A-1] [Table 4A-2]

[0099] The TGA results showed a weight loss of 3.1% between 120 and 170 °C and a weight loss of 13.5% between 170 and 250 °C. The DSC results showed two endothermic peaks at 132 and 194 °C (onset temperatures), respectively (Figure 4B). 1 Approximately 5.2% toluene was observed in the 1 H NMR spectrum (Figure 4C).

[0100] Example 5: Sonlotoclax

[0101] Step 1: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid

[0102] Methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate was synthesized according to the method (e.g., Example F43) in WO2019210828 (incorporated herein by reference in its entirety).

[0103] To a solution of methyl (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoate (105 g, 181.7 mmol) in THF (525 mL) and MeOH (525 mL) was added aqueous NaOH (3.5 M). The mixture was stirred at room temperature overnight. After the THF and MeOH were removed in vacuo, 3.5 L of water was added to the residue. The resulting mixture was adjusted to pH 5-6 with 3N HCl acid while stirring at room temperature. The precipitate was filtered and dried in vacuo to give the product as a white solid (102.4 g, yield: 99%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.13 (s, 1H), 11.58 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 - 7.40 (m, 2H), 7.35 (s, 1H), 7.27 - 7.04 (m, 3H), 6.68 (d, J = 8.0 Hz, 1H), 6.32 (s, 2H), 3.62 (s, 1H), 3.32 - 3.26 (m, 1H), 3.10 - 3.04 (m, 4H), 2.35-2.30 (m, 1 H), 2.9-2.15 (m, 1 H), 1.74 -1.64 (m, 4H), 1.52-1.37 (m, 6H), 1.28 - 1.06 (m, 6H). MS (ESI, m / e) [M+1] + 564.9.

[0104] Step 2: Sonrotoclax

[0105] A mixture of (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid (44 g, 78 mmol), 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide (26.8 g, 78 mmol), TEA (15.7 g, 156 mmol), EDCI (19.4 g, 101 mmol), and DMAP (19 g, 156 mmol) in anhydrous DCM (880 mL) was stirred overnight at room temperature. The reaction was monitored by HPLC. After complete consumption of the (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid starting material, the reaction mixture was heated to about 35° C. and N 1 ,N 117.2 g (195 mmol) of 1,2-dimethylethane-1,2-diamine was added in one portion. The reaction was stirred for an additional 12 h. The mixture was washed twice with 10 wt% aqueous AcOH (300 mL × 2) and then with saturated aqueous NaHCO3 (300 mL × 2). The organic layer was collected and concentrated to approximately 90 mL. 22 g of silica gel was added and stirred for 2 h. After filtration, 180 mL of EA was added to the refluxing filtrate and stirred for an additional 5 h. After cooling the mixture to room temperature, the precipitate was filtered, and the wet cake was washed twice with EA (180 mL). After drying in vacuo at 80-90 °C, sonlotoclax was obtained (48 g, yield: 69.5%). 1 H NMR (DMSO-d6) δ ppm: 11.65 (s, 1H), 11.11 (br, 1H), 8.58-8.39 (m, 2H), 8.00 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.57-7.37 (m, 4H), 7.30-7.10 (m, 3H), 7.00 (d, J = 9.2 Hz, 1H), 6.65 (d, J = 1.2 Hz, 1H), 6.35 (s, 1H), 6.17 (s, 1H), 4.24 (s, 1H), 3.39-3.20 (m, 5H), 3.04-2.88 (m, 4H), 2.23 (s, 1H), 1.94-1.47 (m, 11H), 1.44-1.26 (m, 7H), 1.19 (d, J = 8.0 Hz, 3H), 1.14 (d, J = 8.0 Hz, 3H), 1.10 (s, 4H). MS (ESI, m / e) [M+1] + 889.9.

Claims

1. A crystalline form of Compound 3, [Chemistry 18] The crystalline form, characterized by a powder X-ray diffraction pattern substantially in accordance with that shown in a figure selected from the group consisting of Figures 1A, 2A, 3A, and 4A.

2. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern is substantially in accordance with that shown in FIG. 1A.

3. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern is substantially in accordance with that shown in FIG. 2A.

4. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern is substantially in accordance with that shown in Figure 3A.

5. 2. The crystalline form of claim 1, wherein the powder X-ray diffraction pattern is substantially in accordance with that shown in Figure 4A.

6. Sonrotoklax 【Chemistry 19】 or a salt thereof, comprising reacting a salt of formula (I) 【Chemistry 20】 and 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide, wherein [acid] is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid, fumaric acid, tartaric acid, lauric acid, stearic acid, gentianic acid, niacin, aspartic acid, succinic acid, adipic acid, malic acid, citric acid, glycolic acid, gluconic acid, lactic acid, acetic acid, benzenesulfonic acid, methanesulfonic acid, benzoic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, (+)-di-1,4-toluoyl-D-tartaric acid (D-DTTA), maleic acid, or oxalic acid; The method wherein n is from about 0.5 to about 3.

7. 7. The method of claim 6, comprising reacting the salt of formula (I) with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP).

8. 7. The method of claim 6, wherein the salt of formula (I) is in the crystalline form of claim 1.

9. Sonrotoklax 【Chemistry 21】 or a salt thereof, comprising reacting the crystalline form of claim 1 with an acid or base to produce (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid 【Chemistry 22】 or a salt thereof.

10. 10. The method of claim 9, wherein the acid is HCl or the base is NaOH.

11. (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid 【Chemistry 23】 10. The method of claim 9, further comprising reacting the compound or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide.

12. 12. The method of claim 11, comprising reacting (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)benzoic acid or a salt thereof with 4-((((1r,4r)-4-hydroxy-4-methylcyclohexyl)methyl)amino)-3-nitrobenzenesulfonamide in the presence of EDCI and DMAP.

13. A method for preparing a pharmaceutical composition comprising sonlotoclax, the method comprising mixing the sonlotoclax with a pharmaceutically acceptable excipient, wherein the sonlotoclax is prepared according to the method of any one of claims 6 to 12.

14. A pharmaceutical composition comprising sonlotoclax or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, wherein the sonlotoclax is prepared according to the method of any one of claims 6 to 11.

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