Salts of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone and solid forms thereof
阅读说明：本技术 (s)-(5-环丁氧基-2-甲基-6-(1-(哌啶-4-基)-1h-吡唑-4-基)-3,4-二氢喹啉-1(2h)-基)(环丙基)甲酮的盐及其固体形式 (Salts of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone and solid forms thereof ) 是由 乔治·P·卢克 于 2019-06-28 设计创作，主要内容包括：本公开报道了(S)-(5-环丁氧基-2-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-3,4-二氢喹啉-1(2H)-基)(环丙基)甲酮的盐、其固体形式以及其制备和使用方法。(The present disclosure reports salts of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone, solid forms thereof, and methods of making and using the same.)
1. A salt form of the following Compound 1,
the salt form is selected from the group consisting of fumaric, adipic and succinic acid salt forms of compound 1.
2. The salt form of claim 1, wherein the salt form is crystalline.
3. The salt form of claim 1 or 2, wherein compound 1 is a succinate salt ("compound 1 succinate").
4. A crystalline solid form of compound 2:
5. the solid form of claim 4, wherein the solid form is solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("Compound 2").
6. The solid form of claim 4 or 5, wherein solid form G of Compound 2 is characterized by an X-ray powder diffraction (XRPD) pattern with diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8.
7. The solid form of any one of claims 4 to 6, wherein solid form G of Compound 2 is characterized by an XRPD pattern with diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8.
8. The solid form of any one of claims 4 to 7, wherein solid form G of Compound 2 is characterized by an X-ray powder diffraction (XRPD) pattern with diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8 corresponding to d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively).
9. The solid form of any one of claims 4 to 8, wherein the solid form G of Compound 2 is characterized by an XRPD pattern with diffraction at the following angles (2 θ ± 0.2):
4.4
6.8
7.7
8.7
9.1
10.5
11.1
11.8
13.1
13.9
14.9
15.3
16.1
16.6
16.9
17.4
18.0
18.2
18.9
19.2
19.6
20.0
20.7
21.1
21.6
21.8
22.1
22.5
23.0
23.5
24.5
25.3
25.8
26.2
26.8
27.5
27.9
28.4
28.7
29.1
29.9
31.0
32.7
33.3
34.0
35.2
36.1
36.6
38.8。
10. the solid form of any one of claims 4 to 9, wherein the solid form G of compound 2 is characterized by an XRPD pattern having diffraction at angles (2 Θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
11. the solid form of any one of claims 4-10, wherein solid form G is characterized by a Differential Scanning Calorimetry (DSC) endotherm with a minimum at about 127 ℃.
12. The solid form of any one of claims 4-11, wherein solid form G is characterized by a thermogravimetric analysis (TGA) with a weight loss of about 0.2% between 21-150 ℃.
13. The solid form of any one of claims 4 to 12, wherein solid form G is characterized by a dynamic gas phase sorption (DVS) of about 0.76 wt% water at less than 70% relative humidity.
14. A pharmaceutical composition comprising the salt form of claims 1 to 3 or the solid form of claims 4 to 13, and a pharmaceutically acceptable excipient.
15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is for oral administration.
16. A method of inhibiting a bromodomain and an additional terminal (BET) bromodomain comprising administering to a subject the salt form of claims 1-3 or the solid form of claims 4-13.
17. A method of treating a disease, disorder or condition responsive to inhibition of BET comprising administering to a subject in need thereof a salt form of claims 1-3 or a solid form of claims 4-13.
18. The method of claim 17, wherein the disease, disorder, or condition is cancer.
19. A process for preparing solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2") comprising suspending at least one of form a, form B, form I, or form O of compound 2 in a solvent to provide a slurry, and maintaining the slurry for a time and under conditions effective to produce solid form G of compound 2.
20. The process according to claim 19, wherein the solvent is selected from isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBK), dichloromethane/methyl tert-butyl ether (CHCl 3/MTBE).
21. The process of claim 19 or 20, wherein after suspension in the solvent, the slurry is heated to a maximum temperature of about 50 ℃.
22. The method of any one of claims 19 to 21, further comprising separating solid form G of compound 2 from the slurry.
23. A process for preparing solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2") comprising the steps of: contacting methyl tert-butyl ether with at least one of form a, form B, form I, or form O of compound 2 in isopropyl acetate under conditions effective to produce solid form G of compound 2.
24. A composition comprising methyl tert-butyl ether, isopropyl acetate, and at least one of form a, form B, form I, or form O of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate.
Technical Field
The present disclosure relates to pharmaceutical compositions useful for inhibiting bromodomains and extra-terminal (BET) bromodomains, including salts of certain compounds and solid forms thereof.
Background
The compounds may be formed into one or more different pharmaceutically acceptable salts and/or solid forms, including amorphous and polymorphic crystalline forms. Various salts and solid forms of the biologically active compound may have different properties. There is a need to identify and select appropriate salt and/or solid forms (including appropriate crystalline forms, where applicable) of a biologically active compound to develop pharmaceutically acceptable dosage forms for the treatment of various diseases or conditions.
The biologically active compound (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("Compound 1")
Are small molecule modulators of bromodomains and extra-terminal (BET) bromodomains. Compound 1 is disclosed in PCT application publication No. WO 2015/074064 as one of many compounds suitable as small molecule modulators of BET bromodomains. Clinical trial number NCT02543879, entitled "study of a novel BET inhibitor FT-1101 in patients with relapsed or refractory hematological malignancies", discloses the use of the BET inhibitor FT-1101 in patients with relapsed or refractory hematological malignancies. There remains a need to identify salt forms and solid forms of compound 1 that are useful for various therapeutic applications.
Disclosure of Invention
Salts and other solid forms of compound 1 disclosed herein include compound 1 in the fumarate salt form (including crystalline fumarate salt form a, form B, and form C), the adipate salt form (including crystalline adipate salt form a), and the succinate salt form (i.e., compound 2, which includes crystalline succinate salt form a, form B, form C, form D, form E, form F, form G, form I, form K, form L, form O, and form P). The present disclosure provides various solid forms of compound 1, including one or more pharmaceutically acceptable salt forms of compound 1 that are useful for therapeutic oral administration of compound 1. Certain salt forms of compound 1 form crystalline solid forms. The various solid forms of compound 1 can be identified by certain unique characteristics. For example, certain crystalline forms of the salt of compound 1 have unique characteristic XRPD peaks not previously reported for compound 1 form (see example 3).
The crystalline fumarate salt form a of novel compound 1 can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.0, 5.3, 7.9, 10.2, 13.3 and 21.2.
The crystalline fumarate salt form B of novel compound 1 can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 13.5, 16.3, 21.1, 23.5, 26.0 and 26.5.
The crystalline fumarate salt form C of novel compound 1 can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.2, 10.0, 18.1, 19.2 and 22.0.
The novel compound 1 crystalline adipate salt form a can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 7.9, 12.3, 15.7, 19.7 and 24.7.
Crystalline succinate salt form a of novel compound 1 can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1 and 37.3.
Applicants have also recognized that novel compound 1 salt forms can be obtained by treating compound 1 with an acid selected from fumaric acid, adipic acid, and succinic acid.
In some embodiments, the present disclosure provides novel solid forms of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2"), including crystalline forms of compound 2. The present disclosure is based, in part, on the identification of various solid forms of compound 2. In particular, applicants have recognized that compound 2 forms various crystalline solid forms, including one or more pharmaceutically acceptable crystalline forms of compound 2, which are useful for therapeutic oral administration of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone (i.e., compound 1). The various crystalline solid forms of compound 2 can be identified by certain characteristic properties. Certain crystalline forms of compound 2 have unique characteristic XRPD peaks not previously reported for compound 1 form (see example 9). For example, the present disclosure provides compound 2 in various solid forms, designated herein as: form a, form B, form C, form D, form E, form F, form G, form I, form K, form L, form M, form O and form P; and a composition comprising a solid form of compound 2 comprising one or more of form a, form B, form C, form D, form E, form F, form G, form I, form K, form L, form M, form O and form P.
Novel compound 2 form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1 and 37.3.
Novel compound 2 form B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.7, 5.9, 8.7, 11.0, 17.2 and 20.4.
Novel compound 2 form C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 8.1, 10.1, 10.9, 16.4, 17.7 and 34.3.
Form D of novel compound 2 can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 14.7, 18.5, 21.8 and 38.6.
Novel compound 2 form E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 11.3, 13.0, 16.3 and 20.3.
The novel compound 2 form F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 13.6, 14.2, 16.3, 21.8 and 26.7.
The novel compound 2 form G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3 and 38.8.
Novel compound 2 form I can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.4, 5.9, 9.2, 10.3, 11.0 and 25.4.
Novel compound 2 form J can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 8.1, 12.4, 13.5, 15.6, 21.0 and 21.7.
The novel compound 2 form K can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.7, 9.7, 22.2 and 24.4.
The novel compound 2 form L is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 9.8, 12.6, 17.8, 18.9, 21.0, 22.2 and 29.2.
Novel compound 2 form M can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 14.5, 19.4, 22.1, 24.9 and 37.7.
The novel compound 2 form O can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.4, 4.6, 6.8, 9.2, 10.1, 10.9, 12.0 and 20.2.
The novel compound 2 form P can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.3, 6.8, 12.3, 15.2 and 39.6.
Applicants have also recognized that novel solid forms of compound 2 (e.g., form a, form B, form C, form D, form E, form F, form G, form I, form J, form K, form M, form O, and form P) can be obtained by maintaining a solid form of compound 2 under physical conditions effective to convert compound 2 in a first solid form to compound 2 in a second solid form.
Drawings
Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of compound 1 fumarate salt form a and the XRPD pattern of fumaric acid. The upper panel corresponds to compound 1 fumarate salt form a. The lower panel corresponds to fumaric acid.
Figure 2 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 1 fumarate salt form a.
Figure 3 depicts an XRPD pattern of compound 1 fumarate form B and an XRPD pattern of fumaric acid. The upper panel corresponds to compound 1 fumarate salt form B. The lower panel corresponds to fumaric acid.
Figure 4 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 1 fumarate salt form B.
Figure 5 depicts the XRPD pattern of compound 1 fumarate salt form C and the XRPD of fumaric acid. The upper panel corresponds to compound 1 fumarate form C. The lower panel corresponds to fumaric acid.
Figure 6 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 1 fumarate salt form C.
Figure 7 depicts the XRPD of compound 1 adipate form a and the XRPD of adipic acid. The upper panel corresponds to compound 1 adipate form a. The lower panel corresponds to adipic acid.
Figure 8 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 1 adipate form a.
Figure 9 depicts the XRPD pattern of one sample of compound 1 succinate form a (i.e., compound 2 form a) and the XRPD of succinic acid. The upper panel corresponds to compound 1 succinate form a (i.e., compound 2 form a). The lower panel corresponds to succinic acid.
Figure 10 depicts an XRPD pattern of another sample of compound 2 form a (i.e., compound 1 succinate form a).
Fig. 11 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of a sample of compound 1 succinate form a (i.e., compound 2 form a).
Fig. 12 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of another sample of compound 2 form a (i.e., compound 1 succinate form a).
Figure 13 depicts an XRPD pattern of maleate form a of compound 1 and an XRPD pattern of maleic acid. The upper panel corresponds to compound 1 maleate form a. The lower panel corresponds to maleic acid.
Figure 14 is a Differential Scanning Calorimetry (DSC) thermogram for maleate form a of compound 1.
Figure 15 is a dynamic gas phase adsorption (DVS) analysis of compound 1 fumarate salt form a.
Figure 16 is a dynamic gas phase adsorption (DVS) analysis of compound 1 fumarate, form B.
Figure 17 is a dynamic gas phase adsorption (DVS) analysis of compound 1 fumarate salt form C.
Figure 18 is a dynamic gas phase adsorption (DVS) analysis of compound 1 adipate form a.
Figure 19 is a dynamic gas phase adsorption (DVS) analysis of compound 1 succinate form a (i.e., compound 2 form a).
Fig. 20 is a series of XRPD patterns depicting the results of slurry conversion of compound 1 fumarate salt form a, form B and form C.
Figure 21 is a series of XRPD patterns depicting the recrystallization of compound 1 adipate form a.
Figure 22 depicts a series of X-ray powder diffraction (XRPD) patterns of compound 2 form a, form B, form C, form D, form E and form F.
Figure 23 depicts a series of XRPD patterns for compound 2 form G, form I, form J, form K, form L and form M.
Figure 24 depicts the XRPD pattern of compound 2 form B.
Figure 25 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form B.
Figure 26 depicts a dynamic gas phase adsorption (DVS) profile for compound 2 form B.
Figure 27 depicts the XRPD pattern of compound 2 form C.
Figure 28 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form C.
Figure 29 depicts the XRPD pattern of compound 2 form D.
Figure 30 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form D.
Figure 31 depicts the XRPD pattern of compound 2 form E.
Figure 32 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form E.
Figure 33 depicts the XRPD pattern of compound 2 form F.
Figure 34 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form F.
Figure 35 depicts the XRPD pattern of compound 2 form G.
Figure 36 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form G.
Figure 37 depicts a dynamic gas phase adsorption (DVS) profile for compound 2 form G.
Fig. 38 depicts an image obtained from polarization microscopy of compound 2 form G.
Figure 39 depicts an XRPD pattern of compound 2 form I.
Figure 40 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form I.
Figure 41 depicts a dynamic gas phase adsorption (DVS) profile for compound 2 form I.
Figure 42 depicts an XRPD pattern of compound 2 form J.
Figure 43 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form J.
Figure 44 depicts an XRPD pattern of compound 2 form K.
Figure 45 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form K.
Figure 46 depicts an XRPD pattern of compound 2 form L.
Figure 47 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form L.
Figure 48 depicts the XRPD pattern of compound 2 form M.
Figure 49 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form M.
Figure 50 depicts a dynamic gas phase adsorption (DVS) profile for compound 2 form M.
Figure 51 depicts an XRPD pattern of compound 2 form O.
Figure 52 is a thermogravimetric analysis (TGA) curve (upper curve) and a Differential Scanning Calorimetry (DSC) thermogram (lower curve) of compound 2 form O.
Figure 53 depicts a dynamic gas phase adsorption (DVS) profile for compound 2 form O.
Figure 54 depicts an XRPD pattern of compound 2 form P.
Figure 55 is a flow diagram illustrating a method of preparing compound 2 form G from compound 2 form B, form I or form O.
Figure 56 depicts a series of XRPD patterns derived from the results of slurry competition between compound 2 form G and form O.
Figure 57 depicts a series of XRPD patterns derived from the results of stability evaluations of compound 2 form G, form B and form I.
Figure 58 depicts a graph showing the criticality a between compound 2 form G and form Iw(for a)w0. 0.20, 0.40, 0.59, and 0.80).
Figure 59 depicts a graph showing the criticality a between compound 2 form G and form Iw(for a)w0. 0.18, 0.36, and 0.55).
Figure 60 depicts a series of XRPD patterns showing solubility comparisons between compound 2 form a and form G.
Figure 61 depicts a series of XRPD patterns showing the stability of compound 2 form G under different conditions.
Detailed Description
The biologically active compound (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1"):
are small molecule modulators of bromodomains and extra-terminal (BET) bromodomains. The present disclosure provides various salt forms of compound 1, solid forms thereof, pharmaceutical compositions thereof, and methods of preparing these novel salt forms of compound 1 and solid forms thereof. Salt forms and solid forms (e.g., crystalline solid forms) impart or may impart characteristics such as improved solubility, stability, and ease of formulation. As used herein, unless otherwise indicated, the term "salt" refers to a salt or co-crystal of two or more (e.g., two) component molecules (e.g., compound 1 and a co-former).
Salt forms of Compound 1
In some embodiments, the novel salt form of compound 1 is the fumarate salt form (i.e., "compound 1 fumarate"). In some embodiments, compound 1 fumarate is amorphous. In some embodiments, compound 1 fumarate is in the form of a crystalline salt. In some embodiments, compound 1 fumarate is a crystalline salt form a (i.e., "compound 1 fumarate form a"). In some embodiments, compound 1 fumarate is the crystalline salt form B (i.e., "compound 1 fumarate form B"). In some embodiments, compound 1 fumarate is the crystalline salt form C (i.e., "compound 1 fumarate form C").
In some embodiments, the novel salt form of compound 1 is the adipate form (i.e., "compound 1 adipate"). In some embodiments, compound 1 adipate is amorphous. In some embodiments, compound 1 adipate is a crystalline salt form. In some embodiments, compound 1 adipate is a crystalline salt form a (i.e., "compound 1 adipate form a").
In some embodiments, the novel salt form of compound 1 is the succinate salt form (i.e., "compound 1 succinate" or "compound 2"). In some embodiments, compound 1 succinate salt (i.e., compound 2) is amorphous. In some embodiments, compound 1 succinate salt (i.e., compound 2) is a crystalline salt form. In some embodiments, the compound 1 succinate salt (i.e., compound 2) is a crystalline salt form a (i.e., "compound 1 succinate salt form a" or "compound 2 form a").
In some embodiments, the novel salt form of compound 1 is the maleate form (i.e., "compound 1 maleate"). In some embodiments, compound 1 maleate is amorphous. In some embodiments, compound 1 maleate is in a crystalline salt form. In some embodiments, compound 1 maleate is a crystalline salt form a (i.e., "compound 1 maleate form a").
Novel salt forms of compound 1 can be obtained by a variety of methods known to those skilled in the art. A suitable preparation method is reported in example 3. For example, in some embodiments, novel salt forms of compound 1 (e.g., compound 1 fumarate, compound 1 adipate, and compound 1 succinate) can be obtained by treating compound 1 with an acid selected from fumaric acid, adipic acid, and succinic acid.
Novel salt forms of compound 1 can be identified by X-ray powder diffraction (XPRD). Novel salt forms of compound 1 disclosed herein include compound 1 fumarate (including amorphous compound 1 fumarate, compound 1 fumarate form a, compound 1 fumarate form B, compound 1 fumarate form C), compound 1 adipate (including amorphous compound 1 adipate and compound 1 adipate form a), and/or compound 1 succinate (including amorphous compound 1 succinate and compound 1 succinate form a (i.e., compound 2 form a), as well as compound 2 form B, compound 2 form C, compound 2 form D, compound 2 form E, compound 2 form F, compound 2 form G, compound 2 form I, compound 2 form K, compound 2 form L, compound 2 form M, compound 2 form O, compound 2 form C, compound 1 adipate (including amorphous compound 1 adipate and compound 1 adipate form a), and/or compound 1 succinate (including amorphous compound 1 succinate and compound 2 succinate form a) Compound 2 form P), and compositions comprising novel salt forms of compound 1, such as compound 1 fumarate (including amorphous compound 1 fumarate, compound 1 fumarate form a, compound 1 fumarate form B, compound 1 fumarate form C), compound 1 adipate (including amorphous compound 1 adipate and compound 1 adipate form a), and/or compound 1 succinate (including amorphous compound 1 succinate and compound 1 succinate form a (i.e., compound 2 form a) and compound 2 form B, compound 2 form C, compound 2 form D, compound 2 form E, compound 2 form F, compound 2 form G, compound 2 form I, compound 2 form K, compound 1 succinate form C), and/or a pharmaceutically acceptable salt form of compound 1, Compound 2 form L, compound 2 form M, compound 2 form O, compound 2 form P).
Compound 1 fumarate salt form A
The novel compound 1 fumarate salt form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.0, 5.3, 7.9, 10.2, 13.3 and 21.2. In some embodiments, compound 1 fumarate salt form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.0, 5.3, 7.9, 10.2, 13.3, and 21.2 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 22.1, 16.7, 11.1, 8.7, 6.7, and 4.2.
The novel compound 1 fumarate salt form a can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 4.0, 5.3, 7.9, 10.2, 13.3 and 21.2. In some embodiments, compound 1 fumarate salt form a can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 4.0, 5.3, 7.9, 10.2, 13.3, and 21.2 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 22.1, 16.7, 11.1, 8.7, 6.7, and 4.2.
In some embodiments, compound 1 fumarate salt form a is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angles (2 Θ ± 0.2) as:
4.0
5.3
6.6
7.9
10.2
13.3
14.8
17.2
18.6
21.2
24.1
26.5
28.4。
in some embodiments, compound 1 fumarate salt form a is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
compound 1 fumarate salt form B
Novel compound 1 fumarate salt form B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 13.5, 16.3, 21.1, 23.5, 26.0 and 26.5. In some embodiments, compound 1 fumarate salt form B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 13.5, 16.3, 21.1, 23.5, 26.0, and 26.5 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.4, 6.6, 5.4, 4.2, 3.8, 3.4, and 3.4.
Novel compound 1 fumarate salt form B can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 13.5, 16.3, 21.1, 23.5, 26.0 and 26.5. In some embodiments, compound 1 fumarate salt form B can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.4, 13.5, 16.3, 21.1, 23.5, 26.0, and 26.5 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.4, 6.6, 5.4, 4.2, 3.8, 3.4, and 3.4.
In some embodiments, compound 1 fumarate salt form B is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angles (2 Θ ± 0.2) as:
5.4
8.1
9.9
10.0
10.9
12.4
13.5
14.2
14.6
16.3
16.8
17.5
18.6
18.9
21.1
21.6
23.5
23.9
26.0
26.5
27.1
34.1
35.5
36.8
in some embodiments, compound 1 fumarate salt form B is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
compound 1 fumarate salt form C
Novel compound 1 fumarate salt form C can be identified by an X-ray powder diffraction (XRPD) pattern having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.2, 10.0, 18.1, 19.2 and 22.0. In some embodiments, compound 1 fumarate salt form C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.2, 10.0, 18.1, 19.2, and 22.0 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.1, 10.7, 8.9, 4.9, 4.6, and 4.0.
The novel compound 1 fumarate salt form C can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.2, 10.0, 18.1, 19.2 and 22.0. In some embodiments, compound 1 fumarate salt form C can be prepared by reacting at least one compound corresponding to (respectively) 16.1, 10.7, 8.9, 4.9,
X-ray powder diffraction (XRPD) identification with three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.2, 10.0, 18.1, 19.2 and 22.0 for d-spacings (angstroms ± 0.2) of 4.6 and 4.0.
In some embodiments, compound 1 fumarate salt form C is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angles (2 Θ ± 0.2) as:
5.5
8.2
10.0
13.7
14.6
18.1
19.2
22.0
24.1
25.3
27.4
in some embodiments, compound 1 fumarate salt form C is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
compound 1 adipate form A
Novel compound 1 adipate form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 7.9, 12.3, 15.7, 19.7 and 24.7. In some embodiments, compound 1 adipate form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 7.9, 12.3, 15.7, 19.7, and 24.7 corresponding to d-spacings (angstroms ± 0.2) of 11.2, 7.2, 5.6, 4.5, and 3.6 (respectively).
Novel compound 1 adipate form a can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 7.9, 12.3, 15.7, 19.7 and 24.7. In some embodiments, compound 1 adipate salt form a can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 7.9, 12.3, 15.7, 19.7, and 24.7 corresponding to d-spacings (angstroms ± 0.2) of 11.2, 7.2, 5.6, 4.5, and 3.6 (respectively).
In some embodiments, compound 1 adipate form a is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
4.0
7.9
11.6
12.3
13.1
14.1
15.3
15.7
16.6
18.8
19.7
21.2
22.2
23.4
24.1
24.7
26.3
28.3
30.8
in some embodiments, compound 1 adipate form a is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
compound 1 succinate salt form A
Novel compound 1 succinate salt form a (i.e., compound 2 form a) can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1 and 37.3. In some embodiments, compound 1 succinate form a (i.e., compound 2 form a) can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 9.0, 5.0, 4.0, 3.6, 3.5, 2.5, and 2.4 (respectively).
Novel compound 1 succinate salt form a (i.e., compound 2 form a) can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1 and 37.3. In some embodiments, compound 1 succinate form a (i.e., compound 2 form a) can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 9.0, 5.0, 4.0, 3.6, 3.5, 2.5, and 2.4 (respectively).
In some embodiments, compound 1 succinate salt form a (i.e., compound 2 form a) is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) as:
5.5
8.3
9.8
10.8
12.5
12.6
13.8
14.4
14.6
16.7
17.1
17.9
18.4
18.7
19.0
19.6
20.0
20.5
20.9
21.3
21.8
22.2
22.5
23.1
23.4
24.2
24.8
25.3
25.6
26.5
26.8
27.3
28.1
28.5
29.1
29.7
30.7
32.3
32.9
33.8
34.9
36.1
37.3
in some embodiments, compound 1 succinate salt form a (i.e., compound 2 form a) is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
compound 1 maleate form A
The novel compound 1 maleate form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.1, 6.1, 9.2, 10.2, 17.7 and 19.3. In some embodiments, compound 1 maleate salt form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.1, 6.1, 9.2, 10.2, 17.7, and 19.3 corresponding to d-spacings (angstroms ± 0.2) of 28.6, 14.5, 9.6, 8.6, 5.0, and 4.6 (respectively).
The novel compound 1 maleate form a can be identified by X-ray powder diffraction (XRPD) with three or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.1, 6.1, 9.2, 10.2, 17.7 and 19.3. In some embodiments, compound 1 maleate salt form a can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 3.1, 6.1, 9.2, 10.2, 17.7, and 19.3 corresponding to d-spacings (angstroms ± 0.2) of 28.6, 14.5, 9.6, 8.6, 5.0, and 4.6 (respectively).
In some embodiments, compound 1 maleate form a is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
3.1
6.1
9.2
10.2
13.9
16.3
17.7
18.5
19.3
20.6
21.5
24.5
in some embodiments, compound 1 maleate form a is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
in some embodiments, the present disclosure provides a process for preparing a salt form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1"), the process comprising contacting compound 1 with an acid selected from the group consisting of: fumaric acid, adipic acid and succinic acid. In some embodiments, the present disclosure provides a method for preparing a salt form of compound 1, the method comprising contacting compound 1 with an acid selected from the group consisting of: fumaric acid, adipic acid, succinic acid and maleic acid.
In some embodiments, the present disclosure provides a solid form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1"), the solid form obtained by a process comprising: contacting compound 1 with succinic acid under conditions and for a time effective to form the succinate salt form of compound 1. In some embodiments, the solid form of compound 1 is obtained by a process comprising the steps of: contacting compound 1 with fumaric acid under conditions and for a time effective to form the fumarate salt form of compound 1. In some embodiments, the solid form of compound 1 is obtained by a process comprising the steps of: compound 1 is contacted with adipic acid under conditions and for a time effective to form the adipate salt form of compound 1. In some embodiments, the solid form of compound 1 is obtained by a process comprising the steps of: compound 1 is contacted with maleic acid under conditions and for a time effective to form the maleate salt form of compound 1.
In some embodiments, the present disclosure provides a composition comprising a crystalline salt form of compound 1. In some embodiments, the composition comprises a crystalline salt form of compound 1 and an amorphous salt form of compound 1, wherein the amorphous salt form of compound 1 is present in an amount selected from the following ranges: about 90 to about 99%, about 80 to about 89%, about 70 to about 79%, about 60 to about 69%, about 50 to about 59%, about 40 to about 49%, about 30 to about 39%, about 20 to about 29%, about 10 to about 19%, about 1 to about 9%, and about 0 to about 0.99%. In some embodiments, a composition comprising a crystalline salt form of compound 1 is substantially free of amorphous compound 1.
In some embodiments, the present disclosure provides a composition comprising compound 1 fumarate salt form a. In some embodiments, the composition comprising compound 1 fumarate salt form a is substantially free of other crystalline forms of compound 1. In some embodiments, the composition comprising compound 1 fumarate salt form a is substantially free of the amorphous form of compound 1.
In some embodiments, the present disclosure provides a composition comprising compound 1 fumarate salt form B. In some embodiments, the composition comprising compound 1 fumarate salt form B is substantially free of other crystalline forms of compound 1. In some embodiments, the composition comprising compound 1 fumarate salt form B is substantially free of the amorphous form of compound 1.
In some embodiments, the present disclosure provides a composition comprising compound 1 fumarate salt form C. In some embodiments, the composition comprising compound 1 fumarate salt form C is substantially free of other crystalline forms of compound 1. In some embodiments, the composition comprising compound 1 fumarate salt form C is substantially free of the amorphous form of compound 1.
In some embodiments, the present disclosure provides a composition comprising compound 1 adipate form a. In some embodiments, the composition comprising compound 1 adipate form a is substantially free of other crystalline forms of compound 1. In some embodiments, the composition comprising compound 1 adipate form a is substantially free of the amorphous form of compound 1.
In some embodiments, the present disclosure provides a composition comprising compound 1 succinate form a (i.e., compound 2 form a). In some embodiments, a composition comprising compound 1 succinate salt form a (i.e., compound 2 form a) is substantially free of other crystalline forms of compound 1. In some embodiments, a composition comprising compound 1 succinate form a (i.e., compound 2 form a) is substantially free of the amorphous form of compound 1.
In some embodiments, the present disclosure provides a composition comprising compound 1 maleate form a. In some embodiments, a composition comprising compound 1 maleate form a is substantially free of other crystalline forms of compound 1. In some embodiments, a composition comprising compound 1 maleate form a is substantially free of the amorphous form of compound 1.
The pharmaceutical compositions reported herein may be combined with a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical compositions as reported herein may be provided in a unit dosage container (e.g. in a vial or a bag or the like). In some embodiments, the pharmaceutical composition as reported herein may be provided in an oral dosage form. In some embodiments, the oral dosage form is a capsule.
In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising a crystalline succinate salt of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone.
In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising the succinate salt of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone.
In some embodiments, the present disclosure provides a pharmaceutical composition for oral administration comprising a crystalline form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate.
In some embodiments, the present disclosure provides methods of inhibiting bromodomains and extra-terminal (BET) bromodomains comprising administering to a subject a salt form of compound 1. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition responsive to inhibition of Bromodomains and Extra Terminal (BET) bromodomains, comprising administering a salt form of compound 1 to a subject in need thereof. In some embodiments, the disease, disorder, or condition is selected from the group consisting of cancer, inflammation, metabolic and neurological disorders, and infectious diseases.
Solid form of compound 2:
as described above, a pharmaceutically acceptable salt of compound 1 is a certain succinate salt, known as (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2"):
compound 2 can be in amorphous solid form, or in crystalline solid form, or in the form of a mixture of solid forms. The crystalline solid form of compound 2 may exist in one or more distinct solid forms, which may additionally comprise one or more equivalents of water or solvent (i.e., hydrates or solvates, respectively). Thus, in some embodiments, the present disclosure provides a crystalline solid form of compound 2.
As disclosed herein, the crystalline form of compound 2 has unique characteristic XRPD peaks not reported in the previous disclosure of compound 1 (see example 9). Accordingly, provided herein are novel crystalline compound 2 solid forms, pharmaceutical compositions thereof, and methods of making and using these crystalline compound 2 solid forms.
The novel compound 2 solid form can be obtained by the methods reported in example 8 and example 9. Different methods of preparation may yield different solid forms. For example, compound 2 form a can be obtained from a solution comprising compound 1 and succinic acid in acetone, as described in example 3.
In some embodiments, certain solid forms of compound 2 are converted from one solid form to another solid form. For example, subjecting compound 2 form a to certain conditions results in at least one of compound 2 form B, form C, form D, form E, form F, form G, form I, form J, form K, form L, form M, form O, and/or form P. Conditions suitable for converting compound 2 form a to any one of compound 2 form B, form C, form D, form E, form F, form G, form I, form J, form K, form L, form M, form O and/or form P include the following conditions: for example 1 addition of anti-solvent; slowly evaporating; rapid cooling (crash cooling); forming a slurry at room temperature; forming a slurry at 50 ℃; solid vapor diffusion; solution vapor diffusion; and grinding.
For example, certain solid forms of compound 2 can be prepared by the following steps: a suspension comprising compound 2 form a and a solvent is formed (i.e., "slurried"), and the suspension is maintained for a period of time sufficient to produce certain solid forms of compound 2 (e.g., form B, form C, form D, form E, form F, form G, form I, form J, form K, form L, form M, form O, and/or form P). For example, suitable solvents for producing form G include IPAc, MTBE, toluene, heptane, MIBK, EtOAc, ACN, acetone, H2O/ACN, AcOH/n-heptane, MeOH/toluene, and CHCl3and/MTBE. In some embodiments, the suspension is maintained at room temperature. In some embodiments, the suspension is heated to a temperature between about 40 ℃ and about 80 ℃. In some embodiments, the suspension is heated to a temperature of about 50 ℃.
In some embodiments, the present disclosure provides a method for preparing solid form G of compound 2, the method comprising suspending compound 2 form a in a solvent to provide a slurry, and maintaining the slurry for a time sufficient to produce compound 2 form G. In some embodiments, the slurry is stirred. Exemplary solvents suitable for producing form G include IPAc, MTBE, MIBK, and CHCl3and/MTBE. In some embodiments, the suspension is maintained at room temperature. In some embodiments, the suspension is heated to a temperature between about 40 ℃ and about 80 ℃. In some embodiments, the suspension is heated to a temperature of about 50 ℃.
In some embodiments, certain solid forms of compound 2 can be prepared by adding an anti-solvent to a solution of compound 2 form a. For example, certain solid forms of compound 2 (e.g., form B, form C, form D, form E, form F, form G, form I, form J, form K, form L, form M, form O, and/or form P) can be prepared by dissolving compound 2 form a in a solvent to obtain a solution, followed by the addition of an amount of an anti-solvent sufficient to precipitate out and/or provide a solid form of compound 2. In some embodiments, the anti-solvent is miscible with the solvent. In some embodiments, compound 2 is partially or completely insoluble in the antisolvent. In some embodiments, the solvent is MeOH, EtOH, AcOH, CHCl3、DCM、H2O, DMSO and/or DMAc. In some embodiments, the anti-solvent is IPAc, MTBE, toluene, EtOAc, n-heptane, MIBK, ACN, and/or acetone.
In some embodiments, the present disclosure provides a method for preparing solid form G of compound 2, the method comprising providing a solution comprising compound 2 form a and a solvent, and adding an amount of an anti-solvent sufficient to precipitate a solid, wherein the solid is compound 2 solid form G. In some embodiments, the solvent is DMAc. In some embodiments, the anti-solvent is MTBE. In some embodiments, the mixture of compound 2 form a, the anti-solvent, and the solvent is stored overnight to precipitate solid form G of compound 2.
In some embodiments, certain solid forms of compound 2 can be prepared by slow evaporation of compound 2 form a. For example, certain solid forms of compound 2 (e.g., form B, form C, form D, form E, form F, form G, form I, form J, form K, form L, form M, form O, and/or form P) can be prepared by dissolving form a in a solvent to form a visually clear solution, followed by evaporating the solvent under ambient conditions to induce precipitation. Suitable examples of solvents include MeOH, EtOH, IPA, CHCl3、DCM、H2O, THF, MeOH/MTBE, EtOH/n-heptane, EtOH/MTBE, DCM/EtOAc, and/or CHCl3/IPAc、CHCl3N-heptane.
In some embodiments, certain solid forms of compound 2 can be prepared by rapidly cooling compound 2 form a. For example, certain solid forms of compound 2 (e.g., form B, form C, form D, form E, form F, form G, form I, form J, form K, form L, form M, form O, and/or form P) can be prepared by suspending form a in a solvent to provide a slurry. The slurry is then heated to about 50 ℃ and then filtered through a membrane, such as a nylon membrane having a pore size of about 0.45 μ M. The filtrate was then cooled to about 5 ℃ and stored under conditions suitable to precipitate the solid. Suitable examples of solvents include MeOH, EtOH, IPA, CHCl3、DCM、H2O, THF, MeOH/MTBE, EtOH/n-heptane, EtOH/MTBE, DCM/EtOAc, CHCl3/IPAc, and/or CHCl3N-heptane.
In some embodiments, certain solid forms of compound 2 can be prepared by solid vapor diffusion of compound 2 form a. For example, certain solid forms of compound 2 (e.g., form B, form C, form D, form E, form F, form G, form I, form J, form D, form E,Form K, form L, form M, form O, and/or form P) may be prepared by contacting compound 2 form a with solvent vapor. Exemplary solvent vapors include H2O、DCM、EtOH、MeOH、ACN、THF、CHCl3Acetone, DMF, EtOAc, 1, 4-dioxane, IPA and/or DMSO.
In some embodiments, certain solid forms of compound 2 can be prepared by solution vapor diffusion of compound 2 form a. For example, certain solid forms of compound 2 (e.g., form B, form C, form D, form E, form F, form G, form I, form J, form K, form L, form M, form O, and/or form P) can be prepared by dissolving compound 2 form a in a first solvent to provide a solution, and contacting the solution with a solvent vapor of a second solvent. Suitable examples of the first solvent include MeOH, EtOH, AcOH, CHCl3DCM, DMSO and DMAc. Suitable examples of solvent vapors include IPAc, MTBE, toluene, n-heptane, MIBK, and EtOAc.
As used herein, the term "precipitation" refers to the formation of a solid material from a solution containing the solid material. The material precipitated from the solution may be amorphous or crystalline. Precipitation may be carried out under a variety of conditions known to those skilled in the art, including treating a solution of the solute (e.g., a solution of solute a in solvent B) with an anti-solvent (i.e., a solvent that is miscible with solvent B, but does not appreciably dissolve solute a). Non-limiting examples of solvent/anti-solvent pairs include dimethylacetamide/methyl tert-butyl ether.
The solid form of compound 2 can be identified by various analytical techniques, such as X-ray powder diffraction (XRPD). Solid forms of compound 2 disclosed herein include compound 2 in form a, form B, form C, form D, form E, form F, form G, form I, form K, form L, form M, form O, and/or form P, as well as compositions comprising solid forms of compound 2 comprising one or more of form a, form B, form C, form D, form E, form F, form G, form I, form K, form L, form M, form O, and/or form P.
Compound 2 form A
The present disclosure provides novel compound 2 form a (i.e., compound 1 succinate form a). As described above, compound 2 form a (i.e., compound 1 succinate form a) can be identified by X-ray powder diffraction (XRPD).
Novel compound 2 form a can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1 and 37.3. In some embodiments, compound 2 form a is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 9.0, 5.0, 4.0, 3.6, 3.5, 2.5, and 2.4 (respectively).
Compound 2 form a can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1 and 37.3. In some embodiments, compound 2 form a is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 9.0, 5.0, 4.0, 3.6, 3.5, 2.5, and 2.4 (respectively).
In some embodiments, compound 2 form a is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.5
8.3
9.8
10.8
12.5
12.6
13.8
14.4
14.6
16.7
17.1
17.9
18.4
18.7
19.0
19.6
20.0
20.5
20.9
21.3
21.8
22.2
22.5
23.1
23.4
24.2
24.8
25.3
25.6
26.5
26.8
27.3
28.1
28.5
29.1
29.7
30.7
32.3
32.9
33.8
34.9
36.1
37.3
in some embodiments, compound 2 form a is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form B
Novel compound 2 form B can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.7, 5.9, 8.7, 11.0, 17.2 and 20.4. In some embodiments, compound 2 form B is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 θ ± 0.2) of 4.7, 5.9, 8.7, 11.0, 17.2, and 20.4 corresponding to d-spacings (angstroms ± 0.2) of 18.7, 15.1, 10.1, 8.1, 5.1, and 4.4 (respectively).
Novel compound 2 form B can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.7, 5.9, 8.7, 11.0, 17.2 and 20.4. In some embodiments, compound 2 form B is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 4.7, 5.9, 8.7, 11.0, 17.2, and 20.4 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 18.7, 15.1, 10.1, 8.1, 5.1, and 4.4.
In some embodiments, compound 2 form B is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
4.7
5.9
8.7
9.7
10.3
11.0
11.7
13.8
14.5
16.2
17.2
17.7
18.5
18.8
19.1
20.4
20.6
21.2
21.6
22.6
23.8
24.3
24.9
25.2
26.1
26.9
27.7
28.5
30.0
32.7
33.6
35.1
in some embodiments, compound 2 form B is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form C
Novel compound 2 form C can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 8.1, 10.1, 10.9, 16.4, 17.7 and 34.3. In some embodiments, compound 2 form C is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 8.1, 10.1, 10.9, 16.4, 17.7, and 34.3 corresponding to d-spacings (angstroms ± 0.2) of 16.3, 10.9, 8.7, 8.1, 5.4, 5.0, and 2.6 (respectively).
Novel compound 2 form C can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.4, 8.1, 10.1, 10.9, 16.4, 17.7 and 34.3. In some embodiments, compound 2 form C is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.4, 8.1, 10.1, 10.9, 16.4, 17.7, and 34.3 corresponding to d-spacings (angstroms ± 0.2) of 16.3, 10.9, 8.7, 8.1, 5.4, 5.0, and 2.6 (respectively).
In some embodiments, compound 2 form C is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.4
8.1
9.9
10.1
10.9
12.4
14.2
14.8
16.4
17.1
17.7
18.6
19.3
19.9
20.7
21.2
21.8
22.6
23.2
24.2
24.6
25.2
26.0
27.3
29.3
30.0
34.3
37.5
in some embodiments, compound 2 form C is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form D
Form D of novel compound 2 can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 14.7, 18.5, 21.8 and 38.6. In some embodiments, compound 2 form D is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 14.7, 18.5, 21.8, and 38.6 corresponding to D-spacings (angstroms ± 0.2) of 16.2, 6.0, 4.8, 4.1, and 2.3 (respectively).
Form D of the novel compound 2 can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.4, 14.7, 18.5, 21.8 and 38.6. In some embodiments, compound 2 form D is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.4, 14.7, 18.5, 21.8, and 38.6 corresponding to D-spacings (angstroms ± 0.2) of 16.2, 6.0, 4.8, 4.1, and 2.3 (respectively).
In some embodiments, compound 2 form D is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.4
8.1
9.8
10.0
10.8
12.4
13.6
14.2
14.7
16.8
17.3
18.5
19.1
19.9
20.5
20.9
21.8
23.5
24.1
25.1
25.7
26.1
27.6
29.6
33.4
35.8
38.6
in some embodiments, compound 2 form D is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding D-spacing (angstroms ± 0.2) as:
compound 2 form E
Novel compound 2 form E can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 11.3, 13.0, 16.3 and 20.3. In some embodiments, compound 2 form E is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 11.3, 13.0, 16.3, and 20.3 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.0, 7.8, 6.8, 5.4, and 4.4.
Novel compound 2 form E can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 11.3, 13.0, 16.3 and 20.3. In some embodiments, compound 2 form E is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 11.3, 13.0, 16.3, and 20.3 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.0, 7.8, 6.8, 5.4, and 4.4.
In some embodiments, compound 2 form E is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.5
8.3
9.8
10.1
10.7
11.3
12.2
13.0
13.8
14.1
15.0
16.3
16.5
17.3
18.2
18.6
19.0
19.6
20.3
20.9
21.2
22.1
22.9
23.6
24.2
26.2
27.2
28.1
30.4
32.8
35.3
36.3
37.0
in some embodiments, compound 2 form E is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form F
The novel compound 2 form F can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 13.6, 14.2, 16.3, 21.8 and 26.7. In some embodiments, compound 2 form F is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 13.6, 14.2, 16.3, 21.8, and 26.7 corresponding to d-spacings (angstroms ± 0.2) of 6.5, 6.2, 5.4, 4.1, and 3.3 (respectively).
The novel compound 2 form F can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 13.6, 14.2, 16.3, 21.8 and 26.7. In some embodiments, compound 2 form F can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 13.6, 14.2, 16.3, 21.8, and 26.7 corresponding to d-spacings (angstroms ± 0.2) of 6.5, 6.2, 5.4, 4.1, and 3.3 (respectively).
In some embodiments, compound 2 form F is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.5
8.2
9.7
9.9
10.7
12.3
13.6
14.2
14.6
16.3
16.8
18.6
18.9
19.1
19.5
20.3
20.8
21.0
21.8
22.9
23.5
23.8
24.1
26.1
26.7
27.4
29.4
in some embodiments, compound 2 form F is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form G
The novel compound 2 form G can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3 and 38.8. In some embodiments, solid form G of compound 2 is identifiable by an XRPD pattern having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8. In some embodiments, solid form G of compound 2 can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8 corresponding to d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively).
The novel compound 2 form G can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3 and 38.8. In some embodiments, solid form G of compound 2 is identifiable by an XRPD pattern having three or more characteristic diffractions at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8. In some embodiments, solid form G of compound 2 can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) corresponding to 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8 d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively).
Solid form G of compound 2 can be characterized by X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) as:
4.4
6.8
7.7
8.7
9.1
10.5
11.1
11.8
13.1
13.9
14.9
15.3
16.1
16.6
16.9
17.4
18.0
18.2
18.9
19.2
19.6
20.0
20.7
21.1
21.6
21.8
22.1
22.5
23.0
23.5
24.5
25.3
25.8
26.2
26.8
27.5
27.9
28.4
28.7
29.1
29.9
31.0
32.7
33.3
34.0
35.2
36.1
36.6
38.8
in some embodiments, compound 2 form G is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form I
Novel compound 2 form I can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.4, 5.9, 9.2, 10.3, 11.0 and 25.4. In some embodiments, compound 2 form I can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 θ ± 0.2) of 3.4, 5.9, 9.2, 10.3, 11.0, and 25.4 corresponding to d-spacings (angstroms ± 0.2) of 25.8, 15.0, 9.7, 8.6, 8.0, and 3.5 (respectively).
Novel compound 2 form I can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.4, 5.9, 9.2, 10.3, 11.0 and 25.4. In some embodiments, compound 2 form I can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 3.4, 5.9, 9.2, 10.3, 11.0, and 25.4 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 25.8, 15.0, 9.7, 8.6, 8.0, and 3.5.
In some embodiments, compound 2 form I is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
3.4
5.9
6.7
8.0
8.8
9.2
9.5
9.8
10.1
10.3
10.8
11.0
12.5
12.9
13.2
13.9
14.5
15.7
16.8
17.4
18.3
18.9
19.8
20.7
21.4
23.6
25.4
27.0
28.3
29.1
29.9
in some embodiments, compound 2 form I is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form J
Novel compound 2 form J can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 8.1, 12.4, 13.5, 15.6, 21.0 and 21.7. In some embodiments, compound 2 form J is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.4, 8.1, 12.4, 13.5, 15.6, 21.0, and 21.7 corresponding to d-spacings (angstroms ± 0.2) of 16.3, 10.9, 7.1, 6.5, 5.7, 4.2, and 4.1 (respectively).
Novel compound 2 form J can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.4, 8.1, 12.4, 13.5, 15.6, 21.0 and 21.7. In some embodiments, compound 2 form J is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.4, 8.1, 12.4, 13.5, 15.6, 21.0, and 21.7 corresponding to d-spacings (angstroms ± 0.2) of 16.3, 10.9, 7.1, 6.5, 5.7, 4.2, and 4.1 (respectively).
In some embodiments, compound 2 form J is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.4
8.1
9.8
10.0
10.8
12.4
13.5
15.6
18.7
19.0
21.0
21.7
23.5
35.6
38.5
in some embodiments, compound 2 form J is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form K
The novel compound 2 form K can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.7, 9.7, 22.2 and 24.4. In some embodiments, compound 2 form K is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.7, 9.7, 22.2, and 24.4 corresponding to d-spacings (angstroms ± 0.2) of 15.9, 10.2, 9.1, 4.0, and 3.7 (respectively).
The novel compound 2 form K can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.7, 9.7, 22.2 and 24.4. In some embodiments, compound 2 form K is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.7, 9.7, 22.2, and 24.4 corresponding to d-spacings (angstroms ± 0.2) of 15.9, 10.2, 9.1, 4.0, and 3.7 (respectively).
In some embodiments, compound 2 form K is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.5
8.3
8.7
9.7
10.9
14.5
16.8
17.6
18.7
20.5
22.2
24.4
in some embodiments, compound 2 form K is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form L
The novel compound 2 form L is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 9.8, 12.6, 17.8, 18.9, 21.0, 22.2 and 29.2. In some embodiments, compound 2 form L is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 9.8, 12.6, 17.8, 18.9, 21.0, 22.2, and 29.2 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.0, 9.0, 7.0, 5.0, 4.7, 4.2, 4.0, and 3.1.
The novel compound 2 form L can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 9.8, 12.6, 17.8, 18.9, 21.0, 22.2 and 29.2. In some embodiments, compound 2 form L is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 9.8, 12.6, 17.8, 18.9, 21.0, 22.2, and 29.2 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.0, 9.0, 7.0, 5.0, 4.7, 4.2, 4.0, and 3.1.
In some embodiments, compound 2 form L is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.5
8.3
9.8
11.0
12.6
13.9
14.6
16.6
17.0
17.8
18.7
18.9
19.5
19.8
21.0
22.2
22.8
23.7
24.1
25.0
25.8
26.5
26.8
28.2
29.2
in some embodiments, compound 2 form L is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form M
Novel compound 2 form M can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 14.5, 19.4, 22.1, 24.9 and 37.7. In some embodiments, compound 2 form M is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 5.5, 8.3, 14.5, 19.4, 22.1, 24.9, and 37.7 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 6.1, 4.6, 4.0, 3.6, and 2.4 (respectively).
The novel compound 2 form M can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.3, 14.5, 19.4, 22.1, 24.9 and 37.7. In some embodiments, compound 2 form M is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 5.5, 8.3, 14.5, 19.4, 22.1, 24.9, and 37.7 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 6.1, 4.6, 4.0, 3.6, and 2.4 (respectively).
In some embodiments, compound 2 form M is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
5.5
8.3
9.8
10.8
12.4
13.8
14.5
16.7
17.8
19.0
19.4
21.5
22.1
24.0
24.2
24.9
26.7
36.4
37.7
in some embodiments, compound 2 form M is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form O
The novel compound 2 form O can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.4, 4.6, 6.8, 9.2, 10.1, 10.9, 12.0 and 20.2. In some embodiments, compound 2 form O is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractions at angles (2 θ ± 0.2) of 3.4, 4.6, 6.8, 9.2, 10.1, 10.9, 12.0, and 20.2 corresponding to d-spacings (angstroms ± 0.2) of 25.7, 19.2, 13.0, 9.7, 8.7, 8.1, 7.4, and 4.4 (respectively).
The novel compound 2 form O can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractograms at angles (2 θ ± 0.2) of 3.4, 4.6, 6.8, 9.2, 10.1, 10.9, 12.0 and 20.2. In some embodiments, compound 2 form O is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 3.4, 4.6, 6.8, 9.2, 10.1, 10.9, 12.0, and 20.2 corresponding to d-spacings (angstroms ± 0.2) of 25.7, 19.2, 13.0, 9.7, 8.7, 8.1, 7.4, and 4.4 (respectively).
In some embodiments, compound 2 form O is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
3.4
4.6
5.5
6.8
8.0
8.7
9.2
9.4
9.9
10.1
10.9
12.0
12.5
12.9
13.2
13.7
14.1
14.6
15.8
16.8
17.4
18.1
18.3
18.6
18.9
19.8
20.2
20.7
21.7
22.3
22.8
23.6
27.0
27.6
28.3
29.1
29.9
31.8
34.6
35.1
in some embodiments, compound 2 form O is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
compound 2 form P
The novel compound 2 form P can be identified by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.3, 6.8, 12.3, 15.2 and 39.6. In some embodiments, compound 2 form P is identifiable by X-ray powder diffraction (XRPD) having one or more characteristic diffractograms at angles (2 θ ± 0.2) of 4.3, 6.8, 12.3, 15.2, and 39.6 corresponding to d-spacings (angstroms ± 0.2) of 20.6, 13.0, 7.2, 5.8, and 2.3 (respectively).
The novel compound 2 form P can be identified by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 4.3, 6.8, 12.3, 15.2 and 39.6. In some embodiments, compound 2 form P is identifiable by X-ray powder diffraction (XRPD) having three or more characteristic diffractions at angles (2 θ ± 0.2) of 4.3, 6.8, 12.3, 15.2, and 39.6 corresponding to d-spacings (angstroms ± 0.2) of 20.6, 13.0, 7.2, 5.8, and 2.3 (respectively).
In some embodiments, compound 2 form P is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 Θ ± 0.2) as:
4.3
6.8
7.6
8.6
9.0
10.3
11.0
11.7
12.3
12.9
13.8
14.0
14.8
15.2
16.0
16.5
16.8
17.3
17.9
18.1
18.8
19.1
19.5
19.9
20.5
20.9
21.5
21.7
22.0
22.3
23.0
23.1
23.4
24.4
24.6
25.2
25.6
26.1
26.7
27.1
27.3
27.8
28.2
28.9
29.4
29.8
30.1
30.5
30.8
31.5
32.1
32.5
33.1
33.8
35.0
36.0
36.5
36.9
37.5
38.7
39.6
in some embodiments, compound 2 form P is characterized by an X-ray powder diffraction having one or more peaks at substantially the same angle (2 θ ± 0.2) and corresponding d-spacing (angstroms ± 0.2) as:
in some embodiments, the present disclosure provides a composition comprising amorphous and crystalline solid forms of compound 2. In some embodiments, the composition comprises crystalline compound 2 and amorphous compound 2, wherein the amorphous compound 2 is present in an amount selected from the following ranges: about 90 to about 99%, about 80 to about 90%, about 70 to about 80%, about 60 to about 70%, about 50 to about 60%, about 40 to about 50%, about 30 to about 40%, about 20 to about 30%, about 10 to about 20%, about 1 to about 10%, and about 0 to about 1%.
In some embodiments, the composition comprises crystalline compound 2 and amorphous compound 2, wherein the crystalline compound 2 is present in an amount selected from the following ranges: about 90 to about 99%, about 80 to about 90%, about 70 to about 80%, about 60 to about 70%, about 50 to about 60%, about 40 to about 50%, about 30 to about 40%, about 20 to about 30%, about 10 to about 20%, about 1 to about 10%, and about 0 to about 1%. In some embodiments, the composition is free of (i.e., contains 0%) amorphous compound 2.
In some embodiments, the present disclosure provides a composition comprising compound 2 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the composition does not contain a significant amount of foreign matter. Such foreign materials may include starting materials, residual solvents, or any other impurities that may result from the preparation and/or isolation of compound 2. In some embodiments, at least 90% by weight of compound 2 is present. In some embodiments, at least 95% by weight of compound 2 is present. In some embodiments, at least 99% by weight of compound 2 is present.
In some embodiments, the crystalline solid form of compound 2 is anhydrous. In some embodiments, the anhydrous crystalline solid form of compound 2 is selected from form G and form O. In some embodiments, the anhydrous crystalline solid form of compound 2 is form G. In some embodiments, the anhydrous crystalline solid form of compound 2 is form O.
In some embodiments, the crystalline solid form of compound 2 is unsolvated. In some embodiments, the unsolvated crystalline solid form of compound 2 is selected from form G and form O. In some embodiments, the unsolvated crystalline solid form of compound 2 is form d. In some embodiments, the unsolvated crystalline solid form of compound 2 is selected from form O.
In some embodiments, the crystalline solid form of compound 2 is a solvate. As used herein, the term "solvate" refers to a solid form that incorporates a stoichiometric amount of solvent in the crystal structure. For example, solvated crystalline solid forms can comprise 0.5, 1.0, 1.5, 2.0, etc. equivalents of solvent incorporated into the crystal lattice.
In some embodiments, the crystalline solid form of compound 2 is an acetone solvate. In some embodiments, the acetone solvate crystalline solid form of compound 2 is form a.
In some embodiments, the crystalline solid form of compound 2 is an ethyl acetate solvate. In some embodiments, the ethyl acetate solvate crystalline solid form of compound 2 is form M.
In some embodiments, the crystalline solid form of compound 2 is a hydrate. As used herein, the term "hydrate" refers to a solid form that incorporates a stoichiometric amount of water in the crystal structure. For example, the hydrated crystalline solid form may comprise 0.5, 1.0, 1.5, 2.0, etc. equivalents of water incorporated into the crystal lattice. In some embodiments, the hydrate crystalline solid form of compound 2 is form I.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising a crystalline solid form of compound 2. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a crystalline solid form G of compound 2. For example, a pharmaceutical composition can comprise and/or be obtained from a solid form of compound 2, referred to as solid form G of compound 2, that produces an X-ray powder diffraction (XRPD) pattern having one or more diffractograms at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8. In some embodiments, the pharmaceutical composition comprises solid form G of compound 2 characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 5.8, and 2.3. In some embodiments, the pharmaceutical composition comprises solid form G of compound 2 characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8. In some embodiments, the pharmaceutical composition comprises solid form G of compound 2 characterized by X-ray powder diffraction (XRPD) with diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8 corresponding to d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively). In some embodiments, the pharmaceutical composition comprises solid form G of compound 2 characterized by an XRPD pattern having diffraction at the following angles (2 θ ± 0.2):
4.4
6.8
7.7
8.7
9.1
10.5
11.1
11.8
13.1
13.9
14.9
15.3
16.1
16.6
16.9
17.4
18.0
18.2
18.9
19.2
19.6
20.0
20.7
21.1
21.6
21.8
22.1
22.5
23.0
23.5
24.5
25.3
25.8
26.2
26.8
27.5
27.9
28.4
28.7
29.1
29.9
31.0
32.7
33.3
34.0
35.2
36.1
36.6
38.8
in some embodiments, the pharmaceutical composition comprises solid form G of compound 2 characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
in some embodiments, the pharmaceutical composition comprises solid form G of compound 2 characterized by a Differential Scanning Calorimetry (DSC) endotherm with a lowest value at about 120.1 ℃.
The pharmaceutical compositions reported herein may be combined with a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical compositions as reported herein may be provided in a unit dosage container (e.g. in a vial or a bag or the like). In some embodiments, the pharmaceutical composition as reported herein may be provided in an oral dosage form. In some embodiments, the oral dosage form is a capsule. In some embodiments, the oral dosage form is a tablet.
In some embodiments, the present disclosure provides methods of inhibiting bromodomains and extra-terminal (BET) bromodomains comprising administering to a subject a solid form of compound 2. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition responsive to inhibition of Bromodomains and Extra Terminal (BET) bromodomains, comprising administering a solid form of compound 2 to a subject in need thereof. In some embodiments, the disease, disorder, or condition is selected from the group consisting of cancer, inflammation, metabolic and neurological disorders, and infectious diseases.
In some embodiments, the present disclosure provides methods of treating cancer comprising administering to a subject in need thereof a solid form of compound 2. In some embodiments, the present disclosure provides methods of treating an inflammatory disorder comprising administering to a subject in need thereof a solid form of compound 2. In some embodiments, the treatment is administered after one or more symptoms have occurred. In other embodiments, the treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., based on history of symptoms and/or based on genetics or other susceptibility factors). In some embodiments, treatment is continued after symptoms have resolved, e.g., to prevent their recurrence, delay their recurrence, or reduce the severity of their recurrence.
In some embodiments, the present disclosure provides a process for preparing a solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2"), the process comprising suspending at least one of form a, form B, form I, or form O of compound 2 in a solvent to provide a slurry, and maintaining the slurry for a time and under conditions effective to produce a solid form G of compound 2. In some embodiments, the solvent is selected from isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBK), methylene chloride/methyl tert-butyl ether (CHCl)3/MTBE). In some embodiments, after suspension in the solvent, the slurry is heated to a maximum temperature of about 50 ℃. In some embodiments, the method further comprises separating solid form G of compound 2 from the slurry.
In some embodiments, the present disclosure provides a process for preparing solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2"), comprising the steps of: contacting methyl tert-butyl ether with at least one of form a, form B, form I, or form O of compound 2 in isopropyl acetate under conditions effective to produce solid form G of compound 2.
In some embodiments, the present disclosure provides a composition comprising methyl tert-butyl ether, isopropyl acetate, and at least one of form a, form B, form I, or form O of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate.
In some embodiments, the present disclosure provides a composition comprising a solid form of compound 2 that is substantially free of other solid forms of compound 2. In some embodiments, a composition comprising compound 2 form G is substantially free of other compound 2 solid forms (e.g., form a, form B, form C, form D, form E, form F, form I, form J, form K, form L, form M, form O, and/or form P). In some embodiments, the composition comprising compound 2 form G is substantially free of compound 2 form a, compound 2 form B, compound 2 form I, and compound 2 form O. In some embodiments, at least 90% by weight of compound 2 form G is present. In some embodiments, at least 95% by weight of compound 2 form G is present. In some embodiments, at least 99% by weight of compound 2 form G is present. In some embodiments, a composition comprising compound 2 form G is substantially free of amorphous compound 2.
Illustrative embodiments
The following numbered embodiments, while non-limiting, illustrate certain aspects of the present disclosure:
embodiment 1. a pharmaceutically acceptable salt form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1").
Embodiment 2. a salt form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1") selected from the group consisting of the fumarate, adipate, or succinate salt forms of compound 1.
Embodiment 3. the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline salt of compound 1.
Embodiment 4. the salt form of any of the preceding embodiments, wherein compound 1 is the succinate salt ("compound 1 succinate salt").
Embodiment 5. the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline succinate salt form of compound 1 characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3.
Embodiment 6. the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline succinate salt form of compound 1 characterized by an X-ray powder diffraction (XRPD) with diffraction at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 9.0, 5.0, 4.0, 3.6, 3.5, 2.5, and 2.4 (respectively).
Embodiment 7 the salt form of any one of the preceding embodiments, wherein the salt form is crystalline succinate form a of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern with diffraction at the following angles (2 Θ ± 0.2):
5.5
8.3
9.8
10.8
12.5
12.6
13.8
14.4
14.6
16.7
17.1
17.9
18.4
18.7
19.0
19.6
20.0
20.5
20.9
21.3
21.8
22.2
22.5
23.1
23.4
24.2
24.8
25.3
25.6
26.5
26.8
27.3
28.1
28.5
29.1
29.7
30.7
32.3
32.9
33.8
34.9
36.1
37.3。
embodiment 8 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline succinate salt form of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
embodiment 9 the salt form of any of the preceding embodiments, wherein the salt form is crystalline succinate salt form a of compound 1 characterized by a Differential Scanning Calorimetry (DSC) endotherm with a minimum at about 80.6 ℃.
Embodiment 10 the salt form of any of the preceding embodiments, wherein the salt form is crystalline succinate form a of compound 1 characterized by a thermogravimetric analysis (TGA) with a weight loss of about 0.4% between about 33.7 ℃ and about 70.0 ℃.
Embodiment 11. the salt form of any of the preceding embodiments, wherein compound 1 is the fumarate salt ("compound 1 fumarate").
Embodiment 12 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 4.0, 5.3, 7.9, 10.2, 13.3, and 21.2.
Embodiment 13 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 4.0, 5.3, 7.9, 10.2, 13.3, and 21.2 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 22.1, 16.7, 11.1, 8.7, 6.7, and 4.2.
Embodiment 14 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2):
4.0
5.3
6.6
7.9
10.2
13.3
14.8
17.2
18.6
21.2
24.1
26.5
28.4。
embodiment 15 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
embodiment 16 the salt form of any of the preceding embodiments, wherein the salt form is crystalline fumarate salt form a of compound 1, characterized by a Differential Scanning Calorimetry (DSC) endotherm with a minimum at about 100.8 ℃.
Embodiment 17 the salt form of any of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form a of compound 1, characterized by a thermogravimetric analysis (TGA) with a weight loss of about 0.7% between about 34.4 ℃ and about 80.0 ℃.
Embodiment 18 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.4, 13.5, 16.3, 21.1, 23.5, 26.0, and 26.5.
Embodiment 19. the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.4, 13.5, 16.3, 21.1, 23.5, 26.0, and 26.5 corresponding to d-spacings (angstroms ± 0.2) of 16.4, 6.6, 5.4, 4.2, 3.8, 3.4, and 3.4 (respectively).
Embodiment 20 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form B of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2):
5.4
8.1
9.9
10.0
10.9
12.4
13.5
14.2
14.6
16.3
16.8
17.5
18.6
18.9
21.1
21.6
23.5
23.9
26.0
26.5
27.1
34.1
35.5
36.8。
embodiment 21 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form B of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
embodiment 22 the salt form of any one of the preceding embodiments, wherein the salt form is crystalline fumarate salt form B of compound 1, characterized by a Differential Scanning Calorimetry (DSC) endotherm with a minimum at about 100.0 ℃.
Embodiment 23 the crystalline form of any one of the preceding embodiments, wherein the salt form is crystalline fumarate salt form B of compound 1, characterized by a thermogravimetric analysis (TGA) with a weight loss of about 1.1% between about 33.7 ℃ and about 90.0 ℃.
Embodiment 24 the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at 5.5, 8.2, 10.0, 18.1, 19.2, and 22.0 angles (2 Θ ± 0.2).
Embodiment 25. the salt form of any one of the preceding embodiments, wherein the salt form is a crystalline fumarate salt form of compound 1, characterized by X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.5, 8.2, 10.0, 18.1, 19.2, and 22.0 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.1, 10.7, 8.9, 4.9, 4.6, and 4.0.
Embodiment 26 the salt form of any one of the preceding embodiments, wherein the salt form is crystalline fumarate salt form C of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2):
5.5
8.2
10.0
13.7
14.6
18.1
19.2
22.0
24.1
25.3
27.4。
embodiment 27 the salt form of any one of the preceding embodiments, wherein the salt form is crystalline fumarate salt form C of compound 1, characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
embodiment 28 the salt form of any of the preceding embodiments, wherein the salt form is crystalline fumarate salt form C of compound 1, characterized by a Differential Scanning Calorimetry (DSC) endotherm with a minimum at about 40.2 ℃ and about 102.9 ℃.
Embodiment 29 the salt form of any of the preceding embodiments, wherein the salt form is crystalline fumarate salt form C of compound 1, characterized by a thermogravimetric analysis (TGA) with a weight loss of about 3.4% between about 61.9 ℃ and about 94.0 ℃.
Embodiment 30. the salt form of any of the preceding embodiments, wherein compound 1 is an adipate salt ("compound 1 adipate").
Embodiment 31 the salt form of any of the preceding embodiments, wherein the salt form is a crystalline adipate salt form of compound 1 characterized by an X-ray powder diffraction (XRPD) pattern with diffraction at angles (2 Θ ± 0.2) of 7.9, 12.3, 15.7, 19.7, and 24.7.
Embodiment 32 the salt form of any of the preceding embodiments, wherein the salt form is a crystalline adipate salt form of compound 1 characterized by X-ray powder diffraction (XRPD) having one or more diffractures at angles (2 θ ± 0.2) of 7.9, 12.3, 15.7, 19.7, and 24.7 corresponding to d-spacings (angstroms ± 0.2) of 11.2, 7.2, 5.6, 4.5, and 3.6 (respectively).
Embodiment 33 the salt form of any of the preceding embodiments, wherein the salt form is a crystalline adipate salt form a of compound 1 characterized by an X-ray powder diffraction (XRPD) pattern with diffraction at the following angles (2 Θ ± 0.2):
4.0
7.9
11.6
12.3
13.1
14.1
15.3
15.7
16.6
18.8
19.7
21.2
22.2
23.4
24.1
24.7
26.3
28.3
30.8。
embodiment 34 the salt form of any of the preceding embodiments, wherein the salt form is a crystalline adipate salt form a of compound 1 characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at the following angles (2 Θ ± 0.2) and corresponding d-spacings (angstroms ± 0.2):
embodiment 35 the salt form of any of the preceding embodiments, wherein the salt form is crystalline adipate salt form a of compound 1 characterized by Differential Scanning Calorimetry (DSC) endotherms with peaks at about 84.9 ℃ and about 99.9 ℃.
Embodiment 36 the salt form of any of the preceding embodiments, wherein the salt form is crystalline adipate form a of compound 1 characterized by a thermogravimetric analysis (TGA) with a weight loss of about 0.5% between about 33.2 ℃ and about 68.0 ℃.
Embodiment 37. a pharmaceutical composition comprising a salt form of any of the foregoing embodiments and a pharmaceutically acceptable carrier or excipient.
Embodiment 38 a process for preparing a salt form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1"), comprising contacting compound 1 with an acid selected from the group consisting of: fumaric acid, adipic acid and succinic acid.
Embodiment 39 a solid form of compound 1 obtained by a process comprising the steps of: contacting compound 1 with succinic acid under conditions and for a time effective to form the succinate salt form of compound 1.
Embodiment 40. the solid form of embodiment 39, wherein the solid form is a crystalline form of compound 1.
Embodiment 41. a pharmaceutical composition for oral administration comprising a crystalline succinate salt of compound 1.
Embodiment 42. a pharmaceutical composition for oral administration comprising the succinate salt of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1").
Embodiment 43. a pharmaceutical composition for oral administration comprising a crystalline form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate.
Embodiment 44. a solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2").
Embodiment 45. the solid form of embodiment 44, wherein the solid form G of compound 2 is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8.
Embodiment 46 the solid form of any one of embodiments 44 to 45, wherein the solid form G of compound 2 is characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8.
Embodiment 47. the solid form of any one of embodiments 44 to 46, wherein the solid form G of compound 2 is characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8 corresponding to d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3 (respectively).
Embodiment 48 the solid form of any one of embodiments 44 to 47, wherein the solid form G of compound 2 is characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
4.4
6.8
7.7
8.7
9.1
10.5
11.1
11.8
13.1
13.9
14.9
15.3
16.1
16.6
16.9
17.4
18.0
18.2
18.9
19.2
19.6
20.0
20.7
21.1
21.6
21.8
22.1
22.5
23.0
23.5
24.5
25.3
25.8
26.2
26.8
27.5
27.9
28.4
28.7
29.1
29.9
31.0
32.7
33.3
34.0
35.2
36.1
36.6
38.8。
embodiment 49 the solid form of any one of embodiments 44 to 48, wherein the solid form G of compound 2 is characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 50 the solid form of any one of embodiments 44 to 49, wherein solid form G is characterized by a Differential Scanning Calorimetry (DSC) endotherm with a minimum at about 127 ℃.
Embodiment 51. the solid form of any one of embodiments 44 to 50, wherein solid form G is characterized by thermogravimetric analysis (TGA) with a weight loss of about 0.2% between 21-150 ℃.
Embodiment 52. the solid form of any one of embodiments 44 to 51, wherein solid form G is characterized by dynamic gas phase adsorption (DVS) of about 0.76 wt% water at less than 70% relative humidity.
Embodiment 53. a pharmaceutical composition comprising form G compound 1 succinate salt and a pharmaceutically acceptable excipient.
Embodiment 54. the pharmaceutical composition of any one of embodiments 44 to 53, wherein the succinate salt of form G compound 1 is solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2").
Embodiment 55 the pharmaceutical composition of any one of embodiments 44 to 54, wherein solid form G is characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8.
Embodiment 56 the pharmaceutical composition of any one of embodiments 44 to 55, wherein solid form G of compound 2 is characterized by an X-ray powder diffraction (XRPD) with diffraction at angles (2 θ ± 0.2) of 4.4, 6.8, 9.1, 15.3, and 38.8 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 5.8, and 2.3.
Embodiment 57 the pharmaceutical composition of any one of embodiments 44 to 56, wherein solid form G of compound 2 is characterized by an XRPD pattern having diffraction at angles (2 Θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8.
Embodiment 58 the pharmaceutical composition of any one of embodiments 44 to 57, wherein solid form G of compound 2 is characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 Θ ± 0.2) of 4.4, 6.8, 9.1, 13.1, 15.3, 16.1, 19.6, 36.6, and 38.8 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 20.1, 13.0, 9.7, 6.8, 5.8, 5.5, 4.5, 2.5, and 2.3.
Embodiment 59 the pharmaceutical composition of any one of embodiments 44 to 58, wherein solid form G of compound 2 is characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
4.4
6.8
7.7
8.7
9.1
10.5
11.1
11.8
13.1
13.9
14.9
15.3
16.1
16.6
16.9
17.4
18.0
18.2
18.9
19.2
19.6
20.0
20.7
21.1
21.6
21.8
22.1
22.5
23.0
23.5
24.5
25.3
25.8
26.2
26.8
27.5
27.9
28.4
28.7
29.1
29.9
31.0
32.7
33.3
34.0
35.2
36.1
36.6
38.8。
embodiment 60 the pharmaceutical composition of any one of embodiments 44 to 59, wherein the solid form G of compound 2 is characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 61 the solid form of any one of embodiments 44 to 60, wherein the solid form G of compound 2 is characterized by a Differential Scanning Calorimetry (DSC) endotherm with a minimum at about 127 ℃.
Embodiment 62 a process for preparing solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2") comprising suspending at least one of form a, form B, form I, or form O of compound 2 in a solvent to provide a slurry, and maintaining the slurry for a time and under conditions effective to produce solid form G of compound 2.
Embodiment 63 the method of any one of embodiments 44 to 62, wherein the solvent is selected from isopropyl acetate (IPAc), methyl tert-butyl ether (MTBE), methyl isobutyl ketone (MIBK), methylene chloride/methyl tert-butyl ether (CHCl)3/MTBE)。
Embodiment 64 the method of any one of embodiments 44 to 63, wherein after suspension in the solvent, the slurry is heated to a maximum temperature of about 50 ℃.
Embodiment 65 the method of any one of embodiments 44 to 64, further comprising isolating solid form G of compound 2 from the slurry.
Embodiment 66. a process for preparing solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2") comprising the steps of: contacting methyl tert-butyl ether with at least one of form a, form B, form I, or form O of compound 2 in isopropyl acetate under conditions effective to produce solid form G of compound 2.
Embodiment 67, a composition comprising methyl tert-butyl ether, isopropyl acetate, and at least one of form a, form B, form I, or form O of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate.
Embodiment 68. a crystalline solid form of compound 2:
embodiment 69 the crystalline solid form of any one of embodiments 44 to 68, wherein the crystalline solid form is form a ("solid form a"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3.
Embodiment 70 the crystalline solid form of any one of embodiments 44 to 69, wherein the crystalline solid form is solid form a, characterized by an X-ray powder diffraction (XRPD) with diffraction at angles (2 θ ± 0.2) of 5.5, 8.3, 9.8, 17.9, 22.2, 24.8, 25.6, 36.1, and 37.3 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 9.0, 5.0, 4.0, 3.6, 3.5, 2.5, and 2.4 (respectively).
Embodiment 71. the crystalline solid form of any one of embodiments 44 to 70, wherein the crystalline solid form is solid form a characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
5.5
8.3
9.8
10.8
12.5
12.6
13.8
14.4
14.6
16.7
17.1
17.9
18.4
18.7
19.0
19.6
20.0
20.5
20.9
21.3
21.8
22.2
22.5
23.1
23.4
24.2
24.8
25.3
25.6
26.5
26.8
27.3
28.1
28.5
29.1
29.7
30.7
32.3
32.9
33.8
34.9
36.1
37.3。
embodiment 72 the crystalline solid form of any one of embodiments 44 to 71, wherein the crystalline solid form is solid form a characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 73 the crystalline solid form of any one of embodiments 44 to 72, wherein the crystalline solid form is form B ("solid form B"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 4.7, 5.9, 8.7, 11.0, 17.2, and 20.4.
Embodiment 74 the crystalline solid form of any one of embodiments 44 to 73, wherein the crystalline solid form is solid form B, characterized by an X-ray powder diffraction (XRPD) with diffraction at angles (2 θ ± 0.2) of 4.7, 5.9, 8.7, 11.0, 17.2, and 20.4 corresponding to d-spacings (angstroms ± 0.2) of 18.7, 15.1, 10.1, 8.1, 5.1, and 4.4 (respectively).
Embodiment 75 the crystalline solid form of any one of embodiments 44 to 74, wherein the crystalline solid form is solid form B characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
4.7
5.9
8.7
9.7
10.3
11.0
11.7
13.8
14.5
16.2
17.2
17.7
18.5
18.8
19.1
20.4
20.6
21.2
21.6
22.6
23.8
24.3
24.9
25.2
26.1
26.9
27.7
28.5
30.0
32.7
33.6
35.1。
embodiment 76 the crystalline solid form of any one of embodiments 44 to 75, wherein the crystalline solid form is solid form B characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 77 the crystalline solid form of any one of embodiments 44 to 76, wherein the crystalline solid form is form C ("solid form C"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.4, 8.1, 10.1, 10.9, 16.4, 17.7, and 34.3.
Embodiment 78 the crystalline solid form of any one of embodiments 44 to 77, wherein the crystalline solid form is solid form C, characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.4, 8.1, 10.1, 10.9, 16.4, 17.7, and 34.3 corresponding to d-spacings (angstroms ± 0.2) of 16.3, 10.9, 8.7, 8.1, 5.4, 5.0, and 2.6 (respectively).
Embodiment 79 the crystalline solid form of any one of embodiments 44 to 78, wherein the crystalline solid form is solid form C characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
5.4
8.1
9.9
10.1
10.9
12.4
14.2
14.8
16.4
17.1
17.7
18.6
19.3
19.9
20.7
21.2
21.8
22.6
23.2
24.2
24.6
25.2
26.0
27.3
29.3
30.0
34.3
37.5。
embodiment 80 the crystalline solid form of any one of embodiments 44 to 79, wherein the crystalline solid form is solid form C characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 81 the crystalline solid form of any one of embodiments 44 to 80, wherein the crystalline solid form is form D ("solid form D"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.4, 14.7, 18.5, 21.8, and 38.6.
Embodiment 82 the crystalline solid form of any one of embodiments 44 to 81, wherein the crystalline solid form is solid form D characterized by X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.4, 14.7, 18.5, 21.8, and 38.6 (respectively) corresponding to D-spacings (angstroms ± 0.2) of 16.2, 6.0, 4.8, 4.1, and 2.3.
Embodiment 83 the crystalline solid form of any one of embodiments 44 to 82, wherein the crystalline solid form is solid form D characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
5.4
8.1
9.8
10.0
10.8
12.4
13.6
14.2
14.7
16.8
17.3
18.5
19.1
19.9
20.5
20.9
21.8
23.5
24.1
25.1
25.7
26.1
27.6
29.6
33.4
35.8
38.6。
embodiment 84 the crystalline solid form of any one of embodiments 44 to 83, wherein the crystalline solid form is solid form D characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following D-spacings (angstroms ± 0.2):
embodiment 85 the crystalline solid form of any one of embodiments 44 to 84, wherein the crystalline solid form is form E ("solid form E"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.5, 11.3, 13.0, 16.3, and 20.3.
Embodiment 86 the crystalline solid form of any one of embodiments 44 to 85, wherein the crystalline solid form is solid form E, characterized by X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.5, 11.3, 13.0, 16.3, and 20.3 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.0, 7.8, 6.8, 5.4, and 4.4.
Embodiment 87 the crystalline solid form of any one of embodiments 44 to 86, wherein the crystalline solid form is solid form E, characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
5.5
8.3
9.8
10.1
10.7
11.3
12.2
13.0
13.8
14.1
15.0
16.3
16.5
17.3
18.2
18.6
19.0
19.6
20.3
20.9
21.2
22.1
22.9
23.6
24.2
26.2
27.2
28.1
30.4
32.8
35.3
36.3
37.0。
embodiment 88 the crystalline solid form of any one of embodiments 44 to 87, wherein the crystalline solid form is solid form E, characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 89 the crystalline solid form of any one of embodiments 44 to 88, wherein the crystalline solid form is form F ("solid form F"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 13.6, 14.2, 16.3, 21.8, and 26.7.
Embodiment 90 the crystalline solid form of any one of embodiments 44 to 89, wherein the crystalline solid form is solid form F, characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 13.6, 14.2, 16.3, 21.8, and 26.7 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 6.5, 6.2, 5.4, 4.1, and 3.3.
Embodiment 91 the crystalline solid form of any one of embodiments 44 to 90, wherein the crystalline solid form is solid form F characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
5.5
8.2
9.7
9.9
10.7
12.3
13.6
14.2
14.6
16.3
16.8
18.6
18.9
19.1
19.5
20.3
20.8
21.0
21.8
22.9
23.5
23.8
24.1
26.1
26.7
27.4
29.4
embodiment 92 the crystalline solid form of any one of embodiments 44 to 91, wherein the crystalline solid form is solid form F characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 93 the crystalline solid form of any one of embodiments 44 to 92, wherein the crystalline solid form is form I ("solid form I"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 3.4, 5.9, 9.2, 10.3, 11.0, and 25.4.
Embodiment 94 the crystalline solid form of any one of embodiments 44 to 93, wherein the crystalline solid form is solid form I, characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 3.4, 5.9, 9.2, 10.3, 11.0, and 25.4 corresponding to d-spacings (angstroms ± 0.2) of 25.8, 15.0, 9.7, 8.6, 8.0, and 3.5 (respectively).
Embodiment 95 the crystalline solid form of any one of embodiments 44 to 94, wherein the crystalline solid form is solid form I characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
3.4
5.9
6.7
8.0
8.8
9.2
9.5
9.8
10.1
10.3
10.8
11.0
12.5
12.9
13.2
13.9
14.5
15.7
16.8
17.4
18.3
18.9
19.8
20.7
21.4
23.6
25.4
27.0
28.3
29.1
29.9。
embodiment 96 the crystalline solid form of any one of embodiments 44 to 95, wherein the crystalline solid form is solid form I characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 97 the crystalline solid form of any one of embodiments 44 to 96, wherein the crystalline solid form is form J ("solid form J"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.4, 8.1, 12.4, 13.5, 15.6, 21.0, and 21.7.
Embodiment 98 the crystalline solid form of any one of embodiments 44 to 97, wherein the crystalline solid form is solid form J, characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.4, 8.1, 12.4, 13.5, 15.6, 21.0, and 21.7 corresponding to d-spacings (angstroms ± 0.2) of 16.3, 10.9, 7.1, 6.5, 5.7, 4.2, and 4.1 (respectively).
Embodiment 99 the crystalline solid form of any one of embodiments 44 to 98, wherein the crystalline solid form is solid form J, characterized by an XRPD pattern having a diffraction at the following angles (2 Θ ± 0.2):
5.4
8.1
9.8
10.0
10.8
12.4
13.5
15.6
18.7
19.0
21.0
21.7
23.5
35.6
38.5。
embodiment 100 the crystalline solid form of any one of embodiments 44 to 99, wherein the crystalline solid form is solid form J characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 101 the crystalline solid form of any one of embodiments 44 to 100, wherein the crystalline solid form is form K ("solid form K"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.5, 8.7, 9.7, 22.2, and 24.4.
Embodiment 102 the crystalline solid form of any one of embodiments 44 to 101, wherein the crystalline solid form is solid form K characterized by X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.5, 8.7, 9.7, 22.2, and 24.4 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 15.9, 10.2, 9.1, 4.0, and 3.7.
Embodiment 103 the crystalline solid form of any one of embodiments 44 to 102, wherein the crystalline solid form is solid form K characterized by an XRPD pattern having a diffraction at the following angles (2 Θ ± 0.2):
5.5
8.3
8.7
9.7
10.9
14.5
16.8
17.6
18.7
20.5
22.2
24.4。
embodiment 104 the crystalline solid form of any one of embodiments 44 to 103, wherein the crystalline solid form is solid form K characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 105. the crystalline solid form of any one of embodiments 44 to 104, wherein the crystalline solid form is form L ("solid form L"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.4, 9.8, 12.6, 17.8, 18.9, 21.0, 22.2, and 29.2.
Embodiment 106 the crystalline solid form of any one of embodiments 44 to 105, wherein the crystalline solid form is solid form L, characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.5, 9.8, 12.6, 17.8, 18.9, 21.0, 22.2, and 29.2 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 16.0, 9.0, 7.0, 5.0, 4.7, 4.2, 4.0, and 3.1.
Embodiment 107. the crystalline solid form of any one of embodiments 44 to 106, wherein the crystalline solid form is solid form L characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
5.5
8.3
9.8
11.0
12.6
13.9
14.6
16.6
17.0
17.8
18.7
18.9
19.5
19.8
21.0
22.2
22.8
23.7
24.1
25.0
25.8
26.5
26.8
28.2
29.2。
embodiment 108 the crystalline solid form of any one of embodiments 44 to 107, wherein the crystalline solid form is solid form L characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 109 the crystalline solid form of any one of embodiments 44 to 108, wherein the crystalline solid form is form M ("solid form M"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 5.5, 8.3, 14.5, 19.4, 22.1, 24.9, and 37.7.
Embodiment 110 the crystalline solid form of any one of embodiments 44 to 109, wherein the crystalline solid form is solid form M, characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 5.5, 8.3, 14.5, 19.4, 22.1, 24.9, and 37.7 corresponding to d-spacings (angstroms ± 0.2) of 16.0, 10.7, 6.1, 4.6, 4.0, 3.6, and 2.4 (respectively).
Embodiment 111 the crystalline solid form of any one of embodiments 44 to 110, wherein the crystalline solid form is solid form M characterized by an XRPD pattern having a diffraction at the following angles (2 Θ ± 0.2):
5.5
8.3
9.8
10.8
12.4
13.8
14.5
16.7
17.8
19.0
19.4
21.5
22.1
24.0
24.2
24.9
26.7
36.4
37.7。
embodiment 112 the crystalline solid form of any one of embodiments 44 to 111, wherein the crystalline solid form is solid form M characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 113 the crystalline solid form of any one of embodiments 44 to 112, wherein the crystalline solid form is form O ("solid form O"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 3.4, 4.6, 6.8, 9.2, 10.1, 10.9, 12.0, and 20.2.
Embodiment 114 the crystalline solid form of any one of embodiments 44 to 113, wherein the crystalline solid form is solid form O, characterized by an X-ray powder diffraction (XRPD) with diffraction at angles (2 θ ± 0.2) of 3.4, 4.6, 6.8, 9.2, 10.1, 10.9, 12.0, and 20.2 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 25.7, 19.2, 13.0, 9.7, 8.7, 8.1, 7.4, and 4.4.
Embodiment 115 the crystalline solid form of any one of embodiments 44 to 114, wherein the crystalline solid form is solid form O, characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
3.4
4.6
5.5
6.8
8.0
8.7
9.2
9.4
9.9
10.1
10.9
12.0
12.5
12.9
13.2
13.7
14.1
14.6
15.8
16.8
17.4
18.1
18.3
18.6
18.9
19.8
20.2
20.7
21.7
22.3
22.8
23.6
27.0
27.6
28.3
29.1
29.9
31.8
34.6
35.1。
embodiment 116 the crystalline solid form of any one of embodiments 44 to 115, wherein the crystalline solid form is solid form O, characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 117 the crystalline solid form of any one of embodiments 44 to 116, wherein the crystalline solid form is form P ("solid form P"), characterized by an X-ray powder diffraction (XRPD) pattern having diffraction at angles (2 Θ ± 0.2) of 4.3, 6.8, 12.3, 15.2, and 39.6.
Embodiment 118 the crystalline solid form of any one of embodiments 44 to 117, wherein the crystalline solid form is a solid form P characterized by an X-ray powder diffraction (XRPD) having diffraction at angles (2 θ ± 0.2) of 4.3, 6.8, 12.3, 15.2, and 39.6 (respectively) corresponding to d-spacings (angstroms ± 0.2) of 20.6, 13.0, 7.2, 5.8, and 2.3.
Embodiment 119 the crystalline solid form of any one of embodiments 44 to 118, wherein the crystalline solid form is a solid form P characterized by an XRPD pattern having diffraction at the following angles (2 Θ ± 0.2):
4.3
6.8
7.6
8.6
9.0
10.3
11.0
11.7
12.3
12.9
13.8
14.0
14.8
15.2
16.0
16.5
16.8
17.3
17.9
18.1
18.8
19.1
19.5
19.9
20.5
20.9
21.5
21.7
22.0
22.3
23.0
23.1
23.4
24.4
24.6
25.2
25.6
26.1
26.7
27.1
27.3
27.8
28.2
28.9
29.4
29.8
30.1
30.5
30.8
31.5
32.1
32.5
33.1
33.8
35.0
36.0
36.5
36.9
37.5
38.7
39.6。
embodiment 120 the crystalline solid form of any one of embodiments 44 to 119, wherein the crystalline solid form is a solid form P characterized by an XRPD pattern having diffraction at angles (2 θ ± 0.2) corresponding to the following d-spacings (angstroms ± 0.2):
embodiment 121. a crystalline solid form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2").
Embodiment 122 a crystalline solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2").
Embodiment 123. a pharmaceutical composition comprising a crystalline solid form of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2").
Embodiment 124. a pharmaceutical composition comprising a crystalline solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2").
Embodiment 125. a pharmaceutical composition for oral administration comprising a crystalline solid form G of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate ("compound 2").
Examples
The present teachings include the description provided in the embodiments, which are not intended to limit the scope of any claims. The following non-limiting examples are provided to further illustrate the present teachings. Those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are provided herein and still obtain a like or similar result without departing from the spirit and scope of the present teachings.
Abbreviations
ACN acetonitrile
AcOH acetic acid
Chemical shift of delta
DCM dichloromethane
DMAc N, N-dimethylacetamide
DMSO dimethyl sulfoxide
EtOAc ethyl acetate
1H NMR proton nuclear magnetic resonance
IPA isopropyl alcohol
IPAc acetic acid isopropyl ester
2-MeTHF 2-methyltetrahydrofuran
MEK methyl Ethyl Ketone
MIBK methyl isobutyl ketone
MTBE methyl tert-butyl ether
THF tetrahydrofuran
Apparatus and method
The following instruments and methods were used in the working examples described herein unless otherwise indicated.
X-ray powder diffraction (XRPD)
The high resolution X-ray powder diffraction experiment is carried out on a Si zero background bracket by using Panalytical X' Pert3Powder XRPD was performed. The 2 θ position is calibrated against a Panalytical 640Si powder standard. The details of the XRPD method are listed in table 1 below:
TABLE 1
Peaks are reported in diffraction angles 2 θ, and d-spacing is measured in angstroms.
Thermal analysis
Thermogravimetric analysis (TGA) experiments were performed on TA Q500 TGA from TA Instruments. The sample was heated from about 20 ℃ to about 250 ℃ at 10 ℃/min using a dry nitrogen purge system. The details of the process are provided in table 2 below:
TABLE 2
Differential Scanning Calorimetry (DSC) experiments were performed on a TA Q2000 DSC from TA Instruments. The sample was heated from about 20 ℃ to about 250 ℃ at 10 ℃/min using a dry nitrogen purge system. Details of the process are provided in table 3 below:
TABLE 3
Modulated differential scanning calorimetry
Modulated differential scanning calorimetry (mDSC) experiments were performed on a TA Q2000 DSC from TA Instruments according to the conditions reported in table 4 below:
TABLE 4
Dynamic gas phase adsorption
Dynamic gas phase adsorption (DVS) was obtained using Surface Measurement Systems (SMS) DVS Intrasic. Relative humidity at 25 ℃ is relative to LiCl, Mg (NO)3)2And deliquescence point calibration of KCl. Typical parameters for the DVS test are listed in table 5 below:
TABLE 5
High pressure liquid chromatography
High Pressure Liquid Chromatography (HPLC) data were obtained according to table 6 or 7 below:
TABLE 6
TABLE 7
In a volumetric flask, a standard stock solution (e.g. 25mg in 25 mL) is dissolved with a diluent. This stock solution was vortexed and sonicated for 10 seconds to dissolve it, then diluted 1:10, 1:4 and 1:2 in volumetric flasks or HPLC vials to generate a standard curve. The standard curve has a minimum of 3 points and r2Minimum correlation of 0.999. Where appropriate, blanks were generated to accurately replicate the matrix of the samples and peaks present in the blanks were identified, followed by integration and quantification using Chemstation software.
Example 1-synthesis of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone (Compound 1)
The synthesis of (S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone ("compound 1") has been previously reported in PCT application publication No. WO 2015/074064, and is reproduced herein, the entire contents of which are incorporated herein by reference.
Step 1- (2S) -6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1, 2,3, 4-tetrahydroquinoline
A250 mL round bottom flask was charged with (2S) -6-bromo-1-cyclopropanecarbonyl-2-methyl-1, 2,3, 4-tetrahydroquinolin-5-ol (2.00g, 6.45mmol), bromocyclobutane (1.81mL, 2.60g, 19.3mmol), cesium carbonate (6.3g, 19.34mmol), and acetonitrile (100 mL). The resulting mixture was stirred at 80 ℃ for 6 hours. The reaction mixture was filtered through a pad of celite and the vacuum was appliedAnd (5) concentrating. The residue was purified by silica gel column chromatography (eluting with a 0-10% ethyl acetate-petroleum ether gradient) to give (2S) -6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1, 2,3, 4-tetrahydroquinoline (2.00g, 85%) as a colorless oil. MS (ES, M/z):364,366[ M + H]+。
Step 2- (S) -4- (4- (5-Cyclobutoxy-1- (cyclopropanecarbonyl) -2-methyl-1, 2,3, 4-tetrahydroquinolin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester
A250 mL round bottom flask was purged with and maintained under an inert nitrogen atmosphere and charged with (2S) -6-bromo-5-cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-1, 2,3, 4-tetrahydroquinoline (2.0g, 5.5mmol), 4- [4- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester (2.5g, 6.63mmol), [1,1' -bis (diphenylphosphino) ferrocene]Dichloropalladium (II) dichloromethane adduct (0.45g, 0.55mmol), potassium carbonate (2.3g, 16.64mmol), 1, 4-dioxane (50mL) and water (5 mL). The resulting mixture was stirred at 100 ℃ overnight. The reaction mixture was cooled to room temperature and then filtered through a pad of celite. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluting with a 0-30% ethyl acetate-petroleum ether gradient) to give tert-butyl (S) -4- (4- (5-cyclobutoxy-1- (cyclopropanecarbonyl) -2-methyl-1, 2,3, 4-tetrahydroquinolin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (2.2g, 75%) as a light yellow solid. MS (ES, M/z) 535[ M + H ]]+。
Step 3- (2S) -5-Cyclobutoxy-1-cyclopropanecarbonyl-2-methyl-6- [1- (piperidin-4-yl) -1H-pyrazol-4-yl ] -1,2,3, 4-tetrahydroquinoline
Trifluoroacetic acid (0.5mL, 6.49mmol) was added to a 0 ℃ solution of (S) -tert-butyl 4- (4- (5-cyclobutoxy-1- (cyclopropanecarbonyl) -2-methyl-1, 2,3, 4-tetrahydroquinolin-6-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (0.032g, 0.060mmol) in dichloromethane (2.0 mL). The ice bath was removed and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give (S) - (5-cyclobutoxy-2-methyl) as an off-white solid-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone (compound 1) (0.022g, 85%).1H NMR (300MHz, chloroform-d) δ ppm 0.57-0.71(m,1H),0.78-0.91(m,1H),0.92-1.04(m,1H),1.13(d, J ═ 6.45Hz,3H),1.19-1.45(m,3H),1.53-1.71(m,2H),1.79-2.42(m,11H),2.74-2.92(m,2H),2.94-3.09(m,1H),3.30(br d, J ═ 12.61Hz,2H),4.04-4.21(m,1H),4.28(ddt, J ═ 11.43,7.62,3.96,3.96Hz,1H),4.66-4.84(m,1H),7.12(d, 8, J ═ 11.43,7.62, 7.96, 3.96Hz,1H),4.66-4.84(m,1H),7.12(d, 8, J ═ 8, 7.88, 7.8H, 7.8 (H, 1H). MS (ESI, Positive ion) M/z 435[ M + H ]]+。
EXAMPLE 2 salt screening of Compound 1
In an effort to find the salt of compound 1, salt/co-crystal screens were performed using 25 salt/co-crystal co-formers and five solvent systems under 127 different conditions. For each condition, approximately 20mg of compound 1 was dispersed in the selected solvent in a glass vial, followed by addition of the salt/co-crystal co-former. After sonication and stirring at Room Temperature (RT), the resulting solid was isolated and analyzed by XRPD. The results are summarized in table 8 below:
TABLE 8
N/A: the jelly or oil obtained after stirring
E: gels or oils obtained after evaporation at room temperature
*: solids obtained from slurries at 4 ℃
+: solids obtained by evaporation
A total of six crystalline salts/co-crystals were identified: compound 1 fumarate salt form a, compound 1 fumarate salt form B, compound 1 fumarate salt form C, compound 1 succinate salt form a, compound 1 adipate salt form a, and compound 1 maleate salt form a.
Example 3 characterization of salt forms of Compound 1
Compound 1 fumarate salt form A
Compound 1 fumarate salt form a ("fumarate salt form a") was obtained from a slurry of fumaric acid and compound 1(1:1 molar ratio) in ACN. The solid was isolated and characterized by XRPD, TGA and DSC. As shown by the XRPD pattern in fig. 1, fumarate salt form a is crystalline and has a different pattern than fumaric acid. The XRPD pattern of crystalline compound 1 fumarate salt form a is depicted in fig. 1, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in fig. 2, the sample had a weight loss of 0.7% before 80 ℃, followed by a continuous weight loss and an endothermic peak at 107.2 ℃ (peak temperature).
Compound 1 fumarate salt form B
Compound 1 fumarate salt form B ("fumarate salt form B") was obtained from a slurry of fumaric acid and compound 1(1:1 molar ratio) in acetone. The solid was isolated and characterized by XRPD, TGA and DSC. As shown by the XRPD pattern in fig. 3, fumarate salt form B is crystalline and has a different pattern than fumaric acid. The XRPD pattern of crystalline compound 1 fumarate salt form B is depicted in fig. 3, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in fig. 4, fumarate salt form B had a weight loss of 1.2% before 90 ℃, followed by a continuous weight loss, and an endothermic peak at 104.1 ℃ (peak temperature).
Compound 1 fumarate salt form C
Compound 1 fumarate salt form C ("fumarate salt form C") was obtained from a slurry of fumaric acid and compound 1(1:1 molar ratio) in EtOAc. The solid was isolated and characterized by XRPD, TGA and DSC. As shown by the XRPD pattern in fig. 5, fumarate salt form C is crystalline and has a different pattern than fumaric acid. The XRPD pattern of crystalline compound 1 fumarate salt form C is depicted in fig. 5, and the corresponding data is summarized below:
as shown by the TGA curve in fig. 6, fumarate salt form C showed a gradual weight loss of 3.4% before 94 ℃ and a weight loss of 2.0% between 94 ℃ and 150 ℃, followed by a continuous weight loss. Two endothermic peaks at 65.9 ℃ and 108.8 ℃ (peak temperatures) were observed in the DSC curve shown in fig. 6.
Compound 1 adipate form A
Compound 1 adipate form a ("adipate form a") was observed from a slurry of adipic acid and compound 1(1:1 molar ratio) in 1, 4-dioxane. The solid was isolated and characterized by XRPD, TGA and DSC. As shown by the XRPD results in fig. 7, adipate form a is crystalline and has a different pattern than adipic acid. The XRPD pattern of crystalline compound 1 adipate form a is depicted in fig. 7, and the corresponding data are summarized below:
as shown by the TGA and DSC curves in figure 8, adipate form a had a weight loss of 0.5% before 68 ℃, followed by a continuous weight loss and two endothermic peaks at 84.6 ℃ and 99.9 ℃ (peak temperatures).
Compound 1 succinate salt form A (i.e., Compound 2 form A)
Compound 1 succinate form a (i.e., compound 2 form a, "succinate form a") was observed from a slurry of succinic acid and compound 1(1:1 molar ratio) in acetone. At 4 ℃, the solid was isolated and characterized by XRPD, TGA and DSC. As shown by the XRPD results in fig. 9, succinate form a is crystalline and has a different pattern than succinic acid. The XRPD patterns of crystalline compound 1 succinate form a, compound 2 form a, are depicted in fig. 9 and 10, and the corresponding data are summarized below:
as shown by the TGA and DSC curves in fig. 11, succinate form a had a weight loss of 0.4% before 70 ℃, followed by a continuous weight loss and an endothermic peak at 87.6 ℃ (peak temperature).
As shown by TGA and DSC curves in fig. 12, succinate form a exhibited a 5.1% weight loss upon reaching 100 ℃ and an endothermic peak at 84.0 ℃ (onset temperature) with subsequent decomposition.
The chemical stability of succinate form a was determined using HPLC-UV at 275nm and 254 nm.
As seen in table 9, succinate form a showed no significant chemical degradation after 42 days at temperatures below 40 ℃ and no significant chemical degradation after 42 days at 25 ℃/60% RH.
TABLE 9
Compound 1 maleate form A
Compound 1 maleate form a ("maleate form a") was observed from a slurry of maleic acid and compound 1(1:1 molar ratio) in EtOAc. At 4 ℃, the solid was isolated and characterized by XRPD and DSC. As shown by the XRPD pattern in fig. 13, maleate salt form a has a different pattern than maleic acid. The XRPD pattern of crystalline compound 1, maleate form a, is depicted in fig. 13, and the corresponding data are summarized below:
the DSC curve for maleate form a is provided in figure 14.
Example 4 evaluation of hygroscopicity of Compound 1 salt form
The hygroscopicity of five solid forms of the compound 1 salt (fumarate salt form a, fumarate salt form B, fumarate salt form C, adipate salt form a and succinate salt form a) was evaluated by DVS and XRPD analysis (against the solid after DVS). The results are shown in FIGS. 15-19. Based on current data, all five solid forms became deliquescent at high humidity (> 60% RH), yielding amorphous or gummy solids after DVS testing.
EXAMPLE 5 evaluation of Water solubility of Compound 1 salt form
Five solid forms of the compound 1 salt (fumarate salt form a, fumarate salt form B, fumarate salt form C, adipate salt form a and succinate salt form a) were evaluated for water solubility. For each of experiments 1 to 5 in table 10, about 100mg of the solid form was suspended in 1.5mL of water and the vial was shaken at room temperature for about 24 hours (25 r/min). Clear solutions were observed after shaking for three hours for all samples except experiment 3 (fumarate form C). After shaking for 24 hours at room temperature, the solution remained clear. The supernatant of experiment 3 was collected by filtration through a 0.45 μm membrane for HPLC analysis. For each of experiments 6 to 10 in table 10, about 40mg of the solid form was dissolved in 0.2mL (0.9 mL for experiment 7) of water and then analyzed by HPLC after 24 hours of storage at room temperature. As shown in table 10 below, fumarate salt form a, fumarate salt form B, adipate salt form a, and succinate salt form a indicated relatively higher solubility in water (>100mg FB/mL), while fumarate salt form C showed lower solubility than the other forms (about 25-50mg FB/mL).
Watch 10
*The nature of the residual solids is unknown due to the scarcity of the sample
**Clear colloidal solution without significant solid particles
Example 6 slurry conversion of certain Compound 1 salt forms
Slurry conversions of fumarate salt forms A, B and C were carried out in three different solvents. The mixture of fumarate salt form A/B/C (1: 1:1 mass ratio) was stirred in ACN, acetone and EtOAc for about 4 days at room temperature. As shown by the results (table 11 and fig. 20), three fumarate salt forms were obtained in the respective solvents, indicating the solvation states of fumarate salt A, B and C.
TABLE 11
Example 7 recrystallization of adipate form A
Recrystallization of adipate salts was carried out in several solvent systems, with or without adipate salt form a seed crystals. A mixture of compound 1 and adipic acid (1:1 molar ratio) was stirred overnight at room temperature in the presence or absence of adipate form a. The residual solid was isolated for XRPD analysis. As shown in table 12 and figure 21, no new crystalline form was observed (adipate form a was labeled, while the remaining series were unlabeled, as no other forms were observed).
TABLE 12
N/A: after stirring overnight at room temperature, a clear solution was obtained
EXAMPLE 8 polymorphic form screening of Compound 2
Polymorphic screening of compound 2((S) - (5-cyclobutoxy-2-methyl-6- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) -3, 4-dihydroquinolin-1 (2H) -yl) (cyclopropyl) methanone succinate) was performed under at least 100 different conditions, including antisolvent addition, evaporation, slurry formation, solid/liquid vapor diffusion, rapid cooling, and trituration. A summary of the experiments performed is reported in table 13:
watch 13
A total of 22 anti-solvent addition experiments were performed. About 20mg of compound 2 form a was dissolved in 0.1-0.3mL of solvent to give a clear solution and the solution was stirred magnetically, followed by addition of anti-solvent until precipitation occurred or the total amount of anti-solvent reached 15.0 mL. The precipitate was isolated and analyzed by XRPD. The clear solution was stirred at 5 ℃ for 4 days, then the solids were tested by XRPD. The final clear solution was allowed to evaporate at ambient conditions. The results are summarized in table 14:
TABLE 14
N/A: after cooling at 5 ℃ and subsequent evaporation at ambient conditions, no solid was obtained.
*: after storage overnight at ambient conditions, the amorphous sample was converted to form G.
**: the clear solution was evaporated at ambient conditions to obtain a solid.
The slow evaporation experiments were performed under 13 conditions. Generally, about 20mg of compound 2 form a is dissolved in 0.5 or 1.0mL of the corresponding solvent in a 2mL glass vial. The resulting visually clear solution was subjected to slow evaporation under ambient conditions to induce precipitation. The solids were isolated for XRPD analysis and the results are summarized in table 15:
watch 15
N/A: after evaporation at ambient conditions, no solid was obtained.
The rapid cooling experiment was performed in a 12 solvent system. Approximately 20mg of compound 2 form a was suspended in 1.0mL of solvent in a 2mL glass vial at room temperature. The suspension was then heated to 50 ℃, equilibrated for 2 hours and filtered into a new vial using a nylon membrane (0.45 μm pore size). The filtrate was cooled from 50 ℃ to 5 ℃ and stored at 5 ℃ without stirring. The solid obtained was kept isothermally at 5 ℃ and subsequently isolated for XRPD analysis. The clear solution was evaporated to dryness at ambient conditions, followed by testing of the solid by XRPD. The results are summarized in table 16:
TABLE 16
N/A: after evaporation at ambient conditions, no solid was obtained.
*: the solution was clarified by evaporation to obtain a solid.
Slurry conversion experiments were performed in 12 different solvent systems at room temperature. In each 2mL glass vial, about 20mg of compound 2 form a was suspended in 0.3mL of solvent. After stirring the suspension at room temperature for 6 days, the residual solid was isolated for XRPD analysis. The results are summarized in table 17:
TABLE 17
Additionally, slurry conversion experiments were performed in 12 different solvent systems at 50 ℃. In each 2mL glass vial, about 20mg of compound 2 form a was suspended in 0.3mL of solvent. After stirring the suspension at 50 ℃ for 6 days, the residual solid was isolated for XRPD analysis. The results are summarized in table 18:
watch 18
Solid vapor diffusion experiments were performed using 13 different solvents. Approximately 15mg of compound 2 form a was weighed into a 4mL vial and placed into a 20mL vial containing 3mL of volatile solvent. The 20mL vial was sealed with a cap and kept at room temperature for 6 days to allow the solvent vapor to interact with the sample. The solids were tested by XRPD. The results are summarized in table 19:
watch 19
N/A: after evaporation at ambient conditions, no solid was obtained.
Fourteen solution vapor diffusion experiments were performed. In a 4mL vial, about 20mg of compound 2 form a was dissolved in 0.5mL of the appropriate solvent to give a clear solution. This solution was then placed in a 20mL vial containing 3mL of volatile solvent. The 20mL vial was sealed with a cap and held at room temperature for a time sufficient for the organic vapor to interact with the solution. The precipitate was isolated and analyzed by XRPD. The results are summarized in table 20:
watch 20
N/A: no solid was obtained.
*: the DSC curve showed two endothermic peaks at 83.3 ℃ and 114.1 ℃ (peak temperature) followed by decomposition.
The milling experiments were performed in both the presence and absence of additives. About 15mg of compound 2 form a was weighed into a mortar and then manually ground using a pestle for about 5 minutes. The solids were analyzed by XRPD and the results are summarized in table 21:
TABLE 21
N/A: no additives were added.
After comparing XRPD patterns, eleven new forms were observed and characterized by TGA and DSC. The specific characterization results are summarized in fig. 22, fig. 23 and table 22.
TABLE 22
Example 9 characterization of solid form of Compound 2
Compound 2 form A
Compound 2 form a (i.e., compound 1 succinate form a) was prepared and characterized as described above in example 3.
Compound 2 form B
As reported above, compound 2 form B was prepared by anti-solvent addition, slurry formation at room temperature or at 50 ℃, or by solution vapor diffusion.
An X-ray powder diffraction pattern of crystalline compound 2 form B is depicted in fig. 24, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 25, form B exhibited a 2.8% weight loss up to 110 ℃ and two endothermic peaks at 102.8 ℃ and 121.9 ℃ (peak temperatures) with subsequent decomposition.
DVS analysis of form B is reported in figure 26. Form B is highly hygroscopic and has greater absorption up to 80% RH. Form B becomes amorphous after DVS testing.
Compound 2 form C
Compound 2 form C was prepared by anti-solvent addition, rapid cooling or solid vapor diffusion as reported above.
An X-ray powder diffraction pattern of crystalline compound 2 form C is depicted in fig. 27, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 28, form C showed a weight loss of 6.2% upon reaching 100 ℃ and an endothermic peak at 59.2 ℃ (onset temperature) with subsequent decomposition.
Compound 2 form D
Compound 2 form D was prepared by anti-solvent addition, rapid cooling or solid vapor diffusion as reported above.
An X-ray powder diffraction pattern of crystalline compound 2 form D is depicted in fig. 29, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 30, form D shows a weight loss of 6.18% upon reaching 100 ℃ and an endothermic peak at 89.5 ℃ (onset temperature) with subsequent decomposition.
Compound 2 form E
Compound 2 form E was prepared by solid vapor diffusion as reported above.
An X-ray powder diffraction pattern of crystalline compound 2 form E is depicted in fig. 31, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 32, form E exhibited a weight loss of 2.5% upon reaching 70 ℃ and an endothermic peak at 76.5 ℃ (onset temperature) with subsequent decomposition.
Compound 2 form F
Compound 2 form F was prepared by slow evaporation as reported above.
An X-ray powder diffraction pattern of crystalline compound 2 form F is depicted in fig. 33, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 34, form F showed a weight loss of 3.9% upon reaching 100 ℃ and an endothermic peak at 74.6 ℃ (onset temperature) with subsequent decomposition.
Compound 2 form G
Compound 2 form G is prepared by at least the following method:
method a. about 20mg of compound 2 form a was suspended in 0.3mL of solvent. The suspension was stirred at room temperature for 6 days. Subsequently, the solid was isolated and analyzed by XRPD. Exemplary solvents that yield form G include IPAc, MTBE, and CHCl3/MTBE(1:9)。
Method b. about 20mg of compound 2 form a was suspended in 0.3mL of solvent. The suspension was stirred at 50 ℃ for 6 days. Subsequently, the solid was isolated and analyzed by XRPD. Exemplary solvents that yield form G include IPAc, MTBE, MIBK, and CHCl3/MTBE(1:9)。
The method C comprises the following steps: about 500g of compound 2 form a was added to a reaction vessel containing about 9980mL (20:1 molar ratio) of isopropyl acetate. The suspension was heated to 50 ℃ and stirred for 18 hours. The temperature was raised to 70 ℃ and the solvent was distilled until the final volume of the suspension was about 5L (about 10:1 molar ratio). The mixture was cooled to room temperature over 1 hour or more. The mixture was then stirred for about 14 hours. The suspension was then filtered under vacuum and washed with isopropyl acetate and dried under vacuum to give compound 2, form G.
The method D comprises the following steps: approximately 20mg of compound 2 form a was dissolved in 0.1-0.3mL of solvent to give a clear solution. The solution was magnetically stirred, followed by addition of anti-solvent until precipitation occurred or the total solvent volume reached 15.0 mL. The solid was isolated and stored overnight at ambient conditions.
Further, according to the illustration in fig. 55, forms B, I and O may be converted to form G. In particular, form G can be obtained according to method a using either form B, I or O in place of form a.
An X-ray powder diffraction pattern of crystalline compound 2 form G is depicted in fig. 35, and the corresponding data is summarized below:
the moisture absorption/desorption characteristics of compound 2 form G are depicted in figure 37. The results of the DVS test indicate that compound 2 form G absorbs only 0.76% water by weight at less than 70% Relative Humidity (RH) and about 25.19% (wt/wt) water at over 70% RH. Referring to the DVS isotherm plot in fig. 37, the lower curve corresponds to the sorption of the sample of compound 2 form G caused by increasing relative humidity, and the upper curve corresponds to the desorption of the sample of compound 2 form G caused by decreasing relative humidity. As shown, the results of the DVS test indicate that compound 2 form G absorbed only 0.76% water by weight at less than 70% Relative Humidity (RH), and about 25.19% (wt/wt) water at over 70% RH.
Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) thermograms are shown in figure 36. An initial weight loss of 0.2% from the initial temperature to 150 ℃ was observed in the TGA thermogram, and subsequently decomposed. The DSC thermogram exhibited an endothermic peak at about 127 ℃ (onset temperature).
Form G showed no significant change in physical form after 42 days, as determined by XRPD, PLM or DSC/TGA under storage conditions below 75% RH (table 23). Stability samples stored at ambient conditions for 42 days, at 25 ℃/75% RH for 42 days, and at 50 ℃ for 21 days showed good flow characteristics as assessed by visual inspection.
Polarization microscopy (PLM) is shown in FIG. 38 and shows that Compound 2 form G is composed of rectangular sheets with 1-50 μm birefringence irregularities.
Compound 2 form G was tested for stability over 42 days under different conditions and is reported in table 23 below and in figure 61:
TABLE 23
It can be seen that the stability samples experienced a temperature excursion at 50 ℃. On day 38, the stability samples at 50 ℃ were exposed to a temperature of about 85 ℃ for 24 hours. However, even with increasing pressure against this sample, these samples appear to be physically stable and there is no significant change in XRPD, DSC/TGA or PLM. The 50 ℃ samples showed a slight decrease in flowability after exposure to higher temperatures as assessed by visual inspection.
To test the solubility of forms a and G, form a was dissolved in acetone to give a saturated solution, then 0.4mg of form G was added to 0.6mL of the saturated solution, and a solid was still observed after vibration and sonication. The suspension was heated to 50 ℃ until the solids were mostly dissolved, then the solution was kept in a cold room (5 ℃) for about 1 hour and the precipitated solids were analyzed by XRPD. The results shown in figure 60 show that most of the peaks are from form a and only two peaks belong to form G.
Form G was chemically stable as determined by HPLC-UV at 275nm and 254 nm.
As seen in table 9 (reported above under compound 2 form a), form G did not show significant chemical degradation after 42 days at temperatures below 40 ℃.
All stability samples showed 95-107% of the target expected compound 2 content, determined by HPLC-UV analysis at 275 nm. Stability samples showed no decrease in purity and no significant increase in impurities at ambient conditions and 25 ℃/60% RH open storage for 42 days as determined by HPLC-UV analysis at 254 nm.
For reference purposes, compound 2 form a was also evaluated for chemical stability at 25 ℃/60% RH for 42 days, and HPLC-UV showed no significant chemical degradation.
Compound 2 form I
Compound 2 form I was prepared by forming a slurry at 50 ℃ in a chamber as reported above.
An X-ray powder diffraction pattern of crystalline compound 2 form I is depicted in fig. 39, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 40, form I shows a 1.4% weight loss upon reaching 100 ℃ and an endothermic peak at 126.8 ℃ (onset temperature) with subsequent decomposition.
DVS analysis of form I is reported in figure 41. DVS analysis showed that form I exhibited minimal weight change before 60% RH, while higher absorption was observed up to 80% RH, indicating that form I is highly hygroscopic. After DVS, form I becomes amorphous.
Compound 2 form J
Compound 2 form J was prepared by slurry formation at 50 ℃ or by solution vapor diffusion, as reported above.
An X-ray powder diffraction pattern of crystalline compound 2 form J is depicted in fig. 42, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 43, form J exhibited a 2.3% weight loss upon reaching 100 ℃ and exhibited one endothermic peak at 57.9 ℃ (peak temperature) and another endothermic peak at 84.1 ℃ (peak temperature) with subsequent decomposition.
Compound 2 form K
Compound 2 form K was prepared by rapid cooling as reported above.
An X-ray powder diffraction pattern of crystalline compound 2 form K is depicted in fig. 44, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 45, form K exhibited a weight loss of 4.7% upon reaching 110 ℃ and an endothermic peak at 121.1 ℃ (onset temperature) with subsequent decomposition.
Compound 2 form L
As reported above, compound 2 form L was prepared at least by forming a slurry at room temperature.
An X-ray powder diffraction pattern of crystalline compound 2 form L is depicted in fig. 46, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 47, form L shows a 5.9% weight loss upon reaching 100 ℃ and three endothermic peaks at 74.4 ℃, 80.8 ℃ and 87.5 ℃ (peak temperatures) with subsequent decomposition.
Compound 2 form M
Compound 2 form M was prepared by evaporation of a rapidly cooled solution of Compound 2 form A in EtOH/EtOAc (1:4 v/v).
An X-ray powder diffraction pattern of crystalline compound 2 form M is depicted in fig. 48, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 49, form M showed a weight loss of 0.2% before 80 ℃ and an endothermic peak at 90.4 ℃ (onset temperature) with subsequent decomposition.
DVS analysis of form M is reported in figure 50. Form M is highly hygroscopic and has greater absorption up to 80% RH. Form M becomes amorphous after DVS testing.
Compound 2 form O
Compound 2 form O was prepared by slurrying compound 2 form a in IPAc at 50 ℃.
An X-ray powder diffraction pattern of crystalline compound 2 form O is depicted in fig. 51, and the corresponding data is summarized below:
as shown by the TGA and DSC curves in figure 52, form O showed a weight loss of 0.2% before 120 ℃ and an endothermic peak at 128.2 ℃ (onset temperature) with subsequent decomposition.
DVS analysis of form O is reported in figure 53. Form O is highly hygroscopic and has greater absorption up to 80% RH. Form O becomes amorphous after DVS testing.
Compound 2 form P
Compound 2 form P was prepared by slurrying compound 2 form a in IPAc at 50 ℃.
An X-ray powder diffraction pattern of crystalline compound 2 form P is depicted in fig. 54, and the corresponding data is summarized below:
example 10 evaluation of stability between Compound 2 form G and Compound 2 form O
Slurry competition experiments between two anhydrates, form G and form O, were performed in two solvents, IPAc and MTBE, at room temperature and 50 ℃ to evaluate stability. Form O was dissolved in IPAc and MTBE, respectively, to give a saturated solution. Next, form G and form O of similar mass were added to a 2mL vial, after which the corresponding saturated solution was added to give a slurry, which was stirred at room temperature or 50 ℃ for 24 hours. The collected solids were analyzed by XRPD to determine the change in form.
As summarized in table 24 and fig. 56, the solids in the slurry were completely converted to form G.
Watch 24
Example 11 stability evaluation between Compound 2 form B, Compound 2 form I and Compound 2 form G
To further investigate the formal properties of form B and form I, slurry conversion experiments were performed in two solvents with the addition of form G. Form B was dissolved in IPAc and MTBE, respectively, to give a saturated solution. Form B, G and I were weighed in similar amounts by mass into a 2mL vial, after which the corresponding saturated solution was added to give a slurry which was stirred at room temperature or 50 ℃. After 24 hours of slurry formation, the obtained solid was analyzed by XRPD.
As summarized in table 25 and fig. 57, the slurry starting from the mixture of forms B, G and I was completely converted to form G.
TABLE 25
wExample 12 Critical a between Compound 2 form G and Compound 2 form IAuthentication
To investigate the criticality a between hydrated form I and the stable anhydrate, form GwAt room temperature and 50 ℃ in the presence of a catalyst having a difference ofwCo-solvent system (H)2O/IPAc) for slurry conversion of form I and form G. Form G and form I of similar mass were added to a 2mL vial followed by addition of solvent and stirring at room temperature or 50 ℃ for 24 hours. The solid obtained by XRPD analysis varied in a defined manner.
As summarized in table 26 and fig. 58 and 59, at room temperature, most of the mixture starting in the slurry was completely converted to form G, but from awA cosolvent of 0.8 gave a sample which was close to amorphous material except.
Watch 26
Example 13 solubility estimation of Compound 2 form G, Compound 2 form O and Compound 2 form I
The two potential anhydrates, forms G and O, and hydrated form I, were tested for water solubility at room temperature. Approximately 3mg of each form was weighed into a 2mL vial. Add 50. mu.L of water and stir well at room temperature at 800 RPM. After stirring for 2 hours, a clear solution was obtained indicating that all three forms showed high solubility (>60mg/mL) in water at room temperature (table 27).
Watch 27
These forms were evaluated using basic techniques. Current transformation data show that form G is the most stable form of IPAc and MTBE at room temperature or 50 ℃. At a different point awIn contrast to form G, hydrate form I does not appear to have any stability under ambient conditions.
Both the anhydrates, form G and form O, as well as form I, showed high solubility (>60mg/mL) in water.
The five forms (form B, form G, form I, form O and form M) show high hygroscopicity and become amorphous after DVS testing.
EXAMPLE 14 polymorphic form screening of Compound 1
Polymorph screening was performed under 28 conditions using compound 1 as the starting material. Four methods were used, including slurry formation, evaporation, anti-solvent addition and solid vapor diffusion, and no crystalline form was found by screening.
Slurry experiments were performed at 4 ℃, room temperature and 50 ℃ in different solvent systems. For each experiment, approximately 100mg of compound 1 was suspended in 0.4-1.0mL of solvent in a 1.5mL glass vial. Next, the suspension was kept under stirring for about one week at the specified temperature, and then the residual solid was collected for XRPD analysis. As summarized in table 28, no crystalline form was observed.
Watch 28
*Under stirring, a clear solution was obtained at 4 ℃ and evaporated at room temperature to give a solid
The evaporation experiments were performed under nine conditions. For each experiment, approximately 20mg of compound 1 was dissolved in approximately 1.5mL of solvent in a 1.8mL glass vial. The resulting clear solution was then subjected to slow evaporation at room temperature to induce precipitation. If solids are observed, the solids are isolated for XRPD analysis. The results are summarized in Table 29. No crystalline form was found.
Watch 29
A total of six anti-solvent addition experiments were performed. Approximately 20mg of compound 1 was dissolved in 0.1-0.3mL of solvent to give an approximately saturated solution. Next, 0.5-5.0mL of antisolvent was added to induce precipitation. After stirring the resulting suspension overnight, the precipitate was isolated for XRPD analysis. The results summarized in table 30 indicate that no crystalline form is observed.
Watch 30
For the solid vapor diffusion experiment, approximately 30mg of compound 1 was weighed into a 3mL vial, which was then placed into a 20mL vial containing 4mL of water. The 20mL vial was sealed and held at room temperature for about two weeks, providing sufficient time for the water vapor to interact with the solid sample. The solid thus obtained was isolated for XRPD testing. No crystalline form was observed.