Crystal forms of SHP2 inhibitors

Abstract

The present invention relates to a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1). The present invention also relates to pharmaceutical compositions comprising this crystalline form, and methods of using the crystalline form and such compositions to treat abnormal cell growth, such as cancer, in a mammal. [Figure 1] TIFF2024513798000011.tif116151

Description

[Technical field]

[0001] The present invention relates to the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1), pharmaceutical compositions containing Form 1, and methods of using Form 1 and such compositions in the treatment of abnormal cell growth, such as cancer, in mammals, particularly humans. [Background technology]

[0002] The compound (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine has the formula (I):

[0003] [ka] It is an SHP2 inhibitor having the following structure:

[0004] The preparation of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine is disclosed in International Patent Publication WO2020 / 201991 (International Application No. PCT / IB2020 / 053019 published October 8, 2020), the contents of which are incorporated herein by reference in their entirety. Summary of the Invention [Problem to be solved by the invention]

[0005] The present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) that has desirable properties such as high crystallinity, high purity and stability. [Means for solving the problem]

[0006] Each of the following embodiments may be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined.

[0007] In one aspect, the present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1). The hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) is characterized by powder X-ray diffraction (PXRD) (2θ).

[0008] In another aspect, the invention provides a method for producing a compound comprising: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 1 at °2θ ± 0.2 °2θ; (b) one, two, three, or four peaks selected from the group consisting of the peaks in Table 1 at °2θ ± 0.2 °2θ; (c) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 2 at °2θ ± 0.2 °2θ; (d) a peak in Table 2 at °2θ ± 0.2 °2θ. or (e) one, two, three or four peaks selected from the group consisting of:

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising the hemihydrate crystalline form (Form 1) of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base according to any of the embodiments and at least one pharma- ceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises two or more pharma- ceutically acceptable excipients.

[0010] In another aspect, the invention provides a method of treating abnormal cell growth in a mammal, including a human, comprising administering to the mammal a therapeutically effective amount of the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the aspects or embodiments described herein.

[0011] In another aspect, the invention provides use of the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1), or a pharmaceutical composition comprising the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the aspects or embodiments described herein, in a method of treating abnormal cell growth in a mammal.

[0012] In yet another aspect, the present invention provides the use of the hemihydrate crystalline form (Form 1) of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base according to any of the aspects or embodiments described herein in the manufacture of a medicament for treating abnormal cell growth in a mammal.

[0013] In another aspect, the invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the aspects or embodiments described herein for use in a method of treating abnormal cell growth in a mammal.

[0014] In many embodiments, the abnormal cell growth is cancer, hi one embodiment, the abnormal cell growth is a SHP2-mediated cancer. [Brief description of the drawings]

[0015] [Figure 1]FIG. 1 is a PXRD pattern for the hemihydrate crystalline form of (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-amine free base (Form 1). [Diagram 2] FIG. 13C ssNMR spectrum of the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1). [Diagram 3] FIG. 1 is a PXRD pattern for the hemihydrate crystalline form of (S)-1′-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4′-piperidine]-1-amine free base (Form 1). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention may be more readily understood by reference to the following detailed description of the preferred embodiments of the present invention and examples contained herein. It should be understood that the terminology used herein is only intended to describe specific embodiments and is not intended to be limiting. Furthermore, it should be understood that unless specifically defined herein, the terminology used herein may be given its conventional meaning known in the relevant field. In the event that one or more of the cited literature and similar materials, including but not limited to defined terms, terminology usage, described techniques, etc., are different from or inconsistent with this application, this application shall take precedence.

[0017] definition As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" substituent includes one or more substituents.

[0018] The term "about" means having a value that falls within an acceptable standard error of the mean, as determined by one of ordinary skill in the art.

[0019] As used herein, the term "essentially the same" means that typical variability for a particular method is taken into account. For example, with respect to X-ray diffraction peak positions, the term "essentially the same" means that typical variability in peak positions and intensities is taken into account. Those skilled in the art will recognize that peak positions (2θ) will typically exhibit some variability, such as ±0.2°. Furthermore, those skilled in the art will recognize that relative peak intensities exhibit instrument-to-instrument variability, as well as variability due to the degree of crystallinity, preferred orientation, sample surface prepared, and other factors known to those skilled in the art, and should be taken merely as a qualitative measure.

[0020] The term "crystalline" as used herein means having a regularly repeating arrangement of molecules or external face planes. Crystal forms can differ with respect to thermodynamic stability, physical parameters, X-ray structure and preparation process.

[0021] The term "hemihydrate" refers to a hydrate in which there are two molecules of a compound, in this case (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base, for each molecule of water.

[0022] The term "substantially pure" means that a particular crystalline form contains less than 10% by weight, preferably less than 5% by weight, preferably less than 3% by weight, preferably less than 1% by weight of any other physical form of the compound.

[0023] Crystalline (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) In one embodiment, the present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1). The crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) is a hemihydrate. The methods described herein provide a hemihydrate crystalline (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) that is substantially pure and free of other forms. In another embodiment, the present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) that is substantially pure and free of other forms. In one embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) is greater than 95% substantially pure. In one embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) is greater than 97% substantially pure. In one embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) is greater than 99% substantially pure.

[0024] The hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base of the present invention (Form 1) has a PXRD pattern that includes (1) characteristic peaks at 2θ values ​​of 10.9, 14.0, 15.4, and 16.0 °2θ ± 0.2 °2θ; or (2) resonance (ppm) values ​​of 44.4, 47.7, 149.2, and 36.6 ppm ± 0.2 ppm. 13 C ssNMR spectrum; or (3) 607, 1462, 1051 and 1573 cm -1 ±0.2cm -1 Wave number (cm -1 The hemihydrate crystalline form of the present invention is also characterized by an FT-Raman spectrum that includes: (1) a PXRD pattern that includes characteristic peaks at 2θ values ​​of 10.9, 14.0, 15.4, and 16.0±0.2 degrees 2θ; (2) a PXRD pattern that includes resonance (ppm) values ​​of 44.4, 47.7, 149.2, and 36.6±0.2 ppm. 13 C ssNMR spectrum; or (3) 607, 1462, 1051 and 1573 ± 0.2 cm -1 Wave number (cm -1 The present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1), characterized by two of the FT-Raman spectra including: (1) a PXRD pattern including characteristic peaks at 2θ values ​​of 10.9, 14.0, 15.4, and 16.0±0.2 degrees 2θ; and (2) a PXRD pattern including resonance (ppm) values ​​of 44.4, 47.7, 149.2, and 36.6±0.2 ppm. 13 C ssNMR spectrum; and (3) 607, 1462, 1051 and 1573 ± 0.2 cm -1 Wave number (cm -1In one embodiment, there is provided a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1), characterized by an FT-Raman spectrum including N,N-dimethylformamide (N=1, N=2) values.

[0025] In yet a further embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 10.9±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 16.0±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 14.0±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 15.4±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 15.5±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 25.1±0.2 degrees 2θ.In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 20.5±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including a peak at a 2θ value of 29.5±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9 and 16.0±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9 and 14.0±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9 and 15.4±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 16.0 and 14.0±0.2 degrees 2θ.In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 16.0 and 15.4±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 14.0 and 15.4±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9, 16.0, and 14.0±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9, 16.0, and 15.4±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 16.0, 14.0, and 15.4±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9, 16.0, and 15.4±0.2 degrees 2θ.In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern comprising peaks at 2θ values ​​of 10.9, 16.0, 14.0, and 15.4±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9, 16.0, 14.0, 15.4, and 15.5±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9, 16.0, 14.0, 15.4, 15.5, and 25.1±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9, 16.0, 14.0, 15.4, 15.5, 25.1, and 20.5±0.2 degrees 2θ. In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a PXRD pattern including peaks at 2θ values ​​of 10.9, 16.0, 14.0, 15.4, 15.5, 25.1, 20.5, and 29.5±0.2 degrees 2θ.

[0026] In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has (a) 1, 2, 3, 4, 5, or more than 5 peaks selected from the group consisting of the peaks in Table 1 at °2θ ± 0.2 °2θ; (b) 1, 2, 3, 4, 5, or more than 5 peaks selected from the group consisting of the peaks in Table 1 at °2θ ± 0.2 °2θ (c) one, two, three, or four peaks selected from the group consisting of peaks in Table 2 at °2θ ± 0.2 °2θ; (d) one, two, three, or four peaks selected from the group consisting of peaks in Table 2 at °2θ ± 0.2 °2θ; or (e) a PXRD pattern (2θ) including peaks at essentially the same 2θ values ​​as shown in Figure 1.

[0027] In yet a further embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) comprises a resonance (ppm) value of 44.4±0.2 ppm. 13 In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) comprises a resonance (ppm) value of 47.7±0.2 ppm. 13 In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) comprises a resonance (ppm) value of 149.2±0.2 ppm. 13In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) comprises a resonance (ppm) value of 36.6±0.2 ppm. 13 In a further embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) comprises a resonance (ppm) value of 26.9±0.2 ppm. 13 It has a C ssNMR spectrum.

[0028] In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) contains: (a) 1, 2, 3, 4, 5, or more than 5 resonance values ​​selected from the group consisting of the values ​​in Table 3 at ppm ± 0.2 ppm; (b) 1, 2, 3, or 4 resonance values ​​selected from the group consisting of the values ​​in Table 3 at ppm ± 0.2 ppm; (c) the resonance values ​​in Table 3 at ppm ± 0.2 ppm; or (d) essentially the same values ​​(ppm) as shown in FIG. 2. 13 It has a C ssNMR spectrum (ppm).

[0029] In still further embodiments, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has a viscosity of 607±0.2 cm -1 Wave number (cm -1In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has an FT-Raman spectrum with a Raman peak at 1462±0.2 cm -1 Wave number (cm -1 In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has an FT-Raman spectrum with a Raman peak at 1051 ± 0.2 cm -1 Wave number (cm -1 In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) has an FT-Raman spectrum with a Raman peak at 1573±0.2 cm -1 Wave number (cm -1 ) values.

[0030] In another embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) is -1 ±0.2cm -1 at 1, 2, 3, 4, 5 or more than 5 wavenumbers (cm -1 ) value;(b)cm -1 ±0.2cm -1 at one, two, three or four wavenumbers (cm -1 ) value;(c)cm -1 ±0.2cm -1 In Table 4, the wave numbers (cm -1 ) value;(d)cm -1 ±0.2cm-1 In the above, one, two, three or four wave numbers (cm -1 ) values; or (d) essentially the same wavenumbers (cm) as shown in FIG. -1 FT-Raman spectrum including values ​​(cm -1 ).

[0031] In another embodiment, the present invention provides a pharmaceutical composition comprising the hemihydrate crystalline form (Form 1) of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base according to any of the embodiments described herein and at least one pharma- ceutically acceptable excipient.

[0032] Typical formulation or composition is prepared by mixing compound and excipient as described herein.Suitable excipient is well known to those skilled in the art and is described in detail in, for example, Ansel, Howard C. et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004;Gennaro, Alfonso R. et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005, the disclosure of which is incorporated herein by reference.

[0033] "Pharmaceutical composition" as used herein means the hemihydrate crystalline form (Form 1) of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base according to any of the embodiments described herein as an active ingredient, and at least one pharma-ceutically acceptable excipient.

[0034] As used herein, "pharmaceutically acceptable carrier" means a carrier or diluent that does not cause significant irritation to the living body and does not eliminate the biological activity and properties of the compound being administered.

[0035] Administration of the pharmaceutical composition may be affected by any method that allows delivery of the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, and rectal administration.

[0036] The pharmaceutical compositions may be in a form suitable for example for oral administration as tablets, capsules, pills, powders, sustained release formulations, or solution suspensions; for parenteral injection as sterile solutions, suspensions, or emulsions; for topical administration as ointments or creams; or for rectal administration as suppositories.

[0037] In another embodiment, the present invention provides a method of treating abnormal cell growth in a mammal, preferably a human, comprising administering to the mammal a therapeutically effective amount of the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the embodiments described herein.

[0038] In another embodiment, the present invention provides a method of treating abnormal cell growth in a mammal, preferably a human, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition comprising the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the embodiments described herein.

[0039] In another embodiment, the present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the embodiments described herein for use in the treatment of abnormal cell growth in a mammal, preferably a human.

[0040] In another embodiment, the present invention provides the use of the hemihydrate crystalline form (Form 1) of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base according to any of the embodiments described herein, in the treatment of abnormal cell growth in a mammal, preferably a human.

[0041] In another embodiment, the present invention provides the use of the hemihydrate crystalline form (Form 1) of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base according to any of the embodiments described herein in the manufacture of a medicament for use in the treatment of abnormal cell growth in a mammal, preferably a human.

[0042] In another embodiment, the present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the aspects or embodiments described herein for use in therapy.

[0043] In another embodiment, the present invention provides a hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) according to any of the aspects or embodiments described herein for use in a method of treating abnormal cell growth in a mammal.

[0044] In many embodiments of the methods provided herein, the abnormal cell proliferation is cancer. As used herein, "cancer" refers to a physiological condition in a mammal that is typically characterized by abnormal or uncontrolled cell proliferation. Cancer includes solid tumors, named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancers that originate from a specific site in the body, metastatic cancers that have spread from where they began to other parts of the body, recurrences from the original primary cancer after remission, and second primary cancers, which are new primary cancers in people with a history of a previous cancer of a different type from the one that followed.

[0045] In some embodiments, the methods provided result in one or more of the following effects: (1) inhibition of cancer cell proliferation; (2) inhibition of cancer cell invasiveness; (3) induction of apoptosis in cancer cells; (4) inhibition of cancer cell metastasis; or (5) inhibition of angiogenesis.

[0046] As used herein, "ameliorating" refers to the reduction or improvement of one or more symptoms upon treatment with a combination as described herein compared to when the combination is not administered. Ameliorating also includes a shortening or reduction in the duration of the symptoms.

[0047] As used herein, an "effective dosage" or "effective amount" of a drug, compound or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired symptoms, including biochemical, histological and / or behavioral symptoms of a disease, its complications and intermediate pathological phenotypes manifested during the development of the disease. In therapeutic applications, a "therapeutically effective amount" refers to an amount of a compound administered that will relieve to some extent one or more of the symptoms of the disorder being treated. In the context of treating cancer, a therapeutically effective amount refers to an amount that has the effect of (1) reducing the size of a tumor, (2) inhibiting (i.e., slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) reducing to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer, (5) reducing the dose of other drugs required to treat the disease, and / or (6) enhancing the effect of another drug, and / or (7) delaying the progression of the disease in a patient.

[0048] "Mammal" as used herein means a warm-blooded animal having or at risk of developing a disease as described herein, including, but not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

[0049] "Subject" as used herein means a human or animal subject. In one embodiment, the subject is a mammal. In a preferred embodiment, the subject is a human.

[0050] "Treat" or "treating" as used herein means administering a compound of formula (I) to a subject having a condition to be treated to achieve at least one positive therapeutic effect. For example, treating cancer means administering a compound of formula (I) to a subject having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, reducing the number of cancer cells, reducing tumor size, reducing the rate of cancer cell invasion into surrounding organs, or reducing the rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting, or preventing the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein means the act of treating as defined immediately above for "treating", unless otherwise indicated. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject.

[0051] In some embodiments, the treatment achieved by the compound of formula (I) is defined by reference to any of partial response (PR), complete response (CR), overall response (OR), progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). PFS, also referred to as "time to tumor progression", refers to the length of time during and after treatment that the cancer is not growing, including the amount of time the patient experiences CR or PR, as well as the amount of time the patient experiences stable disease (SD). DFS refers to the length of time during and after treatment that the patient remains disease-free. OS refers to the extension of life expectancy compared to naive or untreated subjects or patients. In some embodiments, the response to the combination of the present invention is any of PR, CR, PFS, DFS, OR or OS, as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response criteria.

[0052] In one embodiment, the abnormal cell proliferation disorder is cancer. In one embodiment, the cancer may be selected from melanoma, juvenile myelomonocytic leukemia, neuroblastoma, Philadelphia chromosome positive chronic myelogenous, Philadelphia chromosome positive acute lymphoblastic leukemia, acute myelogenous leukemia, myeloproliferative neoplasms (such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis), breast cancer, lung cancer, liver cancer, colorectal cancer, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, glioblastoma, anaplastic large cell lymphoma, thyroid cancer, and spizoid neoplasm. In one embodiment, the cancer is melanoma. In one embodiment, the cancer is juvenile myelomonocytic leukemia. In one embodiment, the cancer is neuroblastoma. In one embodiment, the cancer is Philadelphia chromosome positive chronic myelogenous. In one embodiment, the cancer is Philadelphia chromosome positive acute lymphoblastic leukemia. In one embodiment, the cancer is acute myelogenous leukemia. In one embodiment, the cancer is a myeloproliferative neoplasm, such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis. In one embodiment, the cancer is selected from the group consisting of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. In one embodiment, the cancer is polycythemia vera. In one embodiment, the cancer is essential thrombocythemia. In one embodiment, the cancer is primary myelofibrosis. In one embodiment, the cancer is breast cancer. In one embodiment, the cancer is lung cancer. In one embodiment, the cancer is liver cancer. In one embodiment, the cancer is colorectal cancer. In one embodiment, the cancer is esophageal cancer. In one embodiment, the cancer is gastric cancer. In one embodiment, the cancer is head and neck squamous cell carcinoma. In one embodiment, the cancer is glioblastoma. In one embodiment, the cancer is anaplastic large cell lymphoma. In one embodiment, the cancer is thyroid cancer. In one embodiment, the cancer is a spitzoid neoplasm. In one embodiment, the cancer is selected from the group consisting of NSCLC, colon cancer, esophageal cancer, rectal cancer, juvenile myelomonocytic leukemia ("JMML"), breast cancer, melanoma, and pancreatic cancer.

[0053] In one embodiment, the abnormal cell growth is a SHP2-mediated cancer.

[0054] In one embodiment, the abnormal cell growth is a cancer that can be treated with an SHP2 inhibitor. In a further embodiment, the abnormal cell growth is a cancer that responds to treatment with an SHP2 inhibitor.

[0055] In one embodiment, the abnormal cell growth comprises cells containing a mutation encoding a KRASG12C variant. See WO2019 / 051084.

[0056] In one embodiment, the abnormal cell proliferation is a disease or disorder involving cells with a mutation encoding an NF1 loss of function ("NF1LOF") variant. In one embodiment, the NF1 mutation is a loss of function mutation. In one embodiment, the disease or disorder is a tumor involving cells with an NF1 loss of function mutation. In one embodiment, the tumor is an NSCLC or melanoma tumor. In one embodiment, the disease is selected from neurofibromatosis type I, neurofibromatosis type II, schwannomatosis, and Watson syndrome.

[0057] In one embodiment, the abnormal cell proliferation is associated with a RAS pathway mutation in the subject's cells that renders the cells at least partially dependent on signaling flux through SHP2. In one embodiment, the RAS pathway mutation is a RAS mutation selected from KRAS mutation, NRAS mutation, SOS mutation, BRAF class III mutation, class I MEKl mutation, class II MEKl mutation, and F1 mutation. In one embodiment, the KRAS mutation is KRAS G12A Mutation, KRAS G12C Mutation, KRAS G12D Mutation, KRAS G12F Mutation, KRAS G12l Mutation, KRAS G12L Mutation, KRAS G12R Mutation, KRAS G12S Mutation, KRAS G12V Mutations, and KRAS G12Y In one embodiment, the KRAS mutation is selected from the KRAS G12A In one embodiment, the KRAS mutation is KRAS G12C In one embodiment, the KRAS mutation is KRAS G12DIn one embodiment, the KRAS mutation is KRAS G12F In one embodiment, the KRAS mutation is KRAS G12l In one embodiment, the KRAS mutation is KRAS G12L In one embodiment, the KRAS mutation is KRAS G12R In one embodiment, the KRAS mutation is KRAS G12S In one embodiment, the KRAS mutation is KRAS G12V In one embodiment, the KRAS mutation is KRAS G12Y In one embodiment, the BRAF class III mutation is selected from one or more of the following amino acid substitutions in human BRAF: D287H; P367R; V459L; G466V; G466E; G466A; S467L; G469E; N581S; N581I; D594N; D594G; D594A; D594H; F595L; G596D; G596R and A762E. In one embodiment, the MEKl class I mutation is selected from one or more of the following amino acid substitutions in human MEKl: D67N; P124L; P124S; and L177V. In one embodiment, the class II MEKl mutation is selected from one or more of the following amino acid substitutions in human MEKl: AE51-Q58; AF53-Q58; E203K; L177M; C121S; F53L; K57E; Q56P; and K57N.

[0058] In one embodiment, the abnormal cell growth is selected from the group consisting of ALK or ROS1 positive non-small cell lung cancer, B-type Raf proto-oncogene V600E mutated colorectal cancer, or RAS mutated, NF1 mutated or BRAF class 3 mutated solid tumor. In one embodiment, the abnormal cell growth is ALK positive non-small cell lung cancer. In one embodiment, the abnormal cell growth is ROS1 positive non-small cell lung cancer. In one embodiment, the abnormal cell growth is B-type Raf proto-oncogene V600E mutated colorectal cancer. In one embodiment, the abnormal cell growth is a RAS mutated solid tumor. In one embodiment, the abnormal cell growth is an NF1 mutated solid tumor. In one embodiment, the abnormal cell growth is a BRAF class 3 mutated solid tumor.

[0059] In one embodiment, the hemihydrate crystalline form of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base (Form 1) is used in combination with one or more additional pharmaceutical compounds. In one embodiment, the additional pharmaceutical compound is selected from the group consisting of lorlatinib, binimetinib, cetuximab, and encorafenib. In one embodiment, the additional pharmaceutical compound is lorlatinib. In one embodiment, the additional pharmaceutical compound is encorafenib and cetuximab. In one embodiment, the additional pharmaceutical compound is binimetinib. EXAMPLES

[0060] The examples and preparations provided below further describe and illustrate certain aspects and embodiments of the present invention. It should be understood that the scope of the following examples does not limit the scope of the present invention. Example 1

[0061] Amorphous (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (R)-N-((S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (20 mg, 0.037 mmol) was diluted with dioxane (1 mL) followed by the addition of HCl (92 μL, 0.37 mmol). After stirring for 30 minutes, the reaction was diluted with dichloromethane ("DCM") and saturated aqueous sodium bicarbonate. The mixture was stirred for 10 minutes before the layers were separated and the DCM was diluted with MgSO 4The material was dried over silica gel, filtered and concentrated. The material was purified eluting with 20% methanol / ethyl acetate to give amorphous (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine (15 mg, 0.034 mmol, 93% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.2 (s, 1H), 7.76 (d, 1H, J = 5.2 Hz), 7.2-7.35 (m, 4H), 6.15 (d, 1H, J = 5.2 Hz), 4.92 (br, 2H), 4.78 (br, 1H), 4.01 (s, 1H), 3.37 (m, 2H), 3.14 (d, 1H, J = 15.6 Hz), 2.78 (d, 1H, J = 15.6), 1.3-1.91 (m, 7H); m / z (esi / APCI) M + 1 = 440.1. Example 2

[0062] [ka] Crystalline (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base hemihydrate (Form 1) (S)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine dihydrochloride (3.89 Kg) and 3,6-dibromo-1,2,4-triazine (3.71 Kg) were reacted with triethylamine (6.45 Kg) in 1,4-dioxane (34.3 Kg) at about 20-30°C to give (S)-1'-(6-bromo-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine in situ. (S)-1'-(6-bromo-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine was reacted with sodium 2-amino-3-chloropyridine-4-thiolate (3.08 Kg) and the mixture was heated to about 70-75°C for about 12.5 hours to give (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine. The mixture was cooled to about 15-30°C. Celite® (1.95 Kg) was added to the reaction at about 15-30°C, stirred for about 1 hour, and the slurry was filtered and rinsed with 1,4-dioxane. A solvent exchange was performed to replace 1,4-dioxane with tetrahydrofuran. The crude (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine was purified by chromatography on silica gel (pretreated with isopropyl alcohol) using a mixture of dichloromethane, methanol, ethanol, n-hexane and triethylamine as eluents. After chromatography, the product was crystallized from methanol and water to obtain purified crystalline (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base hemihydrate (Form 1) (1.39 Kg).

[0063] Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Endeavor diffractometer equipped with a copper (Cu) radiation source. The divergence slit was set to 15 mm continuous illumination. Diffracted radiation was detected by a PSD-Lynx Eye detector with the detector PSD aperture set to 2.99 degrees. The X-ray tube voltage and amperage were set to 40 kV and 40 mA, respectively. Data was collected from Cu wavelengths (CuK) from 3.0 to 40.0 degrees 2-theta using a step width of 0.00998 degrees and a step time of 1.0 seconds. α = 1.5418 λ) on a theta-theta goniometer. The anti-scatter screen was set at a fixed distance of 3.0 mm. Samples were rotated at 15 / min during collection. Samples were prepared by placing them in a silicon low background sample holder and rotated during collection. Data was collected using Bruker DIFFRAC Plus software and analysis was performed with EVA diffract plus software. PXRD data files were not processed prior to peak search. Preliminary peak assignments were made using peaks selected at a threshold of 1 using the peak search algorithm in the EVA software. Adjustments were made manually to ensure validity; the output of the automatic assignment was visually confirmed and peak positions were adjusted to the peak maximum. Peaks with a relative intensity of 3% or greater were generally selected. Peaks that were not resolved or matched noise were typically not selected. The typical error associated with peak positions from PXRD as stated in the USP is a maximum of ± 0.2 ° 2θ (USP-941).

[0064] The PXRD pattern of Example 2, free base hemihydrate Form 1, is shown in Figure 1. The PXRD peak list and relative intensity data (2 theta°) for the compound of Example 2, free base hemihydrate Form 1 is provided in Table 1 below:

[0065] [Table 1]

[0066] The characteristic PXRD peak list and relative intensity data (2 theta°) for the compound of Example 2, free base hemihydrate Form 1, is provided in Table 2 below:

[0067] [Table 2]

[0068] Solid-state NMR ("ssNMR") analysis was performed using a Bruker-BioSpin Avance III 500 MHz ( 1 The measurements were performed on a cross-polarization magic angle spinning ("CPMAS") probe located within a 1 H frequency NMR spectrometer. The material was a 4 mm ZrO 2 The rotor was tightly packed. A magic angle spinning speed of 14.0 kHz was used. Spectra were collected at ambient temperature (uncontrolled temperature).

[0069] 13 C ssNMR spectra were collected using a proton decoupled CPMAS experiment. A phase-adjusted proton decoupling field of 80-100 kHz was applied during spectral acquisition. The cross-polarization contact time was set to 2 ms and the recycle delay was set to 11.4 s. The number of scans was adjusted to obtain an adequate signal-to-noise ratio. 13 C chemical shift scale, 13 C CPMAS experiments were used and referenced to an external standard of crystalline adamantane, setting its upfield resonance to 29.5 ppm.

[0070] Automated peak picking was performed using Bruker-BioSpin TopSpin version 3.6 software. A threshold of 5% relative intensity was generally used for preliminary peak selection. The output of the automated peak picking was visually checked to ensure validity and manually adjusted if necessary. Although specific solid-state NMR peak values ​​are reported herein, due to differences in instruments, samples, and sample preparation, there is actually a range of these peak values. This is a common practice in the field of solid-state NMR due to the inherent variation in peak positions. 13Typical changes in C chemical shift x-axis values ​​are on the order of plus or minus 0.2 ppm in crystalline solids. Solid-state NMR peak heights reported herein are relative intensities. Solid-state NMR intensities may vary depending on the actual setting of CPMAS experimental parameters and the thermal history of the sample.

[0071] Five characteristic peaks were identified for crystalline (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base hemihydrate (Form 1): 44.4, 47.7, 149.2, 36.6, and 26.9 ± 0.2 ppm. 13 C chemical shift.

[0072] Example 2, Free Base Hemihydrate Form 1 13 The C ssNMR spectrum is shown in Figure 2. Example 2, Free Base Hemihydrate Form 1 13 The C ssNMR spectra (ppm) are provided in Table 3 below:

[0073] [Table 3]

[0074] Raman spectra were collected using a Thermo Scientific iS50 FT-Raman accessory mounted on an FT-IR bench. In the FT-Raman configuration, a CaF2 beam splitter is utilized. The spectrometer is equipped with a 1064 nm diode laser and a room temperature InGaAs detector. Prior to data acquisition, instrument performance and calibration verification was performed using polystyrene. Samples were analyzed in glass NMR tubes as tablets or in a suitable sample holder that held stationary during data collection. Spectra were collected using a laser power between 0.1 and 0.5 W and 512 simultaneous scans. The collection range was 3700-100 cm. -1 The API spectrum was measured using a 2 cm -1Decomposition was used and Happ-Genzel apodization was utilized for all spectra. Multiple spectra were recorded, but the spectra reported are representative of two spots.

[0075] Prior to peak collection, the intensity scale was normalized to 1. Peaks were manually identified using Thermo Nicolet Omnic 9.7.46 software. Peak positions were collected at the peak maximum, but if there was a slope on either side, the peak was only identified as such; peak shoulders were not included. For the solvent-free free base hemihydrate form 1, an absolute threshold of 0.006 with a sensitivity of 75 was utilized during peak collection. Peak positions were rounded to the nearest integer using standard practice (0.5 rounds up, 0.4 rounds down). Peaks with normalized peak intensities between (1-0.75), (0.74-0.30), and (0.29-0) were labeled as strong, medium, and weak, respectively.

[0076] The FT-Raman spectrum of Example 2, free base hemihydrate form 1 is shown in Figure 3. The FT-Raman spectrum wavenumber list and normalized intensity data (cm) for the compound of Example 2, free base hemihydrate form 1. -1 ) are provided in Table 4 below:

[0077] [Table 4-1]

[0078] [Table 4-2]

[0079] Characteristic FT-Raman wavenumbers (cm) for the compound of Example 2, free base hemihydrate form 1 -1 ) value list and normalized intensity data (cm -1 ) are provided in Table 5 below:

[0080] [Table 5] Example 3

[0081] Comparative Analysis of Crystalline (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine Free Base Hemihydrate Form 1 vs. Amorphous (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine Chemical stability data was evaluated using HPLC between the free base hemihydrate Form 1 and the amorphous form for samples stored at several conditions listed in Table 6. HPLC method Column: LC / 027 Agilent Poroshell 120 EC-C18 150×4.6mm, 2.7μm Column temperature: 40℃ Autosampler temperature: ambient UV wavelength: 220nm Injection volume: 4.00μL Flow rate: 1.5mL / min Mobile phase A: 0.02% TFA in H2O Mobile phase B: 0.02% TFA in MeCN Time (min) Solvent B [%] 0 20 3 20 15 70 15.1 95 16 95 16.1 20 20.0 20

[0082] [Table 6]

[0083] All publications and patent applications cited herein are hereby incorporated by reference in their entirety. Those skilled in the art will recognize that certain changes and modifications can be made thereto without departing from the spirit and scope of the appended claims.

Claims

1. (1) a PXRD pattern containing characteristic peaks at 2θ values ​​of 10.9, 14.0, 15.4, and 16.0±0.2 degrees 2θ; (2) a PXRD pattern containing resonance (ppm) values ​​of 44.4, 47.7, 149.2, and 36.6±0.2 ppm. １３ C ssNMR spectrum; or (3) 607, 1462, 1051 and 1573±0.2 cm －１ Wave number (cm －１ A crystalline hemihydrate of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base, characterized by an FT-Raman spectrum including .alpha.-(.alpha.) values.

2. 2. The crystal of claim 1, having a powder X-ray diffraction pattern including peaks at 2θ values ​​of 10.9, 14.0, 15.4 and 16.0±0.2°2θ.

3. Includes resonance (ppm) values ​​of 44.4, 47.7, 149.2 and 36.6±0.2 ppm １３ The crystal according to claim 1 or 2, having a C ssNMR spectrum.

4. 607, 1462, 1051 and 1573±0.2 cm －１ Wave number (cm －１ The crystal according to any one of claims 1 to 3, having an FT-Raman spectrum including a .alpha.-.alpha. value.

5. 5. The crystal of claim 1, having a powder X-ray diffraction pattern further including a peak at a 2θ value of 25.1±0.2°2θ.

6. 6. The crystal of claim 1, having a powder X-ray diffraction pattern further including a peak at a 2θ value of 20.5±0.2°2θ.

7. 7. The crystal of any one of claims 1 to 6, having a powder X-ray diffraction pattern further including a peak at a 2θ value of 29.5±0.2°2θ.

8. Further including a resonance (ppm) value of 26.9±0.2 ppm １３ 8. The crystal of claim 1 having a C ssNMR spectrum.

9. 9. The crystal of any one of claims 1 to 8, which is substantially pure.

10. A pharmaceutical composition comprising the hemihydrate crystals of (S)-1'-(6-((2-amino-3-chloropyridin-4-yl)thio)-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-amine free base according to any one of claims 1 to 9, and at least one pharma- ceutically acceptable excipient.

11. 11. The pharmaceutical composition of claim 10 for use in treating abnormal cell proliferation in a mammal.

12. The pharmaceutical composition of claim 11, wherein the mammal is a human.

13. The pharmaceutical composition of claim 11 or 12, wherein the abnormal cell proliferation is cancer.

14. 14. The pharmaceutical composition of claim 13, wherein the cancer is selected from the group consisting of ALK or ROS1 positive non-small cell lung cancer, B-type Raf proto-oncogene V600E mutated colorectal cancer, or RAS mutated, NF1 mutated or BRAF class 3 mutated solid tumors.

15. A pharmaceutical composition according to any one of claims 11 to 14 for use in combination with one or more additional pharmaceutical compounds.

16. 16. The pharmaceutical composition of claim 15, wherein the additional pharmaceutical compound is selected from the group consisting of lorlatinib, binimetinib, cetuximab, and encorafenib.

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