CN117460725A - Crystal forms of SHP2 inhibitor - Google Patents

Crystal forms of SHP2 inhibitor Download PDF

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Publication number
CN117460725A
CN117460725A CN202280038008.XA CN202280038008A CN117460725A CN 117460725 A CN117460725 A CN 117460725A CN 202280038008 A CN202280038008 A CN 202280038008A CN 117460725 A CN117460725 A CN 117460725A
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China
Prior art keywords
dihydrospiro
triazin
chloropyridin
amino
thio
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Chinese (zh)
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K·K·布朗
A·K·古德温
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Array Biopharma Inc
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Array Biopharma Inc
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Priority claimed from PCT/IB2022/052982 external-priority patent/WO2022208408A1/en
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Abstract

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

Description

Crystal forms of SHP2 inhibitor
Background
Technical Field
The present invention relates to (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base hemihydrate form (form 1), pharmaceutical compositions comprising form 1, and methods of using form 1 and such compositions for treating abnormal cell growth, such as cancer, in mammals, particularly humans.
Description of the state of the art
The compound (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio-1, 2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine is an SHP2 inhibitor having the formula (I):
the preparation of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine is disclosed in international patent publication WO 2020/201991 (published under international application No. PCT/IB2020/053019, published under month 10, 2020), the contents of which are incorporated herein by reference in their entirety.
The present invention provides a crystalline form (form 1) of the hemihydrate of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base having desirable properties such as high crystallinity, high purity and stability.
Summary of The Invention
Each of the embodiments described below may be combined with any of the other embodiments described herein, which are not inconsistent with the embodiments combined therewith.
In one aspect, the invention provides a crystalline form (form 1) of the hemihydrate of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base. The crystalline form (form 1) of the hemihydrate of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base is characterized by powder X-ray diffraction (PXRD) (2θ).
In another aspect, the invention provides a crystalline hemihydrate (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base (form 1) characterized as having a powder X-ray diffraction (PXRD) pattern (2θ) comprising: (a) One, two, three, four, five, or more than five of the peaks expressed in 2θ±0.2° 2θ in table 1; (b) One, two, three or four peaks selected from the peaks expressed in 2θ±0.2° 2θ in table 1; (c) One, two, three, four, five, or more than five of the peaks expressed in 2θ±0.2° 2θ selected from table 2; (d) One, two, three or four peaks selected from the peaks expressed in 2θ±0.2° 2θ in table 2; or (e) peaks at substantially the same 2 theta values as shown in figure 1.
In another aspect, the invention provides a pharmaceutical composition comprising (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base hemihydrate form (form 1) according to any embodiment, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable excipients.
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 a 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 [ inden-2, 4' -piperidin ] -1-amine free base according to any aspect or embodiment described herein.
In another aspect, the invention provides the use of a crystalline form of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base (form 1) or a pharmaceutical composition comprising a crystalline form of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base (form 1) in a method of treating abnormal cell growth in a mammal.
In a further aspect, the invention provides the use of a 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 [ inden-2, 4' -piperidin ] -1-amine free base according to any aspect or embodiment described herein in the manufacture of a medicament for the treatment of abnormal cell growth in a mammal.
In another aspect, the invention provides a crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any aspect or embodiment described herein for use in a method of treating abnormal cell growth in a mammal.
In a common embodiment, the abnormal cell growth is cancer. In one embodiment, the abnormal cell growth is a cancer mediated by SHP 2.
Drawings
FIG. 1 shows the PXRD pattern 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 [ inden-2, 4' -piperidin ] -1-amine free base.
FIG. 2 shows (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]Crystalline form (form 1) of the hemihydrate of the 1-amine free base 13 C ssNMR spectrum.
FIG. 3 shows the PXRD pattern 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 [ inden-2, 4' -piperidin ] -1-amine free base.
Detailed Description
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the examples included herein. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It will be further understood that terms used herein are to be given their ordinary meaning as known in the relevant art unless specifically defined herein. If one or more of the cited documents and similar materials are different from or contradicted by this application, including but not limited to defined terms, use of terms, described techniques, etc., this application controls.
Definition of the definition
As used herein, the singular forms "a", "an" and "the" include plural referents unless otherwise indicated. For example, an "a" substituent includes one or more substituents.
The term "about" means that the value falls within the accepted error criteria for the average value when considered by one of ordinary skill in the art.
As used herein, the term "substantially identical" means that typical variability of a particular method is considered. For example, with respect to the X-ray diffraction peak positions, the term "substantially the same" means that typical variability in peak positions and intensities is considered. Those skilled in the art will appreciate that peak position (2θ) may exhibit some variability, typically up to ±0.2°. Furthermore, those skilled in the art will appreciate that the relative peak intensities will exhibit inter-device variability, as well as variability due to crystallinity, preferred orientation, surface of the prepared sample, and other factors known to those skilled in the art, and should be taken as a qualitative measurement only.
The term "crystal" as used herein refers to a regular repeating arrangement of molecules or external face planes. The crystalline forms may differ in thermodynamic stability, physical parameters, x-ray structure, and method of preparation.
The term "hemihydrate" refers to a hydrate in which two molecules of the compound are present for each water molecule, in this case (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base.
The term "substantially pure" means that a particular crystalline form comprises 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.
Crystalline (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidin ] -1-amine free base (form 1)
In one embodiment, the invention provides a 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 [ inden-2, 4' -piperidin ] -1-amine free base. The crystalline form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base is the hemihydrate. The methods described herein provide a crystalline (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base (form 1) that is substantially pure and free of other forms. In another embodiment, the invention provides a crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base that is substantially pure and free of other forms. In one embodiment, the crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base is substantially greater than 95% pure. In one embodiment, the crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base is substantially greater than 97% pure. In one embodiment, the crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base is substantially greater than 99% pure.
(S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]The crystalline form of the hemihydrate of the 1-amine free base (form 1) is characterized by: (1) PXRD patterns including characteristic peaks at 2Θ values of 10.9, 14.0, 15.4, and 16.0 °2Θ ± 0.2 °2Θ; or (2) resonance (ppm) values including 44.4, 47.7, 149.2 and 36.6ppm + -0.2 ppm 13 C ssNMR spectrum; or (3) 607, 1462, 1051 and 1573cm -1 ±0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values. The hemihydrate crystalline forms of the present invention may also provide (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]-a crystalline form of the hemihydrate of the 1-amine free base (form 1), characterized by two of the following: (1) PXRD patterns including characteristic peaks at 2Θ values of 10.9, 14.0, 15.4, and 16.0 ± 0.2 °2Θ; (2) Including resonance (ppm) values of 44.4, 47.7, 149.2 and 36.6.+ -. 0.2ppm 13 C ssNMR spectrum; or (3) 607, 1462, 1051 and 1573.+ -. 0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values. The hemihydrate crystalline forms of the present invention may also provide (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]-a crystalline form of the hemihydrate of the 1-amine free base (form 1), characterized by: (1) PXRD patterns including characteristic peaks at 2Θ values of 10.9, 14.0, 15.4, and 16.0 ± 0.2 °2Θ; (2) Including resonance (ppm) values of 44.4, 47.7, 149.2 and 36.6.+ -. 0.2ppm 13 C ssNMR spectrum; and (3) include 607, 1462, 1051 and 1573.+ -. 0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values.
In a further embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 10.9±0.2° 2θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 16.0±0.2° 2θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 14.0±0.2° 2θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 15.4±0.2° 2θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 15.5±0.2° 2θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 25.1±0.2° 2θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 20.5±0.2° 2θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 29.5±0.2° 2θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 10.9 and 16.0 ± 0.2 °2θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 10.9 and 14.0±0.2° 2θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 10.9 and 15.4±0.2° 2θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at values of 2 theta at 16.0 and 14.0 ± 0.2 °2Θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 16.0 and 15.4±0.2° 2θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 14.0 and 15.4±0.2° 2θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2Θ values of 10.9, 16.0 and 14.0 ± 0.2 °2Θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2Θ values of 10.9, 16.0 and 15.4 ± 0.2 °2Θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2θ values of 16.0, 14.0 and 15.4 ± 0.2 °2θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2Θ values of 10.9, 16.0 and 15.4 ± 0.2 °2Θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2 theta values of 10.9, 16.0, 14.0 and 15.4 ± 0.2 °2Θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2 theta values of 10.9, 16.0, 14.0, 15.4 and 15.5 ± 0.2 °2Θ. In another embodiment, the hemihydrate form (form 1) of the (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2 theta values of 10.9, 16.0, 14.0, 15.4, 15.5 and 25.1 ± 0.2 °2Θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2 theta values of 10.9, 16.0, 14.0, 15.4, 15.5, 25.1 and 20.5 ± 0.2 °2Θ. In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern comprising peaks at 2 theta values of 10.9, 16.0, 14.0, 15.4, 15.5, 25.1, 20.5 and 29.5 ± 0.2 °2 theta.
In another embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base has a PXRD pattern (2θ) comprising: (a) One, two, three, four, five, or more than five of the peaks expressed in 2θ±0.2° 2θ in table 1; (b) One, two, three or four peaks selected from the peaks expressed in 2θ±0.2° 2θ in table 1; (c) One, two, three, four, five, or more than five of the peaks expressed in 2θ±0.2° 2θ in table 2; (d) One, two, three or four peaks selected from the peaks expressed in 2θ±0.2° 2θ in table 2; or (e) peaks at substantially the same 2 theta values as shown in figure 1.
In still further embodiments, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The hemihydrate form of the 1-amine free base (form 1) has a resonance (ppm) value comprising 44.4.+ -. 0.2ppm 13 C ssNMR spectrum. In another embodiment, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]The hemihydrate form of the 1-amine free base (form 1) has a resonance (ppm) value comprising 47.7.+ -. 0.2ppm 13 C ssNMR spectrum. In another embodiment, (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 baseThe hemihydrate form (form 1) has a resonance (ppm) value that includes 149.2.+ -. 0.2ppm 13 CssNMR spectrum. In another embodiment, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The hemihydrate form of the 1-amine free base (form 1) has a resonance (ppm) value comprising 36.6.+ -. 0.2ppm 13 C ssNMR spectrum. In another embodiment, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The hemihydrate form of the 1-amine free base (form 1) has a resonance (ppm) value comprising 26.9.+ -. 0.2ppm 13 C ssNMR spectrum.
In another embodiment, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The crystalline form of the hemihydrate of the 1-amine free base (form 1) has a structure comprising 13 C ssNMR spectrum (ppm): (a) One, two, three, four, five or more than five resonance values selected from the values expressed in ppm±0.2ppm in table 3; (b) One, two, three or four resonance values selected from the values expressed in ppm±0.2ppm in table 3; (c) resonance values expressed in ppm.+ -. 0.2ppm in Table 3; or (d) substantially the same value (ppm) as shown in FIG. 2.
In still further embodiments, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The crystalline form of the hemihydrate of the free base of 1-amine (form 1) has a composition comprising 607.+ -. 0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values. In another embodiment, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The crystalline form of the hemihydrate of the free base of 1-amine (form 1) has a composition comprising 1462.+ -. 0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values. In another embodiment, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine]The crystalline form of the hemihydrate of the free base of 1-amine (form 1) has a composition of 1051.+ -. 0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values. In another embodiment, (S) -1' - (6- ((2-amino-3-chloropyridin-4-yl)) Thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidines]The crystalline form of the hemihydrate of the free base of 1-amine (form 1) has a composition comprising 1573.+ -. 0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values.
In another embodiment, (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine ]The crystalline form of the hemihydrate of the 1-amine free base (form 1) has a FT-Raman spectrum (cm) comprising -1 ): (a) Selected from Table 4 in cm -1 ±0.2cm -1 One, two, three, four, five or more than five wave numbers (cm) of the values represented -1 ) A value; (b) Selected from Table 4 in cm -1 ±0.2cm -1 One, two, three or four wavenumbers (cm) of the values represented -1 ) A value; (c) Selected from Table 4 in cm -1 ±0.2cm -1 Expressed wave number (cm) -1 ) A value; (d) Selected from Table 5 in cm -1 ±0.2cm -1 One, two, three or four wavenumbers (cm) of the wave values represented -1 ) A value; or (d) wavenumbers (cm) substantially the same as those shown in FIG. 3 -1 ) Values.
In another embodiment, the invention provides a pharmaceutical composition comprising a 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 [ inden-2, 4' -piperidin ] -1-amine free base according to any embodiment described herein, and at least one pharmaceutically acceptable excipient.
Typical formulations or compositions are prepared by mixing the compounds described herein with excipients. Suitable excipients are well known to those skilled in the art and are described, for example, in 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 experilents.Chicago, pharmaceutical Press,2005, the disclosure of which is incorporated herein by reference.
As used herein, "pharmaceutical composition" refers to the crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base as an active ingredient according to any of the embodiments described herein, and at least one pharmaceutically acceptable excipient.
As used herein, a "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
Administration of the pharmaceutical composition may be effected by any method capable of delivering 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 [ inden-2, 4' -piperidin ] -1-amine free base 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.
The pharmaceutical composition may be in a form suitable for oral administration (as a tablet, capsule, pill, powder, slow release formulation, solution, suspension), for parenteral injection (as a sterile solution, suspension or emulsion), for topical administration (as an ointment or cream) or for rectal administration (as a suppository), for example.
In another embodiment, the 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 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 [ inden-2, 4' -piperidin ] -1-amine free base according to any embodiment described herein.
In another embodiment, the 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 (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base hemihydrate form (form 1) according to any of the embodiments described herein.
In another embodiment, the invention provides a crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any of the embodiments described herein for use in treating abnormal cell growth in a mammal (preferably a human.
In another embodiment, the invention provides the use of a 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 [ inden-2, 4' -piperidin ] -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.
In another embodiment, the invention provides the use of a 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 [ inden-2, 4' -piperidin ] -1-amine free base according to any of the embodiments described herein in the manufacture of a medicament for the treatment of abnormal cell growth in a mammal (preferably a human.
In another embodiment, the invention provides a crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any aspect or embodiment described herein for use in therapy.
In another embodiment, the invention provides a crystalline hemihydrate form (form 1) of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any aspect or embodiment described herein for use in a method of treating abnormal cell growth in a mammal.
In a common embodiment of the methods provided herein, the abnormal cell growth is cancer. As used herein, "cancer" refers to a physiological condition in a mammal that is typically characterized by abnormal or unregulated cell growth. Cancers include solid tumors, blood cancers, bone marrow cancers, or cancers of the lymphatic system, named cell types that form solid tumors. Examples of solid tumors include sarcomas and carcinomas. Hematological cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancers also include primary cancers that originate in a particular part of the body, metastatic cancers that spread from their starting location to other parts of the body, recurrent cancers that are remitted by the primary cancer, and secondary primary cancers, i.e., new primary cancers in humans that have a history of previous cancers of a different type than the previous cancers.
In some embodiments, the provided methods result in one or more of the following effects: (1) inhibiting proliferation of cancer cells; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting metastasis of cancer cells; or (5) inhibiting angiogenesis.
As used herein, "ameliorating" refers to alleviating or ameliorating one or more symptoms upon treatment with a combination described herein, as compared to the absence of administration of the combination. Improvement also includes shortening or reducing the duration of symptoms.
As used herein, an "effective dose" or "effective amount" of a drug, compound or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired effects (including biochemical, histological and/or behavioral symptoms of the disease) of the disease, its complications, and intermediate pathological phenotypes that occur during the course of disease progression. For therapeutic use, a "therapeutically effective amount" refers to the amount of a compound that is administered that will alleviate one or more symptoms of the disease being treated to some extent. With respect to the treatment of cancer, a therapeutically effective amount refers to an amount that has the following effects: (1) reduce the size of a tumor, (2) inhibit (i.e., slow to some extent, preferably stop) tumor metastasis, (3) inhibit to some extent (i.e., slow to some extent, preferably stop) tumor growth or tumor invasion, (4) alleviate (or preferably eliminate) to some extent one or more signs or symptoms associated with cancer, (5) reduce the dosage of other drugs required to treat the disease, and/or (6) enhance the effect of another drug, and/or (7) delay the progression of the disease in the patient.
As used herein, "mammal" refers to a warm-blooded animal, including but not limited to guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans, that have or are at risk of having the diseases described herein.
As used herein, "individual" refers to a human or animal individual. In one embodiment, the subject is a mammal. In a preferred embodiment, the individual is a human.
As used herein, "treatment" refers to the administration of 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 refers to administering a compound of formula (I) to an individual having or diagnosed with cancer to achieve at least one positive therapeutic effect, such as reducing the number of cancer cells, reducing the size of a tumor, reducing the rate of infiltration of cancer cells into peripheral organs, or reducing the rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progression of, or preventing the disease or disorder or one or more symptoms of the disease or disorder to which the term applies. The term "treatment" as used herein refers to the therapeutic behavior of "treatment" as defined above, unless otherwise indicated. The term "treatment" also includes adjuvant and neoadjuvant treatment of an individual.
In some embodiments, the treatment achieved by the compounds of formula (I) is defined by reference to any one of the following: partial Remission (PR), complete Remission (CR), total remission (OR), progression-free survival (PFS), disease-free survival (DFS), and total survival (OS). PFS is also referred to as "tumor progression time" and refers to the length of time during and after treatment that the cancer does not grow, including the amount of time the patient experiences CR or PR, and the amount of time the patient experiences Stable Disease (SD). DFS refers to the length of time a patient remains disease free during and after treatment. OS refers to an increase in life expectancy compared to a new or untreated individual or patient. In some embodiments, the response to the combination of the invention is PR, CR, PFS, DFS OR any of OR OS, which is evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 reaction criteria.
In one embodiment, the abnormal cell growth disorder is cancer. In one embodiment, the cancer may be selected from the group consisting of melanoma, childhood granulocytic leukemia (juvenile myelomoncytic leukemias), neuroblastoma, philadelphia chromosome positive chronic myelogenous leukemia (Philadelphia chromosome positive chronic myeloid), philadelphia chromosome positive acute lymphocytic leukemia, acute myelogenous leukemia, myeloproliferative neoplasms (e.g., polycythemia vera, essential thrombocythemia, and essential 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 spitzoid tumor. In one embodiment, the cancer is melanoma. In one embodiment, the cancer is a juvenile granulocytic leukemia. In one embodiment, the cancer is a neuroblastoma. In one embodiment, the cancer is philadelphia chromosome positive chronic myelogenous leukemia. 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 essential myelofibrosis. In one embodiment, the cancer is selected from polycythemia vera, essential thrombocythemia, and essential myelofibrosis. In one embodiment, the cancer is polycythemia vera. In one embodiment, the cancer is primary 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 squamous cell carcinoma of the head and neck. 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 spizoid tumor. In one embodiment, the cancer is selected from NSCLC, colon cancer, esophageal cancer, rectal cancer, childhood myelomonocytic leukemia ("JMML"), breast cancer, melanoma, and pancreatic cancer.
In one embodiment, the abnormal cell growth is a cancer mediated by SHP 2.
In one embodiment, the abnormal cell growth is a cancer that can be treated by an SHP2 inhibitor. In another embodiment, the abnormal cell growth is a cancer responsive to treatment with an SHP2 inhibitor.
In one embodiment, abnormal cell growth includes cells containing a mutation encoding a KRASG12C variant. See WO 2019/051084.
In one embodiment, the abnormal cell growth is a disease or disorder comprising cells having a mutation encoding a NF1 loss of function ("NF 1 LOF") variant. In one embodiment, the NF1 mutation is a loss-of-function mutation. In one embodiment, the disease or disorder is a tumor comprising cells having NF 1-function-deleting mutations. In one embodiment, the tumor is a NSCLC or melanoma tumor. In one embodiment, the disease is selected from the group consisting of type I neurofibromatosis, type II neurofibromatosis, schwannoma, and Watson syndrome.
In one embodiment, abnormal cell growth is associated with a RAS pathway mutation in a cell of the subject, which mutation makes the cell at least partially dependent on signal flux through SHP 2. In one embodiment, the RAS pathway mutation is a RAS mutation selected from KRAS mutation, NRAS mutation, SOS mutation, BRAF class III mutation, MEKl class I mutation, MEKl class II mutation, and F1 mutation. In one embodiment, the KRAS mutation is selected from KRAS G12A Mutation, KRAS G12C Mutation, KRAS G12D Mutation, KRAS G12F Mutation, KRAS G12I Mutation, KRAS G12L Mutation, KRAS G12R Mutation, KRAS G12S Mutation, KRAS G12V Mutation and KRAS G12Y Mutation. In one embodiment, the KRAS mutation is KRAS G12A Mutation. In one embodiment, the KRAS mutation is KRAS G12C Mutation. In one embodiment, the KRAThe S mutation is KRAS G12D Mutation. In one embodiment, the KRAS mutation is KRASG 12F Mutation. In one embodiment, the KRAS mutation is KRAS G12I Mutation. In one embodiment, the KRAS mutation is KRAS G12L Mutation. In one embodiment, the KRAS mutation is KRAS G12R Mutation. In one embodiment, the KRAS mutation is KRAS G12S Mutation. In one embodiment, the KRAS mutation is KRAS G12V Mutation. In one embodiment, the KRAS mutation is KRAS G12Y Mutation. In one embodiment, the class III BRAF 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 class I MEKl 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.
In one embodiment, the abnormal cell growth is selected from ALK or ROS1 positive non-small cell lung cancer, a B Raf proto-oncogene V600E mutated colorectal cancer, or a RAS mutation, NF1 mutation, or BRAF 3-like 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 a type B Raf proto-oncogene V600E mutated colorectal cancer. In one embodiment, the abnormal cell growth is a RAS mutant solid tumor. In one embodiment, the abnormal cell growth is NF1 mutant solid tumor. In one embodiment, the abnormal cell growth is a BRAF-like mutant solid tumor.
In one embodiment, 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 [ inden-2, 4' -piperidin ] -1-amine free base 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 lafutinib (lorlatinib), bemetinib (binimetinib), cetuximab (cetuximab), and Kang Naifei ni (encorafenib). In one embodiment, the additional pharmaceutical compound is loratidine. In one embodiment, the additional pharmaceutical compounds are Kang Naifei ni and cetuximab. In one embodiment, the additional pharmaceutical compound is bemetinib.
Examples
The examples and preparations provided below further illustrate and exemplify specific aspects and embodiments of the invention. It should be understood that the scope of the present invention is not limited by the scope of the following examples.
Example 1
Amorphous (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -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-methylpropan-2-sulfinamide (20 mg,0.037 mmol) was diluted with dioxane (1 mL) followed by HCl (92. Mu.L, 0.37 mmol). After stirring for 30 min, the reaction was diluted with dichloromethane ("DCM") and saturated aqueous sodium bicarbonate. After stirring the mixture for 10 min, the layers were separated, DCM was dried over magnesium sulfate, filtered and concentrated. The material was purified by eluting with 20% methanol in ethyl acetate on silica gel 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,0.034mmol,93% yield). 1 H NMR(400MHz,CDCl 3 )δ8.2(s,1H),7.76(d,1H,J＝5.2Hz),7.2-7.35(m,4H),6.15(d,1H,J＝5.2Hz),4.92(br,2H),4.78(br,1H),4.01(s,1H),3.37(m,2H),3.14(d,1H,J＝15.6Hz),2.78(d,1H,J＝15.6),1.3-1.91(m,7H)；m/z(esi/APCI)M + 1＝440.1。
Example 2
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-dihydro-spiro [ indene-2, 4' -piperidine]-1-amine dihydrochloride (3.89 Kg) and 3, 6-dibromo-1, 2, 4-triazine (3.71 Kg) reacted with triethylamine (6.45 Kg) in 1, 4-dioxane (34.3 Kg) at about 20-30 ℃ to provide (S) -1'- (6-bromo-1, 2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine in situ]-1-amine. (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-chloropyridin-4-thiolate (3.08 Kg) and the mixture was heated to about 70-75℃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 ℃. Adding to the reaction at about 15-30deg.C(1.95 Kg) and stirred for about 1 hour, the slurry was filtered and rinsed with 1, 4-dioxane. Solvent exchange was performed and tetrahydrofuran was used instead of 1, 4-dioxane. The crude product (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine was eluted using a mixture of dichloromethane, methanol, ethanol, n-hexane and triethylamine as eluent]The 1-amine was purified by chromatography on silica gel (pretreated with isopropanol). After chromatography, the product is crystallized from methanol and water to give 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).
Powder X-ray diffraction analysis was performed using a Bruker AXSD8 Endeavor diffractometer equipped with a copper (Cu) radiation source. The divergent slit was set to 15mm continuous irradiation. The diffracted radiation was detected by a PSD-Lynx Eye detector with a detector PSD opening set at 2.99 degrees. The X-ray tube voltage and current were set to 40kV and 40mA, respectively. A step size of 0.00998 degrees and a step size time of 1.0 seconds are used at a Cu wavelength of 3.0 to 40.0 degrees 2-thetaData were collected in a theta-theta goniometer. The anti-scatter screen is set at a fixed distance of 3.0 mm. During the collection, the sample was rotated at a speed of 15/min. The sample is prepared by placing the sample in a silicon low background sample holder and rotating during collection. Data were collected using Bruker DIFFRAC Plus software and analyzed by EVA DIFFRAC Plus software. The PXRD data files were not processed prior to peak searching. Using a peak search algorithm in EVA software, the peak selected at threshold 1 is used to make a preliminary peak assignment. To ensure effectiveness, adjustments are made manually; the output of the automatic dispense is visually inspected and the peak position is adjusted to the peak maximum. Peaks having a relative intensity of 3% or more are generally selected. Typically, peaks that are not resolved or coincide with noise are not selected. Typical errors associated with the PXRD peak positions specified in USP are up to +/-0.2 deg. 2-theta (USP-941).
The PXRD pattern for the free base hemihydrate form 1 of example 2 is shown in figure 1. The list of PXRD peaks (2-theta) and relative intensity data for the free base hemihydrate form 1 of the compound of example 2 are provided in table 1 below:
TABLE 1
Angle (2θ°) ±0.2° 2θ Relative intensity (%) Angle (2θ°) ±0.2° 2θ Relative intensity (%)
5.4 6.8 26.8 13.9
10.9 60.1 27.1 51.2
12.1 5.2 27.3 50.9
13.5 3.4 27.8 11.6
14.0 40.2 28.2 71.3
15.4 54.9 29.3 16.6
15.5 44.5 29.5 41.5
16.0 61.8 30.0 5.6
16.4 23.1 31.5 12.6
17.2 49.8 31.9 3.9
17.7 16.5 32.2 9.9
19.0 19.1 33.2 12.1
19.3 45.5 33.3 10.0
19.6 41.2 33.9 4.5
19.7 41.5 34.1 5.7
20.5 39.6 34.7 7.4
21.8 33.4 35.2 11.7
22.2 15.0 35.4 12.6
22.5 100.0 36.1 5.9
23.5 5.5 36.9 3.3
24.3 18.4 37.2 5.0
25.1 68.5 37.5 3.2
25.4 5.3 38.0 5.6
25.7 12.5 38.6 3.5
26.0 7.2 39.0 4.5
A list of characteristic PXRD peaks (2-theta °) and relative intensity data for the free base hemihydrate form 1 of the compound of example 2 are provided in table 2 below:
TABLE 2
Angle (° 2-theta) ± 0.2 ° 2 theta Relative intensity (%)
10.9 60.1
16.0 61.8
14.0 40.2
15.4 54.9
15.5 44.5
25.1 68.5
20.5 39.6
29.5 41.5
Solid state nuclear magnetic resonance ("ssNMR") analysis was performed at a temperature of Bruker-BioSpin Avance III MHz 1 H frequency) is performed on a cross-polarized magic angle spinning ("CPMAS") probe in a nuclear magnetic resonance spectrometer. The material was packed into 4mm ZrO 2 In the rotor. A magic angle turning rate of 14.0kHz was used. Spectra were collected at ambient temperature (temperature uncontrolled).
CPMAS experimental acquisition with proton decoupling 13 C ssNMR spectrum. A phase modulated proton decoupling field of 80-100kHz is applied during spectral acquisition. The cross-polarization contact time was set to 2ms and the recycling delay was set to 11.4 seconds. The number of scans is adjusted to obtain a sufficient signal-to-noise ratio. 13 The C chemical shift scale is based on external standard of crystal adamantane 13 The CPMAS experiment was referenced and its upper field resonance was set at 29.5ppm.
Automatic peak picking was performed using Bruker-Biospin TopSpin version 3.6 software. Typically, a threshold of 5% relative intensity is used for preliminary peak selection. The output of the automatic peak pick-up is visually inspected to ensure validity and manually adjusted if necessary. Although specific solid state NMR peaks are reported herein, there is indeed a range for these peaks due to differences in instrumentation, samples and sample preparation. This is common practice in solid state NMR techniques due to inherent variations in peak position. In the case of a crystalline solid, 13 typical variability of C chemical shift x-axis values is about ±0.2ppm. The solid state NMR peak heights reported herein are relative intensities. The solid state NMR intensity may vary depending on the actual setting of CPMAS experimental parameters and the thermal history of the sample.
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), five characteristic peaks are defined: 44.4, 47.7, 149.2, 36.6 and 26.9.+ -. 0.2ppm 13 C chemical shift.
Example 2 free base hemihydrate form 1 13 The C ssNMR spectrum is shown in FIG. 2. Example 2 free base hemihydrate form 1 13 The C ssNMR spectrum (ppm) is provided in table 3 below:
TABLE 3 Table 3
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Raman spectra were acquired using a Thermo Scientific iS FT-Raman fitting connected to a FT-IR bench. CaF2 beam splitters are used in FT-Raman configurations. The spectrometer was equipped with a 1064nm diode laser and a room temperature InGaAs detector. Prior to data acquisition, instrument performance and calibration verification was performed using polystyrene. During data collection, samples are analyzed in glass NMR tubes as tablets or in a suitable sample holder that remains stationary. Spectra were collected using a laser power of 0.1 to 0.5W and 512 co-sweeps. The acquisition range is 3700-100cm -1 . Using 2cm -1 The API spectra were recorded at resolution and Happ-Genzel cut-outs were used for all spectra. Multiple spectra were recorded, the reported spectra representing two spots.
The intensity scale is normalized to 1 prior to peak picking. Peaks were identified manually using Thermo Nicolet omnic9.7.46 software. Selecting a peak position at a peak maximum value, and identifying the peak as such only if there is a slope on each side; the shoulder on the peak is not included. For pure free base hemihydrate form 1, an absolute threshold of 0.006 and a sensitivity of 75 were used during peak picking. Using standard practice (0.5 round up, 0.4 round down), the peak positions have been rounded to the nearest integer. Peaks with normalized peak intensities between (1-0.75), (0.74-0.30), and (0.29-0) were marked as strong, medium and weak, respectively.
The FT-Raman spectrum of the free base hemihydrate form 1 of example 2 is shown in FIG. 3. Free base of the Compound of example 2FT-Raman spectral wavenumber value list (cm) of hemihydrate form 1 -1 ) And normalized intensity data are provided in table 4 below:
TABLE 4 Table 4
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Free base hemihydrate form 1 (cm) of the Compound of example 2 -1 ) Characteristic FT-Raman wavenumbers (cm) -1 ) The list of values and normalized intensity data are provided in table 5 below:
TABLE 5
Peak position (cm) -1 ) Normalized intensity Grading
607 0.69 w
1462 0.58 w
1051 0.52 w
1573 0.21 w
Example 3
Comparative analysis of crystalline (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base hemihydrate form 1 with amorphous (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine
The chemical stability data for the free base hemihydrate form 1 and amorphous form samples stored under several conditions listed in table 6 were evaluated using HPLC.
HPLC method
TABLE 6
All publications and patent applications cited in the specification are herein incorporated by reference in their entirety. It will be apparent to those of ordinary skill in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims (20)

1. (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ indene-2, 4' -piperidine)]-a crystalline hemihydrate form of the 1-amine free base, characterized by: (1) PXRD patterns including characteristic peaks at 2Θ values of 10.9, 14.0, 15.4, and 16.0 ± 0.2 °2Θ; (2) Including 44.4, 47.7, 149.2 and 3Resonance (ppm) value of 6.6.+ -. 0.2ppm 13 C ssNMR spectrum; or (3) 607, 1462, 1051 and 1573.+ -. 0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values.
2. The crystalline form of claim 1 having a powder X-ray diffraction pattern comprising peaks at 2Θ values of 10.9, 14.0, 15.4, and 16.0 ± 0.2 °2Θ.
3. The crystalline form of claim 1 or 2 having a resonance (ppm) value comprising 44.4, 47.7, 149.2 and 36.6 ± 0.2ppm 13 C ssNMR spectrum.
4. The crystalline form of any one of claims 1 to 3 having a composition comprising 607, 1462, 1051 and 1573±0.2cm -1 Wavenumber (cm) -1 ) FT-Raman spectra of the values.
5. The crystalline form of any one of claims 1 to 4, having a powder X-ray diffraction pattern further comprising peaks at 2Θ values of 25.1 ± 0.2 ° 2Θ.
6. The crystalline form of any one of claims 1 to 5 having a powder X-ray diffraction pattern further comprising peaks at 2Θ values of 20.5 ± 0.2 ° 2Θ.
7. The crystalline form of any one of claims 1 to 6 having a powder X-ray diffraction pattern further comprising peaks at 2Θ values of 29.5 ± 0.2 ° 2Θ.
8. The crystalline form of any one of claims 1 to 7, having a resonance (ppm) value further comprising 26.9 ± 0.2ppm 13 C ssNMR spectrum.
9. The crystalline form of any one of claims 1 to 8, which is substantially pure.
10. A pharmaceutical composition comprising a hemihydrate crystalline form of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any one of claims 1 to 9, and at least one pharmaceutically acceptable excipient.
11. A method of treating abnormal cell growth in a mammal comprising administering to the mammal a therapeutically effective amount of a hemihydrate crystalline form of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any one of claims 1 to 9.
12. The method of claim 11, wherein the mammal is a human.
13. The method of claim 11 or 12, wherein the abnormal cell growth is cancer.
14. Use of a crystalline hemihydrate form of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any one of claims 1 to 9 in a method of treating abnormal cell growth.
15. The use of claim 14, wherein the abnormal cell growth is cancer.
16. A crystalline hemihydrate form of (S) -1'- (6- ((2-amino-3-chloropyridin-4-yl) thio) -1,2, 4-triazin-3-yl) -1, 3-dihydrospiro [ inden-2, 4' -piperidin ] -1-amine free base according to any one of claims 1 to 9 for use in a method of treating abnormal cell growth.
17. The crystalline form for use of claim 16, wherein the abnormal cell growth is cancer.
18. The method, use or crystalline form of claim 13, 15 or 17, wherein the cancer is selected from ALK or ROS1 positive non-small cell lung cancer, raf proto-B gene V600E mutated colorectal cancer, or RAS mutant, NF1 mutant or BRAF 3-like mutant solid tumors.
19. The method, use or crystalline form of any one of claims 11 to 18, wherein the crystalline form of claims 1 to 9 is used in combination with one or more additional pharmaceutical compounds.
20. The method, use or crystalline form of claim 19, wherein the additional pharmaceutical compound is selected from the group consisting of loratidine, bemetinib, cetuximab and Kang Naifei.
CN202280038008.XA 2021-04-01 2022-03-30 Crystal forms of SHP2 inhibitor Pending CN117460725A (en)

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US63/169,340 2021-04-01
US202263321902P 2022-03-21 2022-03-21
US63/321,902 2022-03-21
PCT/IB2022/052982 WO2022208408A1 (en) 2021-04-01 2022-03-30 Crystalline form of a shp2 inhibitor

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