Solid forms of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3s,4s)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, which is SHP2 inhibitor

Abstract

To provide: novel crystalline forms of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol (Compound 1) useful for treating or preventing a disease associated with SHP2 modulation; pharmaceutical compositions; methods of treating a disease associated with SHP2 modulation; and methods of use.SOLUTION: The invention provides Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, and Compound 1 Form D, which are characterized by X-ray diffraction patterns, infrared spectra, differential scanning calorimetry thermograms, and the like. The figure shows the X-ray diffraction pattern of Compound 1 Form A.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 858,837, filed June 7, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Field of the Disclosure The present disclosure relates to crystalline solid forms of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, also known as 6-((2-amino-3-chloropyridin-4-yl)thio)-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methylpyrazin-2-yl)methanol, or pharmaceutically acceptable salts thereof, methods of making the forms, and pharmaceutical compositions, and methods of using the same. [Background technology]

[0003] Src homology domain 2-containing protein tyrosine phosphatase (SHP2), encoded by the PTPNl1 gene, is a non-receptor protein tyrosine phosphatase that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signal transduction through the Ras mitogen-activated protein kinase, JAK-STAT, or phosphoinositol 3-kinase-AKT pathways.

[0004] SHP2 contains two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular localization and regulation of SHP2 function. The protein exists in an inactive, autoinhibited conformation stabilized by a network of bonds involving residues from both the N-SH2 and PTP domains. Stimulation by, for example, cytokines or growth factors, leads to the exposure of the catalytic site, resulting in the enzymatic activation of SHP2.

[0005] Mutations in the PTPNl1 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast cancer, lung cancer, and colon cancer.Therefore, SHP2 is a very attractive target for the development of new therapeutic approaches for the treatment of various diseases.The compounds of the present disclosure meet the need for small molecules to inhibit the activity of SHP2. Summary of the Invention [Means for solving the problem]

[0006] The present disclosure relates to crystalline solid forms of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, or a pharmaceutically acceptable salt thereof, methods for making the forms, and pharmaceutical compositions, and methods of using the same.

[0007] The present disclosure provides Compound 1 Form D, characterized as {6-[(2-amino-3-chloro

[0003] The present invention provides a crystalline form of {(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, or a pharmaceutically acceptable salt thereof.

[0008] The present disclosure provides a crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form B, or a pharmaceutically acceptable salt thereof.

[0009] The present disclosure provides a crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form C, or a pharmaceutically acceptable salt thereof.

[0010] The present disclosure provides a crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form A, or a pharmaceutically acceptable salt thereof.

[0011] Another aspect of the present disclosure is directed to pharmaceutical compositions comprising one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further comprise an excipient, diluent, or surfactant. The pharmaceutical composition may be effective for treating diseases associated with SHP2 modulation in a subject in need of such treatment.

[0012] Another aspect of the present disclosure relates to a method of treating a disease associated with SHP2 regulation in a subject in need thereof, comprising administering to the subject an effective amount of one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof).

[0013] Another aspect of the present disclosure relates to a method of inhibiting SHP2, comprising administering to a patient in need of SHP2 inhibition an effective amount of one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof).

[0014] Another aspect of the present disclosure relates to a method of treating a disease associated with SHP2 modulation in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof).

[0015] Another aspect of the present disclosure relates to a method of inhibiting SHP2, comprising administering to a patient in need of inhibition of SHP2 an effective amount of a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof).

[0016] Another aspect of the present disclosure relates to one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 2 Form B, Compound 3 Form C, Compound 4 Form D, Compound 5 Form E, Compound 6 Form F, Compound 7 Form F, Compound 8 Form F, Compound 9 Form F, Compound 10 Form F, Compound 11 Form F, Compound 12 Form F, Compound 13 Form F, Compound 14 Form F, Compound 15 Form F, Compound 16 Form F, Compound 17 Form F, Compound 18 Form F, Compound 19 ... One aspect of the present disclosure relates to a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable carrier for use in treating or preventing diseases associated with SHP2 modulation.

[0017] Another aspect of the present disclosure relates to the use of one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation. Another aspect of the present disclosure relates to the use of a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) and a pharmaceutically acceptable carrier, in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation.

[0018] Another aspect of the disclosure relates to one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) for use as a medicament. Another aspect of the disclosure relates to a pharmaceutical composition comprising one or more compounds disclosed herein (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) for use as a medicament. In some embodiments, the medicament is used for the treatment or prevention of a disease associated with SHP2 modulation.

[0019] The present disclosure also provides compounds and pharmaceutical compositions that are useful for inhibiting SHP2. [Brief explanation of the drawings]

[0020] [Figure 1A] FIG. 1A is an X-ray diffraction pattern of Compound 1 Form A. [Figure 1B] FIG. 1B is an X-ray diffraction pattern of Compound 1 Form A with observed peaks. [Figure 2] FIG. 2 is an ellipsoid diagram of atoms for Compound 1 Form B from the single crystal structure. [Figure 3A] FIG. 3A is an X-ray diffraction pattern of Compound 1 Form B with an intensity maximum of about 25,000 counts. [Figure 3B] FIG. 3B is an X-ray diffraction pattern of Compound 1 Form B with an intensity maximum of about 30,000 counts. [Figure 3C] FIG. 3C is an X-ray diffraction pattern of Compound 1 Form B with observed peaks up to about 26,000 counts in intensity. [Figure 3D] FIG. 3D is an X-ray diffraction pattern of Compound 1 Form B with observed peaks up to about 35,000 counts in intensity. [Figure 4] FIG. 4 is an infrared spectrum of Compound 1 Form B. [Figure 5A] FIG. 5A is an infrared spectrum of Compound 1 Form B in the spectral region from about 3600 to 2500 cm −1 . [Figure 5B] FIG. 5B is an infrared spectrum of Compound 1 Form B in the spectral region from about 1800 to 675 cm −1 . [Figure 6] FIG. 6 is a differential scanning calorimetry thermogram of Compound 1 Form B. [Figure 7] FIG. 7 is an ellipsoid diagram of atoms for Compound 1 Form C from the single crystal structure. [Figure 8A] FIG. 8A is an X-ray diffraction pattern of Compound 1 Form C. [Figure 8B] FIG. 8B is an X-ray diffraction pattern of Compound 1 Form C with observed peaks. [Figure 9] FIG. 9 is an ellipsoid diagram of atoms for Compound 1 Form D from the single crystal structure. [Figure 10A]FIG. 10A is an X-ray diffraction pattern of Compound 1 Form D. [Figure 10B] FIG. 10B is an X-ray diffraction pattern of Compound 1 Form D with observed peaks. [Figure 11] FIG. 11 is an infrared spectrum of Compound 1 Form D. [Figure 12A] FIG. 12A is an infrared spectrum of Compound 1 Form D in the spectral region from about 3600 to 2500 cm −1 . [Figure 12B] FIG. 12B is an infrared spectrum of Compound 1 Form D in the spectral region from about 1800 to 675 cm −1 . [Figure 13] FIG. 13 is a differential scanning calorimetry thermogram of Compound 1 Form D. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present disclosure provides a crystalline solid form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, also known as 6-((2-amino-3-chloropyridin-4-yl)thio)-3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-methylpyrazin-2-yl)methanol (Compound 1). The present disclosure also provides pharmaceutical compositions comprising the crystalline solid form of Compound 1. The present disclosure also provides methods of making and using the crystalline solid form.

[0022] Details of the present disclosure are set forth in the accompanying description below. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, and illustrative methods and materials are now described. Other features, objects, and advantages of the present disclosure will be apparent from the description and from the claims. Also, in this specification and the appended claims, the singular forms include the plural forms unless the context clearly dictates otherwise. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety.

[0023] Each embodiment described herein may be considered alone or in combination with any one or more other embodiments.

[0024] term The articles "a" and "an" are used in this disclosure to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0025] The term "and / or" is used in this disclosure to mean either "and" or "or," unless stated otherwise.

[0026] An "effective amount" when used in reference to a compound is an amount effective to treat or prevent a disease in a subject as described herein.

[0027] The term "carrier" as used in this disclosure encompasses carriers, excipients, and diluents and means a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that delivers a pharmaceutical agent to one organ or body of a subject. involved in transmitting or transporting from one part of the body to another organ or part of the body.

[0028] The term "treatment" with respect to a subject refers to improving at least one symptom of a disorder in a subject. Treating includes curing, improving, or at least partially ameliorating a disorder.

[0029] The term "preventing" or "prevention" with respect to a subject refers to preventing a disease or disorder from afflicting the subject. Preventing includes prophylactic treatment. For example, preventing can include administering one or more compounds disclosed herein to a subject before the subject is afflicted with a disease, which administration results in the subject not afflicting the disease.

[0030] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise specified.

[0031] As used in this disclosure, the terms "administer," "administering," or "administration" refer to administering one or more compounds of the present disclosure, pharmaceutically acceptable salts of one or more compounds of the present disclosure, or a composition comprising one or more compounds of the present disclosure directly to a subject, or administering a prodrug derivative or analog of the compound, pharmaceutically acceptable salt of the compound, or composition to a subject, thereby allowing an equivalent amount of the active compound to be formed in the subject's body.

[0032] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or rhesus monkey.

[0033] An "XRPD pattern" is an xy graph with diffraction angle (i.e., °2θ) on the x-axis and intensity on the y-axis. Peaks within this pattern can be used to characterize crystalline solid forms. As with any data measurement, variability exists in XRPD data. The data is often expressed exclusively in terms of the diffraction angles of the peaks, rather than including their intensities. Because peak intensities can be particularly sensitive to sample preparation (e.g., particle size, water content, solvent content, and preferred orientation effects affect sensitivity), samples of the same material prepared under different conditions can give slightly different patterns; this variability is usually greater than that of diffraction angles. Diffraction angle variability can also be sensitive to sample preparation. Other sources of variability stem from instrument parameters and processing of the raw X-ray data: different X-ray instruments may be operated with different parameters, resulting in slightly different XRPD patterns from the same solid form, and similarly, different software packages may process X-ray data differently, also contributing to variability. These and other sources of variability are known to those skilled in the pharmaceutical arts, and due to such sources of variability, it is common to allocate about ±0.2° 2θ variability for diffraction angles in XRPD patterns.

[0034] solid form Forms A, B, C, and D are anhydrous polymorphs of Compound 1. Thermal techniques provide data that the relative stability of the forms varies with temperature. Forms A and C are both enantiotropically related to each other and to Form D; Form A is thermodynamically stable above approximately 80°C. Form C is the stable form between approximately 80 and 43°C. And Form D is physically stable below approximately 43°C. The conversion between Forms A, C, and D is immediate (and reversible) once the corresponding relevant temperatures are reached. Form B appears to be monotropically related to Form A. Consequently, Forms C and D (enantiotropic) Due to the relationship of Form A to Form B (monotropic) and Form A to Form C (monotropic), Form B is qualified as a metastable form at all temperatures. Tables 1 and 2 show the relationship between form and temperature.

[0035] [Table 1]

[0036] [Table 2]

[0037] Form A The present disclosure provides a crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form A, or a pharmaceutically acceptable salt thereof.

[0038] Compound 1 Form A is a high-temperature anhydrous form that is thermodynamically stable above approximately 80°C and exhibits melting near 213°C (onset temperature measured by differential scanning calorimetry). The tentative unit cell parameters and calculated volume (derived from indexing) for Form A at ambient temperature are: a = 14.310 Å, b = 15.892 Å, c = 9.586 Å, α = 90°, β = 90°, γ = 90°, V = 2180.0 Å 3 The space group was determined to be P21212.

[0039] Generally, Compound 1 Form A is generated from either Form C or D (or a mixture thereof) through spontaneous polymorphic transformation when exposed to temperatures above 80° C. Compound 1 Form A can be generated from Form B (or a mixture of Form B with Form C and / or D) and spontaneously crystallize when exposed to temperatures above the melting point of Form B (about 188° C.) but below the melting point of Form A (about 213° C.). In certain embodiments, Compound 1 Form A has an onset melting temperature of about 213° C.

[0040] In certain embodiments, Compound 1 Form A exhibits an XRPD pattern comprising the peaks shown in Table 3 below: Table 4 shows representative peaks for the XRPD pattern of Compound 1 Form A.

[0041] [Table 3]

[0042] [Table 4]

[0043] In certain embodiments, Compound 1 Form A exhibits one or more peaks at about 16.50 to about 16.90 degrees and about 18.30 to about 18.70 degrees in X-ray powder diffraction. In certain embodiments, Compound 1 Form A is characterized by one or more peaks at about 10.50 to about 10.90 degrees, about 10.90 to about 11.30 degrees, about 12.10 to about 12.50 degrees, about 16.50 to about 16.90 degrees, about 18.30 to about 18.70 degrees, about 18.80 to about 19.20 degrees, about 19.30 to about 19.70 degrees, about 20.60 to about 21.00 degrees, and about 25.40 to about 25.80 degrees in X-ray powder diffraction.

[0044] In certain embodiments, Compound 1 Form A is characterized by its X-ray powder diffractogram comprising peaks at about 16.66 and about 18.50 degrees 2θ. In certain embodiments, the diffractogram further comprises one or more additional peaks selected from the following peaks at about 10.76, about 11.11, about 12.35, about 19.08, about 19.52, about 20.85, and about 25.63 degrees 2θ. Compound 1 Form A is also characterized by its X-ray powder diffractogram substantially as depicted in Figure 1A or Figure 1B.

[0045] Form B The present disclosure provides a crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form B, or a pharmaceutically acceptable salt thereof.

[0046] Form B is a level-free stable form with the potential for melting near 188°C (onset temperature measured by differential scanning calorimetry). The unit cell parameters and calculated volume for Form B derived from the single crystal structure are: a = 9.65334(16) Å, b = 10.28825(18) Å, c = 11.62614(19) Å, α = 76.0621(15)°, β = 89.6714(13)°, γ = 76.4043(15)°, V = 1087.68(3) Å 3 The space group was determined to be P1. The asymmetric unit contains two Compound 1 molecules. The absolute configuration was finally determined, and Compound 1 was found to be bonded at C120 (C220) and C118 (C218) in an S and S configuration, respectively. Figure 2 shows a substitution ellipsoid diagram of atoms for Compound 1 Form B from the single crystal structure.

[0047] The differential scanning calorimetry thermogram of Compound 1 Form B shows two endotherms with onsets near 188° C. and 211° C. The endotherm near 188° C. is likely the melting of Form B, which is immediately followed by recrystallization to Compound 1 Form A and melting of Compound 1 Form A.

[0048] The infrared spectra of Compound 1 Form B are shown in Figure 4, Figure 5A, and Figure 5B, respectively. In certain embodiments, Compound 1 Form B exhibits an infrared spectrum comprising the peaks shown in Table 5 below.

[0049] [Table 5]

[0050] In certain embodiments, Compound 1 Form B exhibits an XRPD pattern comprising the peaks shown in Table 6 below. Table 7 shows representative peaks for the XRPD of Compound 1 Form B.

[0051] [Table 6]

[0052] [Table 7]

[0053] In certain embodiments, Compound 1 Form B is characterized by one or more peaks at about 19.80 to about 20.20 degrees and about 17.70 to about 18.10 degrees in X-ray powder diffraction. In certain embodiments, Compound 1 Form B is characterized by one or more peaks at about 7.6 to about 8.0 degrees, about 8.9 to about 9.3 degrees, about 9.2 to about 9.6 degrees, about 11.2 to about 11.6 degrees, about 12.6 to about 13.0 degrees, about 13.2 to about 13.6 degrees, about 15.5 to about 15.9 degrees, about 17.7 to about 18.1 degrees, about 18.7 to about 19.1 degrees, about 19.8 to about 20.2 degrees, about 20.7 to about 21.1 degrees, about 22.9 to about 23.3 degrees, and about 24.8 to about 25.2 degrees in X-ray powder diffraction.

[0054] In certain embodiments, Compound 1 Form B is characterized by its X-ray powder diffractogram comprising peaks at about 20.0 and about 17.9 degrees 2θ. In certain embodiments, the diffractogram further comprises one or more additional peaks selected from the following peaks at about 7.8, about 9.1, about 9.4, about 11.4, about 12.8, about 13.4, about 15.7, about 18.9, about 20.9, about 23.1, and about 25.0 degrees 2θ. Compound 1 Form B is also characterized by its X-ray powder diffractogram substantially as shown in Figure 3A, 3B, 3C, or 3D.

[0055] In certain embodiments, Compound 1 Form B is characterized by its differential scanning calorimetry (DSC) curve comprising an endotherm at about 188° C. or about 211° C. In certain embodiments, the differential scanning calorimetry (DSC) curve of Compound 1 Form B comprises an endotherm at about 188° C. and / or about 211° C. Compound 1 Form B is also characterized by its complete DSC curve substantially as shown in FIG.

[0056] Form C The present disclosure provides a crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form C, or a pharmaceutically acceptable salt thereof.

[0057] Form C is an anhydrous form that is thermodynamically stable between approximately 43 and 80° C. The unit cell parameters and calculated volume of Form C derived from the single crystal structure are: a = 47.6458(8) Å, b = 14.4005(2) Å, c = 9.5460(2) Å, α = 90°, β = 90°, γ = 90°, V = 6549.8(2) Å 3 The space group is determined to be P21212. The asymmetric unit shown contains three Compound 1 molecules. From the structure, the absolute configuration was finally determined, and Compound 1 was found to be bonded in an S and S configuration at C120 (C220, C320) and C118 (C218, C318), respectively. Figure 7 shows a substitution ellipsoid diagram of atoms for Compound 1 Form C from the single crystal structure.

[0058] Generally, Compound 1 Form C is produced from either Compound 1 Form D or A (or a mixture thereof) through spontaneous polymorphic transformation upon exposure to temperatures between approximately 43°C and 80°C.

[0059] In certain embodiments, Compound 1 Form C exhibits an XRPD pattern comprising the peaks shown in Table 8 below: Table 9 shows representative peaks for the XRPD pattern of Compound 1 Form C.

[0060] [Table 8]

[0061] [Table 9]

[0062] In certain embodiments, Compound 1 Form C is characterized by one or more peaks at about 18.30 to about 18.70 degrees and about 16.40 to about 16.80 degrees in X-ray powder diffraction. In certain embodiments, Compound 1 Form C is characterized by one or more peaks at about 10.60 to about 11.00 degrees, about 10.90 to about 11.30 degrees, about 12.10 to about 12.50 degrees, about 16.40 to about 16.80 degrees, about 18.30 to about 18.70 degrees, about 18.80 to about 19.20 degrees, about 19.40 to about 19.80 degrees, about 20.60 to about 21.00 degrees, and about 25.40 to about 25.70 degrees in X-ray powder diffraction.

[0063] In certain embodiments, Compound 1 Form C is characterized by its X-ray powder diffractogram comprising peaks at about 18.56 and about 16.62 degrees two-theta. In certain embodiments, the diffractogram further comprises one or more additional peaks selected from the following peaks at about 10.78, about 11.11, about 12.29, about 19.06, about 19.57, about 20.83, and about 25.61 degrees two-theta. Compound 1 Form C is also characterized by its X-ray powder diffractogram substantially as depicted in Figure 8A or Figure 8B.

[0064] Form D The present disclosure provides a crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form D, or a pharmaceutically acceptable salt thereof.

[0065] Compound 1 Form D is an anhydrous form that is thermodynamically stable below approximately 43° C. The unit cell parameters and calculated volume of Compound 1 Form D from the single crystal structure are: a = 14.0679(4) Å, b = 16.0057(4) Å, c = 19.1837(6) Å, α = 90°, β = 90°, γ = 90°, V = 4319.5(2) Å 3 The space group was determined to be P21212. The asymmetric unit shown contains three Compound 1 molecules. From the structure, the absolute configuration was finally determined, and Compound 1 was found to be bonded in an S and S configuration at C120 (C220, C320) and C118 (C218, C318), respectively. Figure 9 shows a substitution ellipsoid diagram of atoms for Compound 1 Form D from the single crystal structure.

[0066] The differential scanning calorimetry thermogram of Compound 1 Form D shows multiple endotherms at approximately 51, 90, and 213° C. (onset temperatures). These events correlate with a phase transition to Compound 1 Form C, another phase transition to Compound 1 Form A, and melting of Compound 1 Form A, respectively.

[0067] The infrared spectra of Compound 1 Form D are shown in Figure 11, Figure 12A, and Figure 12B, respectively. In certain embodiments, Compound 1 Form D exhibits an infrared spectrum comprising the peaks shown in Table 10 below.

[0068] [Table 10]

[0069] In certain embodiments, Compound 1 Form D exhibits an XRPD pattern comprising the peaks shown in Table 11 below: Table 12 shows representative peaks for the XRPD pattern of Compound 1 Form D.

[0070] [Table 11]

[0071] [Table 12]

[0072] In certain embodiments, Compound 1 Form D is characterized by one or more peaks at about 18.30 to about 18.70 degrees and about 16.50 to about 16.80 degrees in X-ray powder diffraction. In certain embodiments, Compound 1 Form D is characterized by one or more peaks at about 10.50 to about 10.90, about 10.80 to about 11.20 degrees, about 10.90 to about 11.30 degrees, about 12.40 to about 12.80 degrees, about 16.50 to about 16.80 degrees, about 18.30 to about 18.70 degrees, about 19.00 to about 19.40 degrees, about 19.30 to about 19.70 degrees, about 20.70 to about 21.10 degrees, about 22.30 to about 22.70 degrees, and about 25.40 to about 25.80 degrees in X-ray powder diffraction.

[0073] In certain embodiments, Compound 1 Form D is characterized by an X-ray powder diffractogram comprising peaks at about 18.48 and about 16.77 degrees 2θ. In certain embodiments, the diffractogram further comprises one or more additional peaks selected from the following peaks at about 10.73, about 11.03, about 11.15, about 12.58, about 19.17, about 19.54, about 20.88, about 22.47, and about 25.59 degrees 2θ. Compound 1 Form D is also characterized by its X-ray powder diffractogram substantially as depicted in Figure 10A or 10B.

[0074] In certain embodiments, Compound 1 Form D is characterized by its differential scanning calorimetry (DSC) curve comprising an endotherm at about 51° C., 90° C., or 211° C. Compound 1 Form D is also characterized by its complete DSC curve substantially as shown in FIG.

[0075] Methods for producing compounds and compositions The compounds of the present disclosure can be made by a variety of methods, including standard chemical techniques. Suitable synthetic routes are illustrated in the schemes provided below.

[0076] The compounds of the formulae described herein can be prepared by methods known in the art of organic synthesis, as illustrated in part by the following synthetic schemes and examples. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used where necessary in accordance with general principles or chemical practice. Protecting groups are manipulated according to standard methods of organic synthesis (TW Greene and PG M Butts, "Protective Groups in Organic Synthesis", 3rd ed., Wiley, New York, 1999). Such groups are removed at a convenient stage in the compound synthesis using methods that will be readily apparent to those skilled in the art. The selected processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of the compounds of the present disclosure.

[0077] Compound production The compounds described herein may be prepared from commercially available starting materials or may be synthesized using known organic, inorganic, and / or enzymatic processes.

[0078] The compounds of the present disclosure can be prepared by several methods well known to those skilled in the art of organic synthesis. As an example, the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon recognized by those skilled in the art. Such methods include, but are not limited to, the methods described below.

[0079] Methods for preparing Compound 1 prior to crystallization are described in WO 2018 / 013597, the entire contents of which are incorporated herein by reference.

[0080] In certain embodiments, a slurry of Compound 1 in methanol is stirred for about 9 days at about 58° C. Compound 1 Form A is recovered from the slurry by water aspirator vacuum filtration.

[0081] In certain embodiments, a solution of Compound 1 in dichloromethane or methanol is prepared at ambient temperature and filtered through a 0.2 μm nylon filter. The filtrate is allowed to evaporate under ambient conditions to provide Compound 1 Form B.

[0082] In certain embodiments, a solution of Compound 1 in methanol is prepared at approximately 50° C., treated with activated carbon, and filtered. The filtrate is slowly cooled to ambient temperature to obtain crystals of Compound 1 Form B.

[0083] In certain embodiments, a slurry of Compound 1 in methanol is heated to reflux and filtered by water aspirator vacuum filtration. The filtrate is returned to a boil, treated with activated carbon, and again filtered by water aspirator vacuum filtration. The filtrate is rotary evaporated to dryness, briefly triturated in diethyl ether, filtered by water aspirator vacuum filtration, and dried under nitrogen. The solid is used to form a slurry in methanol and stirred at about 58°C for about 6 days to obtain crystals of Compound 1 Form C.

[0084] In certain embodiments, a slurry of Compound 1 in methanol is heated to reflux and filtered by water aspirator vacuum filtration. The filtrate is treated with activated carbon and again filtered by water aspirator vacuum filtration. The activated carbon treatment by filtration is repeated three times. The volume of the filtrate is reduced to less than one-quarter of its original volume under a nitrogen purge to obtain a solid. The solid is harvested by water aspirator vacuum filtration and washed with methanol. The slurry of solids in methanol is stirred at ambient temperature for about 14 days. Compound 1 Form D is recovered from the slurry by water aspirator vacuum filtration.

[0085] In a specific embodiment, a slurry of Compound 1 in methanol is heated to reflux and filtered by water aspirator vacuum filtration. The filtrate is returned to a boil, treated with activated carbon, and again filtered by water aspirator vacuum filtration. The filtrate is rotary evaporated to dryness, briefly triturated in diethyl ether, filtered by water aspirator vacuum filtration, and dried under nitrogen. The resulting solid particles are heated in mineral oil until plate-shaped crystals form. The crystals are stored in mineral oil at ambient temperature for approximately 1 month. If left standing for a period of months, it can be converted to Compound 1 Form D and then isolated.

[0086] Methods of Using the Disclosed Compounds and Compositions Methods and Uses of the Disclosure Another aspect of the present disclosure relates to a method for treating a disease associated with SHP2 regulation in a subject in need of such treatment. The method comprises administering to a patient in need of treatment for a disease or disorder associated with SHP2 regulation an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) or one or more pharmaceutical compositions of the present disclosure. In some embodiments, the disease may be, but is not limited to, Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, as well as breast cancer, lung cancer, and colon cancer. SHP2 is an important downstream signaling molecule for various receptor tyrosine kinases, including platelet-derived growth factor receptor (PDGF-R), fibroblast growth factor receptor (FGF-R), and epidermal growth factor receptor (EGF-R). SHP2 is also an important downstream signaling molecule for the activation of the mitogen-activated protein (MAP) kinase pathway, which can lead to cell transformation (a prerequisite for cancer development). Knockdown of SHP2 significantly inhibited cell growth in lung cancer cell lines harboring SHP2 mutations or EML4 / ALK translocations, as well as in EGFR-amplified breast and esophageal cancers. SHP2 is also activated downstream of oncogenes in gastric cancer, anaplastic large cell lymphoma, and glioblastoma.

[0087] SHP2 also plays a role in the transmission of signals from immune checkpoint molecules, including, but not limited to, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In this context, modulation of SHP2 function can lead to immune activation, specifically anti-cancer immune responses.

[0088] Another aspect of the present disclosure is directed to a method of inhibiting SHP2, comprising administering to a patient in need of SHP2 inhibition an effective amount of one or more compounds of the present disclosure (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof), or one or more pharmaceutical compositions of the present disclosure.

[0089] The present disclosure relates to compounds or compositions disclosed herein that can modulate (e.g., inhibit) the activity of SHP2. The present disclosure also relates to therapeutic uses of such compounds and compositions.

[0090] One or more compounds or compositions of the present disclosure are administered in an amount effective to treat or prevent a disorder and / or prevent its progression in a subject. In some embodiments, SHP2 is inhibited after treatment with less than 1000 nM of a compound of the present disclosure. In some embodiments, SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the present disclosure. In some embodiments, SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the present disclosure. In some embodiments, SHP2 is inhibited after treatment with less than 10 nM of a compound of the present disclosure.

[0091] Another aspect of the present disclosure relates to one or more compounds of the present disclosure (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof), or one or more compositions of the present disclosure, for use in treating or preventing a disease associated with SHP2 modulation. In some embodiments, the disease is Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancer. SHP2 is a platelet-derived SHP2 is an important downstream signaling molecule for various receptor tyrosine kinases, including PDGF-R, fibroblast growth factor receptor (FGF-R), and epidermal growth factor receptor (EGF-R). SHP2 is also an important downstream signaling molecule for the activation of mitogen-activated protein (MAP) kinase pathways, which can contribute to cell transformation (a prerequisite for cancer development). Knockdown of SHP2 significantly inhibited cell growth in lung cancer cell lines harboring SHP2 mutations or EML4 / ALK translocations, as well as in EGFR-amplified breast and esophageal cancers. SHP2 is also activated downstream of oncogenes in gastric cancer, anaplastic large cell lymphoma, and glioblastoma.

[0092] In another aspect, the disclosure relates to the use of one or more compounds of the disclosure (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) in the manufacture of a medicament for the treatment or prevention of a disease. In some embodiments, the disease is associated with SHP2 modulation.

[0093] In another aspect, the disclosure relates to one or more compounds of the disclosure (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) for use as a medicament. In some embodiments, the medicament is used to treat or prevent a disease associated with SHP2 modulation.

[0094] In one aspect, the disclosure relates to one or more compositions comprising one or more compounds of the disclosure (e.g., Compound 1 Form A, Compound 1 Form B, Compound 1 Form C, or Compound 1 Form D, and pharmaceutically acceptable salts thereof) for use as a medicament. In some embodiments, the medicament is used to treat or prevent a disease associated with SHP2 modulation.

[0095] Pharmaceutical Compositions and Modes of Administration of the Present Disclosure Another aspect of the present disclosure relates to a pharmaceutical composition comprising one or more crystalline forms of the present disclosure and a pharmaceutically acceptable carrier, which may further comprise an excipient, diluent, or surfactant.

[0096] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising at least two crystalline forms selected from Compound 1 Form A, or a pharmaceutically acceptable salt thereof; Compound 1 Form B, or a pharmaceutically acceptable salt thereof; Compound 1 Form C, or a pharmaceutically acceptable salt thereof; and Compound 1 Form D, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0097] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0098] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In accordance with the present disclosure, a pharmaceutical composition comprising Compound 1 Form C or a pharmaceutically acceptable salt thereof, and Compound 1 Form D or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0099] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0100] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0101] The compositions can be prepared according to conventional mixing, granulating, filling, encapsulating, compressing, solution-casting, or coating methods, respectively, and the pharmaceutical compositions may contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume of a compound of the present disclosure.

[0102] Administration of the compounds and pharmaceutical compositions of the present disclosure can be achieved via any mode of administration for therapeutic agents, including systemic or local administration, such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, intravaginal, buccal, rectal, or topical modes of administration.

[0103] Depending on the intended mode of administration, the compounds or pharmaceutical compositions of the disclosure may be in solid, semi-solid, or liquid dosage forms, such as injectables, tablets, suppositories, pills, elixirs, tinctures, emulsions, syrups, powders, solutions, or suspensions, in immediate or modified release form, sometimes in unit dosage amounts, and consistent with conventional pharmaceutical practice. They may also be administered intravenously (both bolus and infusion), intraperitoneally, subcutaneously, intramuscularly, and in other forms well known to those skilled in the art of medicine.

[0104] Illustrative pharmaceutical compositions include one or more compounds of the present disclosure and a pharmaceutically acceptable carrier, such as, but not limited to, a) a diluent, such as purified water, triglyceride oils such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oil such as EPA or DHA, or esters thereof, triglycerides, or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, magnesium or calcium salts thereof, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polysaccharides; ethylene glycol (also for tablets); c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as gum arabic, tragacanth, or sodium alginate, waxes, and / or polyvinylpyrrolidone (if necessary); d) disintegrants, for example, starch, agar, methylcellulose, bentonite, xanthan gum, alginic acid or its sodium salt, or effervescent mixtures; e) absorbents, colorants, flavors, and sweeteners; f) emulsifiers or dispersants, for example, Tween 80, Labrasol, HPMC, DOS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E. TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound, such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200, etc.

[0105] Liquid, particularly injectable, compositions can be prepared, for example, by dissolving, dispersing, etc. For example, one or more compounds of the present disclosure can be dissolved or mixed in a pharmaceutically acceptable solvent, such as water, saline, aqueous dextrose, glycerin, ethanol, etc., to form an injectable isotonic solution or suspension. Proteins, such as albumin, chylomicron particles, or serum proteins, can also be used to solubilize the compounds of the present disclosure.

[0106] One or more compounds or compositions of the present disclosure may also be formulated as suppositories which can be made from fatty emulsions or suspensions, using polyalkylene glycols, for example, propylene glycol, as the carrier.

[0107] One or more compounds or compositions of the present disclosure may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from various phospholipids containing cholesterol, stearylamine, or phosphatidylcholine. In some embodiments, a membrane of lipid components is hydrated with an aqueous solution of a drug to form a lipid layer that encapsulates the drug, as described, for example, in U.S. Patent No. 5,262,564 (the contents of which are incorporated herein by reference).

[0108] One or more compounds or compositions of the present disclosure may also be delivered by using monoclonal antibodies as individual carriers to which the compounds of the present disclosure are coupled. The compounds of the present disclosure may also be coupled to soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, one or more compounds of the present disclosure may be coupled to crosslinked or amphiphilic block copolymers of biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyepsiloncaprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels. In some embodiments, one or more compounds of the present disclosure are not covalently bound to polymers, such as polycarboxylic acid polymers or polyacrylates.

[0109] One or more compounds or compositions of the present disclosure can be delivered by parenteral administration. Injectable parenteral administration is usually used for subcutaneous, intramuscular, or intravenous injection and infusion. Injectable drugs can be prepared in conventional forms, either as liquid solutions or suspensions, or in solid forms suitable for dissolving in liquid prior to injection.

[0110] Dosage Regimen of the Present Disclosure Dosage regimens utilizing the compounds of the present disclosure are selected according to various factors, including the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the patient's renal or hepatic function; and the particular compound of the present disclosure being used. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter, or suppress the progression of the condition.

[0111] When used for the indicated effects, the effective dosage of the compound of the present disclosure ranges from about 0.5 mg to about 5000 mg of the compound of the present disclosure, as needed to treat symptoms.The composition for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the compound of the present disclosure, or ranges from one amount to another amount in the dosage list.In some embodiments, the composition is in the form of a tablet that can be scored.

[0112] If desired, the effective daily dose of one or more compounds or compositions of the present disclosure may be administered as 1, 2, 3, 4, 5, 6 or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form.In some embodiments of the present disclosure, one or more compounds or compositions of the present disclosure, or a mixture thereof, may be administered two or three times a day.In some embodiments, one or more compounds or compositions of the present disclosure will be administered once a day.

[0113] In some embodiments, one or more compounds or compositions described herein may be used alone, together with another type of therapeutic agent, or administered jointly or in combination. Concurrent administration or combined use refers to any form of administration of two or more different therapeutic compounds or compositions, such that the second compound or composition is administered while the previously administered therapeutic compound or composition is still effective in the body. For example, different therapeutic compounds or compositions can be administered in the same formulation or in separate formulations, either simultaneously, sequentially, or by separate administration of individual components of the treatment. In some embodiments, different therapeutic compounds or compositions can be administered within 1 hour, 12 hours, 24 hours, 36 hours, 48 ​​hours, 72 hours, or 1 week of each other's administration. Thus, individuals receiving such treatment can benefit from the combined effects of different therapeutic compounds or compositions.

[0114] kit In some embodiments, the present disclosure also provides pharmaceutical packages or kits comprising one or more containers filled with at least one compound or composition of the present disclosure. Optionally, associated with such containers may be a notice in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceutical or biological products, the notice reflecting (a) agency approval for manufacture, use, or sale for human administration, (b) instructions for use, or both. In some embodiments, the kit comprises at least two containers, at least one of which contains at least one compound or composition of the present disclosure. In some embodiments, the kit comprises at least two containers, and each of the at least two containers contains at least one compound or composition of the present disclosure. Contains ingredients.

[0115] In some embodiments, the kits include additional materials to facilitate delivery of the subject compounds and compositions. For example, the kits may include one or more of a catheter, tubing, an IV bag, a syringe, and the like. In some embodiments, the compounds and compositions are packaged in lyophilized form, and the kits include at least two containers: a container containing the lyophilized compound or composition, and a container containing a suitable amount of water, buffer, or other suitable liquid to reconstitute the lyophilized material.

[0116] The foregoing applies to any of the compounds, compositions, methods, and uses described herein. The present disclosure specifically contemplates any combination of the features of such compounds, compositions, methods, and uses (alone or in combination) with the features described for the various kits described in this section.

[0117] Illustrative Embodiments Some embodiments of the present disclosure are the following Embodiment I:

[0118] Embodiment I-1. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form D, or a pharmaceutically acceptable salt thereof.

[0119] Embodiment I-2. The crystalline form of embodiment I-1, wherein the X-ray powder diffraction pattern comprises 2θ values ​​of about 18.48 and about 16.77.

[0120] Embodiment I-3. The crystalline form of embodiment I-2, wherein the X-ray powder diffraction pattern further comprises one or more 2θ values ​​at about: 10.73, 11.03, 11.15, 12.58, 19.17, 19.54, 20.88, 22.47, and 25.59.

[0121] Embodiment I-4. The crystalline form of embodiment I-1, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in Figure 10A.

[0122] Embodiment I-5. The crystalline form of any one of embodiments I-1 to I-4, wherein the differential scanning calorimetry (DSC) curve comprises an endotherm at about 51°C, about 90°C, or about 211°C.

[0123] Embodiment I-6. The crystalline form of any one of embodiments I-1 to I-4, wherein the DSC curve is substantially as shown in FIG.

[0124] Embodiment I-7. Unit cell dimensions: a = 14.0679(4) Å, b = 16.0057(4) Å, c = 19.1837(6) Å, α = 90°, β = 90°, γ = 90°; unit cell volume (V) 4319.5(2) Å 3 and the space group P21212.

[0125] Embodiment I-8. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol characterized as Compound 1 Form B, or a pharmaceutically acceptable salt thereof.

[0126] Embodiment I-9. The X-ray powder diffraction pattern includes 2θ values ​​of about 20.0 and about 17.9. Include the crystalline form described in embodiment I-8.

[0127] Embodiment I-10. The crystalline form of embodiment I-9, wherein the X-ray powder diffraction pattern further comprises one or more 2θ values ​​at about: 7.8, 9.1, 9.4, 11.4, 12.8, 13.4, 15.7, 18.9, 20.9, 23.1, and 25.0.

[0128] Embodiment I-11. The crystalline form of embodiment I-8, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in Figure 3A.

[0129] Embodiment I-12. The crystalline form of any one of embodiments I-8 to I-11, wherein the differential scanning calorimetry (DSC) curve comprises an endotherm at about 188°C and / or about 211°C.

[0130] Embodiment I-13. The crystalline form of any one of embodiments I-8 to I-11, wherein the DSC curve is substantially as shown in FIG.

[0131] Embodiment I-14. Unit cell dimensions: a = 9.65334(16) Å, b = 10.28825(18) Å, c = 11.62614(19) Å, α = 76.0621(15)°, β = 89.6714(13)°, γ = 76.4043(15)°; unit cell volume (V) 1087.68(3) Å 3 and the crystalline form of any one of embodiments I-8 to I-11 having space group P1.

[0132] Embodiment I-15. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form C, or a pharmaceutically acceptable salt thereof.

[0133] Embodiment I-16. The crystalline form of embodiment I-15, wherein the X-ray powder diffraction pattern comprises 2θ values ​​of about 18.56 and about 16.62.

[0134] Embodiment I-17. The crystalline form of embodiment I-16, wherein the X-ray powder diffraction pattern further comprises one or more 2θ values ​​at about: 10.78, 11.11, 12.29, 19.06, 19.57, 20.83, and 25.61.

[0135] Embodiment I-18. The crystalline form of embodiment I-15, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in Figure 8A.

[0136] Embodiment I-19. Unit cell dimensions: a = 47.6458(8) Å, b = 14.4005(2) Å, c = 9.5460(2) Å, α = 90°, β = 90°, γ = 90°; unit cell volume (V) 6549.8(2) Å 3 and the space group P21212.

[0137] Embodiment I-20. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form A, or a pharmaceutically acceptable salt thereof.

[0138] Embodiment I-21. The crystalline form of embodiment I-20, wherein the X-ray powder diffraction pattern comprises 2θ values ​​of about 16.66 and about 18.50.

[0139] Embodiment I-22. The X-ray powder diffraction pattern is about: 10.76, 11.11, 12.3 The crystalline form of embodiment I-21, further comprising one or more 2θ values ​​at: 5, 19.08, 19.52, 20.85, and 25.63.

[0140] Embodiment I-23. The crystalline form of embodiment I-20, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in Figure IA.

[0141] Embodiment I-24. The crystalline form of embodiment I-20 having an onset melting temperature of about 213°C.

[0142] Embodiment I-25. A pharmaceutical composition comprising the crystalline form of any one of embodiments I-1 to I-24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0143] Embodiment I-26. The pharmaceutical composition of embodiment I-25, comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0144] Embodiment I-27. The pharmaceutical composition of embodiment I-25, comprising Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0145] Embodiment I-28. The pharmaceutical composition of embodiment I-25, comprising Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0146] Embodiment I-29. The pharmaceutical composition of embodiment I-25, comprising Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0147] Embodiment I-30. Compound 1 Form A, or a pharmaceutically acceptable salt thereof; Compound 1 Form B, or a pharmaceutically acceptable salt thereof; Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and Compound 1 Form D, or a pharmaceutically acceptable salt thereof; at least two crystalline forms selected from and a pharmaceutically acceptable carrier. The pharmaceutical composition of embodiment I-25, comprising:

[0148] Embodiment I-31. The pharmaceutical composition of embodiment I-25, comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0149] Embodiment I-32. The pharmaceutical composition of embodiment I-25, comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0150] Embodiment I-33. The pharmaceutical composition of embodiment I-25, comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0151] Embodiment I-34. A method of treating a disease associated with SHP2 regulation in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline form according to any one of embodiments I-1 to I-24, or a pharmaceutically acceptable salt thereof.

[0152] Embodiment I-35. The method of embodiment I-34, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast cancer, lung cancer, and colon cancer.

[0153] Embodiment I-36. A crystalline form according to any one of embodiments I-1 to I-24, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0154] Embodiment I-37. A crystalline form according to any one of embodiments I-1 to I-24, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseases associated with SHP2 modulation.

[0155] Embodiment I-38. Use of a crystalline form according to any one of embodiments I-1 to I-24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease associated with SHP2 modulation.

[0156] Embodiment I-39. A method for treating a disease associated with SHP2 regulation in a subject in need thereof, comprising administering to the subject an effective amount of a pharmaceutical composition described in any one of embodiments I-25 to I-33.

[0157] Embodiment I-40. The method of embodiment I-39, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast cancer, lung cancer, and colon cancer.

[0158] Embodiment I-41. A pharmaceutical composition according to any one of embodiments I-25 to I-33 for use as a medicament.

[0159] Embodiment I-42. A pharmaceutical composition according to any one of embodiments I-25 to I-33 for use in the treatment or prevention of diseases associated with SHP2 modulation.

[0160] Embodiment I-43. Use of a pharmaceutical composition according to any one of embodiments I-25 to I-33 in the manufacture of a medicament for the treatment or prevention of diseases associated with SHP2 modulation. [Example]

[0161] The present disclosure is further illustrated by the following examples and synthetic examples, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. It should be understood that the examples are provided to illustrate particular embodiments and that no limitation to the scope of the present disclosure is intended thereby. It should further be understood that resort is provided to various other embodiments, modifications, and equivalents thereof, which will be suggested to those skilled in the art without departing from the spirit of the present disclosure and / or the scope of the appended claims.

[0162] Differential scanning calorimetry Differential scanning calorimetry was performed using a TA Instruments Q2000; temperature calibration was performed using NIST-traceable indium metal. Samples were placed in aluminum Tzero crimped pans and the weight was accurately recorded. A weighed aluminum pan, configured as the sample pan, was placed on the reference surface of the cell. Samples were analyzed from -30°C to 250°C at a ramp rate of 10°C / min.

[0163] Differential scanning calorimetry was carried out using a Mettler-Toledo DSC3+: Temperature calibration was performed using adamantane, phenyl salicylate, indium, tin, and zinc. Samples were placed in hermetically sealed or open aluminum DSC pans, and the weight was accurately recorded. A weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. Samples were analyzed from -30°C to 250°C at a ramp rate of 10°C / min. Thermograms are plotted by reference temperature (x-axis), but results are reported according to the sample temperature.

[0164] Infrared spectroscopy Infrared spectra were recorded on a Nexus 670® Fourier transform infrared (FT-IR) spectrophotometer (Thermo) equipped with an Ever-Glo mid / far IR source, a potassium bromide (KBr) beam splitter, and a deuterated triglycine sulfate (DTGS) detector. Spectra were acquired on a 4 cm (Nicolet) quartz crystal. Wavelength confirmation was performed using NIST SRM 1921b (polystyrene). A germanium (Ge) crystal attenuated total reflectance (ATR) accessory (Thunderdome™, Thermo Spectra-Tech) was used for data acquisition. Each spectrum was captured at 4 cm -1 The graph represents 256 co-additive scans collected at a spectral resolution of 100 kHz. A background data set was acquired with a clean Ge crystal. The Log 1 / R (R = reflectance) spectrum was obtained by taking the ratio of these two data sets relative to each other.

[0165] IR peak position variability is 2cm -1 Data point interval (4cm -1 resolution) based on the observed sharpness of the selected peaks and the acquisition of the data, ±4 cm -1 Peak selection was performed using OMNIC software, version 7.2, Thermo Electron Corporation. The observed peaks include all IR peaks for a given form, but exclude peaks of very low intensity and broad peaks with poorly defined maxima.

[0166] Single crystal data collection Standard uncertainties are given in crystallographic bracket notation. For example, 0.123(4) is equal to 0.123±0.004. Calculated XRPD patterns were generated for Cu radiation from single crystal structures using MERCURY and atomic coordinates, space group, and unit cell parameters. Atomic substitution ellipsoid diagrams were generated using MERCURY. Atoms are represented by 50% probability anisotropic thermal ellipsoids.

[0167] X-ray powder diffraction XRPD patterns were collected on a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation generated using an Optix long, fine-focus source. An elliptical, gradient multilayer mirror was used to focus the Cu Kα X-rays through the specimen onto the detector. Prior to analysis, a silicon specimen (NIST SRM 640e) was analyzed to confirm that the observed position of the Si 111 peak matched the NIST-certified position. Sample specimens were sandwiched between 3 μm-thick films and analyzed in transmission geometry. A beam stop, a short anti-scatter extension, and an anti-scatter knife edge were used to minimize background caused by air. A Soller slit for the incident diffracted beam was used to minimize spread from the axial divergence. Diffraction patterns were collected using a scanning-position high-sensitivity detector (X'Celerator) positioned 240 mm from the specimen and Data Collector software v.2.2b. Data acquisition parameters for each pattern are displayed on the images in the Data section of this report, including the divergence slit (DS) before the mirror.

[0168] The data presented herein contain X-ray diffraction patterns with a peak list table. The exact peak positions are given in the table. Under most circumstances, the peaks are within a range of up to about 30° (2θ). Peaks within the range were selected. A rounding algorithm was used to round each peak to the nearest 0.01° 2θ. Peak positions along the horizontal axis, °2θ, in both figures and tables were automatically determined using proprietary software and rounded to two significant decimal places. Peak position variability was taken as ±0.2° 2θ, based on the recommendations outlined in the USP Discussion of Variability in X-ray Powder Diffraction. The accuracy and precision associated with any specific measurement reported herein were not determined. Furthermore, third-party measurements on samples independently prepared on different instruments may introduce variability greater than ±0.2° 2θ. The wavelength used to calculate d-spacings was 1.541874 Å (weighted average of the Cu Kα1 and Cu Kα2 wavelengths). The variability associated with d-spacing estimates was calculated from the USP recommendations at each d-spacing and provided in each data table.

[0169] According to USP guidelines, variable hydrates and solvates may exhibit peak dispersions greater than 0.2° 2θ, so a peak dispersion of 0.2° 2θ is not applicable to these materials.

[0170] For samples with only one XRPD pattern and no other means of assessing whether the sample provides a good approximation of the powder average, the peak table contains data identified only as "prominent peaks." Such peaks are a subset of the entire observed peak list. Prominent peaks were selected from the observed peaks by identifying high intensity, preferably non-overlapping, low angle peaks.

[0171] The availability of multiple diffraction patterns allows for the assessment of particle statistics (PS) and / or preferred orientation (PO). Reproducibility between XRPD patterns from multiple samples analyzed on a single diffractometer indicates adequate particle statistics. Consistency in relative intensities (i.e., reflection vs. transmission) between XRPD patterns from different diffractometer geometries indicates good orientation statistics. Alternatively, the observed XRPD pattern may be compared to a calculated XRPD pattern based on a single crystal structure, if available. Two-dimensional scattering patterns using an area detector can also be used to assess PS / PO. If the contributions of both PS and PO are determined to be insignificant, the XRPD pattern represents the powder average intensity for the sample, and prominent peaks can be identified as "representative peaks." In general, the more data collected to determine representative peaks, the more confidence can be gained in classifying those peaks.

[0172] To the extent present, "characteristic peaks" are a subset of the representative peaks and are used to distinguish one crystalline polymorph from another (polymorphs are crystalline forms with the same chemical composition). Characteristic peaks were determined by assessing which representative peaks, if any, are present in one crystalline polymorph of a compound within ±0.2° (2θ) of all other known crystalline polymorphs of the compound. Not all crystalline polymorphs of a compound necessarily have at least one characteristic peak.

[0173] Example 1 - Form A Upon exposure to temperatures above 80° C., Compound 1 Form A arises from either Form C or D (or a mixture thereof) through spontaneous polymorphic transformation. Upon exposure to temperatures above the melting point of Form B (approximately 188° C.), but below the melting point of Form A (approximately 213° C.), Compound 1 Form A can arise from Form B (or a mixture of Form B with Forms C and / or D) and spontaneously crystallize.

[0174] A slurry of Compound 1 in methanol was stirred for about 9 days at about 58° C. Compound 1 Form A was recovered from the slurry by water aspirator vacuum filtration.

[0175] Compound 1 Form A was characterized by X-ray powder diffraction (XRPD) as described herein. The X-ray powder diffractogram of Compound 1 Form A is shown in Figures 1A and 1B, and the peaks in the XRPD pattern and their relative intensities are shown in Table 3.

[0176] Example 2 - Form B Preparation A: A solution of Compound 1 in dichloromethane or methanol was made at ambient temperature and filtered through a 0.2 μm nylon filter. The filtrate was allowed to evaporate under ambient conditions to give Compound 1 Form B.

[0177] Preparation B: A solution of Compound 1 in methanol was prepared at approximately 50° C., treated with activated carbon, and filtered. The filtrate was slowly cooled to ambient temperature to give crystals of Compound 1 Form B.

[0178] The quality of the obtained structure is high, as indicated by a fit residual R of 0.0437 (4.37%). R factors in the range of 2% to 6% indicate the most reliably determined structure.

[0179] Data collection Approximate dimensions: 0.13 x 0.08 x 0.03 mm 3 A colorless plate of 1000 nm was mounted in a random orientation on a polymer loop. Preliminary investigations and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus shielded X-ray tube (CuKαλ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector.

[0180] The unit cell constants and orientation matrix for the data collection were obtained from least-squares refinement using setting angles of 8262 reflections in the range 3.9000° < θ < 75.6370°. The space group was determined to be P1 (international table no. 1) by the program CRYSALISPRO.

[0181] Data were collected at room temperature at a maximum diffraction angle (2θ) of 155.036°.

[0182] Table 13 below shows the crystallographic data and data collection parameters for Compound 1 Form B.

[0183] [Table 13]

[0184] Data organization Frames were stitched together in CRYSALISPRO. A total of 19,826 reflections were collected, of which 7,360 were unique. Lorentzian and polarization corrections were applied to the data. The linear absorption coefficient was 2.698 mm for CuKα radiation. -1 Experimental absorption correction using CRYSALISPRO was used. Transmission coefficients ranged from 0.906 to 1.000. The intensities of equal reflections were averaged. The agreement factor for the average, based on intensity, was 3.55%.

[0185] Structure elucidation and refinement The structure was solved by charge flipping using OLEX2. The remaining atoms were located by subsequent difference Fourier synthesis. The structure was refined using SHELXL-2014. The hydroxyl and aminopyridine hydrogen atoms were refined independently. All other hydrogen atoms were included in the refinement but were restrained as they are on bonded atoms. The structure was refined with full-matrix least-squares by minimizing the following function:

number

[0186] Scattering factors were taken from the "International Tables for Crystallography." Of the 7360 reflections used in the refinement, only 6171 reflections with intensities twice greater than their uncertainty [I > 2σ(I)] were used to calculate the fit residuals R. The final cycle of refinement included 569 variable parameters, 3 restraints,

number

[0187] The observed standard deviation of unit weight (Gof (goodness of fit)) was 1.07. The highest peak in the final difference Fourier transform had an electron density of 0.433 e / Å. 3 The minimum negative peak was -0.255e / Å 3 had a value of

[0188] Compound 1 Form B was characterized by X-ray powder diffraction (XRPD) as described herein. The X-ray powder diffractograms of Compound 1 Form B are shown in Figures 3A, 3B, 3C, and 3D, and the peaks in the XRPD pattern and their relative intensities are shown in Table 6.

[0189] Example 3 - Form C Generally, upon exposure to temperatures of approximately 43-80° C., Compound 1 Form C arises from Compound 1 Form D or A (or a mixture thereof) through spontaneous polymorphic transformation.

[0190] A slurry of Compound 1 in methanol was heated to reflux and filtered by water aspirator vacuum filtration. The filtrate was returned to a boil, treated with activated carbon, and again filtered by water aspirator vacuum filtration. The filtrate was rotary evaporated to dryness, briefly triturated in diethyl ether, filtered by water aspirator vacuum filtration, and dried under nitrogen. The solid was used to form a slurry in methanol and stirred at about 58°C for about 6 days to obtain crystals of Compound 1 Form C.

[0191] The quality of the obtained structure is high, as indicated by the fit residual R of 0.0523 (5.23%). R factors in the range of 2% to 6% indicate the most reliably determined structure.

[0192] Data collection Approximate dimensions: 0.11 x 0.08 x 0.02 mm 3 A colorless plate of 1000 nm was mounted in a random orientation on a polymer loop. Preliminary investigations and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus shielded X-ray tube (CuKαλ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector.

[0193] The unit cell constants and orientation matrix for the data collection were obtained from least-squares refinement using setting angles of 9466 reflections in the range 3.6150° < θ < 76.7550°. The space group was determined to be P21212 (international table no. 18) by the program CRYSALISPRO.

[0194] Data were collected at room temperature at a maximum diffraction angle (2θ) of 155.666°.

[0195] Table 14 below shows the crystallographic data and data collection parameters for Compound 1 Form C.

[0196] [Table 14]

[0197] Data organization Frames were stitched together in CRYSALISPRO. A total of 35,304 reflections were collected, of which 13,544 were unique. Lorentzian and polarization corrections were applied to the data. The linear absorption coefficient was 2.688 mm for CuKα radiation. -1 Experimental absorption correction using CRYSALISPRO was used. Transmission coefficients ranged from 0.848 to 1.000. The intensities of equal reflections were averaged. The agreement factor for the average, based on intensity, was 4.25%.

[0198] Structure elucidation and refinement The structure was solved by direct methods using SHELXT. The remaining atoms were subsequently The position was determined by difference Fourier synthesis. The structure was refined using SHELXL-2014. The hydrogen atoms present on the aminopyridine-NH2 moiety were refined independently. All other hydrogen atoms were included in the refinement but were restrained as they are on the bonded atoms. The structure was refined by full matrix least squares by minimizing the following function:

number

[0199] Scattering factors were taken from the "International Tables for Crystallography." Of the 13,544 reflections used in the refinement, only 9,187 reflections with intensities twice greater than their uncertainty [I > 2σ(I)] were used to calculate the fit residuals R. The final cycle of refinement included 860 variable parameters, zero suppression,

number

[0200] Compound 1 Form C was characterized by X-ray powder diffraction (XRPD) as described herein. The X-ray powder diffractogram of Compound 1 Form C is shown in Figures 8A and 8B, and the peaks in the XRPD pattern and their relative intensities are shown in Table 8.

[0201] Example 4 - Form D Preparation A: A slurry of Compound 1 in methanol was heated to reflux and filtered by water aspirator vacuum filtration. The filtrate was treated with activated carbon and again filtered by water aspirator vacuum filtration. The activated carbon treatment by filtration was repeated three times. The volume of the filtrate was reduced to less than one-quarter of its original volume under a nitrogen purge to obtain a solid. The solid was harvested by water aspirator vacuum filtration and washed with methanol. The slurry of the solid in methanol was stirred at ambient temperature for about 14 days. Compound 1 Form D was recovered from the slurry by water aspirator vacuum filtration.

[0202] Preparation B: A slurry of Compound 1 in methanol was heated to reflux and filtered by water aspirator vacuum filtration. The filtrate was returned to a boil, treated with activated carbon, and again filtered by water aspirator vacuum filtration. The filtrate was rotary evaporated to dryness, briefly triturated in diethyl ether, filtered by water aspirator vacuum filtration, and dried under nitrogen. The resulting solid particles were heated in mineral oil until plate-shaped crystals formed. The crystals were allowed to stand in the mineral oil at ambient temperature for approximately one month to convert to Compound 1 Form D, which could then be isolated.

[0203] The quality of the obtained structure was good as indicated by the residual fit R of 0.0411 (4.11%). R factors in the range of 2% to 6% indicate the most reliably determined structures.

[0204] Data collection Approximate dimensions: 0.19 x 0.08 x 0.02 mm 3 A colorless plate of 1000 nm was mounted in a random orientation on a polymer loop. Preliminary investigations and data collection were performed on a Rigaku SuperNova diffractometer equipped with a copper anode microfocus shielded X-ray tube (CuKαλ=1.54184 Å) and a Dectris Pilatus3 R 200K hybrid pixel array detector.

[0205] The unit cell constants and orientation matrix for the data collection were obtained from least-squares refinement using setting angles of 7387 reflections in the range 3.6090° < θ < 75.8260°. The space group was determined to be P21212 (international table no. 19) by the program CRYSALISPRO.

[0206] Data were collected at room temperature at a maximum diffraction angle (2θ) of 155.176°.

[0207] Data organization Frames were stitched together in CRYSALISPRO. A total of 22901 reflections were collected, of which 8903 were unique. Lorentzian and polarization corrections were applied to the data. The linear absorption coefficient was 2.717 mm for CuKα radiation. -1 Experimental absorption correction using CRYSALISPRO was used. Transmission coefficients ranged from 0.888 to 1.000. The intensities of equal reflections were averaged. The agreement factor for the average, based on intensity, was 3.54%.

[0208] Structure elucidation and refinement The structure was solved by direct methods using SHELXT. The remaining atoms were located by subsequent difference Fourier synthesis. The structure was refined using SHELXL-2014. The hydrogen atoms present on the carbon and one hydroxyl were included in the refinement but were suppressed as they are on the atom to which they are bonded. All other non-carbon hydrogen atoms were refined independently. The structure was refined with full matrix least squares by minimizing the following function:

number

[0209] Scattering factors were taken from the "International Tables for Crystallography." Of the 8903 reflections used in the refinement, only 6898 reflections with intensities twice greater than their uncertainty [I > 2σ(I)] were used to calculate the fit residuals R. The final cycle of refinement included 582 variable parameters, zero suppression,

number

[0210] Compound 1 Form D was characterized by X-ray powder diffraction (XRPD) as described herein. The X-ray powder diffractogram of Compound 1 Form D is shown in Figures 10A and 10B, and the peaks in the XRPD pattern and their relative intensities are shown in Table 11.

[0211] equivalent While the present disclosure has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present disclosure.

Claims

1. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form D, or a pharmaceutically acceptable salt thereof.

2. 2. The crystalline form of claim 1, wherein the X-ray powder diffraction pattern comprises 2θ values ​​of about 18.48 and about 16.

77.

3. 3. The crystalline form of claim 2, wherein the X-ray powder diffraction pattern further comprises one or more 2θ values ​​at about: 10.73, 11.03, 11.15, 12.58, 19.17, 19.54, 20.88, 22.47, and 25.

59.

4. 10. The crystalline form of claim 1, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in FIG. 10A.

5. 5. The crystalline form of any one of claims 1 to 4, wherein a differential scanning calorimetry (DSC) curve comprises an endotherm at about 51°C, about 90°C, or about 211°C.

6. The crystalline form of any one of claims 1 to 4, wherein the DSC curve is substantially as shown in Figure 13.

7. Unit cell dimensions: a = 14.0679 (4) Å, b = 16.0057 (4) Å, c = 19.1837 (6) Å, α = 90°, β = 90°, γ = 90°; Unit cell volume (V) 4319.5 (2) Å ３ and space group P2 １ 2 １ 7. The crystalline form of any one of claims 1 to 6, having a molecular weight of 2.

8. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form B, or a pharmaceutically acceptable salt thereof.

9. 9. The crystalline form of claim 8, wherein the X-ray powder diffraction pattern comprises 2θ values ​​of about 20.0 and about 17.

9.

10. 10. The crystalline form of claim 9, wherein the X-ray powder diffraction pattern further comprises one or more 2θ values ​​at about: 7.8, 9.1, 9.4, 11.4, 12.8, 13.4, 15.7, 18.9, 20.9, 23.1, and 25.

0.

11. 9. The crystalline form of claim 8, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in Figure 3A.

12. 12. The crystalline form of any one of claims 8 to 11, wherein the differential scanning calorimetry (DSC) curve comprises an endotherm at about 188°C and / or about 211°C.

13. The crystalline form of any one of claims 8 to 11, having a DSC curve substantially as shown in Figure 6.

14. Unit cell dimensions: a = 9.65334(16) Å, b = 10.28825(18) Å, c = 11.62614 (19) Å, α = 76.0621 (15) °, β = 89.6714 (13) °, γ = 76.4043 (15) °; unit cell volume (V) 1087.68 (3) Å ３ 12. The crystalline form of any one of claims 8 to 11, having a space group P1.

15. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form C, or a pharmaceutically acceptable salt thereof.

16. 16. The crystalline form of claim 15, wherein the X-ray powder diffraction pattern comprises 2θ values ​​of about 18.56 and about 16.

62.

17. 17. The crystalline form of claim 16, wherein the X-ray powder diffraction pattern further comprises one or more 2θ values ​​at about: 10.78, 11.11, 12.29, 19.06, 19.57, 20.83, and 25.

61.

18. 16. The crystalline form of claim 15, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in Figure 8A.

19. Unit cell dimensions: a = 47.6458 (8) Å, b = 14.4005 (2) Å, c = 9.5460 (2) Å, α = 90°, β = 90°, γ = 90°; Unit cell volume (V) 6549.8 (2) Å ３ and space group P2 １ 2 １ 2. The crystalline form of any one of claims 15 to 18, having a molecular weight of 2.

20. A crystalline form of {6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-methylpyrazin-2-yl}methanol, characterized as Compound 1 Form A, or a pharmaceutically acceptable salt thereof.

21. 21. The crystalline form of claim 20, wherein the X-ray powder diffraction pattern comprises 2θ values ​​of about 16.66 and about 18.

50.

22. 22. The crystalline form of claim 21, wherein the X-ray powder diffraction pattern further comprises one or more 2θ values ​​at about: 10.76, 11.11, 12.35, 19.08, 19.52, 20.85, and 25.

63.

23. 21. The crystalline form of claim 20, wherein the X-ray powder diffraction pattern substantially corresponds to the X-ray powder diffraction pattern shown in Figure 1A.

24. 21. The crystalline form of claim 20, having an onset melting temperature of about 213°C.

25. 25. A pharmaceutical composition comprising the crystalline form of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. 26. The pharmaceutical composition of claim 25, comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. 26. The pharmaceutical composition of claim 25, comprising Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

28. 26. The pharmaceutical composition of claim 25, comprising Compound 1 Form B, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. 26. The pharmaceutical composition of claim 25, comprising Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

30. Compound 1 Form A, or a pharmaceutically acceptable salt thereof; Compound 1 Form B, or a pharmaceutically acceptable salt thereof; Compound 1 Form C, or a pharmaceutically acceptable salt thereof, and Compound 1 Form D, or a pharmaceutically acceptable salt thereof; At least two crystalline forms selected from and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25, comprising:

31. 26. The pharmaceutical composition of claim 25, comprising Compound 1 Form D, or a pharmaceutically acceptable salt thereof, and Compound 1 Form A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

32. 26. The pharmaceutical composition of claim 25, comprising Compound 1 Form D or a pharmaceutically acceptable salt thereof, and Compound 1 Form B or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

33. 26. The pharmaceutical composition of claim 25, comprising Compound 1 Form D or a pharmaceutically acceptable salt thereof, and Compound 1 Form C or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

34. 25. A method of treating a disease associated with SHP2 regulation in a subject in need thereof, comprising administering to the subject an effective amount of the crystalline form of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof.

35. 35. The method of claim 34, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast cancer, lung cancer, and colon cancer.

36. 25. The crystalline form of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use as a medicament.

37. 25. The crystalline form of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of diseases associated with SHP2 modulation.

38. 25. Use of the crystalline form of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of diseases associated with SHP2 modulation.

39. 34. A method of treating a disease associated with SHP2 regulation in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of any one of claims 25 to 33.

40. 40. The method of claim 39, wherein the disease is selected from Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, and breast, lung, and colon cancer.

41. A pharmaceutical composition according to any one of claims 25 to 33 for use as a medicament.

42. A pharmaceutical composition according to any one of claims 25 to 33 for use in the treatment or prevention of diseases which are associated with SHP2 regulation.

43. Use of a pharmaceutical composition according to any one of claims 25 to 33 in the manufacture of a medicament for the treatment or prevention of diseases which are associated with SHP2 regulation.

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