SHP2 phosphatase inhibitors and methods of making and using the same

Abstract

The present disclosure relates, in part, to crystalline forms of (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine, salts thereof, and variants thereof.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 904,986, filed September 24, 2019, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0003] Protein tyrosine phosphatase 2 (SHP2), containing the Src homology region 2 (SH2), is a protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 contains two Src homology 2 (SH2) NH2-terminal domains and one C-terminal protein tyrosine phosphatase domain. It is universally expressed in various tissues and cell types. SHP2 plays a crucial role in multiple signal transduction pathways to regulate cellular biological processes and is involved in the signal transduction pathways of various growth factors and cytokines. In individual signal transduction pathways, SHP2 can exert both positive (signal enhancement) and negative (signal attenuation) effects in intracellular signal transduction. It is believed that SHP2 exerts its effects by dephosphorylating its associated signal transduction molecules, thereby attenuating local signal transduction flux. However, the primary effect of SHP2 in most signal transduction pathways (e.g., growth factors, cytokines, and extracellular matrix receptors) is to enhance signal transduction. For example, SHP2 is a positive regulator of the ERK / MAPK signaling pathway, playing a vital role in regulating cell proliferation and survival. (For a review of SHP2 phosphatase, see, for example, KSGrossman et al., Adv. Cancer Res. 2010, 106, 53-89; and the references cited therein.)

[0004] In its basal state, SHP2 is typically self-repressed due to the intramolecular interaction between its N-terminal SH2 (N-SH2) domain and its catalytic (PTP) domain, thus blocking access to the catalytic site. Activation of the protein interacting with the SH2 domain induces a conformational change that reverses this inhibition and allows substrate access to the catalytic site. Mutations in the PTPN11 gene affecting the N-SH2 or PTP domain residues involved in basal SHP2 inhibition produce a more readily activated form of the SHP2 protein, which may result in unregulated or increased SHP2 activity. Such activated mutants of SHP2 are associated with developmental disorders such as Noonan syndrome, in which almost all mutant forms of SHP2 exhibit increased PTP activity. Therefore, there is a need for SHP2 phosphatase inhibitor compounds and methods for treating cancer and other diseases with these compounds.

[0005] Polymorphism is the ability of a substance to crystallize in more than one lattice arrangement. Crystallization or polymorphism can affect many aspects of the solid state properties of a drug substance. A crystalline substance can be significantly different from an amorphous form, and different crystal modifications of a substance can be significantly different from each other in many respects, including solubility, rate of dissolution, and / or bioavailability. In general, it is difficult to predict whether a given compound will form various crystalline solid state forms. It is even more difficult to predict the physical properties of these crystalline solid state forms. In addition, for some formulations, such as those suitable for subcutaneous use, it can be advantageous to have a crystalline form of a therapeutic agent. SUMMARY

[0006] The present disclosure generally relates to (R)-1'-(3-(3,4-dihydro-1,5- naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'- piperidin]-3-amine, and salts thereof, and the like. Further, the present disclosure generally relates to crystalline forms of (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine, and salts thereof, and the like.

[0007] For example, provided herein is a compound of Formula (I):

[0008]

[0009] or a solvate thereof;

[0010] wherein,

[0011] m is 1-9;

[0012] n is 0-3; and

[0013] X is hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid, L-aspartic acid, maleic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, succinic acid, or glutaric acid.

[0014] Pharmaceutical compositions comprising a disclosed compound or crystalline form provided herein and a pharmaceutically acceptable excipient, e.g., compositions formulated for subcutaneous, intravenous, or oral administration, are contemplated. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1A FIG. 1 depicts the X-ray diffraction pattern of Compound I-1 in various solvents following a temperature cycling procedure.

[0016] Figure 1BDepicted is the characterization of Form A of compound I-1 by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0017] Figure 2A Depicted is the characterization of the X-ray diffraction pattern of compound I-2 compared to the X-ray diffraction pattern of Form A of compound I-1.

[0018] Figure 2B Depicted is the characterization of the X-ray diffraction pattern of compound I-2 after the re-pulping experiment compared to the X-ray diffraction pattern of Form A of compound I-1.

[0019] Figure 2C Depicted is the characterization of Form S1-I of compound I-2 by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0020] Figure 3A Depicted is the characterization of the X-ray diffraction pattern of compound I-3 compared to the X-ray diffraction pattern of Form A of compound I-1.

[0021] Figure 3B Depicted is the characterization of the X-ray diffraction pattern of compound I-3 after the re-pulping experiment compared to the X-ray diffraction pattern of Form A of compound I-1.

[0022] Figure 4A Depicted is the characterization of the X-ray diffraction pattern of compound I-4 compared to the X-ray diffraction pattern of Form A of compound I-1.

[0023] Figure 4B Depicted is the characterization of the X-ray diffraction pattern of compound I-4 after the re-pulping experiment compared to the X-ray diffraction pattern of Form A of compound I-1.

[0024] Figure 5A Depicted is the characterization of the X-ray diffraction pattern of compound I-5 compared to the X-ray diffraction pattern of Form A of compound I-1.

[0025] Figure 5B Depicted is the characterization of the X-ray diffraction pattern of compound I-5 after the re-pulping experiment compared to the X-ray diffraction pattern of Form A of compound I-1.

[0026] Figure 6A Depicted is the characterization of the X-ray diffraction pattern of compound I-6 compared to the X-ray diffraction pattern of Form A of compound I-1.

[0027] Figure 6BDepicted is the characterization of the X-ray diffraction pattern of compound I-6 compared to the X-ray diffraction pattern of Pattern A of compound I-1 after repulping experiments.

[0028] Figure 7A Depicted is the characterization of the X-ray diffraction pattern of compound I-7 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0029] Figure 7B Depicted is the characterization of Pattern S6-I of compound I-7 by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0030] Figure 7C Depicted is the characterization of the X-ray diffraction pattern of compound I-7 compared to the X-ray diffraction pattern of Pattern A of compound I-1 after repulping experiments.

[0031] Figure 8A Depicted is the characterization of the X-ray diffraction pattern of compound I-8 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0032] Figure 8B Depicted is the characterization of Pattern S7-I of compound I-8 by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0033] Figure 8C Depicted is the characterization of Pattern S7-II of compound I-8 by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0034] Figure 9A Depicted is the characterization of the X-ray diffraction pattern of compound I-9 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0035] Figure 9B Depicted is the characterization of the X-ray diffraction pattern of compound I-9 compared to the X-ray diffraction pattern of Pattern A of compound I-1 after repulping experiments.

[0036] Figure 10 Depicted is the characterization of the X-ray diffraction pattern of compound I-10 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0037] Figure 11A Depicted is the characterization of the X-ray diffraction pattern of compound I-11 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0038] Figure 11BDepicted is the characterization of the X-ray diffraction pattern of compound I- 11 compared to the X-ray diffraction pattern of Pattern A of compound I-1 after re-slurry experiment.

[0039] Figure 12A Depicted is the characterization of the X-ray diffraction pattern of compound I- 12 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0040] Figure 12B Depicted is the characterization of the X-ray diffraction pattern of compound I- 12 compared to the X-ray diffraction pattern of Pattern A of compound I-1 after re-slurry experiment.

[0041] Figure 12C Depicted is the characterization of the X-ray diffraction pattern of compound I- 12 after polymorph screening experiment.

[0042] Figure 12D Depicted is the characterization of Pattern A of compound I-12 by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0043] Figure 12E Depicted is the characterization of Pattern S11-I* of compound I-12 (as 12) by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0044] Figure 13A Depicted is the characterization of the X-ray diffraction pattern of compound I- 13 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0045] Figure 13B Depicted is the characterization of the X-ray diffraction pattern of compound I- 13 compared to the X-ray diffraction pattern of Pattern A of compound I-1 after re-slurry experiment.

[0046] Figure 14A Depicted is the characterization of the X-ray diffraction pattern of compound I- 14 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0047] Figure 14B Depicted is the characterization of the X-ray diffraction pattern of compound I- 14 compared to the X-ray diffraction pattern of Pattern A of compound I-1 after re-slurry experiment.

[0048] Figure 15A Depicted is the characterization of the X-ray diffraction pattern of compound I- 15 compared to the X-ray diffraction pattern of Pattern A of compound I-1.

[0049] Figure 15BA depiction of the characterization of the X-ray diffraction pattern of compound I- 15 compared to Pattern A of compound I-1 after re-slurry experiment.

[0050] Figure 16A A depiction of the characterization of the X-ray diffraction pattern of compound I- 16 compared to Pattern A of compound I-1.

[0051] Figure 16B A depiction of the characterization of the X-ray diffraction pattern of compound I- 16 compared to Pattern A of compound I-1 after re-slurry experiment.

[0052] Figure 17A A depiction of the characterization of the X-ray diffraction pattern of compound I- 17 compared to Pattern A of compound I-1.

[0053] Figure 17B A depiction of the characterization of Pattern A of compound I-17 by differential scanning calorimetry (DSC) (green) and thermogravimetric analysis (TGA) (blue).

[0054] Figure 17C A depiction of the characterization of the X-ray diffraction pattern of compound I- 17 compared to Pattern A of compound I-1 after re-slurry experiment.

[0055] Figure 17D A depiction of the characterization of the X-ray diffraction pattern of compound I- 17 after polymorph screening experiment. DETAILED DESCRIPTION

[0056] The present disclosure relates, at least in part, to (R)-1'-(3-(3,4-dihydro-1,5- naphthyridin-1 (2H)-yl)-1 H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'- piperidin]-3-amine and salts thereof, salts thereof, and crystalline forms thereof. The present disclosure also provides a pharmaceutical composition comprising (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'- piperidin]-3-amine and salts thereof, salts thereof, and crystalline forms thereof, and a pharmaceutically acceptable carrier. The term "crystalline form" refers to a crystal form or modification that is characterizable by analytical methods such as, for example, X-ray powder diffraction.

[0057] In one embodiment, provided herein is a compound of Formula (I):

[0058]

[0059] or a solvate thereof;

[0060] wherein,

[0061] m is 1-9;

[0062] n is 0-3; and

[0063] X is hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid, L-aspartic acid, maleic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, succinic acid, or glutaric acid.

[0064] In some embodiments, provided herein is a compound of Formula (I):

[0065]

[0066] or a solvate thereof;

[0067] wherein,

[0068] m is 1-9;

[0069] n is 1-3; and

[0070] X is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, oxalic acid, L-aspartic acid, maleic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, succinic acid, and glutaric acid.

[0071] One of ordinary skill in the art will appreciate that the acid moiety represented as "X" is ionically bonded to (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H-pyrazolo[3,4- b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine to form a compound of Formula (I).

[0072] It is contemplated that the compounds of Formula (I) can exist in a variety of physical forms. For example, the compounds of Formula (I) can exist in solution, suspension, or solid form. In certain embodiments, the compounds of Formula (I) are in solid form. When the compounds of Formula (I) are in solid form, the compounds can be amorphous compounds, crystalline compounds, or mixtures thereof. Exemplary solid forms are described in more detail below.

[0073] In some embodiments, Formula (I) can be in a hydrate form. In some embodiments, Formula (I) can be in a hemihydrate form.

[0074] In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9.

[0075] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 0.5. In some embodiments, n is 1.5. In some embodiments, n is 2.5.

[0076] In some embodiments, X is hydrochloric acid. In some embodiments, X is hydrobromic acid. In some embodiments, X is sulfuric acid. In some embodiments, X is methanesulfonic acid. In some embodiments, X is phosphoric acid. In some embodiments, X is p-toluenesulfonic acid. In some embodiments, X is benzenesulfonic acid. In some embodiments, X is oxalic acid. In some embodiments, X is L-aspartic acid. In some embodiments, X is maleic acid. In some embodiments, X is malonic acid. In some embodiments, X is L-tartaric acid. In some embodiments, X is fumaric acid. In some embodiments, X is citric acid. In some embodiments, X is succinic acid. In some embodiments, X is glutaric acid.

[0077] In one aspect, provided herein is (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H- pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine. In some embodiments, the compound of Formula (I) is Compound I-1:

[0078]

[0079] or a solvate thereof.

[0080] In some embodiments, Compound I-1 is an amorphous solid. In other embodiments, Compound I-1 is a crystalline solid. For example, a solid crystalline form of Compound I-1 can be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks in degrees 2-theta each selected from the group consisting of about 24.6 2-theta, about 19.9 2-theta, and about 16.0 2-theta. For example, a solid crystalline form of Compound I-1 can be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks in degrees 2-theta each selected from the group consisting of about 24.6 2-theta, about 19.9 2-theta, about 16.0 2-theta, about 6.7 2-theta, about 12.8 2-theta, about 13.4 2-theta, and about 20.7 2-theta. In some embodiments, a solid crystalline form of Compound I-1 can be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks in degrees 2-theta each selected from the group consisting of about 24.6 2-theta, about 19.9 2-theta, about 16.0 2-theta, about 6.7 2-theta, about 12.8 2-theta, about 13.4 2-theta, and about 20.7 2-theta. In some embodiments, a solid crystalline form of Compound I-1 can be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks in degrees 2-theta each selected from the group consisting of about 24.6 2-theta, about 19.9 2-theta, about 16.0 2-theta, about 6.7 2-theta, about 12.8 2-theta, about 13.4 2-theta, and about 20.7 2-theta. According to another aspect, the X-ray diffraction pattern of Compound I-1 is substantially similar to the X-ray diffraction pattern depicted in FIG. 1. In some embodiments, a solid crystalline form of Compound I-1 can be characterized by a powder X-ray diffraction pattern having at least two characteristic peaks in degrees 2-theta each selected from the group consisting of peaks listed in Table 2. In some embodiments, a solid crystalline form of Compound I-1 can be characterized by a powder X-ray diffraction pattern having at least three characteristic peaks in degrees 2-theta each selected from the group consisting of peaks listed in Table 2. In some embodiments, a solid crystalline form of Compound I-1 can be characterized by a powder X-ray diffraction pattern having at least four characteristic peaks in degrees 2-theta each selected from the group consisting of peaks listed in Table 2. Figure 1A

[0081] In the context of peaks at degrees 2-theta, the term“about” means that there is an uncertainty of ±0.5 in the measurement of 2-theta, or, for example, means that there is an uncertainty of ±0.2 in the measurement of 2-theta.

[0082] According to another aspect, the thermogravimetric analysis profile of Compound I-1 is substantially similar to the thermogravimetric analysis profile depicted in FIG. 2. According to yet another aspect, the differential scanning calorimetry profile of Compound I-1 is substantially similar to the differential scanning calorimetry profile depicted in FIG. 3. Figure 1B Figure 1B ​​the differential scanning calorimetry profile depicted in FIG. 2. For example, a solid crystalline form of Compound I-1 is expected to be characterized by a differential scanning calorimetry (DSC) profile showing an endothermic peak with an onset at about 196 °C, a peak at about 197 °C. Compound I-1 can be characterized by being substantially similar to both of these figures simultaneously.

[0083] In another embodiment, the compound of Formula (I) is Compound I-2, wherein Compound I-2 is a hydrobromide salt. In some embodiments, Compound I-2 is a monohydrobromide salt. In some embodiments, Compound I-2 is a dihydrobromide salt. In some embodiments, Compound I-2 is a trihydrobromide salt. In some embodiments, Compound I-2 is a crystalline solid. In some embodiments, Compound I-2 is a crystalline solid and is Pattern S1-I. According to another aspect, the X-ray diffraction pattern of Compound I-2 is substantially similar to the X-ray diffraction pattern depicted in FIG. 1. Figure 2A In another embodiment, the compound of Formula (I) is Compound I-2, wherein Compound I-2 is a hydrobromide salt. In some embodiments, Compound I-2 is a monohydrobromide salt. In some embodiments, Compound I-2 is a dihydrobromide salt. In some embodiments, Compound I-2 is a trihydrobromide salt. In some embodiments, Compound I-2 is a crystalline solid. In some embodiments, Compound I-2 is a crystalline solid and is Pattern S1-I. According to another aspect, the X-ray diffraction pattern of Compound I-2 is substantially similar to the X-ray diffraction pattern depicted in FIG. 1. Figure 2B In another embodiment, the compound of Formula (I) is Compound I-2, wherein Compound I-2 is a hydrobromide salt. In some embodiments, Compound I-2 is a monohydrobromide salt. In some embodiments, Compound I-2 is a dihydrobromide salt. In some embodiments, Compound I-2 is a trihydrobromide salt. In some embodiments, Compound I-2 is a crystalline solid. In some embodiments, Compound I-2 is a crystalline solid and is Pattern S1-I. According to another aspect, the X-ray diffraction pattern of Compound I-2 is substantially similar to the X-ray diffraction pattern depicted in FIG. 1. Figure 2C In another embodiment, the compound of Formula (I) is Compound I-2, wherein Compound I-2 is a hydrobromide salt. In some embodiments, Compound I-2 is a monohydrobromide salt. In some embodiments, Compound I-2 is a dihydrobromide salt. In some embodiments, Compound I-2 is a trihydrobromide salt. In some embodiments, Compound I-2 is a crystalline solid. In some embodiments, Compound I-2 is a crystalline solid and is Pattern S1-I. According to another aspect, the X-ray diffraction pattern of Compound I-2 is substantially similar to the X-ray diffraction pattern depicted in FIG. 1. Figure 2C In another embodiment, the compound of Formula (I) is Compound I-2, wherein Compound I-2 is a hydrobromide salt. In some embodiments, Compound I-2 is a monohydrobromide salt. In some embodiments, Compound I-2 is a dihydrobromide salt. In some embodiments, Compound I-2 is a trihydrobromide salt. In some embodiments, Compound I-2 is a crystalline solid. In some embodiments, Compound I-2 is a crystalline solid and is Pattern S1-I. According to another aspect, the X-ray diffraction pattern of Compound I-2 is substantially similar to the X-ray diffraction pattern depicted in FIG. 1.

[0084] In another embodiment, the compound of Formula (I) is Compound I-3, wherein Compound I-3 is a hydrochloride salt. In some embodiments, Compound I-3 is a monohydrochloride salt. In some embodiments, Compound I-3 is a dihydrochloride salt. In some embodiments, Compound I-3 is a trihydrochloride salt. In some embodiments, Compound I-3 is a solid. According to another aspect, the X-ray diffraction pattern of Compound I-3 is substantially similar to the X-ray diffraction pattern depicted in FIG. 3. Figure 3A In another embodiment, the compound of Formula (I) is Compound I-3, wherein Compound I-3 is a hydrochloride salt. In some embodiments, Compound I-3 is a monohydrochloride salt. In some embodiments, Compound I-3 is a dihydrochloride salt. In some embodiments, Compound I-3 is a trihydrochloride salt. In some embodiments, Compound I-3 is a solid. According to another aspect, the X-ray diffraction pattern of Compound I-3 is substantially similar to the X-ray diffraction pattern depicted in FIG. 3. Figure 3B In another embodiment, the compound of Formula (I) is Compound I-3, wherein Compound I-3 is a hydrochloride salt. In some embodiments, Compound I-3 is a monohydrochloride salt. In some embodiments, Compound I-3 is a dihydrochloride salt. In some embodiments, Compound I-3 is a trihydrochloride salt. In some embodiments, Compound I-3 is a solid. According to another aspect, the X-ray diffraction pattern of Compound I-3 is substantially similar to the X-ray diffraction pattern depicted in FIG. 3.

[0085] In another embodiment, the compound of Formula (I) is Compound I-4, wherein Compound I-4 is a sulfate salt. In some embodiments, Compound I-4 is a solid. According to another aspect, the X-ray diffraction pattern of Compound I-4 is substantially similar to the X-ray diffraction pattern depicted in FIG. 4. Figure 4A In another embodiment, the compound of Formula (I) is Compound I-4, wherein Compound I-4 is a sulfate salt. In some embodiments, Compound I-4 is a solid. According to another aspect, the X-ray diffraction pattern of Compound I-4 is substantially similar to the X-ray diffraction pattern depicted in FIG. 4.Figure 4B The X-ray diffraction patterns depicted in the figures. Compound I-4 can be characterized by being substantially similar to two of these figures.

[0086] In another embodiment, the compound of formula (I) is compound I-5, wherein compound I-5 is a methanesulfonate. In some embodiments, compound I-5 is a solid. According to another aspect, the X-ray diffraction pattern of compound I-5 is substantially similar to... Figure 5A The X-ray diffraction pattern depicted in [the text]. According to another aspect, the X-ray diffraction pattern of compound I-5 is essentially similar to [the text]. Figure 5B The X-ray diffraction patterns depicted in the figures. Compound I-5 can be characterized by being substantially similar to two of these figures.

[0087] In another embodiment, the compound of formula (I) is compound I-6, wherein compound I-6 is a phosphate. In some embodiments, compound I-6 is a solid. According to another aspect, the X-ray diffraction pattern of compound I-6 is substantially similar to... Figure 6A The X-ray diffraction pattern depicted in [the text]. According to another aspect, the X-ray diffraction pattern of compound I-6 is essentially similar to [the text]. Figure 6B The X-ray diffraction patterns depicted in the figures. Compound I-6 can be characterized by being substantially similar to two of these figures.

[0088] In another embodiment, the compound of formula (I) is compound I-7, wherein compound I-7 is a p-toluenesulfonate. In some embodiments, compound I-7 is a crystalline solid. In some embodiments, compound I-7 is a crystalline solid and is of pattern S6-I. According to another aspect, the X-ray diffraction pattern of compound I-7 is substantially similar to... Figure 7A The X-ray diffraction pattern depicted in [the image / document]. According to another aspect, the thermogravimetric analysis pattern of compound I-7 is essentially similar to [the image / document ... Figure 7B The X-ray diffraction pattern depicted in the diagram. According to another aspect, the differential scanning calorimetry (DSC) pattern of compound I-7 is essentially similar to... Figure 7B The differential scanning calorimetry (DSC) plots depicted in the figures. Compound I-7 can be characterized by being substantially similar to two or more plots in these figures.

[0089] In another embodiment, the compound of formula (I) is compound I-8, wherein compound I-8 is a benzenesulfonate. In some embodiments, compound I-8 is a crystalline solid. In some embodiments, compound I-8 is a crystalline solid and is in pattern S7-I. In some embodiments, compound I-8 is a crystalline solid and is in pattern S7-II. According to another aspect, the X-ray diffraction pattern of compound I-8 is substantially similar to... Figure 8Athe thermogravimetric analysis profile depicted in FIG. 16. According to another aspect, the compound I-8 can be characterized by a differential scanning calorimetry profile substantially similar to that depicted in FIG. 17. Figure 8B the thermogravimetric analysis profile depicted in FIG. 16. According to another aspect, the compound I-8 can be characterized by a differential scanning calorimetry profile substantially similar to that depicted in FIG. 17. Figure 8B the differential scanning calorimetry profile depicted in FIG. 17. Compound I-8 can be characterized by a simultaneous substantial similarity to two or more of these figures.

[0090] In another embodiment, the compound of Formula (I) is Compound I-9, wherein Compound I-9 is an oxalate salt. In some embodiments, Compound I-9 is a solid. According to another aspect, the compound I-9 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 18. Figure 9A the X-ray diffraction pattern depicted in FIG. 18. According to another aspect, the compound I-9 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 19. Figure 9B the X-ray diffraction pattern depicted in FIG. 18. According to another aspect, the compound I-9 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 19.

[0091] In another embodiment, the compound of Formula (I) is Compound I-10, wherein Compound I-10 is an L-aspartate salt. In some embodiments, Compound I-10 is a solid. In some embodiments, Compound I-10 is a crystalline solid. According to another aspect, the compound I-10 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 20. Figure 10 the X-ray diffraction pattern depicted in FIG. 20.

[0092] In another embodiment, the compound of Formula (I) is Compound I-11, wherein Compound I-11 is a maleate salt. In some embodiments, Compound I-11 is a solid. According to another aspect, the compound I-11 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 21. Figure 11A the X-ray diffraction pattern depicted in FIG. 21. According to another aspect, the compound I-11 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 22. Figure 11B the X-ray diffraction pattern depicted in FIG. 21. According to another aspect, the compound I-11 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 22.

[0093] In another embodiment, the compound of Formula (I) is Compound I-12, wherein Compound I-12 is a malonate salt. In some embodiments, Compound I-12 is a solid. In some embodiments, Compound I-12 is a crystalline solid. According to another aspect, the compound I-12 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 23. Figure 12A the X-ray diffraction pattern depicted in FIG. 23. According to another aspect, the compound I-12 can be characterized by an X-ray diffraction pattern substantially similar to that depicted in FIG. 24. Figure 12Bthe X-ray diffraction pattern depicted in FIG. 1-12. According to another aspect, the X-ray diffraction pattern of compound I-12 is substantially similar to Figure 12C the thermogravimetric analysis pattern depicted in FIG. 1-12. According to another aspect, the thermogravimetric analysis pattern of compound I-12 is substantially similar to Figure 12D the thermogravimetric analysis pattern depicted in FIG. 1-12. According to another aspect, the thermogravimetric analysis pattern of compound I-12 is substantially similar to Figure 12D the thermogravimetric analysis pattern depicted in FIG. 1-12. Compound I-12 can be characterized by a simultaneous substantial similarity to two or more of these figures.

[0094] In another embodiment, the compound of formula (I) is compound I-13, wherein compound I-13 is an L-tartrate salt. In some embodiments, compound I-13 is a solid. According to another aspect, the X-ray diffraction pattern of compound I-13 is substantially similar to Figure 13A the X-ray diffraction pattern depicted in FIG. 1-12. According to another aspect, the X-ray diffraction pattern of compound I-13 is substantially similar to Figure 13B the X-ray diffraction pattern depicted in FIG. 1-12. Compound I-13 can be characterized by a simultaneous substantial similarity to two or more of these figures.

[0095] In another embodiment, the compound of formula (I) is compound I-14, wherein compound I-14 is a fumarate salt. In some embodiments, compound I-14 is a solid. According to another aspect, the X-ray diffraction pattern of compound I-14 is substantially similar to Figure 14A the X-ray diffraction pattern depicted in FIG. 1-12. According to another aspect, the X-ray diffraction pattern of compound I-14 is substantially similar to Figure 14B the X-ray diffraction pattern depicted in FIG. 1-12. Compound I-14 can be characterized by a simultaneous substantial similarity to two or more of these figures.

[0096] In another embodiment, the compound of formula (I) is compound I-15, wherein compound I-15 is a citrate salt. In some embodiments, compound I-15 is a solid. According to another aspect, the X-ray diffraction pattern of compound I-15 is substantially similar to Figure 15A the X-ray diffraction pattern depicted in FIG. 1-12. According to another aspect, the X-ray diffraction pattern of compound I-15 is substantially similar to Figure 15B the X-ray diffraction pattern depicted in FIG. 1-12. Compound I-15 can be characterized by a simultaneous substantial similarity to two or more of these figures.

[0097] In another embodiment, the compound of formula (I) is compound I-16, wherein compound I-16 is a succinate. In some embodiments, compound I-16 is a solid. According to another aspect, the X-ray diffraction pattern of compound I-16 is substantially similar to... Figure 16A The X-ray diffraction pattern depicted in [the text]. According to another aspect, the X-ray diffraction pattern of compound I-17 is essentially similar to [the text]. Figure 16B The X-ray diffraction patterns depicted in the figures. Compound I-16 can be characterized by being substantially similar to two of the patterns in these figures.

[0098] In another embodiment, the compound of formula (I) is compound I-17, wherein compound I-17 is a glutarate. In some embodiments, compound I-17 is a solid. In some embodiments, compound I-17 is a crystalline solid. In some embodiments, compound I-17 is a crystalline solid and is of pattern S16-I. According to another aspect, the X-ray diffraction pattern of compound I-17 is substantially similar to... Figure 17A The X-ray diffraction pattern depicted in [the text]. According to another aspect, the X-ray diffraction pattern of compound I-17 is essentially similar to [the text]. Figure 17B The X-ray diffraction pattern depicted in [the text]. According to another aspect, the X-ray diffraction pattern of compound I-17 is essentially similar to [the text]. Figure 17C The X-ray diffraction pattern depicted in [the image]. According to another aspect, the thermogravimetric analysis pattern of compound I-17 is essentially similar to [the image described in the image]. Figure 17D The thermogravimetric analysis diagram depicted in [the text]. According to another aspect, the differential scanning calorimetry (DSC) diagram of compound I-17 is essentially similar to [the text's description]. Figure 17D The differential scanning calorimetry (DSC) plots depicted in the figures. Compound I-17 can be characterized by being substantially similar to two or more plots in these figures.

[0099] Method

[0100] In some embodiments, this document discloses a method for inhibiting SHP2 phosphatase activity in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of the solid form, compound, or pharmaceutical composition disclosed herein. In other embodiments, this document discloses a method for treating a condition in a subject with this need, the method comprising administering to the subject a therapeutically effective amount of the solid form, compound, or pharmaceutical composition disclosed herein. In some embodiments, the subject is a human.

[0101] In some embodiments, the methods disclosed herein can further comprise administering a therapeutically effective amount of an antibody, an antibody-drug conjugate, an immunomodulator, or a histone deacetylase inhibitor. In some embodiments, the condition to be treated is Noonan Syndrome. In some embodiments, the condition to be treated is neutropenia. In some embodiments, the condition to be treated is diabetes. In some embodiments, the condition to be treated is neuroblastoma. In some embodiments, the condition to be treated is melanoma. In some embodiments, the condition to be treated is acute myelogenous leukemia. In some embodiments, the condition to be treated is juvenile leukemia. In some embodiments, the condition to be treated is juvenile myelomonocytic leukemia. In some embodiments, the condition to be treated is breast cancer. In some embodiments, the condition to be treated is lung cancer. In some embodiments, the condition to be treated is colorectal cancer.

[0102] The disclosed compounds or compositions can be used for applications that benefit from inhibition of SHP2 phosphatase. For example, inhibition of SHP2 phosphatase can provide a therapeutic approach for treating cancer. (See, e.g., Y.-N. P. Chen et al., Nature, 2016, doi: 10.1038 / nature18621; and references cited therein; each of these references is hereby incorporated by reference in its entirety herein.) It has also been found that inhibition of SHP2 phosphatase improves the pathogenesis of systemic lupus erythematosus. (See, e.g., J. Wang et al., J. Clin. Invest. 2016, 126, 2077-2092; and references cited therein; each of these references is hereby incorporated by reference in its entirety herein.)

[0103] In some embodiments, the compounds or compositions of the present disclosure can be used to inhibit tumor cell growth. In some embodiments, the compounds or compositions of the present disclosure can be used to improve the pathogenesis of systemic lupus erythematosus. In some embodiments, the compounds or compositions of the present disclosure can be used to treat various other conditions, including Noonan Syndrome (NS), Leopard Syndrome (Noonan Syndrome with multiple lentigines), diabetes, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia, acute myelogenous leukemia, HER2-positive breast cancer, triple-negative breast cancer, breast ductal carcinoma, breast invasive ductal carcinoma, non-small cell lung cancer (including lung adenocarcinoma), colorectal cancer (SW480, SW620, CACO2, HCT116, HT29 colon cancer cell lines), esophageal cancer, gastric cancer, head and neck squamous cell carcinoma (SCCHN), and neutropenia (Kostmann Syndrome).

[0104] In some embodiments, the compounds or compositions of the present disclosure can be used in combination with other treatments and / or cancer therapies. For example, the compounds or compositions of the present disclosure can be used in combination with, without limitation, antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. The compounds or compositions of the present disclosure can also be used in combination with other treatments and / or cancer therapies disclosed in WO 2015 / 107495 and references cited therein, each of which is hereby incorporated by reference in its entirety.

[0105] For example, a compound disclosed herein (or a pharmaceutical composition containing them) can be used alone or in combination with another therapeutic agent for the treatment of one or more of the diseases mentioned herein. For example, a compound of Formula I, Formula II, or Formula III can be used in combination with the following agents: BCR-ABL inhibitors: imatinib mesylate, nilotinib hydrochloride, nilotinib, dasatinib, bosutinib, ponatinib, baricitinib, darusutnib, selpercatinib, N-[2-[(1S,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4- tetrahydronaphthalen-1,4-ylimino]-2-oxoethyl]-acetamide; ALK inhibitors: crizotinib, 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1- yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine, ceritinib, alectinib, brigatinib, entrectinib; BRAF inhibitors: vemurafenib and dabrafenib; FGFR inhibitors: infigratinib, dovitinib, erdafitinib, BLU-554, AZD4547; FLT3 inhibitors: sunitinib malate, midostaurin, tanutinib, sorafenib, lestaurtinib, quizartinib, and crenolanib; KRAS inhibitors: MRTX849, AMG510; MEK inhibitors - trametinib, cobimetinib, binimetinib, selumetinib; VEGF receptor inhibitors: bevacizumab, axitinib, aflibercept, (N-methyl-2-[[3-[(E)-2-pyridin-2-ylvinyl]-1H-indazol-6-yl]thio]benzamide, alanine brigatinib ((S)-(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl) 2-aminopropanoate), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3- pyridinecarboxamide, peptichemio, sorafenib; tyrosine kinase inhibitors: erlotinib hydrochloride, linifanib, sunitinib malate, pazopanib; epidermal growth factor receptor (EGFR) inhibitors: gefitinib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors: trastuzumab, neratinib, lapatinib, or lapatinib ditosylate; MET inhibitors: crizotinib, cabozantinib; CD20 antibodies: rituximab, tositumumab, ofatumumab; DNA synthesis inhibitors: capecitabine, gemcitabine hydrochloride, nelarabine, hydroxycarbamide; antineoplastic agents: oxaliplatin; HER dimerization inhibitors: pertuzumab; human granulocyte colony-stimulating factor (G-CSF) modulators: filgrastim; immunomodulators: atacicept, lenalidomide, thalidomide;CD40 inhibitors: Dacetuzumab; Pro-apoptotic receptor agonists (PARA): Duvelitiib; Heat shock protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethylgeldanamycin); Hedgehog antagonists: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4- (methylsulfonyl)-benzamide; Proteasome inhibitors: Bortezomib; PI3K inhibitors: 4-[2-(1H- indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl] morpholine, 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5- c]quinolin-1-yl]phenyl]propanenitrile, buparlisib, taselisib, idelalisib, duvelitiib, TGR 1202; Phospholipase A2 inhibitors: Anagrelide; BCL-2 inhibitors: 4-[4-[[2-(4-chlorophenyl)-5,5- dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1- [(phenylsulfanyl)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl] benzamide; Mitogen-activated protein kinase (MEK) inhibitors: XL-518; Aromatase inhibitors: Exemestane, Letrozole, Anastrozole, Fulvestrant, Tamoxifen; Topoisomerase I inhibitors: Irinotecan, Topotecan hydrochloride; Topoisomerase II inhibitors: Etoposide, Teniposide; mTOR inhibitors: Temsirolimus, Deforolimus, Everolimus; Osteoclastic bone resorption inhibitors: (1-hydroxy-2-imidazol-1-yl- phosphinoyl ethyl)phosphonic acid monohydrate; CD33 antibody-drug conjugates: Gemtuzumab ozogamicin; CD22 antibody-drug conjugates: Inotuzumab ozogamicin; CD20 antibody-drug conjugates: Ibritumomab; Somatostatin analogues: Octreotide; Synthetic interleukin 11 (IL-11): Oprelvekin; Synthetic erythropoietin: Darbepoetin alfa. Receptor activator of nuclear factor kappa B (RANK) inhibitors: Denosumab; Thrombopoietin mimetic peptides: Romiplostim; Cell growth stimulators: Palifermin; Anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: Figitumumab; Anti-CSl antibodies: Elotuzumab; CD52 antibodies: Alemtuzumab; CTLA-4 inhibitors: Tremelimumab, Ipilimumab; PD1 inhibitors: Nivolumab, Pembrolizumab, Immuno-adhesins, Pidilizumab, and AMP-224; PDL1 inhibitors: MSB0010718C, YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105;LAG-3 inhibitors: BMS-986016. GITR agonists: GITR fusion protein and anti-GITR antibodies; histone deacetylase inhibitors (HDIs): vorinostat; anti-CTLA4 antibodies: tremelimumab and ipilimumab; alkylating agents: temozolomide, dactinomycin, melphalan, hexamethylmelamine, carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, hexamethylmelamine, ifosfamide, procarbazine, mechlorethamine hydrochloride and mechlorethamine hydrochloride, streptozocin, thiotepa; biological response modifiers: bacillus Calmette-Guerin, denileukin diftitox; antitumor antibiotics: doxorubicin, bleomycin, daunorubicin, daunorubicin liposomal, mitoxantrone, epirubicin, idarubicin, mitomycin C; anti-microtubule agents: estramustine; cathepsin K inhibitors: onalespib; epothilone B analog: ixabepilone; TpoR agonists: eltrombopag; anti-mitotic agents: docetaxel; adrenocortical steroid inhibitors: aminoglutethimide; anti-androgens: nilutamide; androgen receptor inhibitors: enzalutamide, abiraterone acetate, orteronel, galeterone and seviteronel, bicalutamide, flutamide; androgens: fluoxymesterone; CDK inhibitors: alvocidib, palbociclib, ribociclib, trilaciclib, abemaciclib; TRK inhibitors: entrectinib, larotrectinib; RET inhibitors: BLU-667, Loxo-292. Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate; taxane antineoplastic agents: cabazitaxel (1-hydroxy-, 10-dimethoxy-9-oxo-5,20-epoxytax-1 1 -ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate], larotaxel ((2a,3a,4a,5b,7a,10b,13a)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclo-tax-11 -en-2-yl benzoate); 5HTla receptor agonists: zavegepant (also known as SR57746, 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine;

[0106] HPC vaccines: Engerix-B® and Diphtheria Tetanus Acellular Pertussis Vaccine (DTPa) sold by GlaxoSmithKline Gardasil® sold by Merck

[0107] Iron chelators: diraros; antimetabolites: claribine (2-chlorodeoxyadenosine), 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine liposomes, decitabine, hydroxyurea, fludarabine, fluorouridine, cladribine, methotrexate, pentostatin; bisphosphonates: pamidronate; demethylators: 5-azacitidine, decitabine;

[0108] Plant alkaloids: protein-bound paclitaxel, vincristine, vinorelbine, paclitaxel;

[0109] Retinoids: Alvitamin (by trade name) (For sale), retinoic acid (all-trans retinoic acid, also known as ATRA, by trade name) (For sale), isotretinoin (13-cis-retinoic acid, under trade name) and For Sale), Besarrotin (as trade name) (For sale); Glucocorticoids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and by trade name) Hydrocortisone Phosphate Hydrocort and For sale), dexamethasone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecylhydro-3H-cyclopentan[a]phenanthrene-3-one), prednisolone (by trade name) and For Sale), Prednisolone (by trade name) Liquid and Methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, by trade name) is sold under the brand name 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, and methylprednisolone sodium succinate. and For Sale). Cytokine: Interleukin-2 (also known as adelleukin and IL-2, under trade names) (for sale), interleukin-11 (also known as Oprevelkin, by trade name) (For sale), alpha interferon alpha (also known as IFN-α, under the trade name) A and (For sale); Estrogen receptor downregulator: fulvestrant (by brand name) (For sale); Anti-estrogenic: Tamoxifen (by brand name) For Sale); Toremifen (by trade name) (For sale); Selective estrogen receptor modulator (SERM): Raloxifene (under brand name) For Sale); Luteinizing Hormone-Releasing Hormone (LHRH) Agonist: Goserelin (by trade name) sell);

[0110] Progesterone: Medroxyprogesterone acetate (also known as medroxyprogesterone acetate, by brand name) (For Sale); Various cytotoxic agents: Arsenic trioxide (by trade name) (for sale), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, by trade name) and (For Sale); Antiemetics: NK-1 receptor antagonists: Cassospiran (by GlaxoSmithKline under the brand name) and (for sale); and

[0111] Cell protectant: Amifotin (by brand name) Leucovorin (also known as calcium leucovorin, citric acid factor, and tetrahydrofolate); Immune checkpoint inhibitors: The term "immune checkpoint" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and LAG3. Immunotherapy agents that can act as immune checkpoint inhibitors in the methods disclosed herein include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFRβ.

[0112] The compounds described herein (in some embodiments) can be used as allosteric inhibitors to block the activation of SHP2 by targeting the self-inhibitory conformation of SHP2.

[0113] The compounds described herein can also inhibit SHP2 function by incorporation into an agent that disrupts catalysis of SHP2. For example, the compounds can be incorporated into a proteolysis targeting chimera (PROTAC). A PROTAC is a bifunctional molecule in which one moiety is capable of engaging an E3 ubiquitin ligase and another moiety is capable of binding to a target protein that is intended to be degraded by intracellular protein quantity control mechanisms. Recruitment of the target protein to a specific E3 ligase results in its tagging for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The moiety of the PROTAC that engages the E3 ligase is connected to the moiety of the PROTAC that engages the target protein via a linker composed of a variable chain of atoms. Thus, recruitment of SHP2 to the E3 ligase will result in destruction of the SHP2 protein. The variable chain of atoms can include, for example, a ring, a heteroatom, and / or a repeating polymeric unit. It can be rigid or flexible. It can be connected to the two moieties described above using standard techniques.

[0114] The compounds described herein can be connected to one end of a variable chain, while the other end of the variable chain can bind to an E3 ligase. Thus, recruitment of SHP2 to the ligase will result in destruction of the SHP2 protein.

[0115] In some embodiments, the compounds or compositions of the present disclosure can be used in conjunction with an antibody. In some embodiments, the compounds or compositions of the present disclosure can be used in conjunction with an antibody-drug conjugate. In some embodiments, the compounds or compositions of the present disclosure can be used in conjunction with a kinase inhibitor. In some embodiments, the compounds or compositions of the present disclosure can be used in conjunction with an immunomodulator. In some embodiments, the compounds or compositions of the present disclosure can be used in conjunction with a histone deacetylase inhibitor.

[0116] In some embodiments, the disclosed compounds are capable of administration to a subject in need of treatment in dosages ranging from about 0.0001 mg / kg body weight of the subject to be treated to about 100 mg / kg body weight of the subject to be treated per day, such as from about 1.0 mg / kg body weight of the subject to be treated to 10 mg / kg body weight of the subject to be treated per day. However, other variations are within the scope of the present disclosure.

[0117] The disclosed compounds can be administered alone or in conjunction with a pharmaceutically acceptable carrier such as a diluent, a filler, an aqueous solution, and even an organic solvent. The compounds and / or compositions of the present disclosure can be administered as tablets, powders, lozenges, syrups, injectable solutions, and the like. Additional ingredients such as flavorings, binders, excipients, and the like are within the scope of the present disclosure.

[0118] In some embodiments, the present disclosure provides a pharmaceutical composition consisting of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and / or the use of a pharmaceutical in a method of treating a disease state and / or disorder caused by or associated with SHP2 phosphatase. For example, provided herein are methods of treating a subject in need thereof (e.g., a subject having cancer (e.g., leukemia, breast cancer, lung cancer, and / or colorectal cancer)) with an effective amount of a disclosed compound and, optionally, an effective amount of an additional compound (e.g., a therapeutic agent) disclosed herein.

[0119] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and (iii) administering a therapeutically effective amount of the compound to treat, inhibit, and / or prevent a disease state or disorder in a subject in need of such treatment.

[0120] In some embodiments, the method of treatment comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and (iii) administering a therapeutically effective amount of the composition to treat, inhibit, and / or prevent a disease state or disorder in a subject in need of such treatment.

[0121] In some embodiments, the subject is an animal. Animals include all members of the animal kingdom, but are not limited to, humans, mice, rats, cats, monkeys, dogs, horses, and pigs. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.

[0122] In some embodiments, the method of treating, preventing, and / or inhibiting a disorder associated with SHP2 phosphatase comprises the steps of: i) identifying a subject in need of such treatment; (ii) providing a compound disclosed herein, or a pharmaceutically acceptable salt thereof; or a composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (iii) administering a therapeutically effective amount of the compound or composition to treat, prevent, and / or inhibit a disease state or disorder associated with SHP2 phosphatase in a subject in need of such treatment.

[0123] According to the methods of the present disclosure, a therapeutically effective amount of a compound of the present disclosure is administered to a subject, for example, to reduce or ameliorate a symptom associated with SHP2 phosphatase activity in the subject. This amount is readily determined by the skilled artisan according to known procedures, including analyzing titration curves established in vivo and the methods and assays disclosed herein.

[0124] In some embodiments, the method comprises administering a therapeutically effective dose of a compound of the present disclosure. In some embodiments, the therapeutically effective dose is at least about 0.0001 mg / kg body weight, at least about 0.001 mg / kg body weight, at least about 0.01 mg / kg body weight, at least about 0.05 mg / kg body weight, at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.3 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg body weight, at least about 25 mg / kg body weight, at least about 30 mg / kg body weight, at least about 40 mg / kg body weight, at least about 50 mg / kg body weight, at least about 75 mg / kg body weight, at least about 100 mg / kg body weight, at least about 200 mg / kg body weight, at least about 250 mg / kg body weight, at least about 300 mg / kg body weight, at least about 350 mg / kg body weight, at least about 400 mg / kg body weight, at least about 450 mg / kg body weight, at least about 500 mg / kg body weight, at least about 550 mg / kg body weight, at least about 600 mg / kg body weight, at least about 650 mg / kg body weight, at least about 700 mg / kg body weight, at least about 750 mg / kg body weight, at least about 800 mg / kg body weight, at least about 900 mg / kg body weight, or at least about 1000 mg / kg body weight. It will be recognized that any of the dosages listed herein can constitute a dosage upper limit or lower limit, and can be combined with any other dosage to constitute a dosage range including upper and lower limits.

[0125] In some embodiments, the therapeutically effective dose is in the range of about 0.1 mg / kg body weight to about 10 mg / kg body weight, about 0.1 mg / kg body weight to about 6 mg / kg body weight, about 0.1 mg / kg body weight to about 4 mg / kg body weight, or about 0.1 mg / kg body weight to about 2 mg / kg body weight.

[0126] In some embodiments, the therapeutically effective dose is in the range of about 1 mg to 500 mg, about 2 mg to 150 mg, about 2 mg to 120 mg, about 2 mg to 80 mg, about 2 mg to 40 mg, about 5 mg to 150 mg, about 5 mg to 120 mg, about 5 mg to 80 mg, about 10 mg to 150 mg, about 10 mg to 120 mg, about 10 mg to 80 mg, about 10 mg to 40 mg, about 20 mg to 150 mg, about 20 mg to 120 mg, about 20 mg to 80 mg, about 20 mg to 40 mg, about 40 mg to 150 mg, about 40 mg to 120 mg, or about 40 to 80 mg.

[0127] In some embodiments, the method comprises a single dose or administration (e.g., as a single injection or deposit). Alternatively, the method comprises administering to the subject in need thereof once per day, twice per day, three times per day, or four times per day for a period of about 2 days to about 28 days, or about 7 days to about 10 days, or about 7 days to about 15 days or more. In some embodiments, the method comprises long-term administration. In other embodiments, the method comprises administration over several weeks, several months, several years, or several decades. In other embodiments, the method comprises administration over several weeks. In other embodiments, the method comprises administration over several months. In other embodiments, the method comprises administration over several years. In other embodiments, the method comprises administration over several decades.

[0128] The dose administered can vary depending on known factors such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; the time and interval of administration of the active ingredient; the age, sex, health, and weight of the recipient; the nature and extent of the symptoms; the kind of concomitant treatment, the frequency and the desired effect of the treatment; and the rate of excretion. These are readily determined by the skilled person and can be used to adjust or titrate the dose and / or the dosing regimen.

[0129] The precise dose to be employed in the compositions will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each subject’s circumstances. In particular embodiments of the present disclosure, a dosage suitable for oral administration of a compound of the present disclosure typically ranges from about 1 mg / day to about 1000 mg / day. In some embodiments, the oral dosage is from about 1 mg / day to about 800 mg / day. In some embodiments, the oral dosage is from about 1 mg / day to about 500 mg / day. In some embodiments, the oral dosage is from about 1 mg / day to about 250 mg / day. In some embodiments, the oral dosage is from about 1 mg / day to about 100 mg / day. In some embodiments, the oral dosage is from about 5 mg / day to about 50 mg / day. In some embodiments, the oral dosage is about 5 mg / day. In some embodiments, the oral dosage is about 10 mg / day. In some embodiments, the oral dosage is about 20 mg / day. In some embodiments, the oral dosage is about 30 mg / day. In some embodiments, the oral dosage is about 40 mg / day. In some embodiments, the oral dosage is about 50 mg / day. In some embodiments, the oral dosage is about 60 mg / day. In some embodiments, the oral dosage is about 70 mg / day. In some embodiments, the oral dosage is about 100 mg / day. It will be recognized that any of the dosages listed herein can constitute a dosage ceiling or floor, and can be combined with any other dosage to constitute a dosage range including a ceiling and a floor.

[0130] Composition

[0131] Another aspect of the present disclosure provides pharmaceutical compositions comprising a compound disclosed herein formulated together with a pharmaceutical carrier. In particular, the present disclosure provides pharmaceutical compositions comprising a compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. The formulations include those suitable for oral, topical, buccal, ocular, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular compound being used. For example, the disclosed compositions can be formulated into dosage units and / or can be formulated for oral, subcutaneous, or intravenous administration.

[0132] Exemplary pharmaceutical compositions of the present disclosure can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid, or liquid form, which contains one or more of the compounds of the present disclosure as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. For example, the active ingredient can be compounded with the usual nontoxic, pharmaceutically acceptable carriers for tablets, capsules, pills, dragees, solutions, suspensions, and any other form suitable for use. The amount of active target compound included in the pharmaceutical composition is sufficient to produce the desired effect on the process or condition of the disease.

[0133] In some embodiments, a pharmaceutical composition can contain a disclosed compound and / or a pharmaceutically acceptable salt thereof in a concentration range from about 0.01 wt% to about 2.0 wt%, such as 0.01 wt% to about 1 wt% or about 0.05 wt% to about 0.5 wt%. The composition can be formulated as a solution, suspension, ointment, or capsule, etc. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-adjusting ingredients, etc.

[0134] To prepare solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present disclosure or a nontoxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that there are no significant variations in the concentration of active ingredient throughout the composition.

[0135] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, excipients, fillers, lubricants, and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant, or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient. Generally, the pharmaceutically acceptable carrier is chemically inert to the active compounds and non-toxic under the conditions of use. Examples of pharmaceutically acceptable carriers can include, for example, aqueous or saline solutions, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids or alcohols. Non-limiting examples of oils as pharmaceutical carriers include petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. The pharmaceutical carrier can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Moreover, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. Other examples of suitable pharmaceutical carriers are described, for example, in Remington’s: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)), each of which is hereby incorporated by reference in its entirety. th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)), each of which is hereby incorporated by reference in its entirety. th Ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)), each of which is hereby incorporated by reference in its entirety.

[0136] In some embodiments, the compounds of the present disclosure are formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration. According to another aspect, the present disclosure provides a pharmaceutical composition comprising a disclosed compound in admixture with a pharmaceutically acceptable diluent and / or carrier. A pharmaceutically acceptable carrier is "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the recipient thereof. Pharmaceutically acceptable carriers employed herein can be selected from a wide variety of organic or inorganic materials that are used in pharmaceutical formulations and are incorporated into pharmaceutical compositions as adjuvants, analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles, and viscosity increasing agents. Pharmaceutical additives such as antioxidants, aromatics, colorants, flavor improvers, preservatives, and sweeteners can also be added. Examples of acceptable pharmaceutical carriers include carboxymethylcellulose, crystalline cellulose, glycerin, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose, starch, talc, and water, and the like. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0137] Surfactants such as, for example, detergents are also suitable for use in the formulation. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymer of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerin, polyoxyethylated esters of sorbitol or sorbitan; lecithin or sodium carboxymethyl cellulose; or acrylic acid derivatives such as methacrylate and the like; anionic surfactants such as basic stearates, in particular sodium, potassium or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium acetyl sulfate; sodium dodecylbenzenesulfonate or dioctyl sodium sulfosuccinate; or fatty acids, in particular those derived from coconut oil; cationic surfactants such as water-soluble quaternary ammonium salts of the formula N + R'R"R"'R""Y - where the R groups are identical or different optionally hydroxylated hydrocarbon radicals and Y - is an anion of a strong acid such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide is one of the cationic surfactants that can be used; water-soluble quaternary ammonium salts of the formula N +amine salts of R'R"R'" where the R groups are the same or different optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants that can be used; non-ionic surfactants such as optionally polyoxyethylated esters of sorbitol, in particular polysorbate 80 or polyoxyethylated alkyl ethers; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide; amphoteric surfactants such as substituted lauryl compounds of betaine.

[0138] The disclosed compounds and pharmaceutical carriers can be sterile when administered to a subject. Suitable pharmaceutical carriers can also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The compositions of the application, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0139] The pharmaceutical formulations of the present disclosure are prepared by methods well known in the art of pharmacy. Optionally, one or more accessory ingredients (e.g., buffers, flavoring agents, surfactants, and the like) are also added. The choice of carrier depends on the solubility and chemical nature of the compound, the route of administration selected, and standard pharmaceutical practice.

[0140] In addition, the compounds and / or compositions of the present disclosure are administered to a human or animal subject by known procedures, including oral administration, sublingual or buccal administration. In some embodiments, the compounds and / or compositions are administered orally.

[0141] In solid dosage forms for oral administration (capsules, tablets, pills, troches, powders, granules, and the like), the subject compositions are mixed with one or more pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acids; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarders, such as paraffin; (6) absoption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions can also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft and hard-filled gelatin capsules. Preferred materials for such fillers include lactose or milk sugar, and high molecular weight polyethylene glycols.

[0142] For oral administration, the formulations of the compounds of the present disclosure can be presented in dosage forms such as capsules, tablets, powders, granules, or as suspensions or solutions. Capsule formulations can be gelatin, soft gel or solid. Tablet and capsule formulations can also contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers, or lubricants, each of which is known in the art. Examples of such materials include carbohydrates such as lactose or sucrose, anhydrous dicalcium phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearate, silica, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffers, disintegrants, and coloring agents. Compositions for oral administration can contain one or more optional agents to provide a pharmaceutically palatable formulation, such optional agents being, for example: sweetening agents such as sucrose or aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents.

[0143] Tablets can optionally be compressed or molded with one or more accessory ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agents. Molded tablets can be prepared by molding a mixture of the subject composition wetted with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms such as dragees, capsules, pills, and granules can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art.

[0144] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable vegetal or organic vehicles, or mixtures thereof, and powders. Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.

[0145] In addition to the subject composition, suspensions can contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0146] Formulations for rectal or vaginal administration can be presented as a suppository, which can be prepared from a mixture of the subject composition with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity to release the active agent.

[0147] Dosage forms for the transdermal administration of the subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active component can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any needed preservatives, buffers, or propellants which can be required.

[0148] In addition to the subject composition, ointments, pastes, creams and gels can contain excipients such as animal and vegetable fats and oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0149] In addition to the subject composition, powders and sprays can also contain excipients such as lactose, talc, aluminim hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays can also contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0150] The compositions and compounds of the present disclosure can alternatively be administered by aerosol. This is achieved by preparing an aqueous aerosol, liposome preparation, or solid particles containing the compound. Non-aqueous (e.g., fluorocarbon propellants) suspensions can be used. Sonic nebulizers can be used as they minimize the degradation of the compound contained in the subject compositions due to shearing. Generally, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycols), innocuous proteins like serum albumin, sorbitol esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0151] Pharmaceutical compositions of the present disclosure suitable for parenteral administration include the subject compositions in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which can be reconstituted into sterile injectable solutions or dispersions just prior to use and which can contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic to the possible recipient's blood, or suspending or thickening agents.

[0152] Examples of suitable aqueous and nonaqueous carriers that can be employed in the pharmaceutical compositions of the present disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, injectable organic esters such as ethyl oleate, and cyclodextrins. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. For example, the crystalline forms provided herein can be milled to obtain a particular particle size, and in at least some embodiments, such crystalline forms can remain substantially stable after milling.

[0153] For example, provided herein are compositions suitable for subcutaneous administration comprising a suspension of the disclosed crystalline forms. Subcutaneous administration can be preferred over intravenous administration because intravenous administration typically requires a visit to a clinic and can be more painful and invasive. When administered to a patient, a typical dose of the crystalline compound can be from about 1 mg to about 8 mg of the compound. In one embodiment, provided herein are pharmaceutical compositions formed from the disclosed crystalline forms, for example, by mixing the crystalline forms with excipients and / or solvents.

[0154] In one embodiment, provided herein is a composition comprising a disclosed crystalline form suitable for subcutaneous administration at a dosage level sufficient to deliver from about 0.001 mg / kg of the subject's body weight to about 100 mg / kg of the subject's body weight, from about 0.01 mg / kg of the subject's body weight to about 50 mg / kg of the subject's body weight, from about 0.1 mg / kg of the subject's body weight to about 40 mg / kg of the subject's body weight, from about 0.5 mg / kg of the subject's body weight to about 30 mg / kg of the subject's body weight, from about 0.001 mg / kg of the subject's body weight to about 4 mg / kg of the subject's body weight, from about 0.1 mg / kg of the subject's body weight to about 10 mg / kg of the subject's body weight, from about 1 mg / kg of the subject's body weight to about 25 mg / kg of the subject's body weight, and administered every day, once or more times per day, every other day, every three or four days, weekly, biweekly, triweekly, or quarterly. In certain embodiments, multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, or ten administrations) can be used to deliver the desired dose. In certain embodiments, administration can occur once, twice, or three times per week.

[0155] Treatment can continue for a long or short period as desired. The compositions can be administered, for example, in a regimen of once to four or more times per day. Suitable treatment periods can be, for example, at least about one week, at least about two weeks, at least about one month, at least about six months, at least about 1 year, or indefinitely. The treatment period can be terminated when a desired result, such as a weight loss goal, is achieved. Treatment regimens can include a correction phase during which a dose sufficient to provide weight loss is administered, and a maintenance phase can follow during which, for example, a lower dose sufficient to increase weight is administered. Suitable maintenance doses can be found in the lower portions of the dosage ranges provided herein, but based on the disclosure herein, one of skill in the art can readily establish correction and maintenance doses for individual subjects without undue experimentation. Maintenance doses can be used to maintain the weight of subjects whose weight has previously been controlled by other means, including diet and exercise, bariatric surgery such as bypass surgery or banding surgery, or treatment with other pharmacological agents.

[0156] For example, provided herein is a drug substance comprising at least a detectable amount of a disclosed crystalline form, such as a crystalline form of a compound of Formula (I). In certain embodiments, an intended drug substance can comprise at least about, for example, 10%, at least about, for example, 50%, or at least about, for example, at least about 90% of a disclosed crystalline form, such as a crystalline form of a compound of Formula (I). In certain embodiments, an intended drug substance can comprise a substantially pure crystalline form of a compound of Formula (I).

[0157] Kit

[0158] In one embodiment, a kit for treating or lessening the impact of a disease or condition is provided. For example, the disclosed kits include a disclosed crystalline compound, e.g., a crystalline form of a compound of Formula (I), disposed in, e.g., a first container. In some embodiments, the kits can also include a pharmaceutical excipient disposed in, e.g., a second container. Such contemplated kits can include written instructions describing the preparation of a pharmaceutical composition suitable for administration to a patient from the crystalline form. For example, the written instructions can describe the preparation of a pharmaceutical form for administration to a patient by, e.g., mixing an excipient and a crystalline compound disclosed herein. The disclosed kits can also include written instructions describing how to administer the resulting composition to a patient.

[0159] Method

[0160] In some embodiments, contemplated herein are methods for preparing a crystalline form of a disclosed compound of Formula (I), e.g., Compound I-1, the method comprising: a) preparing a solution of Compound I-1 in a solvent comprising at least one of EtOH, ACN, MEK, EtOAc, IPAc, THF, MtBE, toluene, 1,4-dioxane, and water; b) heating the solution to completely dissolve Compound I-1; c) adjusting the temperature such that solids precipitate out of solution; and d) isolating the crystalline form of Compound I-1.

[0161] In some embodiments, the solvent is EtOH. In some embodiments, the solvent comprises ACN. In some embodiments, the solvent comprises EtOAc. In some embodiments, the solvent comprises IPAc. In some embodiments, the solvent comprises THF. In some embodiments, the solvent comprises MtBE. In some embodiments, the solvent comprises toluene. In some embodiments, the solvent comprises 1,4-dioxane. In some embodiments, the solvent comprises EtOH and water (9v / 1v). In some embodiments, heating the solution comprises heating the solution to about 50 °C. In some embodiments, adjusting the temperature comprises cooling the solution to about 5 °C.

[0162] Also disclosed herein are methods for preparing a compound of Formula I-1, the method comprising the step of neutralizing a compound of Formula I-3 with NaOH, thereby forming a compound of Formula I-1:

[0163]

[0164] In some embodiments, the disclosed methods further comprise the step of reacting a compound of Formula 18 with HC1, thereby forming a compound of Formula I-3:

[0165]

[0166] In other embodiments, the disclosed methods further comprise the step of coupling a compound of Formula 17 with a compound of Formula 9, thereby forming a compound of Formula 18:

[0167]

[0168] Examples

[0169] The compounds described herein can be prepared in a variety of ways based on the teachings contained herein and synthetic procedures known in the art. The following non-limiting examples illustrate the disclosed disclosure.

[0170] X-ray powder diffraction (XRPD): XRPD analysis was performed on a Bruker D8 Advance. The following method was used to run samples on XRPD:

[0171] - Tube: Cu: K-alpha

[0172] - Generator: Voltage: 40 kV; Current: 40 mA.

[0173] - Scan range: 3 to 40 degrees;

[0174] - Sample rotation speed: 15 rpm.

[0175] - Scan rate: 10 degrees / minute.

[0176] Differential scanning calorimetry (DSC) DSC analysis was performed on a TA Instruments Q2000. The details of the DSC method used in the test are as follows:

[0177] - Heating from 30 °C to 250 °C at 10 °C / min

[0178] The cycle DSC method used:

[0179] - Cycle 1: Heating from 30 °C to 300 °C at 10 °C / min

[0180] - Cycle 2: Heating from 300 °C to 30 °C at 10 °C / min

[0181] - Cycle 3: Heating from 30 °C to 300 °C at 10 °C / min

[0182] Thermogravimetric analysis (TGA): TGA was performed on a TA Instruments Q5000 IR. The details of the TGA method used for characterization are described below:

[0183] - Heating from 30 °C to 300 °C at 10 °C / min

[0184] Dynamic vapor sorption (DVS):Approximately 10–20 mg of sample was used to test its moisture adsorption / desorption curves under cycling at 25°C and 0%–90%–0% relative humidity (RH), with the following parameters:

[0185] - Balance: dm / dt: 0.01% / min (for minimum: 10min and maximum: 180min).

[0186] - Drying: 0% relative humidity within 120 minutes.

[0187] -RH (%) Measurement Steps: 10%

[0188] -RH (%) Measurement range: 0%~90%~0%

[0189] Hygroscopicity classification Water absorption criteria Deliquescent Will absorb enough water to form a liquid Very hygroscopic W％≥15％ Hygroscopicity W％≥2％ Slightly hygroscopic W％≥0.2％ Non-hygroscopic W％<0.2％

[0190] * Stored at 25°C and 80±2% RH (European Pharmacopoeia 6.0)

[0191] Example 1: (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H-pyrazolo[3,4- b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (Compound I-1) Example 2: Polymorph analysis of (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)- 1 H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine (Compound I-1)

[0192] Step 1. Preparation of Compound 1

[0193]

[0194] 75.0 L of DCM was loaded into a 200 L enamel reactor and stirred with a powerful magnetic stirrer. 15.0 kg of compound 1 was added at once. 0.931 kg of I2 was added at once. 13.5 kg of compound 2 was added dropwise at 25-35 °C. The reaction mixture was stirred at 20-25 °C for 8 hours. TLC analysis (petroleum ether = 1) showed that compound 1 (R... f =0.7) was consumed, and a new spot was observed. A Na₂SO₃ solution (6.00 kg Na₂SO₃ dissolved in 60.0 L H₂O) was added to the reaction mixture, and the mixture was stirred at 25–30 °C for 0.5 hours. The organic layer was separated and washed with brine (40.0 L). The organic layer was dried with Na₂SO₄ (10.0 kg), filtered, and the filtrate was concentrated under reduced pressure at 40 °C. When approximately 90% of the DCM was removed, petroleum ether was added to the mixture, and the mixture was stirred at 25–30 °C for 2 hours. The mixture was filtered, and the solid was dried in a drying oven at 40 °C for 8 hours. Compound 3 (20.0 kg, yield: 77%) was given as a white solid, which was obtained by… 1 H NMR confirmed. 1H NMR: (400 MHz CDCl3) δ 7.66-7.62 (m, 1H), 7.32-7.26 (m, 1H), 7.19-7.15 (m, 1H), 7.09-7.04 (m, 1H), 5.57 (s, 1H), 3.17-3.10 (m, 2H), 2.96-2.91 (m, 2H), 2.23-2.16 (m, 1H), 2.04-1.89 (m, 1H).

[0195] Step 2. Preparation of compound 5

[0196]

[0197] A 60.0 L THF was charged into a 500 L glass-lined reactor and stirred by a powerful magnetic stirrer. 20.0 kg of compound 3 was added at one time. 60.0 L of LDA (1.28 eq) was added dropwise at -5 to 5 °C and under N2. The reaction mixture was stirred for 1 h at -5 to 5 °C and under N2. A solution of 20.0 kg of compound 4 in 40.0 L of THF was added dropwise at -5 to 5 °C and under N2. The reaction mixture was stirred for 1 h at -5 to 5 °C and under N2. TLC analysis (petroleum ether / ethyl acetate = 5 / 1) showed that about 10% of compound 3 (Rf = 0.7) was retained and a new spot (Rf = 0.3) was observed. f f A saturated aqueous NH4Cl solution (250 L) was charged into the 500 L glass-lined reactor and stirred by a powerful magnetic stirrer. The reaction mixture was added and stirred for 0.5 h. The organic layer was separated and washed with a saturated aqueous NH4Cl solution (250 L). The organic layer was dried with Na2SO4 (15.0 kg), filtered and the filtrate was concentrated under reduced pressure at 40 °C. When about 90% of THF was removed, petroleum ether (50.0 L) was added and the mixture was stirred at 25 °C for 1 h. The mixture was filtered and the white solid was dried under reduced pressure at 45 °C. Compound 5 (28.0 kg, yield: 72.5%) was obtained as a white solid.

[0198] Step 3. Preparation of compound 6

[0199]

[0200] A 112 L of DCM, 41.0 kg of Py and 28.0 kg of H2O were charged into a 500 L glass-lined reactor and stirred with a powerful magnetic stirrer. 28.0 kg of compound 5 and 2.20 kg of TBAB were added at one time. 70.0 kg of Py.HBr3 was added portionwise at 10-20 °C. The reaction mixture was stirred at 10-20 °C for 0.5 h. TLC analysis (petroleum ether / ethyl acetate = 3 / 1) showed that compound 5 (Rf = 0.3) was consumed and a new spot (Rf = 0.9) was observed. f ​= 0.3) was consumed and a new spot (R f = 0.3). To the reaction mixture was added 90.0 L H2O and the mixture was stirred for 1 h. The organic layer was separated and washed with a citric acid solution (10.0 kg citric acid dissolved in 100 L H2O). The organic layer was washed with a saturated NaHCO3solution (100 L). The organic layer was dried over Na2SO4(15.0 kg), filtered and the filtrate was concentrated at 45 °C under reduced pressure. Compound 6 was obtained as a red oil which was used directly in the next step.

[0201] Step 4. Preparation of compound 7

[0202]

[0203] Compound 6 (21.9 kg) was dissolved in 80.0 L 2-MeTHF, the mixture was charged into a 200 L lined reactor and stirred with a powerful magnetic stirrer. 8.80 kg t-BuOK was added portionwise at 25-40 °C. The reaction mixture was stirred at 40 °C for 1 h. TLC analysis (petroleum ether / ethyl acetate = 3 / 1) indicated that compound 6 was consumed and a new spot (R f = 0.6). The reaction mixture was cooled to 25 °C. 80.0 L H2O was added slowly to the mixture at 20-25 °C and stirred for 0.5 h. The organic layer was separated and dried over Na2SO4(10.0 kg), filtered and the filtrate was concentrated at 45 °C under reduced pressure. When about 90% of the 2-MeTHF was removed, MTBE (30.0 L) was added. The mixture was stirred at 20 °C for 1 h. The mixture was filtered to give a white solid. The white solid was dried at 45 °C under reduced pressure. Compound 7 (8.20 kg) was obtained as a white solid, which was confirmed by 1 HNMR. 1 H NMR: (400 MHz CDCl3) δ 7.64-7.54 (m, 2H), 7.09-6.99 (m, 2H), 4.08 (br s, 2H), 3.34-3.01 (m, 2H), 1.92-1.84 (m, 2H), 1.51 (br d, J = 16.0 Hz, 2H), 1.42 (s, 9H).

[0204] Step 5. Preparation of compound 8

[0205]

[0206] The reaction disclosed in step 5 was performed in 2 parallel batches.

[0207] 16.0 L of 2-MeTHF was still added to a 50 L reactor and stirred with a powerful magnetic stirrer. 4.10 kg of compound 7, 3.28 kg of compound 7-1, and 10.2 kg of Ti(OEt)4 were added at once. The reaction mixture was heated to 75 °C and stirred at 75-80 °C under N2 for 40 h. TLC analysis (petroleum ether / ethyl acetate = 3 / 1) showed that a small amount of compound 7 (R... f =0.7) was preserved, and a new point (R) was observed. f =0.5). Cool the reaction mixture to 0°C. Add 300 g LiBH4 in portions at 0-10°C and N2. Stir the mixture for 0.5 h at 0-10°C and N2. TLC analysis (petroleum ether / ethyl acetate = 3 / 1) showed that at this point (R f =0.5) was consumed, and a new point (R) was observed. f =0.3). MeOH (4.00 L) was slowly added to the reaction mixture at 25-30 °C. Approximately 80.0 L of mixture was obtained. 8.00 kg of EDTE was added to the mixture and stirred for 1 h. 10.0 L of the mixture was added to citric acid (20.0 L, 10% aqueous solution) and ethyl acetate (10.0 L). The organic layers were separated and washed with NaHCO3 (10.0 L, 10% aqueous solution). Eight batches of organic layers were obtained and dried with Na2SO4 (10.0 kg), filtered, and the filtrate was concentrated under reduced pressure at 45 °C. MTBE (20.0 L) was added to the crude product and the mixture was stirred for 1 h. The mixture was filtered, and a filter cake was obtained. DCM (40.0 L) was added to the filter cake and filtered with silica gel (3.00 kg). The filtrate was concentrated under reduced pressure at 45 °C. Then MTBE (15.0 L) was added to the crude product and stirred for 1 h. The mixture was filtered, and a white solid was obtained. The white solid was dried under reduced pressure at 40 °C. Compound 8 (5.40 kg, yield: 50%) was given, which was determined by HPLC and... 1 H NMR confirmed. 1 H NMR: (400MHz CDCl3)δ7.26-7.12(m,2H),6.86-6.83(m,1H),6.74(d,J=8.0Hz,1H),4.56(br d,J=8.0Hz,1H),4.01(br s,2H),3.61(br d,J=8.0Hz,1H),3.2-2.90(m,2H),2.03-1.57(m,4H),1.39(s,9H),1.18(s,9H).

[0208] Step 6. Preparation of Compound 9

[0209]

[0210] The 6.00 L MeOH was still charged into the 50 L reactor and stirred by a strong magnetic stirrer. 5.40 kg of compound 8 was added at one time. To the mixture, HCl / MeOH (22.0 L) was slowly added at 20-25 °C. The mixture was stirred at 20-25 °C for 4 h. TLC analysis (ethyl acetate = 1) showed that compound 8 was consumed and one new spot (R f = 0) was observed. The reaction mixture was concentrated at 45 °C under reduced pressure. Then MTBE (20.0 L) was added when most of the MeOH was removed. The mixture was stirred for 0.5 h. The mixture was filtered and white solid was obtained. The white solid was dried at 45 °C under reduced pressure. Compound 9 (3.30 kg, yield: 91%) was obtained as a white solid, which was confirmed by 1 H NMR, LCMS, HPLC and SFC. 1 H NMR: (400 MHz DMSO_d6) δ 9.69-9.27 (m, 2H), 9.03 (br s, 3H), 7.76 (d, J = 8.0 Hz, 1H), 7.43-7.29 (m, 1H), 7.09-6.89 (m, 2H), 4.73 (br s, 1H), 3.44 (br d, J = 12.0 Hz, 1H), 3.22 (br d, J = 12.0 Hz, 1H), 3.16 (s, 1H), 3.14-2.95 (m, 2H), 2.42 (dt, J = 4.0, 13.4 Hz, 1H), 2.15 (br d, J = 12.0 Hz, 1H), 2.08-1.94 (m, 1H), 1.85 (br d, J = 12.0 Hz, 1H).

[0211] Step 7. Preparation of compound 11

[0212]

[0213] The procedure was performed in fifteen batches. To a solution of n-BuLi (2.5 M in hexanes, 6.50 L, 1.21 eq) in 2-methyltetrahydrofuran (10.0 L) was added TMP (2.87 kg, 20.3 mol, 3.45 L, 1.51 eq) at -30 °C under N2over 0.5 h. The reaction mixture was allowed to warm to 0 °C to 10 °C and stirred for an additional 0.5 h. The reaction mixture was cooled to -75 °C and a solution of compound 10 (2.00 kg, 13.4 mol, 1.00 eq) in 2-methyltetrahydrofuran (10.0 L) was added dropwise to the mixture at -75 °C to -70 °C over 2 h. After the mixture was stirred for 0.5 h, ethyl formate (1.52 kg, 20.5 mol, 1.65 L, 1.53 eq) was cooled to -70 °C to -60 °C and then added to the reaction mixture at -75 °C in one portion. The reaction mixture was stirred for an additional 0.5 h. TLC analysis (petroleum ether / ethyl acetate = 5 / 1) indicated that compound 1 (R f = 0.80) was consumed and a new spot (R f = 0.50) was observed. Acetic acid (4.00 L) was added to the reaction mixture at -75 °C to -30 °C in one portion, allowed to warm to 25 °C and stirred for 0.5 h. The mixture was poured into 30.0 L of water and extracted with ethyl acetate (5.00 L x 3). The combined organic layers were washed with brine (5.00 L x 3), dried over Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to give a black-brown liquid. The crude product was used directly in the next step without further purification. The fifteen batches were performed in parallel to give compound 11 (52.5 kg, crude) as a black-brown liquid, which was confirmed by 1 H NMR. 1 H NMR: 400 MHz, DMSO-d6 10.12 (s, 1H), 9.05 (s, 1H).

[0214] Step 8. Preparation of compound 12

[0215]

[0216] The procedure was performed in eight batches. To a solution of compound 11 (6.56 kg, 37.1 mol, 1.00 eq) in EtOAc (22.0 L) and EtOH (13.0 L) was added an aqueous solution of NaHSO3(1.54 kg, 14.8 mol, 0.40 eq) (2.30 L) at 0 °C and the reaction mixture was stirred at 25 °C for 12 h. TLC analysis (petroleum ether / ethyl acetate = 5 / 1) indicated that compound 11 (R f = 0.15) was consumed and a new spot (R f= 0). The reaction mixture was filtered at 25 °C and the filter cake was dried under reduced pressure to give the crude product. The crude product was used directly in the next step without further purification. Eight batches were prepared in parallel to give compound 12 (35.6 kg, crude) as a grey solid, which was confirmed by 1 H NMR confirmation. 1 H NMR: 400 MHz, DMSO-d614.30 (s, 1H), 8.66 (s, 1H), 8.49 (s, 1H). 1 Residual DMF was observed in the H NMR spectrum to perform a quantitative test.) 8.63 (s, 1H), 5.67 (s, 1H).

[0217] Step 9. Preparation of compound 13

[0218]

[0219] The process was carried out in thirteen batches. To a solution of compound 12 (3.0 kg, 10.7 mol, 1.00 equiv) in DMSO (30.0 L) was added N2H4.H2O (1.26 kg, 21.4 mol, 1.22 L, 85.0% purity, 2.00 equiv) dropwise at 10 °C and the reaction mixture was stirred at 25 °C for 1 h. HPLC analysis of the reaction mixture indicated that compound 12 (Rt = 1.003 min) was consumed. The reaction mixture was warmed to 100 °C and stirred at 100 °C for 12 h. TLC analysis (petroleum ether: ethyl acetate = 2: 1) indicated that a major new spot (R f = 0.6). HPLC of the reaction mixture indicated that the reaction intermediates (Rt = 1.488 min, Rt = 1.662 min) were consumed and a new peak (Rt = 1.555 min) was observed. The mixture was cooled to 25 °C, ethyl acetate (10.0 L) was poured into the reaction mixture and stirred at 25 °C for 1 h. The mixture was poured into water (60.0 L) and filtered through celite. The filtrate was extracted with EtOAc (30.0 L*2). The combined organic layers were washed with brine (30.0 L*2), dried over Na2S04and filtered. The filtrate was concentrated to give the crude residue. The residue was triturated with EtOAc: petroleum ether = 1:4 (1.00 L) at 25 °C for 1 h. Thirteen batches were prepared in parallel to give compound 13 (5.5 kg, ca. 90% purity) as a grey solid, which was confirmed by 1 H NMR confirmation. 1 H NMR: 400 MHz, DMSO-d614.30 (s, 1H), 8.66 (s, 1H), 8.49 (s, 1H).

[0220] Step 10. Preparation of compound 14

[0221]

[0222] The process was carried out in two batches. To a solution of compound 13 (2.50 kg, 14.1 mol, 1.00 equiv) in DMF (12.5 L) was added NIS (4.12 kg, 18.3 mol, 1.30 equiv) and TFA (160 g, 1.41 mol, 104 mL, 0.10 equiv) at 25 °C. The mixture was heated to 80 °C and stirred at 80 °C for 14 h. TLC analysis (petroleum ether: ethyl acetate = 3: 1) indicated that compound 13 (R f = 0.3) was consumed and a new spot (R f = 0.4) was observed. HPLC analysis also indicated that compound 13 (Rt= 1.487 min) was consumed and a new peak (Rt= 2.080 min) was observed. The reaction mixture was poured into 5% Na2S03ice water (10.0 L), stirred at 0 °C to 5 °C for 1 h, then diluted with water (30.0 L), filtered, and the filter cake was washed with water (5.00 L) and dried to give the crude product. The crude product was triturated with H20: ACN = 2: 1 (15.0 L). Two batches were carried out in parallel to give compound 14 (6.2 kg, 100% purity) as a grey solid, which was confirmed by 1 H NMR and LCMS. 1 H NMR: 400 MHz, DMSO-d614.66 (s, 1H), 8.66 (s, 1H).

[0223] Step 11. Preparation of compound 15

[0224]

[0225] To a solution of compound 14 (6.38 kg, 22.8 mol, 1.00 equiv) in DCM (30.0 L) was added TsOH.H20 (433 g, 2.27 mol, 0.10 equiv) at 0 °C, then DHP (3.83 kg, 45.5 mol, 4.16 L, 2.00 equiv) was added dropwise to the mixture at 0 °C. The mixture was stirred at 25 °C for 2 h. TLC analysis (petroleum ether: ethyl acetate = 3: 1) indicated that compound 14 (R f = 0.6) was consumed and a new spot (R f= 0.7). HPLC analysis also indicated that compound 14 (Rt = 2.059 min) was consumed and a new peak (Rt = 2.927 min) was observed. The reaction mixture was poured into saturated NaHC03(30.0 L) aqueous solution and the organic layer was washed with brine (30.0 L), dried over Na2S04, filtered and concentrated. The residue was triturated with MTBE (10.0 L), the mixture was stirred at 25 °C for 2 h, filtered, the filter cake was washed with MTBE (3.0 L) and dried to get compound 15 (5.1 kg, 97.9% purity) as a grey solid, which was confirmed by 1 H NMR and LCMS. 1 H NMR: 400 MHz, CDC13 8.56 (s, 1H), 5.98 (dd, J = 10.5, 2.5 Hz, 1H), 4.27-4.10 (m, 1H), 3.83-3.65 (m, 1H), 2.70-2.64 (m, 1H), 2.19-2.18 (m, 1H), 2.01-1.97 (m, 1H), 1.81-1.78 (m, 2H), 1.66-1.63 (m, 1H).

[0226] Step 12. Preparation of compound 17

[0227]

[0228] To a 50 L jacketed reactor was added compound 15 (2000 g, 5.206 mol), compound 16 (700 g, 5.206 mol), K3P04(3320 g, 15.64 mol), Xantphos (151 g, 262.41 mmol), Pd2(dba)3(119 g, 130.16 mmol) and toluene (20 L) under nitrogen. The reaction mixture was stirred at 80 °C to 85 °C for 15 h until the reaction was complete. The reaction mixture was cooled to 20 °C to 30 °C and washed with H20 (10 kg) twice. The organic layer was filtered through a 2 kg silica thiol and 8 kg silica gel column eluted with EA. Concentration and crystallization with THF: heptane = 1:3 gave a wet filter cake. The wet filter cake was dried at 45 °C to 50 °C under vacuum for 20-24 h to get 1.25 kg of compound 17.

[0229] Step 13. Preparation of compound 18

[0230]

[0231] To a 5 L jacketed reactor was added compound 17 (217 g, 586 mmol), compound 9 (192 g, 704 mmol), K2CO3 (324 g, 2.35 mol), DMSO (900 mL) under nitrogen. The reaction mixture was stirred at 60-65 °C for 3-4 h until the reaction was complete. The reaction mixture was cooled to 20-30 °C. DMSO (900 mL) was added followed by dropwise addition of H2O (1800 g). The reaction mixture was stirred at 20-30 °C for 2-5 h. The resulting slurry was filtered and the wet cake was washed with H2O (1200 g). The cake was dried at 45-50 °C under vacuum for 36-40 h to provide compound 18.

[0232] Step 14. Preparation of compound I-3

[0233]

[0234] To a 5 L jacketed reactor was added compound 18 (292 g, 532 mmol) and MeOH (900 mL) under nitrogen at ambient temperature. The reaction mixture was cooled to 0-5 °C, 4M HCl (2660 mL) was added and the mixture was stirred at 25-30 °C for 20 h. The mixture was concentrated and 4M HCl (1300 mL) was added again at 0-5 °C. The mixture was stirred at 25-30 °C for 5-12 h, concentrated to about 1500 mL, then diluted by dropwise addition of 1500 mL MTBE. The mixture was stirred for 12-20 h, filtered and washed with 200 mL MTBE. The resulting wet cake was washed with water (1V) and dried at 45-55 °C for 24-36 h to give 295 g of compound I-3.

[0235] Step 15. Preparation of compound I-3

[0236]

[0237] To a 500 mL jacketed reactor was charged with compound I-3 (37 g, 66.5 mmol) and H2O (250 mL) at 0-5 °C under nitrogen. The reaction mixture was stirred at 0-5 °C for 0.5-1 h. The mixture was diluted with 220 mL of 1 M NaOH solution and stirred at 0-5 °C for 1-2 h. Then 2-MeTHF (800 mL) was added and the mixture was stirred for 0.5-1 h. The organic layer was separated and washed with water (500 mL*2). The organic layer was concentrated by distillation below 45 °C, then diluted with MeOH. 0.35 g of compound I-1 seed was added, the mixture was stirred at 25-30 °C for 2-5 h. 500 mL of water was added, and the mixture was stirred at 25-30 °C for 5-12 h. The solid was collected by filtration, washed with water and the wet cake was dried under vacuum at 60-70 °C for 48-60 h to provide compound I-1.

[0238] Figure 1B Figure 1B

[0239] Polymorph analysis of compound I-1 (also known as (R)-1'-(3-(3,4-dihydro-1,5- naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'- piperidin]-3-amine) was performed in 12 different solvents by temperature cycling method. If no suspended solids were observed when the system was cooled to 25 °C, the solution was evaporated. The details of the procedure are as follows:

[0240] About 50 mg of compound I-1 was weighed into a 2.0-mL glass vial, then 0.5-1.0 mL of the selected solvent was added. The vial was then placed, stirring at 600 r / min, then heated or cooled according to the following temperature program: heated to 50 °C over 1 h, then held at 50 °C for 1 h; then cooled to 5 °C over 3 h, then held at 5 °C for 1 h. This temperature program was cycled 4 times for a total of about 24 h. The system was then stirred at 25 °C for an additional 1 h. For samples that resulted in a suspension, the system was centrifuged at 8000 r / min for 5 min. The mother liquor was removed, and the wet solid was dried in a vacuum oven at 50 °C for 3 h. The resulting dry solid was then characterized by XRPD. If a new XRPD pattern was identified, the dry solid with the new XRPD pattern can also be characterized by PLM, DSC, and TGA. For clear solutions, the vial was then placed in a fume hood at 25 °C to evaporate the remaining solvent. After 4 days of evaporation, some solid precipitated out. The solid was then dried in a vacuum oven at 30 °C for 21.5 h. The resulting dry solid was then characterized by XRPD. If a new XRPD pattern was identified, the dry solid with the new XRPD pattern can also be characterized by PLM, DSC, and TGA.

[0241] A summary of the solvents examined can be found in Table 1 :

[0242] Table 1

[0243]

[0244] The starting material for Compound I-1 was in crystalline form, but the crystallinity was very low. After polymorph screening experiments, the resulting solids all showed the same XRPD pattern, and this pattern was named Pattern A. Pattern A of Compound I-1 was subsequently characterized by PLM, DSC, TGA and 1 H-NMR characterization. Figure 1A The DSC scan of Pattern A in the middle shows a single endothermic peak with an onset value of 196.2 °C (enthalpy: 75.0 J / g). The TGA scan Figure 1B ) shows a weight loss of 1.08% from 30 °C to 200 °C. In summary, Pattern A is a pure crystalline form of Compound I-1.

[0245] The XRPD of Pattern A of Compound I-1 is shown in the middle. The TGA and DSC analysis of Pattern A of Compound I-1 is shown in the bottom. Angle (2 theta) ° Intensity %

[0246] The following Table 2 lists the observed X-ray diffraction peaks for Pattern A of Compound I-1, where each value is in units of 2 theta degrees:

[0247] Table 2

[0248] Example 3: Preparation of salt forms of (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)- yl)-1 H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine Figure 2A 6.7 34.5 9.7 2.9 10.3 8.4 11.2 15.6 12.2 18.4 12.8 30.3 13.4 24.9 15.2 3.4 15.5 3.1 16.0 45.6 16.6 9.3 17.2 10.9 19.3 14.4 19.9 74.8 20.3 3.0 20.7 28.9 21.1 8.3 21.4 4.4 21.7 16.4 22.5 14.4 23.0 3.1 24.0 7.2 24.6 100.0 25.4 4.4 26.0 6.0 26.7 19.7 26.8 6.9 27.4 4.6 28.4 3.8 29.4 6.3 30.2 12.8 30.7 6.8 31.1 5.6 31.3 3.6 32.0 3.3 32.2 3.3 32.8 2.7 33.3 2.9 34.1 4.5 35.4 3.3

[0249] Figure 2C Figure 7A

[0250] To identify salts of Compound I-1, salt experiments were performed with 16 different counterions (acids) dissolved in 3 selected solvents (ACN, acetone and EtOAc). If no solid was obtained when the system was cooled to 25 °C, the solution was subjected to the evaporation method. The details of the procedure are as follows:

[0251] To form a salt with a solid acid, about 50 mg of Compound I-1 and 1.1 equivalents of the corresponding solid acid were weighed into a 2.0-mL glass vial. Then 1.0 mL of the selected solvent was added to the vial with the API and the acid.

[0252] To form a salt with a liquid acid, about 50 mg of the starting Compound I-1 was weighed into a 2.0-mL glass vial and 760 μΐ^of the selected solvent was added. Then 1.1 equivalents of the corresponding acid solution (242 μΐ^, 0.5 mmol / mL) was added to the vial with the API and the solvent.​​

[0253] Additionally, about 50 mg of Compound I-1 was weighed into a 2.0-mL glass vial, and 1.0 mL of the selected solvent was added as a control system.

[0254] All vials were then stirred at 600 r / min and heated or cooled according to the following temperature program: heated to 50 °C over 1 h, then held at 50 °C for 1 h; then cooled to 5 °C over 3 h, then held at 5 °C for 1 h. This temperature program was cycled 4 times for a total of about 24 h. The system was then stirred at 25 °C for an additional 40 h. For samples that resulted in a suspension, the system was centrifuged at 8000 r / min for 5 min, and the mother liquor was removed. The wet solid was dried in a vacuum oven at 30 °C for 17-21.5 h. The resulting dry solid was then characterized by XRPD. If a new XRPD pattern was identified, the dry solid with the new XRPD pattern was also characterized by PLM, DSC, and TGA. For clear solutions, the vials were then placed in a fume hood at 25 °C to evaporate the remaining solvent. After evaporation, if a solid was produced, the solid was characterized by XRPD. If a new XRPD pattern was identified, the dry solid with the new XRPD pattern was also characterized by PLM, DSC, and TGA.

[0255] The salt results are listed in Table 3.

[0256] In the salt formation experiments, five new XRPD patterns were found with four different counterions, including hydrobromic acid (Pattern S1-I), p-toluenesulfonic acid (Pattern S6-I), benzenesulfonic acid (Patterns S7-I and S7-II), and glutaric acid (Pattern S16-I). Most of the obtained solids were amorphous solids or crystalline solids with low crystallinity. From the results, it can be seen that the salt with glutaric acid exhibited high crystallinity in all systems.

[0257] Table 3

[0258]

[0259] *The obtained solid readily absorbed moisture from the air and then formed a liquid during XRPD analysis.

[0260] Notes: 1. Roman numerals indicate different XRPD patterns of the salt. “A” indicates the XRPD pattern of the starting free base. 2. LC is an abbreviation for “low crystallinity”

[0261] The XRPD of Compound I-2 Pattern S1-I is shown in Figure 7B . The TGA and DSC analysis of Compound I-2 Pattern S1-I is shown in Figure 8A .

[0262] XRPD of Pattern S6-I of compound I-7 is shown in Figure 8B TGA and DSC analysis of Pattern S6-I of compound I-7 is shown in Figure 8C

[0263] XRPD of Patterns S7-I and S7-II of compound I-8 is shown in Figure 17A TGA and DSC analysis of Pattern S7-I of compound I-8 is shown in Figure 17B TGA and DSC analysis of Pattern S7-II of compound I-8 is shown in Example 4: Assisted preparation of salt forms of (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin- 1 (2H)-yl)-1 H-pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine

[0264] XRPD of Pattern S16-I of compound I-17 is shown in Figure 2B TGA and DSC analysis of Pattern S16-I of compound I-17 is shown in Figure 4B

[0265] Figure 9B Figure 12B

[0266] Amorphous solids obtained from Example 3 were re-slurried in more solvents (EtOH, THF or 95% aqueous IPA) to try to find more crystalline salts. Details of the procedure are as follows:

[0267] Amorphous solids were re-slurried in 500 μΐ^of selected solvent (EtOH, THF or 95% aqueous IPA) in 2.0-mL vials. All slurries were then stirred at 700 r / min and then heated or cooled according to the following temperature program: heated to 50 °C over 1 h and then held at 50 °C for 1 h; then cooled to 5 °C over 3 h and then held at 5 °C for 1 h. This temperature program was cycled 8 times for a total time of about 48 h. For samples that caused suspensions, the system was centrifuged at 8000 r / min for 5 min, the mother liquor was removed, and the wet solid was dried in a vacuum oven at 60 °C for 4 h. The resulting dried solid was then characterized by XRPD. If a new XRPD pattern was identified, the dried solid with the new XRPD pattern can also be characterized by PLM, DSC and TGA. For clear solutions, the vials were then placed in a fume hood at 25 °C to evaporate the remaining solvent. After evaporation, if a solid was produced, the obtained solid was characterized by XRPD. If a new XRPD pattern was identified, the dried solid with the new XRPD pattern can also be characterized by PLM, DSC and TGA.

[0268] Salt results are listed in Table 4.

[0269] Table 4

[0270] ​​​

[0271] Note: 1. Roman numerals indicate different XRPD patterns of the salt. 2. LC is short for "low crystallinity". 3. For clear solutions, an evaporation crystallization process was performed.

[0272] In the reslurry experiments, five more new XRPD patterns were found with four different counterions, including hydrobromic acid (pattern S1-II) (see Figure 7C ), sulfonic acid (pattern S3-I) (see Figure 17C ), oxalic acid (patterns S8-I and S8-II) (see Example 5: (R)-1'-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H-pyrazolo[3,4-b]pyrazin- 6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine glutarate (Compound I-17) and (R)-1'-(3-(3,4- ), and malonic acid (pattern S11-I) (see ​ ). Only pattern S11-I showed relatively high crystallinity, while the other patterns were of low crystallinity.

[0273] Considering that the crystallinity of the prepared p-toluenesulfate and glutarate salts was somewhat low, reslurry experiments were performed in ethanol with 95% IPA and 5% water solvent.

[0274] About 30 mg of p-toluenesulfate and glutarate salts were suspended in 0.5 mL EtOH or 95% IPA and 5% water, respectively. The suspensions were stirred at 500 r / min for 18 h at 25 °C. Then a small amount of solid was taken and dried in a vacuum oven at 60 °C for 5 h before being characterized by XRPD.

[0275] As shown in the XRPD results of the obtained solids of compound I-7 in ​ and compound I-17 in ​ , the crystallinity of the products was improved after the reslurry experiments.

[0276] ​ ​ Hydrogen-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)-3H- spiro[benzofuran-2,4'-piperidin]-3- Polymorph study of aminomalonate hydrogen salt (compound i-12)

[0277] Polymorph screening of (R)-1 '-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H- pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine glutarate was performed by temperature cycling method in 12 different solvents. If no suspension was observed when the system was cooled to 25 °C, the solution was evaporated. The detailed information of the procedure is as follows:

[0278] Approximately 50 mg of (R)-1 '-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H- pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine glutarate or malonate salt was weighed into a 2.0-mL glass vial, followed by 0.5 mL of the selected solvent. The sample was stirred at 700 r / min and then heated or cooled according to the following temperature program: heating to 50 °C over 1 h, then holding at 50 °C for 1 h; then cooling to 5 °C over 3 h, then holding at 5 °C for 1 h. This temperature program was cycled 8 times for a total of approximately 48 h. For samples that caused the suspension, the system was centrifuged at 8000 r / min for 5 min. The mother liquor was removed, and the wet solid was dried in a vacuum oven at 30 °C for 17 h. The resulting dry solid was then characterized by XRPD. For clear solutions, the vials were then placed in a fume hood at 25 °C to evaporate the remaining solvent.

[0279] The initial glutarate salt of (R)-1 '-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H- pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine was in a crystalline form, and this pattern was named Pattern S16-I. After polymorph screening experiments, the resulting solids all showed the same XRPD pattern as the initial glutarate salt.

[0280] Table 5

[0281]

[0282]

[0283] The initial malonate salt of (R)-1 '-(3-(3,4-dihydro-1,5-naphthyridin-1 (2H)-yl)-1 H- pyrazolo[3,4-b]pyrazin-6-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-amine was also in a crystalline form, and this pattern was named Pattern S11 -I. After polymorph screening experiments, the resulting solids all showed the same XRPD pattern as the initial malonate salt.

[0284] Table 6

[0285]

[0286] *The pattern from the EtOH system had some differences from the initial form.

[0287] Note: When MeOH was used as the solvent, a small amount of malonate salt solid was observed.

[0288] For the malonate salt system, some differences were observed from the XRPD pattern of the ethanol system to the original malonate salt (Pattern S11-I). This pattern was temporarily named Pattern S11-I*. S11-I* pattern was further characterized by PLM, DSC, TGA and 1H-NMR.

[0289] Figure 12E The DSC scan of Pattern S11-I* is shown in Figure 6, which exhibits a large endothermic peak with an onset value of 166.16 °C (247.4 J / g). While the TGA scan shows a weight loss of 0.99% from 35 °C to 140 °C. Meanwhile, according to the 1H-NMR results of Pattern S11-I*, a small amount of residual ethanol (about 0.45%) was observed in the final product. It has been confirmed that Pattern S11-I* should be a polymorph of malonate salt, not a solvate. The difference between S11-I and S11-I* can be due to the preferred orientation effect.

[0290] By reference

[0291] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent application was specifically and individually incorporated by reference. In case of conflict between the specifications in this patent application, including any definitions generally prevailing in this specification, and those in the above- incorporated publications and patents, the specifications in this patent application, including any definitions generally prevailing in this specification, shall control.

[0292] Equivalents

[0293] While specific embodiments of the disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those of skill in the art upon review of this specification. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0294] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and claims are approximations. Thus, it should be understood that the numerical parameters set forth in the specification and claims are approximations. Variations to these numerical parameters can result in changes in a desired, end result within the scope of the disclosure.

Claims

1. A compound I-1 in solid form: The solid form described therein is crystalline; and The solid form is characterized in that its XRPD pattern is consistent with the XRPD pattern depicted in Figure 1A, or is characterized in that... The powder X-ray diffraction pattern has peaks at 24.6±0.5 degrees 2θ, 19.9±0.5 degrees 2θ, 16.0±0.5 degrees 2θ, 6.7±0.5 degrees 2θ, 12.8±0.5 degrees 2θ, 13.4±0.5 degrees 2θ and 20.7±0.5 degrees 2θ.

2. The solid form according to claim 1, characterized in that... The differential scanning calorimetry (DSC) curve shows an endothermic peak with an initial value of approximately 196°C and a peak value of approximately 197°C.

3. A compound of formula (I) in, m is 1-9; n is 1-3; and X can be selected from hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, and p-toluenesulfonic acid. The group consisting of benzenesulfonic acid, oxalic acid, L-aspartic acid, maleic acid, malonic acid, L-tartaric acid, fumaric acid, citric acid, succinic acid, and glutaric acid, wherein the compounds are in solid form.

4. The compound according to claim 3, wherein the compound is selected from the group consisting of: compound I-2, wherein compound I-2 is a hydrobromide; compound I-3, wherein compound I-3 is a hydrochloride; and compound I-4, wherein compound I-4 is a sulfate. Compound I-5, wherein compound I-5 is a methanesulfonate; Compound I-6, wherein compound I-6 is a phosphate; compound I-7, wherein compound I-7 is p-toluenesulfonate; compound I-8, wherein compound I-8 is benzenesulfonate; compound I-9, wherein compound I-9 is oxalate; compound I-10, wherein compound I-10 is L-aspartate; compound I-11, wherein compound I-11 is maleate; compound I-12, wherein compound I-12 is malonate; compound I-13, wherein compound I-13 is L-tartrate; compound I-14, wherein compound I-14 is fumarate; compound I-15, wherein compound I-15 is citrate; compound I-16, wherein compound I-16 is succinate; and compound I-17, wherein compound I-17 is glutarate.

5. The compound according to claim 3 or 4, wherein the compound is amorphous.

6. The compound according to claim 3 or 4, wherein the compound is compound I-2, which is crystalline and characterized in that... The XRPD map is basically consistent with the XRPD map depicted in Figure 2A or Figure 2B.

7. The compound according to claim 3 or 4, wherein the compound is compound I-4, which is crystalline and characterized in that... The XRPD map is basically consistent with the XRPD map depicted in Figure 4B.

8. The compound according to claim 3 or 4, wherein the compound is compound I-8, which is crystalline and characterized in that... The XRPD map is basically consistent with the XRPD map depicted in Figure 8A.

9. The compound according to claim 3 or 4, wherein the compound is compound I-12, which is crystalline and characterized in that... The XRPD map is basically consistent with the XRPD map depicted in Figure 12B.

10. The compound according to claim 3 or 4, wherein the compound is compound I-17, which is crystalline and characterized in that... The XRPD map is basically consistent with the XRPD map depicted in Figure 17A, Figure 17C, or Figure 17D.

11. A pharmaceutical composition comprising a compound in solid form according to claim 1 or 2, or according to any one of claims 3 to 10, and a pharmaceutical carrier.

12. Use of the solid form of claim 1 or 2, the compound of any one of claims 3 to 10, or the pharmaceutical composition of claim 11 in the preparation of a medicament for inhibiting SHP2 phosphatase activity in a subject with such need.

13. The use according to claim 12, wherein the drug is further administered in combination with a therapeutically effective amount of an antibody, antibody-drug conjugate, immunomodulator, or histone deacetylase inhibitor.

14. The use according to claim 12 or 13, wherein the subject is a human being.

15. Use of the solid form of claim 1 or 2, the compound of any one of claims 3 to 10, or the pharmaceutical composition of claim 11 in the preparation of a medicament for treating a disease in a subject with such need, wherein the disease is selected from Noonan syndrome, neutropenia, diabetes, neuroblastoma, melanoma, acute myeloid leukemia, juvenile leukemia, juvenile myelomonocytic leukemia, breast cancer, lung cancer, and colorectal cancer.

16. The use according to claim 15, wherein the drug is further administered in combination with a therapeutically effective amount of an antibody, antibody-drug conjugate, immunomodulator, or histone deacetylase inhibitor.

17. The use according to claim 15 or 16, wherein the disease is Noonan syndrome.

18. The use according to claim 15 or 16, wherein the condition is neutropenia.

19. The use according to claim 15 or 16, wherein the disease is diabetes.

20. The use according to claim 15 or 16, wherein the disease is neuroblastoma.

21. The use according to claim 15 or 16, wherein the disease is melanoma.

22. The use according to claim 15 or 16, wherein the disease is acute myeloid leukemia.

23. The use according to claim 15 or 16, wherein the disease is juvenile leukemia.

24. The use according to claim 15 or 16, wherein the disease is juvenile myelomonocytic leukemia.

25. The use according to claim 15 or 16, wherein the disease is breast cancer.

26. The use according to claim 15 or 16, wherein the disease is lung cancer.

27. The use according to claim 15 or 16, wherein the disease is colorectal cancer.

28. A kit comprising the solid form of claim 1 or the compound of any one of claims 3 to 10.

29. The kit according to claim 28, further comprising a written instruction describing the preparation of a pharmaceutical composition suitable for administration to a patient from the solid form or compound.

30. The kit of claim 29, further comprising written instructions describing how to administer the obtained composition to the patient.

31. The kit according to claim 28, further comprising a pharmaceutical excipient.

32. A method for preparing the crystalline form according to claim 1, comprising: a) Prepare a solution of compound I-1 in a solvent containing at least one of EtOH, ACN, MEK, EtOAc, IPAc, THF, MtBE, toluene, 1,4-dioxane, and water; b) Heat the solution to completely dissolve compound I-1; c) Adjust the temperature to cause a solid to precipitate from the solution. And d) the crystalline form of the isolated compound I-1.

33. The method according to claim 32, wherein the solvent is EtOH.

34. The method of claim 32, wherein the solvent comprises ACN.

35. The method of claim 32, wherein the solvent comprises EtOAc.

36. The method of claim 32, wherein the solvent comprises IPAc.

37. The method of claim 32, wherein the solvent comprises THF.

38. The method of claim 32, wherein the solvent comprises MtBE.

39. The method of claim 32, wherein the solvent comprises toluene.

40. The method of claim 32, wherein the solvent comprises 1,4-dioxane.

41. The method of claim 32, wherein the solvent comprises 9 v / 1 v of EtOH and water.

42. The method of claim 32, wherein heating the solution comprises heating the solution to 50°C.

43. The method of claim 32, wherein adjusting the temperature comprises cooling the solution to 5°C.

44. A method for preparing a compound of formula I-1, the method comprising the step of neutralizing a compound of formula I-3 with NaOH to form the compound of formula I-1:

45. The method of claim 44, further comprising the step of reacting the compound of formula 18 with HCl to form the compound of formula I-3:

46. ​​The method of claim 45, further comprising the step of coupling the compound of formula 17 with the compound of formula 9 to form the compound of formula 18:

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