Solid forms, salts and preparation processes of CDK2 inhibitors

Abstract

The present application relates to a compound of formula (I): [Formula 1] Provided herein are solid forms and salts of the compound of formula (I), pharmaceutical compositions thereof, methods of treating diseases or disorders associated with CDK2 using the same, and processes for preparing the compound and solid forms and salts of formula (I).

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 317,308, filed March 7, 2022, which is incorporated by reference in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically as an XML file named 20443-0746WO1_SL_ST26.xml. This XML file, created on Mar. 6, 2023, is 5,121 bytes in size. The material in the XML file is incorporated herein by reference in its entirety.

[0003] The present application relates to solid forms and salts of CDK2 inhibitors, pharmaceutical compositions thereof, methods of treating diseases or disorders associated with CDK2 using same, and processes for preparing the compounds of formula (I) and the solid forms and salts thereof. [Background technology]

[0004] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases. Upon heterodimerization with regulatory subunits known as cyclins, CDKs become fully active and regulate key cellular processes, including cell cycle progression and cell division (Morgan, DO, Annu Rev Cell Dev Biol, 1997.13:261-91). Uncontrolled proliferation is a hallmark of cancer cells. Deregulation of CDK activity is associated with dysregulation of the cell cycle, which is detected in virtually all forms of human cancer (Sherr, CJ, Science, 1996.274(5293):1672-7).

[0005] CDK2 is of particular interest because deregulation of CDK2 activity occurs frequently in various human cancers. CDK2 plays an essential role in promoting the G1 / S transition and S-phase progression. When complexed with cyclin E (CCNE), CDK2 phosphorylates retinoblastoma pocket protein family members (p107, p130, pRb), leading to derepression of E2F transcription factors, expression of G1 / S transition-associated genes, and transition from G1 to S phase (Henley, SA and FA Dick, Cell Div, 2012, 7(1): p. 10). This in turn enables activation of CDK2 / cyclin A, which phosphorylates endogenous substrates, allowing DNA synthesis, replication, and centrosome duplication (Ekholm, SV and SI Reed, Curr Opin Cell Biol, 2000. 12(6): 676-84). The CDK2 pathway has been reported to affect tumor development primarily through amplification and / or overexpression of CCNE1 and mutations that inactivate CDK2 endogenous inhibitors (e.g., p27), respectively (Xu, X., et al., Biochemistry, 1999.38(27):8713-22).

[0006] Copy number gain and overexpression of CCNE1 have been identified in ovarian, gastric, endometrial, breast, and other cancers and are associated with poor outcome in these tumors (Keyomarsi, K., et al., N Engl J Med, 2002. 347(20): 1566-75; Nakayama, N., et al., Cancer, 2010. 116(11): 2621-34; Au-Yeung, G., et al., Clin Cancer Res, 2017. 23(7): 1862-1874; Rosen, DG, et al., Cancer, 2006. 106(9): 1925-32). Amplification and / or overexpression of CCNE1 also reportedly contributes to trastuzumab resistance in HER2+ breast cancer and resistance to CDK4 / 6 inhibitors in estrogen receptor positive breast cancer (Scaltriti, M., et al., Proc Natl Acad Sci USA, 2011. 108(9): 3761-6; Herrera-Abreu, MT, et al., Cancer Res, 2016. 76(8): 2301-13). Various approaches targeting CDK2 have been shown to induce cell cycle arrest and inhibition of tumor growth (Chen, YN, et al., Proc Natl Acad Sci USA, 1999. 96(8): 4325-9; Mendoza, N., et al., Cancer Res, 2003. 63(5): 1020-4). Inhibition of CDK2 also reportedly restores sensitivity to trastuzumab treatment in resistant HER2+ breast tumors in preclinical models (Scaltriti, see above).

[0007] These data provide evidence for considering CDK2 as a potential target for new drug development in cancers associated with deregulated CDK2 activity. In the past decade, there has been growing interest in developing CDK-selective inhibitors. Despite significant efforts, to date, there are no approved drugs that target CDK2 (Cicenas, J., et al., Cancers (Basel), 2014.6(4):p.2224-42). Thus, there remains a need to discover new forms of CDK2 inhibitors and preparation processes for such inhibitors and solid forms. This application is directed to this and other needs. Summary of the Invention

[0008] The present disclosure relates, inter alia, to a compound of formula (I): [ka] wherein the solid form is Form I, Form II, or Form III.

[0009] The disclosure further provides a salt of a compound of formula (I), the salt being Monomaleate salt of the compound of formula (I), The dibesylate salt of the compound of formula (I), The monomesylate salt of the compound of formula (I), A ditosylate salt of the compound of formula (I), The monohydrochloride salt of the compound of formula (I), and The dihydrochloride salt of the compound of formula (I), is selected from.

[0010] The present disclosure further provides a pharmaceutical composition comprising a solid form of the compound of formula (I) described herein and a pharma- ceutically acceptable carrier.The present disclosure also provides a pharmaceutical composition comprising a salt of the compound of formula (I) described herein and a pharma- ceutically acceptable carrier.

[0011] The present disclosure further provides a method of inhibiting CDK2, comprising contacting CDK2 with a solid form of formula (I) as described herein.The present disclosure further provides a method of inhibiting CDK2, comprising contacting CDK2 with a salt of a compound of formula (I) as described herein.

[0012] The present disclosure further provides a method of inhibiting CDK2 in a patient, comprising administering to the patient a solid form of a compound of formula (I) as described herein.The present disclosure further provides a method of inhibiting CDK2 in a patient, comprising administering to the patient a salt of a compound of formula (I) as described herein.

[0013] The present disclosure further provides a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a solid form of a compound of formula (I) as described herein.The present disclosure further provides a method of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a salt of a compound of formula (I) as described herein.

[0014] The present disclosure further provides a solid form of the compound of formula (I) described herein for use in any of the methods described herein.The present disclosure further provides a salt of the compound of formula (I) described herein for use in any of the methods described herein.

[0015] The present disclosure further provides the use of a solid form of the compound of formula (I) described herein for preparing a medicament for use in any of the methods described herein.The present disclosure further provides the use of a salt of the compound of formula (I) described herein for preparing a medicament for use in any of the methods described herein.

[0016] The present disclosure further provides a process for preparing a solid form of the compound of formula (I) described herein, comprising cooling a solution of the compound of formula (I) in a solvent component comprising ethanol and water.

[0017] The present disclosure also provides processes for the preparation of the salts of the compounds of formula (I) described herein.

[0018] The present disclosure further provides a process for preparing a compound of formula (I) as described herein or a pharma- ceutically acceptable salt thereof, a solid form of a compound of formula (I) as described herein, or a salt of a compound of formula (I) as described herein, the process comprising: Formula (1c): [ka] With a compound of formula (1b): [ka] or a salt thereof via a Buchwald coupling reaction to obtain a compound of formula (1a): [ka] wherein X 1 is a halo. [Brief description of the drawings]

[0019] [Figure 1] 1 shows the XRPD pattern for Form I of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Diagram 2] FIG. 1 shows a DSC thermogram for Form I of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Diagram 3]FIG. 2 shows a TGA thermogram for Form I of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Figure 4] 1 shows the XRPD pattern for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) maleate salt. [Diagram 5] FIG. 2 shows a DSC thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) maleate salt. [Figure 6] Figure 2 shows a TGA thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) maleate salt. [Figure 7] 1 shows the XRPD pattern for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) besylate salt. [Figure 8] FIG. 1 shows a DSC thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) besylate salt. [Figure 9]Figure 2 shows a TGA thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) besylate salt. [Figure 10] 1 shows the XRPD pattern for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) mesylate. [Figure 11] FIG. 1 shows a DSC thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) mesylate. [Figure 12] Figure 2 shows a TGA thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) mesylate. [Figure 13] 1 shows the XRPD pattern for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) tosylate salt. [Figure 14] FIG. 1 shows a DSC thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) tosylate salt. [Figure 15]Figure 2 shows a TGA thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) tosylate salt. [Figure 16] 1 shows the XRPD pattern for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) monohydrochloride salt. [Figure 17] FIG. 1 shows a DSC thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) monohydrochloride salt. [Figure 18] Figure 2 shows a TGA thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) monohydrochloride salt. [Figure 19] 1 shows the XRPD pattern for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) dihydrochloride. [Figure 20] FIG. 1 shows a DSC thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) dihydrochloride. [Figure 21]Figure 2 shows a TGA thermogram for crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) dihydrochloride. [Figure 22] 1 shows the XRPD pattern for Form II of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Diagram 23] FIG. 1 shows a DSC thermogram for Form II of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Figure 24] FIG. 2 shows a TGA thermogram for Form II of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Diagram 25] 1 shows the XRPD pattern for Form III of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Figure 26] FIG. 1 shows a DSC thermogram for Form III of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Figure 27]FIG. 2 shows a TGA thermogram for Form III of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Figure 28] 1 shows the XRPD pattern for Form I of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. [Figure 29] FIG. 1 shows a DSC thermogram for Form I of crystalline 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) free base. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] Solid Forms and Salts The present application relates in particular to a compound of formula (I): [ka] The present invention provides a solid form of a compound of formula (I), the solid form being Form I. Form I is the free base of the compound of formula (I). In some embodiments, the solid form is unsolvated. In some embodiments, the solid form is crystalline.

[0021] In some embodiments, the solid form has at least one XRPD peak selected from: 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0022] In some embodiments, the solid form has at least two XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0023] In some embodiments, the solid form has at least three XRPD peaks selected from: 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0024] In some embodiments, the solid form has at least four XRPD peaks selected from: 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0025] In some embodiments, the solid form has at least five XRPD peaks selected from: 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0026] In some embodiments, the solid form has at least 10 XRPD peaks selected from: 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0, two theta (±0.2 degrees).

[0027] In some embodiments, the solid form has at least one XRPD peak selected from 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.1 two theta (±0.2 degrees).

[0028] In some embodiments, the solid form has at least two XRPD peaks selected from 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.1 two theta (±0.2 degrees).

[0029] In some embodiments, the solid form has at least three XRPD peaks selected from: 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.1 two theta (±0.2 degrees).

[0030] In some embodiments, the solid form has at least four XRPD peaks selected from: 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.1, two theta (±0.2 degrees).

[0031] In some embodiments, the solid form has at least five XRPD peaks selected from: 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.1 two theta (±0.2 degrees).

[0032] In some embodiments, the solid form has at least 10 XRPD peaks selected from: 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.1, two theta (±0.2 degrees).

[0033] In some embodiments, the solid form has an XRPD pattern substantially as shown in FIG.

[0034] In some embodiments, the solid form has an XRPD pattern substantially as shown in FIG.

[0035] In some embodiments, the solid form has an endothermic peak with an onset temperature (±3°C) of 191.7°C and a maximum of 193.6°C.

[0036] In some embodiments, the solid form has an endothermic peak with an onset temperature (±3°C) of 191.3°C and a maximum of 193.3°C.

[0037] In some embodiments, the solid form has a DSC thermogram substantially as shown in FIG.

[0038] In some embodiments, the solid form has a DSC thermogram substantially as shown in FIG.

[0039] In some embodiments, the solid form has a TGA thermogram substantially as shown in FIG.

[0040] The present application also relates to a solid form of a compound of formula (I), Also provided is the solid form, which is Form II. Form II is the free base of the compound of formula (I). In some embodiments, the solid form is not solvated. In some embodiments, the solid form is crystalline.

[0041] In some embodiments, the solid form has at least one XRPD peak selected from 5.8, 7.6, 11.4, 12.5, 14.4, 17.2, 17.9, and 25.3, 2 theta (±0.2 degrees).

[0042] In some embodiments, the solid form has at least two XRPD peaks selected from 5.8, 7.6, 11.4, 12.5, 14.4, 17.2, 17.9, and 25.3 two theta (±0.2 degrees).

[0043] In some embodiments, the solid form has at least three XRPD peaks selected from: 5.8, 7.6, 11.4, 12.5, 14.4, 17.2, 17.9, and 25.3, two theta (±0.2 degrees).

[0044] In some embodiments, the solid form has at least four XRPD peaks selected from: 5.8, 7.6, 11.4, 12.5, 14.4, 17.2, 17.9, and 25.3, two theta (±0.2 degrees).

[0045] In some embodiments, the solid form has at least five XRPD peaks selected from: 5.8, 7.6, 11.4, 12.5, 14.4, 17.2, 17.9, and 25.3, two theta (±0.2 degrees).

[0046] In some embodiments, the solid form has at least 10 XRPD peaks selected from 5.8, 7.6, 11.4, 12.5, 14.4, 17.2, 17.9, and 25.3, 2 theta (±0.2 degrees).

[0047] In some embodiments, the solid form has an XRPD pattern substantially as shown in FIG.

[0048] In some embodiments, the solid form has an endothermic peak with an onset temperature (±3°C) of 191.0°C and a maximum of 193.4°C.

[0049] In some embodiments, the solid form has a DSC thermogram substantially as shown in FIG.

[0050] In some embodiments, the solid form has a TGA thermogram substantially as shown in FIG.

[0051] The present application also relates to a solid form of a compound of formula (I), Also provided is the solid form, which is Form III. Form III is the free base of the compound of formula (I). In some embodiments, the solid form is solvated. In some embodiments, the solid form is a 1,4-dioxane solvate. In some embodiments, the 1,4-dioxane solvate of the compound of formula (I) has a stoichiometric ratio of the compound of formula (I) to 1,4-dioxane of 4:1. In some embodiments, the solid form is crystalline.

[0052] In some embodiments, the solid form has at least one XRPD peak selected from 5.5, 9.8, 10.5, 12.1, 13.9, 16.3, 19.8, 22.0, 24.4, and 27.3 two theta (±0.2 degrees).

[0053] In some embodiments, the solid form has at least two XRPD peaks selected from 5.5, 9.8, 10.5, 12.1, 13.9, 16.3, 19.8, 22.0, 24.4, and 27.3 two theta (±0.2 degrees).

[0054] In some embodiments, the solid form has at least three XRPD peaks selected from 5.5, 9.8, 10.5, 12.1, 13.9, 16.3, 19.8, 22.0, 24.4, and 27.3 two theta (±0.2 degrees).

[0055] In some embodiments, the solid form has at least four XRPD peaks selected from 5.5, 9.8, 10.5, 12.1, 13.9, 16.3, 19.8, 22.0, 24.4, and 27.3 two theta (±0.2 degrees).

[0056] In some embodiments, the solid form has at least five XRPD peaks selected from: 5.5, 9.8, 10.5, 12.1, 13.9, 16.3, 19.8, 22.0, 24.4, and 27.3 two theta (±0.2 degrees).

[0057] In some embodiments, the solid form has at least 10 XRPD peaks selected from 5.5, 9.8, 10.5, 12.1, 13.9, 16.3, 19.8, 22.0, 24.4, and 27.3, two theta (±0.2 degrees).

[0058] In some embodiments, the solid form has an XRPD pattern substantially as shown in FIG.

[0059] In some embodiments, the solid form has an endothermic peak with an onset temperature (±3°C) of 192.6°C and a maximum of 194.3°C.

[0060] In some embodiments, the solid form has a DSC thermogram substantially as shown in FIG.

[0061] In some embodiments, the solid form has a TGA thermogram substantially as shown in FIG.

[0062] In the present application, the compound of formula (I): [ka] Also provided is a salt of the compound of formula (I), the salt being selected from the monomaleate salt of the compound of formula (I), the dibesylate salt of the compound of formula (I), the monomesylate salt of the compound of formula (I), the ditosylate salt of the compound of formula (I), the monohydrochloride salt of the compound of formula (I), and the dihydrochloride salt of the compound of formula (I).

[0063] In some embodiments, the salt is a mono-maleate salt of the compound of formula (I). In some embodiments, the mono-maleate salt is crystalline.

[0064] In some embodiments, the monomaleate salt has at least one XRPD peak selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9 two theta (±0.2 degrees).

[0065] In some embodiments, the monomaleate salt has at least two XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9 two theta (±0.2 degrees).

[0066] In some embodiments, the monomaleate salt has at least three XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9 two theta (±0.2 degrees).

[0067] In some embodiments, the monomaleate salt has at least four XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9 two theta (±0.2 degrees).

[0068] In some embodiments, the monomaleate salt has at least five XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9 two theta (±0.2 degrees).

[0069] In some embodiments, the monomaleate salt has at least 10 XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9, two theta (±0.2 degrees).

[0070] In some embodiments, the monomaleate salt has an XRPD pattern substantially as shown in FIG.

[0071] In some embodiments, the monomaleate salt has an endothermic peak with an onset temperature (±3° C.) of 180.4° C. and a maximum temperature (±3° C.) of 181.8° C.

[0072] In some embodiments, the monomaleate salt has a DSC thermogram substantially as shown in FIG.

[0073] In some embodiments, the monomaleate salt has a TGA thermogram substantially as shown in FIG.

[0074] In some embodiments, the salt is a dibesylate salt of the compound of formula (I). In some embodiments, the dibesylate salt is crystalline.

[0075] In some embodiments, the dibesylate salt has at least one XRPD peak selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1 two theta (±0.2 degrees).

[0076] In some embodiments, the dibesylate salt has at least two XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1 two theta (±0.2 degrees).

[0077] In some embodiments, the dibesylate salt has at least three XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1 two theta (±0.2 degrees).

[0078] In some embodiments, the dibesylate salt has at least four XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1 two theta (±0.2 degrees).

[0079] In some embodiments, the dibesylate salt has at least five XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1 two theta (±0.2 degrees).

[0080] In some embodiments, the dibesylate salt has at least 10 XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1, two theta (±0.2 degrees).

[0081] In some embodiments, the dibesylate salt has an XRPD pattern substantially as shown in FIG.

[0082] In some embodiments, the dibesylate salt has an endothermic peak with an onset temperature (±3° C.) of 160.4° C. and a maximum temperature (±3° C.) of 163.4° C.

[0083] In some embodiments, the dibesylate salt has a DSC thermogram substantially as shown in FIG.

[0084] In some embodiments, the dibesylate salt has a TGA thermogram substantially as shown in FIG.

[0085] In some embodiments, the salt is a monomesylate salt of the compound of formula (I). In some embodiments, the monomesylate salt is crystalline.

[0086] In some embodiments, the monomesylate salt has at least one XRPD peak selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1 two theta (±0.2 degrees).

[0087] In some embodiments, the monomesylate salt has at least two XRPD peaks selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1 two theta (±0.2 degrees).

[0088] In some embodiments, the monomesylate salt has at least three XRPD peaks selected from: 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1 two theta (±0.2 degrees).

[0089] In some embodiments, the monomesylate salt has at least four XRPD peaks selected from: 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1 two theta (±0.2 degrees).

[0090] In some embodiments, the monomesylate salt has at least five XRPD peaks selected from: 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1 two theta (±0.2 degrees).

[0091] In some embodiments, the monomesylate salt has at least 10 XRPD peaks selected from: 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1, two theta (±0.2 degrees).

[0092] In some embodiments, the monomesylate salt has an XRPD pattern substantially as shown in FIG.

[0093] In some embodiments, the monomesylate salt has a first endothermic peak with a maximum temperature (±3°C) of 61.1°C and a second endothermic peak with an onset temperature (±3°C) of 134.4°C and a maximum temperature (±3°C) of 150.1°C.

[0094] In some embodiments, the monomesylate salt has a DSC thermogram substantially as shown in FIG.

[0095] In some embodiments, the monomesylate salt has a TGA thermogram substantially as shown in FIG.

[0096] In some embodiments, the salt is a ditosylate salt of the compound of formula (I). In some embodiments, the ditosylate salt is crystalline.

[0097] In some embodiments, the ditosylate salt has at least one XRPD peak selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6 two theta (±0.2 degrees).

[0098] In some embodiments, the ditosylate salt has at least two XRPD peaks selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6 two theta (±0.2 degrees).

[0099] In some embodiments, the ditosylate salt has at least three XRPD peaks selected from 65.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6 two theta (±0.2 degrees).

[0100] In some embodiments, the ditosylate salt has at least four XRPD peaks selected from: 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6 two theta (±0.2 degrees).

[0101] In some embodiments, the ditosylate salt has at least five XRPD peaks selected from: 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6 two theta (±0.2 degrees).

[0102] In some embodiments, the ditosylate salt has at least eight XRPD peaks selected from: 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6 two theta (±0.2 degrees).

[0103] In some embodiments, the ditosylate salt has an XRPD pattern substantially as shown in FIG.

[0104] In some embodiments, the ditosylate salt has an exothermic peak with an onset temperature (±3° C.) of 99.6° C. and a maximum temperature (±3° C.) of 110.5° C., and an endothermic peak with an onset temperature (±3° C.) of 216.1° C. and a maximum temperature (±3° C.) of 218.7° C.

[0105] In some embodiments, the ditosylate salt has a DSC thermogram substantially as shown in FIG.

[0106] In some embodiments, the ditosylate salt has a TGA thermogram substantially as shown in FIG.

[0107] In some embodiments, the salt is a monohydrochloride salt of the compound of formula (I). In some embodiments, the monohydrochloride salt is crystalline.

[0108] In some embodiments, the monohydrochloride salt has at least one XRPD peak selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7 two theta (±0.2 degrees).

[0109] In some embodiments, the monohydrochloride salt has at least two XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7 two theta (±0.2 degrees).

[0110] In some embodiments, the monohydrochloride salt has at least three XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7 two theta (±0.2 degrees).

[0111] In some embodiments, the monohydrochloride salt has at least four XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7 two theta (±0.2 degrees).

[0112] In some embodiments, the monohydrochloride salt has at least five XRPD peaks selected from: 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7 two theta (±0.2 degrees).

[0113] In some embodiments, the monohydrochloride salt has at least 10 XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7, two theta (±0.2 degrees).

[0114] In some embodiments, the monohydrochloride salt has an XRPD pattern substantially as shown in FIG.

[0115] In some embodiments, the monohydrochloride salt has an endothermic peak with an onset temperature (±3° C.) of 196.0° C. and a maximum temperature (±3° C.) of 212.2° C.

[0116] In some embodiments, the monohydrochloride salt has a DSC thermogram substantially as shown in FIG.

[0117] In some embodiments, the monohydrochloride salt has a TGA thermogram substantially as shown in FIG.

[0118] In some embodiments, the salt is a dihydrochloride salt of the compound of formula (I). In some embodiments, the dihydrochloride salt is crystalline.

[0119] In some embodiments, the dihydrochloride salt has at least one XRPD peak selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8 two theta (±0.2 degrees).

[0120] In some embodiments, the dihydrochloride salt has at least two XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8 two theta (±0.2 degrees).

[0121] In some embodiments, the dihydrochloride salt has at least three XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8 two theta (±0.2 degrees).

[0122] In some embodiments, the dihydrochloride salt has at least four XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8 two theta (±0.2 degrees).

[0123] In some embodiments, the dihydrochloride salt has at least five XRPD peaks selected from: 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8 two theta (±0.2 degrees).

[0124] In some embodiments, the dihydrochloride salt has at least 10 XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8, two theta (±0.2 degrees).

[0125] In some embodiments, the dihydrochloride salt has an XRPD pattern substantially as shown in FIG.

[0126] In some embodiments, the dihydrochloride salt has an endothermic peak with an onset temperature (±3° C.) of 182.1° C. and a maximum temperature (±3° C.) of 206.4° C.

[0127] In some embodiments, the dihydrochloride salt has a DSC thermogram substantially as shown in FIG.

[0128] In some embodiments, the dihydrochloride salt has a TGA thermogram substantially as shown in FIG.

[0129] Different forms of the same substance have different bulk properties, for example, with respect to hygroscopicity, solubility, stability, etc. Forms with high melting points often have good thermodynamic stability, which is advantageous for extending the shelf life of drug formulations containing the solid form. Forms with lower melting points often have lower thermodynamic stability, but they are advantageous in that they have higher solubility in water and therefore higher bioavailability of the drug. Forms with low hygroscopicity are desirable due to their stability to heat and humidity, and resist degradation during long-term storage.

[0130] In some embodiments, the solid form or salt of the compound of formula (I) provided herein is crystalline.As used herein, "crystalline" is intended to refer to a certain lattice arrangement of crystalline material.Different crystal forms of the same material typically have different crystal lattices (e.g., unit cells), which are due to the different physical properties inherent to each crystal form.In some cases, different lattice arrangements have different water or solvent contents.

[0131] As used herein, "slurrying" is intended to refer to forming a mixture of insoluble materials in a liquid.

[0132] The solid and salt forms can be identified by solid state characterization methods such as X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, etc. can further help identify the form as well as determine stability and solvent / water content.

[0133] XRPD patterns of reflections (peaks) are typically considered as fingerprints of a particular solid form. It is well known that the relative intensities of XRPD peaks can vary widely depending on, among other things, sample preparation techniques, crystal size distribution, various filters used, sample mounting procedures, and the particular instrument employed. In some cases, new peaks may be observed or existing peaks may disappear depending on the type or settings of the instrument. As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 4% of the maximum peak height / intensity. Moreover, instrumental variations and other factors may affect 2-theta values. Thus, peak assignments such as those reported herein may vary by plus or minus about 0.2° (2-theta), and the terms "substantially" and "about" as used herein in the context of XRPD are intended to encompass the aforementioned variations.

[0134] Similarly, temperature readings associated with DSC, TGA, or other thermal experiments can vary by about ±3° C. depending on the instrument, the particular settings, sample preparation, etc. Thus, it is understood that solid forms or salts reported herein having DSC thermograms "substantially" as shown in any of the figures, or the term "about," take such variations into account.

[0135] In some embodiments, the solid forms or salts described herein are substantially isolated. "Substantially isolated" means that the solid forms or salts are at least partially or substantially separated from the environment in which they were formed or found. Partial separation can include, for example, compositions enriched with the solid forms or salts described herein. Substantial separation can include compositions that contain at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the solid forms or salts described herein.

[0136] Preparation process The present application further provides a process for preparing the solid form, Form I, comprising cooling a solution of a compound of formula (I) in a solvent component comprising ethanol and water.

[0137] In some embodiments, the solvent component comprises about 5% to about 20% water and about 80% to about 95% ethanol. In some embodiments, the solvent component comprises about 5% to about 10% water and about 90% to about 95% ethanol. In some embodiments, the solvent component comprises about 6% water and about 94% ethanol. In some embodiments, the solvent component comprises about 10% water and about 90% ethanol.

[0138] In some embodiments, the solution is cooled to a temperature of 0°C ± 3°C.

[0139] In some embodiments, the solution is prepared by heating a slurry of the compound of formula (I) in the solvent component prior to cooling.

[0140] The present application further provides a process for preparing a solid form, which is Form II, comprising evaporating a solution of a compound of formula (I) in a solvent selected from CH2Cl2, CH3CN, EtOH, and IPA at 25°C. In some embodiments, the solvent is CH2Cl2. In some embodiments, the solvent is CH3CN. In some embodiments, the solvent is EtOH. In some embodiments, the solvent is IPA.

[0141] The present application further provides a process for preparing the solid form, which is Form III, comprising evaporating a solution of compound of formula (I) in 1,4-dioxane at 25°C.

[0142] Also provided is a process for preparing Form III, comprising preparing a saturated or nearly saturated solution of the compound of formula (I) in 1,4-dioxane at 25° C., quenching the solution to a temperature of about −20° C. to about −30° C., and precipitating a solid form, which is Form III.

[0143] The present application further provides a process for preparing a salt form of the compound of formula (I) selected from the monomaleate, dibesylate, monomesylate, ditosylate, monohydrochloride, and dihydrochloride salts.

[0144] The present application provides a process for preparing a mono-maleate salt of a compound of formula (I), comprising reacting a compound of formula (I) with maleic acid. In some embodiments, about 1 equivalent to about 2 equivalents of maleic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 equivalent to about 1.5 equivalents of maleic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 equivalent to about 1.2 equivalents of maleic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, the reaction of a compound of formula (I) with maleic acid is carried out in a solvent component. In some embodiments, the solvent component comprises an alcohol and a halogenated alkane. In some embodiments, the solvent component comprises about 30% to about 70% by weight of a halogenated alkane and about 30% to about 70% by weight of an alcohol. In some embodiments, the solvent component comprises about 40% to about 60% by weight of a halogenated alkane and about 40% to about 60% by weight of an alcohol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of a halogenated alkane and about 45% to about 55% by weight of an alcohol. In some embodiments, the halogenated alkane is a chlorinated alkane. In some embodiments, the solvent component comprises dichloromethane and methanol. In some embodiments, the solvent component comprises about 30% to about 70% by weight of dichloromethane and about 30% to about 70% by weight of methanol. In some embodiments, the solvent component comprises about 40% to about 50% by weight of dichloromethane and about 40% to about 50% by weight of methanol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of dichloromethane and about 45% to about 55% by weight of methanol. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol.

[0145] In some embodiments, after the reaction of the compound of formula (I) with maleic acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetone.

[0146] In some embodiments, the process for preparing the mono-maleate salt of the compound of formula (I) comprises reacting the compound of formula (I) with maleic acid in a solvent component comprising dichloromethane and methanol, and then evaporating the solvent component. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol. In some embodiments, the compound of formula (I) is dissolved in the solvent component prior to the addition of maleic acid. In some embodiments, the solvent component is evaporated from the solution at room temperature. In some embodiments, the solution is evaporated to dryness. In some embodiments, evaporating the solvent component results in a solid. In some embodiments, acetone is added to the resulting solid, followed by filtration.

[0147] The present application provides a process for preparing a dibesylate salt of a compound of formula (I), comprising reacting a compound of formula (I) with benzenesulfonic acid. In some embodiments, about 1 equivalent to about 2 equivalents of benzenesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 equivalent to about 1.5 equivalents of benzenesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 equivalent to about 1.2 equivalents of benzenesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, the reaction of a compound of formula (I) with benzenesulfonic acid is carried out in a solvent component. In some embodiments, the solvent component comprises an alcohol and a halogenated alkane. In some embodiments, the solvent component comprises about 30% to about 70% by weight of a halogenated alkane and about 30% to about 70% by weight of an alcohol. In some embodiments, the solvent component comprises about 40% to about 60% by weight of a halogenated alkane and about 40% to about 60% by weight of an alcohol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of a halogenated alkane and about 45% to about 55% by weight of an alcohol. In some embodiments, the halogenated alkane is a chlorinated alkane. In some embodiments, the solvent component comprises dichloromethane and methanol. In some embodiments, the solvent component comprises about 30% to about 70% by weight of dichloromethane and about 30% to about 70% by weight of methanol. In some embodiments, the solvent component comprises about 40% to about 50% by weight of dichloromethane and about 40% to about 50% by weight of methanol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of dichloromethane and about 45% to about 55% by weight of methanol. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol.

[0148] In some embodiments, after the reaction of the compound of formula (I) with benzenesulfonic acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetonitrile.

[0149] In some embodiments, after the reaction of the compound of formula (I) with benzenesulfonic acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetone.

[0150] In some embodiments, the process for preparing the dibesylate salt of the compound of formula (I) comprises reacting the compound of formula (I) with benzenesulfonic acid in a solvent component comprising dichloromethane and methanol, and then evaporating the solvent component. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol. In some embodiments, the compound of formula (I) is dissolved in the solvent component prior to the addition of benzenesulfonic acid. In some embodiments, the solvent component is evaporated from the solution at room temperature. In some embodiments, the solution is evaporated to a first oil. In some embodiments, acetonitrile is added to the first oil, and the solution is evaporated to a second oil. In some embodiments, acetonitrile is evaporated from the solution at room temperature. In some embodiments, acetone is added to the second oil to form a solution, and the solution is slurried to a solid. In some embodiments, the solution is slurried at room temperature. In some embodiments, the solid is filtered.

[0151] The present application provides a process for preparing a monomesylate salt of a compound of formula (I), comprising reacting a compound of formula (I) with methanesulfonic acid. In some embodiments, about 1 to about 2 equivalents of methanesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 to about 1.5 equivalents of methanesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 to about 1.2 equivalents of methanesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, the reaction of a compound of formula (I) with methanesulfonic acid is carried out in a solvent component. In some embodiments, the solvent component comprises an alcohol and a halogenated alkane. In some embodiments, the solvent component comprises about 30% to about 70% by weight of a halogenated alkane and about 30% to about 70% by weight of an alcohol. In some embodiments, the solvent component comprises about 40% to about 60% by weight of a halogenated alkane and about 40% to about 60% by weight of an alcohol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of a halogenated alkane and about 45% to about 55% by weight of an alcohol. In some embodiments, the halogenated alkane is a chlorinated alkane. In some embodiments, the solvent component comprises dichloromethane and methanol. In some embodiments, the solvent component comprises about 30% to about 70% by weight of dichloromethane and about 30% to about 70% by weight of methanol. In some embodiments, the solvent component comprises about 40% to about 50% by weight of dichloromethane and about 40% to about 50% by weight of methanol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of dichloromethane and about 45% to about 55% by weight of methanol. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol.

[0152] In some embodiments, after the reaction of the compound of formula (I) with methanesulfonic acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetone.

[0153] In some embodiments, the process for preparing the monomesylate salt of the compound of formula (I) comprises reacting the compound of formula (I) with methanesulfonic acid in a solvent component comprising dichloromethane and methanol, and then evaporating the solvent component. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol. In some embodiments, the compound of formula (I) is dissolved in the solvent component prior to the addition of methanesulfonic acid. In some embodiments, the solvent component is evaporated from the solution at room temperature. In some embodiments, the solution is evaporated to an oil. In some embodiments, acetone is added to the oil to form a solution, and the solution is slurried to a solid. In some embodiments, the solution is slurried at room temperature. In some embodiments, the solid is filtered.

[0154] The present application provides a process for preparing a ditosylate salt of a compound of formula (I), comprising reacting a compound of formula (I) with p-toluenesulfonic acid. In some embodiments, the p-toluenesulfonic acid is a monohydrate. In some embodiments, about 1 to about 2 equivalents of p-toluenesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 to about 1.5 equivalents of p-toluenesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 to about 1.2 equivalents of p-toluenesulfonic acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, the reaction of a compound of formula (I) with p-toluenesulfonic acid is carried out in a solvent component. In some embodiments, the solvent component comprises an alcohol and a halogenated alkane. In some embodiments, the solvent component comprises about 30% to about 70% by weight of a halogenated alkane and about 30% to about 70% by weight of an alcohol. In some embodiments, the solvent component comprises about 40% to about 60% by weight of a halogenated alkane and about 40% to about 60% by weight of an alcohol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of a halogenated alkane and about 45% to about 55% by weight of an alcohol. In some embodiments, the halogenated alkane is a chlorinated alkane. In some embodiments, the solvent component comprises dichloromethane and methanol. In some embodiments, the solvent component comprises about 30% to about 70% by weight of dichloromethane and about 30% to about 70% by weight of methanol. In some embodiments, the solvent component comprises about 40% to about 50% by weight of dichloromethane and about 40% to about 50% by weight of methanol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of dichloromethane and about 45% to about 55% by weight of methanol. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol.

[0155] In some embodiments, after the reaction of the compound of formula (I) with p-toluenesulfonic acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetonitrile.

[0156] In some embodiments, after the reaction of the compound of formula (I) with p-toluenesulfonic acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetone.

[0157] In some embodiments, the process for preparing the ditosylate salt of the compound of formula (I) comprises reacting the compound of formula (I) with p-toluenesulfonic acid monohydrate in a solvent component comprising dichloromethane and methanol, and then evaporating the solvent component. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol. In some embodiments, the compound of formula (I) is dissolved in the solvent component prior to the addition of p-toluenesulfonic acid monohydrate. In some embodiments, the solvent component is evaporated from the solution at room temperature. In some embodiments, the solution is evaporated to an oil. In some embodiments, acetonitrile is added to a first oil, and the solution is evaporated to an oil / semi-solid. In some embodiments, acetonitrile is evaporated from the solution at room temperature. In some embodiments, acetone is added to the oil / semi-solid to form a solution, and the solution is slurried to a solid. In some embodiments, the solution is slurried at room temperature. In some embodiments, the solid is filtered.

[0158] The present application provides a process for preparing a monohydrochloride salt of a compound of formula (I), comprising reacting a compound of formula (I) with hydrochloric acid. In some embodiments, about 1 equivalent to about 2 equivalents of hydrochloric acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 equivalent to about 1.5 equivalents of hydrochloric acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 1 equivalent to about 1.2 equivalents of hydrochloric acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, the reaction of a compound of formula (I) with hydrochloric acid is carried out in a solvent component. In some embodiments, the solvent component comprises an alcohol and a halogenated alkane. In some embodiments, the solvent component comprises about 30% to about 70% by weight of a halogenated alkane and about 30% to about 70% by weight of an alcohol. In some embodiments, the solvent component comprises about 40% to about 60% by weight of a halogenated alkane and about 40% to about 60% by weight of an alcohol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of a halogenated alkane and about 45% to about 55% by weight of an alcohol. In some embodiments, the halogenated alkane is a chlorinated alkane. In some embodiments, the solvent component comprises dichloromethane and methanol. In some embodiments, the solvent component comprises about 30% to about 70% by weight of dichloromethane and about 30% to about 70% by weight of methanol. In some embodiments, the solvent component comprises about 40% to about 50% by weight of dichloromethane and about 40% to about 50% by weight of methanol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of dichloromethane and about 45% to about 55% by weight of methanol. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol.

[0159] In some embodiments, after said reaction of the compound of formula (I) with hydrochloric acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetone.

[0160] In some embodiments, the process for preparing the monohydrochloride salt of the compound of formula (I) comprises reacting the compound of formula (I) with about 1 to about 1.5 equivalents of hydrochloric acid in a solvent component comprising dichloromethane and methanol, and then evaporating the solvent component. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol. In some embodiments, the compound of formula (I) is dissolved in the solvent component prior to the addition of hydrochloric acid. In some embodiments, the hydrochloric acid is a 6M aqueous hydrochloric acid solution. In some embodiments, the solvent component is evaporated from the solution at room temperature. In some embodiments, the solution is evaporated to dryness. In some embodiments, evaporating the solvent component provides a solid.

[0161] The present application provides a process for preparing a dihydrochloride salt of a compound of formula (I), comprising reacting a compound of formula (I) with hydrochloric acid. In some embodiments, about 2 to about 3 equivalents of hydrochloric acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 2 to about 2.5 equivalents of hydrochloric acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, about 2 to about 2.2 equivalents of hydrochloric acid are utilized for 1 equivalent of a compound of formula (I). In some embodiments, the reaction of a compound of formula (I) with hydrochloric acid is carried out in a solvent component. In some embodiments, the solvent component comprises an alcohol and a halogenated alkane. In some embodiments, the solvent component comprises about 30% to about 70% by weight of a halogenated alkane and about 30% to about 70% by weight of an alcohol. In some embodiments, the solvent component comprises about 40% to about 60% by weight of a halogenated alkane and about 40% to about 60% by weight of an alcohol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of a halogenated alkane and about 45% to about 55% by weight of an alcohol. In some embodiments, the halogenated alkane is a chlorinated alkane. In some embodiments, the solvent component comprises dichloromethane and methanol. In some embodiments, the solvent component comprises about 30% to about 70% by weight of dichloromethane and about 30% to about 70% by weight of methanol. In some embodiments, the solvent component comprises about 40% to about 50% by weight of dichloromethane and about 40% to about 50% by weight of methanol. In some embodiments, the solvent component comprises about 45% to about 55% by weight of dichloromethane and about 45% to about 55% by weight of methanol. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol.

[0162] In some embodiments, after said reaction of the compound of formula (I) with hydrochloric acid, the process further comprises removing the solvent component and then slurrying the product of the reaction in acetone.

[0163] In some embodiments, the process for preparing the dihydrochloride salt of the compound of formula (I) comprises reacting the compound of formula (I) with about 1 to about 2.5 equivalents of hydrochloric acid in a solvent component comprising dichloromethane and methanol, and then evaporating the solvent component. In some embodiments, the solvent component comprises 1:1 dichloromethane:methanol. In some embodiments, the compound of formula (I) is dissolved in the solvent component prior to the addition of hydrochloric acid. In some embodiments, the hydrochloric acid is a 6M aqueous hydrochloric acid solution. In some embodiments, the solvent component is evaporated from the solution at room temperature. In some embodiments, the solution is evaporated to dryness.

[0164] In some embodiments, acetone is added to the resulting solid, followed by filtration.

[0165] The present application also provides a process for preparing a compound of formula (I), or a solid form or salt thereof. Thus, the present application provides a process for preparing any of the compounds of formula (I) or pharma- ceutically acceptable salts thereof described herein; a solid form of the compound of formula (I) that is Form I, Form II, or Form III; or a salt of the compound of formula (I), the process comprising: Formula (1c): [ka] With a compound of formula (1b): [ka] or a salt thereof via a Buchwald coupling reaction to obtain a compound of formula (1a): [ka] wherein X 1 is a halo.

[0166] In some embodiments, X 1 is Br.

[0167] In some embodiments, the compound of formula (1b) or a salt thereof is an HCl salt. In some embodiments, the Buchwald coupling reaction comprises reacting a compound of formula (1c) with a compound of formula (1b) or a salt thereof in the presence of a Buchwald catalyst or pre-catalyst and a base.

[0168] In some embodiments, the Buchwald catalyst or pre-catalyst is a palladium catalyst. In some embodiments, the palladium catalyst or pre-catalyst is selected from the group consisting of [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrett Phos Pd G3), [tBuBrettPhos Pd(allyl)]OTf(Pd-175), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2), [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XantPhos Pd G3), tBuBrettPhos Pd G3, SPhos Pd G3, cataCXium® A Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'-amino-1,1'-Biphenyl)] Palladium(II) Methanesulfonate, JackiePhos Pd G3, CPhos Pd G3, RuPhos Pd G3, APhos Pd G3, RockPhos Pd G3, AdBrettPhos Pd G3, Neopentyl (t-Bu)2P Pd G3, TrixiePhos Pd G3, N-XantPhos Pd G3, DTBPF-Pd-G3, DPPF Pd G3, DavePhos-Pd-G3, (t-Bu)2PhP Pd G3, rac-BINAP-Pd-G3, CyJohnPhos Pd G3, MorDalphos Pd G3, Josiphos SL-J009-1 Pd G3, P(Cy3)Pd G3, Me3(OMe)tBuXPhos-Pd-G3, 4MetBuXPhos Pd G3, (t-Bu)PhCPhos Pd G3, CyJohnPhos Pd G3, Mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), DTBPF-Pd-G3, P(o-tol)3Pd G3, VPhos Pd G3, QPhos Pd G3, RuPhos Pd G4, SPhos Pd G4, BrettPhos Pd G4, XPhos Pd G4, APhos Pd G4, rac-BINAP Pd G4, P(t-Bu)3Pd G4, (t-Bu)PhCPhos Pd G4, cataCXium Pd G4, CPhos Pd G4, CyJohnPhos Pd G4, DavePhos Pd G4, DPPF Pd G4, EPhos Pd G4, MorDalPhos Pd G4, neopentyl(tBu)2P Pd G4, PCy3Pd G4, (tBu)2PMe Pd G4, (tBu)2PPh Pd G4, 1,3,5,7-tetramethyl-6-phenyl-2,4,6-Trioxa-6-phosphaadamantane Pd G4, (R)-TolBINAP Pd G4, VPhos Pd G4, XantPhos Pd G4, N-XantPhos Pd G4, t-BuDavePhos Pd G4, XPhos Pd G2, RuPhos Pd G2, SPhos Pd G2, Bis(triphenylphosphine)palladium(II) dichloride, tBuXPhos Pd G1, RuPhos Pd G1 methyl t-butyl ether adduct, SPhos Pd G1 methyl t-butyl ether adduct, 2'-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex, chloro(η2-P,C-tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II), di-μ-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino-κN)methyl]phenyl-κC]palladium dimer, DavePhos Pd G2, (Ad-BippyPhos)2PdCl2, APhos Pd G2, sSPhos Pd G2, P(t-Bu)3Pd G3, BrettPhos Pd G1 methyl t-butyl ether adduct, dichloro[2-(4,5-dihydro-2-oxazolyl)quinoline]palladium(II), salicylaldehyde thiosemicarbazone palladium(II) chloride, XPhos Pd G1, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), di-μ-chlorobis[5-hydroxy-2-[1-(hydroxyimino-κN)ethyl]phenyl-κC]palladium(II) dimer, 2-(2'-di-tert-butylphosphine)biphenylpalladium(II) acetate, or 2-(dimethylaminomethyl)ferrocen-1-yl-palladium(II) chloride dinorbornylphosphine complex.

[0169] In some embodiments, the palladium catalyst or pre-catalyst is XPhos Pd G3.

[0170] In some embodiments, the base is an alkali metal alkoxide. In some embodiments, the base is sodium t-butoxide.

[0171] In some embodiments, about 1 to about 1.5 equivalents of a compound of formula (1b) or a salt thereof are utilized per equivalent of a compound of formula (1c). In some embodiments, about 1.2 equivalents of a compound of formula (1b) or a salt thereof are utilized per equivalent of a compound of formula (1c).

[0172] In some embodiments, about 4 to about 6 equivalents of base are utilized per equivalent of the compound of Formula (1c).

[0173] In some embodiments, about 0.0001 to about 0.1 equivalents of a Buchwald catalyst or pre-catalyst are utilized per equivalent of the compound of Formula (1c).In some embodiments, about 0.01 to about 0.05 equivalents of a Buchwald catalyst or pre-catalyst are utilized per equivalent of the compound of Formula (1c).

[0174] In some embodiments, the reaction of the compound of Formula (1c) with the compound of Formula (1b) or a salt thereof is carried out at a temperature of about 80° C. to about 100° C. In some embodiments, the reaction of the compound of Formula (1c) with the compound of Formula (1b) or a salt thereof is carried out at a temperature of about 90° C.

[0175] In some embodiments, the reaction of the compound of formula (1c) with the compound of formula (1b) or a salt thereof is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (1c) with the compound of formula (1b) or a salt thereof comprises a cyclic ether. In some embodiments, the solvent component for the reaction of the compound of formula (1c) with the compound of formula (1b) or a salt thereof comprises dioxane.

[0176] In some embodiments, the process further comprises reacting the compound of Formula (1a) with an organic acid to form a salt of the compound of Formula (1a).

[0177] In some embodiments, the organic acid is succinic acid.

[0178] In some embodiments, the salt of the compound of Formula (1) is the hemisuccinate salt of the compound of Formula (1a).

[0179] In some embodiments, the process further comprises reacting the compound of Formula (1a) with succinic acid to form a hemisuccinate salt of the compound of Formula (1a).

[0180] In some embodiments, about 2 equivalents to about 2.5 equivalents of succinic acid are utilized per equivalent of the compound of Formula (1a).

[0181] In some embodiments, the reaction of the compound of formula (1a) with succinic acid is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (1a) with succinic acid comprises acetonitrile.

[0182] In some embodiments, the reaction of the compound of Formula (1a) with succinic acid is carried out at a temperature of about 50°C to about 60°C.

[0183] In some embodiments, the process further comprises deprotecting the compound of Formula (1a) or a salt thereof to form a compound of Formula (I).

[0184] In some embodiments, the process further comprises deprotecting the compound of Formula (1a) to form a compound of Formula (I).

[0185] In some embodiments, the deprotection is accomplished by reacting the compound of formula (1a) with a strong acid. In some embodiments, the strong acid is hydrochloric acid.

[0186] In some embodiments, about 2 to about 3 equivalents of strong acid are utilized per equivalent of the compound of Formula (1a).

[0187] In some embodiments, the deprotection of the compound of formula (1a) is carried out at a temperature of about 50° C. to about 70° C. In some embodiments, the deprotection of the compound of formula (1a) is carried out at a temperature of about 60° C.

[0188] In some embodiments, the deprotection of the compound of formula (1a) is carried out in a solvent component. In some embodiments, the solvent component for the deprotection of the compound of formula (1a) comprises a cyclic ether. In some embodiments, the solvent component for the deprotection of the compound of formula (1a) comprises tetrahydrofuran (THF).

[0189] In some embodiments, the compound of formula (1c) is Formula (1d): [ka] or a salt thereof with a halogenating agent to form a compound of formula (1c).

[0190] In some embodiments, the halogenating agent is a brominating agent.

[0191] In some embodiments, the halogenating agent is Cu(X 1 )2.

[0192] In some embodiments, the halogenating agent is CuBr2.

[0193] In some embodiments, about 1 to about 1.5 equivalents of halogenating agent are utilized per equivalent of the compound of formula (1d) or salt thereof. In some embodiments, about 1 to about 1.1 equivalents of halogenating agent are utilized per equivalent of the compound of formula (1d) or salt thereof.

[0194] In some embodiments, the reaction of the compound of formula (1d) or a salt thereof with the halogenating agent is carried out at a temperature of about 0° C. to about 10° C. In some embodiments, the reaction of the compound of formula (1d) or a salt thereof with the halogenating agent is carried out at a temperature of about 5° C., followed by warming to room temperature.

[0195] In some embodiments, the reaction of the compound of formula (1d) or a salt thereof with a halogenating agent is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (1d) or a salt thereof with a halogenating agent comprises acetonitrile.

[0196] In some embodiments, the compound of formula (1d) or salt thereof is Equation 1(e): [ka] with hydroxylamine HCl and a base component to form a compound of formula (1d) or a salt thereof.

[0197] In some embodiments, the base component is a tertiary amine. In some embodiments, the tertiary amine is ethyldiisopropylamine.

[0198] In some embodiments, about 1 equivalent to about 2 equivalents of hydroxylamine HCl are utilized relative to about 1 equivalent of the compound of Formula (1e).

[0199] In some embodiments, the reaction of the compound of formula (1e) or a salt thereof with hydroxylamine HCl and a base component is carried out at a temperature of about 40° C. to about 60° C. In some embodiments, the reaction of the compound of formula (1e) or a salt thereof with hydroxylamine HCl and a base component is carried out at a temperature of about 50° C.

[0200] In some embodiments, the reaction of the compound of formula (1e) or a salt thereof with hydroxylamine HCl and a base component is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (1e) or a salt thereof with hydroxylamine HCl and a base component comprises an alcohol. In some embodiments, the solvent component for the reaction of the compound of formula (1e) or a salt thereof with hydroxylamine HCl and a base component comprises an alcohol. In some embodiments, the solvent component for the reaction of the compound of formula (1e) or a salt thereof with hydroxylamine HCl and a base component comprises ethanol.

[0201] In some embodiments, the compound of formula (1e) is Formula (1f): [ka] with CH3CH2OC(O)-N=C=S to form a compound of formula (1e).

[0202] In some embodiments, about 1 to about 1.5 equivalents of CH3CH2OC(O)-N=C=S are used relative to the compound of Formula (1f).

[0203] In some embodiments, the reaction of a compound of formula (1f) with CH3CH2OC(O)-N=C=S is carried out at a temperature of about 0° C. to about 20° C., followed by warming to room temperature. In some embodiments, the reaction of a compound of formula (1f) with CH3CH2OC(O)-N=C=S is carried out at a temperature of about 10° C., followed by warming to room temperature.

[0204] In some embodiments, the reaction of the compound of formula (1f) with CH3CH2OC(O)-N=C=S is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (1f) with CH3CH2OC(O)-N=C=S comprises a cyclic ether. In some embodiments, the solvent component for the reaction of the compound of formula (1f) with CH3CH2OC(O)-N=C=S comprises dioxane.

[0205] In some embodiments, the compound of formula (1f) is Formula (1h): [ka] or a salt thereof, [ka] via a Buchwald coupling reaction to form a compound of formula (1f).

[0206] In some embodiments, the Buchwald coupling reaction comprises reacting a compound of Formula (1h) or a salt thereof with a compound of Formula (1g) in the presence of a Buchwald catalyst or pre-catalyst and a base.

[0207] In some embodiments, the Buchwald catalyst or pre-catalyst is a palladium catalyst. In some embodiments, the palladium catalyst or pre-catalyst is selected from the group consisting of [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrett Phos Pd G3), [tBuBrettPhos Pd(allyl)]OTf(Pd-175), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos-Pd-G2), [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XantPhos Pd G3), tBuBrettPhos Pd G3, SPhos Pd G3, cataCXium® A Pd G3, BrettPhos Pd G3, tBuXPhos Pd G3, [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'-amino-1,1'-Biphenyl)] Palladium(II) Methanesulfonate, JackiePhos Pd G3, CPhos Pd G3, RuPhos Pd G3, APhos Pd G3, RockPhos Pd G3, AdBrettPhos Pd G3, Neopentyl (t-Bu)2P Pd G3, TrixiePhos Pd G3, N-XantPhos Pd G3, DTBPF-Pd-G3, DPPF Pd G3, DavePhos-Pd-G3, (t-Bu)2PhP Pd G3, rac-BINAP-Pd-G3, CyJohnPhos Pd G3, MorDalphos Pd G3, Josiphos SL-J009-1 Pd G3, P(Cy3)Pd G3, Me3(OMe)tBuXPhos-Pd-G3, 4MetBuXPhos Pd G3, (t-Bu)PhCPhos Pd G3, CyJohnPhos Pd G3, Mesyl[(tri-t-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), DTBPF-Pd-G3, P(o-tol)3Pd G3, VPhos Pd G3, QPhos Pd G3, RuPhos Pd G4, SPhos Pd G4, BrettPhos Pd G4, XPhos Pd G4, APhos Pd G4, rac-BINAP Pd G4, P(t-Bu)3Pd G4, (t-Bu)PhCPhos Pd G4, cataCXium Pd G4, CPhos Pd G4, CyJohnPhos Pd G4, DavePhos Pd G4, DPPF Pd G4, EPhos Pd G4, MorDalPhos Pd G4, neopentyl(tBu)2P Pd G4, PCy3Pd G4, (tBu)2PMe Pd G4, (tBu)2PPh Pd G4, 1,3,5,7-tetramethyl-6-phenyl-2,4,6-Trioxa-6-phosphaadamantane Pd G4, (R)-TolBINAP Pd G4, VPhos Pd G4, XantPhos Pd G4, N-XantPhos Pd G4, t-BuDavePhos Pd G4, XPhos Pd G2, RuPhos Pd G2, SPhos Pd G2, Bis(triphenylphosphine)palladium(II) dichloride, tBuXPhos Pd G1, RuPhos Pd G1 methyl t-butyl ether adduct, SPhos Pd G1 methyl t-butyl ether adduct, 2'-(dimethylamino)-2-biphenylyl-palladium(II) chloride dinorbornylphosphine complex, chloro(η2-P,C-tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II), di-μ-chlorobis[5-chloro-2-[(4-chlorophenyl)(hydroxyimino-κN)methyl]phenyl-κC]palladium dimer, DavePhos Pd G2, (Ad-BippyPhos)2PdCl2, APhos Pd G2, sSPhos Pd G2, P(t-Bu)3Pd G3, BrettPhos Pd G1 methyl t-butyl ether adduct, dichloro[2-(4,5-dihydro-2-oxazolyl)quinoline]palladium(II), salicylaldehyde thiosemicarbazone palladium(II) chloride, XPhos Pd G1, bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride, bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), di-μ-chlorobis[5-hydroxy-2-[1-(hydroxyimino-κN)ethyl]phenyl-κC]palladium(II) dimer, 2-(2'-di-tert-butylphosphine)biphenylpalladium(II) acetate, or 2-(dimethylaminomethyl)ferrocen-1-yl-palladium(II) chloride dinorbornylphosphine complex.

[0208] In some embodiments, the compound of Formula (1h) or salt thereof is an HBr salt.

[0209] In some embodiments, the Buchwald catalyst or pre-catalyst present for the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) is a palladium catalyst. In some embodiments, the Buchwald catalyst or pre-catalyst present for the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate (XPhos Pd G3).

[0210] In some embodiments, the base present for the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) is an alkali metal phosphate. In some embodiments, the base present for the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) is trisodium phosphate.

[0211] In some embodiments, the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) is carried out at a temperature of about 75° C. to about 95° C. In some embodiments, the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) is carried out at a temperature of about 85° C.

[0212] In some embodiments, the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) comprises water and a cyclic ether. In some embodiments, the solvent component for the reaction of the compound of formula (1h) or a salt thereof with the compound of formula (1g) comprises water and dioxane.

[0213] In some embodiments, about 1 to about 1.5 equivalents of a compound of formula (1g) are utilized per equivalent of a compound of formula (1h).

[0214] In some embodiments, about 2 to about 4 equivalents of base are utilized per equivalent of the compound of Formula (1h).

[0215] In some embodiments, about 0.0001 to about 0.1 equivalents of a Buchwald catalyst or pre-catalyst are utilized per equivalent of the compound of Formula (1h). In some embodiments, about 0.001 to about 0.005 equivalents of a Buchwald catalyst or pre-catalyst are utilized per equivalent of the compound of Formula (1h).

[0216] In some embodiments, the compound of formula (1h) or salt thereof is Formula (1i): [ka] or a salt thereof with an ethyl halide in the presence of a base to form a compound of formula (1h) or a salt thereof.

[0217] In some embodiments, the ethyl halide is ethyl iodide.

[0218] In some embodiments, about 1 equivalent to about 2 equivalents of an ethyl halide is utilized relative to the compound of Formula (1i) or salt thereof.

[0219] In some embodiments, about 2 to about 3 equivalents of base are utilized relative to the compound of Formula (1i) or salt thereof.

[0220] In some embodiments, the base present for the reaction of the compound of formula (1i) or a salt thereof with an ethyl halide is a basic carbonate. In some embodiments, the basic carbonate is cesium carbonate. In some embodiments, the compound of formula (1i) or a salt thereof is an HBr salt.

[0221] In some embodiments, the reaction of the compound of formula (1i) or a salt thereof with an ethyl halide is carried out at a temperature of about 55° C. to about 80° C. In some embodiments, the reaction of the compound of formula (1i) or a salt thereof with an ethyl halide is carried out at a temperature of about 65° C. to about 70° C.

[0222] In some embodiments, the reaction of the compound of formula (1i) or a salt thereof with an ethyl halide is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (1i) or a salt thereof with an ethyl halide comprises acetonitrile.

[0223] In some embodiments, the compound of formula (1c) is Formula (2a): [ka] With a compound of formula (2b): [ka] in the presence of a Suzuki catalyst and a base to form a compound of formula (1c), wherein X 1 is a halo.

[0224] In some embodiments, X 1 is Br.

[0225] In some embodiments, about 1 to about 1.5 equivalents of a compound of Formula (2b) are utilized per equivalent of a compound of Formula (2a).

[0226] In some embodiments, the Suzuki catalyst is a palladium catalyst. In some embodiments, the Suzuki catalyst is formed from a mixture of a phosphine ligand and a palladium (II) compound. In some embodiments, the Suzuki catalyst is formed from a mixture of CataCXium A and palladium acetate.

[0227] In some embodiments, the base present for the reaction of the compound of formula (2a) with the compound of formula (2b) is an alkali metal phosphate. In some embodiments, the base present for the reaction of the compound of formula (2a) with the compound of formula (2b) is trisodium phosphate.

[0228] In some embodiments, the reaction of the compound of formula (2a) with the compound of formula (2b) is carried out at a temperature of about 40° C. to about 60° C. In some embodiments, the reaction of the compound of formula (2a) with the compound of formula (2b) is carried out at a temperature of about 50° C.

[0229] In some embodiments, the reaction of the compound of formula (2a) with the compound of formula (2b) is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (2a) with the compound of formula (2b) comprises a cyclic ether. In some embodiments, the solvent component for the reaction of the compound of formula (2a) with the compound of formula (2b) comprises dioxane.

[0230] In some embodiments, the compound of formula (1b) or salt thereof is Formula (3a): [ka] to form a compound of formula (1b) or a salt thereof.

[0231] In some embodiments, the reduction is accomplished by reacting the compound of formula (3a) with hydrogen gas in the presence of a palladium catalyst. In some embodiments, the reduction is accomplished by reacting the compound of formula (3a) with hydrogen gas in the presence of Pd(OH).

[0232] In some embodiments, the reduction of the compound of Formula (3a) is carried out at room temperature.

[0233] In some embodiments, the reduction of the compound of formula (3a) is carried out in a solvent component. In some embodiments, the solvent component for the reduction of the compound of formula (3a) comprises an alcohol. In some embodiments, the solvent component for the reduction of the compound of formula (3a) comprises methanol.

[0234] In some embodiments, the compound of formula (3a) is Formula (3c): [ka] With a compound of formula (3b): [ka] with a compound of formula (3a), followed by crystallization to obtain a compound of formula (3b).

[0235] In some embodiments, about 1 to about 2 equivalents of a compound of Formula (3b) are utilized per equivalent of a compound of Formula (3c).

[0236] In some embodiments, the reaction of the compound of formula (3c) with the compound of formula (3b) is carried out in the presence of a coupling agent and a base. In some embodiments, the coupling agent present for the reaction of the compound of formula (3c) with the compound of formula (3b) is borohydride. In some embodiments, the coupling agent present for the reaction of the compound of formula (3c) with the compound of formula (3b) is NaBH(OAc)2. In some embodiments, the base present for the reaction of the compound of formula (3c) with the compound of formula (3b) is a tertiary amine. In some embodiments, the base present for the reaction of the compound of formula (3c) with the compound of formula (3b) is diisopropylethylamine.

[0237] In some embodiments, the reaction of the compound of Formula (3c) with the compound of Formula (3b) is carried out at a temperature of about 10° C. to about 35° C. In some embodiments, the reaction of the compound of Formula (3c) with the compound of Formula (3b) is carried out at a temperature of about 20° C. to about 25° C.

[0238] In some embodiments, the reaction of the compound of formula (3c) with the compound of formula (3b) is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (3c) with the compound of formula (3b) comprises a cyclic ether. In some embodiments, the solvent component for the reaction of the compound of formula (3c) with the compound of formula (3b) comprises tetrahydrofuran.

[0239] In some embodiments, the crystallization is carried out by dissolving the product of the reaction of the compound of formula (3c) with the compound of formula (3b) in a solvent component and then cooling the solution to form the compound of formula (3c). In some embodiments, the solvent component for dissolution is ethyl acetate (EtOAc).

[0240] In some embodiments, the compound of formula (3c) is Formula (3d): [ka] or a salt thereof with methanesulfonyl chloride to form a compound of formula (3c).

[0241] In some embodiments, the reaction of the compound of formula (3d) with methanesulfonyl chloride is carried out in the presence of a base. In some embodiments, the base present for the reaction of the compound of formula (3d) with methanesulfonyl chloride is a tertiary amine. In some embodiments, the base present for the reaction of the compound of formula (3d) with methanesulfonyl chloride is triethylamine.

[0242] In some embodiments, about 1 to about 1.5 equivalents of methanesulfonyl chloride are utilized per equivalent of a compound of Formula (3d) or salt thereof.

[0243] In some embodiments, the reaction of the compound of Formula (3d) with methanesulfonyl chloride is carried out at room temperature.

[0244] In some embodiments, the reaction of the compound of formula (3d) with methanesulfonyl chloride is carried out in a solvent component. In some embodiments, the solvent component for the reaction of the compound of formula (3d) with methanesulfonyl chloride comprises dichloromethane.

[0245] In some embodiments, the present application also provides: [ka] Also provided is a compound selected from:

[0246] In some embodiments, the present application provides a compound of formula (1a): [ka] The present invention provides a hemisuccinate salt of the compound of formula (I).

[0247] It will be further understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0248] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, halo is F, Cl, or Br. In some embodiments, halo is F or Cl. In some embodiments, halo is F. In some embodiments, halo is Cl.

[0249] In some embodiments, the compounds provided herein or salts thereof are substantially isolated. "Substantially isolated" means that the compounds are at least partially or substantially separated from the environment in which they are formed or detected. Partial separation can include, for example, that the composition is concentrated in the compounds provided herein. Substantial separation can include a composition that contains at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds provided herein or salts thereof. Methods for isolating compounds and their salts are routine in the art.

[0250] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, within the scope of prudent medical judgment, commensurate with a reasonable benefit / risk ratio.

[0251] The processes described herein can also be used to prepare pharma- ceutically acceptable salts of the compounds of formula (I). As used herein, the term "pharma- ceutically acceptable salts" refers to salts formed by adding a pharma- ceutically acceptable acid or base to a compound disclosed herein. As used herein, the phrase "pharma- ceutically acceptable" refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological standpoint and does not adversely interact with the active ingredient. Pharmaceutically acceptable salts, including mono- and di-salts, include, but are not limited to, salts derived from organic and inorganic acids such as, but not limited to, acetic acid, lactic acid, citric acid, cinnamic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, oxalic acid, propionic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid, and similarly known acceptable acids. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0252] The reactions for preparing the compounds described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (for example, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a suitable solvent for a particular reaction step can be selected by those skilled in the art.

[0253] As used herein, the expressions "ambient temperature" or "room temperature" or "rt" are understood in the art and generally refer to a temperature, e.g., a reaction temperature, i.e., about the temperature of the room in which the reaction is carried out, e.g., a temperature of about 20° C. to about 30° C.

[0254] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those skilled in the art. The chemistry of protecting groups is described, for example, in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., "Protecting Groups in Carbohydrate Chemistry," J.Chem.Educ., 1997, 74(11), 1297, and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).

[0255] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-Vis), mass spectrometry, or by chromatographic methods such as high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LCMS), or thin layer chromatography (TLC). Compounds can be purified by one of skill in the art by a variety of methods, including high performance liquid chromatography (HPLC) and normal phase silica chromatography.

[0256] How to use The solid forms and salts of the present disclosure can inhibit CDK2 and are therefore useful for treating diseases whose underlying pathology is mediated in whole or in part by CDK2. Such diseases include cancer and other diseases involving proliferation disorders. In some embodiments, the present disclosure provides for the treatment of an individual or patient in vivo using the solid forms and salts of the present disclosure, such that the growth of the cancerous tumor is inhibited. The solid forms and salts described herein can be used to inhibit the growth of cancerous tumors with abnormalities that activate CDK2 kinase activity. These include, but are not limited to, diseases (e.g., cancers) characterized by amplification or overexpression of CCNE1, such as ovarian cancer, uterine carcinosarcoma, and breast cancer, and characterized by p27 inactivation, such as breast cancer and melanoma. Thus, in some embodiments of the method, the patient has previously been determined to have amplification of the cyclin E1 (CCNE1) gene and / or an expression level of CCNE1 that is higher than a control expression level of CCNE1 in a biological sample obtained from the human subject. Alternatively, the solid forms and salts described herein can be used in combination with other drugs or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting tumor cell proliferation in vitro. The method includes contacting tumor cells in vitro with a solid form and a salt. In another embodiment, the present disclosure provides a method for inhibiting tumor cell proliferation with CCNE1 amplification and overexpression in an individual or patient. The method includes administering to an individual or patient in need thereof a therapeutically effective amount of the solid forms and salts described herein.

[0257] In some embodiments, provided herein are methods of inhibiting CDK2 comprising contacting CDK2 with the solid forms and salts described herein.In some embodiments, provided herein are methods of inhibiting CDK2 in a patient comprising administering to the patient the solid forms and salts described herein.

[0258] In some embodiments, a method of treating cancer is provided herein. The method comprises administering to a patient (in need thereof) a therapeutically effective amount of the solid forms and salts described herein. In another embodiment, the cancer is characterized by CCNE1 amplification or overexpression. In some embodiments, the cancer is ovarian cancer or breast cancer characterized by CCNE1 amplification or overexpression.

[0259] In some embodiments, provided herein are methods of treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of the solid forms and salts described herein. In some embodiments, the disease or disorder associated with CDK2 is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

[0260] In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31):12968-12973), K-Ras mutated lung cancer (see Hu, S., et al., Mol Cancer Ther, 2015.14(11):2576-85), and cancer with FBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017.77(18):4881-4893).

[0261] In some embodiments, the disease or disorder associated with CDK2 is lung squamous cell carcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, invasive breast carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, gastric adenocarcinoma, esophageal carcinoma, bladder urothelial carcinoma, mesothelioma, or sarcoma.

[0262] In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, invasive breast cancer, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

[0263] In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0264] In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

[0265] In some embodiments, the CDK2-related disease or disorder is cancer.

[0266] In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer characterized by amplification or overexpression of CCNE1.

[0267] In some embodiments, the breast cancer is chemotherapy- or radiotherapy-resistant breast cancer, endocrine therapy-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / 6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

[0268] Examples of cancers treatable using the compounds of the present disclosure include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, and uterine cancer. Cancers that may be treated with the present invention include, but are not limited to, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers including asbestos-induced cancer, and combinations of said cancers. The compounds of the present disclosure are also useful for treating metastatic cancers.

[0269] In some embodiments, cancers treatable with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate cancer), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma, urothelial carcinoma (e.g., bladder), and microsatellite instability high (MSI) 高 Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0270] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., leukemias such as lymphoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and follicular lymphoma, including relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of said cancers.

[0271] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct cancer, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, pancreatic islet cell cancer, oral cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, ocular cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

[0272] In some embodiments, compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0273] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, blood cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, cancer of the nervous system, gynecological cancer, and skin cancer.

[0274] Exemplary hematological cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), lymphomas and leukemias such as Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0275] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0276] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchial) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma.

[0277] Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (pancreatic ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0278] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilms' tumor [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriomas, sarcomas, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma).

[0279] Exemplary liver cancers include hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0280] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0281] Exemplary cancers of the nervous system include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cancer (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0282] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical carcinoma, precancerous cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecocytoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), and fallopian tube cancer (carcinoma).

[0283] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, cholangiocarcinoma, esophageal cancer, and urothelial cancer.

[0284] It is believed that the solid forms and salts described herein may have satisfactory pharmacological profiles and promising biopharmaceutical properties, such as toxicological profiles, metabolic and pharmacokinetic properties, solubility, and permeability, etc. It will be understood that the determination of appropriate biopharmaceutical properties, such as determining cytotoxicity in cells, or inhibition of certain targets or channels to determine potential toxicity, is within the knowledge of one of ordinary skill in the art.

[0285] The terms "individual," "patient," and "subject," used interchangeably, refer to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate, most preferably a human.

[0286] The phrase "therapeutically effective amount" refers to an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual, or human that is desired by a researcher, veterinarian, physician, or other clinician.

[0287] As used herein, the term "treating" or "treatment" refers to one or more of: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder (i.e., halting further progression of the symptoms and / or symptomology), and (2) ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the symptoms or symptomology of the disease, condition, or disorder (i.e., reversing the symptoms and / or symptomology), such as reducing the severity of the disease.

[0288] In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein, for example, in preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or exhibited the symptoms or symptomology of the disease.

[0289] Combination therapy I. Cancer Treatment Cancer cell growth and survival can be affected by the malfunction of multiple signaling pathways.Therefore, it is useful to combine different enzyme / protein / receptor inhibitors that show different preferences in the target that regulates activity to treat such pathology.Targeting more than one signaling pathway (or more than one biomolecule involved in a given signaling pathway) can reduce the possibility of drug resistance occurring in cell population and / or reduce the toxicity of treatment.

[0290] For example, one or more additional pharmaceutical agents, such as chemotherapeutic agents, anti-inflammatory agents, steroids, immunosuppressants, cancer immunotherapeutic agents, metabolic enzyme inhibitors, chemokine receptor inhibitors, and phosphatase inhibitors, as well as targeted therapies, such as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET, VEGFR, PDGFR, c-Kit, IGF-1R, RAF, FAK, and CDK4 / 6 kinase inhibitors, such as those described in WO2006 / 056399, can be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. Other agents, such as therapeutic antibodies, can be used in combination with the compounds of the present disclosure for the treatment of CDK2-related diseases, disorders, or conditions. The one or more additional pharmaceutical agents can be administered to the patient simultaneously or sequentially.

[0291] In some embodiments, the solid forms and salts described herein are administered or used in combination with a BCL2 inhibitor or a CDK4 / 6 inhibitor.

[0292] Compounds as disclosed herein can be used in combination with one or more other enzyme / protein / receptor inhibitor therapy for the treatment of diseases such as cancer and other diseases or disorders described herein. Examples of diseases and indications treatable with combination therapy include diseases and indications as described herein. Examples of cancer include solid tumors and non-solid tumors such as liquid tumors and hematological cancers. Examples of infectious diseases include viral infections, bacterial infections, fungal infections, or parasitic infections. For example, compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, BCL2, CDK4 / 6, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IDH2, IGF-1R, IR-R, PDGFαR, PDGFβR, PI3K (alpha, beta, gamma, delta, and multiple or selected kinases). In some embodiments, the compounds of the present disclosure may be combined with one or more of the following inhibitors for the treatment of cancer or infectious diseases: Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for the treatment of cancer and infectious diseases include FGFR inhibitors (FGFR1, FGFR2, FGFR3, or FGFR4, e.g., pemigatinib (INCB54828), INCB62079), EGFR inhibitors (also known as ErB-1 or HER-1, e.g., erlotinib, gefitinib, vandetanib, osimertinib, cetuximab, necitumumab, or panitumumab), VEGFR inhibitors or pathway blockers (e.g., bevacizumab, pazopanib,sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, ziv-aflibercept), PARP inhibitors (e.g., olaparib, rucaparib, veliparib, or niraparib), JAK inhibitors (JAK1 and / or JAK2, e.g., ruxolitinib or baricitinib; JAK1, e.g., itacitinib (INCB39110), INCB052793, or INCB054707), IDO inhibitors (e.g., epacadostat, NLG919, or BMS-986205, MK7162), LSD1 inhibitors (e.g., GSK2979552, INCB59872, and INCB60003), TDO inhibitors, PI3K-delta inhibitors anti-inflammatory agents (e.g., palsaclisib (INCB50465) or INCB50797), PI3K-gamma inhibitors, e.g., PI3K-gamma selective inhibitors, Pim inhibitors (e.g., INCB53914), CSF1R inhibitors, TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer, e.g., INCB081776), adenosine receptor antagonists (e.g., A2a / A2b receptor antagonists), HPK1 inhibitors, chemokine receptor inhibitors (e.g., CCR2 or CCR5 inhibitors), SHP1 / 2 phosphatase inhibitors, histone deacetylase inhibitors (HDACs), e.g., HDAC8 inhibitors, angiogenesis inhibitors, interleukin receptor inhibitors, bromo and extraterminal (bromo and extra terminal (BET) family member inhibitors (e.g., bromodomain inhibitors or BET inhibitors, e.g., INCB54329 and INCB57643), c-MET inhibitors (e.g., capmatinib), anti-CD19 antibodies (e.g., tafasitamab), ALK2 inhibitors (e.g., INCB00928), or combinations thereof.

[0293] In some embodiments, the solid forms and salts described herein are administered with a PI3Kδ inhibitor. In some embodiments, the compounds or salts described herein are administered with a JAK inhibitor. In some embodiments, the solid forms and salts described herein are administered with a JAK1 or JAK2 inhibitor (e.g., baricitinib or ruxolitinib). In some embodiments, the solid forms and salts described herein are administered with a JAK1 inhibitor. In some embodiments, the solid forms and salts described herein are administered with a JAK1 inhibitor that is more selective than JAK2.

[0294] Exemplary antibodies for use in combination therapy include, but are not limited to, trastuzumab (e.g., anti-HER2), ranibizumab (e.g., anti-VEGF-A), bevacizumab (AVASTIN™, e.g., anti-VEGF), panitumumab (e.g., anti-EGFR), cetuximab (e.g., anti-EGFR), Rituxan (e.g., anti-CD20), and antibodies directed against c-MET.

[0295] One or more of the following agents may be used in combination with the solid forms and salts described herein, which are presented as a non-limiting list: cytostatic agents, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSA™ (gefitinib), TARCEVA™ (erlotinib), antibodies against EGFR, Intron, Ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, da Carbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Oxaliplatin, Leucovorin, ELOXATIN™ (Oxaliplatin), Pentostatin, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin C, L-Asparaginase, Teniposide 17.Alpha.- ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbine, anastrozole, letrozole, capecitabine, raloxifene, droloxifene, hexamethylmelamine, avastin, HERCEPTIN (trastuzumab), BEXXAR™ (tositumomab), VELCADE™ (bortezomib), ZEVALIN™ (ibritumomab tiuxetan), TRISENOX™ (arsenic trioxide), XELODA™ (capecitabine), vinorelbine, porfimer, ERBITUX™ (cetuximab), thiotepa, altretamine, melphalan, trastuzumab, retrozole le, fulvestrant, exemestane, ifosfamide, rituximab, C225 (cetuximab), campath (alemtuzumab), clofarabine, cladribine, aphidicolin, rituxan, sunitinib, dasatinib, tezacitabine, Sml1, fludarabine, pentostatin, triapin, didox, trimidox, amidox, 3-AP, and MDL-101,731.

[0296] The solid forms and salts described herein can also be used in combination with other methods of treating cancer, such as chemotherapy, radiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy, or surgery. Examples of immunotherapy include cytokine therapy (e.g., interferon, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccines, monoclonal antibodies, bispecific or multispecific antibodies, antibody drug conjugates, adoptive T cell transfer, Toll receptor agonists, RIG-I agonists, oncolytic virus therapy, and immunomodulatory small molecules, including thalidomide or JAK1 / 2 inhibitors, PI3Kδ inhibitors, and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as chemotherapeutic agents. Examples of chemotherapy drugs include abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezomib, intravenous busulfan, oral busulfan, calcitinib, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, propionib, dromostanolone phosphate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate,Methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, leuprolide ... Examples of the anticancer drugs include xolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat, and zoledronate.

[0297] Additional examples of chemotherapeutic agents include proteasome inhibitors (eg, bortezomib), thalidomide, revlimid, and DNA damaging agents such as melphalan, doxorubicin, cyclophosphamide, vincristine, etoposide, carmustine, and the like.

[0298] Exemplary steroids include corticosteroids such as dexamethasone or prednisone.

[0299] Exemplary Bcr-Abl inhibitors include imatinib mesylate (GLEEVAC™), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts. Other exemplary suitable Bcr-Abl inhibitors include the genera and species of compounds disclosed in U.S. Pat. No. 5,521,184, WO 04 / 005281, and U.S. Ser. No. 60 / 578,491, and pharmaceutically acceptable salts thereof.

[0300] Exemplary suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397, and ASP2215, and pharmaceutically acceptable salts thereof. Other exemplary suitable Flt-3 inhibitors include compounds as disclosed in WO03 / 037347, WO03 / 099771, and WO04 / 046120, and pharmaceutically acceptable salts thereof.

[0301] Exemplary suitable RAF inhibitors include dabrafenib, sorafenib, and vemurafenib, and pharmaceutically acceptable salts thereof. Other exemplary suitable RAF inhibitors include compounds as disclosed in WO00 / 09495 and WO05 / 028444, and pharmaceutically acceptable salts thereof.

[0302] Exemplary suitable FAK inhibitors include VS-4718, VS-5095, VS-6062, VS-6063, BI853520, and GSK2256098, and pharma- ceutically acceptable salts thereof. Other exemplary suitable FAK inhibitors include those compounds disclosed in WO04 / 080980, WO04 / 056786, WO03 / 024967, WO01 / 064655, WO00 / 053595, and WO01 / 014402, and pharma- ceutically acceptable salts thereof.

[0303] Exemplary suitable CDK4 / 6 inhibitors include palbociclib, ribociclib, trilaciclib, ribociclib, and abemaciclib, and pharmaceutically acceptable salts thereof. Other exemplary suitable CDK4 / 6 inhibitors include compounds as disclosed in WO09 / 085185, WO12 / 129344, WO11 / 101409, WO03 / 062236, WO10 / 075074, and WO12 / 061156, and pharmaceutically acceptable salts thereof.

[0304] In some embodiments, the solid forms and salts described herein can be used in combination with one or more other kinase inhibitors, including imatinib, particularly to treat patients who are resistant to imatinib or other kinase inhibitors.

[0305] In some embodiments, the solid forms and salts described herein can be used in combination with chemotherapy drugs in the treatment of cancer, and can improve the treatment response compared to the response to the chemotherapy drug alone, without exacerbating its toxic effects. In some embodiments, the solid forms and salts described herein can be used in combination with chemotherapy drugs provided herein. For example, additional pharmaceutical agents used in the treatment of multiple myeloma can include, but are not limited to, melphalan, melphalan and prednisone [MP], doxorubicin, dexamethasone, and Velcade (bortezomib). Further additional agents used in the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF, and FAK kinase inhibitors. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM). Additive or synergistic effects are desirable outcomes of combining the CDK2 inhibitors of the present disclosure with additional agents.

[0306] The agents can be combined with the solid forms and salts described herein in a single or consecutive dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

[0307] The solid forms and salts described herein can be used in combination with one or more other inhibitors or one or more therapies for the treatment of infectious diseases, including viral, bacterial, fungal, or parasitic infections.

[0308] In some embodiments, a corticosteroid such as dexamethasone is administered to a patient in combination with the solid forms and salts described herein, where the dexamethasone is administered intermittently rather than continuously.

[0309] The solid forms and salts described herein can be combined with other immunogenic substances, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune-stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of gp100, MAGE antigens, melanoma antigens such as Trp-2, MARTI, and / or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.

[0310] The solid forms and salts described herein can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancers, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's herpes sarcoma virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, the solid forms and salts described herein can be combined with dendritic cell immunization to activate a strong anti-tumor response.

[0311] The solid forms and salts described herein can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor expressing effector cells to tumor cells. The solid forms and salts described herein can also be combined with macrocyclic peptides that activate the host's immune responsiveness.

[0312] In some further embodiments, the solid forms and salts described herein in combination with other therapeutic agents can be administered to a patient before, during, and / or after bone marrow or stem cell transplantation. The solid forms and salts described herein can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0313] The solid forms and salts described herein can be used in combination with vaccines to stimulate immune responses against pathogens, toxins, and self-antigens. Examples of pathogens for which this therapeutic approach may be particularly useful include those for which there is currently no effective vaccine or for which traditional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, and C), influenza, herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, and Pseudomonas Aeruginosa.

[0314] Viruses causing infectious diseases treatable by the methods of the present disclosure include, but are not limited to, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), flavivirus, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum contagiosum virus, poliovirus, rabies virus, JC virus, and arboviral encephalitis virus.

[0315] Pathogenic bacteria causing infections treatable by the methods of the present disclosure include, but are not limited to, chlamydia, rickettsia bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci, and conococci, Klebsiella, Proteus, Serratia, Pseudomonas, Legionella, diphtheria, Salmonella, bacillus, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme disease bacteria.

[0316] Pathogenic fungi causing infections treatable by the methods of the present disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis, and Histoplasma capsulatum.

[0317] Pathogenic parasites causing infections treatable by the methods of the present disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleria fowleri, Acanthamoeba spp., Giardia lambia, Cryptosporidium spp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.

[0318] When more than one pharmaceutical agent is administered to a patient, they may be administered simultaneously, separately, sequentially, or in combination (eg, in the case of more than two agents).

[0319] Methods for safely and effectively administering most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in standard references. For example, the administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety.

[0320] II. Immune checkpoint therapy The solid forms and salts described herein can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases such as cancer or infectious diseases. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CBL-B, CD20, CD28, CD40, CD70, CD122, CD96, CD73, CD47, CDK2, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, TLR (TLR7 / 8), TIGIT, CD112R, VISTA, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the solid forms and salts described herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0321] In some embodiments, the solid forms and salts described herein can be used in combination with one or more agonists of immune checkpoint molecules, such as OX40, CD27, GITR, and CD137 (also known as 4-1BB).

[0322] In some embodiments, the inhibitor of an immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0323] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1 or PD-L1, such as an anti-PD-1 or anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-1 or anti-PD-L1 antibody is selected from the group consisting of nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, cemiplimab, atezolizumab, avelumab, tislelizumab, spartalizumab (PDR001), cetrelimab (JNJ-63723283), toripalimab (JS001), camrelizumab (SHR-1210), sintilimab (IBI308), AB122 (GLS-010), AMP-224, AMP-514 / MEDI-0 680, BMS936559, JTX-4014, BGB-108, SHR-1210, MEDI4736, FAZ053, BCD-100, KN035, CS1001, BAT1306, LZM009, AK105, HLX10, SHR-1316, CBT-502(TQB2450), A167(KL-A167), STI-A101(ZKAB001), CK-301, BGB-A333, MSB-2311, HLX20, TSR-042, or LY3300054. In some embodiments, the PD-1 or PD-L1 inhibitor is one disclosed in U.S. Pat. Nos. 7,488,802, 7,943,743, 8,008,449, 8,168,757, 8,217,149, WO03042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, or WO2011161699, each of which is incorporated by reference in its entirety.

[0324] In some embodiments, the antibody is an anti-PD-1 antibody, for example, an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, sintilimab, AB122, AMP-224, JTX-4014, BGB-108, BCD-100, BAT1306, LZM009, AK105, HLX10, or TSR-042. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, cetrelimab, toripalimab, or sintilimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the anti-PD-1 antibody is spartalizumab. In some embodiments, the anti-PD-1 antibody is camrelizumab. In some embodiments, the anti-PD-1 antibody is cetrelimab. In some embodiments, the anti-PD-1 antibody is toripalimab. In some embodiments, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is AB122. In some embodiments, the anti-PD-1 antibody is AMP-224. In some embodiments, the anti-PD-1 antibody is JTX-4014. In some embodiments, the anti-PD-1 antibody is BGB-108. In some embodiments, the anti-PD-1 antibody is BCD-100. In some embodiments, the anti-PD-1 antibody is BAT1306. In some embodiments, the anti-PD-1 antibody is LZM009. In some embodiments, the anti-PD-1 antibody is AK105. In some embodiments, the anti-PD-1 antibody is HLX10. In some embodiments, the anti-PD-1 antibody is TSR-042. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210.Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g., urelumab, utomilumab). In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, avelumab, durvalumab, tislelizumab, BMS-935559, MEDI4736, atezolizumab (MPDL3280A (also known as RG7446)), avelumab (MSB0010718C), FAZ053, KN035, CS1001, SHR-1316, CBT-502, A167, STI-A101, CK-301, BGB-A333, MSB-2311, HLX20, or LY3300054. In some embodiments, the anti-PD-L1 antibody is atezolizumab, avelumab, durvalumab, or tislelizumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is durvalumab. In some embodiments, the anti-PD-L1 antibody is tislelizumab. In some embodiments, the anti-PD-L1 antibody is BMS-935559. In some embodiments, the anti-PD-L1 antibody is MEDI4736. In some embodiments, the anti-PD-L1 antibody is FAZ053. In some embodiments, the anti-PD-L1 antibody is KN035. In some embodiments, the anti-PD-L1 antibody is CS1001. In some embodiments, the anti-PD-L1 antibody is SHR-1316. In some embodiments, the anti-PD-L1 antibody is CBT-502. In some embodiments, the anti-PD-L1 antibody is A167. In some embodiments, the anti-PD-L1 antibody is STI-A101. In some embodiments, the anti-PD-L1 antibody is CK-301. In some embodiments, the anti-PD-L1 antibody is BGB-A333. In some embodiments, the anti-PD-L1 antibody is MSB-2311. In some embodiments, the anti-PD-L1 antibody is HLX20. In some embodiments, the anti-PD-L1 antibody is LY3300054.

[0325] In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to PD-L1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a small molecule that binds to and internalizes PD-L1, or a pharma- ceutically acceptable salt thereof. In some embodiments, the inhibitor of an immune checkpoint molecule is a compound or a pharma- ceutically acceptable salt thereof selected from those in US2018 / 0179201, US2018 / 0179197, US2018 / 0179179, US2018 / 0179202, US2018 / 0177784, US2018 / 0177870, US 16 / 369,654 (filed March 29, 2019), and US 62 / 688,164, each of which is incorporated herein by reference in its entirety.

[0326] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR, TIGIT, LAIR1, CD160, 2B4, and TGFRbeta.

[0327] In some embodiments, the inhibitor is MCLA-145.

[0328] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab, AGEN1884, or CP-675,206.

[0329] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016, LAG525, INCAGN2385, or eftilagimod alpha (IMP321).

[0330] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is oleculab.

[0331] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TIGIT. In some embodiments, the inhibitor of TIGIT is OMP-31M32.

[0332] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of VISTA. In some embodiments, the inhibitor of VISTA is JNJ-61610588 or CA-170.

[0333] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of B7-H3. In some embodiments, the inhibitor of B7-H3 is enoblituzumab, MGD009, or 8H9.

[0334] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of KIR. In some embodiments, the inhibitor of KIR is lirilumab or IPH4102.

[0335] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of A2aR. In some embodiments, the inhibitor of A2aR is CPI-444.

[0336] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of TGF-beta. In some embodiments, the inhibitor of TGF-beta is travedersen, galusertinib, or M7824.

[0337] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PI3K-gamma. In some embodiments, the inhibitor of PI3K-gamma is IPI-549.

[0338] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD47. In some embodiments, the inhibitor of CD47 is Hu5F9-G4 or TTI-621.

[0339] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD73. In some embodiments, the inhibitor of CD73 is MEDI9447.

[0340] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD70. In some embodiments, the inhibitor of CD70 is cusatuzumab or BMS-936561.

[0341] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of TIM3, such as an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

[0342] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0343] In some embodiments, the agonist of an immune checkpoint molecule is an agonist of OX40, CD27, CD28, GITR, ICOS, CD40, TLR7 / 8, and CD137 (also known as 4-1BB).

[0344] In some embodiments, the agonist of CD137 is urelumab. In some embodiments, the agonist of CD137 is utomirumab.

[0345] In some embodiments, the agonist of immune checkpoint molecule is an inhibitor of GITR. In some embodiments, the agonist of GITR is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228, BMS-986156, GWN323, MEDI1873, or MEDI6469. In some embodiments, the agonist of immune checkpoint molecule is an agonist of OX40, for example, an OX40 agonist antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562 (tavolimab), MOXR-0916, PF-04518600, GSK3174998, BMS-986178, or 9B12. In some embodiments, the OX40L fusion protein is MEDI6383.

[0346] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD40. In some embodiments, the agonist of CD40 is CP-870893, ADC-1013, CDX-1140, SEA-CD40, RO7009789, JNJ-64457107, APX-005M, or Chi Lob 7 / 4.

[0347] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of ICOS. In some embodiments, the agonist of ICOS is GSK-3359609, JTX-2011, or MEDI-570.

[0348] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD28. In some embodiments, the agonist of CD28 is ceralizumab.

[0349] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of CD27. In some embodiments, the agonist of CD27 is varlilumab.

[0350] In some embodiments, the agonist of the immune checkpoint molecule is an agonist of TLR7 / 8. In some embodiments, the agonist of TLR7 / 8 is MEDI9197.

[0351] The solid forms and salts described herein can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptor. In some embodiments, the bispecific antibody binds to PD-1 and PD-L1. In some embodiments, the bispecific antibody that binds to PD-1 and PD-L1 is MCLA-136. In some embodiments, the bispecific antibody binds to PD-L1 and CTLA-4. In some embodiments, the bispecific antibody that binds to PD-L1 and CTLA-4 is AK104.

[0352] In some embodiments, the solid forms and salts described herein can be used in combination with one or more metabolic enzyme inhibitors.In some embodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.Examples of IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099, and LY338196.

[0353] As provided throughout, the additional compounds, inhibitors, agents, etc. can be combined with the present compounds in a single or sequential dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.

[0354] Pharmaceutical Formulations and Dosage Forms When used as pharmaceuticals, the solid forms and salts described herein can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and the area to be treated. Administration can be topical (including transdermal, epithelial, ocular, and mucous membranes, including intranasal, intravaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or can be, for example, by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

[0355] The present disclosure also includes pharmaceutical compositions that contain the solid forms and salts described herein as active ingredients in combination with one or more pharma- ceutically acceptable carriers (excipients). In some embodiments, the compositions are suitable for topical administration. When preparing compositions of the present disclosure, the active ingredients are typically mixed with excipients, diluted by excipients, or enclosed within such carriers, for example, in the form of capsules, sachets, paper, or other containers. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredients. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0356] When preparing formulation, active compound can be milled to provide suitable particle size before being combined with other components.If active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh.If active compound is substantially water-soluble, particle size can be adjusted by milling to provide substantially uniform distribution in formulation, for example, about 40 mesh.

[0357] The solid forms and salts described herein may be milled using known milling procedures, such as wet milling, to obtain a particle size appropriate for tablet formation and other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the present disclosure may be prepared by processes known in the art, see, for example, International Application No. WO2002 / 000196.

[0358] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose.The formulation can additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl benzoate and propyl hydroxybenzoate; sweeteners; and flavoring agents.The composition of the present disclosure can be formulated to provide quick, sustained, or delayed release of active ingredient after administration to a patient by using procedures known in the art.

[0359] The compositions can be formulated in unit dosage form, each dosage containing from about 5 to about 1000 mg (1 g) or more, e.g., about 100 to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce a desired therapeutic effect in association with a suitable pharmaceutical excipient.

[0360] In some embodiments, the compositions of the present disclosure contain about 5 to about 50 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing about 5 to about 10, about 10 to about 15, about 15 to about 20, about 20 to about 25, about 25 to about 30, about 30 to about 35, about 35 to about 40, about 40 to about 45, or about 45 to about 50 mg of active ingredient.

[0361] In some embodiments, the compositions of the present disclosure contain about 50 to about 500 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing about 50 to about 100, about 100 to about 150, about 150 to about 200, about 200 to about 250, about 250 to about 300, about 350 to about 400, or about 450 to about 500 mg of active ingredient.

[0362] In some embodiments, the compositions of the present disclosure contain about 500 to about 1000 mg of active ingredient. One of skill in the art will appreciate that this embodies compositions containing about 500 to about 550, about 550 to about 600, about 600 to about 650, about 650 to about 700, about 700 to about 750, about 750 to about 800, about 800 to about 850, about 850 to about 900, about 900 to about 950, or about 950 to about 1000 mg of active ingredient.

[0363] Similar dosages of the compounds described herein may be used in the methods and uses of the present disclosure.

[0364] The active compound may be effective over a wide dosage range and is generally administered in a pharma- ceutically effective amount. However, it will be understood that the amount of compound actually administered will usually be determined by the physician depending on the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0365] When preparing solid compositions such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the solid forms and salts described herein. When these preformulation compositions are referred to as homogeneous, the active ingredient is typically evenly dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above, for example, containing about 0.1 to about 1000 mg of the active ingredient of the present disclosure.

[0366] The tablets or pills of the present disclosure can be coated or otherwise compounded to provide a dosage form that provides the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. These two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including some polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0367] Liquid forms into which the compounds and compositions of the present disclosure may be incorporated for oral or injection administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0368] Compositions for inhalation or insufflation include solutions and suspensions in pharma- ceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharma- ceutically acceptable excipients as described above. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. Compositions may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask, tent, or intermittent positive airway pressure machine. Solution, suspension, or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0369] Topical formulations may contain one or more conventional carriers. In some embodiments, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. Cream carrier compositions may be based on water in combination with glycerol and one or more other components, for example, glyceryl monostearate, PEG-glyceryl monostearate, and cetylstearyl alcohol. Gels may be formulated using isopropyl alcohol and water in suitable combination with other components, for example, glycerol, hydroxyethylcellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5% by weight of the compound of the present disclosure. Topical formulations may be suitably packaged, for example, in 100 g tubes, which are optionally associated with instructions for the treatment of the selected indication, for example, psoriasis or other skin conditions.

[0370] The amount of active ingredient or composition administered to a patient will vary depending on what is being administered, the purpose of administration, such as prophylactic or therapeutic, the condition of the patient, the mode of administration, etc. In therapeutic applications, the compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dose will depend on the condition being treated and the judgment of the attending clinician depending on such factors as the severity of the disease, the age, weight, and general condition of the patient, etc.

[0371] The compositions administered to a patient may be in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions may be packaged for use as is or may be lyophilized, with the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation will typically be 3-11, more preferably 5-9, and most preferably 7-8. It will be understood that the use of certain of the above-mentioned excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0372] Therapeutic dosages of the solid forms and salts described herein may vary depending, for example, on the particular application for which the treatment is being made, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The percentage or concentration of the compound of the present disclosure in a pharmaceutical composition may vary depending on several factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the solid forms and salts described herein may be provided in an aqueous physiological buffer solution containing about 0.1 to about 10 w / v% of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage may depend on such variables as the type and extent of progression of the disease or disorder, the overall health of the particular patient, the relative biological effectiveness of the selected compound, the formulation of the excipient, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0373] The compositions of the present disclosure may further comprise one or more additional pharmaceutical agents, such as chemotherapeutic agents, steroids, anti-inflammatory compounds, or immunosuppressants, examples of which are listed herein.

[0374] kit The present disclosure also includes pharmaceutical kits useful in the treatment or prevention of CDK2-related diseases or disorders (e.g., cancer, inflammatory diseases, cardiovascular diseases, or neurodegenerative diseases, etc.), which include one or more containers housing a pharmaceutical composition comprising a therapeutically effective amount of the solid forms and salts described herein. As would be readily apparent to one of skill in the art, such kits can further include one or more of a variety of conventional pharmaceutical kit components, if desired, such as, for example, a container containing one or more pharma-ceutically acceptable carriers, additional containers, etc. Instructions, either as a package insert or label, indicating the amounts of components to be administered, guidelines for administration, and / or guidelines for mixing of the components, can also be included in the kit.

[0375] Biomarkers and Pharmacodynamic Markers The present disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, e.g., gene copy number, gene sequence, expression level, or phosphorylation level) for identifying human subjects having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 that is likely to benefit from administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to the solid forms and salts described herein). The present disclosure also provides pharmacodynamic markers (e.g., phosphorylation levels) for identifying human subjects having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 that is responsive to a CDK2 inhibitor. The use of CCNE1, p16, and Rb S780 is further described in U.S. Patent Publication No. 2020 / 0316064, the figures and disclosure of which are incorporated herein by reference in their entirety.

[0376] The method is based, at least in part, on the discovery that the functional status of cyclin-dependent kinase inhibitor 2A ("CDKN2A" (also referred to as "p16")) is a biomarker for predicting sensitivity to CDK2-targeted therapy in G1 / S-specific cyclin-E1- ("CCNE1-") amplified cells, suitable for use in patient stratification. In addition, the present disclosure is based, at least in part, on the discovery that the level of phosphorylation of human retinoblastoma-related protein ("Rb") at serine corresponding to amino acid position 780 of SEQ ID NO:3 in CCNE1 amplified cell lines is a pharmacodynamic marker for CDK2 activity, suitable for use in measuring CDK2 enzyme activity in cellular assays or preclinical and clinical applications, such as, for example, monitoring the progress of or responsiveness to treatment with CDK2 inhibitors.

[0377] CCNE1 and p16 CCNE1 and p16, in combination, are identified in the Examples as genes useful in predicting responsiveness (e.g., improvement of disease as evidenced by disease remission / resolution) of a subject having a CDK2-related disease or disorder to a CDK2 inhibitor.

[0378] p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a) acts as a negative regulator of normal cell growth by interacting with CDK4 and CDK6. p16 is encoded by the cyclin-dependent kinase inhibitor 2A ("CDKN2A") gene (GenBank Accession No. NM_000077). The cytogenic location of the CDKN2A gene is 9p21.3, which is the short (p) arm of chromosome 9, position 21.3. The molecular location of the CDKN2A gene is at base pairs 21,967,752 to 21,995,043 on chromosome 9 (Homo sapiens Annotation Release 109, GRCh38.p12). Genetic and epigenetic abnormalities in the gene encoding p16 are believed to lead to escape from aging and cancer formation (Okamoto et al., 1994, PNAS 91(23):11045-9). Non-limiting examples of genetic abnormalities in the gene encoding p16 are listed in Table A below. The amino acid sequence of human p16 is provided below (GenBank Accession No. NP_000068 / UniProtKB Accession No. P42771). [ka]

[0379] CCNE1 is a cell cycle factor essential for the control of the cell cycle at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2, which interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides the substrate specificity of the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank Accession No. NM_001238). The amino acid sequence of human CCNE1 is provided below (GenBank Accession No. NP_001229 / UniProtKB Accession No. P24864). [ka]

[0380] The examples demonstrate that CDK2 knockdown inhibits the proliferation of CCNE1-amplified cell lines, but not CCNE1-non-amplified cell lines. Conversely, the examples show that CDK4 / 6 inhibition inhibits the proliferation of CCNE1-non-amplified cell lines, but not CCNE1-amplified cell lines. The examples further demonstrate that the presence of a normal (e.g., non-mutated or non-deleted) p16 gene is required for the observed inhibition of cell proliferation in CCNE1-amplified cells treated with CDK2 inhibitors. Thus, CCNE1 and p16 together are combination biomarkers. That is, cells that respond to treatment with a CDK2 inhibitor will exhibit amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and will have a nucleotide sequence (e.g., a gene or mRNA) encoding a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1) and / or will have the presence of p16 protein, whereas control cells that do not respond to treatment with a CDK2 inhibitor will not exhibit amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than the control expression level of CCNE1, and will tend to have a mutation or deletion in the gene encoding the p16 protein and / or will lack expression of the p16 protein.

[0381] Thus, the present disclosure provides a method of treating a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, comprising administering a CDK2 inhibitor to the human subject, the human subject having (i) (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) expressing a p16 protein, and (ii) (a) an amplification of the CCNE1 gene, and / or (b) an expression level of CCNE1 in a biological sample obtained from the human subject that is higher than a control expression level of CCNE1. In certain embodiments, the predictive methods described herein predict with at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or 100% accuracy that the subject will respond to treatment with a CDK2 inhibitor. For example, in some embodiments, if the prediction methods described herein are applied to 10 subjects having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, and 8 of those 10 subjects are predicted to respond to treatment with a CDK2 inhibitor based on the prediction methods described herein, and 7 of those 8 subjects actually respond to treatment with a CDK2 inhibitor, then the prediction method has an accuracy of 87.5% (7 divided by 8). A subject is considered to be responsive to a CDK2 inhibitor if the subject shows any improvement in disease status as evidenced, for example, by reduction or alleviation of symptoms, disease remission / resolution, etc.

[0382] In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the human subject has (i) (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, and / or (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) has previously been determined to have an amplification of the CCNE1 gene in a biological sample obtained from the human subject. In some embodiments, the CDKN2A gene encodes a protein comprising the amino acid sequence of SEQ ID NO:1. In a specific embodiment, the CDKN2A gene encodes a protein comprising the amino acid sequence of SEQ ID NO:1.

[0383] In specific embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Table A. In specific embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999, Liggett and Sidransky, Biology of Neoplasia, Journal of Oncology, 16(3):1197-1206, 1998, and Cairns et al., Nature Genetics, 11:210-212, 1995, each of which is incorporated herein by reference in its entirety. [Table 1-1] [Table 1-2] [Table 1-3]

[0384] The present disclosure also deals with a method of treating a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2, comprising: (i) identifying in a biological sample obtained from the human subject the presence of (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions, and / or (c) a p16 protein; (ii) identifying in a biological sample obtained from the human subject the presence of (a) an amplification of the CCNE1 gene, and / or (b) an expression level of CCNE1 higher than a control expression level of CCNE1; and (iii) administering a CDK2 inhibitor to the human subject. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having, or at risk of developing a disease or disorder associated with CDK2. In some embodiments, the method includes: (i) identifying in a biological sample obtained from the human subject the presence of (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) a p16 protein; (ii) identifying in the biological sample obtained from the human subject an amplification of (a) the CCNE1 gene; and (iii) administering a CDK2 inhibitor to the human subject.

[0385] The present disclosure also features a method for predicting the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, the method comprising: (i) determining from a biological sample obtained from the human subject (a) the nucleotide sequence of the CDKN2A gene, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of p16 protein; and (ii) determining from the biological sample obtained from the human subject (a) the copy number and and / or (b) determining an expression level of CCNE1, wherein (1) (a) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of a p16 protein, and (2) (a) an amplification of the CCNE1 gene, and / or (b) an expression level of CCNE1 higher than a control expression level of CCNE1, is predictive that the human subject will respond to a CDK2 inhibitor. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having or is at risk of developing a disease or disorder associated with CDK2. In some embodiments, the method comprises: (i) determining from a biological sample obtained from the human subject the presence of (a) the nucleotide sequence of the CDKN2A gene, and / or (b) the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions; and (ii) determining from the biological sample obtained from the human subject the copy number of (a) the CCNE1 gene, wherein (1) the presence of (a) the CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, and / or (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (2) (a) amplification of the CCNE1 gene, is predictive that the human subject will respond to a CDK2 inhibitor.

[0386] In specific embodiments, (i) the determination of (a) the nucleotide sequence of the CDKN2A gene, (b) the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or (c) the presence of a p16 protein is performed prior to administration of a CDK2 inhibitor to the human subject (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or between 6 hours and 16 hours, between 6 hours and 20 hours, or between 6 hours and 24 hours, between 2 days, between 2 days and 4 days, between 2 days and 5 days, between 2 days and 6 days, between 2 days and 7 days, between 1 week and 2 weeks, between 1 week and 3 weeks, or between 1 week and 4 weeks prior). In a specific embodiment, (ii) the determination of (a) the copy number of the CCNE1 gene and / or (b) the expression level of CCNE1 in a biological sample obtained from a human subject is performed prior to (e.g., at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 2 weeks, at least 3 weeks, or at least 4 weeks, or 6 hours to 16 hours, 6 hours to 20 hours, or 6 hours to 24 hours, 2 days to 3 days, 2 days to 4 days, 2 days to 5 days, 2 days to 6 days, 2 days to 7 days, 1 week to 2 weeks, 1 week to 3 weeks, or 1 week to 4 weeks prior to) administering a CDK2 inhibitor to the human subject.

[0387] The presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), in combination with amplification of the CCNE1 gene and / or an expression level of CCNE1 higher than a control expression level of CCNE1, is indicative / predictive that a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 will respond to a CDK2 inhibitor.

[0388] In some embodiments, the CCNE1 gene is amplified to a gene copy number of 3 to 25. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 3. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 5. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 7. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 10. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 12. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 14. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 21.

[0389] In a specific embodiment, the expression level of CCNE1 is the level of CCNE1 mRNA. In a specific embodiment, the expression level of CCNE1 is the level of CCNE1 protein.

[0390] In some embodiments of the above-mentioned method, the control CCNE1 expression level is a preset cut-off value.In some embodiments of the above-mentioned method, the control CCNE1 expression level is the CCNE1 expression level in the sample(s) obtained from one or more subjects who do not respond to the treatment with CDK2 inhibitor.

[0391] In some embodiments of the above-mentioned method, the expression level of CCNE1 is the expression level of CCNE1 mRNA. In some embodiments of the above-mentioned method, the expression level of CCNE1 is the expression level of CCNE1 protein. In some embodiments, the expression level of CCNE1 is the expression level of CCNE1 mRNA, the expression level of CCNE1 is measured by RNA sequencing, quantitative polymerase chain reaction (PCR), in situ hybridization, nucleic acid array or RNA sequencing. In some embodiments, the expression level of CCNE1 is the expression level of CCNE1 protein, the expression level of CCNE1 is measured by Western blot, enzyme-linked immunosorbent assay or immunohistochemical staining.

[0392] Rb S780 The present disclosure also features a method for assessing the CDKN2A gene and the CCNE1 gene, the method comprising determining (i) (a) the nucleotide sequence of the CDKN2A gene, or (b) the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and (ii) the copy number of the CCNE1 gene, from a biological sample or samples obtained from a human subject having a disease or disorder associated with CDK2.

[0393] The present disclosure also deals with a method for evaluating the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, the method comprising: (a) administering a CDK2 inhibitor to the human subject, where the human subject has previously been determined to have an amplification of the CCNE1 gene and / or an expression level of CCNE1 higher than a control expression level of CCNE1; and (b) measuring the level of phosphorylation of retinoblastoma (Rb) protein at serine corresponding to amino acid position 780 of SEQ ID NO:3 in a biological sample obtained from the subject following administration of step (a), where a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 indicates that the human subject is responsive to a CDK2 inhibitor. In some embodiments, the subject has a disease or disorder associated with CDK2. In some embodiments, the subject is suspected of having, or at risk of developing a disease or disorder associated with CDK2. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample.

[0394] Phosphorylation of Rb at the serine corresponding to amino acid position 780 of SEQ ID NO:3 (referred to herein as "Ser780" or "S780") has been identified in the Examples as a pharmacodynamic marker useful in assessing the responsiveness of human subjects having a disease or disorder with CCNE1 amplification to CDK2 inhibitors (e.g., inhibition by CDK2).

[0395] Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795 and cyclin E / CDK2 at Ser807 and Ser811. Rb is encoded by the RB-coupled transcriptional repressor 1 ("RB1") gene (GenBank Accession No. NM_000321). The amino acid sequence of human Rb is provided below (GenBank Accession No. NP_000312 / UniProtKB Accession No. P06400) (S780 is bold and underlined): [ka]

[0396] As mentioned above, the examples demonstrate that CDK2 knockdown inhibits proliferation in CCNE1-amplified cell lines, but not in CCNE1-non-amplified cell lines. The examples further demonstrate that CDK2 knockdown or inhibition blocks Rb phosphorylation at S780 in CCNE1-amplified cell lines, but not in CCNE1-non-amplified cell lines. Thus, Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 is a pharmacodynamic marker for assessing the response to CDK2 inhibition in CCNE1-amplified cancer cells or patients with diseases or disorders that have CCNE1 amplification. Thus, methods are provided herein for the use of the level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3 as a marker for indicating the response of a human subject to a CDK2 inhibitor in a human subject that has, is suspected of having, or is at risk of developing a disease or disorder associated with CDK2, and the human subject has an increased expression level of CCNE1.

[0397] Thus, the present disclosure features a method for measuring the amount of a protein in a sample, the method comprising: (a) providing a biological sample obtained from a human subject having a disease or disorder associated with CDK2; and (b) measuring in the biological sample the level of phosphorylation of Rb protein at serine corresponding to amino acid position 780 of SEQ ID NO: 3. In some embodiments, the biological sample comprises a blood sample or a tumor biopsy sample. In a specific embodiment, provided herein is a method of assessing the response of a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 to a CDK2 inhibitor, the method comprising: (a) administering a CDK2 inhibitor to the human subject, where the human subject has previously been determined to have CCNE1 gene amplification and / or a CCNE1 expression level higher than a control expression level of CCNE1; and (b) measuring the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 in a biological sample obtained from the human subject following administration of step (a), where a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 indicates that the human subject is responsive to a CDK2 inhibitor. In a specific embodiment, the human subject has a disease or disorder associated with CDK2.

[0398] A reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3, combined with an amplification of the CCNE1 gene and / or an expression level of CCNE1 higher than a control expression level of CCNE1, indicates that a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 will respond to a CDK2 inhibitor. For example, in a subject having an amplification of the CCNE1 gene and / or an expression level of CCNE1 higher than a control expression level of CCNE1, a biological sample obtained from the subject after treatment with a CDK2 inhibitor has a low (e.g., reduced compared to a control) or undetectable level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 indicates that the subject will respond to a CDK2 inhibitor.

[0399] In combination with (i) amplification of the CCNE1 gene and / or an expression level of CCNE1 that is greater than a control expression level of CCNE1, and (ii) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), a biological sample obtained from the subject following administration of a CDK2 inhibitor to the subject has a reduced level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3 compared to a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3, indicates that a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2 will respond to a CDK2 inhibitor. For example, in a human subject having (i) amplification of the CCNE1 gene and / or an expression level of CCNE1 that is higher than a control expression level of CCNE1, and (ii) the presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, the presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, and / or the presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), a biological sample obtained from the human subject following administration of a CDK2 inhibitor to the subject has a low (e.g., reduced compared to a control) or undetectable level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3, indicating that the human subject will respond to the CDK2 inhibitor.

[0400] In some embodiments, the CCNE1 gene is amplified to a gene copy number of 3 to 25. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 3. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 5. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 7. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 10. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 12. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 14. In specific embodiments, the CCNE1 gene is amplified to a gene copy number of at least 21. In specific embodiments, the expression level of CCNE1 is the level of CCNE1 mRNA. In specific embodiments, the expression level of CCNE1 is the level of CCNE1 protein.

[0401] Control As discussed above, methods relating to biomarkers and pharmacodynamic markers may involve measuring one or more markers (e.g., biomarkers or pharmacodynamic markers, e.g., amplification of the CCNE1 gene, expression levels of CCNE1, presence of a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, presence of a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, presence of a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1), and Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO:3) in a biological sample from a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2. In a specific embodiment, the human subject has a disease or disorder associated with CDK2. In a specific embodiment, the human subject is suspected of having, or at risk of developing a disease or disorder associated with CDK2. In certain aspects, the level of one or more biomarkers (e.g., amplification (e.g., for the CCNE1 gene), expression level (e.g., for CCNE1 or p16 protein), or phosphorylation level (e.g., for Rb)) relative to a control level of the one or more biomarkers is predictive / indicative of a human subject's response to a treatment comprising a CDK2 inhibitor. In certain embodiments, a human subject is identified as likely to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than the control expression level of CCNE1, and (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1) is present.In other embodiments, a human subject is identified as responsive to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than a control expression level of CCNE1, and (ii) the level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO:3 in a biological sample from the human subject after the human subject is administered a CDK2 inhibitor is less than the control level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO:3. In yet another embodiment, a human subject is identified as responding to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE1 is higher than a control expression level of CCNE1, (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present, and (iii) the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample from the human subject after the human subject is administered a CDK2 inhibitor is less than a control level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3. In this context, the term "control" includes a sample (from the same tissue type) obtained from a human subject known to be unresponsive to CDK2 inhibitors. The term "control" also includes samples (from the same tissue type) previously obtained from human subjects known not to respond to CDK2 inhibitors and used as a reference for future comparison to test samples obtained from human subjects whose therapeutic response is predicted. A "control" level (e.g., gene copy number, expression level, or phosphorylation level) for a particular biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in a particular cell type or tissue may be pre-established by analysis of the biomarker level (e.g., expression level or phosphorylation level) in one or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, or 40 or more) human subjects who did not respond to treatment with a CDK2 inhibitor.This pre-established reference value (which may be the average or median of levels (e.g., gene copy number, expression level, or phosphorylation level) obtained from multiple human subjects who did not respond to the treatment) may then be used for the "control" level of the biomarker (e.g., CCNE1, p16, or Rb phosphorylation) in comparison with the test sample. In such a comparison, a human subject is predicted to respond to a CDK2 inhibitor if the CCNE1 gene is amplified and / or the expression level of CCNE is higher than the pre-established reference, and a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO:1) is present. In another such comparison, a human subject is predicted to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than a pre-established reference, and (ii) after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than a pre-established reference. In yet another such comparison, a human subject is shown to respond to a CDK2 inhibitor if (i) the CCNE1 gene is amplified and / or the expression level of CCNE is higher than a pre-established reference, (ii) a CDKN2A gene encoding a p16 protein comprising the amino acid sequence of SEQ ID NO: 1 is present, a CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is present, and / or a p16 protein (e.g., a p16 protein comprising the amino acid sequence of SEQ ID NO: 1) is present, and (iii) after administration of a CDK2 inhibitor to the human subject, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 is lower than a pre-established reference.

[0402] Alternatively, the "control" level for a particular biomarker in a particular cell type or tissue may be preset by analyzing the biomarker level in one or more human subjects who have responded to treatment with a CDK2 inhibitor. This preset reference value (which may be the average or median of the levels (e.g., expression level or phosphorylation level) obtained from multiple human subjects who have responded to treatment) may then be used as the "control" level (e.g., expression level or phosphorylation level) in comparison with the test sample. In such a comparison, a human subject is shown to be responsive to a CDK2 inhibitor if the level of the biomarker being analyzed (e.g., the copy number of the CCNE1 gene, the expression level of CCNE1, the expression level of p16, or the phosphorylation level of Rb at the serine corresponding to amino acid position 780 of SEQ ID NO:3) is equal to or comparable to the preset reference (e.g., at least 85% thereof, but less than 115%).

[0403] In certain embodiments, the "control" is a pre-established cut-off value. The cut-off value is typically a level of a biomarker (e.g., copy number, expression level, or phosphorylation level) above or below which is considered to be predictive of the responsiveness of a human subject to a treatment of interest. Thus, according to the methods and compositions described herein, a reference level (e.g., of CCNE1 gene copy number, CCNE1 expression, p16 expression, or Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO:3) is identified as a cut-off value above or below which is predictive of the responsiveness to a CDK2 inhibitor. The cut-off value determined for use in the methods described herein can be compared, for example, to a published concentration range, but can be individualized to the method and patient population used.

[0404] In some embodiments, the expression level of CCNE1 is increased compared to the expression level of CCNE1 in a control. For example, the expression level of CCNE1 analyzed is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 20 times, at least 25 times, at least 50 times, at least 75 times, or at least 100 times higher than the expression level of CCNE1 in a control, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 100% higher than the expression level of CCNE1 in a control. at least 70%, at least 80%, at least 90%, at least 100%, at least 200%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1,000%, at least 1,500%, at least 2,000%, at least 2,500%, at least 3,000%, at least 3,500%, at least 4,000%, at least 4,500%, or at least 5,000% more likely.

[0405] The p16 protein is present if it is detectable by any assay known in the art or described herein, such as Western blot, immunohistochemistry, fluorescent activated cell sorting, enzyme-linked immunosorbent assay, etc. In some embodiments, the p16 protein is present at an expression level that is within at least 5%, at least 10%, at least 20%, or at least 30% of the p16 expression level in healthy controls.

[0406] In some embodiments, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 being analyzed is reduced compared to the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a control. For example, the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 being analyzed can be at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, or at least 100-fold lower, or at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% lower than the level of Rb phosphorylation at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a control.

[0407] Biological samples Suitable biological samples for the methods described herein include any sample containing blood or tumor cells obtained or derived from a human subject in need of treatment.For example, the biological sample may contain tumor cells from a biopsy from a patient suffering from a solid tumor.Tumor biopsies can be obtained by various means known in the art.Alternatively, blood samples can be obtained from patients suffering from blood cancer.

[0408] The biological sample can be obtained from a human subject having, suspected of having, or at risk of developing a CDK2-associated disease or disorder. In some embodiments, the CDK2-associated disease or disorder is cancer (such as those described above).

[0409] Methods of obtaining samples and / or storing samples that preserve the activity or integrity of molecules (e.g., nucleic acids or proteins) in the sample are well known to those of skill in the art. For example, the biological sample can be further contacted with one or more additional agents, such as buffers and / or inhibitors, including one or more of nuclease, protease, and phosphatase inhibitors, that preserve or minimize alteration of the molecules in the sample.

[0410] Evaluation of biomarkers and pharmacodynamic markers The expression level of CCNE1 or p16 can be detected, for example, as RNA expression of the target gene (i.e., the gene encoding CCNE1 or p16). That is, the expression level (amount) of CCNE1 or p16 can be determined by detecting and / or measuring the level of mRNA expression of the gene encoding CCNE1. Alternatively, the expression level of CCNE1 or p16 can be detected, for example, as protein expression of the target gene (i.e., the gene encoding CCNE1 or p16). That is, the expression level (amount) of CCNE1 or p16 can be determined by detecting and / or measuring the level of protein expression of the gene encoding CCNE1 or p16.

[0411] In some embodiments, the expression level of CCNE1 or p16 is determined by measuring RNA level.Various suitable methods can be used to detect and / or measure the level of mRNA expression of genes.For example, mRNA expression can be determined using Northern blot or dot blot analysis, reverse transcriptase-PCR (RT-PCR, e.g., quantitative RT-PCR), in situ hybridization (e.g., quantitative in situ hybridization), nucleic acid array (e.g., oligonucleotide array or gene chip), and RNA sequencing analysis. Details of such methods are described below, as well as in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual Second Edition vol. 1, 2 and 3. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York, USA, Nov. 1989, Gibson et al. (1999) Genome Res., 6(10): 995-1001, and Zhang et al. (2005) Environ. Sci. Technol., 39(8): 2777-2785, U.S. Publication No. 2004086915, European Patent No. 0543942, and U.S. Patent No. 7,101,663, Kukurba et al. (2015) Cold Spring Harbor Protocols., 2015(11): 951-69, the disclosures of each of which are incorporated herein by reference in their entireties.

[0412] In one example, the presence or amount of one or more distinct mRNA populations in a biological sample can be determined by isolating total mRNA from the biological sample (see, e.g., Sambrook et al., supra, and U.S. Patent No. 6,812,341) and subjecting the isolated mRNA to agarose gel electrophoresis to separate the mRNA by size. The size-separated mRNA is then transferred (e.g., by diffusion) to a solid support such as a nitrocellulose membrane. The presence or amount of one or more mRNA populations in a biological sample can then be determined using one or more detectably labeled polynucleotide probes complementary to the mRNA sequences of interest that bind to the corresponding mRNA populations, thereby rendering them detectable. Detectable labels include, for example, fluorescent (e.g., umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, allophycocyanin, or phycoerythrin), luminescent (e.g., europium, terbium, Qdot™ nanoparticles supplied by Quantum Dot Corporation, Palo Alto, Calif.), radiological (e.g., 125 I, 131 I, 35 S, 32 P, 33 P, or 3 H), and enzyme (horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase) labels.

[0413] In some embodiments, the expression level of CCNE1 or p16 is determined by measuring protein levels. Various suitable methods can be used to detect and / or measure the level of protein expression of the target gene. For example, CCNE1 or p16 protein expression can be determined using Western blot, enzyme-linked immunosorbent assay ("ELISA"), fluorescent-activated cell sorting, or immunohistochemical analysis (e.g., using CCNE1-specific or p16-specific antibodies, respectively). Details of such methods are described below, and for example, in Sambrook et al. (see above).

[0414] In one example, the presence or amount of one or more individual protein populations (e.g., CCNE1 or p16) in a biological sample can be determined by Western blot analysis, for example, by isolating total protein from the biological sample (see, e.g., Sambrook et al., supra) and subjecting the isolated proteins to agarose gel electrophoresis to separate the proteins by size. The size-separated proteins are then transferred (e.g., by diffusion) to a solid support such as a nitrocellulose membrane. The presence or amount of one or more protein populations in a biological sample can then be determined using one or more antibody probes, such as a first antibody specific to the protein of interest (e.g., CCNE1 or p16) and a detectably labeled second antibody specific to the first antibody, which binds to the corresponding protein population and thereby makes it detectable. Detectable labels suitable for use in Western blot analysis are known in the art.

[0415] Methods for detecting or measuring gene expression (e.g., mRNA or protein expression) can optionally be performed in a format that allows for rapid preparation, processing, and analysis of multiple samples. This can be, for example, a multi-well assay plate (e.g., 96-well or 386-well) or an array (e.g., a nucleic acid chip or a protein chip). Stock solutions for various reagents can be prepared manually or robotically, and subsequent sample preparation (e.g., RT-PCR, labeling, or cell fixation), pipetting, dilution, mixing, dispensing, washing, incubation (e.g., hybridization), sample reading, data collection (optical data), and / or analysis (computer-assisted image analysis) can be performed robotically using commercially available analysis software, robotics, and detection equipment capable of detecting signals generated from the assay. Examples of such detectors include, but are not limited to, spectrophotometers, luminometers, fluorometers, and devices that measure the decay of radioisotopes. Exemplary high throughput cell-based assays (e.g., detecting the presence or levels of a target protein in cells) may utilize ArrayScan® VTI HCS Reader or KineticScan® HCS Reader technology (Cellomics Inc., Pittsburg, PA).

[0416] In some embodiments, the presence of the CDKN2A gene encoding the p16 protein comprising the amino acid sequence of SEQ ID NO:1 and / or the presence of the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions is determined by evaluating the DNA sequence (e.g., genomic DNA or cDNA) of the CDKN2A gene or by evaluating the RNA sequence (e.g., RNA, e.g., mRNA) of the CDKN2A gene. Methods for performing nucleic acid sequencing analysis are known in the art and described above. Non-limiting examples of inactivating nucleic acid substitutions and / or deletions that prevent the CDKN2A gene from encoding a protein comprising the amino acid sequence of SEQ ID NO:1 are described in Table A above. In specific embodiments, the one or more inactivating nucleic acid substitutions and / or deletions in the CDKN2A gene are as described in Yarbrough et al., Journal of the National Cancer Institute, 91(18):1569-1574, 1999; Liggett and Sidransky, Biology of Neoplasia, Journal of Oncology, 16(3):1197-1206, 1998; and Cairns et al., Nature Genetics, 11:210-212, 1995, each of which is incorporated by reference in its entirety.

[0417] In some embodiments, the expression level or the presence of a gene lacking one or more inactivating nucleic acid substitutions or deletions is determined by evaluating the copy number variation (CNV) of the gene. The CNV of a gene (e.g., CCNE1 gene and / or CDKN2A gene) can be determined / identified by various suitable methods. For example, CNV can be determined using fluorescent in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), single nucleotide polymorphism (SNP) array, and next generation sequencing (NGS) technology.

[0418] In one example, copy number polymorphisms of one or more individual genes in a biological sample can be determined by MLPA, for example, by extracting a DNA sample from the biological sample (see, e.g., Sambrook et al., supra, and U.S. Pat. No. 6,812,341) and amplifying a DNA sequence of interest (e.g., CCNE1 or CDKN2A) using a mixture of MLPA probes. Each MLPA probe consists of two oligonucleotides that hybridize to directly adjacent target DNA sequences (e.g., CCNE1 or CDKN2A) to be ligated into a single probe. The ligated probes are amplified by PCR, one of the PCR primers being fluorescently labeled to allow the amplification products to be visualized during separation of the fragments by capillary electrophoresis. The presence, absence, or amplification of one or more genes of interest in a biological sample is calculated by measuring the fluorescence from PCR, quantifying the amount of PCR product after normalization, and comparing it to a control DNA sample.

[0419] The level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO:3 can be detected by various suitable methods. For example, the phosphorylation status can be determined using Western blot, ELISA, fluorescent activated cell sorting, or immunohistochemical analysis. Details of such methods are described below, as well as, for example, in Sambrook et al. (see above).

[0420] Similar to the methods for detecting or measuring gene expression (above), the methods for detecting or measuring the level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO:3 can optionally be performed in a format that allows for rapid preparation, processing, and analysis of multiple samples.

[0421] Embodiment 1. Formula (I): [ka] 2. A solid form of the compound of formula (I), wherein the solid form is Form I.

[0422] 2. The solid form of embodiment 1, which is not solvated.

[0423] 3. The solid form of embodiment 1, which is crystalline.

[0424] 4. The solid form of embodiment 1, wherein the form has at least one XRPD peak selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0425] 5. The solid form of embodiment 1, wherein the form has at least two XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0426] 6. The solid form of embodiment 1, wherein the form has at least three XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0427] 7. The solid form of embodiment 1, wherein the form has at least four XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0428] 8. The solid form of embodiment 1, wherein the form has at least five XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0429] 9. The solid form of embodiment 1, wherein the form has at least 10 XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 two theta (±0.2 degrees).

[0430] 10. The solid form of any one of embodiments 1-9, wherein the form has an XRPD pattern substantially as shown in FIG. 1.

[0431] 11. The solid form of any one of the preceding embodiments, having an endothermic peak with an onset temperature (±3° C.) of 191.7° C. and a maximum of 193.6° C.

[0432] 12. The solid form of any one of embodiments 1-9, wherein said form has a DSC thermogram substantially as shown in FIG. 2.

[0433] 13. The solid form of any one of embodiments 1-12, wherein said form has a TGA thermogram substantially as shown in FIG. 3.

[0434] 14. Formula (I): [ka] A salt of a compound of A monomaleate salt of the compound of formula (I), A dibesylate salt of the compound of formula (I), The monomesylate salt of the compound of formula (I), A ditosylate salt of the compound of formula (I), the monohydrochloride salt of the compound of formula (I), and The dihydrochloride salt of the compound of formula (I), The salt is selected from the group consisting of

[0435] 15. The salt according to embodiment 14, which is a monomaleate salt of the compound of formula (I).

[0436] 16. The salt of embodiment 15, which is crystalline.

[0437] 17. The salt of embodiment 15 or 16, wherein the salt has at least one XRPD peak selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9, 2 theta (±0.2 degrees).

[0438] 18. The salt of embodiment 15 or 16, wherein the salt has at least two XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9, two theta (±0.2 degrees).

[0439] 19. The salt of embodiment 15 or 16, wherein the salt has at least three XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9, two theta (±0.2 degrees).

[0440] 20. The salt of embodiment 15 or 16, wherein the salt has at least four XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9, two theta (±0.2 degrees).

[0441] 21. The salt of embodiment 15 or 16, wherein the salt has at least five XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9, two theta (±0.2 degrees).

[0442] 22. The salt of embodiment 15 or 16, wherein the salt has at least 10 XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9, 2 theta (±0.2 degrees).

[0443] 23. The salt of embodiment 15 or 16, wherein the salt has an XRPD pattern substantially as shown in FIG. 4.

[0444] 24. The salt according to any one of embodiments 15 to 23, having an endothermic peak with an onset temperature (±3°C) of 180.4°C and a maximum temperature (±3°C) of 181.8°C.

[0445] 25. The salt according to any one of embodiments 15-23, wherein the salt has a DSC thermogram substantially as shown in FIG. 5.

[0446] 26. The salt according to any one of embodiments 15-25, wherein the salt has a TGA thermogram substantially as shown in FIG. 6.

[0447] 27. The salt according to embodiment 14, which is a dibesylate salt of the compound of formula (I).

[0448] 28. The salt of embodiment 27, which is crystalline.

[0449] 29. The salt of embodiment 27 or 28, wherein the salt has at least one XRPD peak selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1, 2 theta (±0.2 degrees).

[0450] 30. The salt of embodiment 27 or 28, wherein the salt has at least two XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1, two theta (±0.2 degrees).

[0451] 31. The salt of embodiment 27 or 28, wherein the salt has at least three XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1, two theta (±0.2 degrees).

[0452] 32. The salt of embodiment 27 or 28, wherein the salt has at least four XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1, two theta (±0.2 degrees).

[0453] 33. The salt of embodiment 27 or 28, wherein the salt has at least five XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1, two theta (±0.2 degrees).

[0454] 34. The salt of embodiment 27 or 28, wherein the salt has at least 10 XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1, 2 theta (±0.2 degrees).

[0455] 35. The salt according to embodiment 27 or 28, wherein the salt has an XRPD pattern substantially as shown in FIG. 7.

[0456] 36. The salt according to any one of embodiments 27 to 35, having an endothermic peak with an onset temperature (±3°C) of 160.4°C and a maximum temperature (±3°C) of 163.4°C.

[0457] 37. The salt according to any one of embodiments 27-35, wherein the salt has a DSC thermogram substantially as shown in FIG. 8.

[0458] 38. The salt according to any one of embodiments 27-37, wherein the salt has a TGA thermogram substantially as shown in FIG. 9.

[0459] 39. The salt according to embodiment 14, which is the monomesylate salt of the compound of formula (I).

[0460] 40. The salt of embodiment 39, which is crystalline.

[0461] 41. The salt of embodiment 39 or 40, wherein the salt has at least one XRPD peak selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1, 2 theta (±0.2 degrees).

[0462] 42. The salt of embodiment 39 or 40, wherein the salt has at least two XRPD peaks selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1, two theta (±0.2 degrees).

[0463] 43. The salt of embodiment 39 or 40, wherein the salt has at least three XRPD peaks selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1, two theta (±0.2 degrees).

[0464] 44. The salt of embodiment 39 or 40, wherein the salt has at least four XRPD peaks selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1, two theta (±0.2 degrees).

[0465] 45. The salt of embodiment 39 or 40, wherein the salt has at least five XRPD peaks selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1, two theta (±0.2 degrees).

[0466] 46. ​​The salt of embodiment 39 or 40, wherein the salt has at least 10 XRPD peaks selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1, 2 theta (±0.2 degrees).

[0467] 47. The salt according to embodiment 39 or 40, wherein the salt has an XRPD pattern substantially as shown in FIG. 10.

[0468] 48. The salt according to any one of embodiments 39 to 47, having a first endothermic peak with a maximum temperature (±3°C) of 61.1°C, and a second endothermic peak with an onset temperature (±3°C) of 134.4°C and a maximum temperature (±3°C) of 150.1°C.

[0469] 49. The salt according to any one of embodiments 39-47, wherein the salt has a DSC thermogram substantially as shown in FIG. 11.

[0470] 50. The salt according to any one of embodiments 39-49, wherein the salt has a TGA thermogram substantially as shown in FIG. 12.

[0471] 51. The salt according to embodiment 14, which is a ditosylate salt of the compound of formula (I).

[0472] 52. The salt of embodiment 51, which is crystalline.

[0473] 53. The salt of embodiment 51 or 52, wherein the salt has at least one XRPD peak selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6, 2 theta (±0.2 degrees).

[0474] 54. The salt of embodiment 51 or 52, wherein the salt has at least two XRPD peaks selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6, 2 theta (±0.2 degrees).

[0475] 55. The salt of embodiment 51 or 52, wherein the salt has at least three XRPD peaks selected from 65.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6, 2 theta (±0.2 degrees).

[0476] 56. The salt of embodiment 51 or 52, wherein the salt has at least four XRPD peaks selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6, 2 theta (±0.2 degrees).

[0477] 57. The salt of embodiment 51 or 52, wherein the salt has at least five XRPD peaks selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6, 2 theta (±0.2 degrees).

[0478] 58. The salt of embodiment 51 or 52, wherein the salt has at least eight XRPD peaks selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6, 2 theta (±0.2 degrees).

[0479] 59. The salt of embodiment 51 or 52, wherein the salt has an XRPD pattern substantially as shown in FIG. 13.

[0480] 60. The salt according to any one of embodiments 51 to 59, having an exothermic peak with an onset temperature (±3°C) of 99.6°C and a maximum temperature (±3°C) of 110.5°C, and an endothermic peak with an onset temperature (±3°C) of 216.1°C and a maximum temperature (±3°C) of 218.7°C.

[0481] 61. The salt according to any one of embodiments 51-59, wherein the salt has a DSC thermogram substantially as shown in FIG. 14.

[0482] 62. The salt according to any one of embodiments 51-61, wherein the salt has a TGA thermogram substantially as shown in FIG. 15.

[0483] 63. The salt according to embodiment 14, which is the monohydrochloride salt of the compound of formula (I).

[0484] 64. The salt according to embodiment 63, which is crystalline.

[0485] 65. The salt according to embodiment 63 or 64, wherein the salt has at least one XRPD peak selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7, 2 theta (±0.2 degrees).

[0486] 66. The salt according to embodiment 63 or 64, wherein the salt has at least two XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7, two theta (±0.2 degrees).

[0487] 67. The salt according to embodiment 63 or 64, wherein the salt has at least three XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7, two theta (±0.2 degrees).

[0488] 68. The salt according to embodiment 63 or 64, wherein the salt has at least four XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7, two theta (±0.2 degrees).

[0489] 69. The salt according to embodiment 63 or 64, wherein the salt has at least five XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7, two theta (±0.2 degrees).

[0490] 70. The salt of embodiment 63 or 64, wherein the salt has at least 10 XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7, two theta (±0.2 degrees).

[0491] 71. The salt according to embodiment 63 or 64, wherein the salt has an XRPD pattern substantially as shown in FIG. 16.

[0492] 72. The salt according to any one of embodiments 63-71, having an endothermic peak with an onset temperature (±3°C) of 196.0°C and a maximum temperature (±3°C) of 212.2°C.

[0493] 73. The salt according to any one of embodiments 63-71, wherein the salt has a DSC thermogram substantially as shown in FIG. 17.

[0494] 74. The salt according to any one of embodiments 63-73, wherein the salt has a TGA thermogram substantially as shown in FIG. 18.

[0495] 75. The salt according to embodiment 14, which is a dihydrochloride salt of the compound of formula (I).

[0496] 76. The salt of embodiment 75, which is crystalline.

[0497] 77. The salt according to embodiment 75 or 76, wherein the salt has at least one XRPD peak selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8, 2 theta (±0.2 degrees).

[0498] 78. The salt according to embodiment 75 or 76, wherein the salt has at least two XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8, 2 theta (±0.2 degrees).

[0499] 79. The salt of embodiment 75 or 76, wherein the salt has at least three XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8, two theta (±0.2 degrees).

[0500] 80. The salt of embodiment 75 or 76, wherein the salt has at least four XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8, two theta (±0.2 degrees).

[0501] 81. The salt according to embodiment 75 or 76, wherein the salt has at least five XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8, two theta (±0.2 degrees).

[0502] 82. The salt according to embodiment 75 or 76, wherein the salt has at least 10 XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8, 2 theta (±0.2 degrees).

[0503] 83. The salt of embodiment 75 or 76, wherein the salt has an XRPD pattern substantially as shown in FIG. 19.

[0504] 84. The salt according to any one of embodiments 75-83, having an endothermic peak with an onset temperature (±3°C) of 182.1°C and a maximum temperature (±3°C) of 206.4°C.

[0505] 85. The salt according to any one of embodiments 75-83, wherein the salt has a DSC thermogram substantially as shown in FIG. 20.

[0506] 86. The salt according to any one of embodiments 75-85, wherein the salt has a TGA thermogram substantially as shown in FIG. 21.

[0507] 87. A pharmaceutical composition comprising a solid form according to any one of embodiments 1 to 13 or a salt according to any one of embodiments 14 to 86, and a pharma- ceutically acceptable carrier.

[0508] 88. A method for inhibiting CDK2, comprising contacting said CDK2 with a solid form according to any one of embodiments 1 to 13 or with a salt according to any one of embodiments 14 to 86.

[0509] 89. A method for inhibiting CDK2 in a patient, comprising administering to the patient a solid form according to any one of embodiments 1 to 13 or a salt according to any one of embodiments 14 to 86.

[0510] 90. A method for treating a disease or disorder associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a solid form according to any one of embodiments 1-13 or a salt according to any one of embodiments 14-86.

[0511] 91. The method of embodiment 90, wherein the disease or disorder is associated with amplification of the Cyclin E1 (CCNE1) gene and / or overexpression of CCNE1.

[0512] 92. A method for treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising administering to the human subject a solid form according to any one of embodiments 1-13 or a salt according to any one of embodiments 14-86, wherein the human subject: (i) (a) having a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1; and / or (b) having a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions and / or deletions; (ii) (a) have an amplification of the cyclin E1 (CCNE1) gene, and / or (b) having an expression level of CCNE1 in a biological sample obtained from the human subject that is greater than a control expression level of CCNE1; wherein said method of treatment has previously been determined to be.

[0513] 93. A method for treating a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2), comprising: (i) in a biological sample obtained from the human subject, (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, and / or (b) identifying a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions; and (ii) in a biological sample obtained from the human subject, (a) amplification of the cyclin E1 (CCNE1) gene, and / or (b) identifying an expression level of CCNE1 that is greater than a control expression level of CCNE1; and (iii) administering to the human subject a solid form according to any one of embodiments 1 to 13 or a salt according to any one of embodiments 14 to 86; The method of treatment comprising:

[0514] 94. (i) in a biological sample obtained from the human subject, (a) a nucleotide sequence encoding a p16 protein comprising the amino acid sequence of SEQ ID NO:1, and / or (b) identifying a CDKN2A gene that lacks one or more inactivating nucleic acid substitutions and / or deletions; and (ii) in a biological sample obtained from the human subject, (a) identifying an amplification of the CCNE1 gene; (iii) administering said compound or said salt to said human subject; and 94. The method of embodiment 93, comprising:

[0515] 95. A method for assessing the response of a human subject having a disease or disorder associated with cyclin-dependent kinase 2 (CDK2) to a solid form according to any one of embodiments 1 to 13 or a salt according to any one of embodiments 14 to 86, comprising: (a) administering said compound or said salt to said human subject, wherein said human subject has previously been determined to have amplification of the Cyclin E1 (CCNE1) gene and / or an expression level of CCNE1 that is higher than a control expression level of CCNE1; (b) following said administering of step (a), measuring in a biological sample obtained from said subject the level of phosphorylation of retinoblastoma (Rb) protein at serine corresponding to amino acid position 780 of SEQ ID NO:3; The evaluation method, wherein a reduced level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3, compared to a control level of Rb phosphorylation at serine corresponding to amino acid 780 of SEQ ID NO: 3, indicates that the human subject is responsive to the compound or salt.

[0516] 96. The method of embodiment 95, wherein the disease or disorder is cancer.

[0517] 97. A process for preparing the solid form according to any one of embodiments 1 to 13, comprising cooling a solution of the compound of formula (I) in a solvent component comprising ethanol and water.

[0518] 98. The process of embodiment 97, wherein the solvent component comprises 6% water and 94% ethanol.

[0519] 99. The process of embodiment 97 or 98, wherein the solution is cooled to a temperature of 0°C ± 3°C.

[0520] 100. The process of any one of embodiments 97-99, wherein the solution is prepared by heating a slurry of the compound of formula (I) in the solvent component prior to said cooling.

[0521] 101. A process for preparing a compound of formula (I) or a pharma- ceutically acceptable salt thereof, a solid form according to any one of embodiments 1 to 13, or a salt according to any one of embodiments 14 to 86, comprising: Formula (1c): [ka] With a compound of formula (1b): [ka] or a salt thereof via a Buchwald coupling reaction to obtain a compound of formula (1a): [ka] wherein X 1 is halo.

[0522] 102.X 1 The process of embodiment 101, wherein is Br.

[0523] 103. The process of embodiment 101 or 102, wherein the compound of formula (1b) or the salt thereof is the HCl salt.

[0524] 104. The process of any one of embodiments 101-103, wherein the Buchwald coupling reaction comprises reacting the compound of formula (1c) with the compound of formula (1b) or the salt thereof in the presence of a Buchwald catalyst or pre-catalyst and a base.

[0525] 105. The process of embodiment 104, wherein the Buchwald catalyst or the pre-catalyst is a palladium catalyst.

[0526] 106. The process of embodiment 104, wherein the palladium catalyst is [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (t-BuBrett Phos Pd G3) or [tBuBrettPhos Pd(allyl)]OTf (Pd-175).

[0527] 107. The process of any one of embodiments 104-106, wherein the base is an alkali metal alkoxide.

[0528] 108. The process of any one of embodiments 104-106, wherein the base is sodium t-butoxide.

[0529] 109. The process according to any one of embodiments 101-108, further comprising deprotecting said compound of formula (1a) to form said compound of formula (I).

[0530] 110. The process of embodiment 109, wherein the deprotection is accomplished by reacting the compound of formula (1a) with a strong acid.

[0531] 111. The process of embodiment 110, wherein the strong acid is hydrochloric acid.

[0532] 112. The compound of formula (1c), Formula (1d): [ka] or a salt thereof with a halogenating agent to form said compound of formula (1c).

[0533] 113. The process of embodiment 112, wherein the halogenating agent is a brominating agent.

[0534] 114. The halogenating agent is Cu(X 1 113. The process of embodiment 112, wherein:

[0535] 115. The process of embodiment 112, wherein the halogenating agent is CuBr2.

[0536] 116. The compound of formula (1d) or the salt thereof, Equation 1(e): [ka] with hydroxylamine HCl and a base component to form said compound of formula (1d) or said salt thereof.

[0537] 117. The process of embodiment 116, wherein the base component is a tertiary amine.

[0538] 118. The process of embodiment 117, wherein the tertiary amine is ethyldiisopropylamine.

[0539] 119. The compound of formula (1e) Formula (1f): [ka] The process according to any one of embodiments 116 to 118, wherein the compound is prepared by a process comprising reacting a compound of formula (1e) with CH3CH2OC(O)-N=C=S to form the compound of formula (1e).

[0540] 120. The compound of formula (1f), Formula (1h): [ka] or a salt thereof, [ka] via a Buchwald coupling reaction to form a compound of formula (1f).

[0541] 121. The process of embodiment 120, wherein the compound of formula (1h) or the salt thereof is the HBr salt.

[0542] 122. The process according to embodiment 120 or 121, wherein the Buchwald coupling reaction comprises reacting the compound of formula (1h) or the salt thereof with the compound of formula (1g) in the presence of a Buchwald catalyst or pre-catalyst and a base.

[0543] 123. The process according to embodiment 122, wherein the Buchwald catalyst or the pre-catalyst present for the reaction of the compound of formula (1h) or the salt thereof with the compound of formula (1g) is a palladium catalyst.

[0544] 124. The process of embodiment 122, wherein the Buchwald catalyst present for the reaction of the compound of formula (1h) or the salt thereof with the compound of formula (1g) is (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd G3).

[0545] 125. The process according to any one of embodiments 122-124, wherein the base present for the reaction of the compound of formula (1h) or the salt thereof with the compound of formula (1g) is an alkali metal phosphate.

[0546] 126. The process according to any one of embodiments 122-124, wherein the base present for the reaction of the compound of formula (1h) or the salt thereof with the compound of formula (1g) is trisodium phosphate.

[0547] 127. The compound of formula (1h) or the salt thereof, Formula (1i): [ka] or a salt thereof with an ethyl halide in the presence of a base to form said compound of formula (1h) or said salt thereof.

[0548] 128. The process of embodiment 127, wherein the ethyl halide is ethyl iodide.

[0549] 129. The process according to embodiment 127 or 128, wherein the base present for the reaction of the compound of formula (1i) or the salt thereof with the ethyl halide is a basic carbonate.

[0550] 130. The process of embodiment 129, wherein the basic carbonate is cesium carbonate.

[0551] 131. The process according to any one of embodiments 127-130, wherein the compound of formula (1i) or the salt thereof is an HBr salt.

[0552] 132. The compound of formula (1c), Formula (2a): [ka] With a compound of formula (2b): [ka] in the presence of a Suzuki catalyst and a base to form a compound of formula (1c), wherein X 1 The process of any one of embodiments 101-111, wherein is halo.

[0553] 133.X1 The process of embodiment 132, wherein is Br.

[0554] 134. The process of embodiment 132 or 133, wherein the Suzuki catalyst is a palladium catalyst.

[0555] 135. The process of embodiment 132 or 133, wherein the Suzuki catalyst is formed from a mixture of a phosphine ligand and a palladium(II) compound.

[0556] 136. The process of embodiment 132 or 133, wherein the Suzuki catalyst is formed from a mixture of CataCXium A and palladium acetate.

[0557] 137. The process according to any one of embodiments 132-136, wherein the base present for the reaction of the compound of formula (2a) with the compound of formula (2b) is an alkali metal phosphate.

[0558] 138. The process according to any one of embodiments 132-136, wherein the base present for the reaction of the compound of formula (2a) with the compound of formula (2b) is trisodium phosphate.

[0559] 139. The compound of formula (1b) or the salt thereof, Formula (3a): [ka] to form said compound of formula (1b) or said salt thereof.

[0560] 140. The process of embodiment 139, wherein the reduction is accomplished by reacting the compound of formula (3a) with hydrogen gas in the presence of a palladium catalyst.

[0561] 141. The compound of formula (3a), Formula (3c): [ka] With a compound of formula (3b): [ka] with a compound of formula (3a) followed by crystallization to obtain said compound of formula (3a).

[0562] 142. The compound of formula (3c), Formula (3d): [ka] or a salt thereof with methanesulfonyl chloride to form a compound of formula (3c).

[0563] 143. [ka] or a salt thereof.

[0564] The present invention will be described in more detail with specific examples.The following examples are presented for illustrative purposes and are not intended to limit the present invention in any way.Those skilled in the art will easily recognize various non-critical parameters that can be changed or modified to produce essentially the same results. EXAMPLES

[0565] The experimental procedures for the compounds, solid forms, and salts of the present disclosure are provided below. Preparative LC-MS purification of some of the compounds prepared was carried out on a Waters mass-directed fractionation system. The basic equipment settings, protocols, and control software for the operation of these systems are described in detail in the literature. See, e.g., "Two-Pump at-Column Dilution Configuration for Preparative LC-MS," K. Blom, J. Combi. Chem., 4, 295 (2002); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification," K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity confirmation under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire™ C 18 , particle size 5 μm, 2.1 × 5.0 mm; buffer: mobile phase A: 0.025% TFA in water and mobile phase B: acetonitrile; flow rate 2.0 mL / min, gradient from 2% to 80% B in 3 min.

[0566] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high performance liquid chromatography (RP-HPLC) with MS detection or flash chromatography (silica gel) as shown in the examples. Typical preparative reversed-phase high performance liquid chromatography (RP-HPLC) column conditions are as follows: Purification at pH=2: Waters Sunfire™ C 18, 5 μm particle size, 19×100 mm column, elution with mobile phase A: 0.1% TFA (trifluoroacetic acid) in water and mobile phase B: acetonitrile. The flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see “Preparative LCMS Purification: Improved Compound Specific Method Optimization,” K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used for the 30×100 mm column was 60 mL / min.

[0567] Purification at pH=10: Waters XBridge C 18 , 5 μm particle size, 19×100 mm column, elution with mobile phase A: 0.15% NH4OH aqueous solution and mobile phase B: acetonitrile. The flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature (see "Preparative LCMS Purification: Improved Compound Specific Method Optimization," K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)). Typically, the flow rate used for the 30×100 mm column was 60 mL / min.

[0568] Example 1 Synthesis of 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) [ka] Intermediate (8). 3-Ethoxy-4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)pyridin-2-amine [ka] 4-Bromo-3-ethoxypyridin-2-amine (4) (prepared according to Example 4) (1.998 kg, 9.205 mol, 1 equiv.) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.94 kg, 11.0 mol, 1.2 equiv.) were charged to a 50 L reactor containing a solution of tripotassium phosphate (5.9 kg, 27.6 mmol, 3 equiv.) in water (10 L, 5 vol.). The slurry was diluted with dioxane (20 L, 10 vol.) and degassed by sparging with nitrogen for 50 min. Catalyst XPhos Pd G2 (21.7 g, 27.6 mmol, 0.003 equiv) was charged and degassing continued for 15 min followed by warming to 85° C. for 2.5 h until complete by HPLC analysis. The reaction mixture was cooled to room temperature and the organic layer separated and washed with brine (6 L, 3 vol). The aqueous layers were combined and extracted with ethyl acetate (10 L, 5 vol). The organic layers were combined, filtered through a plug of celite and concentrated to approximately 6 L (3 vol). The concentrated mixture was diluted with MTBE (18 L, 9 vol) and warmed to 50° C. forming a clear solution. Heptane (18 L, 9 vol) was charged slowly over approximately 10 min and the solution was cooled to 1° C. over 2 h. The slurry was filtered, washed with heptane (4 L, 2 vol) and dried on the filter to give 8 (2.033 kg, 80% yield, >99% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.00 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.77 (s, 2H), 5.62 (dd, J = 8.0, 4.0 Hz, 1H), 3.72 (q, J = 8.0 Hz, 2H), 3.46 (m, 1H), 3.23 (m, 1H), 1.63 (d, J = 8.0 Hz, 3H), 1.33 (t, J = 8.0 Hz, 3H), 1.05 (t, J = 8.0 Hz, 3H);C 14 H 20 N4O2, (MW 276.34), LCMS (EI) m / e 277.13 (M + + H).

[0569] Intermediate (9) [ka] A slurry of 8 (1.0 kg, 3.62 mol, 1 equiv) in dioxane (5 L, 5 vol) was cooled to 10° C. and O-ethyl carbonisothiocyanate (512 mL, 4.34 mol, 1.2 equiv) was charged in one portion. The addition caused a mild exotherm from 9.1° C. to 21.7° C. and the reaction was stirred at room temperature for 16 h at which point it was deemed complete by HPLC. The reaction was quenched by the addition of brine (2.5 L, 2.5 vol) and water (1 L, 1 vol) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2.5 L, 2.5 vol) and the organic layers were combined and concentrated to dryness. The crude 9 (assuming 1.475 kg quantitative) was used directly in the next reaction as a thick orange oil. 1H NMR (400 MHz, DMSO) δ 11.56 (s, 1H), 11.43 (s, 1H), 8.52 (s, 1H), 8.17 (d, J = 5.1 Hz, 1H), 8.13 (s, 1H), 7.63 (d, J = 5.1 Hz, 1H), 5.65 (q, J = 5.9 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.89 (q, J = 7.0 Hz, 2H), 3.48 (dq, J = 9.6, 7.0 Hz, 1H), 3.25 (dq, J = 9.6, 7.0 Hz, 1H), 1.64 (d, J = 6.0 Hz, 3H), 1.29 (m, 6H), 1.06 (t, J = 7.0 Hz, 3H).C 18 H 25 N5O4S, (M + Hcalc: 408.1700), LCMS (EI) m / e 408.3 (M + + H).

[0570] Intermediate (10). 8-Ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka] Hunig's base (790 mL, 4.53 mol, 1.25 equiv) was charged to a slurry of hydroxylamine hydrochloride (377 g, 5.43 mol, 1.5 equiv) in ethanol (3 L, 2 vol). A bleach scrubber was installed to capture hydrogen sulfide off-gassing. 9 (1.475 kg, 3.62 mol, 1 equiv) in ethanol (4 L, 2.7 vol) was charged slowly over 1 h and the lines were rinsed with ethanol (400 mL, 0.3 vol). Upon addition, off-gassing began immediately with a mild exotherm (final temperature 28° C.). The reaction mixture was warmed to 50° C., resulting in a homogeneous solution. After 3 h at 50° C. the reaction was deemed complete by HPLC and a thick solid product had precipitated. Water (2.2 L, 1.5 vol) was charged to dissolve the product and precipitate any sulfur-containing by-products. The reaction mixture was filtered and the solids washed with ethanol / water (2:1, 700 mL, 0.5 vol). The filtrate was concentrated to remove ethanol (~7 L) leaving a slurry of 10 in water. The solids were dissolved in dichloromethane (7.3 L, 5 vol) and charged with 30% ammonium hydroxide (2.9 L, 2 vol). The layers were separated and the aqueous layer was extracted with dichloromethane (700 mL, 0.5 vol). The organics were washed twice with 15% ammonium hydroxide (1.5 L, 1 vol) and the aqueous layer was back extracted with dichloromethane (700 mL, 0.5 vol). The combined organic layers were washed with brine (3 L, 2 vol) and the aqueous layer was extracted with dichloromethane (700 mL, 0.5 vol). The combined organics were concentrated to ~4-5 vol (removing ~7 L) and charged with isopropyl acetate (6.3 L, 4.3 vol). The remaining dichloromethane (approximately 3 L) was removed in vacuo and the slurry was transferred to a 22 L round bottom flask with isopropyl acetate (1 L, 0.7 vol). The slurry was diluted with heptane (3.7 L, 2.5 vol) and stirred at 80° C. for 1 h, then allowed to cool slowly to room temperature overnight. The slurry was filtered, washed with isopropyl acetate / heptane (2:1, 700 mL, 0.5 vol) and dried in a vacuum oven at 40° C. to give 10 (920 g, 80% yield) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.47 (s, 1H), 8.27 (d, J = 7.0 Hz, 1H), 8.12 (s, 1H), 7.17 (d, J = 7.0 Hz, 1H), 5.99 (s, 2H), 5.62 (q, J = 5.9 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 3.47 (dq, J = 9.6, 7.0 Hz, 1H), 3.26 (dq, J = 9.6, 7.1 Hz, 1H), 1.64 (d, J = 5.9 Hz, 3H), 1.35 (t, J = 7.0 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H). C 15 H 20 N6O2, (M + Hcalc: 317.1721), LCMS (EI) m / e 317.1 (M + + H).

[0571] Intermediate (11). 2-Bromo-8-ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine [ka] Copper(II) bromide (449 g, 2.0 mol, 1.05 equiv) was charged to an ambient temperature slurry of 10 (605 g, 1.9 mol, 1 equiv) in acetonitrile (9 L, 15 vol), resulting in a dark solution. The reaction mixture was cooled to 5° C. and tert-butyl nitrite (607 mL, 4.6 mol, 2.4 equiv) was added in one portion. The reaction mixture was allowed to warm slowly to room temperature overnight (the ice bath was melted to allow a slower warming). After 16 h, the reaction was complete by HPLC and it was quenched by the addition of 15% ammonium hydroxide (5 L, 8 vol). The acetonitrile (ca. 6-8 L) was removed in vacuo and the mixture was diluted with dichloromethane (3 L, 5 vol). The layers were separated and the aqueous portion was extracted with dichloromethane (0.5 L, 1 vol). The organics were washed with 15% ammonium hydroxide (1.8 L, 3 vol) and the aqueous layer was extracted with dichloromethane (0.5 L, 1 vol). The cloudy organic layer was washed twice with brine (1.2 L, 2 vol), each time extracting the aqueous layer with dichloromethane (0.5 L, 1 vol). The organic layer was slurried with SiliaMetS thiol (150 g, 0.25× wt) at room temperature for 1 h, then filtered through a small bed of celite and washed with dichloromethane (3× 0.5 L, 1 vol). The filtrate was concentrated in vacuo to 1.2–1.5 L (approximately 2–2.5 vol) and the resulting slurry was warmed to reflux and diluted with heptane (3 L, 5 vol). The slurry was warmed at 40° C. for 1 h, then cooled to room temperature and aged for 30 min. The slurry was filtered and washed with heptane / DCM (2:1, 1.4 L, 2 vol). The solid was dried in a vacuum oven at 40° C. to give 11 (536 g, 74%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.68 (d, J = 7.1 Hz, 1H), 8.58 (s, 1H), 8.21 (s, 1H), 7.58 (d, J = 7.1 Hz, 1H), 5.65 (q, J = 5.9 Hz, 1H), 4.65 (q, J = 7.0 Hz, 2H), 3.48 (dq, J = 9.6, 7.0 Hz, 1H), 3.27 (dq, J = 9.6, 7.0 Hz, 1H), 1.65 (d, J = 6.0 Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H), 1.07 (t, J = 7.0 Hz, 3H).C 15 H 18 BrN5O2, (M + Hcalc: 380.0717), LCMS (EI) m / e 380.0717 (M + + H).

[0572] Intermediate (12). 8-Ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka] A solution of 11 (1.5 kg, 3.9 mol, 1 equiv), 3 (1.08 kg, 4.7 mol, 1.2 equiv) (prepared according to Example 3), sodium tert-butoxide (1.9 kg, 19.7 mol, 5 equiv) and t-BuBrettPhos Pd G3 (101 g, 118 mmol, 0.03 equiv) in dioxane was degassed by bubbling with nitrogen for 1 h. The slurry was heated to 90° C. to form a homogeneous solution and stirred at that temperature for 2 h until complete by HPLC analysis. The reaction mixture was cooled to room temperature and quenched by the addition of water (7.5 L, 5 vol). The layers were separated and the aqueous layer was extracted twice with ethyl acetate (15 L and 7.5 L, 10 vol and 5 vol). The combined organic layers were treated with a solution of N-acetylcysteine ​​(690 g) and tripotassium phosphate (990 g) in water (7.5 L) at 60° C. for 3 hours. The wash to remove palladium was cooled to room temperature and the layers were separated. The aqueous layer was extracted twice with ethyl acetate (7.5 L, 5 vol), and the organics were concentrated in vacuo to approximately 20 L (13 vol) and slurried with carbon C-941 (300 g, 0.20 wt) and SiliMetS thiol (300 g, 0.20 wt) at room temperature for up to 8 hours. The slurry was filtered through a Celite pad rinsing with ethyl acetate (7.5 L, 5 vol). The filtrate was concentrated to give a crude oil (assumed quantitative) of 12, which was used directly in the next step. 1H NMR (600 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.33 (d, J = 6.0 Hz, 1H), 8.13 (s, 1H), 7.18 (d, J = 12.0 Hz, 1H), 6.76 (d, J = 6.0 Hz, 1H), 5.62 (q, J = 6.0 Hz, 1H), 4.55 (q, J = 6.0 Hz, 2H), 3.88 (m, 1H), 3.47 (m, 1H), 3.26 (m, 2H), 3.12 (m, 3H), 2.87 (s, 3H), 2.18 (m, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.64 (d, J = 6.0 Hz, 3H), 1.36 (t, J = 6.0 Hz, 3H), 1.06 (t, J = 6.0 Hz, 3H), 0.93 (d, J = 6.0 Hz, 3H);C 22 H 33 N7O4S, (MW 491.61), LCMS (EI) m / e 492.2 (M + + H).

[0573] Compound of formula (I): 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka] To a solution of 12 (1.9 kg, 3.9 mol, 1 equiv) (or 12 hemisuccinate) in THF (14 L, 7 vol) was added 1N hydrochloric acid (9 L, 9.0 mol, 2.3 equiv) and the solution was warmed to 60° C. for 2 h until complete by HPLC. The reaction mixture was cooled to room temperature and neutralized with 16% sodium hydroxide (2 L, 9.3 mol). The reaction mixture was extracted twice with ethyl acetate (14 L and 8 L, 7 vol and 4 vol) and the combined organic layers were stirred with activated carbon C-941 (600 g, 0.32 wt) and SiliaMetS thiol (600 g, 0.32 wt) for 16 h. The slurry was filtered through a pad of Celite and washed with ethyl acetate (7.5 L, 5 vol). The filtrate was concentrated to about 7.5 L (5 volumes) and the slurry was diluted with heptane (4.5 L, 3 volumes), stirred at room temperature for 30 minutes, then cooled to 0° C. The solid was filtered and washed with ethyl acetate / heptane (5:3, 1.5 L, 1 volume). The solid was dried on the filter to give crude compound of formula (I) (1.312 kg, 80% yield).

[0574] Crude compound of formula (I) (1.4 kg, 3.3 mol) was slurried in 6% water / ethanol (7 L, 5 vol) and the slurry was warmed to reflux to give a clear solution. The mixture was slowly cooled to 0° C. and filtered, rinsing with ethanol (500 mL, 0.35 vol). The solid was dried under vacuum at 45° C. for 3 days to give compound of formula (I) (1.163 kg, 83% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1H), 8.33 (s, 1H), 8.31 (d, J = 10.0 Hz, 1H), 8.12 (s, 1H), 7.17 (d, J = 10.0 Hz, 1H), 6.73 (d, J = 10.0 Hz, 1H), 4.54 (dd, J = 15.0, 10.0 Hz, 2H), 3.88 (m, 1H), 3.26 (m, 1H), 3.12 (m, 3H), 2.87 (s, 3H), 2.19 (m, 1H), 1.85 (m, 1H), 1.76 (m, 1H), 1.36 (t, J = 10.0 Hz, 3H), 0.93 (d, J = 5.0 Hz, 3H);C18H25N7O3S, (M+H calculated: 420.1812), LCMS (EI) m / e 420.1818 (M+ + H).

[0575] Example 2 Synthesis of 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (Formula (I)) [ka] Intermediate (11). 2-Bromo-8-ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine (alternative synthesis) [ka] Degassed dioxane (0.84 L) was charged with Pd(OAc)2 (7.35 g, 0.5 mol%) and CataCXium A (25.8 g, 1.1 mol%) under nitrogen, and the mixture was evacuated and backfilled with nitrogen three times. The mixture was stirred under nitrogen at room temperature for up to 20 minutes. A separate reactor was charged with 7 (prepared according to Example 4) (2.10 kg), cesium carbonate (4.26 kg, 2 eq.), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.05 kg, 1.2 eq.), dioxane (9.7 L, 5 volumes in total including the dioxane utilized for in situ catalyst formation) and water (5.3 L, 2.5 volumes). The mixture was then purged with nitrogen for up to 30 minutes. After that period, the catalyst prepared above was added to the mixture. The combined mixture was purged with nitrogen for 5 minutes. The mixture was then heated to 50° C. for up to 10 hours. The reaction was monitored by HPLC until complete. Water (15.8 L, 7.5 volumes) was then charged slowly via the addition funnel. The resulting slurry was cooled slowly to room temperature, further cooled to 0° C., and stirred for up to 30 minutes. The slurry was filtered and the solid was washed with water (3.2 L). The solid was dried at up to 50° C. to give 2.49 kg of 11.

[0576] Crude 11 (4.61 kg) was mixed with THF (18.4 L, 4 volumes based on the weight of the isolated solid) and stirred at 50 °C to give a clear solution. Heptane (36.8 L, 8 volumes) was then charged at 50 °C. The resulting slurry was allowed to cool slowly to 15-30 °C and then further cooled to 0 °C. The slurry was filtered and the solid was washed with heptane (4.6 L) and dried below 50 °C to give 4.91 kg (84%) of 11 with a purity of >99A%. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 8.0 Hz, 1H), 8.58 (s, 1H), 8.21 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 5.65 (dd, J = 12.0, 8.0 Hz, 1H), 4.65 (dd, J = 12.0, 8.0 Hz, 2H), 3.48 (m, 1H), 3.27 (m, 1H), 1.65 (d, J = 8.0 Hz, 3H), 1.40 (t, J = 8.0 Hz, 3H), 1.07 (t, J = 8.0 Hz, 3H);C 15 H 18 BrN5O2, (MW 380.25), LCMS (EI) m / e 380.0, 382.0 (M + + H).

[0577] Intermediate (12). 8-Ethoxy-7-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka] 11 (4.1 kg, 1.0 equiv), 3 (2.71 kg, 1.1 equiv) (prepared according to Example 3), and NaOtBu (3.63 kg, 3.5 equiv) were combined in 2-MeTHF (10 volumes). The solution was degassed and charged with Pd-175 (8.41 g, 0.001 equiv). The solution was further degassed and heated to 70° C. until complete by HPLC. The reaction was then cooled to room temperature and quenched by the addition of brine (4 volumes). The organics were then washed with brine (3 volumes). The crude 12 in 2-MeTHF was concentrated to approximately 10 volumes and used directly in the next reaction (assumed to be quantitative).

[0578] Alternative synthesis of intermediate 12 as a hemisuccinate Alternatively, 11 (10 g, 1.0 equiv), 3 (6.62 g, 1.1 equiv), and NaOtBu (8.85 g, 3.5 equiv) were combined in 2-MeTHF (10 vol). The solution was degassed and charged with Pd-175 (21 mg, 0.001 equiv). The solution was further degassed and heated to 70° C. until complete by HPLC. The reaction was then cooled to room temperature and quenched by the addition of ammonium chloride (aqueous, 20 wt%, 6 vol). The organics were then washed with brine (6 vol). Crude 12 in 2-MeTHF was concentrated to approximately 5 vol and azeotropically dried by constant distillation with 2-MeTHF until KF<1.5%. Acetonitrile (5 vol) was charged followed by succinic acid (2.3 g, 0.75 equiv) in small portions at 55° C. The resulting slurry was aged at 55° C. for 1 h and cooled to room temperature overnight. Filtration followed by washing with acetonitrile / 2-MeTHF (1:1, 2 vol) afforded the 12-hemisuccinate as a white solid (13.8 g, 95% yield). 1H NMR (400 MHz, DMSO) δ 12.18 (s, 1H), 8.48 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H), 8.13 (s, 1H), 7.18 (d, J = 7.0 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 5.62 (q, J = 5.9 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 3.88 (dp, J = 10.8, 3.8 Hz, 1H), 3.47 (dq, J = 9.6, 7.0 Hz, 1H), 3.25 (dt, J = 9.8, 6.9 Hz, 2H), 3.13 (m, 3H), 2.86 (s, 3H), 2.42 (s, 2H), 2.18 (tt, J = 7.7, 4.3 Hz, 1H), 1.90 - 1.71 (m, 1H), 1.64 (d, J = 6.0 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H), 0.93 (d, J = 6.9 Hz, 3H). C22H33N7O4S, (M+H calculated value: 492.2387), LCMS (EI) m / e 492.2389 (M+ + H).

[0579] Compound of formula (I): 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (crude) [ka] A clean, inerted reactor was charged with 12 (or 12 hemisuccinate) in 2-MeTHF followed by 1N aqueous HCl (32.3 L, 3 equiv). The mixture was heated to 70±5°C while concentrating the reaction mixture to remove acetaldehyde until the reaction was complete as shown by HPLC. Upon completion, the reaction was cooled to 15-30°C and the aqueous layer containing the product was removed. The organic layer was extracted twice with 1N HCl (2×5.3 L, 2 volumes total) and the combined aqueous layers were diluted with 2-MeTHF (45 L). The reaction mixture was neutralized to a pH of approximately 8-9 by the addition of 5N sodium hydroxide (8.4 L). The organic layer containing the product was separated and the aqueous layer was extracted with 2-MeTHF (10.6 L, 2 volumes). The combined organic layers were treated with carbon C-941 (530 g, 20 w / w%) and SiliaMetS imidazole (530 g, 20 w / w%) at 40° C. for up to 12 hours. The mixture was cooled to 15-30° C. and filtered through Celite. The collected solid was washed with 2-MeTHF (21.2 L). The filtrate containing the product was washed twice with water (7.95 L). The organic layers were concentrated while charging 2-Me THF at up to 50° C. to remove residual water. The reaction mixture was then diluted with heptane (10 volumes) while maintaining a temperature of >45° C. Following aging at 50° C. for approximately 30 minutes, the reaction mixture was cooled to 15-30° C. and filtered. The product was washed with heptane (10.6 L, 2 volumes) and dried at up to 50° C. to give the crude compound of formula (I).

[0580] A solid form of the compound of formula (I). 8-ethoxy-N-((3R,4S)-3-methyl-1-(methylsulfonyl)piperidin-4-yl)-7-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (formula (I)) [ka] A 10% aqueous solution of ethanol (42 L) was prepared in a clean, inert reactor. The crude compound of formula (I) from the previous step (4.2 kg) was then charged and the reactor contents were heated to 50-80° C. until a solution was observed. The solution was cooled to 47-57° C. and C-941 activated carbon (420 g) and SiliaMetS imidazole (420 g) were added. The mixture was stirred for up to 12 hours. The mixture was cooled to 35-50° C. and filtered through Celite. The filtrate was then passed through a polishing filter into a clean, inert reactor. Polishing filtered ethanol was charged and water was removed from the solution by distillation until the Karl Fischer analysis met the criteria specified in the batch record. The mixture was cooled to -5-5° C. The solids were washed with cold ethanol (4.2 L) and dried in a vacuum oven at up to 50° C.

[0581] Example 3 Synthesis of (3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-amine hydrochloride (3) [ka] Intermediate (1). 3-Methyl-1-(methylsulfonyl)piperidin-4-one [ka] To a 3-L, 3-necked round bottom flask equipped with a mechanical stirrer and thermocouple under nitrogen was added 3-methylpiperidin-4-one hydrochloride (106.2 g, 710 mmol), DCM (708 mL), and methanesulfonyl chloride (60.4 mL, 781 mmol). The reaction mixture was swirled and within minutes a solution was formed. Triethylamine (218 mL, 1562 mmol) was added slowly via addition funnel over 30 minutes. Stirring was continued at room temperature overnight (12 hours). The suspended solids were filtered off as waste and the solids were rinsed with three portions of DCM (300 mL). The filtrate was then washed with 0.5 N aqueous HCl to remove TEA residues. The DCM layer was further washed with brine (60 mL). The DCM layer was then concentrated to dryness under reduced pressure on a rotary evaporator as a pale yellow solid (132 g, 97% yield). The resulting crude product, 3-methyl-1-(methylsulfonyl)piperidin-4-one (1, 132.1 g, 691 mmol, 97% yield), was used in the next reaction without further purification. 1 H NMR (400 MHz, DMSO) δ 3.85 - 3.74 (m, 2H), 3.21 (td, J = 11.9, 3.8 Hz, 1H), 2.98 (s, 3H), 2.88 (t, J = 11.5 Hz, 1H), 2.78 - 2.67 (m, 1H), 2.70 - 2.59 (m, 1H), 2.34 (dt, J = 14.7, 3.6 Hz, 1H), 0.95 (d, J = 6.6 Hz, 3H). C7H 13 NO3S, (M+H calculated value: 192.0689), LCMS (EI) m / e 192.1 (M + + H).

[0582] Intermediate (2). (3R,4S)-3-Methyl-1-(methylsulfonyl)-N-((S)-1-phenylethyl)piperidin-4-amine [ka] A solution of 1 (132.4 g, 1 equiv) in THF (1324 mL, 10 vol) was charged with (S)-1-phenylethan-1-amine (134 mL, 1.5 equiv) and DIPEA (145 mL, 1.2 equiv). Sodium triacetoxyborohydride (STAB; 220 g, 1.5 equiv) was added in small portions while maintaining 20-25 °C (a delayed exotherm can be observed). The reaction mixture was stirred for 1 h until complete by HPLC and then quenched by slow addition of methanol (132 mL, 1 vol). The mixture was concentrated to a minimum volume and diluted with dichloromethane (1324 mL, 10 vol). The organics were washed twice with saturated sodium bicarbonate (6 vol and 4 vol), then with brine (2 vol), then concentrated to near dryness. The crude was diluted with EtOAc (4 vol) and concentrated to a minimum volume to remove residual DCM. The crude solid was then slurried in EtOAc (4 vol) and warmed to 70° C. to form a homogeneous mixture. The reaction mixture was cooled to 60° C., seeded with 2, cooled to 50° C., and aged for 6 h for crystal growth, followed by slow cooling to 0° C. The solid was filtered, washed with EtOAc (1 vol) and dried to give 2 (115 g, 56.3% yield, diastereomeric ratio 94:0.5:5:5) as a white solid.

[0583] A diastereomeric mixture of 2 (115 g, 1 equiv, diastereomeric ratio 94:0.5:5:5) was warmed at reflux in EtOAc (693 mL, 6 vol) to give a clear to nearly clear solution. The solution was cooled at 60 °C and seeds were added as no auto seeding was observed. The mixture was aged at 50-60 °C for 5 h to give a thick slurry and continued to cool slowly to room temperature. The solid was isolated via filtration, washed with EtOAc (1 vol) and dried in a vacuum oven to give 2 (92.4 g, 80% yield, diastereomeric ratio 99.27:0:0.73:0) as a white solid. Crystallization was repeated (typically 2 recrystallizations) until the desired diastereomeric ratio was obtained. 1H NMR (400 MHz, DMSO) δ 7.39 - 7.32 (m, 2H), 7.35 - 7.26 (m, 2H), 7.25 - 7.16 (m, 1H), 3.77 (q, J = 6.6 Hz, 1H), 3.37 - 3.27 (m, 1H), 3.18 (ddd, J = 11.7, 4.5, 1.8 Hz, 1H), 2.75 (s, 3H), 2.70 - 2.59 (m, 2H), 2.37 (dt, J = 9.1, 4.5 Hz, 1H), 1.99 (q, J = 4.8, 4.0 Hz, 2H), 1.45 (m, 2H), 1.23 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H).C 15 H 24 N2O2S, (M+H calculated value: 297.1631), LCMS (EI) m / e 297.2 (M + + H).

[0584] Intermediate (3). (3R,4S)-3-Methyl-1-(methylsulfonyl)piperidin-4-amine hydrochloride [ka] A solution of 2 (10.31 g, 1 equiv.) in methanol (200 mL, 20 vol.) was charged with Pd(OH)2 (2.4 g, 20 wt.%) and HCl (3N in MeOH, 11.6 mL, 1 equiv.). The reaction mixture was degassed and subjected to H2 (60 psi) for 24 h. Additional Pd(OH)2 (0.73 g, 20 wt.%) was charged and the mixture was subjected to H2 for an additional 6 h at which time it was complete by HPLC analysis. The reaction mixture was filtered through celite, washed with methanol (3 x 60 mL, 6 vol.) and concentrated to dryness in vacuo. The crude solid was triturated in heptane (40 mL, 4 vol.) at 60 °C for 6 h. The slurry was cooled to room temperature, filtered, and washed with heptane (20 mL, 2 vol.) to give 3 (7.5 g, 94% yield) as the HCl salt. 1H NMR (400 MHz, DMSO) δ 8.38 - 8.33 (s, 3H), 3.49 - 3.39 (m, 1H), 3.33 - 3.24 (m, 2H), 3.02 (dd, J = 12.1, 3.3 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.87 (s, 3H), 2.24 - 2.14 (m, 1H), 1.83 (m, 2H), 0.97 (d, J = 7.0 Hz, 3H). C7H 16 N2O2S, (M+H calculated value: 193.1005), LCMS (EI) m / e 193.1 (M + + H).

[0585] Example 4 Synthesis of 2,7-dibromo-8-ethoxy-[1,2,4]triazolo[1,5-a]pyridine (7) [ka]

[0586] Intermediate (4). 4-Bromo-3-ethoxypyridin-2-amine [ka] In a 5 L round bottom flask equipped with a mechanical stirrer and reflux condenser under nitrogen, 2-amino-4-bromopyridin-3-ol hydrobromide (245.0 g, 871 mmol), cesium carbonate (568 g, 1743 mmol) and acetonitrile (2000-2500 mL, 711 mmol) were combined. The mixture was stirred for 15 min and iodoethane (105 mL, 1307 mmol) was added. The reaction mixture was heated at 65-70 °C for 18 h, at which time it was deemed complete by HPLC analysis. The reaction mixture was cooled and allowed to stir at room temperature for 30 min. The resulting reaction slurry was filtered through Celite to remove salts and the cake was washed with dichloromethane. The filtrate containing the product was concentrated to dryness and 500 mL of methylene chloride was added. Additional cesium carbonate precipitated and was removed by filtration. The filtrate was concentrated and loaded onto a silica plug using a 750 g Biotage column with a gradient of 0 to 25% ethyl acetate / dichloromethane. Clean fractions were combined and concentrated on a rotary evaporator.

[0587] The resulting solid was slurried in 1.25-1.5 volumes of heptane and heated to 98° C. The mixture was then cooled to 0° C. The solid was filtered and washed with ice-cold heptane. The solid was dried by passing air through the cake. 4-Bromo-3-ethoxypyridin-2-amine (4) was obtained in 70-75% yield. 1 H NMR (400 MHz, DMSO) δ 7.53 (d, J = 5.4 Hz, 1H), 6.73 (d, J = 5.3 Hz, 1H), 6.13 (s, 2H), 3.91 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). C7H9BrN2O, (M+H calculated value: 216.9971), LCMS (EI) m / e 216.9 (M + + H).

[0588] Intermediate (5) [ka] To a solution of 4 (44.7 g, 1 equiv.) in DCM (400 mL, 9 vol.) was added ethoxycarbonyl isothiocyanate (26.7 mL, 1.1 equiv.) while maintaining the temperature at 20° C. The reaction mixture was stirred for 16 h until complete by HPLC, then concentrated to dryness to give 5 (71.7 g, quant.), which was used directly in the next reaction. 11 H 14 BrN3O3S (M+H calculated value: 348.0012), LCMS (EI) m / e 348.1 (M + + H).

[0589] Intermediate (6). 7-Bromo-8-ethoxy-[1,2,4]triazolo[1,5-a]pyridin-2-amine [ka] To a slurry of hydroxylamine hydrochloride (42.9 g, 3 eq) in methanol (300 mL, 4 vol) was added Hunig's base (N,N-diisopropylethylamine) (71.9 mL, 2 eq) and the mixture was stirred at room temperature for 50 min. The reaction mixture was then added to a separate flask containing 5 (71.7 g, 1 eq) in ethanol (300 mL, 4 vol) and warmed to reflux for 2 h until complete by HPLC. The reaction mixture was cooled to room temperature and concentrated to approximately 1.5 vol. The resulting slurry was cooled to 0° C. and quenched by the addition of ammonium hydroxide (28%, 57.3 mL, 2 eq) and then diluted with water (120 mL, 2 vol.). The slurry was stirred for 15 min, filtered, washed with water (2×100 mL) and dried to give 6 (48.8 g, 92% yield). 1 H NMR (400 MHz, DMSO) δ 8.25 (d, J = 7.0 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.16 (s, 2H), 4.55 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). C8H 10 BrN4O, (M+H calculated value: 257.0032), LCMS (EI) m / e 257.0 (M + + H).

[0590] Intermediate (7). 2,7-Dibromo-8-ethoxy-[1,2,4]triazolo[1,5-a]pyridine [ka] To a mixture of 6 (150 g, 583 mmol) and CuBr2 (134 g, 600 mmol) in acetonitrile (1500 mL) at 0° C., t-BuONO (144.3 g, 1399 mmol) was added dropwise over 30 min. The resulting mixture was stirred at 0° C. for 2 h, followed by 2 h at room temperature (TLC showed that all of the starting material was consumed). The reaction mixture was concentrated under reduced pressure. DCM (3 L) was added to the residue and stirred for 30 min. The mixture was then passed through a pad of silica gel (300 g), eluting with DCM until no product was detected by TLC. The collected fractions were evaporated to give the desired product (137 g). Charcoal (45 g, ca. 100 mesh size) was added to the product (137 g) in EtOAc (1500 mL) and the resulting suspension was stirred at room temperature for 2 h. The mixture was filtered through a pad of Celite and washed with EtOAc (1500 mL). The filtrate was concentrated under reduced pressure. Hexane (500 mL) was added to the residue (125 g) and it was agitated. The solid was collected by filtration and washed with hexane (500 mL). The filter cake was air-dried to give 7 as a light beige solid (111 g). 1 H NMR (400 MHz, DMSO) δ 8.65 (d, J = 7.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 4.65 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H). C8H7Br2N3O, (M+H calculated value: 319.9029), LCMS (EI) m / e 319.9 (M + + H).

[0591] Example 5 Solid state characterization of formula (I) X-ray powder diffraction (XRPD) X-ray powder diffraction (XRPD) was obtained from a Bruker D8 Advance ECO X-ray powder diffractometer (XRPD) instrument. The general experimental procedure for XRPD was as follows: (1) X-ray irradiation from copper at 1.5418 Å and a LYNXEYE™ detector, (2) X-ray power at 40 kV, 25 mA, and (3) sample powder was dispersed on a zero-background sample holder. The general measurement conditions for XRPD were as follows: start angle 3 degrees, stop angle 30 degrees, sampling 0.015 degrees, and scan speed 2 degrees / min.

[0592] Differential Scanning Calorimetry (DSC) DSC was obtained from a TA Instruments Differential Scanning Calorimeter, Discovery DSC2500 equipped with an autosampler. DSC instrument conditions were as follows: 20-300 °C at 10 °C / min, Tzero aluminum sample pans and lids, and a nitrogen gas flow rate of 50 mL / min.

[0593] Thermogravimetric analysis (TGA) TGA was obtained from a TA Instruments Thermogravimetric Analyzer, Discovery TGA5500 equipped with an autosampler. General experimental conditions for the TGA were as follows: 25° C. to 300° C. ramp at 10° C. / min, nitrogen purge gas flow rate of 25 mL / min, platinum sample holder.

[0594] Form I, the free base of formula (I) The crystalline free base of the compound of formula (I) as obtained in Examples 1 and 2 was characterized and is referred to herein as Form I. Form I of the free base was characterized by XRPD, DSC, and TGA. The XRPD patterns are shown in Figures 1 and 28, and the XRPD data are provided in Tables 1a and 1b. This confirms that Form I is a crystalline solid.

[0595] The DSC thermogram is shown in Figure 2. The DSC thermogram revealed a large endothermic event with an onset temperature of 191.7°C and a peak temperature of 193.6°C, which is believed to be the melting / decomposition temperature of the compound.

[0596] A second DSC was obtained using a Q200 V24.11 DSC using a ramp from 10° C. to 300° C. per minute, and is shown in Figure 29. The DSC thermogram revealed a large endothermic event with an onset temperature of 191.3° C. and a peak temperature of 193.3° C., which is believed to be the melting / decomposition temperature of the compound.

[0597] The TGA thermogram is shown in Figure 3. A weight loss of 0.96% was observed below 200°C. The compound began to decompose above 200°C. [Table 2-1] [Table 2-2] [Table 3]

[0598] Maleate salt of formula (I) Preparation of the maleate salt of formula (I) 574.0 mg of the free base was dissolved in 8 mL of 1:1 dichloromethane (DCM) / methanol in a 20 mL clear glass vial with stirring. To this solution, 191.3 mg of maleic acid (1.2 equiv.) was added and mixed well. The solution was allowed to evaporate to dryness overnight at room temperature, uncapped. To the resulting solid, 5 mL of acetone was added and stirred at room temperature for 2 hours. The solid was collected by filtration, washed with acetone, and dried in vacuum at 50° C. for 2 hours. The salt ratio between the free base and maleic acid was determined to be 1.0 by NMR analysis.

[0599] The maleate salt was confirmed as a crystalline solid according to XRPD analysis, the XRPD pattern is shown in FIG. 4 and the peak data is provided in Table 1.

[0600] The DSC thermogram is shown in Figure 5. The DSC thermogram revealed a large endothermic event with an onset temperature of 180.4°C and a peak temperature of 181.9°C, which is believed to be the melting / decomposition temperature of the compound.

[0601] The TGA thermogram is shown in Figure 6. A weight loss of 19.9% ​​was observed between 100 and 260°C. [Table 4]

[0602] Besylate salt of formula (I) Preparation of the besylate salt of formula (I) 104.98 mg of the free base of formula (I) was dissolved in 2 mL of 1:1 dichloromethane (DCM) / methanol in a 4 mL clear glass vial with stirring. To this solution, 47.75 mg of benzenesulfonic acid (1.2 equiv.) was added and mixed well. The solution was allowed to evaporate to an oil overnight at room temperature, uncapped. To the resulting oil, 1 mL of acetonitrile was added with stirring at room temperature to obtain a solution. The solution was allowed to evaporate again to an oil overnight at room temperature, uncapped. 1 mL of acetone was then added to the oil and slurried at room temperature for 1-2 hours until solid. The besylate salt was collected by filtration, washed with acetone, and dried in vacuum at 50° C. for 1 hour. The salt ratio between the free base and benzenesulfonic acid was determined to be 2.0 by NMR analysis.

[0603] The besylate salt was confirmed as a crystalline solid according to XRPD analysis, the XRPD pattern is shown in Figure 7 and the peak data is provided in Table 3.

[0604] The DSC thermogram is shown in Figure 8. The DSC thermogram revealed a large endothermic event with an onset temperature of 160.4°C and a peak temperature of 163.4°C, which is believed to be the melting / decomposition temperature of the compound.

[0605] The TGA thermogram is shown in Figure 9. A weight loss of 1.0% was observed below 150°C, and significant weight loss occurred above 150°C due to compound decomposition. [Table 5]

[0606] Mesylate salt of formula (I) Preparation of the mesylate salt of formula (I) 108.57 mg of the free base of formula (I) was dissolved in 2 mL of 1:1 dichloromethane (DCM) / methanol in a 4 mL clear glass vial with swirling. To this solution, 20.2 μL of methanesulfonic acid (1.2 equiv.) was added and mixed well. The solution was allowed to evaporate to an oil overnight at room temperature, uncapped. To the resulting oil, 1 mL of acetone was added and slurried at room temperature for 1 hour until solid. The mesylate salt was collected by filtration, washed with acetone, and dried in vacuum at 50° C. for 1 hour. The salt ratio between the free base and methanesulfonic acid was determined to be 1.2 by NMR analysis.

[0607] The mesylate salt was confirmed as a crystalline solid according to XRPD analysis, the XRPD pattern is shown in Figure 10 and the peak data is provided in Table 4.

[0608] The DSC thermogram is shown in Figure 11. The DSC thermogram revealed a first dehydration event with an onset of 24.6°C and a peak temperature of 61.1°C, and a second endothermic event with an onset of 134.4°C and a peak temperature of 150.1°C, which is believed to be the melting / decomposition temperature of the compound.

[0609] The TGA thermogram is shown in Figure 12. A weight loss of 0.65% was observed below 125°C, and significant weight loss occurred above 150°C due to compound decomposition. [Table 6]

[0610] Tosylate salt of formula (I) Preparation of the tosylate salt of formula (I) 121.81 mg of the free base of formula (I) was dissolved in 2 mL of 1:1 dichloromethane (DCM) / methanol in a 4 mL clear glass vial with stirring. To this solution, 67.03 mg of p-toluenesulfonic acid monohydrate (1.2 eq.) was added and mixed well. The solution was allowed to evaporate to an oil overnight at room temperature, uncapped. To the resulting oil, 1 mL of acetonitrile was added with stirring at room temperature to obtain a solution. The solution was allowed to evaporate again to an oil / semi-solid overnight at room temperature, uncapped. 1 mL of acetone was then added and slurried at room temperature for 1 hour until solid. The tosylate salt was collected by filtration, washed with acetone, and dried under vacuum at 50° C. for 1 hour. The salt ratio between the free base and toluenesulfonic acid was determined to be 2.0 by NMR analysis.

[0611] The tosylate salt was confirmed as a crystalline solid according to XRPD analysis, the XRPD pattern is shown in Figure 13 and the peak data is provided in Table 5.

[0612] The DSC thermogram is shown in Figure 14. The DSC thermogram revealed one exothermic event with an onset temperature of 99.6°C and a peak temperature of 110.5°C, and one endothermic event with an onset temperature of 216.1°C and a peak temperature of 218.7°C, which is believed to be the melting / decomposition temperature of the compound.

[0613] The TGA thermogram is shown in Figure 15. A weight loss of 0.76% was observed below 150°C, and significant weight loss occurred above 200°C due to decomposition of the compound. [Table 7]

[0614] Monohydrochloride salt of formula (I) Preparation of the monohydrochloride salt of formula (I) 102.7 mg of the free base of formula (I) was dissolved in 2 mL of 1:1 dichloromethane (DCM) / methanol in a 4 mL clear glass vial with stirring. To this solution, 49 μL of 6 M aqueous hydrochloric acid (1.2 equiv.) was added and mixed well. The solution was allowed to evaporate uncapped at room temperature overnight to a dry solid. To the resulting solid, 1 mL of acetone was added and slurried at room temperature for 1 hour. The monohydrochloride salt was collected by filtration, washed with acetone, and dried in vacuum at 50° C. for 1 hour. The salt ratio between the free base and hydrochloric acid was determined to be 1.08 by ion chromatography analysis.

[0615] The monohydrochloride salt was confirmed as a crystalline solid according to XRPD analysis, the XRPD pattern is shown in Figure 16 and the peak data is provided in Table 6.

[0616] The DSC thermogram is shown in Figure 17. The DSC thermogram revealed one large endothermic event with an onset temperature of 196.0°C and a peak temperature of 212.2°C, which is believed to be the melting / decomposition temperature of the compound.

[0617] The TGA thermogram is shown in Figure 18. A weight loss of 9.4% was observed below 225°C. Weight loss continued above 225°C due to decomposition of the compound. [Table 8]

[0618] Dihydrochloride salt of formula (I) Preparation of the dihydrochloride salt of formula (I) 100.35 mg of the free base of formula (I) was dissolved in 2 mL of 1:1 dichloromethane (DCM) / methanol in a 4 mL clear glass vial with stirring. To this solution, 88 μL of 6 M aqueous hydrochloric acid (2.2 equiv.) was added and mixed well. The solution was allowed to evaporate uncapped at room temperature overnight to 0.2-0.3 mL with solids. 1 mL of acetone was then added and slurried at room temperature for 1 hour. The dihydrochloride salt was collected by filtration, washed with acetone, and dried in vacuum at 50 °C for 1 hour. The salt ratio between the free base and hydrochloric acid was determined to be 1.50 by ion chromatography analysis.

[0619] The dihydrochloride salt was confirmed as a crystalline solid according to XRPD analysis, the XRPD pattern is shown in Figure 19 and the peak data is provided in Table 7.

[0620] The DSC thermogram is shown in Figure 20. The DSC thermogram revealed one large endothermic event with an onset temperature of 182.1°C and a peak temperature of 206.4°C, which is believed to be the melting / decomposition temperature of the compound.

[0621] The TGA thermogram is shown in Figure 21. Weight loss was observed in multiple steps, 8.3% below 175° C. and 7.3% from 170° C. to 240° C. Weight loss continued above 240° C. due to decomposition of the compound. [Table 9-1] [Table 9-2]

[0622] Example 6 Study of formula (I) Solubility measurement The solubility of Form I of compound of formula (I) was measured at 25°C and 50°C.

[0623] Solubility measurements at 25°C were carried out according to the following procedure: 5 mL of solvent (see Table 8) was added to each vial. Form I of the compound of formula (I) was added to the vial to obtain a cloudy solution at 25°C. Another approximately 20 mg of Form I of the compound of formula (I) was added to the cloudy solution. The mixture was stirred at 25±1°C for 48 hours, which was controlled by an IKA® ETS-D5 temperature controller and an IKA® RCT Basic Safety Control. The supernatant was filtered using a syringe filter (0.22 μm). The saturated solution was pipetted into HPLC vials and diluted with MeOH or acetone. The samples were analyzed by HPLC and the corresponding solubilities were calculated as shown in Table 8.

[0624] Solubility measurements at 50°C were performed according to the following procedure: 5 mL of solvent (see Table 8) was added to each vial. Form I of the compound of formula (I) was added to the vial to obtain a cloudy solution at 50°C. Another approximately 20-25 mg of Form I of the compound of formula (I) was added. The mixture was stirred at 50±1°C for 24 hours, which was controlled by an IKA® ETS-D5 temperature controller and an IKA® RCT Basic Safety Control. The supernatant was quickly filtered at 50±1°C using a warmed syringe filter (0.22 μm). The saturated solution was pipetted into HPLC vials and diluted with MeOH or acetone. The samples were analyzed by HPLC and the corresponding solubilities were calculated as shown in Table 8. [Table 10]

[0625] At 25°C, Form I of the compound of formula (I) was well soluble (>50mg / mL) in CHCl3, dimethylformamide (DMF), 1,4-dioxane, 2-methoxyethanol, DMSO, and THF. It was relatively soluble (15mg / mL<solubility<50mg / mL) in dichloromethane, MeOH, acetone, and methyl ethyl ketone. It was slightly soluble (1mg / mL<solubility<15mg / mL) in acetonitrile, methyl iso-butyl ketone, EtOH, n-propanol, iso-propanol, n-butanol, EtOAc, iso-propyl acetate, iso-butyl acetate, ethyl formate, 2-methylTHF, 3% water in EtOH, and 6% water in EtOH. It was sparingly soluble (<1 mg / mL) in toluene, tert-butyl methyl ether (MTBE), water, 2-methyl-THF / H2O / heptane (volume ratio 1:1.5%:1), and 2-methyl-THF / H2O / heptane (volume ratio 1:3%:1). It was completely insoluble in heptane.

[0626] At 50°C, Form I of the compound of formula (I) was highly soluble (>50mg / mL) in CHCl3, dimethylformamide (DMF), 1,4-dioxane, 2-methoxyethanol, DMSO, and THF. It was relatively soluble (15mg / mL<solubility<50mg / mL) in acetonitrile, dichloromethane, MeOH, EtOH, acetone, methyl ethyl ketone, ethyl formate, 2-methylTHF, 3% water in EtOH, and 6% water in EtOH. It was slightly soluble (1mg / mL<solubility<15mg / mL) in methyl iso-butyl ketone, n-propanol, iso-propanol, n-butanol, EtOAc, iso-propyl acetate, and iso-butyl acetate. It was sparingly soluble (<1 mg / mL) in toluene, tert-butyl methyl ether (MTBE), water, 2-methyl-THF / H2O / heptane (volume ratio 1:1.5%:1), and 2-methyl-THF / H2O / heptane (volume ratio 1:3%:1). It was completely insoluble in heptane.

[0627] phase equilibrium Phase equilibration studies were performed to identify the predominant crystalline form for phase identification. Based on its solubility in various solvent systems (Table 8), Form I of the compound of formula (I) was equilibrated at 25±1°C and 50±1°C in a representative group of solvents. Form I of the compound of formula (I) was added to the solvent until a cloudy solution was obtained, and then approximately 20 mg of Form I of the compound of formula (I) was added to the cloudy solution. The mixture was agitated at 25±1°C or 50±1°C for 48 or 24 hours, respectively. The solid was filtered, dried in vacuum, and analyzed by XRPD.

[0628] The resulting material appeared as crystalline Form I upon phase equilibration at 25° C. and 50° C. in all solvents tested. The results are shown in Table 9 (N / A indicates not tested). [Table 11]

[0629] Evaporation Research Evaporation studies were performed to identify the predominant crystalline form during uncontrolled precipitation. XRPD was used to study the solid morphology of the crystalline form of the evaporated samples at 25±1° C. and 50±1° C. The results are shown in Table 10 (N / A indicates that the amount of precipitate was too small to analyze by XRPD). [Table 12]

[0630] The solid of the compound of formula (I) obtained after evaporation in dichloromethane, acetonitrile, ethanol, and IPA at 25° C. has a different XRPD pattern when compared to that of the starting material (Form I of the compound of formula (I)) and is designated as Form II. The solid obtained after evaporation in 1,4-dioxane at 25° C. has a different XRPD pattern when compared to that of Form I and Form II and is designated as Form III.

[0631] Antisolvent addition Saturated and nearly saturated solutions of Form I of the compound of formula (I) were prepared at room temperature in the solvents listed in Table 11. Anti-solvent was added dropwise to induce precipitation. As shown in Table 11, only Form I was observed. [Table 13]

[0632] reverse addition Saturated and nearly saturated solutions of compound of formula (I) Form I were prepared in the solvents listed in Table 12 at 25° C. and added dropwise to a larger volume of miscible antisolvent. As shown in Table 12, no new polymorphic forms were identified in the reverse addition experiments. [Table 14]

[0633] Quenching of saturated solutions Saturated or nearly saturated solutions of compound of formula (I) prepared at 25° C. were rapidly cooled to about −20 to about −30° C. to induce precipitation of the higher energy form. Representative solvents were selected based on solubility data measured at 25° C. and 50° C. As shown in Table 13, Form III solids were observed in 1,4-dioxane. [Table 15]

[0634] Crystallization of saturated solutions using heating and cooling cycles This experiment was carried out to identify a more stable form of the compound of formula (I) than Form I. A saturated solution of the compound of formula (I) was prepared at 50° C. and slowly cooled in a liquid bath by using a programmable circulating liquid bath. To the clear solution, about 10 mg of Form I of the compound of formula (I) was added to obtain a slurry. The formed slurry was then heated at 50° C. for 2 hours and then cooled to 5° C. for 2 hours. This process was repeated for 3 days and the solid was filtered for further analysis. The solvents used were 1,4-dioxane, methanol, or THF. This experiment yielded only Form I.

[0635] Stability Relationship The relative stability of the three forms (Forms I-III) of the compound of formula (I) was studied and compared by phase equilibration experiments of mixtures in three solvent systems (3% water [by volume] in EtOH using 3 volumes of solvent, 3% water in EtOH using 5 volumes of solvent, and 6% water in EtOH using 5 volumes of solvent). The three crystalline forms were mixed and slurried at 50° C. for more than 6 hours. The mixture of the three forms transitioned to Form I in these three specific solvents after 6 hours of stirring of the competitive slurries.

[0636] Example 7 Characterization of Form II Form II of the compound of formula (I) was prepared by evaporation in CH2Cl2, CH3CN, EtOH, and IPA at 25°C (see Example 6, Table 10). Form II (obtained in CH2Cl2) was purified by HPLC, 1 It was characterized by H NMR, XRPD, DSC, and TGA, with the XRPD pattern shown in Figure 22 and the XRPD data provided in Table 14.

[0637] The DSC thermograms are shown in Figure 23. When comparing the DSC of Form I and Form II, it was observed that the Form II solid contained two peaks (Figure 23), with a later peak onset (~191.0 °C) and T max (193.4°C) is the peak onset and T max(Figure 2). Form II transformed into Form I during the heating process (see Example 6).

[0638] The TGA thermogram is shown in FIG. [Table 16]

[0639] Example 8 Characterization of Form III Form III of the compound of formula (I) was prepared by evaporation in 1,4-dioxane at 25° C. (see Example 6, Table 10) and quenching experiments were carried out in 1,4-dioxane (see Example 6, Table 13). Form III was identified by HPLC, 1 It was characterized by H NMR, XRPD, DSC, and TGA, with the XRPD pattern shown in Figure 25 and the XRPD data provided in Table 15.

[0640] quantitative 1 H NMR showed that the residual 1,4-dioxane (wt%) in the solid was approximately 4.98%. The residual solvent could not be removed by conventional drying methods. This suggested that the obtained solid may be a solvate, as supported by TGA experiments (maximum weight loss of 5.00% up to 180° C.; FIG. 27). The stoichiometric ratio of the compound of formula (I) to 1,4-dioxane may be 4:1. DSC of the solid (FIG. 26) showed a peak onset, a later peak onset (≈192.6° C.) and a T max (194.3° C.), which includes the peak onset of Form I (191.3° C.) and the T max (193.3° C.) (FIG. 2). Form III transformed into Form I during the heating process (see Example 6). [Table 17]

[0641] Example A. CDK2 / Cyclin E1 HTRF Enzyme Activity Assay The CDK2 / cyclin E1 enzyme activity assay utilizes full-length human CDK2 co-expressed as an N-terminal GST-tagged protein with FLAG-cyclin E1 in a baculovirus expression system (Carna product number 04-165). The assay was performed in a white 384-well polystyrene plate with a final reaction volume of 8 μL. CDK2 / cyclin E1 (0.25 nM) was incubated with example compounds (40 nL serially diluted in DMSO) in assay buffer (containing 50 mM HEPES (pH 7.5), 1 mM EGTA, 10 mM MgCl2, 2 mM DTT, 0.05 mg / mL BSA, and 0.01% Tween 20) in the presence of ATP (50 μM or 1 mM) and 50 nM ULight™-labeled eIF4E binding protein 1 (THR37 / 46) peptide (PerkinElmer) at room temperature for 60 minutes. The reaction was stopped by the addition of EDTA and europium-labeled anti-phospho 4E-BP1 antibody (PerkinElmer) to final concentrations of 15 mM and 1.5 nM, respectively. HTRF signals were read after 1 h at room temperature on a PHERAstar FS plate reader (BMG Labtech). The IC for each compound was 50 Data was analyzed using 3-parameter or 4-parameter dose-response curves with IDBS XLFit and GraphPad Prism 5.0 software to determine the IC measured for compounds of formula (I) at 1 mM ATP in the assay of Example A. 50 The data are shown in Table 16. [Table 18]

[0642] In addition to those described herein, various modifications of the present invention will become apparent to those skilled in the art from the above description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety.

Claims

1. Equation (I): 【Chemistry 1】 The solid form of the compound, which is crystalline, and is form I.

2. (a) The embodiment has at least four XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0 in a 2-theta (±0.2 degree) range; (b) The embodiment has two theta (±0.2 degrees) and at least four XRPD peaks selected from 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.1; (c) The embodiment has 2 theta (±0.2 degrees) and at least 10 XRPD peaks selected from 7.3, 10.5, 12.8, 14.5, 15.2, 16.4, 20.3, 21.3, 21.6, and 27.0; or (d) The embodiment has a 2-theta (±0.2 degrees) and at least 10 XRPD peaks selected from 7.5, 13.0, 14.7, 15.3, 16.2, 16.6, 20.5, 20.8, 21.4, 23.3, 24.0, and 27.

1. The solid form according to claim 1.

3. The solid form according to claim 1, having an endothermic peak with an initial temperature (±3°C) of 191.7°C and a maximum temperature of 193.6°C.

4. (a) The embodiment has substantially the XRPD pattern shown in Figure 1; (b) The embodiment has substantially the same DSC thermogram as shown in Figure 2; or (c) The above embodiment has a TGA thermogram substantially as shown in Figure 3 The solid form according to claim 1.

5. Equation (I): 【Chemistry 2】 The solid form of the compound, which is crystalline, and is form II.

6. The solid form according to claim 5, wherein the form has two theta (±0.2 degrees) and at least four XRPD peaks selected from 5.8, 7.6, 11.4, 12.5, 14.4, 17.2, 17.9, and 25.

3.

7. The solid form according to claim 5, wherein the form substantially has an XRPD pattern as shown in Figure 22.

8. The solid form according to claim 5, having an endothermic peak with an initial temperature (±3°C) of 191.0°C and a maximum temperature of 193.4°C.

9. Equation (I): 【Transformation 3】 The solid form of the compound, which is crystalline and is of form III.

10. The solid form according to claim 9, wherein the form has at least four XRPD peaks selected from 5.5, 9.8, 10.5, 12.1, 13.9, 16.3, 19.8, 22.0, 24.4, and 27.3, with a 2-theta (±0.2 degree) range.

11. The solid form according to claim 9, wherein the form substantially has an XRPD pattern as shown in Figure 25.

12. The solid form according to claim 9, having an endothermic peak with an initial temperature (±3°C) of 192.6°C and a maximum temperature of 194.3°C.

13. Equation (I): 【Chemistry 4】 A salt of the compound, The compound monomaleate of formula (I) above, Dibesylate of the compound of formula (I) above, The compound monomesylate of formula (I) above, The ditosylate of the compound of formula (I) above, The monohydrochloride salt of the compound of formula (I), and The dihydrochloride salt of the compound of formula (I) above, The salt selected from the above.

14. The salt according to claim 13, which is a crystalline monomaleate of the compound of formula (I).

15. The salt according to claim 14, wherein the salt has at least four XRPD peaks selected from 10.4, 11.6, 12.0, 14.1, 15.1, 17.2, 18.1, 19.1, 21.3, 21.9, 22.9, 24.2, and 25.9 at 2 theta (±0.2 degrees).

16. The salt according to claim 14, having an endothermic peak with an initial temperature (±3°C) of 180.4°C and a maximum temperature (±3°C) of 181.8°C.

17. The salt according to claim 13, which is a crystalline dibesylate salt of the compound of formula (I).

18. The salt according to claim 17, wherein the salt has at least four XRPD peaks selected from 6.3, 9.9, 12.1, 12.6, 15.9, 17.4, 18.7, 19.0, 19.6, and 25.1 at 2 theta (±0.2 degrees).

19. The salt according to claim 17, having an endothermic peak with an initial temperature (±3°C) of 160.4°C and a maximum temperature (±3°C) of 163.4°C.

20. The salt according to claim 13, which is a crystalline monomesylate salt of the compound of formula (I).

21. The salt according to claim 20, wherein the salt has at least four XRPD peaks selected from 4.8, 7.0, 11.9, 14.1, 14.9, 17.7, 18.9, 20.2, 22.1, and 26.1 at 2 theta (±0.2 degrees).

22. The salt according to claim 20, having a first endothermic peak with a maximum temperature (±3°C) of 61.1°C, and a second endothermic peak with an onset temperature (±3°C) of 134.4°C and a maximum temperature (±3°C) of 150.1°C.

23. The salt according to claim 13, which is a crystalline ditosylate of the compound of formula (I).

24. The salt according to claim 23, wherein the salt has at least four XRPD peaks selected from 5.7, 7.8, 8.1, 9.3, 13.7, 13.9, 16.2, 18.8, and 20.6 at 2 theta (±0.2 degrees).

25. The salt according to claim 23, having an exothermic peak with an initial temperature (±3°C) of 99.6°C and a maximum temperature (±3°C) of 110.5°C, and an endothermic peak with an initial temperature (±3°C) of 216.1°C and a maximum temperature (±3°C) of 218.7°C.

26. The salt according to claim 13, which is a crystalline monohydrochloride salt of the compound of formula (I).

27. The salt according to claim 26, wherein the salt has at least four XRPD peaks selected from 5.7, 8.5, 11.3, 14.1, 15.0, 18.4, 19.3, 20.5, 21.8, 22.8, and 25.7 at 2 theta (±0.2 degrees).

28. The salt according to claim 26, having an endothermic peak with an initial temperature (±3°C) of 196.0°C and a maximum temperature (±3°C) of 212.2°C.

29. The salt according to claim 13, which is a crystalline dihydrochloride salt of the compound of formula (I).

30. The salt according to claim 29, wherein the salt has at least four XRPD peaks selected from 9.9, 10.7, 12.3, 13.0, 14.0, 15.2, 19.9, 21.8, 22.3, and 24.8 at 2 theta (±0.2 degrees).

31. The salt according to claim 29, having an endothermic peak with an initial temperature (±3°C) of 182.1°C and a maximum temperature (±3°C) of 206.4°C.

32. A pharmaceutical composition comprising a solid form according to any one of claims 1 to 12 or a salt according to any one of claims 13 to 31, and a pharmaceutically acceptable carrier.

33. A composition for inhibiting CDK2, comprising the solid form described in any one of claims 1 to 12 or the salt described in any one of claims 13 to 31.

34. A pharmaceutical for treating a disease or disorder related to CDK2 in a patient, comprising a solid form according to any one of claims 1 to 12 or a salt according to any one of claims 13 to 31, The disease or disorder is cancer. The aforementioned pharmaceutical.

35. The pharmaceutical agent according to claim 34, wherein the disease or disorder is related to amplification and / or overexpression of the cyclin E1 (CCNE1) gene.

36. A pharmaceutical agent for treating a human subject having a disease or disorder related to cyclin-dependent kinase 2 (CDK2), comprising the solid form described in any one of claims 1 to 12 or the salt described in any one of claims 13 to 31, The aforementioned human subject, (i) (a) Having a nucleotide sequence that encodes a p16 protein, including the amino acid sequence of Sequence ID No. 1, and / or (b) Having a cyclin-dependent kinase inhibitor 2A (CDKN2A) gene lacking one or more inactivating nucleic acid substitutions and / or deletions, (ii) (a) Having amplification of the cyclin E1 (CCNE1) gene, and / or (b) A biological sample obtained from the human subject having a CCNE1 expression level higher than the control CCNE1 expression level, This had been decided previously. The disease or disorder is cancer. The aforementioned pharmaceutical.

37. The human subject is (i) (a) Having a nucleotide sequence that encodes a p16 protein, including the amino acid sequence of Sequence ID No. 1, and / or (b) Having the CDKN2A gene lacking one or more inactivating nucleic acid substitutions and / or deletions, (ii) (a) Having CCNE1 gene amplification The pharmaceutical product according to claim 36, which has been previously determined.

38. A method for assisting the evaluation of the response of a human subject having a disease or disorder related to cyclin-dependent kinase 2 (CDK2) to a solid form according to any one of claims 1 to 12 or a salt according to any one of claims 13 to 31, The aforementioned human subjects have been previously determined to have amplified cyclin E1 (CCNE1) genes and / or a higher CCNE1 expression level than the control expression level of CCNE1. The method comprises measuring the level of phosphorylation of the retinoblastoma (Rb) protein at serine corresponding to amino acid position 780 of SEQ ID NO: 3 in a biological sample obtained from the human subject administered the solid form or the salt, A reduced level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3, compared to a control level of Rb phosphorylation at the serine corresponding to amino acid position 780 of SEQ ID NO: 3, indicates that the human subject responds to the solid form or the salt. The disease or disorder is cancer. The aforementioned method.

39. The pharmaceutical product according to claim 34, wherein the cancer is selected from breast cancer, ovarian cancer, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, fallopian tube cancer, endometrial cancer, gastrointestinal cancer, uterine cancer, urothelial carcinoma, anal cancer, bile duct cancer, small intestine cancer, small intestine adenocarcinoma, small intestine lymphoma, small intestine carcinoid tumor, small intestine Kaposi's sarcoma, small intestine leiomyoma, small intestine hemangioma, small intestine lipoma, small intestine neurofibroma, small intestine fibroma, colorectal cancer, colorectal adenocarcinoma, tubular adenoma, chorioadenoma, colonic hamartoma, colonic leiomyoma, colon cancer, colorectal cancer, rectal cancer, small intestine cancer, esophageal cancer, islet cell carcinoma, liver cancer, hepatocellular carcinoma, pancreatic cancer, and gastric cancer.

40. A preparation process according to any one of claims 1 to 4, comprising cooling a solution of the compound of formula (I) in a solvent component comprising ethanol and water.

41. CH ２ Cl ２ ,CH ３ A process for preparing a solid form according to any one of claims 5 to 8, comprising evaporating a solution of the compound of formula (I) in a solvent selected from CN, EtOH, and IPA at 25°C.

42. A process for preparing a solid form according to any one of claims 9 to 12, comprising evaporating a solution of the compound of formula (I) in 1,4-dioxane at 25°C.

43. A process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the solid form according to any one of claims 1 to 4, or the salt according to any one of claims 13 to 31, Formula (1c): 【Transformation 5】 The compound is given by formula (1b): 【Transformation 6】 The compound or a salt thereof is reacted with a Buchwald coupling reaction to produce formula (1a): 【Transformation 7】 This includes forming a compound of the following, where X １ However, the preparation process is a halo.

44. The compound of formula (1c) above, Formula (1d): 【Transformation 8】 The process according to claim 43, which is prepared by a process comprising reacting a compound or a salt thereof with a halogenating agent to form a compound of formula (1c).

45. The compound of formula (1d) or the salt thereof, Formula 1(e): 【Chemistry 9】 The process according to claim 44, which is prepared by a process comprising reacting the compound with hydroxylamine HCl and a basic component to form the compound of formula (1d) or a salt thereof. 【Request Item 46】 【Chemistry 10】 A compound selected from, or a salt thereof.

47. Formula (1a): 【Chemistry 11】 The compound hemisuccinate.

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