Solid forms of CDK2 inhibitors

Abstract

The compound N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Compound (I)) can be prepared as the free base in various crystalline solid forms and various salt forms, each having one or more solid forms. Methods for preparing specific crystalline forms of the free base and salts of Compound (I) are also disclosed.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 478,413, filed January 4, 2023, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that play a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and selective activation of specific CDKs allows for the proper sequencing of steps in cell cycle progression. CDK activation requires heterodimerization with regulatory subunits known as cyclins. Cell cycle deregulation is a common feature of human cancers.

[0003] Cyclin-dependent kinase 2 (Cdk2) is involved in a range of biological activities. CDK2 is a key cell cycle regulator, active throughout late G1 and S phases. CDK2 participates in the DNA damage response (DDR) via the homologous recombination (HR) pathway. CDK2 also regulates aspects of the apoptotic pathway. Cyclin E1 (CCNE1), cyclin E2 (CCNE2), cyclin A1 (CCNA1), and cyclin A2 (CCNA2), as well as p21Cip1 / Waf1, p27Kip1, and p57Kip2 (cyclin-dependent kinase inhibitors of the cyclin-CDK2 complex), are key regulators of CDK2 activity. Dysregulation of CDK2 binding by cyclin E1, E2, A1, or A2, or the activity of cyclin-dependent kinase inhibitor proteins, can occur in cancer. (See S. Tadesse et al., Drug Discovery Today, Volume 25, Number 2, February 2020)

[0004] Dysregulation of CDK2 can occur through several mechanisms. Amplification and / or overexpression of CCNE1 has been identified in ovarian and breast cancer (see Scaltriti, M. et al., Proc. Natl. Acad. Sci. USA 108, 3761-3766 (2011) and Etemadmoghadam, D. et al., Proc. Natl. Acad. Sci. USA 110, 19489-19494 (2013)). Poor outcomes in gastric, endometrial, and other cancers are associated with overexpression and / or amplification of CCNE1 (see Ooi et al., Hum Pathol. (2017) 61:58-67 and Noske et al., Oncotarget (2017) 8:14794-14805).

[0005] These findings indicate that CDK2 is a potential target for cancers with unregulated CDK2 activity, but no drugs that selectively target CDK2 are currently approved, necessitating the development of new CDK2 inhibitors.

[0006] The structure of one of the inhibitors, referred to herein as "Compound (I)" or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine, is shown below: [ka] or a pharmaceutically acceptable salt thereof. There is a need to develop new salt and / or solid forms of Compound (I) that are suitable for bulk production, formulation, and commercialization. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] S. Tadesse et al.,Drug Discovery Today,Volume 25,Number 2 February 2020 [Non-patent document 2] Scaltriti, M.et al., Proc.Natl Acad.Sci.USA 108, 3761-3766(2011) [Non-patent document 3] Etemadmoghadam, D.et al.Proc.Natl Acad.Sci.USA 110, 19489-19494(2013) [Non-patent document 4] Ooi et al.Hum Pathol.(2017)61:58-67 [Non-patent document 5] Noske et al, Oncotarget(2017)8:14794-14805 Summary of the Invention [Means for solving the problem]

[0008] In a first aspect, the present disclosure provides a crystalline solid form of the free base of Compound (I), wherein Compound (I) is represented by the following structural formula: [ka] This crystalline solid form is referred to as crystalline solid form A and is characterized by an X-ray powder diffraction (XRPD) pattern containing three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 18.1°±0.2, 23.1°±0.2, and 25.1°±0.2.

[0009] In another aspect, the disclosure provides a crystalline solid form of the free base of Compound (I), wherein this crystalline solid form is designated Crystalline Solid Form A, and is characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 21.4°±0.2, 25.1°±0.2, and 27.3°±0.2.

[0010] In another aspect, the present disclosure provides a crystalline solid form of the free base of Compound (I), wherein Compound (I) is represented by the following structural formula: [ka] This crystalline solid form is referred to as crystalline solid form B and is characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 14.9°±0.2, 17.3°±0.2, 23.9°±0.2, and 24.6°±0.2.

[0011] In another aspect, the disclosure provides a crystalline solid form of the free base of Compound (I), wherein this crystalline solid form is designated as crystalline solid form B, and is characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 17.3°±0.2, 21.5°±0.2, 25.3°±0.2, and 29.1°±0.2.

[0012] In another aspect, the present disclosure provides a crystalline solid form of the free base of Compound (I) represented by the following structural formula: [ka] This crystalline solid form is referred to as crystalline solid form C and is characterized by an XRPD pattern comprising three, four, five, or six peaks at diffraction angles (2θ) selected from the group consisting of 8.7°±0.2, 10.6°±0.2, 13.4°±0.2, 15.3°±0.2, 19.0°±0.2, and 25.8°±0.2.

[0013] In another aspect, the present disclosure provides an amorphous form of the free base of Compound (I), represented by the following structural formula: [ka]

[0014] In another aspect, the present disclosure provides a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) represented by the following structural formula: [ka] wherein the salt is selected from the group consisting of methanesulfonate, ethanesulfonate, benzenesulfonate, tosylate, naphthalene-2-sulfonate, glycine salt, succinate, citrate, tartrate, adipate, aspartate, histidine salt, vanillin salt, phosphate, hydrochloride, hydrobromide, nitrate, and sulfate.

[0015] In another aspect, the present disclosure provides a pharmaceutical composition comprising a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, and a pharmaceutically acceptable carrier.

[0016] In another aspect, the present disclosure provides a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein at least 0.1%, 0.5%, 1%, 5% by weight, or more of Compound (I) or a pharmaceutically acceptable salt thereof is present in a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein.

[0017] The present disclosure provides a method of treating a subject having cancer, comprising administering to the subject an effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition of the present disclosure. In one embodiment, the cancer is selected from the group consisting of uterine cancer (including uterine carcinosarcoma (UCS), uterine endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including breast invasive carcinoma in situ (BRCA), TNBC (triple-negative breast cancer), HR+ breast cancer (hormone receptor positive breast cancer), ER+ breast cancer (estrogen receptor positive breast cancer), HR+HER2- breast cancer (hormone receptor positive, human epidermal growth factor 2 negative breast cancer), ER+HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer), HER2- breast cancer (human epidermal growth factor 2 negative breast cancer), HER2- low breast cancer (human epidermal growth factor 2 low level breast cancer), and HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer)), ovarian cancer (e.g. For example, ovarian serous cystadenocarcinoma (OV), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal carcinoma (ESCA)), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma (ACC), or mesothelioma. In some embodiments, the cancer is breast cancer. In one embodiment, the subject has a CCNE1-amplified advanced / recurrent tumor. In one embodiment, the subject has CCNE1-amplified platinum-resistant or platinum-refractory ovarian cancer. In one embodiment, the subject has endometrial cancer (previously treated with platinum therapy, e.g., the patient has been previously treated with platinum therapy) that has progressed after two or more lines of therapy (including platinum therapy). In one embodiment, the subject has CCNE1-amplified endometrial cancer that has failed two or more lines of therapy (which may include previous platinum therapy).In one embodiment, the subject has gastric cancer that has progressed after two or more lines of therapy (including platinum therapy) (previously received platinum therapy, e.g., the patient has been previously treated with platinum therapy). In one embodiment, the subject has ER+ HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors.

[0018] In one embodiment, the cancer described herein (e.g., a cancer described in paragraphs

[0017] ,

[0027] ,

[0148] to

[0157] ,

[0159] , and

[0161] to

[0176] , e.g., breast cancer) to be treated has CCNE1 amplification and / or overexpression.

[0019] In one embodiment, the cancer described herein (e.g., a cancer described in paragraphs

[0017] ,

[0027] ,

[0148] to

[0157] ,

[0159] , and

[0161] to

[0176] , e.g., breast cancer) to be treated does not have CCNE1 amplification and / or overexpression.

[0020] The therapeutic methods disclosed herein further include administering to a patient a therapeutically effective amount of palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., Giotrif®), osimertinib (e.g., ribozyme), ...ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozyme (e.g., ribozyme), ribozy , Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), EGFR inhibitors, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, beruzosertib, selalasertib, SRA-737, LY2603618 (ravusertib), or trastuzumab (e.g., Herceptin®), or a combination thereof, are administered to the subject. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST2818), aumoretinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, and nafatinib. It may be selected from zarutinib (EGF816), avitinib, PCC-0208027, resivertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759) or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, necitumumab, HLX07, JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372)).

[0021] The present disclosure provides a method of inhibiting CDK2 in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition of the present disclosure.

[0022] The present disclosure also provides the use of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition of the present disclosure, for the preparation of a medicament for the treatment of cancer.

[0023] In another aspect, provided herein is a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition of the disclosure, for use in the treatment of cancer.

[0024] In one aspect, the disclosure provides a method of treating a subject having or at risk of developing a disease or disorder associated with CDK2, comprising administering a therapeutically effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein to the subject, wherein the subject has amplification of the CCNE1 gene and / or has a CCNE1 expression level higher than a control expression level of CCNE1. In some embodiments, the CDK2-associated disease or disorder is cancer.

[0025] The present disclosure also provides a method of treating a subject having or at risk of developing a disease or disorder associated with CDK2, comprising administering to the subject a therapeutically effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein, wherein the subject has amplification of the CCNE1 gene and / or has an expression level of CCNE1 similar to a control expression level of CCNE1. In some embodiments, the disease or disorder associated with CDK2 is cancer.

[0026] Also provided herein is a method of treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein.

[0027] Contemplated solid tumor cancers may be at least one of the following: uterine cancer (including uterine carcinosarcoma, uterine endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including breast invasive carcinoma, TNBC (triple-negative breast cancer), ER (estrogen receptor)+HER2 (human epidermal growth factor 2)- breast cancer, HR (hormone receptor)+HER2 (human epidermal growth factor 2)- breast cancer, HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), tumor), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma and esophageal adenocarcinoma), bladder cancer (including bladder urothelial carcinoma (BLCA)), lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), bile duct carcinoma, adrenocortical carcinoma, or mesothelioma.

[0028] In another aspect, provided herein is a method for preparing Compound (I), comprising: [ka] A first compound represented by formula (1): [ka] and a second compound represented by formula (2): [ka] wherein reacting the first and second compounds further comprises a base to activate the diamine compound (2), which then reacts with the heteroaryl chloride compound (1). [Brief explanation of the drawings]

[0029] [Figure 1] 1 is a powder X-ray diffraction (XRPD) pattern from 4 to 30 degrees 2θ, designated as Pattern A, obtained from the free base of Compound (I), designated as crystalline solid Form A.

[0030] [Figure 2] 2 is a differential scanning calorimetry (DSC) thermogram of the material analyzed in FIG. 1 obtained from a sample of Compound (I) free base designated as crystalline solid form A.

[0031] [Figure 3] 1 is an XRPD pattern, designated Pattern B, obtained from the free base of Compound (I), designated crystalline solid Form B.

[0032] [Figure 4] 4 is a DSC thermogram of the material tested in FIG. 3 obtained from a sample of Compound (I) designated as crystalline solid form B.

[0033] [Figure 5] 1 is an XRPD pattern, designated Pattern C, obtained from the free base of Compound (I), designated crystalline solid Form C.

[0034] [Figure 6] 6 is a DSC thermogram of the material analyzed in FIG. 5 obtained from a sample of Compound (I) free base designated as crystalline solid form C.

[0035] [Figure 7] 1 is an XRPD pattern, designated Pattern D, obtained from the free base of Compound (I), designated as crystalline solid Form D.

[0036] [Figure 8] 6 is a simultaneous thermogravimetric analysis (TGA) / DSC thermogram of the material tested in FIG. 5 obtained from a sample of Compound (I) designated crystalline solid form D.

[0037] [Figure 9] 1 is an XRPD pattern, designated pattern E+A+B, obtained from the free base of Compound (I), designated crystalline solid form E+A+B. Peaks marked with an asterisk represent only the most prominent form of pattern E.

[0038] [Figure 10] 10 is a simultaneous TGA / DSC thermogram of the material tested in FIG. 9 obtained from a sample of Compound (I) designated as crystalline solid form E+A+B.

[0039] [Figure 11] 1 is an XRPD pattern, designated Pattern F, obtained from the free base of Compound (I), designated crystalline solid form F.

[0040] [Figure 12] FIG. 1 is a schematic diagram providing exemplary conditions for converting between different crystalline solid forms of the free base of Compound (I).

[0041] [Figure 13] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 6-B, obtained from the tosylate salt of Compound (I), designated crystalline solid form 6-B.

[0042] [Figure 14] 14 is a DSC thermogram of the material analyzed in FIG. 13 obtained from a sample of the tosylate salt of Compound (I) designated crystalline solid form 6-B.

[0043] [Figure 15] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 6-C, obtained from the tosylate salt of Compound (I), designated crystalline solid form 6-C.

[0044] [Figure 16] 16 is a DSC thermogram of the material analyzed in FIG. 15 obtained from a sample of the tosylate salt of Compound (I), designated crystalline solid form 6-C.

[0045] [Figure 17] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 6-D, obtained from the tosylate salt of Compound (I), designated crystalline solid form 6-D.

[0046] [Figure 18] 18 is a DSC thermogram of the material tested in FIG. 17 obtained from a sample of the tosylate salt of Compound (I) designated crystalline solid form 6-D.

[0047] [Figure 19] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 7-A, obtained from the ethanesulfonic acid salt of Compound (I), designated crystalline solid form 7-A.

[0048] [Figure 20]19 is a DSC thermogram of the material analyzed in FIG. 19 obtained from a sample of the ethanesulfonic acid salt of Compound (I), designated crystalline solid form 7-A.

[0049] [Figure 21] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 8-A, obtained from the naphthalene-2-sulfonate salt of Compound (I), designated crystalline solid form 8-A.

[0050] [Figure 22] 22 is a DSC thermogram of the material analyzed in FIG. 21 obtained from a sample of the naphthalene-2-sulfonate salt of Compound (I) designated as crystalline solid form 8-A.

[0051] [Figure 23] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 1-B, obtained from the HCl salt of Compound (I), designated crystalline solid form 1-B.

[0052] [Figure 24] 24 is a simultaneous TGA / DSC thermogram of the material tested in FIG. 23 obtained from a sample of the HCl salt of Compound (I) designated as crystalline solid form 1-B.

[0053] [Figure 25] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 2-A, obtained from the HBr salt of Compound (I), designated crystalline solid form 2-A.

[0054] [Figure 26] 1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 3-A, obtained from the besylate salt of Compound (I), designated crystalline solid form 3-A.

[0055] [Figure 27]1 is an XRPD pattern from 4 to 30 degrees 2θ, designated Pattern 4-A, obtained from the mesylate salt of Compound (I), designated crystalline solid form 4-A. DETAILED DESCRIPTION OF THE INVENTION

[0056] Provided herein, in part, is a crystalline solid form of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (herein Compound (I)), represented by the following structural formula: [ka]

[0057] The term "crystalline solid Form A" when used alone refers to the crystalline polymorph Form A of Compound (I). The terms "crystalline solid Form A," "crystalline Form A," "solid Form A," "pattern A," "form A," "Form A of Compound (I)," or "Form A of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine" are used interchangeably. Form A can be characterized, for example, by XRPD alone or in combination with any one or more of DSC and TGA.

[0058] The term "crystalline solid Form B" when used alone refers to the crystalline polymorph Form B of Compound (I). The terms "crystalline solid Form B," "crystalline Form B," "solid Form B," "pattern B," "Form B," "Form B of Compound (I)," or "Form B of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine" are used interchangeably. Form B can be characterized, for example, by XRPD alone or in combination with any one or more of DSC and TGA.

[0059] The term "crystalline solid Form C" when used alone refers to crystalline polymorph Form C of Compound (I). The terms "crystalline solid Form C," "crystalline Form C," "solid Form C," "pattern C," "form C," "form C of Compound (I)," or "form C of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine" are used interchangeably. Form C can be characterized, for example, by XRPD alone or in combination with any one or more of DSC and TGA.

[0060] The term "crystalline solid Form D" when used alone refers to crystalline polymorph Form D of Compound (I). The terms "crystalline solid Form D," "crystalline Form D," "solid Form D," "pattern D," "Form D," "Form D of Compound (I)," or "Form D of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine" are used interchangeably. Form D can be characterized, for example, by XRPD alone or in combination with any one or more of DSC and TGA.

[0061] The term "crystalline solid Form E" when used alone refers to crystalline polymorph Form E of Compound (I). The terms "crystalline solid Form E," "crystalline Form E," "solid Form E," "pattern E," "form E," "form E of Compound (I)," or "form E of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine" are used interchangeably. Form E can be characterized, for example, by XRPD alone or in combination with any one or more of DSC and TGA.

[0062] The term "crystalline solid Form F" when used alone refers to crystalline polymorph Form F of Compound (I). The terms "crystalline solid Form F," "crystalline Form F," "solid Form F," "pattern F," "form F," "form F of Compound (I)," or "form F of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine" are used interchangeably. Form F can be characterized, for example, by XRPD alone or in combination with any one or more of DSC and TGA.

[0063] As used herein, the term "crystalline" refers to a solid having a crystal structure in which the individual molecules have a highly uniform and regular three-dimensional organization.

[0064] The solid-state order of a solid can be determined by standard techniques known in the art, such as X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or dynamic vapor sorption (DVS). Amorphous solids can also be distinguished from crystalline solids by birefringence, for example, using polarized light microscopy. Amorphous solids consist of a disordered arrangement of molecules and do not have a distinct crystal lattice.

[0065] Relative intensity is calculated as the ratio of the peak intensity of the peak of interest to the peak intensity of the largest peak. In certain embodiments, the relative intensity of peaks can vary due to preferred orientation of the sample. Preferred orientation in the sample affects the intensity of various reflections, making some more intense and others weaker than would be expected from a completely random sample. Typically, many crystalline particle morphologies tend to give samples that exhibit some degree of preferred orientation in the sample holder. This is particularly evident for needle-like or plate-like crystals, where size reduction produces finer needles or platelets.

[0066] In some embodiments, Form A is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure. The purity of Form A is determined by dividing the weight of Form A of Compound (I) in a composition comprising Compound (I) by the total weight of Compound (I) in the composition.

[0067] In some embodiments, Form B is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure. The purity of Form B is determined by dividing the weight of Form B of Compound (I) in a composition comprising Compound (I) by the total weight of Compound (I) in the composition.

[0068] In some embodiments, Form C is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure. The purity of Form C is determined by dividing the weight of Form C of Compound (I) in a composition comprising Compound (I) by the total weight of Compound (I) in the composition.

[0069] In some embodiments, Form D is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure. The purity of Form D is determined by dividing the weight of Form D of Compound (I) in a composition comprising Compound (I) by the total weight of Compound (I) in the composition.

[0070] In some embodiments, Form E is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure. The purity of Form E is determined by dividing the weight of Form E of Compound (I) in a composition comprising Compound (I) by the total weight of Compound (I) in the composition.

[0071] In some embodiments, Form F is at least 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% pure. The purity of Form F is determined by dividing the weight of Form F of Compound (I) in a composition comprising Compound (I) by the total weight of Compound (I) in the composition.

[0072] When a crystalline Compound (I) salt or free base is defined as a specified percentage of one particular crystalline form of Compound (I) salt or free base, the remainder is made up of amorphous and / or crystalline forms other than the one or more specific forms identified. Solid Form of the Free Base of Compound (I)

[0073] In some embodiments, the solid forms disclosed herein comprise the free base of Compound (I): [ka]

[0074] The free base form of Compound (I) can exist in an amorphous solid form or in different solid forms, or a mixture of solid forms, which may additionally contain one or more equivalents of water (e.g., anhydrous or hydrated forms). In some embodiments, the free base solid form of Compound (I) is amorphous. As provided herein, crystalline solid form(s) of Compound (I) can be identified by an XRPD pattern containing distinct XRPD peaks, for example, characteristic diffraction peaks at 2θ angles. In some embodiments, the crystalline solid form of Compound (I) is the free base. In some embodiments, the crystalline solid form of Compound (I) is the anhydrous free base. Provided herein are specific crystalline solid forms of the free base of Compound (I) and related methods of preparing and using these solid form materials.

[0075] In one aspect, provided herein is a first crystalline solid form of the free base of Compound (I), referred to as crystalline solid Form A. In some embodiments, Form A is anhydrous. In some embodiments, provided herein is a crystalline solid form of the free base of Compound (I), wherein Compound (I) is represented by the following structural formula: [ka] This crystalline solid form is referred to as crystalline solid form A and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 18.1°±0.2, 23.1°±0.2, and 25.1°±0.2. In some embodiments, provided herein is a crystalline solid form of the free base of Compound (I), referred to as crystalline solid form A and characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 21.4°±0.2, 25.1°±0.2, and 27.3°±0.2. In some embodiments, crystalline solid form A is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, or 10 peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 18.1°±0.2, 19.1°±0.2, 21.4°±0.2, 23.1°±0.2, 25.1°±0.2, 26.6°±0.2, 27.3°±0.2, and 29.4°±0.2. In some embodiments, crystalline solid form A is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.3°±0.2, 17.6°±0.2, 18.1°±0.2, 18.8°±0.2, 19.0°±0.2, 19.1°±0.2, 21.0°±0.2, 21.4°±0.2, 23.1°±0.2, 25.1°±0.2, 25.5°±0.2, 26.6°±0.2, 27.3°±0.2, and 29.4°±0.2. In some embodiments, crystalline solid form A is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 5.9°±0.2, 17.6°±0.2, 21.4°±0.2, 23.1°±0.2, and 25.1°±0.2. In some embodiments, crystalline solid form A is also characterized by an XRPD pattern substantially similar to FIG.

[0076] Table 1A lists the XRPD (2-theta) peaks obtained from a sample of crystalline solid Form A of the free base of Compound (I). In some embodiments, crystalline solid Form A is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 1A. [Table 1]

[0077] In some embodiments, crystalline solid form A is also characterized by a differential scanning calorimetry (DSC) thermogram having two endotherms with onset peaks at 186.2±2° C. and 197.5±2° C. In some embodiments, crystalline solid form A is also characterized by a DSC thermogram substantially similar to FIG.

[0078] In one aspect, provided herein is a second crystalline solid form of the free base of Compound (I), referred to as crystalline solid Form B. In some embodiments, Form B is anhydrous. In some embodiments, provided herein is a crystalline solid form of the free base of Compound (I), wherein Compound (I) is represented by the following structural formula: [ka] This crystalline solid form is referred to as crystalline solid form B and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 14.9°±0.2, 17.3°±0.2, 23.9°±0.2, and 24.6°±0.2. In some embodiments, provided herein is a crystalline solid form of the free base of Compound (I), which is referred to as crystalline solid form B and is characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 17.3°±0.2, 21.5°±0.2, 25.3°±0.2, and 29.1°±0.2. In some embodiments, crystalline solid form B is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, or 10 peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 14.9°±0.2, 17.3°±0.2, 19.5°±0.2, 21.0°±0.2, 21.5°±0.2, 23.9°±0.2, 24.6°±0.2, 25.3°±0.2, and 29.1°±0.2. In some embodiments, crystalline solid form B is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 12.6°±0.2, 14.9°±0.2, 17.3°±0.2, 17.8°±0.2, 18.6°±0.2, 19.5°±0.2, 21.0°±0.2, 21.5°±0.2, 23.3°±0.2, 23.9°±0.2, 24.6°±0.2, 25.3°±0.2, 28.9°±0.2, and 29.1°±0.2. In some embodiments, crystalline solid form B is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 5.8°±0.2, 17.3°±0.2, 21.5°±0.2, 25.3°±0.2, and 29.1°±0.2. In some embodiments, crystalline solid form B is also characterized by an XRPD pattern substantially similar to that of FIG.

[0079] Table 2A lists the XRPD (2-theta) peaks obtained from a sample of crystalline solid Form B of the free base of Compound (I). In some embodiments, crystalline solid Form B is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 2A. [Table 2]

[0080] In some embodiments, crystalline solid form B is also characterized by a DSC thermogram having a broad endotherm with an onset peak at 198.5±2° C. In some embodiments, crystalline solid form B is also characterized by a DSC thermogram substantially similar to FIG.

[0081] In one aspect, provided herein is a third crystalline solid form of the free base of Compound (I), referred to as crystalline solid form C. In some embodiments, crystalline solid form C is anhydrous. In some embodiments, provided herein is a crystalline solid form of the free base of Compound (I), which is a crystalline solid form of the free base of Compound (I) represented by the following structural formula: [ka] This crystalline solid form is referred to as crystalline solid form C and is characterized by an XRPD pattern comprising three, four, five, or six peaks at diffraction angles (2θ) selected from the group consisting of 8.7°±0.2, 10.6°±0.2, 13.4°±0.2, 15.3°±0.2, 19.0°±0.2, and 25.8°±0.2. In some embodiments, crystalline solid form C is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, or 10 peaks at diffraction angles (2θ) selected from the group consisting of 8.7°±0.2, 10.6°±0.2, 13.4°±0.2, 15.3°±0.2, 16.2°±0.2, 19.0°±0.2, 19.8°±0.2, 21.4°±0.2, 22.6°±0.2, and 25.8°±0.2. In some embodiments, crystalline solid form C is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 8.7°±0.2, 15.3°±0.2, and 25.8°±0.2. In some embodiments, crystalline solid form C is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 8.7°±0.2, 15.3°±0.2, 19.0°±0.2, 19.8°±0.2, and 25.8°±0.2. In some embodiments, crystalline solid form C is also characterized by an XRPD pattern substantially similar to that shown in FIG.

[0082] Table 3A lists the XRPD (2-theta) peaks obtained from a sample of crystalline solid Form C of the free base of Compound (I). In some embodiments, crystalline solid Form C is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 3A or 3B. [Table 3]

[0083] In some embodiments, crystalline solid form C is also characterized by a DSC thermogram having three broad endotherms with onset peaks at 30.6±2° C., 170.5±2° C., and 198.4±2° C. and two broad exotherms with onset peaks at 176.8±2° C. and 253.7±2° C. In some embodiments, crystalline solid form C is also characterized by a DSC thermogram having two broad endotherms with onset peaks at 170.5±2° C. and 198.4±2° C., and optionally two broad exotherms with onset peaks at 176.8±2° C. and 253.7±2° C. In some embodiments, crystalline solid form C is also characterized by a DSC thermogram substantially similar to FIG. 6.

[0084] In one aspect, provided herein is a fourth crystalline solid form of the free base of Compound (I), designated crystalline solid form D. In some embodiments, crystalline solid form D is a hydrate. In some embodiments, crystalline solid form D is characterized by an XRPD pattern substantially similar to that of Figure 7.

[0085] Tables 4A-4D list the XRPD (2-theta) peaks obtained from a sample of crystalline solid Form D of the free base of Compound (I). In some embodiments, crystalline solid Form D is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 4A, 4B, 4C, or 4D (up to the maximum number of peaks in each table). [Table 4]

[0086] In some embodiments, crystalline solid form D is also characterized by a DSC thermogram having a broad endotherm with an onset peak at 198.9±2° C. In some embodiments, crystalline solid form D is also characterized by a DSC thermogram substantially similar to FIG.

[0087] In one aspect, provided herein is a fifth crystalline solid form of the free base of Compound (I), designated crystalline solid form E. In some embodiments, crystalline solid form E is a hydrate.

[0088] In some embodiments, crystalline solid form E is a mixture of crystalline solid forms A and B and is characterized by an XRPD pattern substantially similar to FIG.

[0089] Tables 5A-5D list the XRPD (2-theta) peaks obtained from a sample of crystalline solid Form E of the free base of Compound (I). In some embodiments, crystalline solid Form E is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 5A, 5B, 5C, or 5D (up to the maximum number of peaks in each table). [Table 5]

[0090] In some embodiments, crystalline solid form E is also characterized by a DSC thermogram comprising two broad endotherms with onset peaks at 89.9±2° C. and 199.9±2° C. In some embodiments, crystalline solid form E is also characterized by a DSC thermogram having two broad endotherms with onset peaks at 89.9±2° C. and 100.6±2° C., and optionally 190.9±2° C. In some embodiments, crystalline solid form E is also characterized by a DSC thermogram having four broad endotherms with onset peaks at 89.9±2° C., 100.1±2° C., 190.9±2° C., and 199.9±2° C., and a broad exotherm with an onset peak at 242.0±2° C. In some embodiments, crystalline solid form E is also characterized by a DSC thermogram substantially similar to FIG. 10.

[0091] In one aspect, provided herein is a sixth crystalline solid form of the free base of Compound (I), designated crystalline solid form F. In some embodiments, crystalline solid form F is a hydrate.

[0092] In some embodiments, crystalline Form F is characterized by an XRPD pattern substantially similar to that of FIG.

[0093] Tables 6A-6D list the XRPD (2-theta) peaks obtained from a sample of crystalline solid Form F of the free base of Compound (I). In some embodiments, crystalline solid Form F is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 6A, 6B, 6C, or 6D (up to the maximum number of peaks in each table). [Table 6]

[0094] In another aspect, the present disclosure provides an amorphous form of the free base of Compound (I), represented by the following structural formula: [ka]

[0095] In one aspect, provided herein is a method for purifying Compound (I), represented by the following structural formula: [ka] recrystallizing said compound (I) in a solvent mixture to obtain a crystalline solid form of compound (I).

[0096] In some embodiments, the crystalline solid forms disclosed herein are obtained by a process comprising one or both of the following steps: a. dissolving the solid form in a solvent mixture to form a solution; and b. Cooling crystallization in said solvent mixture.

[0097] In some embodiments, the solvent mixture is selected from a solvent mixture comprising acetone, diethyl ether, ethanol, ethyl acetate, n-heptane, isopropyl alcohol, methanol, and trifluoroethanol.

[0098] In some embodiments, the crystalline solid Form A of the free base is obtained by a process comprising recrystallizing Compound (I) in a solvent mixture comprising methanol, water, and optionally ethanol.

[0099] In some embodiments, the crystalline solid form A of the free base is obtained by a process further comprising one or both of the following steps: a. dissolving compound (I) in methanol at elevated temperature to form a solution; and b. Evaporation and cooling crystallization in a solvent mixture containing methanol, ethanol, and water.

[0100] In some embodiments, the crystalline solid Form A of the free base is obtained by a process comprising recrystallizing Compound (I) in a solvent mixture comprising acetone and n-heptane.

[0101] In some embodiments, the crystalline solid form A of the free base is obtained by a process further comprising one or both of the following steps: a. dissolving compound (I) in acetone at elevated temperature to form a solution; and b. Evaporation and cooling crystallization in a solvent mixture containing acetone and n-heptane.

[0102] In some embodiments, the crystalline solid form B of the free base is obtained by a process comprising one or both of the following steps: a. dissolving compound (I) in a solvent mixture at elevated temperature to form a solution; and b. Evaporating the solvent mixture.

[0103] In some embodiments, the solvent mixture is selected from a solvent mixture comprising acetone, acetonitrile, ethanol, ethyl acetate, isopropyl acetate, isopropyl alcohol, and 2-methyltetrahydrofuran.

[0104] In some embodiments, the crystalline solid form B of the free base is obtained by a process comprising one or both of the following steps: a. dissolving compound (I) in acetone at elevated temperature to form a solution; and b. Evaporating the acetone.

[0105] In some embodiments, the free base crystalline solid form B is obtained by a process comprising heating Compound (I) at an elevated temperature. In some embodiments, crystalline solid form A, form C, form D, or form E of the free base is heated at an elevated temperature to obtain crystalline solid form B of the free base. In some embodiments, the elevated temperature is at least about 150°C. In some embodiments, the elevated temperature is about 150°C, about 187°C, or about 195°C. In some embodiments, the free base crystalline solid form D or form F is dried overnight at about 50°C to obtain crystalline solid form B of the free base.

[0106] In some embodiments, the crystalline solid form C of the free base is obtained by a process comprising one or both of the following steps: a. dissolving compound (I) in a solvent mixture comprising acetonitrile and water; and b.Lyophilization.

[0107] In some embodiments, a process for converting between different crystalline solid forms of the free base of Compound (I) is shown in the schematic diagram of FIG. Compound (I) solid salt form

[0108] In another aspect, the present disclosure provides a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) represented by the following structural formula: [ka]

[0109] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic reaction, within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmacologically acceptable salts in J.Pharm.Sci., 1977, 66, 1-19.

[0110] In some embodiments, the present specification provides a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) represented by the following structural formula: [ka] wherein the salt is selected from the group consisting of methanesulfonate, ethanesulfonate, benzenesulfonate, tosylate, naphthalene-2-sulfonate, glycine salt, succinate, citrate, tartrate, adipate, aspartate, histidine salt, vanillin salt, phosphate, hydrochloride, hydrobromide, nitrate, and sulfate. In some embodiments, the crystalline solid form comprises a pharmaceutically acceptable salt of Compound (I) selected from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-4-sulfonic acid, naphthalene-2-sulfonic acid, hydrochloric acid, hydrobromide, nitric acid, and sulfuric acid. In some embodiments, the crystalline solid form is a methanesulfonic acid salt or a methanesulfonate salt. In some embodiments, the crystalline solid form is an ethanesulfonic acid salt or an ethanesulfonate salt. In some embodiments, the crystalline solid form is a benzenesulfonic acid salt or a besylate salt. In some embodiments, the crystalline solid form is a salt of toluene-4-sulfonic acid or a tosylate salt. In some embodiments, the crystalline solid form is a salt of naphthalene-2-sulfonic acid or a naphthalene-2-sulfonate salt. In some embodiments, the crystalline solid form is a salt of succinic acid or a succinate salt. In some embodiments, the crystalline solid form is a salt of citric acid or a citrate salt. In some embodiments, the crystalline solid form is a salt of succinic acid or a succinate salt. In some embodiments, the crystalline solid form is a salt of tartaric acid or a tartrate salt. In some embodiments, the crystalline solid form is a salt of adipic acid or an adipic acid salt. In some embodiments, the crystalline solid form is a salt of aspartic acid or an aspartate salt. In some embodiments, the crystalline solid form is a salt of phosphoric acid or a phosphate salt. In some embodiments, the crystalline solid form is a salt of hydrochloric acid or a hydrochloride salt. In some embodiments, the crystalline solid form is a salt of hydrobromic acid or a hydrobromide salt. In some embodiments, the crystalline solid form is a salt of nitric acid or a nitrate salt. In some embodiments, the crystalline solid form is a salt of sulfuric acid or a sulfate salt. In some embodiments, the crystalline solid form is a salt of vanillin. In some embodiments, the crystalline solid form is a salt of histidine.In some embodiments, the crystalline solid form is a salt of glycine.

[0111] In some embodiments, the crystalline solid form is a tosylate salt form.

[0112] In one aspect, disclosed herein is crystalline Compound (I) tosylate Form 6-B. In one embodiment, crystalline Compound (I) tosylate Form 6-B is characterized by an XRPD pattern substantially similar to Figure 13. In some embodiments, crystalline Compound (I) tosylate Form 6-B is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 7A, 7B, 7C, or 7D (up to the maximum number of peaks in each table). [Table 7]

[0113] In some embodiments, crystalline tosylate Form 6-B is also characterized by a DSC thermogram comprising two broad endotherms with onset peaks at 157.3±2° C. and 185.8±2° C. In one embodiment, crystalline Compound (I) tosylate Form 6-B has a DSC with five broad endotherms with onset peaks at 30.8±2° C., 102.5±2° C., 106.3±2° C., 157.3±2° C., and 185.8±2° C., and two exotherms with onset peaks at 173.1±2° C. and 177.6±2° C. In one embodiment, crystalline Compound (I) tosylate Form 6-B has a DSC substantially similar to the DSC shown in FIG. 14.

[0114] In one aspect, disclosed herein is crystalline Compound (I) tosylate Form 6-C. In some embodiments, the crystalline solid form is referred to as crystalline tosylate Form 6-C and is characterized by one or both of the following: a) an XRPD pattern substantially similar to Figure 15; and b) a DSC having an endotherm with an onset peak at 165.5±2°C. In one embodiment, crystalline Compound (I) tosylate Form 6-C is characterized by an XRPD pattern substantially similar to Figure 15. In some embodiments, crystalline Compound (I) tosylate Form 6-C is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks (up to the maximum number of peaks in each table) selected from Table 8A, 8B, 8C, or 8D. [Table 8]

[0115] In some embodiments, crystalline tosylate salt Form 6-C is also characterized by a DSC thermogram comprising an endotherm with an onset peak at 165.5±2° C. In one embodiment, crystalline Compound (I) tosylate salt Form 6-C has a DSC substantially similar to the DSC shown in FIG.

[0116] In one aspect, disclosed herein is crystalline Compound (I) tosylate Form 6-D. In one embodiment, crystalline Compound (I) tosylate Form 6-D is characterized by an XRPD pattern substantially similar to Figure 17. In some embodiments, crystalline Compound (I) tosylate Form 6-D is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 9A, 9B, 9C, or 9D (up to the maximum number of peaks in each table). [Table 9]

[0117] In some embodiments, crystalline tosylate salt Form 6-D is also characterized by a DSC thermogram comprising two broad endotherms with onset peaks at 172.3±2° C. and 195.3±2° C. In some embodiments, tosylate salt Form 6-D is also characterized by a DSC thermogram comprising two broad endotherms with onset peaks at 172.3±2° C. and 195.3±2° C., and a broad exotherm with onset peak at 177.9±2° C. In one embodiment, crystalline Compound (I) tosylate salt Form 6-D has a DSC / TGA substantially similar to the DSC shown in FIG.

[0118] In some embodiments, the crystalline solid form is an ethanesulfonate salt form.

[0119] In one aspect, disclosed herein is crystalline Compound (I) ethanesulfonate salt Form 7-A. In some embodiments, the crystalline solid form is designated crystalline tosylate salt Form 7-A and is characterized by one or both of the following: a) an XRPD pattern substantially similar to Figure 19; and b) a DSC having an endotherm with an onset peak at 183.8±2°C. In one embodiment, crystalline Compound (I) ethanesulfonate salt Form 7-A is characterized by an XRPD pattern substantially similar to Figure 19. In one embodiment, crystalline Compound (I) ethanesulfonate salt Form 7-A is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 10A, 10B, 10C, or 10D (up to the maximum number of peaks in each table). [Table 10]

[0120] In some embodiments, crystalline ethanesulfonate salt Form 7-A is also characterized by a DSC thermogram comprising an endotherm with an onset peak at 183.8±2° C. In one embodiment, crystalline Compound (I) ethanesulfonate salt Form 7-A has a DSC with two broad endotherms with onset peaks at 163.9±2° C. and 183.8±2° C. In one embodiment, crystalline Compound (I) tosylate salt Form 7-A has a DSC substantially similar to the DSC shown in FIG.

[0121] In some embodiments, the crystalline solid form is a naphthalene-2-sulfonate salt form.

[0122] In one aspect, disclosed herein is crystalline Compound (I) naphthalene-2-sulfonate Form 8-A. In one embodiment, crystalline Compound (I) naphthalene-2-sulfonate Form 8-A is characterized by an XRPD pattern substantially similar to Figure 21. In some embodiments, the crystalline solid form is designated crystalline naphthalene-2-sulfonate Formula 8-A and is characterized by one or both of the following: a) an XRPD pattern substantially similar to Figure 21; and b) a DSC having an endotherm with an onset peak at 199.9 ± 2 °C. In one embodiment, crystalline Compound (I) naphthalene-2-sulfonate Form 8-A is characterized by an XRPD pattern containing at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 11A, 11B, or 11C (up to the maximum number of peaks in each table). [Table 11]

[0123] In one embodiment, crystalline Compound (I) naphthalene-2-sulfonate Form 8-A has a DSC with a broad endotherm with an onset peak at 199.9±2° C. In one embodiment, crystalline Compound (I) naphthalene-2-sulfonate Form 8-A has a DSC substantially similar to the DSC shown in FIG.

[0124] In some embodiments, the crystalline solid form is a hydrochloride salt form.

[0125] In one aspect, disclosed herein is crystalline Compound (I) HCl salt Form 1-B. In some embodiments, the crystalline solid form is designated crystalline hydrochloride salt Form 1-B and is characterized by one or both of the following: a) an XRPD pattern substantially similar to Figure 23; and b) a DSC having an endotherm with an onset peak at 199.7±2°C. In one embodiment, crystalline Compound (I) HCl salt Form 1-B is characterized by an XRPD pattern substantially similar to Figure 23. In one embodiment, crystalline Compound (I) HCl salt Form 1-B is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 12A, 12B, 12C, or 12D (up to the maximum number of peaks in each table). [Table 12]

[0126] In one embodiment, crystalline Compound (I) HCl salt Form 1-B has a DSC comprising a broad endotherm with an onset peak at 199.7±2° C. In one embodiment, crystalline Compound (I) hydrochloride Form 1-B has a DSC with two broad endotherms with onset peaks at 199.7±2° C. and 204.2±2° C. In one embodiment, crystalline Compound (I) HCl salt Form 1-B has a DSC substantially similar to the TGA / DSC shown in FIG. 24.

[0127] In some embodiments, the crystalline solid form is a hydrobromide salt form.

[0128] In one aspect, disclosed herein is crystalline Compound (I) HBr salt Form 2-A. In one embodiment, crystalline Compound (I) HBr salt Form 2-A is characterized by an XRPD pattern substantially similar to Figure 25. In one embodiment, crystalline Compound (I) HBr salt Form 2-A is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 13A, 13B, 13C, or 13D (up to the maximum number of peaks in each table). [Table 13]

[0129] In some embodiments, the crystalline solid form is a besylate salt form.

[0130] In one aspect, disclosed herein is crystalline Compound (I) besylate Form 3-A. In one embodiment, crystalline Compound (I) besylate Form 3-A is characterized by an XRPD pattern substantially similar to Figure 26. In one embodiment, crystalline Compound (I) besylate Form 3-A is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Tables 14A, 14B, 14C, or 14D (up to the maximum number of peaks in each table). [Table 14]

[0131] In some embodiments, the crystalline solid form is a mesylate salt form.

[0132] In one aspect, disclosed herein is crystalline Compound (I) mesylate Form 4-A. In one embodiment, crystalline Compound (I) mesylate Form 4-A is characterized by an XRPD pattern substantially similar to Figure 27. In one embodiment, crystalline Compound (I) mesylate Form 4-A is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 15A, 15B, 15C, or 15D (up to the maximum number of peaks in each table). [Table 15]

[0133] In some embodiments, the crystalline solid form is a sulfate salt form.

[0134] In one aspect, disclosed herein is crystalline Compound (I) sulfate Form 5-B. In one embodiment, crystalline Compound (I) sulfate Form 5-B is characterized by an XRPD pattern comprising at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks selected from Table 16A, 16B, 16C, or 16D (up to the maximum number of peaks in each table). [Table 16]

[0135] Pharmaceutical Composition The pharmaceutical compositions of the present disclosure (also referred to herein as "disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein.

[0136] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of, and / or absorption by, an active agent to a subject and that can be included in the pharmaceutical compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, saline, lactated Ringer's solution, regular sucrose, regular glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and coloring agents. Such preparations may be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not deleteriously react with or interfere with the activity of the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein.

[0137] Pharmaceutical compositions of the present disclosure may optionally include one or more pharmaceutically acceptable carriers and / or diluents therefor, such as lactose, starch, cellulose, and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included. See, e.g., Handbook of Pharmaceutical Excipients (5 thA more complete list of suitable excipients can be found in Remington's Pharmaceutical Sciences (2003-20th edition), Pharmaceutical Press (2005). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2003-20th edition), and The United States Pharmacopeia: The National Formulary, 1999 (USP 24 NF19). A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0138] In one aspect, the description provides a pharmaceutical composition comprising a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, and a pharmaceutically acceptable carrier.

[0139] In one aspect, the description provides a pharmaceutical composition comprising Compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein at least 0.1%, 0.5%, 1%, 5%, or more by weight of Compound (I) or a pharmaceutically acceptable salt thereof is present in a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein.

[0140] Treatment method The solid forms disclosed herein inhibit CDK2 and are therefore useful for treating diseases in which CDK2 is dysregulated, such as cancer. The present disclosure also provides a method for inhibiting CDK2 in a subject in need thereof, comprising administering to the subject an effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein.

[0141] In some embodiments, the disclosure provides a method of treating a disease or disorder associated with CDK2 in a patient, the method comprising administering to the patient a therapeutically effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein. In some embodiments, the CDK2-associated disease or disorder is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1. In some embodiments, the disease or disorder is cancer.

[0142] A subject "in need of inhibiting CDK2" is a subject having a disease in which inhibiting CDK2 can achieve a beneficial therapeutic effect, e.g., slowing the progression of the disease, alleviating one or more symptoms associated with the disease, or extending the lifespan of a subject given the disease.

[0143] In some embodiments, the present disclosure provides a method for treating a disease / condition / cancer associated with or modulated by CDK2, wherein inhibition of CDK2 is therapeutically beneficial, including but not limited to, treating cancer in a subject in need thereof. The method comprises administering to the subject an effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein.

[0144] In another embodiment, the present disclosure provides a method of treating a subject having cancer, comprising administering to the subject an effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein. In another embodiment, the cancer is characterized by amplification and / or overexpression of CCNE1 or CCNE2.

[0145] Thus, in some embodiments of the method, the subject or patient has been previously determined to have amplification of the cyclin E1 (CCNE1) gene and / or a CCNE1 expression level higher than the control expression level of CCNE1 in a biological sample obtained from the subject or patient.

[0146] In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells in vitro. The method comprises contacting tumor (e.g., cancer) cells in vitro with a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein. In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells associated with amplification and / or overexpression of CCNE1 in a subject or patient. The method comprises administering to a subject or patient in need thereof a therapeutically effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein.

[0147] In another embodiment, the present disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject an effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein, in combination with other agents or standard cancer treatments, as described below.

[0148] As used herein, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation. Cancers include solid tumors, named for the type of cells that form the cancer, and cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancers that begin at a specific site in the body, metastatic cancers that have spread from their original location to other parts of the body, recurrence of a first primary cancer after remission, and second primary cancers (new primary cancers in people with a history of a previous cancer of a different type from the latter). In some such embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0149] Cancers that may be treated according to the disclosed methods include breast cancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterine carcinosarcoma), prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma (e.g., lung squamous cell carcinoma (LUSC)) or adenocarcinoma (e.g., lung adenocarcinoma (LUAD))), esophageal cancer, head and neck cancer, colorectal cancer (e.g., colon cancer, colorectal adenocarcinoma (COADREAD)), kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer (i.e., cancer of the stomach), urothelial carcinoma, brain cancer, mesothelioma (MESO), skin cancer (e.g., melanoma), sarcoma, or thyroid cancer, including metastases (particularly brain metastases) of all of the listed cancers. In some embodiments, the cancer is characterized by overexpression and / or amplification of CCNE1 and / or CCNE2 as described herein. In some embodiments of the methods provided herein, the subject has been confirmed to have a cancer characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0150] In further embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or gastric cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0151] In further embodiments of the methods provided herein, the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and pulmonary adenosarcoma. In some embodiments, the cancer is characterized by overexpression and / or amplification of CCNE1. In some embodiments, the cancer is progressing despite platinum therapy.

[0152] In some embodiments, the cancer is platinum-resistant and / or platinum-refractory, hi some embodiments, the cancer is progressing despite platinum therapy.

[0153] In some embodiments, the CDK2-associated disease or disorder is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0154] In other embodiments, the cancer is breast cancer, including, for example, ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC) or inflammatory breast cancer. In some embodiments, the breast cancer is chemotherapy- or radiotherapy-resistant breast cancer, endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0155] In some embodiments, the cancer is HR-positive breast cancer. In some embodiments, the breast cancer is ER-positive breast cancer. In some embodiments, the breast cancer is HR-positive, HER2-negative breast cancer. In some embodiments, the breast cancer is ER-positive, HER2-negative breast cancer. In some embodiments, the breast cancer is responsive to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is responsive to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer has progressed despite treatment with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the breast cancer has progressed despite a first treatment with palbociclib, ribociclib and / or fulvestrant and a second treatment with abemaciclib and / or fulvestrant. In some embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib and ribociclib, or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In one embodiment, the breast cancer has CCNE amplification and / or overexpression.

[0156] In some embodiments, the breast cancer is triple-negative breast cancer.

[0157] In some embodiments, the cancer is ovarian cancer. In some such embodiments, the cancer is ovarian cancer characterized by amplification and / or overexpression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) ovarian cancer; (b) a cancer characterized by amplification and / or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the cancer is ovarian cancer.

[0158] In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein is administered as a first-line therapy. In other embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein is administered as a second (or subsequent) line therapy. In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein is administered as a second (or subsequent) line therapy after treatment with an endocrine therapy and / or a CDK4 / CDK6 inhibitor. In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein is administered as a second (or subsequent) line therapy after treatment with an endocrine therapy, such as an aromatase inhibitor, a SERM, or a SERD. In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein is administered as a second (or subsequent) line therapy after treatment with a CDK4 / CDK6 inhibitor. In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein is administered as a second (or subsequent) line therapy following treatment with one or more chemotherapy regimens, such as a taxane or a platinum agent.In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein is administered as a second (or subsequent) line therapy following treatment with a HER2-targeting agent, e.g., trastuzumab.

[0159] In some embodiments, the CDK2-associated disease or disorder 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).

[0160] In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein can be used to treat sickle cell disease and sickle cell anemia.

[0161] Examples of cancers that can be treated using a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein include, but are not limited to, 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 carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, These include cancers of the endocrine system, thyroid cancer, parathyroid cancer, adrenal gland 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, cancer of the kidney or urethra, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, 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 the foregoing cancers. The crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein are also useful in the treatment of metastatic cancer.

[0162] In some embodiments, cancers treatable by a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein include, but are not limited to, melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition resistant melanoma, cutaneous melanoma (SKCM), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., These cancers include, for example, non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancers (e.g., head and neck squamous cell carcinoma (NHSC)), urothelial carcinomas (e.g., bladder), and cancers with high microsatellite instability (MSI high). Additionally, the present disclosure includes refractory or recurrent malignancies whose growth may be inhibited using a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid of a pharmaceutically acceptable salt of Compound (I) disclosed herein.

[0163] In some embodiments, cancers treatable using a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid of a pharmaceutically acceptable salt of Compound (I) disclosed herein include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, and the like). cervical cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancer (e.g., lymphoma, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (relapsed or refractory NHL and follicular lymphoma, including relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of the above cancers.

[0164] In some embodiments, cancers treatable using a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid of a pharmaceutically acceptable salt of Compound (I) disclosed herein include, but are not limited to, cholangiocarcinoma, bile duct carcinoma, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma (e.g., liver cancer), Hepatocellular carcinoma (LIHC), 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, islet cell carcinoma, oral cavity cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, eye cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular adenocarcinoma, urethral cancer, and ureteral cancer.

[0165] In some embodiments, cancers treatable with a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein include Genomic Identification of Significant Targets in Cancer (GISTIC), and pheochromocytoma and paraganglioma (PCPG).

[0166] In some embodiments, cancers treatable with a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein include advanced / recurrent tumors; CCNE1-amplified platinum-resistant or platinum-refractory ovarian cancer; endometrial cancer that has progressed after two or more lines of therapy (previously received platinum therapy); and gastric cancer that has progressed after two or more lines of therapy (previously received platinum therapy); and ER+HER2-BC that has progressed despite a CDK4 / 6i. In some embodiments, cancers treatable with the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein include platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer; CCNE1-amplified endometrial cancer that has failed two or more lines of therapy; CCNE1-amplified advanced / recurrent tumors not belonging to other groups; ER+HER2-BC that has progressed despite CDK4 / 6i; platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer; and ER+HER2-BC that has progressed despite CDK4 / 6i.

[0167] In some embodiments, diseases and indications treatable using the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein include, but are not limited to, hematological cancers, sarcoma, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0168] Exemplary hematological cancers include lymphomas and leukemias, such as 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), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0169] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0170] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial carcinoma, squamous cell, small cell undifferentiated, large cell undifferentiated, adenocarcinoma, alveolar epithelial (bronchiolar) carcinoma, bronchial adenoma, chondroid hamartoma, and mesothelioma. Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (tubular 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.

[0171] 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 (PRAD), sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoroid tumor, lipoma).

[0172] Exemplary liver cancers include hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0173] 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 chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0174] Exemplary nervous system cancers include skull cancers (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancers (meningioma, meningeal sarcoma, gliomatosis), brain cancers (astrocytoma, medulloblastoma, glioma, brain low-grade glioma (LGG), ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme (GBM), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cancers (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0175] Exemplary gynecological cancers include uterine cancer (endometrial carcinoma), cervical cancer (cervical carcinoma, cervical squamous cell carcinoma (CESC), preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, 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 cancer of the fallopian tubes (epithelial carcinoma).

[0176] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lentil dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial carcinoma.

[0177] combination The crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein may be administered as a single agent or in combination with other anti-cancer therapeutic agents, particularly standard of care agents appropriate for the particular cancer.

[0178] As used herein, the term "additional anti-cancer therapeutic agent" refers to any one or more therapeutic agents other than a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, i.e., that are used in the treatment of cancer or that can be used to treat cancer. In some embodiments, such additional anti-cancer therapeutic agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors, e.g., inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immuno-oncology agents, and the like.

[0179] In some embodiments, the additional anti-cancer agent is an endocrine agent, such as an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM).

[0180] In some embodiments, the additional anticancer agent is a PIK3CA inhibitor, including but not limited to alpelisib (PIQRAY), BEBT-908, BPI-21668, buparlisib, inavolisib, TQB-3525, RLY-2608, milansertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolicib, and fimepinostat.

[0181] In some embodiments, the additional anti-cancer agent includes, but is not limited to, trastuzumab deruxtecan (Enhertu), trastuzumab duocarmazine, trastuzumab emtansine (Kadcyla), upifitamab rxodotin (Upifitamab Antibody-drug conjugates include rilsodotin, mirvetuximab sorafutansine, tisotumab vedotin (Tivdak), pralzatamaravtansine, sacituzumab govitecan or sacituzumab govitecan-hziy (Trodelvy), datopotamab deruxtecan, ladiratuzumab vedotin, patritumab deruxtecan, STRO-002, MORab-202, DS-6000, anetumab, avatansine, XMT-2056, and dicitamab vedotin (RC48-ADC, Aidexi).

[0182] In some embodiments, the additional anti-cancer agent is a PLK1 inhibitor, including but not limited to onvansertib, BI2536, BI6727, GSK461364A, TAK960, rigosertib.

[0183] In some embodiments, the additional anti-cancer agent is an estrogen PROTAC (ARV-471, H3B-5942).

[0184] In other embodiments, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein may be administered in combination with a standard therapeutic agent. In some embodiments, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein may be administered in combination with an endocrine therapy, such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein may be administered in combination with a chemotherapeutic agent, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin. In other embodiments, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein may be administered in combination with an anti-HER2 agent, such as trastuzumab or pertuzumab.

[0185] In some embodiments, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein may be administered in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

[0186] In some embodiments, the additional anti-cancer agent is an anti-angiogenic agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (alpha-v / beta-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG13736), SU14813 (Pfizer), and AG13958 (Pfizer). Additional antiangiogenic agents include vatalanib (CGP79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE941), tetrathiomolybdate (Coprexa™), AMG706 (Amgen), VEGF Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), telatinib (BAY57-9352), and CP-868,596 (Pfizer). Other antiangiogenic agents include enzastaurin (LY317615), midostaurin (CGP41251), perifosine (KRX0401), teprenone (Selbex™), and UCN01 (Kyowa Hakko). Other examples of antiangiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™).Additional anti-angiogenic agents include exilind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Additional anti-angiogenic agents include ABT510 (Abbott), aplatastat (TMI005), AZD8955 (AstraZeneca), incyclinide (Metastat™), and PCK3145 (Procyon).

[0187] Additional antiangiogenic agents (including VEGFR / PDGFR inhibitors) include, but are not limited to, ponatinib (Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab.

[0188] Additional antiangiogenic agents include acitretin (Neotigasone™), plitidepsin (Aplidine™), cilentide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), revimastat (BMS275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI522), and zoledronic acid (Zometa™).

[0189] In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (e.g., an agent that inhibits the intracellular transmission of regulatory molecules that govern fundamental processes of cell proliferation, differentiation, and survival). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, inhibitors of the WNT pathway, and so-called multi-targeted kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in conjunction with the compounds of the invention and pharmaceutical compositions described herein include BMS214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), peritrexol (AG2037), matuzumab (EMD7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB 786034), ALT110 (Alteris Therapeutics), BIBW2992 (Boehringer Ingelheim), and Cervene™ (TP38).Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatricisib (Pfizer), canertinib (CI1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB569), miltefosine (Miltefosin™), BMS599626 (Bristol-Myers Squibb), and others. Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Toricel™), AP23573 (ARIAD), and VX680 (Vertex), XL647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT751 (Abbott), alvocidib (flavopiridol), BMS387032 (Bristol Myers), EM1421 (Erimos), indisulam (E7070), seliciclib (CYC200), BIO112 (Onc Bio), BMS387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0190] In other embodiments, the additional anticancer agent is a so-called classical antitumor agent. Classical antitumor agents include, but are not limited to, hormone regulators, such as hormones, antihormones, androgen agonists, androgen antagonists, and antiestrogenic therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing or gene activating agents, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (e.g., talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib, etc.), microtubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.Examples of classical anti-tumor agents useful in combination therapy with the compounds of the present invention (which may be used in combination with one or more other drugs) include, but are not limited to, glucocorticoids (dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), progestins such as medroxyprogesterone, megestrol acetate (MegaAce), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, CHF4227 (Cheisi), etc.), selective estrogen receptor downregulators (SERDs; fulvestrant, LSZ102, G1T48, RAD1901, elastase, etc.). Trant, GDC-9545, Gildestrant, SAR439859, Amsenestrant, AZD9833, Camizetrant, LY3484356, Zn-c5, D-0502), Exemestane (Aromasin), Anastrozole (Arimidex), Atamestane, Fadrozole, Letrozole (Femara), Formestane; Gonadotropin-Releasing Hormone (GnRH; commonly luteinizing hormone-releasing hormone [ LHRH [also known as LHRH] agonists (such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar)), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandrone), and osaterone, dutasteride, epristeride, finasteride, saw palmetto, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogens such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof.Other examples of classical anti-tumor agents that may be used in combination with the compounds of the present invention include, but are not limited to, suberanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate, and PXD-101; onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, ibuprofen, riboflavin ... Rinotecan HCl (Camptosar), lurtotecan, olathecin (Rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, anamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin , Novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, These include ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds (e.g., cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin), and combinations thereof.

[0191] In still other embodiments, the additional anticancer agent is a so-called dihydrofolate reductase inhibitor (such as methotrexate and Nutrexin (trimetresate glucuronate)), a purine antagonist (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), a pyrimidine antagonist (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), tegafur (UFT Orzel or Uforal, and the TS-1 combination of tegafur, gimestat, and otostat), doxifluridine, carmofur, cytarabine (including ocphosphate, phosphate stearate, sustained-release, and liposomal forms), enocitabine, 5-azacytidine (Vidaza), decitabine, and ethinylcytidine), and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitac), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals), and GPI 18180 (Guilford Pharm) Inc), and combinations thereof.

[0192] Other examples of classical antitumor cytotoxic agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), vatabulin (Amgen), EPO906 (Novartis), vinflunine (Bristol-Myers Squibb), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (zinostatin), vinblastine, vincristine, vindesine, vinorelbine (navelbine), docetaxel (Taxotere), ortataxel, paclitaxel (including taxoplexin, a DHA / paclitaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (eloxatin), satraplatin, camptosar, capecitabine (Xeloda), oxaliplatin (Eloplatin), cisplatin, ... Xatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), Ibandronic acid, L-asparaginase, Pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), Bexarotene (Targretin™), Tesmilifene (DPPE - enhances the effectiveness of cytotoxic drugs), Seratope™ (Biomira), Tretinoin (Vesanoid™), Tirapazamine (Trizaone™), Motexafin Gadolinium (Xcytrin™), Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), Polyglutamic Acid-Paclitaxel (Xyotax™) and combinations thereof.Further examples of classical anti-tumor agents include, but are not limited to, Advexin (ING201), TNFerade (GeneVec, a compound that induces TNFα expression in response to radiation therapy), RB94 (Baylor College of Medicine), Genasense (Oblimmersen, Genta), combretastatin A4P (CA4P), Oxy-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), provastatin (Pravachol, Bristol-Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycol, Bayer), rosuvastatin (Crestor, AstraZeneca), lovostatin, niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

[0193] In other embodiments, the additional anticancer agent is an epigenetic modulator, such as an inhibitor or EZH2, Smalca4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2, or BCL6.

[0194] In further embodiments, the additional anti-cancer agent is an immunomodulatory agent, examples of which include, but are not limited to, inhibitors of CTLA-4 (e.g., ipilimumab), PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dostarlimab), LAG-3 (e.g., leratolimab, TIM-3, TIGIT, 4-1BB, OX40, GITR, CD40, or CAR-T cell therapy).

[0195] In some embodiments, the additional anticancer agent is an EGFR inhibitor, e.g., afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, or gefitinib, or an EGFR antibody, e.g., cetuximab, panitumumab, or necitumumab.

[0196] Alternatively, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein, may be combined with other anti-cancer agents that are not EGFR inhibitors, such as MEK inhibitors, including mutant MEK inhibitors (trametinib, cobimutetinib, binimetinib, selumetinib, refametinib); c-MET inhibitors, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (e.g., methicillinib). betuzumab); mitotic kinase inhibitors (CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib, relociclib, trilaciclib, dalpiciclib, BPI-16350); antiangiogenic agents such as bevacizumab, nintedanib; apoptosis inducers such as Bcl-2 inhibitors (e.g., venetoclax, obatoclax, navitoclax) and Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, S-64315); and mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, lidofolomus).

[0197] In some embodiments, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or the pharmaceutical composition disclosed herein also includes palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., sucralose), ribocilib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., sucralose), sucralose, ... CIVARGA®), afatinib (e.g., Giotrif®), osimertinib (e.g., Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), an EGFR inhibitor, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, beruzosertib, selalasertib, SRA-737, LY2603618 (ravusertib), and trastuzumab (e.g., Herceptin®), or a combination thereof.EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST2818), aumoretinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, and nafatinib. It may be selected from zarutinib (EGF816), avitinib, PCC-0208027, resivertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759) or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, necitumumab, HLX07, JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372)).

[0198] 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) to identify human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder that is likely to be responsive to administration of a CDK2 inhibitor (as used herein, a "CDK2 inhibitor" refers to a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein).

[0199] CCNE1 In one embodiment, the biomarker is CCNE1. In particular, amplification of the cyclin E1 (CCNE1) gene and / or expression levels of CCNE1 in a biological sample indicates that a patient or subject may benefit from administration of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein.

[0200] CCNE1 is a cell cycle factor essential for cell cycle regulation at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2 and interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity for the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank accession number NM_001238). The amino acid sequence of human CCNE1 can be found in GenBank accession number NP_001229 / UniProtKB accession number P24864).

[0201] In one aspect, the disclosure provides a method of treating a subject having or at risk of developing a disease or disorder associated with CDK2, comprising administering a therapeutically effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein to the subject, wherein the subject has amplification of the CCNE1 gene and / or has a CCNE1 expression level higher than a control expression level of CCNE1. In some embodiments, the CDK2-associated disease or disorder is cancer.

[0202] Also provided herein is a method of treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition disclosed herein.

[0203] Amplification of the CCNE1 gene and / or a CCNE1 expression level higher than a control expression level of CCNE1 indicates / predicts that a human subject having or at risk of developing a CDK2-related disease or disorder will respond to a CDK2 inhibitor. In some embodiments, the CCNE1 expression level may be the CCNE1 mRNA level. In other embodiments, the CCNE1 expression level may be the CCNE1 protein level.

[0204] Other biomarkers In some embodiments, a contemplated biomarker may be p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a), which acts as a negative regulator of normal cell proliferation by interacting with CDK4 and CDK6. In other embodiments, a contemplated biomarker may be phosphorylation of Rb at the serine corresponding to amino acid position 780. 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.

[0205] Contemplated biomarkers may also be selected from the group consisting of RB1, RBL1, RBL2, CDKN2A, CDKN1A, CDKN1B, FBXW7, CCNE1, CCNE2, CCNA1, CCNA2, CCND1, CCND2, CCND3, CDK2, CDK3, CDK4, CDK6, CDKN2A, CDNK1A, CDKN1B, E2F1, E2F2, E2F3, MYC, MYCL, MYCN, EZH2, ER, HER2, HER3, HPV+ and EGFR.

[0206] biological samples Biological samples suitable 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 obtained from a biopsy of a patient suffering from a solid tumor. Tumor biopsies may be obtained by various means known in the art. Alternatively, blood samples may be obtained from patients suffering from blood cancer.

[0207] The biological sample may 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).

[0208] Methods of obtaining 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, a biological sample may 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.

[0209] Administration method and dosage form The exact amount of compound administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the cancer, and the subject's characteristics (such as overall health, age, sex, weight, and tolerance to the drug). Those skilled in the art will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with anti-cancer agents, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable doses are known for approved therapeutic agents and can be adjusted by those skilled in the art depending on the condition of the subject, the type of condition(s) being treated, and the amount of the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein used according to dosages reported in the literature and recommended in the Physician's Desk Reference (57th ed., 2003).

[0210] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of the disease, condition, or cancer; ameliorating or improving clinical symptoms or indicators associated with the disease, condition, or cancer; delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or cancer; or reducing the likelihood of recurrence of the disease, condition, or cancer.

[0211] The term "effective amount" means an amount that, when administered to a subject, produces a beneficial or desired result (including a clinical result), e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in a subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively 1 mg to about 5 grams per day, and further alternatively 10 mg to 1 gram per day).

[0212] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0213] Furthermore, a crystalline solid form of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition of the present disclosure, can be co-administered with other therapeutic agents. As used herein, the terms "co-administration," "administered in combination with," and their grammatical equivalents are intended to encompass the administration of two or more therapeutic agents to a single subject, and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, one or more crystalline solid forms of the free base of Compound (I) disclosed herein, an amorphous form of the free base of Compound (I) disclosed herein, or a crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, or a pharmaceutical composition of the present disclosure are co-administered with other agents. These terms encompass administering two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. These include simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, and the other agent(s) are administered in a single composition. In some embodiments, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein, and the other agent(s) are mixed in a composition.

[0214] The particular mode of administration and dosage regimen will be selected by the attending clinician, taking into account the specifics of the case (e.g., subject, disease, disease state involved, particular treatment). Treatment may involve daily or multiple daily or less-than-daily (weekly, monthly, etc.) administration over a period ranging from several days to several months, or even years. However, one of skill in the art will readily recognize appropriate and / or equivalent dosage amounts, looking at the dosage amounts of approved compositions for treating diseases using CDK2 inhibitors disclosed as guidance.

[0215] The crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein can be administered to a patient in various forms depending on the selected administration route, as will be understood by those skilled in the art. The solid forms of the present teachings may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, via patch, pump, or transdermal administration, and by pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, pulmonary, intrathecal, rectal, and topical administration modes. Parenteral administration may also be by continuous infusion over a selected period of time.

[0216] The pharmaceutical composition of the present disclosure is formulated to be suitable for its intended route of administration.In some embodiments, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0217] Typically, for oral therapeutic administration, the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0218] Typically, for parenteral administration, solutions of the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or the crystalline solid form of a pharmaceutically acceptable salt of Compound (I) disclosed herein can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. These preparations contain a preservative to prevent the growth of microorganisms under ordinary storage and use conditions.

[0219] Generally, for the extemporaneous preparation of sterile injectable solutions or dispersions, sterile aqueous solutions or dispersions and powders of the crystalline solid form for injectable use of the crystalline solid form of the free base of Compound (I) disclosed herein, the amorphous form of the free base of Compound (I) disclosed herein, or a pharmaceutically acceptable salt of Compound (I) disclosed herein are suitable. Synthesis of Compound (I)

[0220] In another aspect, provided herein is a method for preparing Compound (I), comprising: [ka] A first compound represented by formula (1): [ka] and a second compound represented by formula (2): [ka] and reacting the compound with the compound.

[0221] Compound (I) may be synthesized according to the following synthetic scheme A: [ka]

[0222] Alternatively, compound (I) may be synthesized according to the following synthetic scheme B: [ka]

[0223] In some embodiments of Step 1, the oxidizing agent for triphenylphosphine (TPP) is selected from the group consisting of diisopropyl azodicarboxylate (DIAD), di-(4-chlorobenzyl) azodicarboxylate (DCAD), di-tert-butyl azodicarboxylate (DBAD), and 4,4'-azopyridine. In some embodiments, the oxidizing agent for triphenylphosphine is DIAD.

[0224] In some embodiments of Step 1, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, methyl tert-butyl ether, toluene, tetrahydrofuran, acetonitrile, 2-methyltetrahydrofuran, dichloromethane, and cyclohexane. In some embodiments, the solvent is ethyl acetate. In some embodiments, the organic solvent is toluene.

[0225] In some embodiments of Step 1, 6-chloro-1H-pyrazolo[3,4-b]pyrazine, tetrahydropyran-4-ylmethanol, and triphenylphosphine were mixed in a solvent, followed by the addition of the oxidizing agent triphenylphosphine (e.g., DIAD). In some embodiments of Step 1, 6-chloro-1H-pyrazolo[3,4-b]pyrazine, triphenylphosphine, and the triphenylphosphine oxidizing agent were mixed in a solvent, followed by the addition of tetrahydropyran-4-ylmethanol.

[0226] In some embodiments of Step 1, reaction temperatures ranging from -40°C to 25°C were studied. In some embodiments, the reaction temperature was maintained at about -5 to about 5°C until the reaction was complete. In some embodiments, the reaction temperature was maintained at about -10 to about 20°C until the reaction was complete.

[0227] In some embodiments of Step 2, the reaction is a Buchwald-Hartwig coupling reaction comprising a palladium catalyst, a ligand, a base, and a solvent. In some embodiments of Step 2, 5-(difluoromethoxy)-1H-pyrazol-3-amine (2) and a solvent are combined, followed by the addition of a palladium catalyst, a ligand, and 6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (1). A base is then added to the mixture.

[0228] In some embodiments of step 2, the palladium catalyst is selected from the group consisting of Pd(OAc)2, [Pd(allyl)Cl]2, Pd(CH3CN)2Cl2, Pd2(dba)3, JackiePhos Pd G3, SL-J009-1 Pd G3, EtCPhos Pd G3, SPhos Pd G1, SPhos Pd G2, PEPPSI-iPr Pd, XPhos Pd G1, BrettPhos Pd G3, RuPhos Pd G2, KeYPhos Pd G2, CyDavePhos Pd G2, CyDavePhos Pd G3, and CyDavePhos Pd G4. In some embodiments, the palladium catalyst is selected from the group consisting of Pd(OAc)2, [Pd(allyl)Cl]2, Pd(CH3CN)2Cl2, Pd2(dba)3, JackiePhos Pd G3, SL-J009-1 Pd G3, EtCPhos Pd G3, SPhos Pd G1, PEPPSI-iPr Pd, XPhos Pd G1, and BrettPhos Pd G3. In some embodiments, the palladium catalyst is [Pd(allyl)Cl]2 or Pd2(dba)3. In some embodiments, the palladium catalyst is [Pd(allyl)Cl]2. In some embodiments, the palladium catalyst is Pd2(dba)3.

[0229] In some embodiments of step 2, the ligand is XantPhos, BINAP-R, t-Bu-XPhos, SL-J009-1, DavePhos, XPhos, tBu-JohnPhos, BIPHEP, vBRIBP, RockPhos, tBu-BrettPhos, QPhos, SPhos, DPEPhos, CPhos, H8-BINAP-R, Tol-BINAP-R, DCyPF, DiPrPF, ChenPhos, SEGPHOS-R, Tedicyp, Quinap-R, KeYPhos, JoYPhos, TrYPhos, MOP-R, SL-J003-1, RuPhos, MePhos, AmPhos, Cy-vBRIDP, TrixiePhos, A Selected from the group consisting of Phos, AlPhos, CX-PCy, CX-POMetBu, Cy-BippyPhos, MorDalPhos, Ad-BrettPhos, Cy-BrettPhos, Cy-DavePhos, JohnPhos, Cy-JohnPhos, vBRIDP, ChiraPhos-RR, ChenPhos-RSR, PCy3-HBF4, SL-A116-1, DM-SEGPHOS-R, DTBM-SEGPHOS-R, and xyl-BINAP-R. In some embodiments, the ligand is selected from the group consisting of XantPhos, BINAP-R, t-Bu-XPhos, SL-J009-1, DavePhos, XPhos, tBu-JohnPhos, BIPHEP, vBRIBP, RockPhos, tBu-BrettPhos, QPhos, SPhos, DPEPhos, CPhos, H8-BINAP-R, Tol-BINAP-R, DCyPF, DiPrPF, ChenPhos, SEGPHOS-R, Tedicyp, Quinap-R, KeYPhos, JoYPhos, TrYPhos, MOP-R, SL-J003-1, RuPhos, MePhos, AmPhos, Cy-vBRIDP, TrixiePhos, AlPhos, CX-PCy, and Cy-BippyPhos.In some embodiments, the ligand is selected from the group consisting of DavePhos, SPhos, CPhos, H8-BINAP-R, Tol-BINAP-R, RuPhos, MePhos, AmPhos, MorDalPhos, Cy-BrettPhos, Cy-DavePhos, and xyl-BINAP-R. In some embodiments, the ligand is selected from the group consisting of DavePhos, H8-BINAP-R, Tol-BINAP-R, and xyl-BINAP-R. In some embodiments, the ligand is DavePhos.

[0230] or palladium-free S for Buchwald-Hartwig coupling N In some embodiments of step 2 for the Ar reaction, the base is selected from the group consisting of potassium tert-butoxide (KOtBu), sodium tert-butoxide (t-BuONa or NaOtBu, lithium tert-butoxide (LiOtBu), LiHMDS (lithium bis(trimethylsilyl)amide), NaHMDS (sodium bis(trimethylsilyl)amide), KHMDS (potassium bis(trimethylsilyl)amide), NaOAc (sodium acetate), KOAc (potassium acetate)), KPO (potassium phosphate), NaCO (sodium carbonate), KCO (potassium carbonate), CsCO (cesium carbonate), and lithium diisopropylamide (LDA). In some embodiments, the base is selected from the group consisting of KOtBu, NaOtBu, LiOtBu, LiHMDS, NaHMDS, KHMDS, KOAc, KPO, CsCO, and LDA. In some embodiments of the Buchwald-Hartwig coupling, or palladium-free S N In some embodiments of the Ar reaction, the base is NaOtBu, LiOtBu, LiHMDS, NaHMDS, KHMDS, or LDA. In some embodiments, the base is NaOtBu. In some embodiments, the base is LiHMDS, NaHMDS, KHMDS, or LDA. In some embodiments, the base is LiHMDS.

[0231] or palladium-free S for Buchwald-Hartwig coupling N In some embodiments of Step 2 for the Ar reaction, the solvent is selected from the group consisting of tert-butanol (t-BuOH), tert-amyl alcohol, isopropanol, ethanol (EtOH), dioxane, dimethoxyethane (DME), toluene, N,N-dimethylformamide (DMF), tetrahydrofuran (THF), 2-methyltetrahydrofuran (Me-THF), anisole, methyl tert-butyl ether (MTBE), N-methyl-2-pyrrolidone (NMP), 1,3-dioxolane, chlorobenzene, or a combination thereof. In some embodiments, the solvent is selected from the group consisting of t-BuOH, tert-amyl alcohol, isopropanol, EtOH, dioxane, DME, toluene, DMF, THF, Me-THF, anisole, MTBE, and NMP. In some embodiments, the solvent is selected from the group consisting of tert-butanol, tert-amyl alcohol, dioxane, DME, THF, and Me-THF. In some embodiments, the solvent is tert-butanol. In some embodiments, the solvent is THF.

[0232] When the reaction is a Buchwald-Hartwig coupling, in some embodiments of Step 2, one or more of the following impurities are formed: [ka] [ka]

[0233] For example, if certain processes are used, the following impurities may be formed: [ka]

[0234] Some of the challenges associated with Buchwald-Hartwig coupling with palladium catalysts for use in preparing compound (I) include, but are not limited to, the generation of complex impurities, inefficient palladium removal by aqueous washes, product loss to aqueous waste, high cost of the palladium catalyst and / or ligand, high loading requirements for the palladium catalyst and / or ligand, the need for a hygroscopic base (e.g., sodium tert-butoxide), and / or a palladium scavenger. In some embodiments, one or more of these challenges are eliminated by removal of the palladium catalyst.

[0235] In certain embodiments, provided herein is a substantially pure Compound (I). For example, provided is a composition comprising Compound (I), which may contain less than 10%, less than 7%, less than 5%, or less than 3 wt % of one or more impurity compounds as disclosed herein, based on the weight of the compound (or based on the weight of the composition).

[0236] In another aspect, provided herein is a method for preparing Compound (I), comprising: [ka] A first compound represented by formula (1): [ka] and a second compound represented by formula (2): [ka] wherein reacting the first compound and the second compound further comprises a base that activates the diamine compound (2), which then reacts with the heteroaryl chloride compound (1). Without being bound by any theory, the reaction is mediated by a base that can activate the diamine compound (2) to form a highly reactive dianion, which can react directly with the heteroaryl chloride compound (1). In some embodiments, the base is a strong non-nucleophilic base. In some embodiments, the base is a strong non-nucleophilic amide base. In some embodiments, the strong non-nucleophilic amide base is LiHMDS, NaHMDS, KHMDS, or LDA.

[0237] In some embodiments of step 2, the reaction is carried out with palladium-free S N In some embodiments of step 2, compound (1) and compound (2) are combined in a solvent, followed by the addition of a strong non-nucleophilic base. In some embodiments of step 2, the reaction is carried out using palladium-free S N In some embodiments of step 2, compound (1) and compound (2) are combined in a solvent, followed by the addition of a strong non-nucleophilic amide base (e.g., LiHMDS, NaHMDS, KHMDS, or LDA).

[0238] In some embodiments of Step 2, the reaction is carried out with palladium-free S N In the case of Ar reactions, the reactions have improved selectivity, high conversion, and high overall purity. In some embodiments, impurities formed by the Buchwald-Hartwig coupling are removed.

[0239] Palladium-free reaction N In some embodiments of step 2, when the reaction is Ar, one or more of the following impurities are formed: [ka]

[0240] The following examples are intended to be illustrative and not to limit the scope of the present disclosure in any way. [Example]

[0241] [Table 21-1] [Table 21-2] 1 H NMR spectra were obtained on an Avance III 400 Bruker 400 MHz NMR (acquisition time = 4.09 seconds, 1 second delay, 16 scans). Unless otherwise indicated, all protons are reported as parts per million (ppm) relative to the residual non-deuterated NMR solvent signal (DMSO (2.50 ± 0.02 ppm) and CDCl (7.26 ± 0.02 ppm)) in either DMSO-d or CDCl NMR solvents. Liquid chromatography-mass spectrometry

[0242] Liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were acquired on an Agilent product line 1290 Infinity II LC stack using an Agilent model G6135C LC / MSD XT spectrometer utilizing AJS (ESI) ionization coupled with a Waters Atlantis T3 column (C18, 3.0 μm particle size, dimensions 4.6 × 150 mm) reversed-phase column at 22°C. The mobile phase consisted of a mixture of 0.1% trifluoroacetic acid in water and acetonitrile. Each step utilized its own acquisition method. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA)

[0243] DSC is Mettler Toledo DSC 3+TGA and DSC were performed using a Mettler Toledo TGA / DSC. Samples (3-5 mg) were weighed directly into 40 μL sealed aluminum pans with a pinhole. DSC was performed using a TA Discovery DSC. Samples (1-5 mg) were weighed directly into 40 μL sealed aluminum pans with a pinhole. TGA and DSC were performed using a Mettler Toledo TGA / DSC. 3+ The protective and purge gases were nitrogen at flow rates of 20-30 mL / min and 50-100 mL / min, respectively. The desired amount of sample (5-10 mg) was weighed directly into a sealed aluminum pan with a pinhole and analyzed by the following parameters: [Table 22] X-ray powder diffraction (XRPD)

[0244] XRPD was performed in reflectance mode (i.e., Bragg-Brentano configuration) using a Rigaku MiniFlex 600. Samples were prepared on Si zero-return wafers. The parameters for the XRPD method used are listed below: [Table 23]

[0245] XRPD of the free bases and salts disclosed herein was performed using a Bruker D8 Advance equipped with a LYNXEYE detector in reflectance mode (i.e., Bragg-Brentano geometry). Samples were prepared on Si zero-return wafers. The parameters for the XRPD method used are listed below: [Table 20] Example 1 Preparation and Characterization of Selected Polymorphic Forms of Free Base Compound (I) 1.1 Form A 1.1A: Synthesis of Compound (I) Based on Scheme A Step 1 based on Scheme A: [ka]

[0246] 6-Chloro-1H-pyrazolo[3,4-b]pyrazine (39.8 kg, 1.0 equiv.), tetrahydropyran-4-ylmethanol (35.9 kg, 1.2 equiv.), triphenylphosphine (TPP) (74.2 kg, 1.1 equiv.), and ethyl acetate (EtOAc) (260 L) were combined to form a suspension. The temperature of the suspension was adjusted to −5 to 3° C. Diisopropyl azodicarboxylate (DIAD) (62.4 kg, 1.2 equiv.) was added to the reaction mixture over 3.7 hours while maintaining the temperature at −5 to 3° C., and the mixture was stirred until completion.

[0247] n-Heptane (520 L) was added at -5 to 10 °C, and the resulting mixture was maintained at this temperature for 1.3 hours. The suspension was filtered, and the filter cake was washed with a mixture of ethyl acetate (12 L) and n-heptane (110 L) at -5 to 10 °C. The combined filtrate and washes were treated with magnesium chloride (9.8 kg, 0.4 equiv.), and the stirred mixture was heated at 45 to 55 °C for 1.7 hours and then filtered. The cake was washed with a mixture of ethyl acetate (4 L) and n-heptane (35 L). The combined filtrate and washes were treated with magnesium chloride (9.8 kg, 0.4 equiv.) at 45 to 55 °C for approximately 1 hour. The slurry was filtered, and the cake was washed with a mixture of ethyl acetate (4 L) and n-heptane (35 L). The combined filtrate and washes were concentrated at atmospheric pressure to a volume of 198 L. Ethanol (200 L) was added and the mixture was concentrated to 198 L. This process was repeated two more times to a final volume of 119 L. The mixture was cooled to 15-23 °C, seeded with the product (200 g, 0.5% (w / w)), further cooled to -7-3 °C, and held for 13.5 h. The suspension was filtered, and the cake was washed with water (3 x 120 L) at 0-5 °C. The material was dried under vacuum at 50 °C to give the desired compound (45.3 kg, 67% yield (assay corrected)) with an AUC purity of 99.1%. 1H NMR:(400MHz,CDCl3)[ppm]δ8.51(s,1H),8.25(s,1H),4.35(d,J=7.2Hz,2H), 3.96-3.92(m,2H),3.37-3.30(m,2H),2.34-2.24(m,1H),1.47-1.44,(m,4H). LC-MS: m / z=253.1 [M+H] + Step 2 based on Scheme A: [ka]

[0248] 5-(Difluoromethoxy)-1H-pyrazol-3-amine (compound represented by Formula (2)) (21.2 kg, 1.1 equivalents) and tert-butanol (t-BuOH) (123 kg) were combined in a vessel under a nitrogen atmosphere at 27-35°C, and the mixture was sparged for 30 minutes. 6-Chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (compound represented by Formula (1)) (32.6 kg, 1.0 equivalents), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) (4402 g, 0.04 equivalents), and 2-dicyclohexylphosphino-2'-(N,N-dimethylamino)biphenyl (DavePhos) (2448 g, 0.05 equivalents) were added to the mixture under nitrogen. Sodium tert-butoxide (t-BuONa) (3 x 10.0 kg, 2.1 equiv.) was added in portions, keeping the temperature below 45 °C. The mixture was heated to 45-55 °C until the reaction was complete. 2-Methyltetrahydrofuran (157 L) was added, and the mixture was concentrated under vacuum to 157 L at <45 °C. This sequence was repeated three more times to a final level of 157 L.

[0249] The mixture was diluted with 2-methyltetrahydrofuran (314 L), and the solution was washed with a mixture of hydrochloric acid (36%, 9.1 kg, 0.66 equiv.) in aqueous sodium chloride (7.9 kg NaCl in 157 L water) at 30-37 °C. The organic layer was separated and washed three times with a solution of sodium bicarbonate (40.4 kg) in water (471 L), and the aqueous layer was discarded. The organic layer was concentrated under vacuum at <45 °C to a minimum agitation level, diluted with dichloromethane (157 L), and the mixture was concentrated to a minimum agitation level. This sequence was repeated two more times. The mixture was cooled to <30 °C and diluted with dichloromethane (35 L) to a level of 157 L.

[0250] The resulting mixture was heated to 40-45°C, diluted with n-heptane (55 L), held for 30 minutes, and then cooled to 10-25°C over 10 hours. The slurry was further cooled to 5-10°C, held for 3 hours, and the solid was collected by filtration. The solid was washed with a mixture of dichloromethane (30 L) and n-heptane (30 L) at 5-10°C and dried under vacuum at 50°C to give the desired compound (35.6 kg, 67% yield (assay corrected)) with an AUC purity of 92.0%. 1 H NMR:(400MHz,DMSO-d6)[ppm]δ 12.2(s,1H),10.8(s,1H),8.20(s,1H),8.15(s,1H),7.3(t,J=73.6Hz,1H), 6.0(s,1H),4.4(m,2H),3.8(m,2H),3.2(m,2H),2.2(m,1H),1.4-1.3(m,4H). LC-MS: m / z=366.2 [M+H] + Step 3 based on Scheme A: [ka]

[0251] The crude material (35.4 kg, 1 equiv.) was combined with methanol (520 L) and heated to 50-55°C until complete dissolution. The solution was cooled to 40-50°C and treated with SiliaMetS thiol (34.8 kg) for 2 hours. The suspension was filtered through a Celite pad, and the cake was washed with methanol (70 L) and combined with the filtrate. This sequence was repeated two more times, and the resulting solution was passed through a 0.2 micron filter. The solution was concentrated under vacuum at <45°C to a level of 284 L. The mixture was cooled to 17-35°C and combined with ethanol (32 L) and water (70 L). The mixture was heated to 60-70°C until complete dissolution was observed. Water (35 L) was added to the solution at 60-70°C. The solution was cooled to 32.5-37.5°C over 1 hour, seeded with product (0.18 kg, 0.5% (w / w)), and held for 2 hours. The suspension was cooled to 15-25°C over 2 hours and held for 12 hours. The suspension was cooled to 7-12°C over 50 minutes and water (35 L) was added over 10 minutes. The mixture was held at 7-12°C for 3 hours and the solid was collected by filtration. The solid was washed with a mixture of water (43 L) and methanol (28 L) at 7-12°C. The material was dried under vacuum at 50°C to give the desired compound (26.5 kg, 72% yield (assay corrected)) with an AUC purity of 99.1%. 1 H NMR:(400MHz,DMSO-d6)[ppm]δ 12.2(s,1H),10.8(s,1H),8.20(s,1H),8.14(s,1H),7.3(t,J=73.6Hz,1H), 6.0(s,1H),4.4(m,2H),3.8(m,2H),3.2(m,2H),2.2(m,1H),1.4-1.3(m,4H). LC-MS: m / z=366.2 [M+H] + 1.1B: Process optimization of reaction conditions for the preparation of compound (I)

[0252] To further optimize the reaction conditions for the preparation of compound (I), several different catalysts, ligands, bases, solvents, and reaction temperatures were investigated. The results of the conditions investigated for the coupling of (1) and (2) (Scheme A, Step 2 (Table 17) and Scheme B, Step 2 (Table 18)) are described below.

[0253] The catalyst was formed in a reaction vial by combining allylpalladium(II) chloride dimer ([Pd(allyl)Cl]) (10 μmol, 0.025 equiv.) with the ligands bisphosphine (20 μmol, 0.05 equiv.) and monophosphine (40 μmol, 0.1 equiv.) in solvent for 30 min followed by solvent removal under high vacuum. 1 (400 μmol, 1.0 equiv.) and 2 (400 μmol, 1 equiv.) were added to the reaction vial as a solution in tetrahydrofuran, followed by solvent removal under high vacuum. Sodium tert-butoxide (t-BuONa) (1200 μmol, 3 equiv.) was added to the reaction vial as a solution in tetrahydrofuran, followed by solvent removal under high vacuum. Solvent (1 mL) was added, and the mixture was kept stirring at 45°C for 18 h. Screening results identified palladium-catalyzed reaction conditions using the DavePhos ligand with sodium tert-butoxide (NaOtBu) as the base in tert-butanol as the solvent that were compatible with the reagents used in Example 1.1A, Step 2. Further screening based on these reaction conditions identified the BINAP ligand using NaOtBu as the base and ethereal solvent. [Table 17]

[0254] Further screening of alternative bases is performed using S NThis led to the discovery of the Ar reaction. In the coupling reaction of Step 2, specific strong non-nucleophilic bases (e.g., strong non-nucleophilic amide bases, including but not limited to LiHMDS, NaHMDS, KHMDS, or LDA) enabled the coupling reaction without palladium catalyst or associated ligand (Scheme B). (1) (100 mg, 1.0 equiv.) and (2) (59 mg, 1.0 equiv.) were combined in solvent (1.5 mL). The base was added while the reaction was maintained at a specific target temperature and monitored by HPLC. Only specific strong non-nucleophilic amide bases provided rapid, selective, and high conversion, yielding the desired compound (I) with high overall purity. [Table 18] 1.1C: Synthesis of Compound (I) Based on Scheme B Step 1 based on Scheme B: [ka]

[0255] A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (50.0 kg, 1.0 equiv.), tetrahydropyran-4-ylmethanol (45.1 kg, 1.2 equiv.), triphenylphosphine (TPP) (93.4 kg, 1.1 equiv.), and toluene (479 L) was combined to form a suspension. The temperature of the suspension was adjusted to -10 to 0 °C. Diisopropyl azodicarboxylate (DIAD) (78.5 kg, 1.2 equiv.) was added to the reaction mixture over 10 hours while maintaining the temperature at -10 to 0 °C. The mixture was stirred at -10 to -5 °C for an additional 3 hours, then adjusted to 15 to 25 °C and stirred for 6 hours until the reaction was complete.

[0256] The reaction mixture was distilled below 60°C to a total volume of approximately 300 L and then adjusted to 35-45°C. n-Heptane (520 L) was added at 35-45°C, and the resulting mixture was maintained at this temperature for 5.5 hours. The suspension was filtered, and the filter cake was washed with a mixture of toluene (29 L) and n-heptane (117 L) at 35-45°C. The combined filtrate and washes were adjusted to 50-60°C and then treated with magnesium chloride (30.5 kg, 1.0 equiv.). The resulting mixture was stirred at 50-60°C for 7.5 hours and then filtered. The cake was washed with a mixture of toluene (40 L) and n-heptane (161 L) at 50-60°C. The combined filtrate and washes were distilled below 60°C to a volume of approximately 250 L. Ethanol (EtOH) (247 L) was then added, and the solvent exchange cycle was repeated two more times to a final target volume of approximately 219 L. Ethanol (51 L) was added to the resulting mixture, and the temperature was adjusted to 40–50 °C. Water (103 L) was added while maintaining the temperature, and the resulting solution was slowly cooled to 10–20 °C over 2 h. The cooled solution was seeded with the product (250 g, 0.5% (w / w)) and further cooled to -10–-5 °C and held for 5.5 h. Water (150 L) was added at -10–-5 °C, and the suspension was stirred at that temperature for 2 h. The suspension was filtered, and the cake was washed with cold (-10–-5 °C) 1:4 ethanol:water (2 × 150 L). The material was dried under vacuum at 35–45 °C for 3 h to obtain the desired compound (61.9 kg, 76% yield) with an AUC purity of 99.8%. 1 H NMR:(400MHz,CDCl3)[ppm]δ8.51(s,1H),8.25(s,1H),4.35(d,J=7.2Hz,2H), 3.96-3.92(m,2H),3.37-3.30(m,2H),2.34-2.24(m,1H),1.47-1.44,(m,4H). LC-MS: m / z=253.1 [M+H] + Step 2 based on Scheme B: [ka]

[0257] 6-Chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (1) (100 mg, 1.0 equiv.), 5-(difluoromethoxy)-1H-pyrazol-3-amine (2) (59 mg, 1.0 equiv.), and anhydrous THF (1.5 mL) were combined to form a solution. At ambient temperature, lithium hexamethyldisilazane (LiHMDS) (1.19 mL, 3.0 equiv.) as a 1 M solution in THF was added to the reaction in one aliquot. The temperature was adjusted to 50°C, and the reaction mixture was stirred at 50°C for 4 hours. The reaction showed very clean and high conversion of the crude product with an AUC purity of 87.1%.

[0258] Alternatively, (1) (61.6 kg, 1.0 equiv.) (2) (40.0 kg, 1.1 equiv.) and anhydrous tetrahydrofuran (THF) (367 L) were combined to form a solution. The temperature was adjusted to 0-5°C. While maintaining the temperature, LiHMDS (597 kg, 3.3 equiv.) as a 24% solution in THF was added over a period of 7 hours. The reaction mixture was stirred at -5-5°C for 2 hours.

[0259] Upon completion of the reaction, the mixture was adjusted to -10 to 10°C. While maintaining the temperature, 3 M hydrochloric acid (518 L) was added over a 9-hour period. The temperature was adjusted to 15 to 25°C, and the aqueous layer was discarded. While maintaining the temperature, 5% aqueous sodium bicarbonate (308 kg) was added; the biphasic mixture was stirred for 1 hour, and the aqueous layer was discarded. While maintaining the temperature, 5% aqueous sodium bicarbonate (308 kg) was added again; the biphasic mixture was stirred for 1 hour, and the aqueous layer was discarded. The resulting mixture was distilled to a total volume of approximately 308 L at ≤66°C. Next, dichloromethane (DCM) (185 L) was added, and the resulting mixture was distilled to a total volume of approximately 308 L at ≤66°C. This solvent exchange cycle was repeated eight more times. The reaction mixture was then distilled to a total volume of approximately 246 L, and the temperature was adjusted to 25 to 35°C. Dichloromethane (60 L) was added and the temperature was adjusted to 35-45°C. While maintaining the temperature, n-heptane (108 L) was added. The reaction mixture was slowly cooled to 10-25°C over a 10.5 hour period, then slowly cooled to 5-10°C over a 2.5 hour period. The resulting suspension was stirred at room temperature for 3.5 hours. The suspension was filtered, and the cake was washed with cold (5-10°C) 1:1 dichloromethane:n-heptane (2 x 124 L). The material was dried under vacuum at 45-55°C for 6 hours. The dried cake was slurried on the filter with water (308 L) at 35-45°C. After draining, the wet cake was washed with n-heptane (2 x 126 L) at 15-30°C. The material was dried under vacuum at 45-55°C for 12.5 hours to give the desired compound (78.4 kg, 88% yield) with an AUC purity of 99.8%. Step 3 based on Scheme B: [ka]

[0260] The crude material (77.9 kg, 1.0 equiv.) was combined with acetone (1,172 L) and heated at 45–55°C until completely dissolved. The resulting solution was polish-filtered and transferred to another reactor. The filter assembly was rinsed with warm (45–55°C) acetone (2 × 160 L), and the rinse was combined with the product filtrate. The resulting solution was distilled below 75°C to a total volume of approximately 818 L and then adjusted to reflux at 55–60°C for 1 hour. The reaction mixture was then cooled to 45–55°C and seeded with product (390 g, 0.5% (w / w)). The mixture was held at that temperature for 2 hours and distilled below 75°C to a total volume of approximately 467 L. The mixture was then held at 45–55°C for 4 hours, after which n-heptane (240 L) was added at that temperature. The resulting slurry was held at 45–55°C for an additional 2 hours. n-Heptane (706 L) was added while maintaining the temperature. The mixture was then held at 45-55 °C for 2 hours and slowly cooled to 15-25 °C over a 4-hour period. The mixture was slowly cooled to 0-10 °C over a 1.5-hour period and held at that temperature for 6 hours. The resulting suspension was filtered, and the cake was washed with cold (0-10 °C) 1:2 acetone:n-heptane (2 × 152 L). The material was dried under vacuum at 45-55 °C for 10 hours to give the desired compound (65.1 kg, 84% yield) with an AUC purity of 99.9%. [Table 19]

[0261] Alternatively, the crude material (5.07 g, 1 equiv.) was combined with 12 volumes of acetone (60.8 mL) and heated to 50° C. until completely dissolved. The solution was heated to 75° C. and concentrated to a level of approximately 6 volumes (30.4 mL). The mixture was cooled to 50° C. and 3 volumes of n-heptane (16.8 mL) were added over 1.5 hours (2 volumes / hour). The mixture was held for 2 hours, then another 8.9 volumes of n-heptane (45.1 mL) were added over 4.5 hours (2 volumes / hour) and held again for 2 hours. The solution was cooled to 5° C. over 4.5 hours and held for 5 hours. The solid was collected by filtration and washed with a mixture of acetone:n-heptane (35:65% by volume) at 5° C. The material was dried under vacuum at 50° C. to give the desired compound (4.31 kg, 85.1% yield (w / w)) with an AUC purity of 99.3%.

[0262] XRPD shows that the product obtained from step 3 is crystalline form A (Figure 1). DSC shows endotherms with onset peaks at about 191.7±2°C and about 197.9±2°C and an exotherm therebetween with an onset at about 194.9±2°C (Figure 2).

[0263] Alternatively, 7 volumes of MeOH:water (8:2 volumes) were added to the free base of Compound (I), and the mixture was stirred and heated to approximately 65°C until dissolved (approximately 10 minutes). The temperature of the solution was reduced to approximately 60°C, and water (1 volume) was added. The solution was seeded with 1 wt.% of crystalline Form A and stirred at approximately 60°C for approximately 1 hour. Water (11 volumes) was added at a rate of 2 volumes / hour to achieve a final MeOH:water composition of 3:7 volumes. The slurry was cooled to approximately 60°C from approximately 10°C at a rate of 10°C / hour over 5 hours, and the resulting slurry was stirred O / N at 10°C. The slurry was filtered and washed with 3 volumes of cold MeOH:water (3:7 volumes). The wet cake material was dried under vacuum (-29 inHg) at 50°C overnight.

[0264] Alternatively, about 25-30 mg of Compound (I) free base was dissolved in a solvent at 50° C. until dissolved.

[0265] In the slow cooling experiments, the solutions (i.e., in 30 volumes of MeOH, 49 volumes of EtOAc, 18 volumes of acetone, or 13 volumes of IPA:water (9:1 by volume)) were cooled to 5°C at 5°C per hour with mixing over 9 hours. This was achieved by decreasing the temperature of the cooling manifold by 0.083°C per minute. The experiments were held at 5°C until a solid was observed, which was then collected for XRPD analysis to give crystalline Form A.

[0266] For fast cooling, the solution (i.e., in 30 volumes of MeOH, 49 volumes of EtOAc, 18 volumes of acetone, or 9 volumes of acetone:water (7:3 volumes)) was transferred to an ice-water bath at approximately 0°C without mixing. After 10 minutes in the ice-water bath, mixing was resumed. If precipitation was observed, the slurry was immediately filtered. If no solids precipitated from solution after 2 hours at 0°C, the solution was further cooled to -20°C by placing in a freezer without mixing to obtain crystalline Form A.

[0267] Alternatively, approximately 25 mg of Compound (I) free base was dissolved in 0.5 mL of THF, and then 1.0 mL of MtBE was added over 60 minutes with mixing to obtain crystalline Form A.

[0268] Alternatively, 101.2 mg of Compound (I) free base was suspended in 1 mL of acetone:water (1:1 by volume) to form a slurry, which was stirred overnight at room temperature (RT). The slurry was filtered, and the solid was dried under vacuum at 50° C. for 3 hours to obtain pure crystalline Form A.

[0269] Alternatively, approximately 25-30 mg of Compound (I) free base was suspended in acetone:water (7:3 by volume) to form a slurry, which was stirred overnight at 50° C. The slurry was filtered and optionally dried to obtain pure crystalline Form A. 1.2 Form B

[0270] 402.5 mg of Compound (I) free base was dissolved in 10 mL of acetone and a stir bar was added. The slurry was heated on a hot plate at 50°C until dissolved, and the solution was syringe filtered through a 0.45 μm filter into a tared 20 mL vial. A light stream of nitrogen gas was blown through the vial while the solution was stirred. After 5 minutes, some solids were visible in the vial, and the mixture was seeded with a spatula tip to form B. After 10 minutes, the solvent was evaporated and the vial was dried under vacuum (-29 inHg) at 50°C overnight.

[0271] Alternatively, 400.7 mg of Compound (I) free base was sonicated in 10 mL of acetone (25 volumes) to form a pale yellow solution. The solution was stirred at room temperature while a stream of nitrogen gas was blown through the vial. Within 15 minutes, the solvent evaporated. The vial was dried under vacuum (-29 inHg) at 50°C for 2.5 hours.

[0272] XRPD analysis confirmed that the resulting product was crystalline form B (Figure 3). DSC has a broad endotherm with an onset peak at about 198.7±2°C (Figure 4).

[0273] 1.3 Form C 409.1 mg of Compound (I) free base was stirred in 20 mL of ACN:water (1:1 by volume) at 50°C for 5 minutes until a thin, cloudy slurry was formed. This mixture was divided equally into two new 20 mL vials, and 2 mL of ACN:water (1:1 by volume) was added. The mixture was completely dissolved and syringe filtered into new 20 mL vials using a 0.45 μm filter. The filtered solutions were frozen in liquid nitrogen for 5 minutes and lyophilized overnight. XRPD analysis of the solids produced by lyophilization revealed crystalline Form C.

[0274] XRPD analysis confirmed that the resulting product was crystalline form C (Figure 5). DSC showed three broad endotherms with onset peaks at about 30.6±2°C, about 170.5±2°C, and about 198.4±2°C, and two broad exotherms with onset peaks at about 176.8±2°C and 253.7±2°C (Figure 6).

[0275] 1.4 Form D After adding 11 volumes of water to the free base of Compound (I), some particles were observed. After adding 13 volumes, the final composition of IPA:water (3:7 by volume) of Compound (I) was reached, but only a very thin, cloudy slurry was observed. This thin slurry was stirred at 50°C for 45 minutes, then every 15 minutes (2 The mixture was cooled to RT (room temperature) by decreasing the temperature by 2.5° C. (over 1 hour). When the temperature reached 46° C., a fluid slurry was observed.

[0276] XRPD analysis confirmed that the resulting product was crystalline form D (Figure 7). DSC showed two broad endotherms with onset peaks at about 90.6±2°C and about 200.1±2°C (Figure 8).

[0277] 1.5 Form E Crystalline form F was dried under active vacuum at RT (room temperature) for up to 28 hours to produce crystalline form E. XRPD analysis confirmed that the resulting product was crystalline form E (Figure 9). DSC has four broad endotherms with onset peaks at about 89.9±2°C, about 100.1±2°C, about 190.9±2°C, and about 199.9±2°C, and a broad exotherm with onset peak at about 242.0±2°C (Figure 10).

[0278] 1.6 Form F Crude material of the free base of Compound (I) was dissolved in MeOH:water (9:1 by volume), and water (5-10 volumes to reach 50-70% by volume of water in the system) was added at a rate of 1 volume / hour to 3 volumes / hour at 35°C or 50°C, followed by cooling to 10°C. The resulting wet cake solid was crystalline form F. XRPD analysis confirmed that the resulting product was crystalline form F (Figure 11).

[0279] Alternatively, crude Compound (I) free base was dissolved in MeOH:EtOH:water (6.87 vol, 0.9 vol, and 2.0 vol, respectively). Water (1 vol) was added at 65° C., followed by additional water (1 vol) over 30 minutes at 35° C., and then the solvent mixture was cooled to 10° C. The resulting wet cake solid was crystalline Form F.

[0280] 1.7 Amorphous Form Approximately 100 mg of Compound (I) free base in each of four vials was placed on a hot plate and the temperature was increased to 220°C. After the temperature was held at 220°C for 5 minutes, the vials were immediately placed in a container of liquid nitrogen and held there for 5 minutes. The vials were then allowed to reach RT (room temperature) on the lab bench over 10 minutes. Each vial was sampled for XRPD, which showed an amorphous solid for each sample.

[0281] Example 2 Preparation and Characterization of Selected Polymorphic Forms of Compound (I) Salts 2.1 Toluene-4-sulfonate or tosylate form 6-B 762.7 mg of Compound (I) free base was dissolved in 25 mL of TFE to a concentration of 30.51 mg / mL. 25 mg of Compound (I) free base in 819.5 μL of TFE was added to 203.0 mg of toluene-4-sulfonic acid in 10 mL of EtOH. The mixture was stirred uncapped at 40°C overnight to evaporate the solvent. The next day, the temperature was increased to 45°C, and a stream of nitrogen gas was used to evaporate the remaining solvent. The vial was then dried under vacuum (-29 inHg) at 50°C overnight to dry the solid. EtOH (0.5 mL) was added to the dried solid, and the mixture was stirred at 45°C for 2 hours, followed by stirring at room temperature for at least 2 hours. The slurry was filtered and plated for XRPD analysis. The plate with the wet material was dried under vacuum (-29 inHg) at 50°C for 2 hours, and the dried solid was analyzed by XRPD.

[0282] XRPD analysis confirmed that the resulting product was crystalline toluene-4-sulfonate salt Form 6-B of Compound (I) (Figure 13). DSC showed five broad endotherms with onset peaks at about 30.8±2°C, about 102.5±2°C, about 106.3±2°C, about 157.3±2°C, and about 185.8±2°C, and two exotherms with onset peaks at about 173.1±2°C and about 177.6±2°C (Figure 14).

[0283] 2.2 Toluene-4-sulfonate or tosylate form 6-C 25 mg of Compound (I) free base in 819.5 μL of TFE was added to 203.0 mg of toluene-4-sulfonic acid in 10 mL of EtOH. The mixture was stirred uncapped at 40° C. overnight to evaporate the solvent. The next day, the temperature was increased to 45° C., and a stream of nitrogen gas was used to evaporate the remaining solvent. The vial was then dried under vacuum (−29 inHg) at 50° C. overnight to dry the solid. IPA:water (9:1 by volume) was added (0.5 mL) to the dried solid, and the mixture was stirred at 45° C. for 2 hours, followed by stirring at room temperature for at least 2 hours. The slurry was filtered and plated for XRPD analysis. The plate with the wet material was dried under vacuum (−29 inHg) at 50° C. for 2 hours, and the dried solid was analyzed by XRPD.

[0284] XRPD analysis confirmed that the resulting product was the crystalline toluene-4-sulfonate salt form 6-C of Compound (I) (Figure 15). DSC has a broad endotherm with an onset peak at approximately 165.5±2°C (Figure 16).

[0285] 2.3 Toluene-4-sulfonate or tosylate form 6-D 233.9 mg (1.1 equiv.) of toluene-4-sulfonic acid was dissolved in 6 mL (15 vol.) of EtOH:MtBE (1:1 vol.). The resulting solution was added via pipette to 400.6 mg of Compound (I) free base as a solid, and the resulting mixture was stirred at room temperature with an additional 2 mL (5 vol.) of EtOH:MtBE (1:1 vol.). After 2 hours, crystalline toluene-4-sulfonic acid salt Form 6-D was obtained from the slurry. The slurry was allowed to stir for 2-3 days, with no change in XRPD observed. The slurry was filtered and washed twice with 2 volumes of EtOH:MtBE (1:1 vol.). The solid was transferred to a tared vial, weighed, and the wet cake was then dried under vacuum (-29 inHg) at 50°C overnight. The dried solid was weighed the next day, yielding 495.1 mg (84 mol%).

[0286] XRPD analysis confirmed that the resulting product was crystalline toluene-4-sulfonate salt form 6-D of Compound (I) (Figure 17). DSC showed two broad endotherms with onset peaks at about 172.3±2°C and about 195.3±2°C, and a broad exotherm with onset peak at about 177.9±2°C (Figure 18).

[0287] 2.4 Ethanesulfonate or Ethanesulfonate Form 7-A 100.25 μL (1.1 equivalents) of ethanesulfonic acid was dissolved in 6 mL (15 volumes) of EtOH. The resulting solution was added via pipette to 400.3 mg of Compound (I) free base as a solid, and the resulting mixture was stirred at room temperature. After 2 hours, the slurry yielded crystalline Form B of the free base. The slurry was seeded with a spatula tip with crystalline ethanesulfonic acid salt Form 7-A. The slurry was stirred over the weekend. The slurry was filtered and washed twice with 2 volumes of EtOH. The solid was transferred to a tared vial, weighed, and the wet cake was dried overnight under vacuum (-29 inHg) at 50°C. The dried solid was weighed the next day, yielding 478.9 mg (92 mol%).

[0288] XRPD analysis confirmed that the resulting product was crystalline toluene-4-sulfonate salt Form 7-A of Compound (I) (Figure 19). DSC showed two broad endotherms with onset peaks at about 163.9±2°C and about 183.8±2°C, and a broad exotherm with onset peak at about 177.9±2°C (Figure 20).

[0289] 2.5 Naphthalene-2-sulfonate or Naphthalene-2-sulfonate Form 8-A 256.6 mg (1.1 equivalents) of naphthalene-2-sulfonic acid was dissolved in 6 mL (15 volumes) of EtOAc. The resulting solution was added via pipette to 400.0 mg of Compound (I) free base as a solid, and the resulting mixture was stirred at room temperature with an additional 2 mL (5 volumes) of EtOAc. After 2 hours, crystalline naphthalene-2-sulfonic acid salt Form 8-A was obtained from the slurry. The slurry was allowed to stir for 2-3 days, with no change in XRPD observed. The slurry was filtered and washed twice with 2 volumes of EtOAc. The solid was transferred to a tared vial, weighed, and the wet cake was then dried under vacuum (-29 inHg) at 50°C overnight. The dried solid was weighed the next day, yielding 519.3 mg (83 mol%).

[0290] XRPD analysis confirmed that the resulting product was crystalline naphthalene-2-sulfonate salt Form 8-A of Compound (I) (Figure 21). DSC has a broad endotherm with an onset peak at about 199.9±2°C (Figure 22).

[0291] 2.6 Hydrochloride or Hydrochloride Form 1-B Approximately 25 mg of Compound (I) free base was dissolved in 819.5 μL of TFE. A volume equivalent to 1.1 equivalents of 313.3 μL of HCl was added. EtOAc was added, and the mixture was stirred uncapped at 40° C. overnight to evaporate the solvent. The next day, the temperature was increased to 45° C., and a stream of nitrogen gas was used to evaporate the remaining solvent from each vial. The vials were then dried under vacuum (−29 inHg) at 50° C. for at least 3 hours.

[0292] XRPD analysis confirmed that the resulting product was crystalline hydrochloride salt Form 1-B of Compound (I) (Figure 23). DSC has two broad endotherms with onset peaks at approximately 199.7±2°C and approximately 204.2±2°C (Figure 24). Alternatively, the recovered solid was purified by slow crystallization by addition of ethanol-2M HCl in DEE solvent-antisolvent. The initial addition of the antisolvent did not result in crystallization. After approximately 1 hour, a bright orange precipitate slowly formed.

Claims

1. A crystalline solid form of the free base of Compound (I), represented by the following structural formula: 【Transformation 36】 The crystalline solid form is designated crystalline solid form A, and is characterized by an X-ray powder diffraction (XRPD) pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 18.1°±0.2, 23.1°±0.2, and 25.1°±0.

2.

2. A crystalline solid form of the free base of Compound (I), said crystalline solid form being designated crystalline solid form A, characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 21.4°±0.2, 25.1°±0.2, and 27.3°±0.

2.

3. 3. The crystalline solid form of any one of claims 1 or 2, wherein the crystalline solid form is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9 or 10 peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.6°±0.2, 18.1°±0.2, 19.1°±0.2, 21.4°±0.2, 23.1°±0.2, 25.1°±0.2, 26.6°±0.2, 27.3°±0.2, and 29.4°±0.

2.

4. The crystalline solid form is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks at diffraction angles (2θ) selected from the group consisting of 5.9°±0.2, 17.3°±0.2, 17.6°±0.2, 18.1°±0.2, 18.8°±0.2, 19.0°±0.2, 19.1°±0.2, 21.0°±0.2, 21.4°±0.2, 23.1°±0.2, 25.1°±0.2, 25.5°±0.2, 26.6°±0.2, 27.3°±0.2, and 29.4°±0.

2. The crystalline solid form of any one of claims 1 to 3.

5. 5. The crystalline solid form of any one of claims 1 to 4, wherein the crystalline solid form is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 5.9°±0.2, 17.6°±0.2, and 25.1°±0.

2.

6. 6. The crystalline solid form of any one of claims 1 to 5, wherein the crystalline solid form is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 5.9°±0.2, 17.6°±0.2, 21.4°±0.2, 23.1°±0.2, and 25.1°±0.

2.

7. 7. The crystalline solid form of any one of claims 1 to 6, wherein the crystalline solid form is characterized by an XRPD pattern substantially similar to Figure 1.

8. 8. The crystalline solid form of any one of claims 1 to 7, wherein the crystalline solid form is characterized by differential scanning calorimetry (DSC) as having two endotherms with onset peaks at 186.2±2°C and 197.5±2°C.

9. 9. The crystalline solid form of any one of claims 1 to 8, obtained by a process comprising recrystallizing compound (I) in a solvent mixture comprising acetone and n-heptane.

10. 10. The crystalline solid form of claim 9, wherein the crystalline solid form is prepared by one or both of the following steps: a. dissolving compound (I) in acetone at elevated temperature to form a solution; and b. The crystalline solid form obtained by a process comprising evaporation in a solvent mixture comprising acetone and n-heptane and cooling crystallization.

11. A crystalline solid form of the free base of Compound (I), represented by the following structural formula: 【Chemistry 37】 The crystalline solid form is designated crystalline solid form B, and is characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 14.9°±0.2, 17.3°±0.2, 23.9°±0.2, and 24.6°±0.

2.

12. A crystalline solid form of the free base of Compound (I), said crystalline solid form being designated crystalline solid form B, characterized by an XRPD pattern comprising three, four, or five peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 17.3°±0.2, 21.5°±0.2, 25.3°±0.2, and 29.1°±0.

2.

13. The crystalline solid form is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9 or 10 peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 14.9°±0.2, 17.3°±0.2, 19.5°±0.2, 21.0°±0.2, 21.5°±0.2, 23.9°±0.2, 24.6°±0.2, 25.3°±0.2, and 29.1°±0.

2.

13. The crystalline solid form of any one of claims 11 or 12.

14. 14. The crystalline solid form of any one of claims 11-13, wherein the crystalline solid form is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 peaks at diffraction angles (2θ) selected from the group consisting of 5.8°±0.2, 12.6°±0.2, 14.9°±0.2, 17.3°±0.2, 17.8°±0.2, 18.6°±0.2, 19.5°±0.2, 21.0°±0.2, 21.5°±0.2, 23.3°±0.2, 23.9°±0.2, 24.6°±0.2, 25.3°±0.2, 28.9°±0.2, and 29.1°±0.

2.

15. 15. The crystalline solid form of any one of claims 11 to 14, wherein the crystalline solid form is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 5.8°±0.2, 17.3°±0.2, and 25.3°±0.

2.

16. 16. The crystalline solid form of any one of claims 11 to 15, wherein the crystalline solid form is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 5.8°±0.2, 17.3°±0.2, 21.5°±0.2, 25.3°±0.2, and 29.1°±0.

2.

17. 17. The crystalline solid form of any one of claims 11 to 16, wherein the crystalline solid form is characterized by an XRPD pattern substantially similar to Figure 3.

18. 18. The crystalline solid form of any one of claims 11 to 17, wherein the crystalline solid form is characterized by DSC having a broad endotherm with an onset peak at 198.5±2°C.

19. 19. The crystalline solid form of any one of claims 11 to 18, comprising one or both of the following steps: a. dissolving the compound (I) in acetone at elevated temperature to form a solution; and b. evaporating said acetone.

20. A crystalline solid form of the free base of Compound (I), represented by the following structural formula: 【Transformation 38】 The crystalline solid form is designated crystalline solid form C and is characterized by an XRPD pattern comprising three, four, five, or six peaks at diffraction angles (2θ) selected from the group consisting of 8.7°±0.2, 10.6°±0.2, 13.4°±0.2, 15.3°±0.2, 19.0°±0.2, and 25.8°±0.

2.

21. 21. The crystalline solid form of claim 20, wherein the crystalline solid form is characterized by an XRPD pattern comprising 3, 4, 5, 6, 7, 8, 9, or 10 peaks at diffraction angles (2θ) selected from the group consisting of 8.7°±0.2, 10.6°±0.2, 13.4°±0.2, 15.3°±0.2, 16.2°±0.2, 19.0°±0.2, 19.8°±0.2, 21.4°±0.2, 22.6°±0.2, and 25.8°±0.

2.

22. 22. The crystalline solid form of claim 20 or 21, wherein the crystalline solid form is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 8.7°±0.2, 15.3°±0.2, and 25.8°±0.

2.

23. 23. The crystalline solid form of any one of claims 20-22, wherein the crystalline solid form is characterized by an XRPD pattern having characteristic peaks at diffraction angles (2θ) of 8.7°±0.2, 15.3°±0.2, 19.0°±0.2, 19.8°±0.2, and 25.8°±0.

2.

24. 24. The crystalline solid form of any one of claims 20-23, wherein the crystalline solid form is characterized by an XRPD pattern substantially similar to Figure 5.

25. 25. The free base of any one of claims 20-24, wherein the crystalline form C is characterized by a DSC with three broad endotherms with onset peaks at 30.6±2°C, 170.5±2°C, and 198.4±2°C, and two broad exotherms with onset peaks at 176.8±2°C and 253.7±2°C.

26. 26. The free base of any one of claims 20 to 25, further comprising one or more steps selected from the group consisting of: a. Dissolving Compound (I) in a solvent mixture comprising acetonitrile and water; and b. lyophilization.

27. An amorphous form of the free base of Compound (I), represented by the following structural formula: 【Chemistry 39】

28. A crystalline solid form of a pharmaceutically acceptable salt of Compound (I), represented by the following structural formula: 【Chemistry 40】 The crystalline solid form, wherein the salt is selected from the group consisting of methanesulfonate, ethanesulfonate, benzenesulfonate, tosylate, naphthalene-2-sulfonate, glycinate, succinate, citrate, tartrate, adipate, aspartate, histidine, vanillin, phosphate, hydrochloride, hydrobromide, nitrate, and sulfate.

29. 29. The salt form of claim 28, wherein the crystalline solid form is a tosylate salt form.

30. 30. The salt of claim 29, wherein the crystalline solid form is designated crystalline tosylate form 6-C, and is one or both of the following: a. An XRPD pattern substantially similar to that in Figure 15; and b. The salt is characterized by a DSC having an endotherm with an onset peak at 165.5±2°C.

31. 29. The crystalline solid form of claim 28, wherein the crystalline solid form is an ethanesulfonate salt form.

32. 32. The salt of claim 31 , wherein the crystalline solid form is designated crystalline ethanesulfonate salt form 7-A, and is one or both of the following: a. An XRPD pattern substantially similar to Figure 19; and b. The salt is characterized by a DSC having a broad endotherm with an onset peak at 183.8±2° C.

33. 29. The crystalline solid form of claim 28, wherein the crystalline solid form is a naphthalene-2-sulfonate salt form.

34. 34. The crystalline solid form of claim 33, designated crystalline naphthalene-2-sulfonate Form 8-A, comprising one or both of the following: a. An XRPD pattern substantially similar to that in Figure 21; and b. The crystalline solid form, characterized by a DSC having a broad endotherm with an onset peak at 199.9±2° C.

35. 29. The crystalline solid form of claim 28, wherein the crystalline solid form is a hydrochloride salt form.

36. 36. The crystalline solid form of claim 35, wherein the crystalline solid form is designated crystalline hydrochloride salt form 1-B and comprises one or both of the following: a. An XRPD pattern substantially similar to Figure 23; and b. The crystalline solid form, characterized by a DSC having a broad endotherm with an onset peak at 199.7±2° C.

37. A pharmaceutical composition comprising a crystalline solid form of the free base of compound (I) according to any one of claims 1 to 26, an amorphous form of the free base of compound (I) according to claim 27, or a crystalline solid form of a pharmaceutically acceptable salt of compound (I) according to any one of claims 28 to 36, and a pharmaceutically acceptable carrier.

38. A pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein at least 0.1%, 0.5%, 1%, 5%, or more by weight of compound (I) or a pharmaceutically acceptable salt thereof is present in a crystalline solid form of the free base of compound (I) according to any one of claims 1 to 26, an amorphous form of the free base of compound (I) according to claim 27, or a crystalline solid form of a pharmaceutically acceptable salt of compound (I) according to any one of claims 28 to 36.

39. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of a crystalline solid form of the free base of compound (I) according to any one of claims 1 to 26, an amorphous form of the free base of compound (I) according to claim 27, or a crystalline solid form of a pharmaceutically acceptable salt of compound (I) according to any one of claims 28 to 36, or a pharmaceutical composition according to claim 37 or 38.

40. 40. The method of claim 39, wherein the cancer is breast cancer.

41. 40. The method of claim 39, wherein the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and pulmonary adenosarcoma.

42. 36. A method of treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, comprising administering to the patient a therapeutically effective amount of a crystalline solid form of the free base of compound (I) according to any one of claims 1 to 26, an amorphous form of the free base of compound (I) according to claim 27, or a crystalline solid form of a pharmaceutically acceptable salt of compound (I) according to any one of claims 28 to 36, or a pharmaceutical composition according to any one of claims 37 or 38.

43. 43. The method of claim 42, wherein the solid tumor cancer is selected from the group consisting of uterine cancer (including uterine carcinosarcoma and uterine endometrial carcinoma), endometrial cancer, breast cancer (including breast invasive carcinoma, TNBC (triple-negative breast cancer), ER (estrogen receptor) + HER2 (human epidermal growth factor 2) - breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), gastric cancer (gastric adenocarcinoma), and gastric cancer (including gastrointestinal stromal tumor). the cancer is at least one of: colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, e.g., epidermal growth factor receptor mutant (EGFRm)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.

44. A process for preparing compound (I), comprising: 【Chemistry 41】 A first compound represented by formula (1): 【Chemistry 42】 and a second compound represented by formula (2): 【Chemistry 43】 and reacting The method, wherein reacting the first and second compounds further comprises a base to activate the diamine compound (2), which then reacts with the heteroaryl chloride compound (1).

45. 45. The method of claim 44, wherein the base is a strong non-nucleophilic amide base.

46. 46. ​​The method of claim 45, wherein the strong non-nucleophilic amide base is LiHMDS (lithium bis(trimethylsilyl)amide), NaHMDS (sodium bis(trimethylsilyl)amide), KHMDS (potassium bis(trimethylsilyl)amide), or lithium diisopropylamide (LDA).

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