Azaindazole macrocycle solid forms

Abstract

This disclosure relates to solid forms of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3',4'-j:4'',3''-n][1,4]oxazacyclopentadecin-14-yl]propan-1-ol that are useful in the treatment of disease, such as cancer, in mammals. This disclosure also relates to the preparation of such solid forms, including polymorphs, salts, cocrystals, solvates, hydrates, or a combination thereof. This disclosure also relates to compositions including such solid forms, and to methods of using such compositions in the treatment of diseases, such as cancer, in mammals, especially in humans.

Description

AZAINDAZOLE MACROCYCLE SOLID FORMSRELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 846,511, filed July 18, 2025, U.S. Provisional Application No. 63 / 815,539, filed May 31, 2025, and U.S. Provisional Application No. 63 / 677,368, filed July 30, 2024, the entire disclosure of each of which is incorporated herein by reference.TECHNICAL FIELD

[0002] This disclosure relates to solid forms of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20- pentamethyl-2,8,10,1 l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’- j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol that are useful in the treatment of disease, such as cancer, in mammals. This disclosure also relates to the preparation of such solid forms, including polymorphs, salts, cocrystals, solvates, hydrates, or a combination thereof. This disclosure also relates to compositions including such solid forms, and to methods of using such compositions in the treatment of diseases, such as cancer, in mammals, especially in humans.BACKGROUND

[0003] The compound, (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (also herein referred to as “Compound I’-), represented by the formula Iis a potent small-molecule kinase inhibitor showing potency against EGFR (epidermal growth factor receptor) having a broad range of mutations, including E709K, K716A, K716Q, L718Q, G719C, G719D, G719S, G724S, K728A, L747P, A746, L747S, D761Y, S768I, D769H, D769Y, D770G / Y, V777L, T790M, L792F, L792H, C797A, C797S, L858R, L861Q, R896C, R999A, Exl9del (such as A746-750 or A752-759), A763-Y764insFHEA, A763-Y764insFQEA, A767- S768insTLA, V769-D770insASV, V769-D770insGE, D770-N771insNPG, D770-N771insSVD, N771-P772insH, H773-V774insNPH, A775-G776insYVMA, V777-G778insCG,K716Q / L718Q, A746-750 / T790M, A746-750 / C797A, A746-750 / C797S, A747-752 / P753S, D770-N771insNPG / Y790M, L858R / T790M, L858R / C797S, L792H / L858R,C775S / T790M / L858R, L858R / T790M / C797S, A746-750 / T790M / C797S,K716A / C797S / L858R, L718V / L858R / T790M, T790M / L792F / L858R, T790M / L792H / L858R, L792H / C797S / L858R, K716A / T790M / C797S / L858R, K728A / T790M / C797S / L858R, A746- 750 / C775S / T790M / L858R, A746-750 / T790M / C797S / L858R, andT790M / L792F / C797S / L858R, while maintaining good selectivity over wild-type EGFR. Compound I has properties, including anti-tumor properties, that are pharmacologically mediated through, for example, mutant-selective inhibition EGFR having a broad range of mutations, including those described herein. Compound I is disclosed in International Patent Application No. PCT / US2024 / 027195, published as WO2024229087A1, which is incorporated herein by reference in its entirety.

[0004] Protein kinases are tightly regulated signaling proteins that orchestrate the activation of signaling cascades by phosphorylating target proteins in response to extracellular and intracellular stimuli. The human genome encodes approximately 518 protein kinases (Manning G, et al., The protein kinase complement of the human genome. Science. 2002, 298: 1912-34). Dysregulation of kinase activity is associated with many diseases, including cancers, and cardiovascular, degenerative, immunological, infectious, inflammatory, and metabolic diseases (Levitzki, A., Protein kinase inhibitors as a therapeutic modality. Acc. Chem. Res. 2003, 36:462- 469). The molecular bases leading to various diseases include kinase gain- and loss-of-function mutations, gene amplifications and deletions, splicing changes, and translocations (Wilson LJ, et al., New Perspectives, Opportunities, and Challenges in Exploring the Human Protein Kinome. Cancer Res. 2018, 78: 15-29). The critical role of kinases in cancer and other diseases makes them attractive targets for drug inventions with 62 small molecule kinase inhibitors have been approved and 55 of them for cancer targeted therapies (Roskoski R Jr, Properties of FDA-approved Small Molecule Protein Kinase Inhibitors: A 2021 Update. Pharmacol Res 2021, 165: 105463). Although kinase inhibitors have achieved dramatic success in cancer targeted therapies, the development of treatment resistance has remained as a challenge for small molecule kinase inhibitors. Acquired secondary mutations within kinase domain during the treatment often lead to treatment resistance to kinase inhibitors (Pottier C, et al., Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy. Cancers (Basel), 2020, 12:731). Resistance can also arise from subpopulations of tolerant / persister cells that survive in the presence of the treatment. Different processes contribute to the emergence of tolerant persister cells, including pathway rebound through the release of negative feedback loops, transcriptional rewiring mediated by chromatin remodeling and autocrine / paracrine communication among tumor cellsand within the tumor microenvironment (Swayden M, et al., Tolerant / Persister Cancer Cells and the Path to Resistance to Targeted Therapy. Cells 2020, 9, 2601). Therefore, it is necessary to invent kinase inhibitors that can target not only the kinase oncogenic drivers, overcome most frequent resistance mutations, but also tolerant persister cancer cells for overcoming resistance, achieving better efficacy and longer disease control.

[0005] Non-small-cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide (World Health Organisation. Cancer Fact Sheet 2017). Activating EGFR mutations have been reported in approximately 10% to 15% of cases of adenocarcinoma in white patients and 50% of cases in Asian patients (Chan BA, Hughes BG, Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Trans! Lung Cancer Res 2015; 4:36-54). The two most frequent EGFR alterations found in NSCLC tumors are short in-frame deletions in exon 19 (dell9) of the EGFR gene and L858R, a single missense mutation in exon 21 (Konduri K. et al., EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discovery 2016, 6:601- 11).

[0006] The first-generation reversible EGFR inhibitors, erlotinib and gefitinib are superior to chemotherapy in patients with advanced EGFR mutation-positive (Dell9 or L858R) NSCLC and have been used as first-line standard of care in this setting. However, most patients will develop resistance to gefitinib or erlotinib with 50% to 70% of tumors developing EGFR T790M gatekeeper mutation with time of treatment (Sequist LV, et al., Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3:75ra26). The second generation of EGFR inhibitors afatinib and dacomitinib are covalent, irreversible EGFR inhibitors that also inhibit HER2 and ERB4 of the ERB family (Li D, et al., BIBW2992, an irreversible EGFR / HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 2008; 27: 4702-11; Ou SH, Soo RA. Dacomitinib in lung cancer: a "lost generation" EGFR tyrosine-kinase inhibitor from a bygone era? Drug Des Devel Ther 2015; 9:5641-53).

[0007] Although afatinib and dacomitinib are more potent EGFR inhibitors approved as first-line therapy for advanced EGFR mutation-positive (Dell9 or L858R) NSCLC with longer progression free survival time (PFS) in comparison with gefitinib and erlotinib, EGFR T790M has been developed with time of treatment with afatinib (Tanaka K, et al., Acquisition of the T790M resistance mutation during afatinib treatment in EGFR tyrosine kinase inhibitor-naive patients with non-small cell lung cancer harboring EGFR mutations. Onco-target 2017; 8:68123- 30). EGFR T790M confers resistance to dacomitinib In vitro studies (Kobayashi Y, et al., EGFR T790M and C797S mutations as mechanisms of acquired resistance to dacomitinib. J Thorac 13: 727-31). The third-generation EGFR inhibitor Osimertinib is also an irreversibleinhibitor targeting both EGFR activating mutations (Dell9 and L858R) and T790M resistant double mutations, with selectivity over the wild-type EGFR (Finlay MR, et al., Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem 2014; 57:8249-67). Osimertinib was first approved for patients with metastatic EGFR T790M mutation-positive NSCLC after failure of first-line EGFR inhibitors, and later approved in the first-line setting for patients with EGFR mutation-positive NSCLC following the phase III FLAURA trial with head- to-head trials comparing with erlotinib or gefitinib (Soria JC, et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378:113-25). The mutation C797S at the EGFR covalent binding residue with irreversible EGFR inhibitor Osimertinib has been detected in Osimertinib-resistant patients (Ramalingam SS, et al., Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Presented at the ESMO 2018). EGFR mutations (L858R or exon 19 deletions (Exl9del)) are classified as EGFR classic mutations, or common mutations, which showed marked efficacy with currently approved EGFR inhibitors.

[0008] While Compound I has found application in treating disease through inhibition of a broad range of classical, atypical, and compound EGFR mutations, while maintaining good selectivity over wild-type EGFR, it is advantageous to have alternative forms (such as salt, cocrystal, hydrate, polymorphic, and combinations thereof) having improved properties, such as improved crystallinity, dissolution properties, and / or decreased hygroscopicity, while maintaining chemical and enantiomeric stability properties, and / or to provide enhanced efficacy through improved or modified PKPD properties (e.g., bioavailability), drug product dissolution properties, and the like.SUMMARY

[0009] In one aspect, the present disclosure provides a solid form of (2S)-2-[(10S,17E)-16- ethoxy-6,8, 10, 12,20-pentamethyl-2,8, 10, 11 ,12,13-hexahydro- 14H-5 ,3- (azenometheno)tripyrazolo[3 ,4-f : 3 ’ ,4’ -j :4 ” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol (Compound I) comprising one or more equivalents of Compound I, wherein the solid form of Compound I comprises a salt, a free base, or a combination thereof, and optionally one or more of an acid or water, provided that when the Compound I comprises a salt, then the solid form comprises one or more of an acid.

[0010] In some embodiments, the disclosure provides a crystalline polymorph form of (2S)-2- [(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l 1,12,13-hexahydro- 14H-5, 3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -olis an anhydrous free base. In some embodiments, the disclosure provides a crystalline polymorph form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14- yl]propan-l-ol comprises a salt. In some embodiments, the crystalline polymorph form of (2S)- 2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8, 10,l l ,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol is a salt. In some embodiments, the crystalline polymorph form of (2S)-2-[(10S,17E)-16-ethoxy- 6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol is an anhydrous salt. In some embodiments, the solid form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a solvate. In some embodiments, the solid form of (2S)-2-[(I0S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a cocrystal. In some embodiments, the solid form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a cocrystal of a salt. In some embodiments, the solid form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,11,12,13 -hexahydro- 14H- 5 , 3 - (azenometheno)tripyrazolo [3 ,4-f :3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a hydrate, such as a hemihydrate, a monohydrate, or a dihydrate, and the like. In some embodiments, the solid form of (2S)-2- [(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol comprises a cocrystal of a salt and a hydrate.[Oil] In some embodiments, the disclosure provides a crystalline polymorph form of (2S)-2- [(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol comprising a cocrystal of a (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol with a salt of a (2S)-2-[(10S,17E)-16-ethoxy- 6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol. In some embodiments, the crystalline polymorph form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a cocrystal of a (2S)-2-[(10S,17E)- 16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol with a salt of a (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol and a hydrate. In some embodiments, the crystalline polymorph form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a cocrystal of a (2S)-2-[(10S,17E)- 16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol with a salt of a (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol, wherein the salt comprises a dicarboxylic acid. In some embodiments, the crystalline polymorph form of (2S)-2-[(10S,17E)-16-ethoxy- 6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a cocrystal of a (2S)- 2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol with a salt of a (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol and a hydrate, wherein the salt comprises a dicarboxylic acid.

[0012] In some embodiments, the disclosure provides a crystalline polymorph form of (2S)-2- [(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol comprises a hemihydrate cocrystal of a salt, wherein the hemihydrate cocrystal of a salt comprises a first Compound I, a second Compound I, one equivalent of water, and one equivalent of a dicarboxylic acid. In some embodiments, the crystalline polymorph form of (2S)-2-[(10S,17E)- 16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol comprises a hemihydrate cocrystal of a salt, wherein the hemihydrate cocrystal of a salt comprises a first Compound I, a second Compound I, a water, and a dicarboxylic acid, wherein one carboxylic acid on the dicarboxylic acid forms a salt with the amine of the first Compound I, andthe other carboxylic acid on the dicarboxylic acid forms a cocrystal with the amine of the second Compound I and the water.

[0013] hi some embodiments, the disclosure provides a crystalline polymorph form of (2S)-2- [(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l 1,12,13-hexahydro-14H-5, 3- (azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”-n][l ,4]oxazacyclopentadecin-14-yl]propan-l -ol comprising a cocrystal of a (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol with a mono-(2S)-2-[(10S,17E)-16-ethoxy- 6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol oxalate and a water.

[0014] In some embodiments, Compound I can be represented by the formulaI wherein the Compound I has been shown to exist as form A (a.k.a. crystalline polymorph formA or anhydrous crystalline polymorph form A of Compound I free base).

[0015] In some embodiments, Compound I has been shown to exist in a crystalline form represented by the formula

[0016] wherein the crystalline form is a cocrystal of a Compound I with a mono-Compound I oxalate and a water.

[0017] In some embodiments, (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8, 10, 11 , 12, 13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4-f:3 ’ ,4 ’ -j :4” ,3 ” - n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol has been shown to exist as crystalline form represented by the formula

[0018] wherein the crystalline form is a cocrystal of a (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol with a mono-(2S)-2- [( 1 OS, 17E)- 16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l 1,12,13-hexahydro-14H-5, 3- (azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”-n][l ,4]oxazacyclopentadecin-14-yl]propan-l -ol oxalate and a water.

[0019] In some embodiments, the present disclosure further provides a pharmaceutical composition comprising a polymorph form A of Compound I of the formula

[0020] In some embodiments, the disclosure provides a pharmaceutical composition comprising a crystalline form of Compound I represented by the formula

[0021] wherein the crystalline form is a cocrystal of a Compound I with a mono-Compound I oxalate and a water.

[0022] The present disclosure further provides a capsule comprising pharmaceutical compositions as described herein.

[0023] In another aspect, the disclosure provides a method of treating disease, such as cancer, in a mammal, including a human, the method comprising administering to the mammal atherapeutically effective amount of a crystalline form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol, as described herein, or a pharmaceutical composition comprising a crystalline form of (2S)-2-[(10S,17E)-16-ethoxy-6.8.10.12.20-pentamethyl-2,8, 10,l 1 ,12, 13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol, as described herein. In some embodiments, the crystalline form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol is polymorph form A of (2S)-2-[(10S,17E)-16- ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol. hi some embodiments, the crystalline form is a cocrystal of a (2S)-2-[(10S,17E)-16-ethoxy-6.8.10.12.20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f : 3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol with a mono-(2S )-2- [( 1 OS , 17E)- 16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol oxalate and a water.

[0024] In another aspect, the present disclosure provides a method of treating abnormal cell growth in a mammal, including a human, in need of such treatment comprising, administering to said mammal a therapeutically effective amount of a solid form (e.g., a crystalline form) of Compound I. In some embodiments, the crystalline form is polymorph form A of Compound I. In some embodiments, the crystalline form is a cocrystal of Compound I with a mono-Compound I oxalate and a water.

[0025] In another aspect, the present disclosure provides a process for preparing a compound of the formula II

[0026] comprising

[0027] a. contacting a compound of the formula Al

[0028] with a compound of the formula BB

[0029] in the presence of a base to provide a compound of the formula Cl

[0030] b. contacting a compound of the formula Cl in the presence of a catalyst to provide a compound of the formula DI

[0031] c. contacting a compound of the formula DI with an acid to provide the compound of the formula I.

[0032] As used herein, the terms “treat” or “treatment” encompass both “preventative” and “curative” treatment. “Preventative” treatment is meant to indicate a postponement ofdevelopment of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.

[0033] Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation. As used herein, the term “cancer” includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER+breast cancer, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid papillary cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph- like acute lymphoblastic leukemia, thyroid carcinoma, skin cutaneous melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancer includes, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophagogastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus. Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease. Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.

[0034] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular EGFR, including EGFR having one or more mutations, such as E709K, K716A, K716Q, L718Q, G719C, G719D, G719S, G724S,K728A, L747P, A746, L747S, D761Y, S768I, D769H, D769Y, D770G / Y, V777L, T790M, L792F, L792H, C797A, C797S, L858R, L861Q, R896C, R999A, Exl9del (such as A746-750, A752-759), A763-Y764insFHEA, A763-Y764insFQEA, A767-S768insTLA, V769- D770insASV, V769-D770insGE, D770-N771insNPG, D770-N771insSVD, N771-P772insH, H773-V774insNPH, A775-G776insYVMA, V777-G778insCG, K716Q / L718Q, A746- 750 / T790M, A746-750 / C797A, A746-750 / C797S, A747-752 / P753S, D770-N771insNPG / Y790M, L858R / T790M, L858R / C797S, L792H / L858R, C775S / T790M / L858R, L858R / T790M / C797S, A746-750 / T790M / C797S, K716A / C797S / L858R,L718V / L858R / T790M, T790M / L792F / L858R, T790M / L792H / L858R, L792H / C797S / / L858R, K716A / T790M / C797S / L858R, K728A / T790M / C797S / L858R, A746-750 / C775S / T790M / L858R, A746-750 / T790M / C797S / L858R, andT790M / L792F / C797S / L858R. In some embodiments, the compounds and pharmaceutical compositions of the disclosure selectively target EGFR having one or more mutations as described herein over wild-type EGFR. In some embodiments, the compounds and pharmaceutical compositions of the disclosure can be used to prevent, reverse, slow, or inhibit the activity of EGFR having one or more mutations as described herein. In certain preferred embodiments, methods of treating a target cancer are described herein, wherein the cancer comprises an EGFR having one or more mutations as described herein. In some embodiments, methods of treating lung cancer, such as non-small cell lung cancer, are described herein, wherein the lung cancer comprises an EGFR having one or more mutations as described herein.

[0035] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of EGFR, including a cancer cell having one or more EGFR mutations, such as E709K, K716A, K716Q, L718Q, G719C, G719D, G719S, G724S, K728A, L747P, A746, L747S, D761Y, S768I, D769H, D769Y, D770G / Y, V777L, T790M, L792F, L792H, C797A, C797S, L858R, L861Q, R896C, R999A, Exl9del (such as A746-750, A752-759), A763-Y764insFHEA, A763-Y764insFQEA, A767-S768insTLA, V769- D770insASV, V769-D770insGE, D770-N771insNPG, D770-N771insSVD, N771-P772insH, H773-V774insNPH, A775-G776insYVMA, V777-G778insCG, K716Q / L718Q, A746- 750 / T790M, A746-750 / C797A, A746-750 / C797S, A747-752 / P753S, D770-N771insNPG / Y790M, L858R / T790M, L858R / C797S, L792H / L858R, C775S / T790M / L858R, L858R / T790M / C797S, A746-750 / T790M / C797S, K716A / C797S / L858R,L718V / L858R / T790M, T790M / L792F / L858R, T790M / L792H / L858R, L792H / C797S / / L858R,K716A / T790M / C797S / L858R, K728A / T790M / C797S / L858R, A746-750 / C775S / T790M / L858R, A746-750 / T790M / C797S / L858R, andT790M / L792F / C797S / L858R, while maintaining good selectivity over wild-type EGFR.

[0036] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular HER2, including HER2 having one or more mutations in the kinase domain of exons 18, 19, 20, or 21, for example HER2 exon 20 mutations such as A775_G776insYVMA, 778insGCP, G780_P781dupGSP, G778_S779insCPG, Y772_A775dup, G778_P780dup, E770_A771insAYVM,A771_Y772insYVMA, V777_G778insGSP, and P780_Y781insGSP. In some embodiments, the compounds and pharmaceutical compositions of the disclosure selectively target HER2 having one or more mutations as described herein over wild-type HER2. In some embodiments, the compounds and pharmaceutical compositions of the disclosure can be used to prevent, reverse, slow, or inhibit the activity of HER2 having one or more mutations as described herein. In certain preferred embodiments, methods of treating a target cancer are described herein, wherein the cancer comprises an HER2 having one or more mutations as described herein. In some embodiments, methods of treating lung cancer, such as non-small cell lung cancer, are described herein, wherein the lung cancer comprises an HER2 having one or more mutations as described herein.

[0037] In the inhibitory methods of the disclosure, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of HER2, including a cancer cell having one or more HER2 mutations, including HER2 having one or more mutations in the kinase domain of exons 18, 19, 20, or 21, for example HER2 exon 20 mutations such as A775_G776insYVMA, 778insGCP, G780_P781dupGSP, G778_S779insCPG, Y772_A775dup, G778_P780dup, E770_A771insAYVM, A771_Y772insYVMA, V777_G778insGSP, and P780_Y781insGSP, while maintaining good selectivity over wild-type HER2.

[0038] In one aspect, the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular EGFR and / or HER2, including EGFR having one or more mutations, and / or HER2 having one or more mutations as described herein.

[0039] In treatment methods according to the disclosure, an “effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the disclosure may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routinefactors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An example dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily. The total dosage may be given in single or divided dosage units (e.g., BID, TID, QID). In some embodiments, the dose is about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID of Compound I. In some embodiments, the dose is about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg QD of Compound I. In some embodiments, the dose is about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID of polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate. In some embodiments, the dose is about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg QD of polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate.

[0040] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.

[0041] Additional embodiments, features, and advantages of the disclosure will be apparent from the following detailed description and through practice of the disclosure. The compounds of the present disclosure can be described as embodiments in any of the following enumerated clauses. It will be understood that any of the embodiments described herein can be used in connection with any other embodiments described herein to the extent that the embodiments do not contradict one another.

[0042] 1. A solid form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (Compound I).

[0043] 2. The solid form of clause 1 , wherein the solid form is a hydrate.

[0044] 3. The solid form of clause 1 or 2, wherein the solid form is a cocrystal including a polymorph form of Compound I with a second molecule of Compound I or a salt thereof.

[0045] 4. The solid form of any one of clauses 1 , 2, or 3, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate.

[0046] 5. The solid form of any one of clauses 1 to 4, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1.

[0047] 6. The solid form of any one of clauses 1 to 5, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.9 +0.1.

[0048] 7. The solid form of any one of clauses 1 to 6, wherein the solid form is a cocrystal of Compound 1 with mono-Compound 1 oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.0+0.1 and 11.9+0.1.

[0049] 8. The solid form of any one of clauses 1 to 7, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0. 1, 7.0+0.1, and 11.9+0. 1.

[0050] 9. The solid form of any one of clauses 1 to 8, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, and 13.8+0.1.

[0051] 10. The solid form of any one of clauses 1 to 9, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, and 15.1+0.1.

[0052] 11. The solid form of any one of clauses 1 to 10, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1 , 11.9+0.1, 13.8+0.1, 15.1+0.1, and 25.1+0.1.

[0053] 12. The solid form of any one of clauses 1 to 11 , wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0. 1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1.

[0054] 13. The solid form of any one of clauses 1 to 12, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern substantially the same as shown in FIG. 3.

[0055] 14. The solid form of any one of clauses 1 to 13, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 12.

[0056] 15. The solid form of any one of clauses 1 to 14, wherein the solid form is a cocrystal of Compound 1 with mono-Compound I oxalate and hydrate having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 11.

[0057] 16. The solid form of clause 1, wherein the solid form is a salt of Compound I.

[0058] 17. The solid form of clause 1 or 16, wherein the solid form is an HC1 salt ofCompound I.

[0059] 18. The solid form of any one of clauses 1 , 16, or 17, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.6+0.1, 24.6+0.1, and 24.8+0.1.

[0060] 19. The solid form of any one of clauses 1 or 16 to 18, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 12.0+0.1.

[0061] 20. The solid form of any one of clauses 1 or 16 to 19, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1 and 12.0+0.1.

[0062] 21. The solid form of any one of clauses 1 or 16 to 20, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 12.0+0.1, and 13.6+0.1.

[0063] 22. The solid form of any one of clauses 1 or 16 to 21, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 12.0+0.1, and 13.6+0.1.

[0064] 23. The solid form of any one of clauses 1 or 16 to 22, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1 , 6.6+0.1, 7.0+0.1, 12.0+0.1, and 13.6+0.1.

[0065] 24. The solid form of any one of clauses 1 or 16 to 23, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.6+0.1, and 24.6+0.1.

[0066] 25. The solid form of any one of clauses 1 or 16 to 24, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.6+0.1, 24.6+0.1, and 24.8+0.1.

[0067] 26. The solid form of any one of clauses 1 or 16 to 25, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 4.

[0068] 27. The solid form of any one of clauses 1 or 16 to 26, wherein the solid form is an HC1 salt of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 14.

[0069] 28. The solid form of any one of clauses 1 or 16 to 27, wherein the solid form is an HC1 salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 13.

[0070] 29. The solid form of clause 1 , 16, or 17, wherein the solid form is a bis-HCl salt of Compound I.

[0071] 30. The solid form of any one of clauses 1, 16, 17, or 29, wherein the solid form is a bis-HCl salt of Compound 1 having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1 , 15.5+0.1, 19.3+0.1, 19.9+0.1, 25.3+0. 1, and 26.6+0.1.

[0072] 31. The solid form of any one of clauses 1, 16, 17, 29 or 30, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 8.2+0.1.

[0073] 32. The solid form of any one of clauses 1, 16, 17, or 29 to 31, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (29) of 8.2+0.1 and 10.6+0.1.

[0074] 33. The solid form of any one of clauses 1, 16, 17, or 29 to 32, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (29) of 8.2+0.1 , 10.6+0.1, and 25.3+0.1.

[0075] 34. The solid form of any one of clauses 1, 16, 17, or 29 to 33, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (29) of 8.2+0. 1 , 10.6+0.1 , 19.9+0.1, and 25.3+0.1.

[0076] 35. The solid form of any one of clauses 1, 16, 17, or 29 to 34, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (29) of 8.2+0.1 , 10.6+0.1, 15.5+0.1, 19.9+0.1, and 25.3+0.1.

[0077] 36. The solid form of any one of clauses 1 , 16, 17, or 29 to 35, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (29) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, and 25.3+0.1.

[0078] 37. The solid form of any one of clauses 1, 16, 17, or 29 to 36, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks atdiffraction angles (20) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 25.3+0.1, and 26.6+0.1.

[0079] 38. The solid form of any one of clauses 1, 16, 17, or 29 to 37, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 5.

[0080] 39. The solid form of any one of clauses 1, 16, 17, or 29 to 38, wherein the solid form is a bis-HCl salt of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 16.

[0081] 40. The solid form of any one of clauses 1, 16, 17, or 29 to 39, wherein the solid form is a bis-HCl salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 15.

[0082] 41. The solid form of clause 1, 2, or 16, wherein the solid form is a phosphate salt of Compound 1.

[0083] 42. The solid form of clause 1 , 2, 16, or 41 , wherein the solid form is a monophosphate salt monohydrate of Compound I.

[0084] 43. The solid form of any one of clauses 1, 2, 16, 41 or 42, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

[0085] 44. The solid form of any one of clauses 1, 2, 16, or 41 to 43, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 12.7+0.1.

[0086] 45. The solid form of any one of clauses 1, 2, 16, or 41 to 44, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1 and 15.1+0.1.

[0087] 46. The solid form of any one of clauses 1, 2, 16, or 41 to 45, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, and 15.8+0.1.

[0088] 47. The solid form of any one of clauses 1, 2, 16, or 41 to 46, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, and 19.1+0.1.

[0089] 48. The solid form of any one of clauses 1, 2, 16, or 41 to 47, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, and 25.0+0.1.

[0090] 49. The solid form of any one of clauses 1, 2, 16, or 41 to 48, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

[0091] 50. The solid form of any one of clauses 1 , 2, 16, or 41 to 49, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

[0092] 51. The solid form of any one of clauses 1, 2, 16, or 41 to 50, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 6.

[0093] 52. The solid form of clause 1 or 16, wherein the solid form is a camphor sulfonic acid salt of Compound 1.

[0094] 53. The solid form of clause 1, 16, or 52, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I.

[0095] 54. The solid form of any one of clauses 1, 16, 52 or 53, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0. 1, 6.9+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 18.8+0.1, and 20.6+0.1.

[0096] 55. The solid form of any one of clauses 1, 16, or 52 to 54, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 6.9+0.1.

[0097] 56. The solid form of any one of clauses 1, 16, or 52 to 55, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.9+0.1 and 12.1+0.1.

[0098] 57. The solid form of any one of clauses 1, 16, or 52 to 56, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, and 12.1+0.1.

[0099] 58. The solid form of any one of clauses 1, 16, or 52 to 57, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0. 1 , 12.1+0.1, and 18.8+0.1.

[0100] 59. The solid form of any one of clauses 1, 16, or 52 to 58, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, and 18.8+0.1.

[0101] 60. The solid form of any one of clauses 1, 16, or 52 to 59, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, 18.8+0.1, and 20.6+0.1.

[0102] 61 . The solid form of any one of clauses 1 , 16, or 52 to 60, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 18.8+0.1, and 20.6+0.1.

[0103] 62. The solid form of any one of clauses 1, 16, or 52 to 61, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 7.

[0104] 63. The solid form of any one of clauses 1, 16, or 52 to 62, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound 1 having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 18.

[0105] 64. The solid form of any one of clauses 1, 16, or 52 to 63, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 17.

[0106] 65. The solid form of clause 1, 16, or 52, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I.

[0107] 66. The solid form of any one of clauses 1, 16, 52, or 65, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0. 1, 7.2+0.1, 11.0+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

[0108] 67. The solid form of any one of clauses 1, 16, 52, 65 or 66, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.0+0.1.

[0109] 68. The solid form of any one of clauses 1, 16, 52, or 65 to 67, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1 and 11.0+0.1.

[0110] 69. The solid form of any one of clauses 1, 16, 52, or 65 to 68, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1, 11.0+0.1, and 14.9+0.1.

[0111] 70. The solid form of any one of clauses 1, 16, 52, or 65 to 69, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.

[0112] 71. The solid form of any one of clauses 1, 16, 52, or 65 to 70, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5.1+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.

[0113] 72. The solid form of any one of clauses 1 , 16, 52, or 65 to 71 , wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.

[0114] 73. The solid form of any one of clauses 1, 16, 52, or 65 to 72, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

[0115] 74. The solid form of any one of clauses 1, 16, 52, or 65 to 73, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound 1 having a X-ray powder diffraction pattern substantially the same as shown in Fig. 8.

[0116] 75. The solid form of any one of clauses 1, 16, 52, or 65 to 74, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 20.

[0117] 76. The solid form of any one of clauses 1, 16, 52, or 65 to 75, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 19.

[0118] 77. The solid form of clause 1, wherein the solid form is a free base of Compound I.

[0119] 78. The solid form of clause 1 or 77, wherein the solid form is an anhydrous solid form of Compound I.

[0120] 79. The solid form of any one of clauses 1, 77, or 78, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, and 21.7+0.1.

[0121] 80. The solid form of any one of clauses 1 or 77 to 79, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.4+0.1.

[0122] 81. The solid form of any one of clauses 1 or 77 to 80, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.4+0.1 and 12.0+0.1.

[0123] 82. The solid form of any one of clauses 1 or 77 to 81 , wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.4+0.1, 12.0+0.1, and 21.7+0.1.

[0124] 83. The solid form of any one of clauses 1 or 77 to 82, wherein the solid form is a free base of Compound T having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.2+0.1, 11.4+0.1, 12.0+0.1, and 21.7+0.1.

[0125] 84. The solid form of any one of clauses 1 or 77 to 83, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 1 1.2+0.1, 11.4+0.1, 12.0+0.1, and 21.7+0.1.

[0126] 85. The solid form of any one of clauses 1 or 77 to 84, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, and 21.7+0.1.

[0127] 86. The solid form of any one of clauses 1 or 77 to 85, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, and 21.7+0.1.

[0128] 87. The solid form of any one of clauses 1 or 77 to 86, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 2.

[0129] 88. The solid form of any one of clauses 1 or 77 to 87, wherein the solid form is a free base of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 10.

[0130] 89. The solid form of any one of clauses 1 or 77 to 88, wherein the solid form is a free base of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 9.

[0131] 90. The solid form of clause 1, 2, or 77, wherein the solid form is a hydrate or solvate polymorph form of the free base of Compound I.

[0132] 91. The solid form of clause 1, 2, 77, or 90, wherein the solid form is an ethanol solvate of Compound I.

[0133] 92. The solid form of any one of clauses 1, 2, 77, 90, or 91, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, 17.5+0.1, and 19.4+0.1.

[0134] 93. The solid form of any one of clauses 1, 2, 77, or 90 to 92, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 8.0+0.1.

[0135] 94. The solid form of any one of clauses 1, 2, 77, or 90 to 93, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1 and 9.6+0.1.

[0136] 95. The solid form of any one of clauses 1, 2, 77, or 90 to 94, wherein the solid form is an ethanol solvate of Compound T having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, and 10.8+0.1.

[0137] 96. The solid form of any one of clauses 1, 2, 77, or 90 to 95, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, and 19.4+0.1.

[0138] 97. The solid form of any one of clauses 1, 2, 77, or 90 to 96, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0. 1, 9.6+0.1, 10.8+0.1, 13.6+0.1, and 19.4+0.1.

[0139] 98. The solid form of any one of clauses 1 , 2, 77, or 90 to 97, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, and 19.4+0.1.

[0140] 99. The solid form of any one of clauses 1, 2, 77, or 90 to 98, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, 17.5+0.1, and 19.4+0.1.

[0141] 100. The solid form of any one of clauses 1, 2, 77, or 90 to 99, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 1.

[0142] 101. A solid form anhydrous crystalline polymorph form A of Compound I free base having at least one of the following characteristics:

[0143] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.0+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 16.6+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.0+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 24.4+0.1, 24.8+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, 28.9+0.1, and 30.6+0.1;

[0144] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 2;

[0145] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of less than about 1% when heated from about 25° C to about 300° C;

[0146] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 10;

[0147] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry(DSC) curve having an endotherm with an onset at about 279 °C to about 284 °C; and

[0148] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 9.

[0149] 102. The solid form of clause 101 , having at least two of characteristics (a)-(f).

[0150] 103. The solid form of clause 101, having at least three of characteristics (a)-(f).

[0151] 104. A solid form cocrystal of Compound I with mono-Compound I oxalate and hydrate having at least one of the following characteristics:

[0152] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1 ;

[0153] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 3;

[0154] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 7% to about 11% when heated from about 25° C to about 300° C;

[0155] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 12;

[0156] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 62 °C to about 67 °C, and an endotherm with an onset at about 183 °C to about 188 °C; and

[0157] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 11.

[0158] 105. The solid form of clause 104, having at least two of characteristics (a)-(f).

[0159] 106. The solid form of clause 104, having at least three of characteristics (a)-(f).

[0160] 107. a solid form crystalline polymorph form A of Compound I HC1 salt having at least one of the following characteristics:

[0161] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0. 1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 22.9+0.1, 23.7+0.1, 24.0+0.1, 24.6+0.1, 24.8+0.1, 25.2+0.1, 25.5+0.1, 26.6+0.1, 27.5+0.1, and 29.3+0.1;

[0162] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 4;

[0163] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 9% to about 13% when heated from about 25° C to about 300° C;

[0164] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 14;

[0165] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 69 °C to about 74 °C, an endotherm with an onset at about 146 °C to about 151 °C, an exotherm with an onset of about 170 °C to about 175 °C, an endotherm with an onset at about 201 °C to about 206 °C, and an exotherm with an onset at about 216 °C to about 221 °C; and

[0166] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 13.

[0167] 108. The solid form of clause 107, having at least two of characteristics (a)-(f).

[0168] 109. The solid form of clause 107, having at least three of characteristics (a)-(f).

[0169] 110. A pharmaceutical formulation comprising a solid form of Compound I according to any one of clauses 1 to 109, and at least one pharmaceutically acceptable excipient.

[0170] 111. The pharmaceutical formulation of clause 110, comprising at least one of a filler, a disintegrant, a lubricant, and a surfactant.

[0171] 1 12. The pharmaceutical formulation of clause 110 or 111, wherein the formulation is for oral administration.

[0172] 113. The pharmaceutical formulation of any one of clauses 110 to 112, comprising about 1 mg to about 500 mg of the solid form.

[0173] 1 14. The pharmaceutical formulation of any one of clauses 110 to 113, comprising about 5 mg to about 500 mg of the solid form.

[0174] 115. The pharmaceutical formulation of any one of clauses 110 to 114, comprising about 5 mg to about 50 mg of the solid form.

[0175] 116. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 5 mg, about 10 mg, or about 40 mg of the solid form.

[0176] 117. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 5 mg of the solid form.

[0177] 118. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 10 mg of the solid form.

[0178] 119. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 20 mg of the solid form.

[0179] 120. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 30 mg of the solid form.

[0180] 121. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 40 mg of the solid form.

[0181] 122. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 50 mg of the solid form.

[0182] 123. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 60 mg of the solid form.

[0183] 124. The pharmaceutical formulation of any one of clauses 110 to 115, comprising about 80 mg of the solid form.

[0184] 125. The pharmaceutical formulation of any one of clauses 1 10 to 124, wherein the formulation comprises a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or any combination thereof.

[0185] 126. The pharmaceutical formulation of clause 125, wherein the formulation comprises at least two of a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof.

[0186] 127. The pharmaceutical formulation of clause 125 , wherein the formulation comprises at least three of a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof.

[0187] 128. The pharmaceutical formulation of clause 125, wherein the formulation comprises a filler and at least two of a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof.

[0188] 129. The pharmaceutical formulation of any one of clauses 110 to 128, wherein the filler is selected from microcrystalline cellulose, mannitol, lactose, calcium phosphate, or any combination thereof.

[0189] 130. The pharmaceutical formulation of clause 129, wherein the filler is a mixture of two or more fillers.

[0190] 131. The pharmaceutical formulation of any one of clauses 1 10 to 130, wherein the binder is copovidone.

[0191] 132. The pharmaceutical formulation of any one of clauses 110 to 131, wherein the acidulant is selected from citric acid, fumaric acid, tartaric acid, or any combination thereof.

[0192] 133. The pharmaceutical formulation of any one of clauses 110 to 132, wherein the disintegrant is selected from crospovidone, croscarmellose, sodium starch glycolate, or any combination thereof.

[0193] 134. The pharmaceutical formulation of clause 133, wherein the disintegrant is a mixture of two or more disintegrants.

[0194] 135. The pharmaceutical formulation of any one of clauses 1 10 to 134, wherein the surfactant is sodium lauryl sulfate, polysorbate, poloxamer, polyoxyethylene stearate, or any combination thereof.

[0195] 136. The pharmaceutical formulation of clause 135, wherein the disintegrant is a mixture of two or more surfactants.

[0196] 137. The pharmaceutical formulation of any one of clauses 110 to 136, wherein the glidant is silica.

[0197] 138. The pharmaceutical formulation of any one of clauses 110 to 137, wherein the lubricant is sodium stearyl fumarate, magnesium stearate, stearic acid, or any combination thereof.

[0198] 139. The pharmaceutical formulation of any one of clauses 110 to 138, wherein the solid form is present at about 3% to about 20% by weight of the formulation.

[0199] 140. The pharmaceutical formulation of clause 139, wherein the solid form is present at about 5% to about 15% by weight of the formulation.

[0200] 141. The pharmaceutical formulation of clause 139, wherein the solid form is present at about 5% to about 6% by weight of the formulation.

[0201] 142. The pharmaceutical formulation of clause 139, wherein the solid form is present at about 10% to about 12% by weight of the formulation.

[0202] 143. The pharmaceutical formulation of any one of clauses 1 10 to 142, wherein the filler is present at about 10% to about 95% by weight of the formulation.

[0203] 144. The pharmaceutical formulation of clause 143, wherein the filler is present at about 50% to about 90% by weight of the formulation.

[0204] 145. The pharmaceutical formulation of any one of clauses 1 10 to 144, wherein the binder is present at about 1% to about 10% by weight of the formulation.

[0205] 146. The pharmaceutical formulation of any one of clauses 110 to 145, wherein the acidulant is present at about 1% to about 10% by weight of the formulation.

[0206] 147. The pharmaceutical formulation of any one of clauses 1 10 to 146, wherein the disintegrant is present at about 1% to about 10% by weight of the formulation.

[0207] 148. The pharmaceutical formulation of any one of clauses 110 to 147, wherein the surfactant is present at about 1% to about 60% by weight of the formulation.

[0208] 149. The pharmaceutical formulation of clause 148, wherein the surfactant is present at about 1% to about 20% by weight of the formulation.

[0209] 150. The pharmaceutical formulation of any one of clauses 110 to 149, wherein the glidant is present at about 0.1% to about 3% by weight of the formulation.

[0210] 151. The pharmaceutical formulation of any one of clauses 110 to 150, wherein the lubricant is present at about 0. 1 % to about 3% by weight of the formulation.

[0211] 152. The pharmaceutical formulation of any one of clauses 110 to 112 or 125 to 138, wherein the formulation comprises

[0212] about 3% to about 20% by weight a solid form according to any one of clauses 1-109;

[0213] about 10% to about 95% by weight filler;

[0214] optionally about 1% to about 10% by weight acidulant;

[0215] about 1% to about 10% by weight disintegrant;

[0216] optionally about 1% to about 60% by weight surfactant;

[0217] about 0.1% to about 3% by weight glidant; and

[0218] about 0.1 % to about 3% by weight lubricant.

[0219] 153. The pharmaceutical formulation of any one of clauses 110 to 152, wherein the formulation is in the form of a tablet.

[0220] 154. The pharmaceutical formulation of clause 153, wherein the formulation comprises

[0221] about 10% to about 12% by weight a solid form according to any one of clauses 1-109;

[0222] about 83% to about 85% by weight filler;

[0223] about 4% by weight disintegrant;

[0224] about 0.25% by weight glidant; and

[0225] about 0.5% by weight lubricant.

[0226] 155. The pharmaceutical composition of clause 153, wherein the formulation comprises

[0227] about 3 mg to about 50 mg of a solid form according to any one of clauses 1-109;

[0228] about 50 mg to about 500 mg filler;

[0229] about 1 mg to about 50 mg disintegrant;

[0230] about 0.1 mg to about 5 mg glidant; and

[0231] about 0.1 mg to about 5 mg lubricant.

[0232] 156. The pharmaceutical formulation of any one of clauses 110 to 143, wherein the formulation is in the form of a capsule.

[0233] 157. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0234] about 10% by weight a solid form according to any one of clauses 1-109;

[0235] about 85% by weight filler;

[0236] about 4% by weight disintegrant;

[0237] about 0.3% by weight glidant; and

[0238] about 0.5% by weight lubricant.

[0239] 158. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0240] about 10% by weight a solid form according to any one of clauses 1-109;

[0241] about 80% by weight filler;

[0242] about 5% by weight surfactant;

[0243] about 4% by weight disintegrant;

[0244] about 0.3% by weight glidant; and

[0245] about 0.5% by weight lubricant.

[0246] 159. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0247] about 10% by weight a solid form according to any one of clauses 1-109;

[0248] about 80% by weight filler;

[0249] about 5% by weight acidulant;

[0250] about 4% by weight disintegrant;

[0251] about 0.3% by weight glidant; and

[0252] about 0.5% by weight lubricant.

[0253] 160. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0254] about 10% by weight a solid form according to any one of clauses 1-109;

[0255] about 75% by weight filler;

[0256] about 5% by weight surfactant;

[0257] about 5% by weight acidulant;

[0258] about 4% by weight disintegrant;

[0259] about 0.3% by weight glidant; and

[0260] about 0.5% by weight lubricant.

[0261] 161. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0262] about 10% by weight a solid form according to any one of clauses 1-109;

[0263] about 83% by weight filler;

[0264] about 2% by weight surfactant;

[0265] about 4% by weight disintegrant;

[0266] about 0.3% by weight glidant; and

[0267] about 0.5% by weight lubricant.

[0268] 162. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0269] about 10% by weight a solid form according to any one of clauses 1-109;

[0270] about 73% by weight filler;

[0271] about 12.5% by weight surfactant;

[0272] about 4% by weight disintegrant;

[0273] about 0.3% by weight glidant; and

[0274] about 0.8% by weight lubricant.

[0275] 163. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0276] about 10% by weight a solid form according to any one of clauses 1-109;

[0277] about 33% by weight filler;

[0278] about 48% by weight surfactant;

[0279] about 5% by weight acidulant;

[0280] about 4% by weight disintegrant;

[0281] about 0.3% by weight glidant; and

[0282] about 0.5% by weight lubricant.

[0283] 164. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0284] about 5% to about 6% by weight a solid form according to any one of clauses 1-109;

[0285] about 90% by weight filler;

[0286] about 4% by weight disintegrant;

[0287] about 0.25% by weight glidant; and

[0288] about 0.4% by weight lubricant.

[0289] 165. The pharmaceutical formulation of clause 156, wherein the formulation comprises

[0290] about 10% to about 12% by weight a solid form according to any one of clauses 1-109;

[0291] about 84% to about 85% by weight filler;

[0292] about 4% by weight disintegrant;

[0293] about 0.25% by weight glidant; and

[0294] about 0.5% by weight lubricant.

[0295] 166. The pharmaceutical composition of any one of clauses 110 to 112 or 125 to 138, wherein the formulation comprises

[0296] about 3 mg to about 50 mg of a solid form according to any one of clauses 1-109;

[0297] about 50 mg to about 500 mg filler;

[0298] optionally about 1 mg to about 50 mg acidulant;

[0299] about 1 mg to about 50 mg disintegrant;

[0300] optionally about 5 mg to about 500 mg surfactant;

[0301] about 0.1 mg to about 5 mg glidant; and

[0302] about 0.1 mg to about 5 mg by weight lubricant.

[0303] 167. A method of treating abnormal cell growth in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a solid form of Compound I according to any one of clauses 1 to 109 or a pharmaceutical formulation according to any one of clauses 110 to 166.

[0304] 168. A method of treating cancer in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a solid form of Compound I according to any one of clauses 1 to 109 or a pharmaceutical formulation according to any one of clauses 110 to 166.

[0305] 169. The method of clause 168, wherein the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndromes (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cellcarcinoma, pediatric renal cell carcinoma, breast cancer, ER+ breast cancer, triple negative breast, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer and lung cancer.

[0306] 170. The method of clause 169, wherein the cancer is non-small cell lung cancer (NSCLC).

[0307] 171. The method of clause 169, wherein the cancer is EGFR+ non-small cell lung cancer (NSCLC).

[0308] 172. The method of clause 169, wherein the cancer is non-small cell lung cancer (NSCLC) that has EGFR and / or HER2 mutations.

[0309] 173. The method of any one of clauses 167-172, wherein the therapeutically effective amount is about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg BID.

[0310] 174. The method of any one of clauses 116-172, wherein the therapeutically effective amount is about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg QD.

[0311] 175. A process for preparing a compound of the formula I1

[0312] comprising

[0313] a. contacting a compound of the formula Al

[0314] with a compound of the formula BB

[0315] in the presence of a base to provide a compound of the formula Cl

[0316] b. contacting a compound of the formula Cl in the presence of a catalyst to provide a compound of the formula DI

[0317] c. contacting a compound of the formula DI with an acid to provide the compound of the formula I.

[0318] 176. The process of clause 175, wherein the base of step (a) is selected from the group consisting of DIEA, triethylamine, diisopropylamine, Na^COs, K2CO3, CS2CO3, MgCCh, and CaCO3.

[0319] 177. The process of clause 176, wherein the base of step (a) is DIEA.

[0320] 178. The process of any one of clauses 175 to 177, wherein step (a) is carried out in the presence of an inorganic salt selected from the group consisting of NaCl, KC1, CsCl, MgCh, CaCh, NaBr, KBr, CsBr, MgBr2, CaBr2, Nal, KI, CsI, Mgl2, and Cal2.

[0321] 179. The process of clause 178, wherein the inorganic salt is Nal.

[0322] 180. The process of any one of clauses 175 to 179, wherein the catalyst of step (b) is a palladium catalyst.

[0323] 181. The process of clause 180, wherein the catalyst of step (b) is selected from the group consisting of Pd(OAc)2, PdCl2, and Pd(PPh3)4.

[0324] 182. The process of clause 180, wherein the catalyst of step (b) is Pd(OAc)2.

[0325] 183. The process of any one of clauses 175 to 182, wherein step (b) is carried out in the presence of a base selected from the group consisting of DIEA, triethylamine, diisopropylamine, K2CO3, Na2CO3, KHCO3, NaHCO3, NaOAc, and KOAc.

[0326] 184. The process of clause 183, wherein the base is NaHCO3.

[0327] 185. The process of any one of clauses 175 to 184, wherein step (b) is carried out in the presence of a phase transfer catalyst selected from tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), and tetrabutylammonium iodide (TBAI).

[0328] 186. The process of clause 185, wherein the phase transfer catalyst is tetrabutylammonium chloride (TBAC).

[0329] 187. The process of any one of clauses 175 to 186, wherein the acid of step (c) is a strong inorganic acid.

[0330] 188. The process of clause 187, wherein the acid of step (c) is HC1.

[0331] 189. The process of any one of clauses 175 to 188 comprising steps (a) and (b).

[0332] 190. The process of any one of clauses 175 to 189 comprising steps (b) and (c).

[0333] 191. The process of any one of clauses 175 to 190, comprising steps (a) and (c).

[0334] 192. The process of any one of clauses 175 to 191, comprising steps (a), (b), and (c).DEFINITIONS

[0335] The term “alkyl” refers to a straight- or branched-chain monovalent hydrocarbon group. The term “alkylene” refers to a straight- or branched-chain divalent hydrocarbon group. In some embodiments, it can be advantageous to limit the number of atoms in an “alkyl” or “alkylene” to a specific range of atoms, such as C1-C20 alkyl or Ci-C2o alkylene, C1-C12 alkyl or C1-C12 alkylene, or Ci-Ce alkyl or Ci-Ce alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that in light of the ordinary skill in the art and the teachings providedherein would be considered equivalent to any one of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CfE-h), n-propylene ((-CEE-h), isopropylene ((C(H)(CHS)CH2-)), n-butylene ((-CH2-)4), and the like. It will be appreciated that an alkyl or alkylene group can be unsubstituted or substituted as described herein. An alkyl or alkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0336] The term “alkenyl” refers to a straight- or branched-chain mono-valent hydrocarbon group having one or more double bonds. The term “alkenylene” refers to a straight- or branched- chain di-valent hydrocarbon group having one or more double bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkenyl” or “alkenylene” to a specific range of atoms, such as C2-C20 alkenyl or C2-C20 alkenylene, C2-C12 alkenyl or C2-C12 alkenylene, or C2-C6 alkenyl or C2-C6 alkenylene. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-l-yl. Examples of alkenylene groups include ethenylene (or vinylene) (- CH=CH-), n-propenylene (-CH=CHCH2-), iso-propenylene (-CH=CH(CH3)-), and the like. Included within this term are cis and trans isomers and mixtures thereof. It will be appreciated that an alkenyl or alkenylene group can be unsubstituted or substituted as described herein. An alkenyl or alkenylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0337] The term “alkynyl” refers to a straight- or branched-chain monovalent hydrocarbon group having one or more triple bonds. The term “alkynylene” refers to a straight- or branched-chain divalent hydrocarbon group having one or more triple bonds. In some embodiments, it can be advantageous to limit the number of atoms in an “alkynyl” or “alkynylene” to a specific range of atoms, such as C2-C20 alkynyl or C2-C20 alkynylene, C2-C12 alkynyl or C2-C12 alkynylene, or C2-C6 alkynyl or C2-C6 alkynylene. Examples of alkynyl groups include acetylenyl ( C=CH) and propargyl (-CH2C=CH), but-3-yn-l,4-diyl (-C=C-CH2CH2-), and the like. It will be appreciated that an alkynyl or alkynylene group can be unsubstituted or substituted as described herein. An alkynyl or alkynylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0338] The term “cycloalkyl” refers to a saturated or partially saturated, monocyclic or polycyclic mono-valent carbocycle. The term “cycloalkylene” refers to a saturated or partially saturated, monocyclic or polycyclic divalent carbocycle. In some embodiments, it can be advantageous to limit the number of atoms in a “cycloalkyl” or “cycloalkylene” to a specific range of atoms, such as having 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiro polycyclic systems. Illustrative examples of cycloalkyl groups include monovalent radicals of the followingentities, while cycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:In particular, a cyclopropyl moiety can be depicted by the structural formulaparticular, a cyclopropylene moiety can be depicted by the structural formulawill be appreciated that a cycloalkyl or cycloalkylene group can be unsubstituted or substituted as described herein. A cycloalkyl or cycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0339] The term “halogen” or “halo” represents chlorine, fluorine, bromine, or iodine.

[0340] The term “haloalkyl” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CFFBr, -CH2CF3, and -CH2CH2F. The term “haloalkylene” refers to an alkyl group with one or more halo substituents. Examples of haloalkyl groups include -CF2-, -C(H)(F)-, -C(H)(Br)-, -CH2CF2-, and -CH2C(H)(F)-.

[0341] The term “aryl” refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. The term “arylene” refers to a divalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated pi-electron system. In some embodiments, it can be advantageous to limit the number of atoms in an “aryl” or “arylene” to a specific range of atoms, such as mono-valent all-carbon monocyclic or fused- ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 aryl), monovalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (Ce-Cio aryl), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 14 carbon atoms (C6-C14 arylene), divalent all-carbon monocyclic or fused-ring polycyclic groups of 6 to 10 carbon atoms (Ce-Cio arylene). Examples, without limitation, of aryl groups are phenyl, naphthalenyl and anthracenyl. Examples, without limitation, of arylene groups are phenylene, naphthalenylene andanthracenylene. It will be appreciated that an aryl or arylene group can be unsubstituted or substituted as described herein. An aryl or arylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0342] The term “heterocycloalkyl” refers to a mono-valent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. The term “heterocycloalkylene” refers to a divalent monocyclic or polycyclic ring structure that is saturated or partially saturated having one or more non-carbon ring atoms. In some embodiments, it can be advantageous to limit the number of atoms in a “heterocycloalkyl” or “heterocycloalkylene” to a specific range of ring atoms, such as from 3 to 12 ring atoms (3- to 12-membered), or 3 to 7 ring atoms (3- to 7-membered), or 3 to 6 ring atoms (3- to 6-membered), or 4 to 6 ring atoms (4- to 6-membered), 5 to 7 ring atoms (5- to 7-membered), or 4 to 10 ring atoms (4- to 10-membered). In some embodiments, it can be advantageous to limit the number and type of ring heteroatoms in “heterocycloalkyl” or “heterocycloalkylene” to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Polycyclic ring systems include fused, bridged, and spiro systems. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities, while heterocycloalkylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:

[0343] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of three-memberedheterocycle groups include monovalent and divalent radicals of oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is a sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocycle groups include monovalent and divalent radicals of azitidine, oxtenane, and thietane. A five-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocycle groups include mono-valent and divalent radicals of pyrrolidine, tetrahydrofuran, 2, 5-dihydro-lH- pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro- IH-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1 -dioxide, imidazolidin-2- one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, l,3-dioxolan-2-one, and oxazolidin-2-one. A six-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocycle groups include mono-valent or divalent radicals of piperidine, morpholine, 4H- 1 ,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, l,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A “heterobicycle” is a fused bicyclic system comprising one heterocycle ring fused to a cycloalkyl or another heterocycle ring.

[0344] It will be appreciated that a heterocycloalkyl or heterocycloalkylene group can be unsubstituted or substituted as described herein. A heterocycloalkyl or heterocycloalkylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0345] The term “heteroaryl” refers to a mono-valent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and having from 3 to 12 ring atoms per heterocycle. The term “heteroarylene” refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms per heterocycle. In some embodiments, it can be advantageous to limit the number of ring atoms in a “heteroaryl” or “heteroarylene” to a specific range of atom members, such as 5- to 10-membered heteroaryl or 5- to 10-membered heteroarylene. In some instances, a 5- to 10-membered heteroaryl can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ring atom is a heteroatom, such as N, O, or S. In some instances, a 5- to 10-membered heteroarylene can be a monocyclic ring or fused bicyclic rings having 5- to 10-ring atoms wherein at least one ringatom is a heteroatom, such as N, O, or S. The ring structure may optionally contain an oxo group or an imino group on a carbon ring member or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of properly bonded moieties:

[0346] In some embodiments, a “monocyclic” heteroaryl can be an aromatic five- or sixmembered heterocycle. A five-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include monovalent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. Non-limiting examples of fivemembered heteroarylene groups include di-valent radicals of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A six-membered heteroaryl or heteroarylene can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. Non-limiting examples of sixmembered heteroarylene groups include divalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A “bicyclic heteroaryl” or “bicyclic heteroarylene” is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1 H-pyrrolo[2,3- >]pyridine, 1 H-benzo[d]imidazole, benzo [d]oxazole,and benzo h / | thiazole. Non-limiting examples of bicyclic heteroarylene groups include divalent radicals of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8- naphthyridine, isoquinolin-3(2H)-one, thieno|3,2-b|lhiophene, I H-pyrrolo|2,3-b|pyridine, 1H- benzo[d]imidazole, benzo [<7]oxazole, and benzo |d|lhi azole.

[0347] In particular, a pyrazolyl moiety can be depicted by the structural formulaparticular, an example of a pyrazolylene moiety can be depicted by the structural formula

[0348] It will be appreciated that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.

[0349] The term “oxo” represents a carbonyl oxygen. For example, a cyclopentyl substituted with oxo is cyclopentanone.

[0350] The term “substituted” means that the specified group or moiety bears one or more substituents. The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. In some embodiments, “substituted” means that the specified group or moiety bears one, two, or three substituents. In other embodiments, “substituted” means that the specified group or moiety bears one or two substituents. In still other embodiments, “substituted” means the specified group or moiety bears one substituent.

[0351] Any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms. For example, a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof. Additionally, any formula given herein is intended to refer also to a hydrate (e.g., hemihydrate, a monohydrate, or a dihydrate), solvate, or polymorph of such a compound, or a mixture thereof.

[0352] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,nC,13C,14C,15N,18O,170,31P,32P,35S,18F,36C1, and125I, respectively. Such isotopically labelled compounds are useful in metabolic studies (preferably with14C), reaction kinetic studies (with, for example2H or3H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients. Further, substitution with heavier isotopes such as deuterium (i.e.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0353] Any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed. For example, reference to disubstituent -J-K-, where J 4 K, refers herein to such disubstituent with J attached to a first substituted member and K attached to a second substituted member, and it also refers to such disubstituent with J attached to the second substituted member and K attached to the first substituted member.

[0354] It will be appreciated that certain of the compounds described herein include one or more position that can exists as stereoisomers. For example, certain of the compounds described herein include one or more carbon atoms that can exist in one or more stereoisomeric arrangements. It will be appreciated that a carbon atom that can exist in stereoisomeric arrangements that is depicted without showing any stereoisomeric arrangement includes as a disclosure each of eh possible stereoisomeric arrangements. For example a carbon atom having four groups that can be prioritized according to the Cahn-Ingold Prelog Rules known to one of skill in the art will be understood herein as describing no particular stereochemical definition as in the structure on the left below, and also as describing both possible stereoisomers (S) and (R) as shown belowwhere Ra> Rb> Rc> Rdaccording to the Cahn-Ingold Prelog Rules. ‘

[0355] The disclosure also includes pharmaceutically acceptable salts of Compound I, preferably of those described above and of the specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.

[0356] A “pharmaceutically acceptable salt” is intended to mean a salt of a free acid or base of a compound represented herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to the subject. See, generally, S.M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response. A compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

[0357] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-1,6- dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates, xylenesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.

[0358] For Compound I that contains a basic nitrogen, a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as mandelic acid, citric acid, or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid, or any compatible mixture of acids such as those given as examples herein, and any other acid and mixture thereof that are regarded as equivalents or acceptable substitutes in light of the ordinary level of skill in this technology.

[0359] The disclosure also relates to pharmaceutically acceptable prodrugs of the Compound I, and treatment methods employing such pharmaceutically acceptable prodrugs. The term “prodrug” means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to Compound I). A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985.

[0360] The present disclosure also relates to pharmaceutically active metabolites of Compound I, and uses of such metabolites in the methods of the disclosure. A “pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a Compound I or salt thereof. Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011- 2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

[0361] As used herein, unless otherwise indicated, the term “abnormal cell growth” refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition).

[0362] A “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal. These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats). In some embodiments, the term “subject” refers to a mammalian patient in need of such treatment, such as a human.

[0363] As used herein, unless otherwise indicated, the term “treating” means reversing, alleviating, inhibiting the progress of (i.e., curative treatment), or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment”, as used herein, unless otherwise indicated, refers to the act of treating as “treating” as defined immediately above. “Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatmentrelative to an untreated control population, and / or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and / or clinically significant amount. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition. Thus, treatment includes ameliorating or preventing the worsening of existing disease symptoms, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0364] “Administering” or “administration of’ a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art. For example, a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct). A compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0365] Appropriate methods of administering a substance, a compound or an agent to a subject will also depend, for example, on the age and / or the physical condition of the subject and the chemical and biological properties of the compound or agent (e.g., solubility, digestibility, bioavailability, stability and toxicity). In some embodiments, a compound or an agent is administered orally, e.g., to a subject by ingestion. In some embodiments, the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.

[0366] As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents). For example, the different therapeutic compounds can be administered either in the sameformulation or in separate formulations, either concomitantly or sequentially. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.

[0367] A “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect. The full therapeutic effect does not necessarily occur hy administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. The precise effective amount needed for a subject will depend upon, for example, the subject’s size, health and age, and the nature and extent of the condition being treated, such as cancer. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.

[0368] As used herein, the term “essentially the same” with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will appreciate that the peak positions (20) will show some interapparatus variability, such as 0.1°, or in some cases 0.2°. Further, one skilled in the art will appreciate that relative peak intensities will show inter-apparatus variability as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art and should be taken as qualitative measures only.

[0369] As used herein, the term “protecting group” or “PG” refers to any group as commonly known to one of ordinary skill in the art that can be introduced into a molecule by chemical modification of a functional group, such as an amine or hydroxyl, to achieve chemoselectivity in a subsequent chemical reaction. It will be appreciated that such protecting groups can be subsequently removed from the functional group at a later point in a synthesis to provide further opportunity for reaction at such functional groups or, in the case of a final product, to unmask such functional group. Protecting groups have been described in, for example, Wuts, P. G. M., Greene, T. W., Greene, T. W., & John Wiley & Sons. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J: Wiley-Interscience. One of skill in the art will readily appreciate the chemical process conditions under which such protecting groups can be installed on a functional group. Suitable amine protecting groups useful in connection with the present disclosure include, but are not limited to, tetrahydropyran, (THP), 9-Fluorenylmethyl-carbonyl (FMOC), p-methoxybenzyl (PMB), t-butylcarbonyl (Boc), benzyloxycarbonyl (Cbz), acetyl (Ac), trifluoroacetyl, phthalimide, benzyl (Bn), triphenylmethyl (trityl, Tr), benzylidene, and p- toluenesulfonyl (Ts).

[0370] The term "about" as used herein means greater or lesser than the value or range of values stated by 10 percent, but is not intended to designate any value or range of values to only thisbroader definition. Each value or range of values preceded by the term "about" is also intended to encompass the embodiment of the stated absolute value or range of values. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about.” It is understood that, whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and / or measurement conditions for such given value. Whenever a yield is given as a percentage, such yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.BRIEF DESCRIPTION OF THE DRAWINGS

[0371] FIG. 1 shows a X-ray powder diffraction pattern of the crystalline polymorph form A of Compound I ((2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol) ethanol solvate.

[0372] FIG. 2 shows a X-ray powder diffraction pattern of anhydrous crystalline polymorph form A of Compound I free base.

[0373] FIG. 3 shows a X-ray powder diffraction pattern of the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate.

[0374] FIG. 4 shows a X-ray powder diffraction pattern of the crystalline polymorph form A of Compound I HC1 salt.

[0375] FIG. 5 shows a X-ray powder diffraction pattern of the crystalline polymorph form A of Compound I bis-HCl salt.

[0376] FIG. 6 shows a X-ray powder diffraction pattern of the crystalline polymorph form A of Compound I monophosphate salt monohydrate.

[0377] FIG. 7 shows a X-ray powder diffraction pattern of the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt.

[0378] FIG. 8 shows a X-ray powder diffraction pattern of the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt.

[0379] FIG. 9 shows a differential scanning calorimetry (DSC) thermogram of anhydrous crystalline polymorph form A of Compound I free base, showing a transition event that is a melting peak at an onset of 281.41 °C, a peak temperature of 283.85 °C, and an enthalpy (normalized) = 171.32 mJ.

[0380] FIG. 10 shows a thermographic analysis (TGA) curve of the crystalline form of anhydrous crystalline polymorph form A of Compound I free base. The curve was generated from a sample size of anhydrous crystalline polymorph form A of Compound I free base of 6.89 mg with a first step showing a loss of -0.4925 % (-33.9841e-03 mg) and a step showing a loss of -0.2006 % (- 13.832e-03 mg).

[0381] FIG. 11 shows a differential scanning calorimetry (DSC) thermogram of polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate, showing a transition event with an enthalpy (normalized) = 42.717 J / g, at an onset of 64.34 °C, and a peak temperature of 84.27 °C and a transition event with an enthalpy (normalized) = 42.717 J / g, at an onset of 185.30 °C, and a peak temperature of 195.28 °C.

[0382] FIG. 12 shows a thermographic analysis (TGA) curve of the crystalline form of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate. The curve was generated from a sample size of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate of 2.85 mg with a step showing a loss of -1.619 % (-0.046 mg), and a step showing a loss of -7.747% (-0.222 mg).

[0383] FIG. 13 shows a differential scanning calorimetry (DSC) thermogram of crystalline polymorph form A of Compound I HC1 salt, showing a transition event with an enthalpy (normalized) = 143.63 mJ, at an onset of 71.18 °C, and a peak temperature of 87.75 °C, a transition event with an enthalpy (normalized) = 42.88 mJ, at an onset of 148.70 °C, and a peak temperature of 153.95 °C, a transition event with an enthalpy (normalized) = -35.01 mJ, at an onset of 172.49 °C, and a peak temperature of 176.66 °C, a transition event with an enthalpy (normalized) = 34.42 mJ, at an onset of 203.17 °C, and a peak temperature of 214.10 °C, and a transition event with an enthalpy (normalized) = 24.76 mJ, at an onset of 218.61 °C, and a peak temperature of 222.16 °C.

[0384] FIG. 14 shows a thermographic analysis (TGA) curve of the crystalline form of crystalline polymorph form A of Compound I HC1 salt. The curve was generated from a sample size of crystalline polymorph form A of Compound I HC1 salt of 4.3 mg with a step showing a loss of - 3.7960 % (-0.1621 mg), a step showing a loss of -0.5537% (-0.02381 mg), and a step showing a loss of -6.6774 % (-0.2871 mg).

[0385] FIG. 15 shows a differential scanning calorimetry (DSC) thermogram of crystalline polymorph form A of Compound I bis-HCl salt, showing a transition event with an enthalpy (normalized) = 82.24 mJ, at an onset of 108.03 °C, and a peak temperature of 1 18.75 °C, a transition event with an enthalpy (normalized) = 86.26 mJ, at an onset of 120.86 °C, and a peak temperature of 140.41 °C, a transition event with an enthalpy (normalized) = 74.96 mJ, at anonset of 160.29 °C, and a peak temperature of 180.41 °C, and a transition event with an enthalpy (normalized) = 107.70 mJ, at an onset of 205.91 °C, and a peak temperature of 221.03 °C.

[0386] FIG. 16 shows a thermographic analysis (TGA) curve of the crystalline form of crystalline polymorph form A of Compound I bis-HCl salt. The curve was generated from a sample size of crystalline polymorph form A of Compound I his-HCl salt of 4.3 mg with a step showing a loss of -3.2575 % (-0.1498 mg), a step showing a loss of -1.4122% (-0.06496 mg), a step showing a loss of -1.9203 % (-0.08833 mg), and a step showing a loss of -7.2775% (-0.3348 mg).

[0387] FIG. 17 shows a differential scanning calorimetry (DSC) thermogram of crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt, showing a transition event with an enthalpy (normalized) = 111 mJ / mg at a peak temperature of 124.5 °C, and a transition event with an enthalpy (normalized) = -237 mJ / mg at a peak temperature of 225.7 °C.

[0388] FIG. 18 shows a thermographic analysis (TGA) curve of the crystalline form of crystalline polymorph form A of Compound 1 (+)-camphor sulfonic acid salt. The curve was generated from a sample size of crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt of 2.5 mg with a step showing a loss of -4.64 %.

[0389] FIG. 19 shows a differential scanning calorimetry (DSC) thermogram of crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt, showing a transition event with an enthalpy (normalized) = -61.7 mJ / mg at a peak temperature of 236.7 °C.

[0390] FIG. 20 shows a thermographic analysis (TGA) curve of the crystalline form of crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt. The curve was generated from a sample size of crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt of 4.35 mg with a step showing a loss of -3.98 %.

[0391] FIG. 21 shows an ortep image of crystal structure of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate obtained using the methods described in Example 17.

[0392] FIG. 22 shows an inter-molecular interaction of crystal structure of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate obtained using the methods described in Example 17.

[0393] FIG. 23 shows a graph of plasma concentration (ng / mL) in a fasted dog model after administration of solid forms of Compound I. Formulation 14 (capsule, see Table 29) includes Compound I hemi-oxalate (crystalline polymorph form A cocrystal of Compound I with mono- Compound I oxalate and hydrate and Formulation 1 (capsule, see Table 26) includes Compound I free base (anhydrous crystalline polymorph form A of Compound I free base).

[0394] FIG. 24 shows a graph of plasma concentration (ng / mL) in a fed dog model after administration of solid forms of Compound I. Formulation 14 (capsule, see Table 29) includesCompound I hemi-oxalate (crystalline polymorph form A cocrystal of Compound I with monoCompound I oxalate and hydrate); Formulation 1 (capsule, see Table 26) includes Compound I free base (anhydrous crystalline polymorph form A of Compound I free base); and suspension includes Compound I free base (anhydrous crystalline polymorph form A of Compound I free base).DETAILED DESCRIPTION

[0395] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0396] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications and other publications referred to herein are incorporated by reference in their entireties. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in a patent, application, or other publication that is herein incorporated by reference, the definition set forth in this section prevails over the definition incorporated herein by reference.

[0397] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0398] A unique physical form of the ethanol solvate of (2S)-2-[(10S,17E)-16-ethoxy- 6,8, 10, 12,20-pentamethyI-2,8, 10, 11 , 12, 13 -hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][I,4]oxazacyclopentadecin-I4-yl]propan-l-ol (a.k.a. crystalline polymorph form A of Compound I ethanol solvate) has been prepared according to the methods described herein. In some embodiments, the solid form is crystalline polymorph form A of Compound I ethanol solvate. The X-ray powder diffraction (XRPD) pattern of crystalline polymorph form A of Compound I ethanol solvate is shown in FIG. 1 , with corresponding tabulated data shown in Table 1.Table 1

[0399] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) as shown in Table 1 and / or Fig. 1.

[0400] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1 , 10.8+0.1, 1 1.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 16.7+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.3+0.1, 21.6+0.1, 22.5+0.1, 24+0.1, 24.5+0.1, 25+0.1, 27.3+0.1, and 28.2+0.1.

[0401] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 16.7+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.3+0.1, 21.6+0.1, 22.5+0.1, 24.0+0.1, 24.5+0.1, 25+0.1, and 27.3+0.1.

[0402] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 16.7+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.3+0.1, 21.6+0.1 , 22.5+0.1, 24.0+0.1, 24.5+0.1, and 25+0.1.

[0403] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 16.7+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.3+0.1, 21.6+0.1, 22.5+0.1, 24.0+0.1, and 24.5+0.1.

[0404] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 16.7+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.3+0.1, 21.6+0.1, 22.5+0.1, and 24.0+0.1.

[0405] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.3+0.1, 21.6+0.1, 22.5+0.1, and 24.0+0.1.

[0406] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.6+0.1, 22.5+0.1, and 24.0+0.1.

[0407] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, 21.6+0.1, and 24.0+0.1.

[0408] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1 , 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 15.4+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, and 24.0+0.1.

[0409] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29)of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 14.6+0.1, 17.5+0.1, 19.4+0.1, 20.9+0.1, and 24.0+0.1.

[0410] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1 , 9.6+0.1 , 10.8+0.1 , 1 1.5+0.1 , 12.6+0.1 , 13.6+0.1 , 14.6+0.1 , 17.5+0.1 , 19.4+0.1 , and 24.0+0.1.

[0411] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0. 1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 12.6+0.1, 13.6+0.1, 17.5+0.1, 19.4+0.1, and 24.0+0.1.

[0412] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0. 1, 10.8+0.1, 11.5+0.1, 13.6+0.1, 17.5+0.1, 19.4+0.1, and 24.0+0.1.

[0413] In some embodiments, the crystalline polymorph form A of Compound 1 ethanol solvate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 13.6+0.1, 17.5+0.1, 19.4+0.1, and 24.0+0.1.

[0414] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 8.0+0. 1.

[0415] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1 and 9.6+0.1.

[0416] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0. 1, 9.6+0.1, and 10.8+0.1.

[0417] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (29) of 8.0+0.1, 9.6+0.1, 10.8+0.1, and 19.4+0.1.

[0418] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 13.6+0.1, and 19.4+0.1.

[0419] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0. 1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, and 19.4+0.1.

[0420] In some embodiments, the crystalline polymorph form A of Compound I ethanol solvate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, 17.5+0.1, and 19.4+0.1.

[0421] In some embodiments, the solid form is crystalline polymorph form A of Compound I ethanol solvate having a X-ray powder diffraction pattern substantially the same as shown in FIG.

[0422] A unique physical form of the free base of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20- pentamethyl-2,8,10,1 l ,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’- j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (a.k.a. anhydrous crystalline polymorph form A of Compound I free base) has been prepared according to the methods described herein. In some embodiments, the solid form is anhydrous crystalline polymorph form A of Compound I free base. The X-ray powder diffraction (XRPD) pattern of anhydrous crystalline polymorph form A of Compound I free base is shown in FIG. 2, with corresponding tabulated data shown in Table 2.Table 2

[0423] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) as shown in Table 2 and / or FIG. 2.

[0424] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.0+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 16.6+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.0+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 24.4+0.1, 24.8+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, 28.9+0.1, and 30.6+0.1.

[0425] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.0+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 16.6+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.0+0.1, 22.9+0.1, 23.4+0.1 , 24.0+0.1 , 24.4+0.1 , 24.8+0.1 , 25.4+0.1 , 25.6+0.1 , 25.7+0.1 , 26.8+0.1 , 27.2+0.1 , 28.0+0.1, and 28.9+0.1.

[0426] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.0+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1 , 14.7+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.0+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 24.4+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, and 28.9+0.1.

[0427] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1 , 9.0+0.1 , 1 1.2+0.1 , 1 1.4+0.1 , 12.0+0.1 , 13.0+0.1 , 14.7+0.1 , 15.2+0.1 , 16.4+0.1 , 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.0+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, and 28.9+0.1.

[0428] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.0+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1 , 14.7+0.1, 15.2+0.1, 16.4+0.1,17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, and 28.9+0.1.

[0429] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1 , 1 1.2+0.1 , 1 1.4+0.1 , 12.0+0.1 , 13.0+0.1 , 14.7+0.1 , 15.2+0.1 , 16.4+0.1 , 17.8+0.1 , 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, and 28.9+0.1.

[0430] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, and 28.0+0.1.

[0431] In some embodiments, the anhydrous crystalline polymorph form A of Compound 1 free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, and 27.2+0.1.

[0432] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, and 27.2+0.1.

[0433] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 24.0+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, and 27.2+0.1.

[0434] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 24.0+0.1, 25.6+0.1, 25.7+0.1, and 26.8+0.1.

[0435] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles(20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 24.0+0.1, 25.6+0.1, 25.7+0.1, and 26.8+0.1.

[0436] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1 , 1 1.2+0.1 , 1 1.4+0.1 , 12.0+0.1 , 13.0+0.1 , 14.7+0.1 , 15.2+0.1 , 16.4+0.1 , 17.8+0.1 , 18.0+0.1, 18.8+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 25.6+0.1, 25.7+0.1, and 26.8+0.1.

[0437] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 20.6+0.1, 21.7+0.1, 22.9+0.1, 25.6+0.1, 25.7+0.1, and 26.8+0.1.

[0438] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 21.7+0.1, 22.9+0.1, 25.6+0.1, 25.7+0.1 , and 26.8+0.1.

[0439] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 21.7+0.1, 22.9+0.1, 25.7+0.1, and 26.8+0.1.

[0440] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 21.7+0.1, and 25.7+0.1.

[0441] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, and 21.7+0.1.

[0442] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 15.2+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, and 21.7+0.1.

[0443] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, and 21.7+0.1.

[0444] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2±0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, 18.0+0.1, and 21.7+0.1.

[0445] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, and 21.7+0.1.

[0446] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.4+0.1.

[0447] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.4+0.1 and 12.0+0.1.

[0448] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.4+0.1, 12.0+0.1, and 21.7+0.1.

[0449] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.2+0.1, 11.4+0.1, 12.0+0.1, and 21.7+0.1.

[0450] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0. 1, 11.2+0.1, 11.4+0.1, 12.0+0.1, and 21.7+0.1.

[0451] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, and 21.7+0.1.

[0452] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, and 21.7+0.1.

[0453] In some embodiments, the solid form is anhydrous crystalline polymorph form A of Compound I free base having a X-ray powder diffraction pattern substantially the same as shown in FIG. 2.

[0454] In some embodiments, the solid form is anhydrous crystalline polymorph form A of Compound I free base having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 279 °C to about 284 °C

[0455] In some embodiments, the solid form is anhydrous crystalline polymorph form A of Compound I free base having a differential scanning calorimetry (DSC) curve as shown in FIG.9.

[0456] In some embodiments, the solid form is anhydrous crystalline polymorph form A of Compound I free base having a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of less than about 1% when heated from about 25° C to about 300° C.

[0457] In some embodiments, the solid form is anhydrous crystalline polymorph form A of Compound I free base having a thermogravimetric analysis (TGA) thermogram as shown in Fig.10.

[0458] In some embodiments, a solid form anhydrous crystalline polymorph form A of Compound I free base has at least one of the following characteristics:

[0459] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.0+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 16.6+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.0+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 24.4+0.1, 24.8+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, 28.9+0.1, and 30.6+0.1;

[0460] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 2;

[0461] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of less than about 1% when heated from about 25° C to about 300° C;

[0462] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 10;

[0463] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 279 °C to about 284 °C; and

[0464] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig- 9.

[0465] In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has at least two of characteristics (a)-(f). In some embodiments, the anhydrous crystalline polymorph form A of Compound I free base has at least three of characteristics (a)-(f).

[0466] A unique physical form of the cocrystal of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20- pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’- j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol with mono-(2S)-2-[(10S,17E)-16- ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3- (azenometheno)tripyrazolo[3,4-f:3 ’ ,4’ -j :4” ,3 ” -n] [ 1 ,4]oxazacyclopentadecin- 14-yl]propan- 1 -ol oxalate and a water (a.k.a. crystalline polymorph form A cocrystal of Compound I with monoCompound I oxalate and hydrate) has been prepared according to the methods described herein.In some embodiments, the solid form is crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate. The X-ray powder diffraction (XRPD) pattern of the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate is shown in Fig. 3, with corresponding tabulated data shown in Table 3.Table 3

[0467] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) as shown in Table 3 and / or FIG. 3.

[0468] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.0+0.1, 11.9+0.1, 13.0+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, 17.4+0.1, 17.8+0.1, 19.4+0.1, 20.7+0.1, 23.8+0.1, 25.1+0.1, and 26.0+0.1.

[0469] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.0+0.1, 11.9+0.1, 13.0+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, 17.4+0.1, 17.8+0.1, 19.4+0.1, 20.7+0.1, 23.8+0.1, and 25.1+0.1.

[0470] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.0+0.1, 11.9+0.1, 13.0+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, 17.4+0.1, 17.8+0.1, 20.7+0.1, 23.8+0.1, and 25.1+0.1.

[0471] In some embodiments, the polymorph form A cocrystal of Compound I with mono- Compound I oxalate and hydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.0+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, 17.4+0.1, 20.7+0.1, and 25.1+0.1.

[0472] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.0+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, 17.4+0.1, and 25.1+0.1.

[0473] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1.

[0474] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.9 +0.1.

[0475] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angle (20) of 7.0+0.1 and 11.9+0.1.

[0476] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angle (20) of 6.6+0.1, 7.0+0.1, and 11.9+0.1.

[0477] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angle (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, and 13.8+0.1.

[0478] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angle (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1 , and 15.1+0.1.

[0479] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angle (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, and 25.1+0.1.

[0480] In some embodiments, the crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angle (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1.

[0481] In some embodiments, the solid form is crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern substantially the same as shown in FIG. 3.

[0482] In some embodiments, the solid form is a crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having an endotherm with an onset at about 62 °C to about 67 °C, and an endotherm with an onset at about 183 °C to about 188 °C.

[0483] In some embodiments, the solid form is a crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a differential scanning calorimetry (DSC) curve as shown in FIG. 11.

[0484] In some embodiments, the solid form is a crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 7% to about 11% when heated from about 25° C to about 300° C

[0485] In some embodiments, the solid form is a crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate having a thermogravimetric analysis (TGA) thermogram as shown in FIG. 12.

[0486] In some embodiments, a solid form cocrystal of Compound I with mono-Compound I oxalate and hydrate has at least one of the following characteristics:

[0487] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1;

[0488] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 3;

[0489] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 7% to about 11% when heated from about 25° C to about 300° C;

[0490] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 12;

[0491] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 62 °C to about 67 °C, and an endotherm with an onset at about 183 °C to about 188 °C; and

[0492] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 11.

[0493] In some embodiments, the solid form cocrystal of Compound I with mono-Compound I oxalate and hydrate has at least two of characteristics (a)-(f). In some embodiments, the solid form cocrystal of Compound I with mono-Compound I oxalate and hydrate has at least three of characteristics (a) -(f).

[0494] A unique HC1 salt form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (a.k.a. crystalline polymorph form A of Compound I HC1 salt) has been prepared according to the methods described herein. In some embodiments, the solid form is crystalline polymorph form A of Compound I HC1 salt. The X- ray powder diffraction (XRPD) pattern of crystalline polymorph form A of Compound I HC1 salt is shown in FIG. 4, with corresponding tabulated data shown in Table 4.Table 4

[0495] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) as shown in Table 4 and / or FIG. 4.

[0496] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 22.9+0.1, 23.7+0.1, 24.0+0.1, 24.6+0.1, 24.8+0.1, 25.2+0.1, 25.5+0.1, 26.6+0.1, 27.5+0.1, and 29.3+0.1.

[0497] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0. 1, 7.0+0. 1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 22.9+0.1, 23.7+0.1, 24.0+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, 26.6+0.1, and 27.5+0.1.

[0498] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0. 1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1 , 21.6+0.1 , 22.6+0.1 , 23.7+0.1 , 24.0+0.1 , 24.6+0.1 , 24.8+0.1 , 25.5+0.1 , 26.6+0.1 , and 27.5+0.1.

[0499] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0. 1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 23.7+0.1, 24.0+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0500] hi some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0. 1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0501] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0502] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0503] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 22.6+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0504] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0. 1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1,16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1 , and 27.5+0.1.

[0505] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1 , 6.6+0.1 , 7.0+0. 1 , 10.9+0.1 , 12.0+0.1 , 12.9+0.1 , 13.1 +0.1 , 13.4+0.1 , 13.6+0.1 , 14.8+0.1 , 16.7+0.1, 16.8+0.1, 17.1+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0506] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 16.7+0.1, 16.8+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0507] In some embodiments, the crystalline polymorph form A of Compound 1 HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 16.7+0.1, 16.8+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0508] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 16.7+0.1, 16.8+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 23.7+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0509] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 16.7+0.1, 16.8+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0510] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0. 1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 16.8+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 20.5+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0511] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0. 1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 16.8+0.1, 18.6+0.1, 19.0+0.1, 20.5+0.1, 24.6+0.1, 24.8+0.1, 25.5+0.1, and 27.5+0.1.

[0512] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.1+0.1 , 13.6+0.1, 14.8+0.1, 16.8+0.1, 18.6+0.1, 19.0+0.1, 20.5+0.1, 24.6+0.1, 24.8+0.1, and 25.5+0.1.

[0513] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1 , 6.6+0.1 , 7.0+0.1 , 12.0+0.1 , 13.1+0.1 , 13.6+0.1 , 14.8+0.1 , 16.8+0.1 , 19.0+0. 1 , 20.5+0.1 , 24.6+0.1, 24.8+0.1, and 25.5+0.1.

[0514] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 16.8+0.1, 19.0+0. 1 , 20.5+0. 1 , 24.6+0.1, and 24.8+0.1.

[0515] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0. 1, 7.0+0.1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 16.8+0.1, 20.5+0.1, 24.6+0.1, and 24.8+0.1.

[0516] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 20.5+0.1, 24.6+0.1, and 24.8+0.1.

[0517] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0. 1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 14.8+0.1, 24.6+0.1, and 24.8+0.1.

[0518] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0. 1, 12.0+0.1, 13.1+0.1, 13.6+0.1, 24.6+0.1, and 24.8+0.1.

[0519] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1 , 7.0+0.1, 12.0+0.1, 13.6+0.1, 24.6+0.1, and 24.8+0.1.

[0520] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 12.0+0.1.

[0521] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0. 1 and 12.0+0.1.

[0522] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1 , 12.0+0.1 , and 13.6+0.1.

[0523] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (26) of 6.5+0.1, 6.6+0.1, 12.0+0.1, and 13.6+0.1.

[0524] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1 , 6.6+0.1 , 7.0+0.1, 12.0+0.1, and 13.6+0.1.

[0525] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0. 1 , 6.6+0.1 , 7.0+0.1, 12.0+0.1, 13.6+0.1, and 24.6+0.1.

[0526] In some embodiments, the crystalline polymorph form A of Compound I HC1 salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.6+0.1, 24.6+0.1, and 24.8+0.1.

[0527] In some embodiments, the solid form is crystalline polymorph form A of Compound 1 HC1 salt having a X-ray powder diffraction pattern substantially the same as shown in FIG. 4.

[0528] In some embodiments, the solid form is a crystalline polymorph form A of Compound I HC1 salt having an endotherm with an onset at about 69 °C to about 74 °C, an endotherm with an onset at about 146 °C to about 151 °C, an exotherm with an onset of about 170 °C to about 175 °C, an endotherm with an onset at about 201 °C to about 206 °C, and an exotherm with an onset at about 216 °C to about 221 °C.

[0529] In some embodiments, the solid form is crystalline polymorph form A of Compound I HC1 salt having a differential scanning calorimetry (DSC) curve as shown in FIG. 13.

[0530] In some embodiments, the solid form is a crystalline polymorph form A of Compound I HC1 salt having a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 9% to about 13% when heated from about 25° C to about 300° C.

[0531] In some embodiments, the solid form is crystalline polymorph form A of Compound I HC1 salt having a thermogravimetric analysis (TGA) thermogram as shown in FIG. 14.

[0532] In some embodiments, a solid form crystalline polymorph form A of Compound I HC1 salt has at least one of the following characteristics:

[0533] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1 , 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 22.9+0.1, 23.7+0.1, 24.0+0.1, 24.6+0.1, 24.8+0.1, 25.2+0.1, 25.5+0.1, 26.6+0.1, 27.5+0.1, and 29.3+0.1;

[0534] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 4;

[0535] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 9% to about 13% when heated from about 25° C to about 300° C;

[0536] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 14;

[0537] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 69 °C to about 74 °C, an endotherm with an onset at about 146 °C to about 151 °C, an exotherm with an onset of about 170 °C to about 175 °C, an endotherm with an onset at about 201 °C to about 206 °C, and an exotherm with an onset at about 216 °C to about 221 °C; and

[0538] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 13.

[0539] hi some embodiments, the solid form crystalline polymorph form A of Compound I HC1 salt has at least two of characteristics (a)-(f). In some embodiments, the solid form crystalline polymorph form A of Compound I HC1 salt has at least three of characteristics (a)-(f).

[0540] A unique bis-HCl salt form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (a.k.a. crystalline polymorph form A of Compound I bis-HCl salt) has been prepared according to the methods described herein. In some embodiments, the solid form is crystalline polymorph form A of Compound I bis-HCl salt. The X-ray powder diffraction (XRPD) pattern of crystalline polymorph form A of Compound I bis- HCl salt is shown in FIG. 5, with corresponding tabulated data shown in Table 5.Table 5

[0541] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) as shown in Table 5 and / or FIG. 5.

[0542] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 6.3+0.1, 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 16.6+0.1, 17.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 23.3+0.1, 23.9+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 26.8+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, 30.4+0.1, and 31.9+0.1.

[0543] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.3+0. 1 , 8.2+0.1, 9.6+0. 1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 16.6+0.1, 17.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 23.3+0.1, 23.9+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, 30.4+0.1, and 31.9+0.1.

[0544] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 6.3+0.1, 8.2+0.1 , 9.6+0.1, 10.6+0.1, 12.1+0.1 , 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 16.6+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1,23.3+0.1, 23.9+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, 30.4+0.1, and 31.9+0.1.

[0545] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1 , 9.6+0.1 , 10.6+0.1 , 12.1+0.1 , 14.5+0.1 , 15.5+0.1 , 16.3+0.1 , 16.4+0.1 , 16.6+0.1 , 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 23.3+0.1, 23.9+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, 30.4+0.1, and 31.9+0.1.

[0546] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 16.6+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 23.3+0.1, 23.9+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, and 30.4+0.1.

[0547] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 16.6+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 23.3+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, and 30.4+0.1.

[0548] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 16.6+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, and 30.4+0.1.

[0549] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, and 30.4+0.1.

[0550] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, and 30.4+0.1.

[0551] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1 , 26.4+0.1 , 26.6+0.1 , 27.1+0.1 , 27.6+0.1 , and 27.8+0.1.

[0552] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.6+0.1, and 27.8+0.1.

[0553] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.6+0.1, and 27.8+0.1.

[0554] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.6+0.1, and 27.8+0.1.

[0555] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.6+0.1, and 27.8+0.1.

[0556] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 27.6+0.1, and 27.8+0.1.

[0557] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, and 27.6+0.1.

[0558] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, and 26.6+0.1.

[0559] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, and 26.6+0.1.

[0560] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 21.2+0.1, 22.0+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, and 26.6+0.1.

[0561] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 21.2+0.1, 22.0+0.1, 24.7+0.1, 25.3+0.1, and 26.6+0.1.

[0562] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 21.2+0.1, 22.0+0.1, 25.3+0.1, and 26.6+0.1.

[0563] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 14.5+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 21.2+0.1, 22.0+0.1, 25.3+0.1, and 26.6+0.1.

[0564] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 15.5+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 21.2+0.1, 22.0+0.1 , 25.3+0.1, and 26.6+0.1.

[0565] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 9.6+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 21.2+0.1, 22.0+0.1, 25.3+0.1, and 26.6+0.1.

[0566] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 21.2+0.1, 22.0+0.1, 25.3+0.1, and 26.6+0.1.

[0567] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (26) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 22.0+0.1, 25.3+0.1, and 26.6+0.1.

[0568] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 25.3+0.1, and 26.6+0.1.

[0569] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising a peaks at diffraction angle (29) of 8.2+0.1.

[0570] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1 and 10.6+0.1.

[0571] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0. 1, 10.6+0.1, and 25.3+0.1.

[0572] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1, 19.9+0.1, and 25.3+0.1.

[0573] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.9+0.1, and 25.3+0.1.

[0574] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0. 1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, and 25.3+0.1.

[0575] In some embodiments, the crystalline polymorph form A of Compound I bis-HCl salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 25.3+0.1, and 26.6+0.1.

[0576] In some embodiments, the solid form is crystalline polymorph form A of Compound I bis-HCl salt having a X-ray powder diffraction pattern substantially the same as shown in FIG.5.

[0577] In some embodiments, the solid form is a crystalline polymorph form A of Compound I bis-HCl salt having an endotherm with an onset at about 106 °C to about 111 °C, an endotherm with an onset at about 118 °C to about 123 °C, an endotherm with an onset of about 158 °C to about 163 °C, and an endotherm with an onset at about 203 °C to about 208 °C.

[0578] hi some embodiments, the solid form is crystalline polymorph form A of Compound I bis-HCl salt having a differential scanning calorimetry (DSC) curve as shown in FIG. 15.

[0579] In some embodiments, the solid form is a crystalline polymorph form A of Compound I bis-HCl salt having a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 12% to about 16% when heated from about 25° C to about 300° C.

[0580] In some embodiments, the solid form is crystalline polymorph form A of Compound I bis-HCl salt having a thermogravimetric analysis (TGA) thermogram as shown in FIG. 16.

[0581] In some embodiments, a solid form crystalline polymorph form A of Compound I bis- HCl salt has at least one of the following characteristics:

[0582] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.3+0.1, 8.2+0.1, 9.6+0.1, 10.6+0.1, 12.1+0.1, 14.5+0.1, 15.5+0.1, 16.3+0.1, 16.4+0.1, 16.6+0.1, 17.4+0.1, 18.0+0.1, 19.3+0.1, 19.9+0.1, 20.0+0.1, 20.3+0.1, 20.6+0.1, 21.2+0.1, 22.0+0.1, 23.1+0.1, 23.3+0.1, 23.9+0.1, 24.3+0.1, 24.7+0.1, 25.3+0.1, 26.4+0.1, 26.6+0.1, 26.8+0.1, 27.1+0.1, 27.6+0.1, 27.8+0.1, 30.4+0.1, and 31.9+0.1;

[0583] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 5;

[0584] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 12% to about 16% when heated from about 25° C to about 300° C;

[0585] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 16;

[0586] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 106 °C to about 111 °C, an endotherm with an onset at about 118 °C to about 123 °C, an endotherm with an onset of about 158 °C to about 163 °C, and an endotherm with an onset at about 203 °C to about 208 °C; and

[0587] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 15.

[0588] In some embodiments, the solid form crystalline polymorph form A of Compound I bis- HCl salt has at least two of characteristics (a)-(f). In some embodiments, the solid form crystalline polymorph form A of Compound I bis-HCl salt has at least three of characteristics (a)- (f).

[0589] A unique monophosphate salt monohydrate form of (2S)-2-[(10S,17E)-16-ethoxy- 6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (a.k.a. crystalline polymorph form A of Compound I monophosphate salt monohydrate) has been prepared according to the methods described herein. In some embodiments, the solid form is crystalline polymorph form A of Compound I monophosphate salt monohydrate. The X-ray powder diffraction (XRPD) pattern of crystalline polymorph form A of Compound I monophosphate salt monohydrate is shown in FIG. 6, with corresponding tabulated data shown in Table 6.Table 6

[0590] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) as shown in Table 6 and / or FIG. 6.

[0591] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 16.2+0.1, 19.1+0.1, 20.9+0.1, 25.0+0.1, 25.8+0.1, and 26.1+0.1.

[0592] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 20.9+0.1, 25.0+0.1, 25.8+0.1, and 26.1+0.1.

[0593] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, 25.8+0.1, and 26.1+0.1.

[0594] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

[0595] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 12.7+0.1.

[0596] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1 and 15.1+0.1.

[0597] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, and 15.8+0.1.

[0598] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, and 19.1+0.1.

[0599] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, and 25.0+0.1.

[0600] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

[0601] In some embodiments, the crystalline polymorph form A of Compound I monophosphate salt monohydrate has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

[0602] In some embodiments, the solid form is crystalline polymorph form A of Compound I monophosphate salt monohydrate having a X-ray powder diffraction pattern substantially the same as shown in FIG. 6.

[0603] A unique (+)-camphor sulfonic acid ((+)-CSA) salt form of (2S)-2-[(10S,17E)-16-ethoxy- 6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (a.k.a. crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt) has been prepared according to the methods described herein. In some embodiments, the solid form is crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt. The X-ray powder diffraction (XRPD) pattern of crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt is shown in FIG. 7, with corresponding tabulated data shown in Table 7.Table 7

[0604] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) as shown in Table 7 and / or FIG. 7.

[0605] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 10.2+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.0+0.1, 16.6+0.1, 17.9+0.1, 18.8+0.1, 20.6+0.1, 24.5+0.1, 25.7+0.1, and 30.6+0.1.

[0606] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 10.2+0.1, 12.1+0.1 , 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.6+0.1, 17.9+0.1, 18.8+0.1, 20.6+0.1, 24.5+0.1, 25.7+0.1, and 30.6+0.1.

[0607] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.6+0.1, 17.9+0.1, 18.8+0.1, 20.6+0.1, 24.5+0.1, 25.7+0.1, and 30.6+0.1.

[0608] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.6+0.1, 17.9+0.1, 18.8+0.1, 20.6+0.1, 24.5+0.1, and 25.7+0.1.

[0609] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.6+0.1, 18.8+0.1, 20.6+0.1, 24.5+0.1, and 25.7+0.1.

[0610] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.6+0.1, 18.8+0.1, 20.6+0.1, and 24.5+0.1.

[0611] In some embodiments, the crystalline polymorph form A of Compound 1 (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.6+0.1, 18.8+0.1, and 20.6+0.1.

[0612] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 16.6+0.1, 18.8+0.1, and 20.6+0.1.

[0613] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 12.1+0.1, 13.8+0.1 , 14.3+0.1, 16.6+0.1, 18.8+0.1, and 20.6+0.1.

[0614] hi some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1 , 12.1+0.1, 13.8+0.1, 14.3+0.1, 18.8+0.1, and 20.6+0.1.

[0615] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0. 1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 18.8+0.1, and 20.6+0.1.

[0616] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising a peaks at diffraction angle (20) of 6.9+0.1.

[0617] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.9±0.1 and 12.1+0.1.

[0618] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, and 12.1+0.1.

[0619] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0. 1, 12.1+0.1, and 18.8+0.1.

[0620] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, and 18.8+0.1.

[0621] In some embodiments, the crystalline polymorph form A of Compound 1 (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, 18.8+0.1, and 20.6+0.1.

[0622] In some embodiments, the crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 18.8+0.1, and 20.6+0.1.

[0623] In some embodiments, the solid form is crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt having a X-ray powder diffraction pattern substantially the same as shown in FIG. 7.

[0624] In some embodiments, the solid form is crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt having an endotherm with a peak temperature of about 122 °C to about 126 °C, and an exotherm having a peak temperature at about 223 °C to about 227 °C.

[0625] In some embodiments, the solid form is crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt having a differential scanning calorimetry (DSC) curve as shown in FIG. 17.

[0626] In some embodiments, the solid form is a crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt having a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 3% to about 8% when heated from about 25° C to about 280° C

[0627] In some embodiments, a solid form crystalline polymorph form A of Compound I (+)- camphor sulfonic acid salt has at least one of the following characteristics:

[0628] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 9.5+0.1, 10.2+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 15.1+0.1, 15.4+0.1, 16.0+0.1, 16.6+0.1, 17.9+0.1, 18.8+0.1, 20.6+0.1, 24.5+0.1, 25.7+0.1, and 30.6+0.1;

[0629] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 7;

[0630] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 3% to about 8% when heated from about 25° C to about 280° C;

[0631] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 18;

[0632] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with a peak temperature of about 122 °C to about 126 °C, and an exotherm having a peak temperature at about 223 °C to about 227 °C; and

[0633] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 17.

[0634] In some embodiments, the solid form crystalline polymorph form A of Compound I (+)- camphor sulfonic acid salt has at least two of characteristics (a)-(f). In some embodiments, the solid form crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt has at least three of characteristics (a)-(f).

[0635] In some embodiments, the solid form is crystalline polymorph form A of Compound I (+)-camphor sulfonic acid salt having a thermogravimetric analysis (TGA) thermogram as shown in FIG. 18.

[0636] A unique (-)-camphor sulfonic acid ((-)-CSA) salt form of (2S)-2-[(10S,17E)-16-ethoxy- 6,8,10,12,20-pentamethyl-2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- f:3’,4’-j:4”,3”-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (a.k.a. crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt) has been prepared according to the methods described herein. In some embodiments, the solid form is crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt. The X-ray powder diffraction (XRPD) pattern of crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt is shown in FIG. 8, with corresponding tabulated data shown in Table 8.Table 8

[0637] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) as shown in Table 8 and / or FIG. 8.

[0638] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 1 1.5+0.1, 13.1+0.1, 13.7+0.1, 14.4+0.1, 14.9+0.1, 15.6+0.1, 17.3+0.1, 18.0+0.1, 20.4+0.1, 23.0+0.1, 23.9+0.1, 25.1+0.1, and 25.4+0.1.

[0639] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 1 1.5+0.1 , 13.1+0.1, 13.7+0.1, 14.4+0.1, 14.9+0.1, 17.3+0.1, 18.0+0.1, 20.4+0.1, 23.0+0.1, 23.9+0.1, 25.1+0.1, and 25.4+0.1.

[0640] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks atdiffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 11.5+0.1, 13.1+0.1, 13.7+0.1, 14.4+0.1, 14.9+0.1, 17.3+0.1, 18.0+0.1, 20.4+0.1, 23.0+0.1, 23.9+0.1, and 25.1+0.1.

[0641] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1 , 5.8+0.1 , 7.2+0.1 , 11.0+0.1 , 1 1.5+0.1 , 13.1+0.1 , 13.7+0.1 , 14.4+0.1, 14.9+0.1, 17.3+0.1, 18.0+0.1, 20.4+0.1, 23.9+0.1, and 25.1+0.1.

[0642] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 1 1.5+0.1 , 13.1+0.1, 13.7+0.1, 14.4+0.1, 14.9+0.1, 17.3+0.1, 18.0+0.1, 23.9+0.1, and 25.1+0.1.

[0643] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 11.5+0.1, 13.1+0.1, 13.7+0.1, 14.4+0.1, 14.9+0.1, 17.3+0.1, 23.9+0.1, and 25.1+0.1.

[0644] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 13.1+0.1, 13.7+0.1, 14.4+0.1, 14.9+0.1, 17.3+0.1, 23.9+0.1, and 25.1+0.1.

[0645] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 13.1+0.1, 13.7+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

[0646] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 13.1+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

[0647] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

[0648] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.0+0.1.

[0649] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0. 1 and 11.0+0.1.

[0650] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1, 11.0+0.1, and 14.9+0.1.

[0651] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.

[0652] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5.1+0.1, 7.2+0. 1, 1 1.0+0.1, 14.9+0.1, and 17.3+0.1.

[0653] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5. 1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.

[0654] In some embodiments, the crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

[0655] In some embodiments, the solid form is crystalline polymorph form A of Compound I (-)- camphor sulfonic acid salt having a X-ray powder diffraction pattern substantially the same as shown in FIG. 8.

[0656] In some embodiments, the solid form is crystalline polymorph form A of Compound I (- )-camphor sulfonic acid salt having an exotherm having a peak temperature at about 234 °C to about 238 °C.

[0657] In some embodiments, the solid form is crystalline polymorph form A of Compound I (-)- camphor sulfonic acid salt having a differential scanning calorimetry (DSC) curve as shown in FIG. 19.

[0658] hi some embodiments, the solid form is a crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt having a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 3% to about 8% when heated from about 25° C to about 280° C.

[0659] In some embodiments, the solid form is crystalline polymorph form A of Compound I (-)- camphor sulfonic acid salt having a thermogravimetric analysis (TGA) thermogram as shown in FIG. 20.

[0660] In some embodiments, a solid form crystalline polymorph form A of Compound I (-)- camphor sulfonic acid salt has at least one of the following characteristics:

[0661] (a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 11.5+0.1, 13.1+0.1, 13.7+0.1, 14.4+0.1, 14.9+0.1, 15.6+0.1, 17.3+0.1, 18.0+0.1, 20.4+0.1, 23.0+0.1, 23.9+0.1, 25.1+0.1, and 25.4+0.1;

[0662] (b) a X-ray powder diffraction pattern substantially the same as shown in FIG. 8;

[0663] (c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 3% to about 8% when heated from about 25° C to about 280° C;

[0664] (d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 20;

[0665] (e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an exotherm having a peak temperature at about 234 °C to about 238 °C; and

[0666] (f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 19.

[0667] In some embodiments, the solid form crystalline polymorph form A of Compound I (-)- camphor sulfonic acid salt has at least two of characteristics (a)-(f). In some embodiments, the solid form crystalline polymorph form A of Compound I (-)-camphor sulfonic acid salt has at least three of characteristics (a)-(f).

[0668] In some embodiments, the methods described herein relate to the treatment of cancer comprising administering to a patient in need of treatment a therapeutically effective amount of a EGFR inhibitor. The definition of an “inhibitor” is well known to one of skill in the art, and the use herein of the general term “inhibitor” is understood to be the usual and customary meaning. It will be appreciated that “a EGFR inhibitor” is a compound that can have affinity for and thereby modulate or block the activity of the protein kinase EGFR. In some embodiments, it can be advantageous for the “EGFR inhibitor” to selectively modulate or block the activity of EGFR having one or more mutations when compared to the wild-type (WT) EGFR protein kinase. In some embodiments, the EGFR inhibitor can be a mutant selective EGFR inhibitor having affinity for EGFR protein kinase having one more mutations, such as E709K, K716A, K716Q, L718Q, G719C, G719D, G719S, G724S, K728A, L747P, A746, L747S, D761Y, S768I, D769H, D769Y, D770G / Y, V777L, T790M, L792F, L792H, C797A, C797S, L858R, L861Q, R896C, R999A, Exl9del (such as A746-750750 or A752-759), A763-Y764insFHEA, A763- Y764insFQEA, A767-S768insTLA, V769-D770insASV, V769-D770insGE, D770-N771insNPG, D770-N771insSVD, N771-P772insH, H773-V774insNPH, A775-G776insYVMA, V777-G778insCG, K716Q / L718Q, A746-750 / T790M, A746-750 / C797A,A746-750 / C797S, A747-752 / P753S, D770-N771insNPG / Y790M, L858R / T790M,L858R / C797S, L792H / L858R, C775S / T790M / L858R, L858R / T790M / C797S, A746-750 / T790M / C797S, K716A / C797S / L858R, L718V / L858R / T790M, T790M / L792F / L858R, T790M / L792H / L858R, L792H / C797S / / L858R, K716A / T790M / C797S / L858R,K728A / T790M / C797S / L858R, A746-750 / C775S / T790M / L858R, A746-750 / T790M / C797S / L858R, and T790M / L792F / C797S / L858R, while maintaining good selectivity over WT EGFR.

[0669] It will be appreciated that the cancer can be a liquid or solid tumor cancer, such as acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndromes (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER+breast cancer, triple negative breast, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer and lung cancer. In some embodiments, the cancer can be a liquid tumor, such as a hematologic cancer, a bone marrow cancer, or a lymphatic system cancer. In some embodiments, the cancer can be a solid tumor, such as NSCLC, breast cancer, colon cancer, and the like. In some embodiments, the cancer is non-small cell lung cancer (NSCLC).

[0670] In some embodiments, the present disclosure provides methods of treating disease in a patient that has received a prior treatment with one or more therapeutic agents. In some embodiments, the patient has been previously treated with one or more anti-cancer agents. In some embodiments, the patient has been previously treated with one or more anti-cancer agents and developed an acquired resistance to the treatment. In some embodiments, the patient has been previously treated with one or more anti-cancer agents and developed resistance to the treatment. In some embodiments, the patient has been previously treated with one or more anti-cancer agents and developed resistance to the treatment. In some embodiments, the patient has been previouslytreated with one or more anti-cancer agents, such as chemotherapy and / or prior EGFR inhibitor treatment, and the patient has developed resistance to the treatment.

[0671] Other anti-cancer agents which the patient may be been treated with prior to treatment with one or more of the compounds described herein include but are not limited to kinase inhibitors, adrenocorticoids and corticosteroids, alkylating agents, peptide and peptidomimetic signal transduction inhibitors, antibodies, bispecific antibodies, antiandrogens, antiestrogens, androgens, aclamycin and aclamycin derivatives, cell therapies, estrogens, antimetabolites, platinum compounds, amanitins, plant alkaloids, mitomycins, discodermolides, microtubule inhibitors, epothilones, inflammatory and proinflammatory agents, purine analogs, pyrimidine analogs, camptothecins and dolastatins. In some embodiments, the patient has treated with one or more prior EGFR inhibitors, such as gefinitib, afatinib, erlotinib, osimertinib, dacomitinib, vandetanib, icotinib, simotinib, poziotinib, pelitinib, canertinib, zipalertinib, brigatinib, olmutinib, almonertinib, mobocertinib, rociletinib, naquotinib, avitinib, nazartinib, sunvozertinib, BLU-701, BLU-525, BTDX-1535, STX-721, BAY2927088, BBT-176, JIN-A02, BBT-207, TRX-221, BLU-945, THE-349, and the like. In some embodiments, the patient has treated with one or more prior EGFR inhibitors, such as gefinitib, afatinib, erlotinib, osimertinib, dacomitinib, vandetanib, icotinib, simotinib, poziotinib, pelitinib, canertinib, zipalertinib, brigatinib, olmutinib, almonertinib, mobocertinib, rociletinib, naquotinib, avitinib, nazartinib, sunvozertinib, BLU-701, BLU-525, BTDX-1535, STX-721, BAY2927088, BBT-176, JIN-A02, BBT-207, TRX-221, BLU-945, THE-349, and the like, and one or more prior treatment selected from chemotherapy, such as platinum-based chemotherapy, antibody treatment, and bispecific antibody treatment.

[0672] An example of cancer, for example one having a complex treatment and resistance profile, is EGFR+non-small cell lung cancer (NSCLC) which is a complex malignancy that can be driven by a heterogenous set of mutations. Two of the most frequently identified mutations in EGFR+NSCLC are the L858R and Exl9del (such as A746-750750 or A752-759). These mutations are also known as classified as EGFR classic mutations or common mutations. After the approval of the first EGFR inhibitors, such as gefinitib and afatinib, new mutations emerged through acquired resistance, including the T790M mutation (a.k.a. the gate-keeper mutation). The emergence of the T790M mutation led to the development of a new generation of EGFR inhibitors, including osimertinib, which was active against the T790M mutation. However, because osimertinib, like many other EGFR inhibitors is an irreversible inhibitor that relies on a covalent bond forming between the inhibitor and a cysteine residue in the target protein, further acquired resistance mutations can occur, such as the C797S mutation that is commonly the cause of cancer resistance to osimertinib. In addition to the classical mutations (L858R and Exl9del), the gate keepermutation (T790M), and the C797S mutation, about 33% of EGFR+NSCLC are shown to have one or more of a wide variety of atypical mutations or combination mutations (e.g., L858R / T790M / C797S). Because of the vast heterogeneity that is possible in EGFR+NSCLC, durable treatment has been difficult to achieve.

[0673] Tn some embodiments, the disclosure provides a method of treating cancer, such as EGFR+NSCLC, having one or more mutations selected from the groups consisting of E709K, K716A, K716Q, L718Q, G719C, G719D, G719S, G724S, K728A, L747P, A746, L747S, D761Y, S768I, D769H, D769Y, D770G / Y, V777L, T790M, L792F, L792H, C797A, C797S, L858R, L861Q, R896C, R999A, Exl9del (such as A746-750750 or A752-759), A763- Y764insFHEA, A763-Y764insFQEA, A767-S768insTLA, V769-D770insASV, V769- D770insGE, D770-N771insNPG, D770-N771insSVD, N771-P772insH, H773-V774insNPH, A775-G776insYVMA, V777-G778insCG, K716Q / L718Q, A746-750 / T790M, A746- 750 / C797A, A746-750 / C797S, A747-752 / P753S, D770-N771insNPG / Y790M, L858R / T790M, L858R / C797S, L792H / L858R, C775S / T790M / L858R, L858R / T790M / C797S, A746- 750 / T790M / C797S, K716A / C797S / L858R, L718V / L858R / T790M, T790M / L792F / L858R, T790M / L792H / L858R, L792H / C797S / / L858R, K716A / T790M / C797S / L858R,K728A / T790M / C797S / L858R, A746-750 / C775S / T790M / L858R, A746-750 / T790M / C797S / L858R, and T790M / L792F / C797S / L858R, wherein the method comprises administering a therapeutically effective amount of Compound I in any of the forms disclosed herein.

[0674] In some embodiments, the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular HER2, including HER2 having one or more mutations in the kinase domain of exons 18, 19, 20, or 21, for example HER2 exon 20 mutations such as A775_G776insYVMA, 778insGCP, G780_P781dupGSP, G778_S779insCPG, Y772_A775dup, G778_P780dup, E770_A771insAYVM,A771_Y772insYVMA, V777_G778insGSP, and P780_Y78 linsGSP. In some embodiments, the compounds and pharmaceutical compositions of the disclosure selectively target HER2 having one or more mutations as described herein over wild-type HER2. In some embodiments, the compounds and pharmaceutical compositions of the disclosure can be used to prevent, reverse, slow, or inhibit the activity of HER2 having one or more mutations as described herein. In certain preferred embodiments, methods of treating a target cancer are described herein, wherein the cancer comprises an HER2 having one or more mutations as described herein. In some embodiments, methods of treating lung cancer, such as non-small cell lung cancer, are described herein, wherein the lung cancer comprises an HER2 having one or more mutations as described herein.

[0675] In some embodiments, an “effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cell is preferably a cancer cell with abnormal signaling due to upregulation of HER2, including a cancer cell having one or more HER2 mutations, including HER2 having one or more mutations in the kinase domain of exons 18, 19, 20, or 21, for example HER2 exon 20 mutations such as A775_G776insYVMA, 778insGCP, G780_P781dupGSP, G778_S779insCPG, Y772_A775dup, G778_P780dup,E770_A771insAYVM, A771_Y772insYVMA, V777_G778insGSP, and P780_Y781insGSP, while maintaining good selectivity over wild-type HER2.

[0676] In some embodiments, the compounds and pharmaceutical compositions of the disclosure specifically target tyrosine receptor kinases, in particular EGFR and / or HER2, including EGFR having one or more mutations, and / or HER2 having one or more mutations as described herein.

[0677] In treatment methods according to the invention, an “effective amount” or a “therapeutically effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment. Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician. An example dose is in the range of about from about 0. 1 mg to about 1 g daily, or about 1 mg to about 500 mg daily, or about 5 mg to about 250 mg daily, or about 10 mg to about 200 mg daily.

[0678] The total dosage may be given in single or divided dosage units (e.g., QD, BID, or TID). In some embodiments, the dose is about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID of Compound I. In some embodiments, the dose is about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg QD of Compound I. In some embodiments, the dose is about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate. In some embodiments, the dose is about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170mg, about 180 mg, about 190 mg, or about 200 mg QD of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate.

[0679] Once improvement of the patient’s disease has occurred, the dose may be adjusted for preventative or maintenance treatment. For example, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained. Of course, if symptoms have been alleviated to an appropriate level, treatment may cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.Pharmaceutical Compositions

[0680] The present disclosure also relates to pharmaceutical compositions comprising a polymorph form of Compound I described herein. Pharmaceutical compositions of the present disclosure may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition may include conventional pharmaceutically-acceptable excipients. In addition, pharmaceutical compositions described herein may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0681] A pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents. In preferred embodiments, pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.

[0682] Sterile compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.

[0683] The pharmaceutical compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders forreconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms. Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. In some embodiments, the compositions are formulated for intravenous or oral administration.

[0684] For oral administration, the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension. To prepare the oral compositions, the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to about 1 g daily, or about 1 mg to about 500 mg daily, or about 5 mg to about 250 mg daily, or about 10 mg to about 200 mg daily. Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, wetting agents, flow-enhancing agents (glidants), sweetening agents, flavoring agents, coloring agents and preservative agents. Suitable inert fillers include microcrystalline cellulose, sodium and calcium carbonate, sodium and calcium phosphate, lactose (e.g., anhydrous lactose and lactose monohydrate), starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, crospovidone (Polyplasdone™ XL), sodium starch glycolate, cross-linked sodium carboxymethylcellulose, microcrystalline cellulose, and alginic acid are exemplary disintegrating agents. Binding agents may include methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, starch and gelatin. Wetting agents are typically surfactants including sodium lauryl sulfate (SLS), polysorbate 80, polyoxy 40 stearate, or poloxamer 188. The lubricating agent, if present, may be sodium stearyl fumarate, magnesium stearate, stearic acid, or talc. The glidant, if present, may be colloidal silicon dioxide or talc. If desired, the tablets may be coated with a material such as Opadry for immediate-release or glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.

[0685] Capsules for oral administration include hard and soft gelatin capsules. Another example of capsules for oral administration includes vegetarian (e.g., hydroxypropyl methylcellulose (HPMC)) capsules. Capsules may be offered in a variety of colors and sizes, including 000, 00, 0, 1, 2, 3, 4 and 5. To prepare capsules, such as hard gelatin capsules or vegetarian capsules, active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0686] In some embodiments, pharmaceutical compositions described herein include about 1 mg to about 1000 mg of a solid form of Compound I. In some embodiments, pharmaceutical compositions described herein include about 1 mg to about 750 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 1 mg to about 500 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 5 mg to about 500 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 5 mg to about 100 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 5 mg to about 50 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 5 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 10 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 20 mg of Compound I. In some embodiments, pharmaceutical compositions described herein include about 40 mg of Compound 1.

[0687] In some embodiments, the composition is in a dosage form, such as a capsule. In some embodiments, the dosage form (e.g., capsule) can contain from about 1 to about 500, about 1 to about 100, or about 1 to about 50 mg of a solid form of Compound I (e.g., about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg, about 10 mg, or about 40 mg) as described herein. The dosage form (e.g., capsule) may further include one or more diluents, (e.g., lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, or dextrose), disintegrant (e.g., natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, crosslinked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone, cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum), lubricants (e.g., stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes), glidants (e.g., colloidal silicon dioxide or talc) , etc. as described herein.

[0688] In some embodiments, a capsule formulation is prepared that includes about 1 to about 1000 mg of a solid form of Compound I (e.g., about 1 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg, about 10 mg, or about 40 mg). In some embodiments, the capsule formulation includes about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of Compound I. In some embodiments, the capsule formulation includes about 40 mg, about 80 mg, about 90 mg,about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of Compound I.

[0689] In some embodiments, the capsule formulation includes about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate. In some embodiments, the capsule formulation includes about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate.

[0690] In some embodiments, 2, 3, 4, or 5 of the capsule formulations are administered daily. In some embodiments, 3 or 4 of the capsules are administered daily. In some embodiments, 3 of the capsules are administered once daily. In some embodiments, 4 of the capsules are administered once daily. In some embodiments, the capsules are administered once daily. In other embodiments, the capsules are administered multiple times a day. In some embodiments, Compound I is provided at about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID. In some embodiments, Compound I is provided at about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg QD. In some embodiments, crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate is provided at about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID. In some embodiments, crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate is provided at about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg QD.

[0691] In some embodiments, a tablet formulation is prepared that includes about 1 to about 1000 mg of a solid form of Compound I (e.g., about 1 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg, about 10 mg, or about 40 mg). In some embodiments, the tablet formulation includes about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of Compound I. In some embodiments, the tablet formulation includes about 40 mg, about 80 mg, about 90 mg, about 100mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of Compound I.

[0692] In some embodiments, the tablet formulation includes about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate. In some embodiments, the tablet formulation includes about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate.

[0693] In some embodiments, 2, 3, 4, or 5 of the tablet formulations are administered daily. In some embodiments, 3 or 4 of the tablets are administered daily. In some embodiments, 3 of the tablets are administered once daily. In some embodiments, 4 of the tablets are administered once daily. In some embodiments, the tablets are administered once daily. In other embodiments, the tablets are administered multiple times a day. In some embodiments, Compound I is provided at about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID. In some embodiments, Compound I is provided at about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg QD. In some embodiments, crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate is provided at about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, or about 100 mg BID. In some embodiments, crystalline polymorph form A cocrystal of Compound I with mono-Compound I oxalate and hydrate is provided at about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg QD.

[0694] In some embodiments, a dosage form is prepared that includes a capsule comprising about 1 to about 1000 mg of a solid form of Compound I (e.g., about 1 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg, about 10 mg, or about 40 mg).

[0695] In some embodiments, a dosage form is prepared that includes a capsule comprising about 1 to about 1000 mg of a solid form of Compound I (e.g., about 1 mg to about 750 mg, about 5 mg to about 500 mg, about 5 mg to about 100 mg, about 5 mg to about 50 mg, about 5 mg, about10 mg, or about 40 mg), and optionally one or more pharmaceutically acceptable additives (e.g., pharmaceutically acceptable excipients).

[0696] The pharmaceutical solid dosage forms described herein can include Compound I and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of Compound I.

[0697] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerin, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

[0698] Suitable filling agents (sometimes referred to as fillers) for use in the solid dosage forms described herein include, but are not limited to, lactose (e.g., anhydrous lactose and lactose monohydrate), calcium carbonate, calcium phosphate, dibasic calcium phosphate, dicalcium phosphate dihydrate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like. In some embodiments provided herein, fillers include microcrystalline cellulose (MCC), lactose (e.g., lactose monohydrate and anhydrous lactose), mannitol, calcium phosphate (e.g., dicalcium phosphate dihydrate), and any combination thereof. In some embodiments provided herein, the filler is a mixture of two or more fillers.

[0699] In general, filler levels of 10-95% may be used in capsule or tablet formulations. In some embodiments, filler levels of 30-90% may be used in capsule or tablet formulations. Filler usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients. Formulators skilled in art can determine the filler level for the formulations, but filler usage level of up to about 90% in tablet formulations is common, hi some embodiments, a filler is present at about 50% to about 90% by weight of the formulation. For example, the filler may be present at about 60% to about 90%, about 70% to about 90%, orabout 75% to about 90% by weight of the formulation. In some embodiments provided herein, the filler is present at about 10% to about 95% by weight of the formulation, such as about 50% to about 90% by weight of the formulation.

[0700] In order to release the Compound I from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, for example when the dosage forms are compressed with binder. Disintegrants (sometimes referred to as disintegrating agents) help in rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, a cellulose such as a wood product, microcrystalline cellulose (e.g., Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vitacel®, Ming Tia Comprecel®, and Solka-Floc®), methylcellulose, croscarmellose, or a cross-linked cellulose, such as crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone (Polyplasdone™ XL), a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination with starch, and the like. In some embodiments provided herein, the disintegrating agent is selected from the group consisting of natural starch, a pregelatinized starch, a sodium starch, methylcrystalline cellulose, methylcellulose, croscarmellose, croscarmellose sodium, cross-linked sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, cross-linked croscarmellose, cross-linked starch such as sodium starch glycolate, cross-linked polymer such as crospovidone (Polyplasdone™ XL), cross-linked polyvinylpyrrolidone, sodium alginate, a clay, or a gum. In some embodiments provided herein, the disintegrating agent is croscarmellose sodium.

[0701] In some embodiments provided herein, the disintegrant includes crospovidone, sodium starch glycolate, croscarmellose, or a combination thereof. In some embodiments provided herein, the disintegrant is a mixture of two or more disintegrants. In some embodiments, a disintegrant is present at about 1% to about 10% by weight (e.g., about 4% by weight) of the formulation. For example, the disintegrant may be present at about 2% to about 10%, about 2% to about 8%, about 3% to about 10%, or about 3% to about 8% by weight of the formulation.

[0702] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603, hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g., Avicel®, such as Avicel® PH101 and Avicel® PH102), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone / vinyl acetate copolymer, crospovidone (Polyplasdone™ XL), povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone® XL-10, and Povidone® K-12), copovidone, larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodium alginate, and the like. In some embodiments provided herein, the binder includes copovidone.

[0703] In general, binder levels of 20-70% may be used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common. In some embodiments, a binder is present at about 1 % to about 50% by weight of the formulation. For example, the binder may be present at about 1% to about 20%, about 1% to about 10%, or about 2% to about 8% by weight of the formulation.

[0704] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumarate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl palmitostearate, glyceryl benzoate, colloidal silicon dioxide, sodium stearyl fumarate, magnesium or sodium lauryl sulfate (SLS), and the like. In some embodiments provided herein, the glidant is silica or colloidal silicon dioxide. In someembodiments, a glidant is present at about 0.1% to about 5% by weight of the formulation. For example, the glidant may be present at about 0.1% to about 3%, about 0.1 % to about 2%, or about 0.1% to about 1% by weight of the formulation. In some embodiments provided herein, the lubricant is selected from the group consisting of stearic acid, calcium hydroxide, talc, com starch, sodium stearyl fumarate, stearic acid, sodium stearates, magnesium stearate, zinc stearate, and waxes. In some embodiments provided herein, the lubricant is magnesium stearate. In some embodiments provided herein, the lubricant is sodium stearyl fumarate, magnesium stearate, stearic acid, or any combination thereof. In some embodiments, a lubricant is present at about 0.1% to about 5% by weight of the formulation. For example, the lubricant may be present at about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1% by weight of the formulation.

[0705] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like. In some embodiments provided herein, the diluent is selected from the group consisting of lactose, sucrose, dextrose, dextrates, maltodextrin, mannitol, xylitol, sorbitol, cyclodextrins, calcium phosphate, calcium sulfate, starches, modified starches, microcrystalline cellulose, microcellulose, and talc. In some embodiments provided herein, the diluent is microcrystalline cellulose. In some embodiments provided herein, diluents include microcrystalline cellulose (MCC), lactose (e.g., lactose monohydrate and anhydrous lactose), mannitol, calcium phosphate (e.g., dicalcium phosphate dihydrate), and any combination thereof. In some embodiments provided herein, the diluent is a mixture of two or more diluents. In some embodiments, a diluent is present at about 10% to about 95% by weight, such as about 50% to about 90% by weight of the formulation. For example, the diluent may be present at about 60% to about 90%, about 70% to about 90%, or about 75% to about 90% by weight of the formulation.

[0706] The term “non water-soluble diluent” represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g / cm3, e.g., Avicel®, powdered cellulose), and talc.

[0707] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, polyoxyethylene stearate (e.g., polyoxyl 40 stearate), sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, polysorbate (e.g., polysorbate 80), poloxamer (e.g., poloxamer 188), quaternary ammonium compounds (e.g., Polyquat 10®), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin ETPGS and the like. In some embodiments, a surfactant can be used as a wetting agent. In some embodiments provided herein, the wetting agent is sodium lauryl sulfate, polysorbate, poloxamer, polyoxyethylene stearate, or any combination thereof. In some embodiments provided herein, the wetting agent is sodium lauryl sulfate. In some embodiments, a wetting agent is present at about 1 % to about 60% by weight, such as about 1 % to about 20% by weight of the formulation. For example, the wetting agent may be present at about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 10% to about 60%, about 10% to about 20%, about 15% to about 60%, or about 15% to about 20% by weight of the formulation.

[0708] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide (e.g., Pluronic® (BASF)), and the like. In some embodiments, a wetting agent can be used as a surfactant. In some embodiments provided herein, the surfactant is selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates (e.g., polysorbate 80), poloxamers (e.g., poloxamer 188), bile salts, glyceryl monostearate, polyoxyethylene stearate (e.g., polyoxyl 40 stearate), copolymers of ethylene oxide and propylene oxide. In some embodiments provided herein, the surfactant is sodium lauryl sulfate, polysorbate, poloxamer, polyoxyethylene stearate, or any combination thereof. In some embodiments provided herein, the surfactant is sodium lauryl sulfate. In some embodiments, a surfactant is present at about 1% to about 60% by weight, such as about 1% to about 20% by weight of the formulation. For example, the surfactant may be present at about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 10% to about 60%, about 10% to about 20%, about 15% to about 60%, or about 15% to about 20% by weight of the formulation.

[0709] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone KI 2, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl pyrrolidone / vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate- 80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate,polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[0710] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and tocopherol.

[0711] Acidulants help maintain the desired pH level in pharmaceutical formulations, which can aid in drug stability and efficacy. Acidulants can also act as preservatives by lowering the pH and inhibiting the growth of microorganisms. Suitable acidulants for use in the solid dosage forms described here include, but are not limited to, citric acid (e.g., anhydrous citric acid), hydrochloric acid, lactic acid, fumaric acid, tartaric acid, and phosphoric acid. In some embodiments provided herein, the acidulant is fumaric acid, tartaric acid, citric acid, or any combination thereof. In some embodiments, the acidulant is fumaric acid. In some embodiments, an acidulant is present at about 1% to about 20% (e.g., about 5%) by weight of the formulation. For example, the acidulant may be present at about 1% to about 20%, about 1% to about 15%, about 1% to about 10%, about 3% to about 20%, about 3% to about 15%, or about 3% to about 10% by weight of the formulation.

[0712] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely examples, and not limiting, of the types of additives that can be included in solid dosage forms described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

[0713] Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may optionally contain: pharmaceutically-acceptable excipients such as suspending agents (for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like); non-aqueous vehicles, e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water; preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if desired, flavoring or coloring agents.

[0714] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multidose forms such as vials from which the appropriate dose may be withdrawn, or in a solid formor pre-concentrate that can be used to prepare an injectable formulation. Illustrative infusion doses range from about 1 to 1000 pg / kg / minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.

[0715] For nasal, inhaled, or oral administration, the inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier. The inventive compositions may be formulated for rectal administration as a suppository.

[0716] For topical applications, the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration. For topical administration, the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle. Another mode of administering the agents of the invention may utilize a patch formulation to affect transdermal delivery.

[0717] Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition (1975).

[0718] In some embodiments, the pharmaceutical formulation may comprise Compound I (e.g., a solid form, such as a polymorph form A of Compound I) and a filler, a disintegrant, a lubricant, and a surfactant. In some embodiments, the pharmaceutical formulation may comprise Compound I and at least one of a filler, a disintegrant, a lubricant, and a surfactant.

[0719] In some embodiments, the pharmaceutical formulation may comprise Compound I and a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or any combination thereof. In some embodiments, the pharmaceutical formulation may comprise Compound I and at least two of a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof. In some embodiments, the pharmaceutical formulation may comprise Compound I and at least three of a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof. In some embodiments, the pharmaceutical formulation may comprise Compound I and a filler and at least two of a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof.

[0720] In some embodiments, the filler is selected from microcrystalline cellulose, mannitol, lactose, calcium phosphate, or any combination thereof. In some embodiments, the filler is a mixture of two or more fillers. In some embodiments, the binder is copovidone. In some embodiments, the acidulant is selected from citric acid, fumaric acid, tartaric acid, or any combination thereof. In some embodiments, the disintegrant is selected from crospovidone, croscarmellose, sodium starch glycolate, or any combination thereof. In some embodiments, thedisintegrant is a mixture of two or more disintegrants. In some embodiments, the surfactant is sodium lauryl sulfate, polysorbate, poloxamer, polyoxyethylene stearate, or any combination thereof. In some embodiments, disintegrant is a mixture of two or more surfactants. In some embodiments, the glidant is silica. In some embodiments, the lubricant is sodium stearyl fumarate, magnesium stearate, stearic acid, or any combination thereof.

[0721] In some embodiments, Compound I (e.g., a solid form) is present at about 3% to about 20% by weight of the formulation. For example, Compound I may be present at about 5% to about 15%, about 5% to about 6%, or about 10% to about 12% by weight of the formulation.

[0722] In some embodiments, the pharmaceutical formulation comprises about 3% to about 20% by weight Compound I (e.g., a solid form); about 10% to about 95% by weight filler; optionally about 1% to about 10% by weight acidulant; about 1% to about 10% by weight disintegrant; optionally about 1% to about 60% by weight surfactant; about 0.1% to about 3% by weight glidant; and about 0. 1% to about 3% by weight lubricant.

[0723] In some embodiments, the pharmaceutical formulation comprising Compound I, for example a solid form thereof, is in the form of a tablet or a capsule.

[0724] In some embodiments, the pharmaceutical formulation, for example in the form of a tablet, may comprise Compound I (e.g., a solid form) and a filler, a disintegrant, a glidant, a lubricant, or any combination thereof. In some embodiments, the pharmaceutical formulation, for example in the form of a tablet, may comprise Compound I (e.g., a solid form), microcrystalline cellulose, lactose monohydrate, crospovidone, sodium stearyl fumarate, and silica.

[0725] In some embodiments, the pharmaceutical formulation, for example in the form of a tablet, comprises about 10% to about 12% by weight Compound I (e.g., a solid form); about 83% to about 85% by weight filler; about 4% by weight disintegrant; about 0.25% by weight glidant; and about 0.5% by weight lubricant.

[0726] hi some embodiments, the pharmaceutical formulation, for example in the form of a tablet, comprises about 3 mg to about 50 mg Compound I (e.g., a solid form); about 50 mg to about 500 mg filler; about 1 mg to about 50 mg disintegrant; about 0.1 mg to about 5 mg glidant; and about 0.1 mg to about 5 mg lubricant.

[0727] In some embodiments, the pharmaceutical formulation comprises about 10 mg ± 10% or about 11 mg ± 10% Compound I (e.g., a solid form); about 50 mg ± 10% microcrystalline cellulose; about 34 mg ± 10% lactose monohydrate; about 4 mg ± 10% crospovidone; about 0.5 mg ± 10% sodium stearyl fumarate; and about 0.25 mg + 10% silica.

[0728] In some embodiments, the pharmaceutical formulation comprises about 20 mg ± 10% or about 22 mg ± 10% Compound I (e.g., a solid form); about 140 mg ± 10% microcrystallinecellulose; about 68 mg ± 10% lactose monohydrate; about 8 mg ± 10% crospovidone; about 1 mg ± 10% sodium stearyl fumarate; and about 0.5 mg ± 10% silica.

[0729] In some embodiments, the pharmaceutical formulation comprises about 40 mg ± 10% or about 44 mg ± 10% Compound I (e.g., a solid form); about 200 mg ± 10% microcrystalline cellulose; about 137 mg + 10% lactose monohydrate; about 16 mg + 10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ± 10% silica.

[0730] In some embodiments, the pharmaceutical formulation, for example in the form of a capsule, may comprise Compound I (e.g., a solid form) and a filler, a surfactant, an acidulant, a disintegrant, a glidant, a lubricant, or a combination thereof. In some embodiments, the pharmaceutical formulation, for example in the form of a capsule, may comprise Compound I (e.g., a solid form), microcrystalline cellulose, lactose anhydrous, lactose monohydrate, crospovidone, sodium lauryl sulfate, polyoxyl 40 stearate, poloxamer 188, polysorbate, fumaric acid, sodium stearyl fumarate, and silica.

[0731] In some embodiments, the pharmaceutical formulation comprises about 3% to about 20% (e.g., about 5% to about 15%) by weight Compound I (e.g., a solid form); about 10% to about 95% by weight filler; optionally about 1% to about 10% by weight acidulant; about 1% to about 10% by weight disintegrant; optionally about 1% to about 60% by weight surfactant; about 0.1% to about 3% by weight glidant; and about 0. 1% to about 3% by weight lubricant.

[0732] In some embodiments, the pharmaceutical formulation, for example in the form of a capsule, comprises about 3 mg to about 50 mg Compound I (e.g., a solid form); about 50 mg to about 500 mg filler; optionally about 1 mg to about 50 mg acidulant; about 1 mg to about 50 mg disintegrant; optionally about 5 mg to about 500 mg surfactant; about 0. 1 mg to about 5 mg glidant; and about 0.1 mg to about 5 mg by weight lubricant.

[0733] In some embodiments, the pharmaceutical formulation comprises about 10% by weight Compound I (e.g., a solid form); about 85% by weight filler; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

[0734] In some embodiments, the pharmaceutical formulation comprises about 40 mg ± 10% Compound I (e.g., a solid form); about 200 mg ± 10% microcrystalline cellulose; about 141 mg ± 10% lactose anhydrous; about 16 mg ± 10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ± 10% silica.

[0735] In some embodiments, the pharmaceutical formulation comprises about 10% by weight Compound I (e.g., a solid form); about 80% by weight filler; about 5% by weight surfactant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

[0736] In some embodiments, the pharmaceutical formulation comprises about 40 mg ± 10% Compound I (e.g., a solid form); about 180 mg ± 10% microcrystalline cellulose; about 141 mg ± 10% lactose anhydrous; about 20 mg ± 10% sodium lauryl sulfate; about 16 mg ± 10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ± 10% silica.

[0737] In some embodiments, the pharmaceutical formulation comprises about 10% by weight Compound I (e.g., a solid form); about 80% by weight filler; about 5% by weight acidulant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

[0738] In some embodiments, the pharmaceutical formulation comprises about 40 mg ±10% Compound I (e.g., a solid form); about 180 mg ± 10% microcrystalline cellulose; about 141 mg ± 10% lactose anhydrous; about 20 mg ±10% fumaric acid; about 16 mg ± 10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ± 10% silica.

[0739] In some embodiments, the pharmaceutical formulation comprises about 10% by weight Compound 1 (e.g., a solid form); about 75% by weight filler; about 5% by weight surfactant; about 5% by weight acidulant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

[0740] In some embodiments, the pharmaceutical formulation comprises about 40 mg ±10% Compound I (e.g., a solid form); about 160 mg ±10% microcrystalline cellulose; about 141 mg ±10% lactose anhydrous; about 20 mg ±10% sodium lauryl sulfate; about 20 mg ±10% fumaric acid; about 16 mg ±10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ±10% silica.

[0741] In some embodiments, the pharmaceutical formulation comprises about 10% by weight Compound I (e.g., a solid form); about 83% by weight filler; about 2% by weight surfactant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

[0742] In some embodiments, the pharmaceutical formulation comprises about 40 mg ± 10% Compound I (e.g., a solid form); about 192 mg ± 10% microcrystalline cellulose; about 141 mg ± 10% lactose anhydrous; about 8 mg ± 10% polyoxyl 40 stearate; about 16 mg ±10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ± 10% silica.

[0743] In some embodiments, the pharmaceutical formulation comprises about 10% by weight Compound I (e.g., a solid form); about 73% by weight filler; about 12.5% by weight surfactant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.8% by weight lubricant.

[0744] In some embodiments, the pharmaceutical formulation comprises about 40 mg ±10% Compound I (e.g., a solid form); about 40 mg ±10% microcrystalline cellulose; about 251 mg±10% lactose monohydrate; about 50 mg ±10% sodium lauryl sulfate; about 16 mg ±10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ±10% silica.

[0745] In some embodiments, the pharmaceutical formulation about 10% by weight Compound I (e.g., a solid form); about 33% by weight filler; about 48% by weight surfactant; about 5% by weight acidulant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

[0746] In some embodiments, the pharmaceutical formulation comprises about 40 mg ±10% Compound I (e.g., a solid form); about 40 mg ±10% microcrystalline cellulose; about 90 mg ±10% lactose monohydrate; about 50 mg ±10% sodium lauryl sulfate; about 141 mg ±10% poloxamer 188; about 20 mg ±10% fumaric acid; about 16 mg ±10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ±10% silica.

[0747] In some embodiments, the pharmaceutical formulation comprises about 5% to about 6% by weight Compound I (e.g., a solid form); about 90% by weight filler; about 4% by weight disintegrant; about 0.25% by weight glidant; and about 0.4% by weight lubricant.

[0748] In some embodiments, the pharmaceutical formulation comprises about 5.5 mg ±10% Compound I (e.g., a solid form); about 55 mg ±10% microcrystalline cellulose; about 34 mg ±10% lactose monohydrate; about 4 mg ±10% crospovidone; about 0.4 mg ± 10% sodium stearyl fumarate; and about 0.25 mg ±10% silica.

[0749] In some embodiments, the pharmaceutical formulation comprises about 10% to about 12% by weight Compound I (e.g., a solid form); about 84% to about 85% by weight filler; about 4% by weight disintegrant; about 0.25% by weight glidant; and about 0.5% by weight lubricant.

[0750] In some embodiments, the pharmaceutical formulation comprises about 11 mg ±10% Compound I (e.g., a solid form); about 50 mg ±10% microcrystalline cellulose; about 34 mg ±10% lactose monohydrate; about 4 mg ±10% crospovidone; about 0.5 mg ± 10% sodium stearyl fumarate; and about 0.25 mg ±10% silica.

[0751] In some embodiments, the pharmaceutical formulation comprises about 44 mg ±10% Compound I (e.g., a solid form); about 200 mg ±10% microcrystalline cellulose; about 137 mg ±10% lactose monohydrate; about 16 mg ±10% crospovidone; about 2 mg ± 10% sodium stearyl fumarate; and about 1 mg ±10% silica.Drug Combinations

[0752] The inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include othertherapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound. The additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition. The additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.

[0753] Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease. For example, compositions and formulations of the invention, as well as methods of treatment, can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions. For cancer indications such as EGFR+NSCLC, additional agents include, but are not limited to, kinase inhibitors, such as CLK inhibitors, Met inhibitors e.g., capmatinib, tepotinib), HER2 inhibitors (e.g., tucatinib) , Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g., crizotinib) standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids, or biological treatments, such as antibodies, bispecific antibodies, and the like. For pain indications, suitable combination agents include anti-inflammatories such as NSAIDs. The pharmaceutical compositions of the invention may additional comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.

[0754] In some embodiments, a method for treating cancer in a host animal, the method comprising the step of administering to the host animal a therapeutically effective amount of an EGFR inhibitor of the disclosure, in combination with a therapeutically effective amount of at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is a CLK inhibitor, a Met inhibitor, ALK inhibitor, VEGFR inhibitor, or a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0755] In some embodiments, an EGFR inhibitor of the disclosure, is for use in the treatment of cancer in a patient, in combination with a therapeutically effective amount of at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is a CLK inhibitor, a Met inhibitor, ALK inhibitor, VEGFR inhibitor, or a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0756] In some embodiments, use of an EGFR inhibitor of the disclosure, in the preparation of a medicament comprising a therapeutically effective amount of the compound, for treating cancer in a patient in combination with a therapeutically effective amount of at least one additional anticancer agent. In some embodiments, the additional anti-cancer agent is a CLK inhibitor, a Met inhibitor, ALK inhibitor, VEGFR inhibitor, or a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0757] In some embodiments, a composition comprising an EGFR inhibitor of the disclosure, in a therapeutically effective amount, for use in the treatment of cancer in a patient, in combination with a therapeutically effective amount of at least one additional anti-cancer agent. In some embodiments, the additional anti-cancer agent is a CLK inhibitor, a Met inhibitor, ALK inhibitor, VEGFR inhibitor, or a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0758] hi some embodiments, a medicament comprising an EGFR inhibitor of the disclosure, combined with a CLK inhibitor, a Met inhibitor, ALK inhibitor, VEGFR inhibitor, or a KRAS inhibitor, or a pharmaceutically acceptable salt thereof.

[0759] In some embodiments, the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndromes (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, ER+breast cancer, triple negative breast, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer and lung cancer.

[0760] In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is EGFR+non-small cell lung cancer (NSCLC).Synthesis Methods

[0761] In some embodiments, the disclosure provides a process for preparing a compound of the formula I

[0762] comprising

[0763] (a) contacting a compound of the formula A

[0764] with a compound of the formula B

[0765] in the presence of a base to provide a compound of the formula C

[0766] (b) contacting a compound of the formula C in the presence of a catalyst to provide a compound of the formula D

[0767] (c) contacting a compound of the formula D with an acid or fluoride source to provide a compound of the formula EE

[0768] (d) contacting a compound of the formula E with an acid to provide the compound of the formula I.

[0769] It will be appreciated that the present disclosure provides processes for preparing a compound of the formula I described in the paragraphs above, comprising more than one of the step listed in the alternative. Accordingly, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a) and (b). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (b) and (c). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (c) and (d). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a) and (c). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a) and (d). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (b) and (d). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a), (b) and (c). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (b), (c) and (d). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a), (c) and (d). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a), (b) and (d).Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a), (b), (c) and (d).

[0770] hi the first step (a), the base can be any base, such as a carbonate base. Suitable bases include, but are not limited to, Na2COi, K2CO3, CS2CO3, MgCCh, CaCCh, and the like. In some embodiments, the base is K2CO3. In some embodiments, step (a) can be carried out in the presence of an inorganic salt. Suitable inorganic salts include, but are not limited to, NaCl, KC1, CsCl, MgCl2, CaCl2, NaBr, KBr, CsBr, MgBr2, CaBr2, Nal, KI, CsI, Mgl2, Cal2, and the like. In some embodiments, the inorganic salt is KI. In some embodiments, step (a) can be carried out in the presence of a polar aprotic solvent, a nonpolar solvent, or mixture thereof. Suitable polar aprotic solvents include, but are not limited to, THF, 2-methyl-THF, Et O, DCM, chloroform, DMAc, EtOAc, DMF, CH3CN, acetone, HMPT, pyridine, DMSO, and the like. In some embodiments, the polar aprotic solvent is DMF. Suitable nonpolar solvents include, but are not limited to, pentane, hexane, heptane, methylcyclohexane (MCH), Et2O, MTBE, benzene, toluene, xylene, and the like. In some embodiments, the nonpolar solvent is MCH. In some embodiments, step (a) can be carried out at a temperature of from about 20 °C to about 30 °C.

[0771] In step (b), the catalyst can be any catalyst, such as a palladium catalyst. Suitable palladium catalysts include, but are not limited to, Pd(OAc)2, PdCh, Pd(PPh3)4, and the like. In some embodiments, the palladium catalyst is Pd(OAc)2. In some embodiments, step (b) can be carried out in the presence of a base. Suitable bases include, but are not limited to, triethylamine, diisopropylamine, K2CO3, Na2CO3, KHCO3, NaHCOs, NaOAc, KOAc, and the like. In some embodiments, the base is NaHCCh. In some embodiments, step (b) can be carried out in the presence of a polar aprotic solvent. Suitable polar aprotic solvents include, but are not limited to, THF, 2-methyl-THF, Et2O, DCM, chloroform, DMAc, EtOAc, DMF, CH3CN, acetone, HMPT, pyridine, DMSO, and the like. In some embodiments, the polar aprotic solvent is DMF. In some embodiments, step (b) can be carried out at a temperature of from about 50 °C to about 150 °C. In some embodiments, the temperature is about 100 °C.

[0772] In step (c), the acid can be any reagent known in the art useful for deprotection of a TBS protecting group. In step (c), the acid can be HC1, PPTS, PTS A, trifluoromethanesulfonic acid and the like. In step (c), the fluoride source can be any reagent known in the art useful for deprotection of a TBS protecting group. In step (c), the fluoride source can be TBAF, HF-pyr, CsF, and the like. For example, a suitable fluoride source for use in step (c) can include CsF. In some embodiments, step (c) can be carried out in the presence of a further polar solvent. Suitable polar solvents include, but are not limited to water, methanol, THF, 2-methyl-THF, Et2O, DCM, chloroform, DMAc, EtOAc, DMF, CH3CN, acetone, HMPT, pyridine, DMSO, and the like. In some embodiments, the polar solvent is water. In some embodiments, step (c) can be carried outat a temperature of from about 50 °C to about 150 °C. In some embodiments, the temperature is about 80 °C.

[0773] In step (d), the acid can be any reagent known in the art useful for deprotection of a THP protecting group. In step (d), the acid can be a strong inorganic acid, such as HC1, such as 12M HC1. In some embodiments, step (d) can be carried out in the presence of a polar solvent. Suitable polar solvents include, but are not limited to water, methanol, THF, 2-methyl-THF, Et2O, DCM, chloroform, DMAc, EtOAc, DMF, CH3CN, acetone, HMPT, pyridine, DMSO, and the like. In some embodiments, the polar solvent is methanol. In some embodiments, step (d) can be carried out at a temperature of from about 0 °C to about 50 °C. In some embodiments, the temperature is about 0 °C to about 10 °C.

[0774] In some embodiments, the disclosure provides a process for preparing a compound of the formula II

[0775] comprising

[0776] a. contacting a compound of the formula AlAl

[0777] with a compound of the formula BB

[0778] in the presence of a base to provide a compound of the formula ClCl

[0779] b. contacting a compound of the formula Cl in the presence of a catalyst to provide a compound of the formula DIDI

[0780] c. contacting a compound of the formula D 1 with an acid to provide the compound of the formula I.

[0781] It will be appreciated that the present disclosure provides processes for preparing a compound of the formula I described in the paragraphs above, comprising more than one of the step listed in the alternative. Accordingly, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a) and (b). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (b) and (c). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a) and (c). Alternatively, the present disclosure provides a process for preparing a compound of the formula I, comprising steps (a), (b) and (c).

[0782] In the first step (a), the base can be any base, such as an amine base. Suitable bases include, but are not limited to, DIEA, triethylamine, diisopropylamine , NazCCh, K2CO3, CS2CO3, MgCO i, CaCOi, and the like. In some embodiments, the base is DIEA. In some embodiments, step (a) can be carried out in the presence of an inorganic salt. Suitable inorganic salts include, but are not limited to, NaCl, KC1, CsCl, MgCh, CaCb, NaBr, KBr, CsBr, MgBr2, CaBr2, Nal, KI, CsI, Mgl2, Cab, and the like. In some embodiments, the inorganic salt is Nal. In some embodiments, step (a) can be carried out in the presence of a polar solvent, a nonpolar solvent, or mixture thereof. Suitable polar solvents include, but are not limited to, water, methanol, THF, 2-methyl-THF, DCM, chloroform, DMAc, EtOAc, DMF, CH3CN, acetone, HMPT, pyridine,DMSO, and the like. In some embodiments, the polar solvent is water, CH3CN, or a combination thereof. Suitable nonpolar solvents include, but are not limited to, pentane, hexane, heptane, methylcyclohexane (MCH), EtzO, methyl tert-butyl ether (MTBE), benzene, toluene, xylene, and the like. In some embodiments, the nonpolar solvent is heptane, MTBE, or a combination thereof. In some embodiments, step (a) can he carried out at a temperature of from about 20 °C to about 50 °C. In some embodiments, step (a) can be carried out at a temperature of from about 20 °C to about 30 °C.

[0783] In step (b), the catalyst can be any catalyst, such as a palladium catalyst. Suitable palladium catalysts include, but are not limited to, Pd(OAc)2, PdCh, Pd(PPh3)4, and the like. In some embodiments, the palladium catalyst is Pd(OAc)2. In some embodiments, step (b) can be carried out in the presence of a base. Suitable bases include, but are not limited to, DIEA, triethylamine, diisopropylamine, K2CO3, Na^COs, KHCO3, NaHCCh, NaOAc, KOAc, and the like. In some embodiments, the base is NaHCOs. In some embodiments, step (b) can be carried out in the presence of a phase transfer catalyst, such as quaternary ammonium salts. Suitable phase transfer catalysts include, but are not limited to, tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), and the like. In some embodiments, the phase transfer catalyst is TBAC. In some embodiments, step (b) can be carried out in the presence of a polar aprotic solvent. Suitable polar aprotic solvents include, but are not limited to, THF, 2-methyl-THF, DCM, chloroform, DMAc, EtOAc, DMF, CH3CN, acetone, HMPT, pyridine, DMSO, and the like. In some embodiments, the polar aprotic solvent is DMF, EtOAc, or a combination thereof. In some embodiments, the polar aprotic solvent is DMF. In some embodiments, step (b) can be carried out at a temperature of from about 50 °C to about 150 °C. In some embodiments, the temperature is about 100 °C.

[0784] In step (c), the acid can be any reagent known in the art useful for deprotection of a THP protecting group. In step (c), the acid can be a strong inorganic acid, such as HC1, such as 12M HC1. In some embodiments, step (c) can be carried out in the presence of a polar solvent. Suitable polar solvents include, but are not limited to water, methanol, THF, 2-methyl-THF, DCM, chloroform, DMAc, EtOAc, IP Ac, DMF, CH3CN, acetone, HMPT, pyridine, DMSO, and the like. In some embodiments, the polar solvent is water, methanol, IPAc, DCM, or any combination thereof. In some embodiments, the polar solvent is water, methanol, or a combination thereof. In some embodiments, step (c) can be carried out in the presence of a base. Suitable bases include, but are not limited to, K2CO3, Na2CO3, KHCO3, NaHCOs, NaOAc, KOAc, and the like. In some embodiments, the base is Na2CO3. In some embodiments, step (c) can be carried out at a temperature of from about 0 °C to about 50 °C. In some embodiments, the temperature is about 0 °C to about 10 °C.EXAMPLES

[0785] The examples and preparations provided below further illustrate and exemplify particular aspects of embodiments of the disclosure. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples.

[0786] Abbreviations

[0787] The examples described herein use materials, including but not limited to, those described by the following abbreviations known to those skilled in the art:

[0788] Example 1 : Preparation of (2S)-2-[(10S,17£)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14Z / -5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (Compound I).

[0789] The compound (2l5’)-2-[(10lS',17£')-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,l l,12,13- hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3”-n][l,4]oxazacyclopentadecin- 14-yl]propan-l-ol (Compound I) was prepared according to the following method as described in International Patent Application PCT / US2024 / 027195.

[0790] Part 1: Preparation of 5-bromo-7-methyl-l-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridine

[0791] Step 1. To a mixture of commercially available 2,4-dimethylpyridin-3-amine (25.0 g, 204.64 mmol, 1 eq) in DCM (500 mL) was added a solution of Br2 (163 g, 1.02 mol, 52.75 mL, 5 eq) in DCM (300 mL) dropwise at 0 °C, and the mixture was stirred at 25 °C for 12 hours. To the mixture was added aq. NaiSCL (300mL) and the mixture was stirred at 25 °C for 1 h. Then the mixture was adjusted to pH= 7 by addition of NaHCCL slowly. The mixture was extracted with DCM (300 mL x 3). The combined organic phase was washed with brine (50 mL), dried with Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiCh, Petroleum ether: Ethyl acetate=l:l) to afford 6-bromo-2,4-dimethyl- pyridin-3-amine (62.0 g, 308 mmol, 75.3% yield, 100% purity) as a yellow oil.]H NMR (400 MHz, CDCh) 5 = 7.02 (s, 1H), 3.45 (d, J = 16.4 Hz, 2H), 2.37 (s, 3H), 2.13 (s, 3H).

[0792] Step 2. To a mixture of 6-bromo-2,4-dimethyl-pyridin-3-amine (30.0 g, 149 mmol, 1 eq) in AcOH (300 mL) was added NaNCL (11.3 g, 164 mmol, 1.1 eq) at 0 °C, and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated in vacuum. The residue was diluted with H2O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layerswere washed with brine (30 mL x 3), dried over Na2SC>4, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1 % FA condition) to afford 5-bromo-7-methyl-lH-pyrazolo[3,4-c]pyridine (20.0 g, 94.3 mmol, 63.2% yield) as a yellow solid. 'H NMR (400 MHz, CDC13) 5 = 11.63 - 11.02 (m, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 2.84 (s, 3H).

[0793] Step 3. To a solution of 5-bromo-7-methyl-lH-pyrazolo[3,4-c]pyridine (34.0 g, 160 mmol, 1 eq) in THF (450 mL) was added t-BuOK (54.0 g, 481 mmol, 3 eq), and was added L (40.7 g, 160 mmol, 32.3 mL, 1 eq). The mixture was stirred at 25 °C for 3 hr. On completion, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by combi flash (12 g silica gel column, THF in PE 0~100%) to give 5- bromo-3-iodo-7-methyl-lH-pyrazolo[3,4-c] pyridine (51.0 g, 151 mmol, 94.1% yield) as yellow solid. LCMS: (M+L337.9).

[0794] Step 4. To a solution of 5-bromo-3-iodo-7-methyl-lH-pyrazolo[3,4-c]pyridine (3.10 g, 9.17 mmol, 1 eq) in toluene (31 mL) was added TsOH (316 mg, 1.83 mmol, 0.2 eq) and 3,4- dihydro-2H-pyran (DHP) (1.93 g, 22.9 mmol, 2.10 mL, 2.5 eq). The mixture was stirred at 90 °C for 16 hr, filtered and the filtrate was concentrated in vacuum. The residue was purified by combi flash (12 g silica gel column, EtOAc in PE 0-100%). 5-bromo-3-iodo-7-methyl-l- tetrahydropyran-2-yl-pyrazolo [3, 4-c] pyridine (2.57 g, 6.09 mmol, 66.38% yield) was obtained as light yellow solid. ’H NMR (400 MHz, DMSO-d6) 5 = 7.53 (s, 1H), 6.12 (dd, J = 9.2, 2.2 Hz, 1H), 3.88 (d, 7 = 11.6 Hz, 1H), 3.73 (d, 7 = 2.4 Hz, 1H), 2.90 (s, 3H), 2.45 - 2.37 (m, 1H), 2.12 - 2.03 (m, 2H), 1.81 - 1.66 (m, 2H), 1.47 - 1.43 (m, 1H). LCMS: (M+L421.9).

[0795] Step 5. To a solution of potassium vinyltrifluoroborate (816 mg, 6.09 mmol, 1 eq), 5- bromo-3-iodo-7-methyl-l-tetrahydropyran-2-yl-pyrazolo[3,4-c]pyridine (2.57 g, 6.09 mmol, 1 eq) in a mixture solvent of dioxane (25 mL) and H2O (5 mL) was added Pd(dppf)C12 (445 mg, 609 umol, 0.1 eq) and Na2COs (1.94 g, 18.3 mmol, 3 eq). The mixture was stirred at 80 °C for 16 hr under N2. The mixture was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by combi flash (20 silica gel column, DCM 100%) to give 5-bromo-7- methyl-l-tetrahydropyran-2-yl-3-vinyl-pyrazolo [3, 4-c] pyridine (1.00 g, 3.10 mmol, 50.9% yield) as black, brown solid. LCMS: (M+l : 322.0).

[0796] Part 2: Preparation of (2S)-2-[2,5-dimethyl-4-(7-methyl-l-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-l-amine

[0797] Step 1. To a mixture of 5-bromo-7-methyl-l-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4- c]pyridine (1.10 g, 3.41 mmol, 1 eq), commercially available 2,5-dimethylpyrazol-3-ol (498 mg, 4.44 mmol, 1.3 eq), K2CO3 (1.42 g, 10.24 mmol, 3 eq) in dioxane (11 mL) was added [2-(2- aminophenyl)phenyl]-methylsulfonyloxy-palladium;ditert-butyl-[3,6-dimethoxy-2-(2,4,6- triisopropylphenyl)phenyl]phosphane (t-BuBrettphos Pd G3) (117 mg, 136 pmol, 0.04 eq and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 1.5 h under N2 atmosphere. On completion, the reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give 2,5-dimethyl-4-(7-methyl-l-tetrahydropyran-2-yl-3- vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol (0.990 g, 2.80 mmol, 82% yield) as a yellow oil. LCMS: (M+l:354.1).

[0798] Step 2. To a solution of 2,5-dimethyl-4-(7-methyl-l-tetrahydropyran-2-yl-3-vinyl- pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-ol (970 mg, 2.74 mmol, 1 eq) in THF (10 mL) was added commercially available tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (962 mg, 5.49 mmol, 2 eq) and PPhs (1.44 g, 5.49 mmol, 2 eq) and DBAD (948 mg, 4.12 mmol, 1.5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-l- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]carbamate (1.75 g, crude) as a yellow oil. ’H NMR (400 MHz, DMSO-de) 5 = 6.79 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.16 (br d, J = 8.0 Hz, 1H), 5.59 (d, 7 = 3.6 Hz, 1H),5.37 (s, 2H), 4.06 (s, 6H), 1.58 (q, 7 = 7.6 Hz, 3H), 0.49 - 0.25 (m, 17H). LCMS: (M+L511.6).

[0799] Step 3. To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-l- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxypropyl]carbamate (1.70 g, 3.33 mmol, 1 eq) in DMF (17 mL) was added NaH (399 mg, 9.99 mmol, 60% purity, 3 eq) and CH3I (709 mg, 4.99 mmol, 311 pL, 1.5 eq). The mixture was stirred at 20 °C for 1 h. On completion, the reaction mixture was quenched by addition H2O (70 mL) at 25 °C, and extracted with EA (50 mL x 3). The combined organic layers were washed with H2O (40 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue the residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give tert-butyl N- [(2S)-2-[2,5-dimethyl-4-(7-methyl-l-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5- yl)pyrazol-3-yl]oxypropyl]-N-methyl-carbamate (1.76 g, 1.68 mmol, 50% yield, 50% purity) as a yellow solid. LCMS: (M+L525.3).

[0800] Step 4. To a solution of tert-butyl N-[(2S)-2-[2,5-dimethyl-4-(7-methyl-l- tetrahy dropyran-2-yl-3 -vinyl-pyrazolo[3 ,4-c]pyridin-5 -yl)pyrazol-3 -yljoxypropy 1] -N -methylcarbamate (1.70 g, 3.24 mmol, 1 eq) in DCM (17 mL) was added ZnBn (3.65 g, 16.2 mmol, 811 pL, 5 eq). The mixture was stirred at 25 °C for 2 h. On completion, the reaction mixture was quenched by addition H2O (25 mL) at 25 °C, and extracted with DCM (15 mL x 4), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (20 g silica gel column, THF in PE from 0-100%) to give (2S)-2-[2,5- dimethyl-4-(7-methyl-l-tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3- yl]oxy-N-methyl-propan- 1 -amine (550 mg, 1.30 mmol, 40% yield) as a white solid. 'H NMR (400 MHz, MeOD-<7 / ) 5 = 7.82 (d, 7 = 3.2 Hz, 1H), 7.O5 (dd, J = 11.6, 18.0 Hz, 1H), 6.16 (d, J = 18.0 Hz, 1H), 6.07 - 6.01 (m, 1H), 5.59 (d, 7 = 1 1.6 Hz, 1H), 4.42 - 4.32 (m, 1H), 4.04 - 3.95 (m, 1H), 3.90 - 3.80 (m, 1H), 3.71 (s, 3H), 3.17 -3.10 (m, 1H), 3.03 - 2.98 (m, 4H), 2.70 - 2.61 (m, 1H), 2.58 (d, 7 = 2.4 Hz, 3H), 2.25(d, 7 = 1.2 Hz, 3H), 2.22 - 2.15 (m, 2H), 1.92 - 1.78 (m, 1H), 1.75 - 1.61 (m, 2H), 1.14 (dd, 7 = 2.8, 6.4 Hz, 3H). LCMS: (M+L425.2).

[0801] Part 3: Preparation of 2-[[5-(bromomethyl)-l-[(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l- methyl-ethyl]-4-iodo-pyrazol-3-yl]oxymethoxy]ethyl-trimethyl-silaneep

[0802] Step 1. Commercially available 5-hydroxy-lH-pyrazole-3-carboxylic acid ethyl ester (10.0 g, 64 mmol, 1 eq), SEM-C1 (42.7 g, 256 mmol, 4 eq), and TEA (38.9 g, 384 mmol, 6 eq) were mixed in DCM (100 mL) at 0 °C and the mixture was stirred at 25 °C for 1 h. On completion, the mixture was diluted with water (500 mL) and extracted with DCM (100 mL x 3). The combined organic phase was dried over Na3SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography on silica gel (120 g silica gel, EA in Petroleum ether from 0% to 100%) to give ethyl 3-(2- trimethylsilylethoxymethoxy)-lH-pyrazole-5-carboxylate (10.6 g, 35.8 mmol, 56% yield) as a colorless oil. LCMS: (M+l-28: 259.0)

[0803] Step 2. To a mixture of ethyl 3-(2-trimethylsilylethoxymethoxy)-lH-pyrazole-5- carboxylate (10.0 g, 34.9 mmol, 1 eq), commercially available (2R)-l-[tert- butyl(dimethyl)silyl]oxypropan-2-ol (13.3 g, 69.8 mmol, 2 eq) and PPI13 (20.1 g, 76.8 mmol, 2.2 eq) in THF (230 mL), was added DIAD (17.7 g, 87.3 mmol, 2.5 eq) at 0 °C, and the resulting mixture was stirred for another 2 h at 25 °C under N2. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (80 g silica gel, EA in Petroleum ether from 0% to 100%) to give ethyl 2-[(lS)-2-[tert- butyl(dimethyl)silyl]oxy-l-methyl-ethyl]-5-(2-trimethylsilylethoxymethoxy)pyrazole-3- carboxylate (16.1 g, 31.6 mmol, 90% yield) as a yellow oil. 'H NMR (400 MHz, DMSO-de) <5 = 6.33 - 6.28 (m, 1H), 5.38 - 5.28 (m, 1H), 5.21 - 5.16 (m, 2H), 4.29 - 4.21 (m, 2H), 3.72 - 3.65 (m, 4H), 0.92 - 0.83 (m, 6H), 0.73 (s, 9H), 0.05 - 0.02 (m, 2H), -0.01 - -0.04 (m, 9H), -0.09 (s, 3H), -0.17 (s, 3H).

[0804] Step 3. To a solution of ethyl 2-[(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]- 5-(2-trimethylsilylethoxymethoxy)pyrazole-3-carboxylate (15.5 g, 33.8 mmol, 1 eq) in THF (155 mL) was added LiAlH4 (2.50 M, 13.5 mL, 1 eq) at 0 °C. The mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was quenched by slow addition of water (1.5 mL), 15%sodium hydroxide solution (1.5 mL) and water (5 mL) at 0 °C. The reaction mixture was filtered and concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (40 g silica gel, EA in Petroleum ether from 0% to 100%) to give [2-[(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]-5-(2- trimethylsilylethoxymethoxy)pyrazol-3-yl]methanol (7.25 g, 17.3 mmol, 51 % yield) as a colorless oil. LCMS: (M+l: 417.1)

[0805] Step 4. To a solution of [2-[(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]-5-(2- trimethylsilylethoxymethoxy)pyrazol-3-yl]methanol (6.70 g, 16.1 mmol, 1 eq) in ACN (70 mL) was added NIS (3.98 g, 17.7 mmol, 1. 1 eq) at 0 °C for 0.5 h. The mixture was then stirred at 25 °C for 1.5 h. On completion, the reaction mixture was quenched by addition of saturated sodium sulfite solution (70 mL) at 0 °C, and then diluted with H2O (260 mL) and extracted with EA (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20 g silica gel, EA in Petroleum ether from 0% to 100%) to give [2-[(lS)-2-[tert- butyl(dimethyl)silyl]oxy-l-methyl-ethyl]-4-iodo-5-(2-trimethylsilylethoxymethoxy)pyrazol-3- yl]methanol (7.60 g, 13.6 mmol, 85% yield) as a colorless oil. LCMS: (M+l: 543.1)

[0806] Step 5. To a solution of [2-[(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]-4- iodo-5-(2-trimethylsilylethoxymethoxy)pyrazol-3-yl]methanol (7.00 g, 12.9 mmol, 1 eq), CBr4 (5.13 g, 15.5 mmol, 1.2 eq) in DCM (70 mL) was added PPI13 (4.06 g, 15.5 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 25 °C for 1.5 h. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (40 g silica gel, EA in Petroleum ether from 0% to 100%) to give 2-[[5-(bromomethyl)-l-[(lS)-2- [tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]-4-iodo-pyrazol-3-yl]oxymethoxy]ethyl- trimethyl-silane (3.50 g crude of -62% purity) as a colorless oil. LCMS: (M+l: 607.0). This crude is used directly to the next alkylation reaction.

[0807] Part 4. Preparation of (10S,17E)-14-[(2S)-l-hydroxypropan-2-yl]-6,8,10,12,20- pentamethyl-2-(oxan-2-yl)-2,10,l l,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- / 7][l,4]oxazacyclopentadecin-16-ol

[0808] Step 1. To a solution of (2S)-2-[2,5-dimethyl-4-(7-methyl-l-tetrahydropyran-2-yl-3- vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-l-amine (190 mg, 447 pmol, 1 eq) and 2-[[5-(bromomethyl)-l-[(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]- 4-iodo-pyrazol-3-yl]oxymethoxy]ethyl-trimethyl-silane (325 mg, 537 pmol, 1.2 eq) in DMF (2 mL) was added K2CO3 (186 mg, 1.34 mmol, 3 eq). The mixture was stirred at 80 °C for 1 h. On completion, the reaction mixture was quenched by addition H2O (8 mL) at 25 °C and extracted with EA (8 mL x 3). The combined organic layers were washed with H2O (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (4 g silica gel column, THF in PE from 0-100%) to give (2S)-N-[[2- [(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]-4-iodo-5-(2- trimethylsilylethoxymethoxy)pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(7-methyl-l- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-l- amine (340 mg, 358 pmol, 80% yield) as a brown oil. LCMS: (M+l: 949.7).

[0809] Step 2. A mixture of (2S)-N-[[2-[(lS)-2-[tert-butyl(dimethyl)silyl]oxy-l-methyl-ethyl]- 4-iodo-5-(2-trimethylsilylethoxymethoxy)pyrazol-3-yl]methyl]-2-[2,5-dimethyl-4-(7-methyl-l- tetrahydropyran-2-yl-3-vinyl-pyrazolo[3,4-c]pyridin-5-yl)pyrazol-3-yl]oxy-N-methyl-propan-l- amine (330 mg, 348 pmol, 1 eq), TBAC (96.6 mg, 348 pmol, 97.2 pL, 1 eq), NaHCOs (73.0 mg, 869 pmol, 33.8 pL, 2.5 eq) and Pd(OAc)2 (15.6 mg, 69.5 pmol, 0.2 eq) in DMF (16.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 130 °C for 1.5 h under N2 atmosphere. On completion, the reaction mixture was quenched by addition H2O (30 mL) at 25 °C and extracted with EA (15 mL x 3). The combined organic layers were washed with H2O (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by combi flash (12 g silica gel column, THF in PE from 0-100%)to give (10S,17£)-14-[(2S)-l-{ | / e / 7-butyl(dimethyl )silyl |oxy|propan-2-yl |-6.8, IO, l 2,20- pentamethyl-2-(oxan-2-yl)- 16- { [2-(trimethylsilyl)ethoxy ]methoxy }-2,10,l l,12,13,14- hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4”,3"-n][l,4]oxazacyclopentadecine (275 mg, 335 pmol, 96% yield) as a brown oil. LCMS: (M+l: 821.8).

[0810] Step 3. To a solution of (10S,17E)-14-[(2S,)-l -{[tert-butyl(dirnethyl)silyl]oxy}propan-2- yl]-6,8, 10, 12,20-pentamethyl-2-(oxan-2-yl)- 16- { [2-(trimethylsilyl)ethoxy]methoxy } -2,10,1 l,12,13,14-hexahydro-8H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- n][l,4]oxazacyclopentadecine (260 mg, 317 pmol, 1 eq) in THF (2.6 mL) was added TBAF (1 M, 1.90 mL, 6 eq) .The mixture was stirred at 70 °C for 3 hr . On completion, the reaction mixture was quenched by addition H2O (10 mL) at 25 °C and extracted with EA (8 mL x 3). The combined organic layers were washed with H2O (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give (105,17£’)-14-[(2lS')-l-hydroxypropan-2-yl]-6,8,10,12,20- pentamethyl-2-(oxan-2-yl)-2,10,l l,12,13,14-hexahydro-87 / -5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-16-ol (200 mg, 243 pmol, 77% yield, 70% purity) as a brown oil. LCMS: (M+l: 577.2).

[0811] Step 4. To a solution of (10S',17£')-14-[(2S)-l-hydroxypropan-2-yl]-6,8,10,12,20- pentamethyL2-(oxan-2-yl)-2,10,l l,12,13,14-hexahydro-8H-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-16-ol (90.0 mg, 156 pmol, 1 eq) in DMF (2 mL) was added K2CO3 (43.1 mg, 312 pmol, 2 eq) and iodoethane (29.2 mg, 187 pmol, 15.0 pL, 1.2 eq). The mixture was stirred at 80 °C for 1 h . On completion, the reaction mixture was quenched by addition H2O (8 mL) at 25 °C, and extracted with EA (5 mL x 3). The combined organic layers were washed with H2O (6 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give (2>S')-2-[(10S',17E)-16-ethoxy-6,8,10,12,20- pentamethyl-2-(oxan-2-yl)-2,8,10,l l,12,13-hexahydro-1477-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (90.0 mg, 149 pmol, 95% yield) as a brown oil. LCMS: (M+l : 605.3).

[0812] Step 5. To a solution of (25)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl-2-(oxan- 2-yl)-2,8, 10,11 , 12, 13-hexahydro- 14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol (80.0 mg, 132 pmol, 1 eq) in DCM (2 mL) was added HCl / EtOAc (4 M, 1 mL, 30.2 eq). The mixture was stirred at 25 °C for 0.25 h. On completion, the mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna Cl 8 150*25mm* 10um;mobile phase: [water(FA)-ACN] gradient: 16%-46% B over 10 min) to give (2S)-2- [(10S’,17£,)-16-ethoxy-6,8,10,12,20-pentamethyl-2,8,10,11,12,13-hexahydro-14 / f-5,3- (azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"-n][l,4]oxazacyclopentadecin-14-yl]propan-l-ol(Compound I, 4.63 mg, 7.96 pmol, 6.02% yield, 97.42% purity, FA) as a yellow solid. 'H NMR (400 MHz, MeOD-A) 5 = 8.28 - 8.19 (m, 2H), 7.24 (d, J = 16.8 Hz, 1H), 4.93 - 4.89 (m, 1H), 4.52 - 4.42 (m,lH), 4.41 - 4.31 (m, 2H), 4.01 - 3.93 (m, 1H), 3.86 - 3.78 (m, 2H), 3.71 - 3.67 (m, 4H), 2.97 - 2.82 (m, 2H), 2.79 (s, 3H), 2.56 (s,3H), 2.43 (s, 3H), 1.48 (t, J= 7.0 Hz, 3H), 1.40 (d, J = 6.8 Hz, 3H), 1 . 10 (d, J = 6.4 Hz, 3H). LCMS: (M+l : 521 .2).

[0813] Example 2; Preparation of (25)-2-[(10S,17£')-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,l l,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4- / :3',4'-j:4",3"- n|| L4|oxazacyclopenladecin- 14-yl Ipropan- 1 -ol (Compound I) ethanol solvate

[0814] Part 1. Preparation of (R)-2,2,2-trifluoro-N-(2-hydroxypropyl)-N-methylacetamide

[0815] Step 1. To a solution of commercially available (2R)-2-methyloxirane (20.0 g, 344 mmol, 1 eq) in MeOH (150 mL) was added methanamine (2 M, 516 mL, 3 eq). The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo to give the compound (R)-l-(methylamino)propan-2-ol (25.0 g, 280 mmol, 81% yield) as a white solid.!H NMR (400 MHz, CDC13) 5 = 3.67 - 3.48 (m, 3H), 3.30 (dt, 7 = 3.2, 5.6 Hz, 1H), 2.86 - 2.78 (m, 1H), 1.91 - 1.83 (m, 2H), 0.69 (tdd, J = 2.4, 4.8, 7.2 Hz, 3H).

[0816] Step 2. To a solution of (R)-l-(methylamino)propan-2-ol (20.0 g, 224 mmol, 1 eq) in DCM (200 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (TFAA) (70.6 g, 336 mmol, 1.5 eq), TEA (113 g, 1.12 mol, 5 eg).The mixture was stirred at 0 °C for 18 hours. On completion, the reaction mixture was quenched by addition H2O (500 mL) and extracted with DCM (200mL x 3). The combined organic layers were washed with saturated solution of NaCl 500 mL, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=l : 1 ) to give (R)-2,2,2-trifluoro- N-(2-hydroxypropyl)-N-methylacetamide (9.80 g, 52.9 mmol, 23% yield) as a white solid.]H NMR (400 MHz, CDCI3) 5 = 4.05 - 3.96 (m, 1H), 3.38 (d, 7 = 3.6 Hz, 1H), 3.34 - 3.24 (m, 2H), 3.16 (d, 7 =1.6 Hz, 3H), 1.12 (d, 7 = 6.4 Hz, 3H).

[0817] Part 2. Preparation of (S)-5-(bromomethyl)-l-(l-((tert-butyldimethylsilyl)oxy)propan-2- y 1) - 3 -ethoxy-4-iodo- 1 H-pyrazoleTBSCI DCM Imidazole

[0818] Step 1. The solution of commercially available dimethyl but-2-ynedioate (100 g, 703 mmol, 1 eq) in toluene (500 mL) was added hydrazine hydrate (46.7 g, 914 mmol, 45.2 mL, 98% purity, 1.3 eq). The mixture was stirred at 25 °C for 4 h. On completion, the mixture was concentrated in vacuo to give a residue. The crude product was triturated with EA (100 mL) at 25 °C for 30 min to give methyl 3-hydroxy-lH-pyrazole-5-carboxylate (92.0 g, 647 mmol, 92% yield) as yellow solid. ’H NMR (400 MHz, DMSO-76) 8 = 5.74 (s, 1H), 3.75 (s, 3H).

[0819] Step 2. To a solution of methyl 3-hydroxy-lH-pyrazole-5-carboxylate (30.0 g, 211 mmol, 1 eq) in DMF (300 mL) was added K2CO3 (43.7 g, 316 mmol, 1.5 eq) and iodoethane (32.9 g, 211 mmol, 1 eq). The mixture was stirred at 80 °C for 2 h. On completion, the mixture was poured into H2O (1000 mL) and extracted with EA (300 mL*4), and the combined organic phase was washed with H2O (300 mLx3) and dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / THF=10:l to 5:1) to give methyl 3-ethoxy-lH-pyrazole-5-carboxylate (7.19 g, 42.2 mmol, 20% yield) as yellow solid. ’H NMR (400 MHz, DMSO-cfc) 8 = 13.11 (s, 1H), 6.23 (s, 1H), 4.12 (q, 7 = 7.2 Hz, 2H), 3.86 - 3.79 (m, 3H), 1.33 - 1.26 (m, 3H).

[0820] Step 3. To a solution of commercially available (R)-propane-l,2-diol (50.0 g, 657 mmol, 48.0 mL, 1 eq) in DCM (500 mL) was added TBSCI (99.0 g, 657 mmol, 1 eq) and imidazole (44.7 g, 657 mmol, 1 eq). The mixture was stirred at 0 °C for 2 h and then at 25 °C for 10 hr. Oncompletion, the mixture was filtered and concentrated to give (R)-l-((tert- butyldimethylsilyl)oxy)propan-2-ol (120 g, 630 mmol, 95% yield) as colorless oil.1H NMR (400 MHz, DMSO-tfc) 8 = 4.75 - 4.22 (m, 1H), 3.64 - 3.53 (m, 1H),...

Claims

WHAT IS CLAIMED IS:

1. A solid form of (2S)-2-[(10S,17E)-16-ethoxy-6,8,10,12,20-pentamethyl- 2,8,10,ll,12,13-hexahydro-14H-5,3-(azenometheno)tripyrazolo[3,4-f:3’,4’-j:4”,3”- n][l,4]oxazacyclopentadecin-14-yl]propan-l-o] (Compound I).

2. The solid form of claim 1 , wherein the solid form is a hydrate.

3. The solid form of claim 1 or 2, wherein the solid form is a cocrystal including a polymorph form of Compound I with a second molecule of Compound I or a salt thereof.

4. The solid form of any one of claims 1, 2, or 3, wherein the solid form is a cocrystal of Compound 1 with mono-Compound T oxalate and hydrate.

5. The solid form of any one of claims 1 to 4, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 6.6+0.1 , 7.0+0.1, 11.9+0.1 , 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1.

6. The solid form of any one of claims 1 to 5, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.9 +0.1.

7. The solid form of any one of claims 1 to 6, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.0+0.1 and 11.9+0.1.

8. The solid form of any one of claims 1 to 7, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, and 11.9+0.1.

9. The solid form of any one of claims 1 to 8, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, and 13.8+0.1.

10. The solid form of any one of claims 1 to 9, wherein the solid form is a cocrystal of Compound 1 with mono-Compound 1 oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, and 15.1+0.1.

11. The solid form of any one of claims 1 to 10, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, and 25.1+0.1.

12. The solid form of any one of claims 1 to 11, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1.

13. The solid form of any one of claims 1 to 12, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a X-ray powder diffraction pattern substantially the same as shown in FIG. 3.

14. The solid form of any one of claims 1 to 13, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 12.

15. The solid form of any one of claims 1 to 14, wherein the solid form is a cocrystal of Compound I with mono-Compound I oxalate and hydrate having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 11.

16. The solid form of claim 1, wherein the solid form is a salt of Compound I.

17. The solid form of claim 1 or 16, wherein the solid form is an HC1 salt of Compound I.

18. The solid form of any one of claims 1, 16, or 17, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1 , 13.6+0.1, 24.6+0.1, and 24.8+0.1.

19. The solid form of any one of claims 1 or 16 to 18, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 12.0+0.1.

20. The solid form of any one of claims 1 or 16 to 19, wherein the solid form is an HC1 salt of Compound 1 having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1 and 12.0+0.1.

21. The solid form of any one of claims 1 or 16 to 20, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.6+0.1, 12.0+0.1, and 13.6+0.1.

22. The solid form of any one of claims 1 or 16 to 21, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 12.0+0.1, and 13.6+0.1.

23. The solid form of any one of claims 1 or 16 to 22, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, and 13.6+0.1.

24. The solid form of any one of claims 1 or 16 to 23, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.6+0.1, and 24.6+0.1.

25. The solid form of any one of claims 1 or 16 to 24, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 12.0+0.1, 13.6+0.1, 24.6+0.1, and 24.8+0.1.

26. The solid form of any one of claims 1 or 16 to 25, wherein the solid form is an HC1 salt of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig- 4.

27. The solid form of any one of claims 1 or 16 to 26, wherein the solid form is an HC1 salt of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 14.

28. The solid form of any one of claims 1 or 16 to 27, wherein the solid form is an HC1 salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 13.

29. The solid form of claim 1, 16, or 17, wherein the solid form is a bis-HCl salt of Compound I.

30. The solid form of any one of claims 1, 16, 17, or 29, wherein the solid form is a bis-HCl salt of Compound 1 having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0. 1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 25.3+0.1, and 26.6+0.1.

31. The solid form of any one of claims 1, 16, 17, 29 or 30, wherein the solid form is a bis- HCl salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 8.2+0.1.

32. The solid form of any one of claims 1, 16, 17, or 29 to 31 , wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1 and 10.6+0.1.

33. The solid form of any one of claims 1, 16, 17, or 29 to 32, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1 , 10.6+0.1, and 25.3+0.1.

34. The solid form of any one of claims 1 , 16, 17, or 29 to 33, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1 , 10.6+0.1, 19.9+0.1, and 25.3+0.1.

35. The solid form of any one of claims 1 , 16, 17, or 29 to 34, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.9+0.1, and 25.3+0.1.

36. The solid form of any one of claims 1, 16, 17, or 29 to 35, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, and 25.3+0.1.

37. The solid form of any one of claims 1, 16, 17, or 29 to 36, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 10.6+0.1, 15.5+0.1, 19.3+0.1, 19.9+0.1, 25.3+0.1, and 26.6+0.1.

38. The solid form of any one of claims 1, 16, 17, or 29 to 37, wherein the solid form is a bis-HCl salt of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 5.

39. The solid form of any one of claims 1, 16, 17, or 29 to 38, wherein the solid form is a bis-HCl salt of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 16.

40. The solid form of any one of claims 1, 16, 17, or 29 to 39, wherein the solid form is a bis-HCl salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 15.

41. The solid form of claim 1, 2, or 16, wherein the solid form is a phosphate salt of Compound I.

42. The solid form of claim 1, 2, 16, or 41, wherein the solid form is a monophosphate salt monohydrate of Compound I.

43. The solid form of any one of claims 1, 2, 16, 41 or 42, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (29) of 12.2+0.1 , 12.7+0. 1 , 15. 1+0.1 , 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

44. The solid form of any one of claims 1, 2, 16, or 41 to 43, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 12.7+0.1.

45. The solid form of any one of claims 1, 2, 16, or 41 to 44, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1 and 15.1+0.1.

46. The solid form of any one of claims 1, 2, 16, or 41 to 45, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, and 15.8+0.1.

47. The solid form of any one of claims 1, 2, 16, or 41 to 46, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, and 19.1+0.1.

48. The solid form of any one of claims 1, 2, 16, or 41 to 47, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, and 25.0+0.1.

49. The solid form of any one of claims 1, 2, 16, or 41 to 48, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction patterncomprising peaks at diffraction angles (20) of 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

50. The solid form of any one of claims 1, 2, 16, or 41 to 49, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 12.2+0.1, 12.7+0.1, 15.1+0.1, 15.8+0.1, 19.1+0.1, 25.0+0.1, and 26.1+0.1.

51. The solid form of any one of claims 1, 2, 16, or 41 to 50, wherein the solid form is a monophosphate salt monohydrate of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 6.

52. The solid form of claim 1 or 16, wherein the solid form is a camphor sulfonic acid salt of Compound I.

53. The solid form of claim 1, 16, or 52, wherein the solid form is a (+)-camphor sulfonic acid salt of Compound I.

54. The solid form of any one of claims 1, 16, 52 or 53, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, 14.3+0.1, 18.8+0.1, and 20.6+0.1.

55. The solid form of any one of claims 1, 16, or 52 to 54, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 6.9+0.1.

56. The solid form of any one of claims 1, 16, or 52 to 55, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 6.9+0.1 and 12.1+0.1.

57. The solid form of any one of claims 1, 16, or 52 to 56, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, and 12.1+0.1.

58. The solid form of any one of claims 1, 16, or 52 to 57, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound 1 having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1 , 12.1+0.1, and 18.8+0.1.

59. The solid form of any one of claims 1, 16, or 52 to 58, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, and 18.8+0.1.

60. The solid form of any one of claims 1, 16, or 52 to 59, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1, 12.1+0.1, 13.8+0.1, 18.8+0.1, and 20.6+0.1.

61. The solid form of any one of claims 1, 16, or 52 to 60, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 4.8+0.1, 6.9+0.1 , 12.1+0.1, 13.8+0.1, 14.3+0.1, 18.8+0.1, and 20.6+0.1.

62. The solid form of any one of claims 1, 16, or 52 to 61, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 7.

63. The solid form of any one of claims 1, 16, or 52 to 62, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 18.

64. The solid form of any one of claims 1, 16, or 52 to 63, wherein the solid form is a (+)- camphor sulfonic acid salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 17.

65. The solid form of claim 1, 16, or 52, wherein the solid form is a (-)-camphor sulfonic acid salt of Compound 1.

66. The solid form of any one of claims 1, 16, 52, or 65, wherein the solid form is a (-)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.1+0.1, 5.8+0.1, 7.2+0. 1, 11.0+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

67. The solid form of any one of claims 1, 16, 52, 65 or 66, wherein the solid form is a (-)- camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 11.0+0.1.

68. The solid form of any one of claims 1, 16, 52, or 65 to 67, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1 and 11.0+0.1.

69. The solid form of any one of claims 1, 16, 52, or 65 to 68, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1, 11.0+0.1, and 14.9+0.1.

70. The solid form of any one of claims 1, 16, 52, or 65 to 69, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.71 . The solid form of any one of claims 1 , 16, 52, or 65 to 70, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5.1+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.

72. The solid form of any one of claims 1, 16, 52, or 65 to 71, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5. 1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, and 17.3+0.1.

73. The solid form of any one of claims 1, 16, 52, or 65 to 72, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 5. 1+0.1, 5.8+0.1, 7.2+0.1, 11.0+0.1, 14.9+0.1, 17.3+0.1, and 25.1+0.1.

74. The solid form of any one of claims 1, 16, 52, or 65 to 73, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound 1 having a X-ray powder diffraction pattern substantially the same as shown in Fig. 8.

75. The solid form of any one of claims 1, 16, 52, or 65 to 74, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 20.

76. The solid form of any one of claims 1, 16, 52, or 65 to 75, wherein the solid form is a (- )-camphor sulfonic acid salt of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 19.

77. The solid form of claim 1, wherein the solid form is a free base of Compound I.

78. The solid form of claim 1 or 77, wherein the solid form is an anhydrous solid form of Compound I.

79. The solid form of any one of claims 1, 77, or 78, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0. 1, 11.2+0.1, 1 1.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, and 21.7+0.1.

80. The solid form of any one of claims 1 or 77 to 79, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 1 1 .4+0.1 .

81. The solid form of any one of claims 1 or 77 to 80, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.4+0.1 and 12.0+0.1.

82. The solid form of any one of claims 1 or 77 to 81 , wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.4+0.1, 12.0+0.1, and 21.7+0.1.

83. The solid form of any one of claims 1 or 77 to 82, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 11.2+0.1, 11.4+0.1, 12.0+0.1 , and 21.7+0.1.

84. The solid form of any one of claims 1 or 77 to 83, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 1 1.2+0.1, 11.4+0.1, 12.0+0.1, and 21.7+0.1.

85. The solid form of any one of claims 1 or 77 to 84, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 1 1.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, and 21.7+0.1.

86. The solid form of any one of claims 1 or 77 to 85, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.2+0.1, 1 1.2+0.1, 11.4+0.1, 12.0+0.1, 16.4+0.1, 17.8+0.1, and 21.7+0.1.

87. The solid form of any one of claims 1 or 77 to 86, wherein the solid form is a free base of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 2.

88. The solid form of any one of claims 1 or 77 to 87, wherein the solid form is a free base of Compound I having a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 10.

89. The solid form of any one of claims 1 or 77 to 88, wherein the solid form is a free base of Compound I having a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 9.

90. The solid form of claim 1 , 2, or 77, wherein the solid form is a hydrate or solvate polymorph form of the free base of Compound I.

91. The solid form of claim 1, 2, 77, or 90, wherein the solid form is an ethanol solvate of Compound T.

92. The solid form of any one of claims 1, 2, 77, 90, or 91, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, 17.5+0.1, and 19.4+0.1.

93. The solid form of any one of claims 1, 2, 77, or 90 to 92, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising a peak at diffraction angle (20) of 8.0+0.1.

94. The solid form of any one of claims 1, 2, 77, or 90 to 93, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0. 1 and 9.6+0.1.

95. The solid form of any one of claims 1, 2, 77, or 90 to 94, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0. 1, 9.6+0.1, and 10.8+0.1.

96. The solid form of any one of claims 1, 2, 77, or 90 to 95, wherein the solid form is an ethanol solvate of Compound 1 having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0. 1, 9.6+0.1, 10.8+0.1, and 19.4+0.1.

97. The solid form of any one of claims 1, 2, 77, or 90 to 96, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1 , 9.6+0.1, 10.8+0.1, 13.6+0.1, and 19.4+0.1.

98. The solid form of any one of claims 1 , 2, 77, or 90 to 97, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, and 19.4+0.1.

99. The solid form of any one of claims 1, 2, 77, or 90 to 98, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern comprising peaks at diffraction angles (20) of 8.0+0.1, 9.6+0.1, 10.8+0.1, 11.5+0.1, 13.6+0.1, 17.5+0.1, and 19.4+0.1.

100. The solid form of any one of claims 1, 2, 77, or 90 to 99, wherein the solid form is an ethanol solvate of Compound I having a X-ray powder diffraction pattern substantially the same as shown in Fig. 1.

101. A solid form anhydrous crystalline polymorph form A of Compound I free base having at least one of the following characteristics:(a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 8.2+0.1, 9.0+0.1, 11.2+0.1, 11.4+0.1, 12.0+0.1, 13.0+0.1, 14.7+0.1, 15.2+0.1, 16.4+0.1, 16.6+0.1, 17.8+0.1, 18.0+0.1, 18.8+0.1, 19.6+0.1, 20.6+0.1, 21.7+0.1, 22.0+0.1, 22.9+0.1, 23.4+0.1, 24.0+0.1, 24.4+0.1, 24.8+0.1, 25.4+0.1, 25.6+0.1, 25.7+0.1, 26.8+0.1, 27.2+0.1, 28.0+0.1, 28.9+0.1, and 30.6+0.1 ;(b) a X-ray powder diffraction pattern substantially the same as shown in Fig. 2;(c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of less than about 1% when heated from about 25° C to about 300° C;(d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 10;(e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 279 °C to about 284 °C; and(f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig- 9.

102. The solid form of claim 101, having at least two of characteristics (a)-(f).

103. The solid form of claim 101, having at least three of characteristics (a)-(f).

104. A solid form cocrystal of Compound I with mono-Compound I oxalate and hydrate having at least one of the following characteristics:(a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.6+0.1, 7.0+0.1, 11.9+0.1, 13.8+0.1, 15.1+0.1, 16.9+0.1, and 25.1+0.1 ;(h) a X-ray powder diffraction pattern substantially the same as shown in Fig. 3;(c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 7% to about 11% when heated from about 25° C to about 300° C;(d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 12;(e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 62 °C to about 67 °C, and an endotherm with an onset at about 183 °C to about 188 °C; and(f) a differential scanning calorimetry (DSC) curve substantially the same as shown in Fig. 11.

105. The solid form of claim 104, having at least two of characteristics (a)-(f).

106. The solid form of claim 104, having at least three of characteristics (a)-(f).

107. a solid form crystalline polymorph form A of Compound I HC1 salt having at least one of the following characteristics:(a) a X-ray powder diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.5+0.1, 6.6+0.1, 7.0+0.1, 10.9+0.1, 12.0+0.1, 12.9+0.1, 13.1+0.1, 13.4+0.1, 13.6+0.1, 14.8+0.1, 15.4+0.1, 16.7+0.1, 16.8+0.1, 17.1+0.1, 17.7+0.1, 18.6+0.1, 19.0+0.1, 19.3+0.1, 19.7+0.1, 20.5+0.1, 21.6+0.1, 22.6+0.1, 22.9+0.1, 23.7+0.1, 24.0+0.1, 24.6+0.1, 24.8+0.1, 25.2+0.1, 25.5+0.1, 26.6+0.1, 27.5+0.1, and 29.3+0.1;(b) a X-ray powder diffraction pattern substantially the same as shown in Fig. 4;(c) a thermogravimetric analysis (TGA) thermogram comprising a total weight loss of about 9% to about 13% when heated from about 25° C to about 300° C;(d) a thermogravimetric analysis (TGA) thermogram substantially the same as shown in Fig. 14;(e) a differential scanning calorimetry (DSC) having a differential scanning calorimetry (DSC) curve having an endotherm with an onset at about 69 °C to about 74 °C, an endotherm with an onset at about 146 °C to about 151 °C, an exotherm with an onset of about 170 °C to about 175 °C, an endotherm with an onset at about 201 °C to about 206 °C, and an exotherm with an onset at about 216 °C to about 221 °C; and(f) a differential scanning calorimetry (DSC) curve substantially the same as shown inFig. 13.

108. The solid form of claim 107, having at least two of characteristics (a)-(f).

109. The solid form of claim 107, having at least three of characteristics (a)-(f).

110. A pharmaceutical formulation comprising a solid form of Compound I according to any one of claims 1 to 109, and at least one pharmaceutically acceptable excipient.

111. The pharmaceutical formulation of claim 110, comprising at least one of a filler, a disintegrant, a lubricant, and a surfactant.

112. The pharmaceutical formulation of claim 110 or 111 , wherein the formulation is for oral administration.

113. The pharmaceutical formulation of any one of claims 110 to 112, comprising about 1 mg to about 500 mg of the solid form.

114. The pharmaceutical formulation of any one of claims 110 to 113, comprising about 5 mg to about 500 mg of the solid form.

115. The pharmaceutical formulation of any one of claims 110 to 114, comprising about 5 mg to about 50 mg of the solid form.

116. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 5 mg, about 10 mg, or about 40 mg of the solid form.

117. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 5 mg of the solid form.

118. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 10 mg of the solid form.

119. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 20 mg of the solid form.

120. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 30 mg of the solid form.

121. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 40 mg of the solid form.

122. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 50 mg of the solid form.

123. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 60 mg of the solid form.

124. The pharmaceutical formulation of any one of claims 110 to 115, comprising about 80 mg of the solid form.

125. The pharmaceutical formulation of any one of claims 110 to 124, wherein the formulation comprises a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or any combination thereof.

126. The pharmaceutical formulation of claim 125, wherein the formulation comprises at least two of a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof.

127. The pharmaceutical formulation of claim 125, wherein the formulation comprises at least three of a filler, a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof.

128. The pharmaceutical formulation of claim 125, wherein the formulation comprises a filler and at least two of a binder, a surfactant, an acidulant, a disintegrant, a wetting agent, a glidant, a lubricant, or a combination thereof.

129. The pharmaceutical formulation of any one of claims 110 to 128, wherein the filler is selected from microcrystalline cellulose, mannitol, lactose, calcium phosphate, or any combination thereof.

130. The pharmaceutical formulation of claim 129, wherein the filler is a mixture of two or more fillers.

131. The pharmaceutical formulation of any one of claims 110 to 130, wherein the binder is copovidone.

132. The pharmaceutical formulation of any one of claims 110 to 131, wherein the acidulant is selected from citric acid, fumaric acid, tartaric acid, or any combination thereof.

133. The pharmaceutical formulation of any one of claims 110 to 132, wherein the disintegrant is selected from crospovidone, croscarmellose, sodium starch glycolate, or any combination thereof.

134. The pharmaceutical formulation of claim 133, wherein the disintegrant is a mixture of two or more disintegrants.

135. The pharmaceutical formulation of any one of claims 110 to 134, wherein the surfactant is sodium lauryl sulfate, polysorbate, poloxamer, polyoxyethylene stearate, or any combination thereof.

136. The pharmaceutical formulation of claim 135, wherein the disintegrant is a mixture of two or more surfactants.

137. The pharmaceutical formulation of any one of claims 110 to 136, wherein the glidant is silica.

138. The pharmaceutical formulation of any one of claims 110 to 137, wherein the lubricant is sodium stearyl fumarate, magnesium stearate, stearic acid, or any combination thereof.

139. The pharmaceutical formulation of any one of claims 110 to 138, wherein the solid form is present at about 3% to about 20% by weight of the formulation.

140. The pharmaceutical formulation of claim 139, wherein the solid form is present at about 5% to about 15% by weight of the formulation.

141. The pharmaceutical formulation of claim 139, wherein the solid form is present at about 5% to about 6% by weight of the formulation.

142. The pharmaceutical formulation of claim 139, wherein the solid form is present at about 10% to about 12% by weight of the formulation.

143. The pharmaceutical formulation of any one of claims 110 to 142, wherein the filler is present at about 10% to about 95% by weight of the formulation.

144. The pharmaceutical formulation of claim 143, wherein the filler is present at about 50% to about 90% by weight of the formulation.

145. The pharmaceutical formulation of any one of claims 110 to 144, wherein the binder is present at about 1% to about 10% by weight of the formulation.

146. The pharmaceutical formulation of any one of claims 110 to 145, wherein the acidulant is present at about 1% to about 10% by weight of the formulation.

147. The pharmaceutical formulation of any one of claims 110 to 146, wherein the disintegrant is present at about 1% to about 10% by weight of the formulation.

148. The pharmaceutical formulation of any one of claims 110 to 147, wherein the surfactant is present at about 1% to about 60% by weight of the formulation.

149. The pharmaceutical formulation of claim 148, wherein the surfactant is present at about 1% to about 20% by weight of the formulation.

150. The pharmaceutical formulation of any one of claims 110 to 149, wherein the glidant is present at about 0.1% to about 3% by weight of the formulation.

151. The pharmaceutical formulation of any one of claims 110 to 150, wherein the lubricant is present at about 0. 1% to about 3% by weight of the formulation.

152. The pharmaceutical formulation of any one of claims 110 to 112 or 125 to 138, wherein the formulation comprises about 3% to about 20% by weight a solid form according to any one of claims 1 to 109; about 10% to about 95% by weight filler; optionally about 1% to about 10% by weight acidulant; about 1% to about 10% by weight disintegrant; optionally about 1% to about 60% by weight surfactant; about 0.1% to about 3% by weight glidant; and about 0.1% to about 3% by weight lubricant.

153. The pharmaceutical formulation of any one of claims 110 to 152, wherein the formulation is in the form of a tablet.

154. The pharmaceutical formulation of claim 153, wherein the formulation comprises about 10% to about 12% by weight a solid form according to any one of claims 1 to109; about 83% to about 85% by weight filler; about 4% by weight disintegrant; about 0.25% by weight glidant; andabout 0.5% by weight lubricant.

155. The pharmaceutical composition of claim 153, wherein the formulation comprises about 3 mg to about 50 mg of a solid form according to any one of claims 1 to 109; about 50 mg to about 500 mg filler; about 1 mg to about 50 mg disintegrant; about 0.1 mg to about 5 mg glidant; and about 0. 1 mg to about 5 mg lubricant.

156. The pharmaceutical formulation of any one of claims 110 to 143, wherein the formulation is in the form of a capsule.

157. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 10% by weight a solid form according to any one of claims 1 to 109; about 85% by weight filler; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

158. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 10% by weight a solid form according to any one of claims 1 to 109; about 80% by weight filler; about 5% by weight surfactant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

159. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 10% by weight a solid form according to any one of claims 1 to 109; about 80% by weight filler; about 5% by weight acidulant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

160. The pharmaceutical formulation of claim 156, wherein the formulation comprisesabout 10% by weight a solid form according to any one of claims 1-109; about 75% by weight filler; about 5% by weight surfactant; about 5% by weight acidulant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

161. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 10% by weight a solid form according to any one of claims 1 to 109; about 83% by weight filler; about 2% by weight surfactant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

162. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 10% by weight a solid form according to any one of claims 1 to 109; about 73% by weight filler; about 12.5% by weight surfactant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.8% by weight lubricant.

163. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 10% by weight a solid form according to any one of claims 1-109; about 33% by weight filler; about 48% by weight surfactant; about 5% by weight acidulant; about 4% by weight disintegrant; about 0.3% by weight glidant; and about 0.5% by weight lubricant.

164. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 5% to about 6% by weight a solid form according to any one of claims 1-109;about 90% by weight filler; about 4% by weight disintegrant; about 0.25% by weight glidant; and about 0.4% by weight lubricant.

165. The pharmaceutical formulation of claim 156, wherein the formulation comprises about 10% to about 12% by weight a solid form according to any one of claims 1-109; about 84% to about 85% by weight filler; about 4% by weight disintegrant; about 0.25% by weight glidant; and about 0.5% by weight lubricant.

166. The pharmaceutical composition of any one of claims 110 to 112 or 125 to 138, wherein the formulation comprises about 3 mg to about 50 mg of a solid form according to any one of claims 1-109; about 50 mg to about 500 mg filler; optionally about 1 mg to about 50 mg acidulant; about 1 mg to about 50 mg disintegrant; optionally about 5 mg to about 500 mg surfactant; about 0.1 mg to about 5 mg glidant; and about 0.1 mg to about 5 mg by weight lubricant.

167. A method of treating abnormal cell growth in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a solid form of Compound I according to any one of claims 1 to 109 or a pharmaceutical formulation according to any one of claims 110 to 166.

168. A method of treating cancer in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a solid form of Compound I according to any one of claims 1 to 109 or a pharmaceutical formulation according to any one of claims 110 to 166.

169. The method of claim 168, wherein the cancer is selected from the group consisting of acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), myelodysplastic syndromes (MDS), small lymphocytic lymphoma (SLL), ALCL, non-small cell lung cancer (NSCLC), neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma,pediatric renal cell carcinoma, breast cancer, ER+breast cancer, triple negative breast, colonic adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, cholangiocarcinoma, ovarian cancer, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic cholangiocarcinoma, thyroid cancer, spitzoid neoplasms, sarcoma, astrocytoma, brain lower grade glioma, secretory breast carcinoma, mammary analogue carcinoma, congenital mesoblastic nephroma, congenital fibrosarcomas, Ph-like acute lymphoblastic leukemia, thyroid carcinoma, head and neck squamous cell carcinoma, chronic myelomonocytic leukemia (CML), pediatric glioma, prostate cancer, lung squamous carcinoma, ovarian serous cystadenocarcinoma, skin cutaneous melanoma, castrate-resistant prostate cancer, Hodgkin lymphoma, serous and clear cell endometrial cancer, oral cancer, endometrial cancer, endocrine cancer, skin cancer, gastric cancer, esophageal cancer, laryngeal cancer, pancreatic cancer, colon cancer, bladder cancer, bone cancer, cervical cancer, uterine cancer, testicular cancer, rectal cancer, kidney cancer, liver cancer and lung cancer.

170. The method of claim 169, wherein the cancer is non-small cell lung cancer (NSCLC).

171. The method of claim 169, wherein the cancer is EGFR+non-small cell lung cancer (NSCLC).

172. The method of claim 169, wherein the cancer is non-small cell lung cancer (NSCLC) that has EGFR and / or HER2 mutations.

173. The method of any one of claims 167 to 172, wherein the therapeutically effective amount is about 20 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, or about 80 mg BID.

174. The method of any one of claims 116 to 172, wherein the therapeutically effective amount is about 40 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, or about 160 mg QD.

175. A process for preparing a compound of the formula Icomprising a. contacting a compound of the formula Alwith a compound of the formula BB in the presence of a base to provide a compound of the formula C 1Cl b. contacting a compound of the formula Cl in the presence of a catalyst to provide a compound of the formula D 1DI c. contacting a compound of the formula D 1 with an acid to provide the compound of the formula I.

176. The process of claim 175, wherein the base of step (a) is selected from the group consisting of DIEA, triethylamine, diisopropylamine, Na2CO3, K2CO3, CS2CO3, MgCOs, and CaCO3.

177. The process of claim 176, wherein the base of step (a) is DIEA.

178. The process of any one of claims 175 to 177, wherein step (a) is carried out in the presence of an inorganic salt selected from the group consisting of NaCl, KC1, CsCl, MgCK CaCl2, NaBr, KBr, CsBr, MgBr2, CaBr2, Nal, KI, CsI, Mgl2, and Cal2.

179. The process of claim 178, wherein the inorganic salt is Nal.

180. The process of any one of claims 175 to 179, wherein the catalyst of step (b) is a palladium catalyst.

181. The process of claim 180, wherein the catalyst of step (b) is selected from the group consisting of Pd(OAc)2, PdCl2, and Pd(PPh3)4.

182. The process of claim 180, wherein the catalyst of step (b) is Pd(OAc)2.

183. The process of any one of claims 175 to 182, wherein step (b) is carried out in the presence of a base selected from the group consisting of DIEA, triethylamine, diisopropylamine, K2CO3, Na2CO3, KHCO3, NaHCCE, NaOAc, and KOAc.

184. The process of claim 183, wherein the base is NaHCCh-185. The process of any one of claims 175 to 184, wherein step (b) is carried out in the presence of a phase transfer catalyst selected from tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), and tetrabutylammonium iodide (TBAI).

186. The process of claim 185, wherein the phase transfer catalyst is tetrabutylammonium chloride (TBAC).

187. The process of any one of claims 175 to 186, wherein the acid of step (c) is a strong inorganic acid.

188. The process of claim 187, wherein the acid of step (c) is HC1.

189. The process of any one of claims 175 to 188 comprising steps (a) and (b).

190. The process of any one of claims 175 to 189 comprising steps (b) and (c).

191. The process of any one of claims 175 to 190, comprising steps (a) and (c).

192. The process of any one of claims 175 to 191, comprising steps (a), (b), and (c).

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