OA20944A - Crystalline salt forms of a kinase inhibitor - Google Patents

Abstract

The present invention relates to crystalline forms of salts of compound 1.

Description

CRYSTALLINE SALT FORMS OF A KINASE INHIBITOR

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application clanns priority to ILS. Provisional Application Serial Number 62/856,404, the entire contents of which is incorporated by reference herein.

TECHNICAL FIELD OF THE INVENTION

[0002] The présent invention relates to crystalline forms of salts of Compound I. The invention also relates to pharmaceutical compositions comprising the solid crystalline salts of Compound 1. The invention further relates to methods of treating a disease, disorder, or syndrome mediated at least in part by modulatîng in vivo activity of a protein kinase.

BACKGROUND OF THE INVENTION

[0003] Human Axl belongs to the Tyro3, Axl, and Mer (TAM) subfamily of receptor tyrosine kinases that încludes Mer. TAM kinases are characterized by an extracellular ligand binding domain consisting of two immunoglobulin-like domains and two fîbronectin type ΙΠ domains. Axl is overexpressed in a number of tumor cell types and was initially cloned from patients with chrome myelogenous leukemia. When overexpressed, Axl exhibits transforming potential. Axl signaling is believed to cause tumor growth through activation of proliférative and anti-apoptotic signaling pathways. Axl has been associated with cancers such as lung cancer, myeloid leukemia, uterine cancer, ovarian cancer, gliomas, melanoma, thyroid cancer, rénal cell carcinoma, osteosarcoma, gastric cancer, prostate cancer, and breast cancer. The over-expression of Axl results in a poor prognosis for patients with the indicated cancers.

[0004] Activation of Mer, like Axl, conveys downstream signaling pathways that cause tumor growth and activation. Mer binds ligands such as the soluble protein Gas-6. Gas-6 binding to Mer induces autophosphorylation of Mer on its intracellular domain, resulting in downstream signal activation. Over-expression of Mer in cancer cells leads to increased metastasis, most likely by génération of soluble Mer extracellular domain protein as a decoy receptor. Tumor cells secrete a soluble form of the extracellular Mer receptor which reduces the ability of soluble Gas-6 ligand to activate Mer on endothélial cells, leadîng to cancer progression.

[0005] A need therefore exists for compounds that inhibit TAM receptor tyrosine kinases such as Axl and Mer for the treatment of selected cancers.

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SUMMARY OF THE INVENTION

[0006] The présent invention provides crystalline forms of salts of Compound 1, N-(4fluorophenyl)-N-(4-((7-methoxy-6-(methylcarbamoyl)quinolin-4-yl)oxy)phenyl)cyclopropane-l,l dicarboxamide, which has the structure:

[0007] Compound 1 is disclosed in WO 2019/148044, the contents of which is incorporated herein by reference in its entirety.

[0008] Spécifie crystalline sait forms of an active pharmaceutical ingrédient (API), such as Compound 1, can hâve several advantages over other polymorphie or amorphous forms, such as increased stability during storage or processing, more favorable solubility, and increased bioavailabiiity. Reported herein are several stable crystalline sait forms of Compound 1.

[0009] In one aspect, the invention includes a crystalline sait form of Compound 1

Compound 1 wherein the crystalline sait form is selected from Compound 1 Besylate Form A, Compound 1 Besylate Form B, Compound 1 Benzoate Form A, Compound 1 Camsylate Form A, Compound 1 Camsylate Form B, Compound 1 Citrate Form A, Compound I Citrate Form B, Compound 1 Esylate Form A, Compound 1 Esylate Form B, Compound 1 HBr Form A, Compound 1 HBr Form B, Compound 1 Lactate Form A, Compound 1 Malate Form A, Compound 1 Maleate Form A, Compound 1 Maleate Form B, Compound 1 Mesylate Form A, Compound 1 Mesylate Fonn B, Compound 1 Mesylate Form C, Compound 1 Oxalate Form A, Compound 1 Oxalate Form B, Compound 1 Oxalate Form C, Compound 1 Propionate Fonn A, Compound 1 Succinate Form A, Compound 1 Sulfate Form A, Compound 1 Sulfate Form B, Compound 1 Sulfate Form C, 2

Compound 1 Tartrate Form A, Compound 1 Hemitartrate Form B, Compound 1 Tartrate Form C, | Compound 1 Tosylate Form A, and Compound 1 Tosylate Form B.

[0010] In one aspect, the invention includes a pharmaceutical composition comprising a | crystalline sait form described herein and a pharmaceutically acceptable excipient.

[0011] In another aspect, the invention includes a method of treating a disease, disorder, or | syndrome mediated at least in part by modulating in vivo activity of a protein kinase, comprising administering to a subject in need thereof a crystalline sait form or pharmaceutical composition | described herein.

[0012] In one embodiment of this aspect, the disease, disorder, or syndrome mediated at least in | part by modulating in vivo activity of a protein kinase is cancer.

[0013] In another aspect, the invention includes a method for inhibiting a protein kinase, the | method comprising contacting the protein kinase with a crystalline sait form or pharmaceutical composition described herein.

| [0014] In one embodiment of this aspect, the protein kinase is Axl, Mer, c-Met, KD R, or a combination thereof.

| [0015] A further aspect provides processes for making the solid fonns described herein.

BRIEF DESCRIPTION OF THE FIGURES

[0016] FIG. 1 is an XRPD pattern of Compound 1 Besylate Form A.

| [0017] FIG. 2 îs a DSC thermogram of Compound 1 Besylate Form A.

[0018| FIG. 3 is a TGA thermogram of Compound 1 Besylate Form A.

[0019] FIG. 4 is an XRPD pattern of Compound 1 Besylate Form B (mixture with Compound 1

Besylate Form A).

| 10020] FIG. 5 is an XRPD pattern of Compound 1 Benzoate Form A.

[0021] FIG. 6 is an XRPD pattern of Compound 1 Camsylate Form A.

| [0022] FIG. 7 is a DSC thermogram of Compound 1 Camsylate Form A.

[0023] FIG. 8 is a TGA thermogram of Compound 1 Camsylate Form A.

| [0024] FIG. 9 is an XRPD pattern of Compound 1 Camsylate Form B.

[0025] FIG. 10 is an XRPD pattern of Compound 1 Citrate Form A (mixture with Compound 1 | Form A).

[0026] FIG. 11 is an XRPD pattern of Compound 1 Citrate Form B.

| [0027] FIG. 12 is a DSC thermogram of Compound l Citrate Form B.

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[0028] FIG. 13 is a TGA thermogram of Compound 1 Citrate Fonn B.

[0029] FIG. 14 is a DVS isotherm plot of Compound 1 Citrate Form B.

[0030] FIG. 15 is an XRPD pattern of Compound 1 Esylate Form A.

[0031] FIG. 16 is a DSC thermogram of Compound 1 Esylate Form A.

[0032] FIG. 17 is a TGA thermogram of Compound 1 Esylate Form A.

[0033] FIG. 18 is an XRPD pattern of Compound 1 Esylate Form B (mixture with Compound 1

Esylate Form A).

[0034] FIG. 19 is an XRPD pattern of Compound 1 HBr Form A.

[0035] FIG. 20 is an XRPD pattern of Compound 1 HBr Form B.

[0036] FIG. 21 is an XRPD pattern of Compound 1 Lactate Form A (mixture with Compound 1

Form A).

[0037] FIG. 22 is an XRPD pattern of Compound 1 Malate Form A (mixture with Compound 1 Fonn A).

[0038] FIG. 23 is an XRPD pattern of Compound 1 Maleate Form A.

[0039] FIG. 24 is a DSC thermogram of Compound 1 Maleate Form A.

[0040] FIG. 25 is a TGA thermogram of Compound 1 Maleate Form A.

[0041] FIG. 26A — 26E are hot stage photomicrographs showing Compound 1 Maleate Form A at (A) 28.0 °C showing the crystalline form at ambient température, (B) 129.3 °C with no change in crystalline form, (C) 133.0 °C with some melting, (D) 140.0 °C with complété melting, and (E) cooled down to 28.3 showing no recrystallization at ambient température.

[0042] FIG. 27 is a DVS isotherm plot of Compound 1 Maleate Form A.

[0043] FIG. 28 is an XRPD pattern of Compound i Maleate Form B (mixture with Compound 1 Maleate Form A).

[0044] FIG. 29 is an XRPD pattern of Compound 1 Mesylate Form A.

[0045] FIG. 30 is an XRPD pattern of Compound 1 Mesylate Form B.

[0046] FIG. 31 is an XRPD pattern of Compound 1 Mesylate Form C.

[0047] FIG. 32 is a DSC thermogram of Compound 1 Mesylate Fonn C.

[0048] FIG. 33 is a TGA thermogram of Compound 1 Mesylate Form C.

[0049] FIG. 34 is a DVS isotherm plot of Compound 1 Mesylate Fonn C.

[0050] FIG. 35 is an XRPD pattern of Compound 1 Oxalate Fonn A.

[0051] FIG. 36 is an XRPD pattern of Compound 1 Oxalate Form B.

[0052] FIG. 37 is an XRPD pattern of Compound 1 Oxalate Form C.

[0053] FIG. 38 is an XRPD pattern of Compound 1 Propionate Form A (mixture with

Compound 1 Form A).

[0054] FIG. 39 is an XRPD pattern of Compound 1 Succinate Form A (mixture with Compound 1 Form A).

[0055] FIG. 40 is an XRPD pattern of Compound 1 Sulfate Form A.

[0056] FIG. 41 is an XRPD pattern of Compound 1 Sulfate Form B.

[0057] FIG. 42 is an XRPD pattern of Compound 1 Sulfate Form C.

[0058] FIG. 43 is an XRPD pattern of Compound 1 Tartrate Form A (mixture with Compound 1

Form A),

[0059] FIG. 44 is an XRPD pattern of Compound 1 Hemitartrate Form B.

[0060] FIG. 45 is a DSC thermogram of Compound 1 Hemitartrate Form B.

[0061] FIG. 46 is a TGA thermogram of Compound 1 Hemitartrate Form B.

[0062] FIG. 47 is an XRPD pattern of Compound 1 Tosylate Form A.

[0063] FIG. 48 is a DSC thermogram of Compound 1 Tosylate Form A.

[0064] FIG. 49 îs a TGA thermogram of Compound 1 Tosylate Form A.

[0065] FIG. 50 is a DVS isothenn plot of Compound 1 Tosylate Form A.

[0066] FIG. 51A - 51D are hot stage photomicrographs showing Compound 1 Tosylate Form A at (A) 29.9 °C showing the crystalline form at ambient température, (B) 199.3 °C with no change in crystalline form, (C) 214.4 °C with some melting, and (D) 217.9 °C with complété melting.

[0067] FIG. 52 is an XRPD pattern of Compound 1 Tosylate Form B.

[0068] FIG. 53 is a DSC thermogram of Compound 1 Tosylate Form B.

[0069] FIG. 54 îs a TGA thermogram of Compound 1 Tosylate Form B.

[0070] FIG. 55 is a DVS isothenn plot of Compound 1 Tosylate Form B.

[0071] FIG. 56A - 56E are hot stage photomicrographs showing Compound 1 Tosylate Form B at (A) 25.5 °C showing the crystalline form at ambient température, (B) 172.0 °C with no change in crystalline fonn, (C) 188.0 °C with very minor melting, (D) 194.0 °C with nearly complété melting, (E) 200.1 °C with complété melting, (E) 28.4 °C with initial recrystallization.

[0072] FIG. 57 is the indexing results for Compound 1 Besylate Form A, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0073] FIG. 58 is the indexing results for Compound 1 Camsylate Form A, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0074] FIG. 59 is the indexing results for Compound 1 Citrate Form B_} including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0075] FIG. 60 is the indexing results for Compound 1 Esylate Form A, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0076] FIG. 61 is the indexing results for Compound 1 HBr Form B, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0077] FIG. 62 is the indexing results for Compound 1 Maleate Form A, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0078] FIG. 63 is the indexing results for Compound 1 Mesylate Form A, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0079] FIG. 64 is the indexing results for Compound 1 Mesylate Form B, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0080] FIG. 65 is the indexing results for Compound 1 Mesylate Form C, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0081] FIG. 66 is the indexing results for Compound 1 Hemitartarate Form B, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0082] FIG. 67 is the indexing results for Compound 1 Tosylate Form A, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0083] FIG. 68 is the indexîng results for Compound l Tosylate Form B, including the tabulated space group consistent with the assigned extinction symbol, unit cell parameters, and derived quantities.

[0084] FIG. 69 is the XRPD pattern of Compound 1 Tartrate Form C.

DETAILED DESCRIPTION OF THE INVENTION

[0085] DEFINITIONS, ABBREVIATIONS AND ACRONYMS

[0086] Analytical Techniques

Abbreviations/Acronyms	Full Name/Description
DSC	Dîfferential scannîng calorimetry
DVS	Dynamic (water) vapor sorption
HSM	Hot stage microscopy
NMR	Nuclear magnetic résonance spectroscopy
OM	Optical microscopy
PLM	Polarized light microscopy
TGA	Thermogravimetry or Thennogravimetric analysis
XRPD	X-ray powder diffraction

[0087] Experimental techniques

Abbreviations/Acronyms	Full Name/Description
CC	Crash cooling
CP	Crash précipitation
FC	Fast cooling
FE	Fast évaporation
RC	Reaction crystallization
SC	Slow cooling
SE	Slow évaporation
VD	Vapor diffusion
VS	Vapor stress

[0088] Miscellaneous

Abbreviations/Acronyms	Full Name/Description
--	About or approximately
API	Active pharmaceutical ingrédient
B/E	Biréfringence and extinction
Endo/endo	Endotherm or endothermie
eq	Equivalent
Exo/exo	Exothenn or exothermic
FB	Free base
FF	Free form

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frz	Freezer
LIMS	Laboratory Information Management System
Max/max	Maximum or maxima
Obs	Observation or observed
PO	Preferred orientation
ppt	Precipitate or précipitation
ref	Refrigerator
RH	Relative humidity
RT	Room température
Soin/soin	Solution
vac	Vacuum
wt%	Weight percent

[0089] Solvents

Abb reviati ons/Acrony m s	Full Name/Description
ACN	Acetonîtrile
AcOH	Acetic acid
DCM	Dichloromethane
DMSO	Dimethylsulfoxide
EtOAc	Ethyl acetate
EtOH	Ethanol
HFIPA	Hexafluoroîsopropanol
IPA	Isopropyl alcohol, 2-propanol
MEK	Methyl ethyl ketone
MeOH	Methanol
MTBE	Methyl-tertiary-butyl ether
TFE	2,2,2-T ri fluoroethanol
THF	Tetrahydrofuran

[0090] As used herein, the following définitions shall apply unless otherwise îndicated.

[0091] For purposes of this invention, the Chemical éléments are identified in accordance with the Periodic Table of the Eléments, CAS version, Handbook of Chemîstry and Physics, 95th Ed. Additîonally, general principles of organic chemistry are described in Organic Chemistry,” 2^nd Ed., Thomas Sorrell, University Science Books, Sausalito: 2006, and March’s Advanced Organic Chemistry,” 7th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are hereby încorporated by reference.

[0092] As used herein, the terni “Low/limited/significant hygroscopisity” refers to a material that exhibits < 0.5/< 2.0/> 2.0 wt% water uptake over a specified RH range.

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[0093] As used herein, the term “stoichiometric hydrate” refers to crystalline material with a defined water content over an extended RH range. Typical stoichiometric hydrates are hemihydrates, monohydrates, sesquihydrates, dihydrates, etc.

[0094] As used herein, the term “variable hydrate” refers to crystalline material with variable water content over an extended RH range, yet with no phase change.

[0095] As used herein, a Chemical term designated as a “Form” refers to a Chemical compound, or sait thereof, that consists of a single phase.

[0096] As used herein, the term “low/limited/intermediate/good/high solubility” refers to a material having a solubility of < 1/1 - 20/20 — 100/100 - 200/> 200 mg/mL.

[0097] As used herein, the term “crystalline” refers to a material that produces an XRPD pattern with sharp peaks (similar to instrumental peak widths) and weak diffuse scattering relative to the peaks.

[0098] As used herein, the term “disordered crystalline” refers to a material that produces XRPD pattern with broad peaks (relative to instrumental peak widths) and/or strong diffuse scattering relative to the peaks. Disordered materials may be:

1) microcrystalline,

2) crystalline with large defect density,

3) mixtures of crystalline and X-ray amorphous phases, or

4) a combination of the above.

[0099] As used herein, the term “insufficient signal” means that spectrographie analysis of a sample produced a spectrum or pattern (output) having insufficient signal above the expected background noise.

[00100] As used herein, the term “single crystalline phase” refers to an XRPD pattern that is judged to contain evidence of a single crystalline form due to the Bragg peaks being indexed with a single unit cell. Indexing is the process of assigning Miller index labels to each peak in a diffraction pattern. Also, the size and shape of the crystal unit cell is determîned during the indexing process.

[00101] As used herein, the term “slurry” refers to a suspension prepared by adding enough solids to a given solvent at ambient conditions so that undissolved solids are présent. A typical slurry includes agitation (typically by stirring or oscillation), an act that is also referred to as “slurrying,” in a sealed vial at a given température for an extended period of time. Typically, the solids are recovered after a given period of time using a method described herein.

[00102] As used herein, the term “X-ray amorphous” or “amorphous” refers to a material having diffuse scatter présent, but no evidence for Bragg peaks in the XRPD pattern.

[00103] As used herein, the term crystalline refers to compounds in a solid State having a periodic and repeating three-dimensional internai arrangement of atoms, ions or molécules characteristic of crystals, for exampie, arranged in fixed géométrie patterns or lattices that hâve rigid long range order. The term crystalline does not necessarily mean that the compound exists as crystals, but that ît has this crystal-like internai structural arrangement.

[00104] As used herein, the term “substantially crystalline” refers to a solid material that is predominately arranged in fixed géométrie patterns or lattices that hâve rigid long range order. For example, substantially crystalline materials hâve more than about 85% crystallmity (e.g., more than about 90% crystallinity, more than about 95% crystallinity, or more than about 99% crystallinity). It is also noted that the term 'substantially crystalline' includes the descriptor 'crystalline,’ which is defined in the previous paragraph.

[00105] “Patient” for the purposes of the présent invention includes humans and any other animais, particularly mammals, and other organisms. Thus the methods are applicable to both human therapy and veterinary applications. In a preferred embodiment the patient is a mammal, and in a most preferred embodiment the patient is human. Examples of the preferred mammals include mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and primates.

[00106] “Kinase-dependent diseases or conditions” refer to pathologie conditions that dépend on the activity of one or more kinases. Kinases either directly or indirectly participate in the signal transduction pathways of a variety of cellular activîties including prolifération, adhesion, migration, différentiation, and invasion. Diseases associated with kinase activîties include tumor growth, the pathologie neovascularization that supports solid tumor growth, and associated with other diseases where excessive local vascularization is involved such as ocular diseases (diabetic retinopathy, agerelated macular degeneration, and the like) and inflammation (psoriasis, rheumatoid arthritis, and the like).

[00107] “Therapeutically effective amount” is an amount of a crystalline sait form of Compound 1 that, when administered to a patient, améliorâtes a symptom of the disease. The amount of a crystalline sait form of Compound 1 which constitûtes a “therapeutically effective amount” will vary depending on the compound, the disease State and its severity, the âge of the patient to be treated,

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[00108] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animais wîthout excessive toxicity, irritation, allergie response, immunogenicity or other problem or complication, commensurate with a reasonabie benefit risk ratio.

[00109] As used herein, the phrase “pharmaceutically acceptable excipient” refers to a phannaceutically-acceptable material, composition, or vehîcle, such as a liquid or solid filter, diluent, solvent, or encapsulating material. Excipients are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is “pharmaceutically acceptable” as defïned herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21 st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Pref or mutation and Formulation, 2nd ed.; Gibson Ed. ; CRC Press LLC: Boca Raton, Fia., 2009.

[00110] “Cancer” refers to cellular-proliferative disease States, including, but not limiting to: Cardîac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Head and neck: squamous cell carcinomas of the head and neck, laryngeal and hypopharyngeal cancer, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, salivary gland cancer, oral and orppharyngeal cancer; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentîated large cell, adenocarcinoma, non-small cell lung cancer), alveolar (bronchiolar) carcinoma, alveolar sarcoma, alveolar soft part sarcoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;

Colon: colorectal cancer, adenocarcinoma, gastrointestinal stromal tumors, lymphoma, carcinoids, Turcot Syndrome; Gastrointestinal: gastric cancer, gastroesophageal junction adenocarcinoma, esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancréas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcînoma, tubular adenoma, vil Ions adenoma, hamartoma, leiomyoma); Breast: metastatic breast cancer, ductal carcinoma in situ, invasive ductal carcinoma, tubular carcinoma, medullary carcinoma, mucinous carcinoma, lobular carcinoma in situ, triple négative breast cancer; Genitourinary tract: kidney (adenocarcînoma, Wîlm's tumor [nephroblastoma], lymphoma, leukemia, rénal cell carcinoma, metastatic rénal cell carcinoma), bladder and urethra (squamous cell carcinoma, transîtional cell carcinoma, adenocarcînoma, urothélial carcinoma), prostate (adenocarcînoma, sarcoma, castrate résistant prostate cancer, bone métastasés, bone métastasés associated with castrate résistant prostate cancer,), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma), clear cell carcinoma, papillary carcinoma, penile cancer, penile squamous cell carrcinoma ; Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: ostéogénie sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (réticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochrondroma (osteocartiiaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors; Thyroid: medullary thyroîd cancer, differentiated thyroid cancer, papillaty thyroid cancer, follicular thyroid cancer, burthle cell cancer, and anaplastic thyroid cancer; Nervous System: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), méningés (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congénital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma), NF1, neurofibromatosis, plexiform neurofibromas; Gynecological: utérus (endométrial cancer), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serons cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithélial carcinoma, adenocarcînoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hématologie: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliférative diseases, multiple myeloma, myelodysplastic syndrome), myelofibrosis,

I polycythemia vera, essential thrombocythemia, Hodgkiris disease, non-Hodgkin’s lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastîc nevi, lîpoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. Thus, the term “cancerous cell” as provided herein, includes a cell afflicted by any one of the above-identified conditions. In some embodiments, a compound or combination as disclosed herein can be used for the treatment of diseases including HIV, sickie cell disease, graft-versus-host disease, acute graft-versus-host disease, chronic graft-versus-host disease, and sickie cell anémia.

[00111] In general, the nomenclature used in this application is based on naming conventions adopted by the International Union of Pure and Applied Chemistry (IUPAC). Chemical structures shown herein were prepared using CHEMDRAW®. Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.

[00112] EMBODIMENTS

[00113] In one aspect, the invention includes a crystalline sait form of Compound 1

Compound 1 which is l-N'-(4-Fluorophenyl)-l-N-[4-[7-methoxy-6-(methylcarbamoyl)quinolin-4yl]oxyphenyl]cyclopropane-l,l-dicarboxamide, or N'-(4-Fluorophenyl)-N-[4-[7-methoxy-6(methylcarbamoyl)quinolm-4-yl]oxyphenyl]cyclopropane-l,l-dicarboxamide, wherein the crystalline sait form is selected from Compound 1 Besylate Form A, Compound 1 Besylate Fonn B, Compound 1 Benzoate Form A, Compound 1 Camsylate Form A, Compound 1 Camsylate Form B, Compound 1 Citrate Form A, Compound 1 Citrate Form B, Compound 1 Esylate Form A, Compound 1 Esylate Form B, Compound 1 HBr Form A, Compound 1 HBr Fonn B, Compound 1 Lactate Form A, Compound 1 Malate Form A, Compound 1 Maleate Form A, Compound 1 Maleate

Form B, Compound 1 Mesylate Form A, Compound 1 Mesylate Form B, Compound 1 Mesylate Form C, Compound 1 Oxalate Form A, Compound 1 Oxalate Fonn B, Compound 1 Oxalate Form C, Compound 1 Propionate Form A, Compound 1 Succinate Form A, Compound 1 Sulfate Form A,

Compound 1 Sulfate Form B, Compound 1 Sulfate Form C, Compound 1 Tartrate Form A, Compound 1 Hemitartrate Form B, Compound 1 Tartrate Form C, Compound 1 Tosylate Form A, and Compound 1 Tosylate Form B.

[00114J In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Besylate Form A.

[00115] In one embodiment, the Compound 1 Besylate Form A îs characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.78, 7.56, 10.08, 10.42, 11.70, 11.78, 12.00, 12.71, 13.20, 13.92, 14.06, 14.44, 14.93, 15.18, 15.96, 16.21, 16.40, 16.73, 16.86, 17.38, 18.32, 19.07, 20.07, 20.26, 20.51,20.94,21.45,21.60,22.30, 22.90, 23.05, 23.28, 23.71, 24.28, 24.97, 25.30, 25.69, 26.33, 26.71, 27.29, 27.65, 28.07, 29.22, and 29.50.

[00116] In another embodiment, the Compound 1 Besylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scaie, wherein the one or more peaks is selected from 3.78, 7.56, 10.42, 20.51, 20.94, 21.60, and 25.30.

[00117] In a further embodiment, the Compound 1 Besylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.78, 7.56, 10.42, 20.51, 20.94,21.60, and 25.30.

[00118] In still a further embodiment, the Compound 1 Besylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.78, 7.56, 10.08, 10.42, 11.70, 11.78, 12.00, 12.71, 13.20, 13.92, 14.06, 14.44, 14.93, 15.18, 15.96, 16.21, 16.40, 16.73, 16.86, 17.38, 18.32, 19.07, 20.07, 20.26, 20.51,20.94, 21.45, 21.60, 22.30, 22.90, 23.05, 23.28,

23.71, 24.28, 24.97, 25.30, 25.69, 26.33, 26.71, 27.29, 27.65, 28.07, 29.22, and 29.50.

[00119] In another embodiment, the Compound 1 Besylate Form A is characterized by a first endotherm at about 144 °C and a second endotherm at a température of about 170 °C in a DSC thermogram.

[00120] In another embodiment, the Compound 1 Besylate Form A is characterized by a weight loss of about 7.9% over a température range of 39-177 °C in a TGA thermogram.

[00121] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Besylate Form B.

[00122] In one embodiment, the Compound 1 Besylate Form B is characterized by an XRPD pattern substantially identical to Figure 4.

[00123J In one embodiment of this aspect, the crystalline form is characterized as Compound 1

Benzoate Form A.

[00124] In one embodiment, the Compound 1 Benzoate Form A is characterized by an XRPD pattern substantially identical to Figure 5.

[00125] In one embodiment of this aspect, the crystalline form is characterized as Compound I Camsylate Form A.

[00126] In one embodiment, the Compound 1 Camsylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.55, 7.90, 8.25, 8.38,9.55,9.87, 10.26, 11.12, 11.34, 12.50, 12.94, 13.40, 13.65, 14.79, 15.83, 16.16, 16.41, 16.54, 16.82, 17.10, 17.69, 18.02, 18.22, 18.47, 18.91, 19.10, 19.47, 20.04, 20.87, 21.05, 22.16, 22.36, 22.93, 23.71, 24.55, 25.33, 26.02, 26.40, 27.09, 27.33, 27.97, 28.32, 28.68, and 28.98. [00127] In another embodiment, the Compound 1 Camsylate Form A îs characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.55, 9.87, 10.26, 16.16, 16.82, 20.87, 22.36, and 23.71.

[00128] In a further embodiment, the Compound 1 Camsylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.55, 9.87, 10.26, 16.16, 16.82,20.87, 22.36, and 23.71.

[00129] In still a further embodiment, the Compound 1 Camsylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.55, 7.90, 8.25, 8.38, 9.55,9.87, 10.26, 11.12, 11.34, 12.50, 12.94, 13.40, 13.65, 14.79, 15.83, 16.16, 16.41, 16.54, 16.82, 17.10, 17.69, 18.02, 18.22, 18.47, 18.91, 19.10, 19.47, 20.04, 20.87, 21.05, 22.16, 22.36, 22.93,

23.71, 24.55, 25.33, 26.02, 26.40, 27.09, 27.33, 27.97, 28.32, 28.68, and 28.98.

[00130J In another embodiment, the Compound 1 Camsylate Form A is characterized by a first endothenn at a température of about 110 °C and a second endotherm at about 174 °C in a DSC thermogram.

[00131] In another embodiment, the Compound 1 Camsylate Form A is characterized by a weight loss of about 5.9% over a température range of 38-170 °C in a TGA thermogram.

[00132] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Camsylate Form B.

[00133] In one embodiment, the Compound 1 Camsylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.25, .32, 8.51, 8.76, 9.05,9.58, 9.88, 10.00, 10.52, 10.80, 11.06, 11.96, 12.24, 12.58, 13.98, 15.62, 15.81, 16.15, 16.70, 17.12, 17.42, 17.71, 18.41, 19.37, 19.55, 20.63, 21.13, 21.56, 21.89, 22.50, 23.04, 24.43, 26.08, 27.07, 27.97, 28.22, and 28.73.

[00134] In another embodiment, the Compound 1 Camsylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.25, 10.52, 16.15,21.13,21.56, and21.89.

[00135] In a further embodiment, the Compound 1 Camsylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.25, 10.52, 16.15, 21.13, 21.56, and21.89.

[00136] In a further embodiment, the Compound 1 Camsylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.25, 8.32, 8.51, 8.76, 9.05,9.58,9.88, 10.00, 10.52, 10.80, 11.06, 11.96, 12.24, 12.58, 13.98, 15.62, 15.81, 16.15, 16.70, 17.12, 17.42, 17.71, 18.41, 19.37, 19.55,20.63, 21.13,21.56,21.89, 22.50,23.04, 24.43,26.08, 27.07, 27.97, 28.22, and 28.73.

[00137] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Citrate Form A.

[00138] In a further embodiment, the Compound 1 Citrate Form A is characterized by an XRPD pattern substantially identical to Figure 10.

[00139J In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Citrate Form B.

[00140] In one embodiment, the Compound 1 Citrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.58, 5.95, 7.61, 8.88, 9.19, 9.94, 11.93, 13.26, 13.79, 14.29, 14.68, 15.26, 15.95, 16.64, 17.11, 17.87, 18.21, 18.43, 18.90, 19.36, 19.67, 20.14, 20.57,21.47, 22.30, 22.64, 23.06, 23.80, 24.25,24.55, 24.81, 25.10, 25.45, 25.54, 25.85, 26.35, 26.51, 26.83, 27.16, 27.57, 27.85, 28.08, and 28.47.

[00141] In another embodiment, the Compound 1 Citrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.58, 5.95, 8.88, 11.93, 13.79, 14.29, 16.64, 18.90, 21.47, 23.80, 24.25, and 25.85.

[00142] In a forther embodiment, the Compound 1 Citrate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.58, 5.95, 8.88, 11.93, 13.79, 14.29, 16.64, 18.90, 21.47, 23.80, 24.25, and 25.85.

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[00143] In still a further embodiment, the Compound 1 Citrate Form B is characterized by ail of the foilowing peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.58, 5.95, 7.61, 8.88, 9.19,9.94, 11.93, 13.26, 13.79, 14.29, 14.68, 15.26, 15.95, 16.64, 17.11, 17.87, 18.21, 18.43, 18.90, 19.36, 19.67, 20.14, 20.57, 21.47, 22.30, 22.64, 23.06, 23.80, 24.25, 24.55, 24.81, 25.10, 25.45, 25.54, 25.85, 26.35, 26.51, 26.83, 27.16, 27.57, 27.85, 28.08, and 28.47.

[00144] In another embodiment, the Compound 1 Citrate Form B is characterized by an endotherm at about 175 °C in a DSC thermogram. In another embodiment, the Compound 1 Citrate Form B is characterized by an endotherm with an onset température at about 175 °C in a DSC thermogram.

[00145] In another embodiment, the Compound 1 Citrate Form B is characterized by a weight loss above a température of 175 °C in a TGA thermogram.

[00146] In another embodiment, the Compound 1 Citrate Form B is characterized by a weight loss beginning at a température of about 159 °C and ending at about 220 °C in a TGA thermogram. [00147] In one embodiment, the Compound 1 Citrate Fonn B is characterized by about a 4.1 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity.

[00148] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Esylate Form A.

[00149] In one embodiment, the Compound 1 Esylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.97, 7.95,9.89, 10.62, 10.92, 11.03, 11.34, 11.77, 12.03, 12.53, 12.71, 13.27, 14.00, 14.70, 15.08, 15.94, 16.17, 16.92, 17.01, 17.19, 17.35, 17.61, 18.15, 18.76, 19.03, 19.66, 19.89, 20.26, 20.65, 20.78, 21.44, 22.08, 23.14, 23.27, 23.99, 24.32, 25.43, 25.66, 25.85, 26.52, 26.87, 27.61, 27.96, 28.18, 28.40, and 28.91.

[00150] In one embodiment, the Compound 1 Esylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.97, 7.95, 9.89, 10.62, 13.27, 15.08, 16.17, 16.92, 17.01, 20.65, 20.78, 21.44, 22.08, 23.99, 25.43, and 26.52.

[00151] In a further embodiment, the Compound 1 Esylate Form A is characterized by ail of the foilowing peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.97, 7.95, 9.89, 10.62, 13.27, 15.08, 16.17, 16.92, 17.01,20.65,20.78,21.44, 22.08, 23.99, 25.43, and 26.52.

[00152] In still a further embodiment, the Compound 1 Esylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.97, 7.95, 9.89, 10.62, 10.92, 11.03, 11.34, 11.77, 12.03, 12.53, 12.71, 13.27, 14.00, 14.70, 15.08, 15.94, 16.17, 16.92, 17.01, 17.19, 17.35, 17.61, 18.15, 18.76, 19.03, 19.66, 19.89,20.26, 20.65,20.78,21.44, 22.08, 23.14, 23.27, 23.99, 24.32, 25.43, 25.66, 25.85, 26.52, 26.87, 27.61, 27.96, 28.18, 28.40, and 28.91. [00153] In another embodiment, the Compound 1 Esylate Form A is characterized by a first endotherm at a température of about 69 °C, a second endotherm at a température of about 156 °C, and a third endotherm at a température of about 190 °C, in a DSC thennogram.

[00154] In another embodiment, the Compound 1 Esylate Form A is characterized by a weight ioss of about 8.5 wt% over a température range of 38-188 °C in a TGA thermogram.

[00155] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Esylate Form B.

[00156] In a further embodiment, the Compound 1 Esylate Form B is characterized by an XRPD pattern substantially identical to Figure 18.

[00157] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 HBr Form A.

[00158] In one embodiment, the Compound 1 HBr Form A is characterized by an XRPD pattern substantially identical to Figure 19.

[00159] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 HBr Form B.

[00160] In one embodiment, the Compound 1 HBr Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.26, 8.29, 9.75,9.91, 10.56, 10.72, 12.25, 12.50, 12.75, 13.31, 13.54, 14.11, 14.72, 14.89, 15.87, 16.29, 16.50, 17.36, 17.78, 18.09, 18.44, 18.75, 19.12, 19.24, 19.56, 19.92, 20.40, 20.55,20.69,21.18, 22.09, 22.64, 23.24, 24.56, 25.80, 26.52, 27.23, 27.43, 28.13, 28.46, 28.76, 29.08, 29.66, and 30.07.

[00161] In another embodiment, the Compound 1 HBr Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein tire one or more peaks is selected from 5.26, 9.91, 10.72,20.55, 20.69, 21.18, 22.09, 23.24, 24.56, and 25.80.

[00162] In a further embodiment, the Compound l HBr Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.26, 9.91, 10.72, 20.55, 20.69, 21.18, 22.09, 23.24, 24.56, and 25.80.

[00163] In still a further embodiment, the Compound 1 HBr Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.26, 8.29, 9.75, 9.91, 10.56, 10.72, 12.25, 12.50, 12.75, 13.31, 13.54, 14.11, 14.72, 14.89, 15.87, 16.29, 16.50, 17.36, 17.78, 18.09, 18.44, 18.75, 19.12, 19.24, 19.56, 19.92, 20.40, 20.55, 20.69, 21.18, 22.09, 22.64, 23.24, 24.56, 25.80, 26.52, 27.23, 27.43, 28.13, 28.46, 28.76, 29.08, 29.66, and 30.07.

[00164] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Lactate Form A.

[00165] In a further embodiment, the Compound 1 Lactate Form A is characterized by an XRPD pattern substantially identical to Figure 21.

[00166] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Malate Form A.

[00167] In a further embodiment, the Compound 1 Malate Form A is characterized by an XRPD pattern substantially identical to Figure 22.

[00168] In one embodiment of this aspect, the crystalline form is Compound 1 Maleate Form A.

[00169] In one embodiment, the Compound 1 Maleate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 7.58, 8.34, 10.92, 12.38, 12.87, 14.17, 15.13, 15.78, 16.43, 16.91, 17.51, 18.09, 18.71,20.30, 21.60, 21.99, 22.30, 22.49, 23.32, 23.56, 23.92, 24.79, 26.04, 26.41, 26.92, 27.62, 28.18, 28.54, and 29.01. [00170] In another embodiment, the Compound 1 Maleate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 10.92, 15.13, 15.78, 16.43, 18.09, 18.71,20.30,21.99, 22.30, 22.49, 23.32,23.56, 24.79, 26.41, 26.92, and 29.01.

[001711 In a further embodiment, the Compound 1 Maleate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 10.92, 15.13, 15.78, 16.43, 18.09, 18.71, 20.30, 21.99, 22.30, 22.49, 23.32, 23.56, 24.79, 26.41, 26.92, and 29.01.

[00172] In still a further embodiment, the Compound 1 Maleate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 7.58, 8.34, 10.92, 12.38, 12.87, 14.17, 15.13, 15.78, 16.43, 16.91, 17.51, 18.09, 18.71, 20.30, 21.60, 21.99, 22.30, 22.49, 23.32, 23.56, 23.92, 24.79, 26.04, 26.41, 26.92, 27.62, 28.18, 28.54, and 29.01.

[00173] In another embodiment, the Compound 1 Maleate Form A is characterized by an endotherm at a température of about 117 °C in a DSC thermograin.

[00174] In another embodiment, the Compound 1 Maleate Form A is characterized by a weight loss of about 3.1 wt% in the température range of 42-146 °C in a TGA thermogram.

[00175] In another embodiment, the Compound 1 Maleate Form A is characterized by about a 2.5 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity.

[00176] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Maleate Form B.

[00177] In a further embodiment, the Compound 1 Maleate Form B is characterized by an XRPD pattern substantially identical to Figure 28.

[00178] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Mesylate Form A.

[00179] In one embodiment, the Compound 1 Mesylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.06, 6.65,7.66, 8.35, 10.16, 10.72, 11.98, 12.62, 13.32, 14.41, 14.79, 15.42, 15.72, 15.89, 16.23, 16.77, 17.20, 17.59, 18.08, 18.40, 18.81, 19.33, 19.53, 19.71,20.14, 20.38,20.73,21.05,21.56,21.83, 22.16, 23.14, 24.06, 24.54, 24.77, 25.75, 26.82, 27.71, 27.94, 28.71, 29.27, and 29.85.

[00180] In another embodiment, the Compound 1 Mesylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.06, 7.66, 14.79, 15.42, 16.23, 17.20, 17.59, 18.40, 19.33, 19.53, 20.38, 20.73, 21.83, 22.16, 23.14, 24.06, and 24.77.

[00181] In a further embodiment, the Compound 1 Mesylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.06, 7.66, 14.79, 15.42, 16.23, 17.20, 17.59, 18.40, 19.33, 19.53,20.38,20.73,21.83, 22.16,23.14,24.06, and 24.77.

[00182J In still a further embodiment, the Compound 1 Mesylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.06, 6.65, 7.66, 8.35, 10.16, 10.72, 11.98, 12.62, 13.32, 14.41, 14.79, 15.42, 15.72, 15.89, 16.23, 16.77, 17.20, 17.59, .08, 18.40, 18.81, 19.33, 19.53, 19.71, 20.14, 20.38, 20.73, 21.05, 21.56, 21.83, 22.16, 23.14,

24.06, 24.54, 24.77, 25.75, 26.82, 27.71, 27.94, 28.71, 29.27, and 29.85.

[00183] In one embodiment of this aspect, the crystalline form is characterized as Compound 1

Mesylate Form B.

[001841 In one embodiment, the Compound 1 Mesylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.14, 6.62, 7.72, 7.89, 10.33, 10.73, 12.74, 13.31, 13.88, 14.23, 14.61, 15.21, 15.52, 15.87, 16.17, 17.18, 17.41, 17.88, 18.15, 18.46, 18.73, 19.13, 19.54, 20.15,20.53,20.75,20.98,21.27,21.60, 22.03, 22.28, 23.07, 23.32, 24.16, 24.42, 24.87, 25.13, 25.64, 26.24, 26.95, 27.17, 27.49, 27.77, 28.42, and 29.54.

[00185] In another embodiment, the Compound 1 Mesylate Fonn B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 14.61, 15.21, 16.17, 17.18, 17.41, 18.46, 19.13, 19.54, 20.15,20.53,20.75,20.98,21.27,21.60, 22.03, 23.32, 24.16, 24.42, 24.87, and 25.13.

[00186] In a further embodiment, the Compound 1 Mesylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 14.61, 15.21, 16.17, 17.18, 17.41, 18.46, 19.13, 19.54, 20.15, 20.53, 20.75, 20.98, 21.27, 21.60, 22.03, 23.32, 24.16, 24.42, 24.87, and 25.13.

[00187] In stiil a further embodiment, the Compound 1 Mesylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.14, 6.62, 7.72, 7.89, 10.33, 10.73, 12.74, 13.31, 13.88, 14.23, 14.61, 15.21, 15.52, 15.87, 16.17, 17.18, 17.41, 17.88,

18.15, 18.46, 18.73, 19.13, 19.54, 20.15, 20.53, 20.75, 20.98, 21.27, 21.60, 22.03, 22.28, 23.07,

23.32, 24.16, 24.42, 24.87, 25.13, 25.64, 26.24, 26.95, 27.17, 27.49, 27.77, 28.42, and 29.54.

[00188] In one embodiment of this aspect, the crystalline fonn is characterized as Compound 1

Mesylate Form C.

[00189] In one embodiment, the Compound 1 Mesylate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 7.55, 9.53, 10.25, 11.04, 11.49, 11.65, 12.24, 12.51, 13.88, 14.44, 15.36, 15.66, 16.29, 16.58, 17.16, 17.54, 19.04, 19.20, 19.79, 20.54, 21.12, 21.24, 21.62, 22.22, 23.15, 23.57, 23.99, 24.61, 24.77, 25.22, 25.61, 25.99, 26.60, 26.89, 27.29, 27.91, 29.03, and 29.29.

[00190] In another embodiment, the Compound 1 Mesylate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 7.55, 9.53, 11.49, 12.51, 14.44, 19.04, 20.54, 21.12, 21.24, and 23.15.

[00191] In a further embodiment, the Compound 1 Mesylate Form C is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 7.55, 9.53, 11.49, 12.51, 14.44, 19.04, 20.54, 21.12, 21.24, and 23.15.

[00192] In still a further embodiment, the Compound 1 Mesylate Form C is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 7.55, 9.53, 10.25, 11.04, 11.49, 11.65, 12.24, 12.51, 13.88, 14.44, 15.36, 15.66, 16.29, 16.58, 17.16, 17.54, 19.04, 19.20, 19.79, 20.54, 21.12, 21.24, 21.62, 22.22, 23.15, 23.57, 23.99, 24.61, 24.77, 25.22, 25.61, 25.99, 26.60, 26.89, 27.29, 27.91, 29.03, and 29.29.

[00193] In another embodiment, the Compound 1 Mesylate Form C is characterized by a first endotherm from a température of about 96-98 °C, and a second endothenn from a température of about 198-203 °C in a DSC thermogram. In another embodiment, the Compound 1 Mesylate Form C is characterized by a first endothenn with a peak at a température of about 69 °C, wherein the first endothenn has a lower limit of a température of about 36 and an upper limit of a température of about 96 °C, and a second endothenn with a peak at a température of about 208 °C, wherein the second endotherm has a lower limit of a température of about 169 and an upper limit of a température of about 219 °C.

[00194] In another embodiment, the Compound 1 Mesylate Form C is characterized by a weight loss of from 0.5 to 3.0 wt% in the température range of 36-130 °C in a TGA thermogram.

[00195] In another embodiment, the Compound 1 Mesylate Form C is characterized by about a 5.1 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an enviromnent of 95% relative humidity.

[00196] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Oxalate Form A.

[00197] In one embodiment, the Compound I Oxalate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.90, 5.25, 6.20, 8.05, 9.87, 10.54, 12.29, 14.79, 15.35, 15.84, 16.49, 16.89, 17.55, 18.27, 18.67, 19.12, 19.40, 19.81, 20.26, 20.50, 21.06, 21.74, 22.17, 22.93, 23.26, 23.50, 23.81, 24.66, 25.06, 25.95, 26.90, 27.82, and 28.24.

[00198] In one embodiment, the Compound 1 Oxalate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.90, 5.25,9.87, 10.54, 12.29, 15.35, 18.67, 19.40, 19.81,20.26, 22.93, and 24.66.

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[00199] In another embodiment, the Compound 1 Oxalate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.90, 5.25, 9.87, 10.54, 12.29, 15.35, 18.67, 19.40, 19.81, 20.26, 22.93, and 24.66.

[00200] In a further embodiment, the Compound 1 Oxalate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.90, 5.25, 6.20, 8.05, 9.87, 10.54, 12.29, 14.79, 15.35, 15.84, 16.49, 16.89, 17.55, 18.27, 18.67, 19.12, 19.40, 19.81,20.26, 20.50, 21.06, 21.74, 22.17, 22.93, 23.26, 23.50, 23.81, 24.66, 25.06, 25.95, 26.90, 27.82, and 28.24. [00201] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Oxalate Form B.

|00202] In one embodiment, the Compound 1 Oxalate Fonn B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.20, 7.59, 8.02, 8.42, 10.53, 12.36, 12.66, 13.09, 13.35, 13.88, 14.15, 14.46, 15.06, 15.23, 17.42, 17.75, 18.28, 19.07, 19.52, 20.33, 21.18, 21.43, 21.74, 22.08, 22.59, 23.53, 24.21, 24.52, 24.71, 25.24, 25.85, 26.24, 26.55, 26.90, 27.43, 28.56, 29.30, and 29.51.

[00203] In another embodiment, the Compound 1 Oxalate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.20, 7.59, 10.53, 15.06, 15.23, 19.52, 21.18,21.43,22.59, 24.21, and 25.85.

[00204] In a further embodiment, the Compound 1 Oxalate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.20, 7.59, 10.53, 15.06, 15.23, 19.52, 21.18, 21.43, 22.59, 24.21, and 25.85.

[00205] In still a further embodiment, the Compound l Oxalate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.20, 7.59, 8.02, 8.42, 10.53, 12.36, 12.66, 13.09, 13.35, 13.88, 14.15, 14.46, 15.06, 15.23, 17.42, 17.75, 18.28, 19.07, 19.52, 20.33, 21.18, 21.43, 21.74, 22.08, 22.59, 23.53, 24.21, 24.52, 24.71, 25.24, 25.85, 26.24, 26.55, 26.90, 27.43, 28.56, 29.30, and 29.51.

[00206] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Oxalate Form C.

[00207] In one embodiment, the Compound 1 Oxalate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.13, 7.70, 10.29, 10.59, 13.09, 13.70, 14.13, 15.33, 15.87, 16.57, 17.19, 17.50, 17.83, 18.15, 18.61,

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19.24, 19.42, 20.11, 20.34, 20.64, 21.07, 21.47, 21.59, 21.91, 22.56, 22.92, 23.37, 23.87, 24.35, 25.35, 25.91, 26.47, 26.68, 27.74, 28.47, and 29.14.

[00208] In another embodiment, the Compound 1 Oxalate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 7.70, 10.29, 10.59, 13.09, 13.70, 15.33, 17.83, 18.15,20.11,21.07,21.91, and 22.56.

[00209] In a further embodiment, the Compound 1 Oxalate Form C is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 7.70, 10.29, 10.59, 13.09, 13.70, 15.33, 17.83, 18.15, 20.11, 21.07, 21.91, and 22.56.

|00210] In still a further embodiment, the Compound I Oxalate Form C is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.13, 7.70, 10.29, 10.59, 13.09, 13.70, 14.13, 15.33, 15.87, 16.57, 17.19, 17.50, 17.83, 18.15, 18.61, 19.24, 19.42,20.11, 20.34, 20.64, 21.07, 21.47, 21.59, 21.91, 22.56, 22.92, 23.37, 23.87, 24.35, 25.35, 25.91, 26.47, 26.68, 27.74, 28.47, and 29.14.

[00211] In one embodiment of this aspect, the crystalline form is characterized as Compound I Propionate Form A.

[00212) In one embodiment, the Compound 1 Propionate Form A îs characterized by an XRPD pattern substantially identical to Figure 38.

[00213] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Succinate Form A.

[00214] In a further embodiment, the Compound 1 Succinate Form A is characterized by an XRPD pattern substantially identical to Figure 39.

[00215] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Sulfate Form A.

[00216] In one embodiment, the Compound 1 Sulfate Form A îs characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.74, 5.85, 9.47, 10.04, 11.74, 11.95, 13.77, 14.99, 15.42, 15.71, 16.48, 17.36, 17.66, 17.92, 18.59, 18.95, 19.36, 19.74, 20.22, 20.77, 21.38, 21.86,22.74, 23.30, 23.70, 24.33, 25.07, 25.32, 25.67, 26.23, and 27.00.

[00217] In another embodiment, the Compound 1 Sulfate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.74, 5.85,9.47, 10.04, 11.74, il.95, 16.48,20.22, and 22.74.

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[00218] In a further embodiment, the Compound 1 Sulfate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.74, 5.85, 9.47, 10.04, 11.74, 11.95, 16.48, 20.22, and 22.74.

[00219] In still a further embodiment, the Compound 1 Sulfate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.74, 5.85, 9.47, 10.04, 11.74, 11.95, 13.77, 14.99, 15.42, 15.71, 16.48, 17.36, 17.66, 17.92, 18.59, 18.95, 19.36, 19.74, 20.22, 20.77, 21.38, 21.86, 22.74, 23.30, 23.70, 24.33, 25.07, 25.32, 25.67, 26.23, and 27.00.

[00220] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Sulfate Form B.

[00221] In one embodiment, the Compound 1 Sulfate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.27, 8.57,9.32, 10.95, 11.29, 12.07, 12.87, 13.25, 13.82, 14.13, 14.67, 16.94, 17.21, 17.64, 19.99, 20.26, 21.03, 21.44, 22.00, 22.71, 23.85, 25.20, and 26.02.

[00222] In another embodiment, the Compound 1 Sulfate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.27, 8.57,9.32, 16.94, 19.99,21.03,21.44, 22.00, and 26.02.

[00223] In a further embodiment, the Compound 1 Sulfate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.27, 8.57, 9.32, 16.94, 19.99, 21.03, 21.44, 22.00, and 26.02.

[00224] In still a further embodiment, the Compound 1 Sulfate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.27, 8.57, 9.32, 10.95, 11.29, 12.07, 12.87, 13.25, 13.82, 14.13, 14.67, 16.94, 17.21, 17.64, 19.99, 20.26, 21.03, 21.44, 22.00, 22.71, 23.85, 25.20, and 26.02.

[00225] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Sulfate Form C.

[00226] In one embodiment, the Compound 1 Sulfate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.19, 5.35, 9.04, 9.62, 10.73, 11.31, 11.60, 12.27, 12.67, 13.76, 14.31, 14.65, 15.21, 15.63, 16.11, 16.33, 16.63, 17.11, 18.32, 18.75, 18.99, 19.36, 19.47, 20.16, 20.55,21.01,21.52,21.62,21.89, 22.19, 22.53, 23.19, 23.79, 24.23, 24.81, 25.07, 25.41, 26.06, 26.73, 27.58, 28.16, 28.63, 28.90, 29.22, 29.47, and 29.73.

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[00227] In another embodiment, the Compound 1 Sulfate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.19, 5.35,9.62, 12.27, 16.33, 17.11, 18.75, 18.99, 19.36, 19.47, 20.55,21.01,21.52,21.62,21.89, 22.19, 23.79, 25.07, and 26.06.

[00228] In a further embodiment, the Compound 1 Sulfate Form C is characterized by ail of the foilowing peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.19, 5.35, 9.62, 12.27, 16.33, 17.11, 18.75, 18.99, 19.36, 19.47,20.55,21.01,21.52,21.62,21.89, 22.19, 23.79, 25.07, and 26.06. [00229] In still a further embodiment, the Compound 1 Sulfate Form C is characterized by ail of the foilowing peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.19, 5.35, 9.04, 9.62, 10.73, 11.31, 11.60, 12.27, 12.67, 13.76, 14.31, 14.65, 15.21, 15.63, 16.11, 16.33, 16.63, 17.11, 18.32, 18.75, 18.99, 19.36, 19.47, 20.16, 20.55,21.01,21.52,21.62, 21.89, 22.19, 22.53,23.19, 23.79, 24.23, 24.81, 25.07, 25.41, 26.06, 26.73, 27.58, 28.16, 28.63, 28.90, 29.22, 29.47, and 29.73. [00230] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Tartrate Form A.

[00231] In a further embodiment, the Compound 1 Tartrate Form A is characterized by an XRPD pattern substantially identical to Figure 43.

[00232] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Hemitartrate Form B.

[00233] In one embodiment, the Compound 1 Hemitartrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.17,5.66, 7.22,9.27, 10.10, 10.40, 11.37, 11.55, 12.77, 13.94, 14.51, 15.60, 16.06, 16.48, 17.09, 17.69, 17.90, 18.27, 18.94, 19.15, 19.59, 19.81, 20.06, 20.32, 21.23, 21.83, 22.34, 22.84, 23.53, 24.26, 24.70, 25.26, 25.80, 26.78, 27.29, 27.90, 29.04, and 29.45.

[00234] In another embodiment, the Compound 1 Hemitartrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.17, 5.66, 10.10, 10.40, 11.37, 11.55, 14.51, 17.09,21.23,21.83,23.53,24.26,25.26, and 26.78.

[00235] In a further embodiment, the Compound 1 Hemitartrate Form B is characterized by ail of the foilowing peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.17, 5.66, 10.10, 10.40, 11.37, 11.55, 14.51, 17.09,21.23,21.83,23.53,24.26, 25.26, and 26.78.

[00236] In still a further embodiment, the Compound 1 Hemitartrate Form B is characterized by ail of the foilowing peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.17, 5.66, 7.22,

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9.27, 10.10, 10.40, 11.37, 11.55, 12.77, 13.94, 14.51, 15.60, 16.06, 16.48, 17.09, 17.69, 17.90, 18.27, 18.94, 19.15, 19.59, 19.81,20.06,20.32,21.23,21.83,22.34,22.84, 23.53, 24.26, 24.70, 25.26, 25.80, 26.78, 27.29, 27.90, 29.04, and 29.45.

[00237] In another embodiment, the Compound 1 Hemitartrate Form B is characterized by a first endotherm at a température of about 111 °C, and a second endotherm at a température of about 148 “C in a DSC thermogram.

[00238J In another embodiment, the Compound 1 Hemitartrate Form B is characterized by a weight loss of about 7.4 wt% in the température range of 39-157 °C in a TGA thermogram.

[00239] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Tartrate Form C.

[00240] In a further embodiment, the Compound 1 Tartrate Form C îs characterized by an XRPD pattern substantially identical to Figure 69.

[00241] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Tosylate Form A.

[00242] In one embodiment, the Compound 1 Tosylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.81, 7.05, 8.52, 9.74, 10.40, 10.99, 11.26, 11.66, 12.58, 12.81, 14.28, 14.62, 15.30, 15.80, 16.03, 16.34, 17.12, 17.55, 18.03, 18.94, 19.26, 19.67, 20.31, 20.65, 21.02, 21,43, 22.11, 22.44, 22.66, 22.94, 23.07, 23.54, 23.79, 24.55, 24.88, 25.42, 25.83, 26.10, 26.53, 27.70, 28.11, 28.62, 29.18, 29.40, 29.66, and 29.83.

[00243] In another embodiment, the Compound 1 Tosylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 8.52, 9.74,14.28, 16.03, 17.55, 18.94, 19.26, 20.31,21.02,21.43,22.11,22.44, 22.66, 23.07, 24.55, and 27.70.

[00244] In a further embodiment, the Compound 1 Tosylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 8.52, 9.74, 14.28, 16.03, 17.55, 18.94, 19.26, 20.31, 21.02, 21.43, 22.11, 22.44, 22.66, 23.07, 24.55, and 27.70.

[00245] In still a further embodiment, the Compound 1 Tosylate Form A is characterized by ali of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.81, 7.05, 8.52, 9.74, 10.40, 10.99, 11.26, 11.66, 12.58, 12.81, 14.28, 14.62, 15.30, 15.80, 16.03, 16.34, 17.12, 17.55,

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18.03, 18.94, 19.26, 19.67,20.31,20.65,21.02, 21.43,22.11,22.44, 22.66, 22.94,23.07,23.54, 23.79, 24.55, 24.88, 25.42, 25.83, 26.10, 26.53, 27.70, 28.11, 28.62, 29.18, 29.40, 29.66, and 29.83. [00246] In another embodiment, the Compound 1 Tosylate Form A is characterized by an endotherm at a température of about 214 °C in a DSC thermogram. In another embodiment, the Compound 1 Tosylate Form A is characterized by an endotherm with an onset température at about 214 °C in a DSC thermogram.

[00247] In another embodiment, the Compound 1 Tosylate Form A is characterized by a weight loss of about 0.9 wt% in the température range of 72-231 °C in a TGA thermogram.

[00248] In another embodiment, the Compound 1 Tosylate Form A is characterized by about a 0.9 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity.

[00249] In one embodiment of this aspect, the crystalline form is characterized as Compound 1 Tosylate Form B.

[00250] In one embodiment, the Compound 1 Tosylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.61, 8.69,9.25, 10.68, 12.44, 12.69, 13.76, 14.42, 14.81, 15.47, 16.08, 16.57, 17.45, 17.76, 18.44, 18.83, 19.01, 19.35, 20.42, 20.84, 21.15, 21.69, 22.09, 22.86, 23.12, 24.08, 24.53, 24.86, 25.22, 25.91, 26.33, 26.82, 27.63, 28.61, 29.11, and 29.77.

[00251] In another embodiment, the Compound 1 Tosylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.61,9.25, 12.44, 15.47, 17.76, 19.01, 19.35, 25.91, 26.33, and 27.63.

[0Q252] In a further embodiment, the Compound I Tosylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.61, 9.25, 12.44, 15.47, 17.76, 19.01, 19.35, 25.91, 26.33, and 27.63.

[00253] In still a further embodiment, the Compound 1 Tosylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.61, 8.69, 9.25, 10.68, 12.44, 12.69, 13.76, 14.42, 14.81, 15.47, 16.08, 16.57, 17.45, 17.76, 18.44, 18.83, 19.01, 19.35, 20.42, 20.84, 21.15, 21.69, 22.09, 22.86, 23.12, 24.08, 24.53, 24.86, 25.22, 25.91, 26.33, 26.82, 27.63, 28.61, 29.11, and 29.77.

[00254] In another embodiment, the Compound 1 Tosylate Form B is characterized by a sharp endotherm at a température of ~183 °C in a DSC thermogram. In another embodiment, the

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Compound 1 Tosylate Form B is characterized by a sharp endotherm with an onset température at — 183 °C in a DSC thermogram. In another embodiment, the Compound 1 Tosylate Form B is characterized by a sharp endotherm with a peak at a température of — 191 °C in a DSC thermogram. [00255] In another embodiment, the Compound 1 Tosylate Form B is characterized by a weight loss of about 0.7 wt% in the température range of 39-214 ^ÜC in a TGA thermogram.

[00256] In another embodiment, the Compound 1 Tosylate Form B is characterized by about a 0.9 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity.

[00257] In one aspect, the invention includes a pharmaceutical composition comprising a crystalline sait form described herein and a pharmaceutically acceptable excipient.

[00258) In another aspect, the invention includes a method of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase, comprising administering to a subject in need thereof a crystalline sait form or pharmaceutical composition described herein.

[00259J In one embodiment of this aspect, the disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase is cancer.

[00260| In another aspect, the invention includes a method for inhibiting a protein kinase, the method comprising contacting the protein kinase with a crystalline sait form or pharmaceutical composition described herein.

[00261] In one embodiment of this aspect, the protein kinase is Axl, Mer, c-Met, KDR, or a combination thereof.

100262] Crystalline forms of the Invention [00263] Compound 1 Besvlate Form A [00264] Compound 1 Besylate Form A is a 1:1 sait of Compound 1 and benzenesulfonic acid, and further includes one molar équivalent of acetone in the crystal lattice.

[00265] The XRPD pattern for Compound 1 Besylate Form A is provided in Figure 1, and a list of peaks from the pattern is provided in Table 1 below.

[00266] Table 1: XRPD peaks of Compound 1 Besylate Form A

20C)	fif-spacing (Â)	Intensity (%)
3.78 ±0.20	23.386 ± 1.238	78
7.56 ±0.20	11.677±0.308	28

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20 0	ίΖ-spacing (Â)	Intensity (%)
10.08 ±0.20	8.766±0.173	12
10.42 ±0.20	8.480 ±0.162	49
11.70 ±0.20	7.561 ±0.129	8
11.78 ±0.20	7.506 ±0.127	6
12.00 ±0.20	7.369 ±0.122	10
12.71 ±0.20	6.958 ±0.109	11
13.20 ± 0.20	6.702 ±0.101	7
13.92 ±0.20	6.358 ±0.091	8
14.06 ±0.20	6.294 ± 0.089	8
14.44 ±0.20	6.128 ±0.084	3
14.93 ±0.20	5.928 ±0.079	3
15.18 ±0.20	5.833 ±0.076	6
15.96 ±0.20	5.547 ±0.069	13
16.21 ±0.20	5.465 ± 0.067	4
16.40 ±0.20	5.401 ±0.065	15
16.73 ±0.20	5.295 ±0.063	21
16.86 ±0.20	5.254 ±0.062	14
17.38 ±0.20	5.099 ±0.058	7
18.32 ±0.20	4.840 ±0.052	2
19.07 ±0.20	4.650 ±0.048	9
20.07 ±0.20	4.420 ± 0.044	10
20.26 ± 0.20	4.380 ±0.043	10
20.51 ±0.20	4.327 ± 0.042	100
20.94 ± 0.20	4.238 ±0.040	66
21.45 ±0.20	4.139 ±0.038	14
21.60 ±0.20	4.112±0.038	27
22.30 ±0.20	3.984 ±0.035	4
22.90 ±0.20	3.880 ±0.033	8
23.05 ± 0.20	3.856 ±0.033	12

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20(°)	//-spacing (Â)	Intensity (%)
23.28 ±0.20	3.818 ±0.032	7
23.71 ±0.20	3.750 ±0.031	4
24.28 ±0.20	3.662 ±0.030	6
24.97 ± 0.20	3.564±0.028	9
25.30 ± 0.20	3.518 ±0.027	48
25.69 ±0.20	3.464 ±0.027	18
26.33 ±0.20	3.382 ±0.025	6
26.71 ±0.20	3.335 ±0.025	20
27.29 ± 0.20	3.265 ±0.023	3
27.65 ± 0.20	3.224 ±0.023	3
28.07 ± 0.20	3.176 ±0.022	7
29.22 ±0.20	3.054 ±0.020	4
29.50 ± 0.20	3.025 ±0.020	5

[00267] The XRPD pattern for Compound 1 Beslylate Form A was successfully indexed, suggesting the material consists primarily or exclusively of a single crystalline phase.

[00268] Unit cell data for Compound 1 Besylate Form A:

1 Ira vais Λ pu	1 riclînic
a ΓΜ	8.913
l AJ	9.121
t[V|	23.727
u [	9.Î.17
β	9K.7D
7 |dea|	12
Volume J Vcellj	1.831.0
Chiral CunlcnK1	hui Spctoiîcd
Γχίπκίίοη SunM	P-
S pave GrmipG)	j’I il!. Pi (2)

[00269] DSC and TGA thermograms for Compound 1 Besylate Form A are provided in Figures 2 and 3, respectively. A weight loss of ~7.9% over the températures of 39-177 °C by TGA

I I

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I I corresponds to 1 molar équivalent of acetone. DSC shows two broad endotherms at -144 °C and

-170°C.

[00270] Compound 1 Besylate Form B

[00271] Compound 1 Besylate Form B is the resulting material after desolvation of Compound 1 Besylate Form A. It was detected as a mixture with Besylate Form A.

[00272] The XRPD pattern for Compound 1 Besylate Form B is provided in Figure 4.

[00273] Compound 1 Benzoate Form A

[00274] Compound 1 Benzoate Form A is a kl sait, fonned by adding benzoic acid to Compound 1 in hot methanol.

[00275] The XRPD pattern for Compound 1 Benzoate Form A is provided in Figure 5.

[00276] Compound 1 Camsylate Form A

[00277] Compound 1 Camsylate Form A is a 1:1 sait of Compound 1 and camphorsulfonic acid, and further includes one molar équivalent of acetone in the crystal lattice.

[00278] The XRPD pattern for Compound 1 Camsylate Form A is provided in Figure 6, and a list of peaks from the pattern is provided in Table 2 below.

[00279] Table 2: XRPD peaks of Compound 1 Camsylate Form A

20 0	J-spacing (Â)	Intensity (%)
5.55 ±0.20	15.916 ±0.573	100
7.90 ± 0.20	11.179 ± 0.282	3
8.25 ± 0.20	10.704 ±0.259	4
8.38 ±0.20	10.545 ±0.251	7
9.55 ± 0.20	9.250 ±0.193	4
9.87 ± 0.20	8.951 ±0.181	18
10.26 ±0.20	8.617±0.168	25
11.12 ± 0.20	7.951 ±0.143	9
11.34 ±0.20	7.800 ±0.137	14
12.50 ±0.20	7.075 ±0.113	7
12.94 ±0.20	6.837 ±0.105	6
13.40 ±0.20	6.601 ±0.098	10
13.65 ±0.20	6.480 ±0.094	5
14.79 ±0.20	5.986 ±0.081	6

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2Θ Ο	J-spacing (Â)	Intensity (%)
15.83 ± 0.20	5.593 ±0.070	10
16.16 + 0.20	5.480 ±0.067	25
16.41 ±0.20	5.397 ±0.065	11
16.54 ±0.20	5.354 ±0.064	9
16.82 ±0.20	5.266 ±0.062	38
17.10 ±0.20	5.180 ±0.060	8
17.69 ±0.20	5.010±0.056	13
18.02 ±0.20	4.918 ±0.054	15
18.22 ±0.20	4.866 ± 0.053	8
18.47 ±0.20	4.799 ± 0.052	7
18.91 ±0.20	4.689 + 0.049	11
19.10 ±0.20	4.643 ±0.048	10
19.47 ±0.20	4.556 ±0.046	6
20.04 ± 0.20	4.427 ± 0.044	4
20.87 ± 0.20	4.254 ±0.040	33
21.05 ±0.20	4.218 ±0.040	18
22.16 ±0.20	4.008 ±0.036	16
22.36 ±0.20	3.973 ±0.035	27
22.93 ± 0.20	3.876 ±0.033	9
23.71 ±0.20	3.750 ±0.031	38
24.55 ± 0.20	3.623 ±0.029	7
25.33 ±0.20	3.513 ±0.027	8
26.02 ± 0.20	3.421 ±0.026	7
26.40 ± 0.20	3.373 ± 0.025	5
27.09 ±0.20	3.289 ±0.024	5
27.33 ± 0.20	3.260 ±0.023	6
27.97 ± 0.20	3.187 ±0.022	4
28.32 ± 0.20	3.149 ±0.022	6
28.68 ±0.20	3.110 ± 0.021	4

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20 (°)	J-spacîng (Â)	Intensity (%)
28.98 ± 0.20	3.078 ±0.021	5

[00280] The XRPD pattern was successfully indexed.

[00281] Unit cell data for Compound 1 Camsylate Form A

---------,---------- -----------	1’1 ÎLllLljvC
Bravais hpc	Monod lu ic
□ Γη	1 1.413
b lAJ	3 1.799
Φ]	1 1.622
u	90
h hk’J	lit 1.91
7 [dcg]	90
Volume [ V cdl]	4.127 1
Chiral Contenir?	t'iiiral
1 XutKlion Symbol	1’ ] 2· 1
Space Croupis)	P2, Fh

[00282] A proton NMR spectrum for Compound 1 Camsylate Form A is consistent with the Chemical structure of Compound 1 with 1 molar équivalent of acetone présent.

[00283] TGA analysis indicates that the material readily desolvates upon heating, losing 5.9 wt% between 38 °C and 170 °C (Figure 8), which corresponds to one molar équivalent of acetone. DSC thermogram shows two broad endotherms at 110 °C and 174 °C (Figure 7).

[00284] Compound 1 Camsylate Form B

[00285] Compound 1 Camsylate Form B is the resulting material after desolvatîon of Compound

Camsylate Form A.

[00286] The XRPD pattern for Compound 1 Camsylate Form B is provided in Figure 9, and a list of peaks from the pattern is provided in Table 3 below.

[00287] Table 3: XRPD peaks of Compound 1 Camsylate Form B

20 0	J-spacing (Â)	Intensity (%)
5.25 ±0.20	16.830 ±0.641	100
8.32 ±0.20	10.620 ±0.255	3
8.51 ± 0.20	10.376 ±0.243	5
8.76 ±0.20	10.084 ±0.230	6

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20 Ο	rf-spacing (Â)	Intensity (%)
9.05 ± 0.20	9.765 ±0.215	5
9.58 ±0.20	9.221 ±0.192	6
9.88 ± 0.20	8.942 ±0.180	10
10.00 ± 0.20	8.838 ±0.176	10
10.52 ±0.20	8.406 ±0.159	14
10.80 ±0.20	8.182 ± 0.151	10
11.06 ±0.20	7.997 ±0.144	7
11.96 ±0.20	7.395 ±0.123	4
12.24 ±0.20	7.225 ±0.118	6
12.58 ±0.20	7.029 ± 0.111	3
13.98 ±0.20	6.331 ±0.090	3
15.62 ±0.20	5.669 ±0.072	9
15.81 ±0.20	5.602 ± 0.070	10
16.15 ±0.20	5.483 ± 0.067	18
16.70 ± 0.20	5.303 ±0.063	7
17.12 ±0.20	5.175 ±0.060	5
17.42 ±0.20	5.086 ±0.058	5
17.71 ±0.20	5.005 ±0.056	9
18.41 ±0.20	4.816±0.052	4
19.37 ± 0.20	4.579 ±0.047	4
19.55 ± 0.20	4.538 ± 0.046	5
20.63 ± 0.20	4.302 ±0.041	4
21.13 ± 0.20	4.200 ±0.039	15
21.56 ±0.20	4.118 ± 0.038	27
21.89 ±0.20	4.057 ±0.037	12
22.50 ± 0.20	3.949 ±0.035	8
23.04 ±0.20	3.857 ± 0.033	3
24.43 ± 0.20	3.641 ±0.029	5
26.08 ± 0.20	3.413 ±0.026	3

20 Q	rf-spacing (Â)	Intensity (%)
27.07 ± 0.20	3.292 ± 0.024	3
27.97 ±0.20	3.187 + 0.022	5
28.22 ±0.20	3.160 ±0.022	4
28.73 ±0.20	3.105 ±0.021	3

[0Û288] Compound 1 Citrate Form A

[00289] Compound 1 Citrate Form A was crystallized from a 1:1 mixture of Compound 1 and citric acid in acetone.

[00290] The XRPD pattern for Compound 1 Citrate Form A shows that the material is a mixture with a free base form of Compound 1, The pattern is provided in Figure 10.

[00291] Compound 1 Citrate Form B

[00292] Compound 1 Citrate Form B is a 1:1 sait, provided by adding 2 molar équivalents of citric acid in acetone to Compound 1 to provide a 1:1 sait of Compound 1 and citric acid.

(00293] The XRPD pattern for Compound 1 Citrate Form B is provided in Figure 11, and the XRPD pattern was also successfully indexed. A list of peaks from the pattern is provided in Table 4 below.

[00294] Table 4: XRPD peaks of Compound 1 Citrate Form B

20 0	tZ-spacing (Â)	Intensity (%)
4.58 ± 0.20	19.296 + 0.843	40
5.95 ±0.20	14.840 + 0.498	72
7.61 ±0.20	11.607 + 0.305	19
8.88 ±0.20	9.945 +0.223	32
9.19 ±0.20	9.619 + 0.209	10
9.94 ±0.20	8.894 + 0.179	12
11.93 ±0.20	7.409 + 0.124	76
13.26 ±0.20	6.673 + 0.100	10
13.79 ±0.20	6.415+0.093	33
14.29 + 0.20	6.193 + 0.086	46
14.68 ±0.20	6.028 ± 0.082	27
15.26 + 0.20	5.801 +0.076	11
15.95 + 0.20	5.553 +0.069	10

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20 Ο	J-spacing (Â)	Intensity (%)
16.64 ± 0.20	5.323 ±0.064	35
17.11 ±0.20	5.177 ±0.060	16
17.87 ±0.20	4.959 ±0.055	27
18.21 ±0.20	4.867 ±0.053	21
18.43 ±0.20	4.811 ±0.052	8
18.90 ±0.20	4.692 ± 0.049	74
19.36 ± 0.20	4.582 ±0.047	31
19.67 ±0.20	4.510 ±0.045	22
20.14 ±0.20	4.406 ± 0.043	19
20.57 ± 0.20	4.315 ±0.042	29
21.47 ±0.20	4.135 ±0.038	55
22.30 ±0.20	3.984 ±0.035	25
22.64 ± 0.20	3.925 ± 0.034	7
23.06 ±0.20	3.853 ±0.033	14
23.80 ± 0.20	3.736 ±0.031	100
24.25 ± 0.20	3.667 ± 0.030	89
24.55 ±0.20	3.623 ± 0.029	28
24.81 ±0.20	3.586 ±0.028	32
25.10 ±0.20	3.545 ±0.028	34
25.45 ± 0.20	3.497 ± 0.027	18
25.54 ±0.20	3.485 ± 0.027	20
25.85 ±0.20	3.444 ±0.026	43
26.35 ±0.20	3.379 ±0.025	13
26.51 ±0.20	3.359 ±0.025	19
26.83 ± 0.20	3.320 ±0.024	16
27.16 ±0.20	3.281 ±0.024	7
27.57 ±0.20	3.232 ± 0.023	11
27.85 ±0.20	3.201 ±0.023	10
28.08 ±0.20	3.I76±0.022	8

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20 0	d-spacîng (Â)	Intensity (%)
28.47 ± 0.20	3.132 ±0.022	31

[00295] Unit cell data for Compound 1 Citrate f	'orm B
	1 ’iiinirivc
Bravais Tvpe	Onhorliornhk
a |À|	38.495
b |A|	23.202
OA|	7.473
u |deg|	90
[1 [de-J	90
7 [dag]	90
Volume [ V ccll]	9.674 ri
Chiral Conlcnis?	Achirul
l.xtitKlion Symbol	F b c a
Space Croupis!	PlKâ(61)

[00296] The TGA thermogram for Compound I Citrate Form B (Figure 13) shows negligible weight loss until décomposition beginning at about 159 °C and ending at about 220 °C. The DSC thermogram (Figure 12) also shows a sharp endotherm with an onset at -175 °C, indicating décomposition.

[00297] DVS analysis (Figure 14) provides that the sample of Compound 1 Citrate Form B experienced a -4.1% weight gain from 5% to 95% relative humidity. The water absorbed by the sample was released as the relative humidity was ramped down from 95% to 5%. XRPD analysis shows that the sample remained as Compound 1 Citrate Form B after DVS analysis.

[00298] Compound 1 Esylate Form A

[00299] Compound 1 Esylate Form A is a 1:1 sait of Compound 1 and ethanesulfonic acid, and further includes one molar équivalent of acetone in the crystal lattice.

[00300] The XRPD pattern for Compound 1 Esylate Form A is provided in Figure 15, and a list of peaks from the pattern is provided in Table 5 below.

[00301] Table 5: XRPD peaks of Compound 1 Esylate Form A

20(°)	d-spacing (Â)	Intensity (%)
3.97 ± 0.20	22.255 ± 1.122	86
7.95 ±0.20	11.119 ± 0.279	100

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20 Q	rf-spacing (Â)	Intensity (%)
9.89 ± 0.20	8.937 ±0.180	38
10.62 ±0.20	8.322 ±0.156	63
10.92 ±0.20	8.096 ±0.148	12
11.03 ±0.20	8.012 ±0.145	12
11.34 ±0.20	7.798 ± 0.137	6
11.77 ±0.20	7.516±0.127	16
12.03 ±0.20	7.348 ±0.122	5
12.53 ±0.20	7.057±0.112	11
12.71 ±0.20	6.960 ±0.109	6
13.27 ±0.20	6.665 ±0.100	54
14.00 ±0.20	6.321 ±0.090	13
14.70 ±0.20	6.021 ±0.081	5
15.08 ±0.20	5.870 ±0.077	42
15.94 ±0.20	5.554 ±0.069	17
16.17 ±0.20	5.477 ±0.067	40
16.92 ±0.20	5.236 ±0.061	32
17.01 ±0.20	5.209 ± 0.061	33
17.19 ±0.20	5.155 ±0.060	7
17.35 ±0.20	5.108±0.058	6
17.61 ±0.20	5.033 ±0.057	7
18.15 ±0.20	4.883 ± 0.053	16
18.76 ±0.20	4.727 ± 0.050	5
19.03 ±0.20	4.661 ±0.049	8
19.66 ±0.20	4.511 ±0.045	18
19.89 ±0.20	4.461 ±0.044	8
20.26 ± 0.20	4.380 ±0.043	22
20.65 ± 0.20	4.297 ±0.041	87
20.78 ±0.20	4.272 ±0.041	81
21.44 ±0.20	4.141 ±0.038	47

2*0	rf-spacing (Â)	Intensity (%)
22.08 ± 0.20	4.022 ±0.036	51
23.14 ±0.20	3.840 ±0.033	10
23.27 ±0.20	3.820 ±0.032	U
23.99 ±0.20	3.706 ±0.030	42
24.32 ± 0.20	3.657 ±0.030	17
25.43 ± 0.20	3.500 ±0.027	62
25.66 ±0.20	3.469 ±0.027	26
25.85 ±0.20	3.444 ±0.026	17
26.52 ±0.20	3.358 ±0.025	35
26.87 ±0.20	3.315 ±0.024	9
27.61 ±0.20	3.228 ±0.023	7
27.96 ±0.20	3.189 ±0.022	18
28.18 ±0.20	3.164 ±0.022	22
28.40 ± 0.20	3.140 ±0.022	13
28.91 ±0.20	3.085 ±0.021	7

[00302] The XRPD pattern was successfully indexed.

[00303] Unit cell data for Compound 1 Esylate Form A

Bravais T} pc	1 riuliniv
a N	8.593
MM	9.223
MM	22439
u	91.60
	95.33
7	103.05
Volume [ V-vJI]	1.715.6
Chiral Cuntcnls?	Not Spccificd
Lxünchnn Symbol	P-
Space Groupisl	P1 il). Pi (2)

[00304] The DSC thermogram for Compound 1 Esylate Form A is provided in Figure 16, and shows endothenns at -69 °C, -156 °C, and -190 °C. The TGA thermogram (Figure 17) shows that

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I the material undergoes a weight loss of-8.5% of the température range of 38-188 °C, which is consistent with the loss of one molar équivalent of acetone.

[00305] Compound 1 Esylate Form B

[00306] Compound 1 Esylate Form B was formed by the desolvation of Compound 1 Esylate Form A, and was determined to be a mixture with Compound 1 Esylate Form A. This form was not characterized further.

[00307] The XRPD pattern for Compound 1 Esylate Form B is provided in Figure 18.

[00308] Compound 1 HBr Form A

[00309] Compound 1 HBr Form A is a 1:1 sait, formed by the addition of HBr to Compound 1 in a hot acetone slurry.

[00310] The XRPD pattern for Compound 1 HBr Form A is provided in Figure 19.

[00311 ] Compound 1 HBr Form B

[00312] Compound 1 HBr Form B is a 1:1 sait, formed by the addition of 1 molar équivalent of HBr to Compound 1 in a hot MEK slurry.

[00313] The XRPD pattern for Compound 1 HBr Form B is provided in Figure 20, and a list of peaks from the pattern is provided in Table 6 below.

[00314] Table 6: XRPD peaks of Compound 1 HBr Form B

2fl(°)	i/-spacing (Â)	Intensîty (%)
5.26 ±0.20	16.777 ±0.637	100
8.29 ±0.20	10.661 ±0.257	5
9.75 ± 0.20	9.068 ±0.186	10
9.91 ±0.20	8.916±0.179	26
10.56 ±0.20	8.367 ±0.158	11
10.72 ± 0.20	8.243 ±0.153	22
12.25 ±0.20	7.219±0.117	4
12.50 ±0.20	7.075 ±0.113	6
12.75 ±0.20	6.938 ±0.108	9
13.31 ±0.20	6.648 ± 0.099	11
13.54±0.20	6.535 ±0.096	10
14.11 ±0.20	6.270 ± 0.088	6
14.72 ± 0.20	6.011 ±0.081	12

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20 0	J-spacing (Â)	Intensity (%)
14.89 ±0.20	5.943 ±0.079	5
15.87 ±0.20	5.581 ±0.070	8
16.29 ±0.20	5.438 ±0.066	7
16.50 ±0.20	5.368 ±0.065	16
17.36 ±0.20	5.104 ±0.058	7
17.78 ±0.20	4.984 ±0.056	12
18.09 ±0.20	4.899 ± 0.054	14
18.44 ±0.20	4.808 ± 0.052	15
18.75 ±0.20	4.728 ±0.050	5
19.12 ±0.20	4.637 ±0.048	12
19.24 ±0.20	4.609 ± 0.047	12
19.56 ±0.20	4.535 ± 0.046	15
19.92 ± 0.20	4.453 ± 0.044	13
20.40 ± 0.20	4.350 ±0.042	19
20.55 ± 0.20	4.319 ±0.042	24
20.69 ± 0.20	4.290 ±0.041	30
21.18 ± 0.20	4.191 ±0.039	31
22.09 ± 0.20	4.021 ±0.036	80
22.64 ± 0.20	3.924 ±0.034	10
23.24 ±0.20	3.825 ±0.032	43
24.56 ±0.20	3.622 ± 0.029	44
25.80 ±0.20	3.450 ±0.026	28
26.52 ±0.20	3.358 ±0.025	11
27.23 ±0.20	3.272 ± 0.024	10
27.43 ± 0.20	3.249 ±0.023	7
28.13 ±0.20	3.169 ±0.022	7
28.46 ± 0.20	3.134±0.022	11
28.76 ±0.20	3.101 ±0.021	6
29.08 ± 0.20	3.069 ±0.021	5

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20 0	rf-spacing (Â)	Intensity (%)
29.66 ± 0.20	3.009 ±0.020	13
30.07 ± 0.20	2.970 ±0.019	13

[00315] The XRPD for Compound 1 HBr Form B was successfully indexed.

[00316] Unit cell data for Compound 1 HBr Form B

Bravai> Type a I M h [ \] u [dce] UMcgl

1^1 Volume [.V’.ccll] Chii<d ton lents ? ] Aime lion Symbol Spnce Croupis)

Priinuivc Monoclinic 1 <1.652 9.46() 33.4% 90 91.13 yo

3.374 7 A t h u ni

P 1 2, c 1 P2, c(l4(

[00317] Compound l Lactate Form A

[00318] Compound 1 Lactate Form A was formed by adding one molar équivalent of lactic acid to Compound 1 in a hot acetone slurry. The material was determined to be a mixture with a crystalline form of the free base of Compound 1.

[00319] The XRPD pattern for Compound 1 Lactate Form A is provided in Figure 21.

[00320] Compound 1 Malate Form A

[00321] Compound 1 Malate Form A was made by adding L-malic acid to Compound 1 in acetone. The material was determined to be a mixture with a crystalline form of the free base of Compound 1.

[00322] The XRPD pattern for Compound 1 Malate Form A is provided in Figure 22.

[00323] Compound 1 Maleate Form A

[00324] Compound 1 Maleate Form A is a 1:1 sait made by adding aqueous maleic acid to a slurry of Compound 1 in hot MEK or acetone.

[00325] The XRPD pattern for Compound 1 Maleate Form A is provided in Figure 23, and a list of peaks from the pattern is provided in Table 7 below.

[00326] Table 7: XRPD peaks of Compound 1 Maleate Form A

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20(°)	//-spacing (Â)	Intensity (%)
7.58 ± 0.20	11.659 ±0.307	9
8.34 ± 0.20	10.593 ±0.254	7
10.92 ±0.20	8.094 ±0.148	34
12.38 ±0.20	7.141 ±0.115	8
12.87 ±0.20	6.874 ±0.106	13
14.17 ±0.20	6.244 ± 0.088	4
15.13 ±0.20	5.852 ±0.077	47
15.78 ±0.20	5.612 ±0.071	20
16.43 ±0.20	5.389 ±0.065	21
16.91 ±0.20	5.238 ±0.061	7
17.51 ±0.20	5.060 ±0.057	7
18.09 ±0.20	4.900 ± 0.054	27
18.71 ±0.20	4.738 ±0.050	21
20.30 ± 0.20	4.372 ± 0.043	23
21.60 ±0.20	4.111 ±0.038	14
21.99 ±0.20	4.039 ±0.036	26
22.30 ±0.20	3.983 ± 0.035	34
22.49 ± 0.20	3.951 ±0.035	100
23.32 ±0.20	3.811 ±0.032	24
23.56 ±0.20	3.773 ±0.032	80
23.92 ±0.20	3.718 ±0.031	11
24.79 ± 0.20	3.588 ±0.028	48
26.04 ± 0.20	3.419 ±0.026	12
26.41 ± 0.20	3.372 ±0.025	30
26.92 ± 0.20	3.309 ±0.024	39
27.62 ±.0.20	3.228 ± 0.023	18
28.18 ±0.20	3.164 ±0.022	8
28.54 ±0.20	3.125 ±0.021	6
29.01 ±0.20	3.075 ±0.021	23

[00327] The XRPD pattern of Compound I Maleate Form A was successfully indexed, which indicates the material is composed of a single crystalline phase.

[00328] Unit cell data for Compound 1 Maleate Form A

Bravais Tvpe	Irichnic
a |Λ]	6.261
b|À|	15.310
e |À|	16,232
u |dep|	95.43
[i [du·· J	96.5]
7 [deg]	94.67
Volume [ VccII]	1.5 15.2
Chiral Coutcms?	Achiral
Extinction Symbol	P-
Space Group(si	P1 (b. Pï (2)

[00329] The curve of the TGA thermogram (Figure 25) shows a weight loss of -3.1% over the température range of 42-146 °C, mostly above —117 °C, likely due to décomposition of maleic acid. The curve of the DSC thermogram (Figure 24) exhibits a single broad endotherm with an onset of

-117 °C.

[00330] Hot stage images (Figures 26A - 26E) for Compound 1 Maleate Form A confirm the event as the melt.

[00331] The DVS isotherm (Figure 27) indicates gains/losses of-2.5% weight through the sorption/desorption experiment (RH = 5% - 95%).

[00332] The material recovered from the experiment remained unchanged and identified as

Compound 1 Maleate Form A by XRPD.

[00333] Compound 1 Maleate Form B

[00334] Compound 1 Maleate Form B was produced in the scaled up procedure to product Compound 1 Maleate Form A in acetone. Compound 1 Maleate Form B was only made as a mixture with Compound 1 Maleate Fonn A.

[00335] The XRPD pattern for Compound 1 Maleate Form B is provided in Figure 28.

[00336] Compound 1 Mesylate Form A

[00337] Compound 1 Mesylate Form A is a 1:1 sait, produced by slurrying Compound 1 and methanesulfonic acid in THF at room température.

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[003381 The XRPD pattern for Compound 1 Mesylate Form A is provided in Figure 29, and a list of peaks from the pattern is provided m Table 8 below.

[00339] Table 8: XRPD peaks of Compound 1 Mesylate Form A

20 0	d-spacing (Â)	Intensity (%)
5.06 ± 0.20	17.449 ±0.689	26
6.65 ± 0.20	13.274 ±0.399	14
7.66 ± 0.20	11.534 ±0.301	100
8.35 ± 0.20	10.587 ±0.253	6
10.16 ±0.20	8.701 ±0.171	11
10.72 ±0.20	8.247 ±0.153	7
11.98 ±0.20	7.385 ±0.123	14
12.62 ± 0.20	7.010 ± 0.111	17
13.32 ±0.20	6.642 ±0.099	16
14.41 ±0.20	6.143 ±0.085	9
14.79 ±0.20	5.984 ±0.080	21
15.42 ±0.20	5.742 ± 0.074	28
15.72 ±0.20	5.631 ±0.071	10
15.89 ±0.20	5.573 ± 0.070	8
16.23 ±0.20	5.457 ±0.067	23
16.77 ±0.20	5.284 ±0.063	11
17.20 ± 0.20	5.151 ±0.059	25
17.59 ±0.20	5.039 ±0.057	36
18.08 ±0.20	4.903 ±0.054	17
18.40 ±0.20	4.819±0.052	24
18.81 ±0.20	4.713 ±0.050	17
19.33 ±0.20	4.588 ±0.047	39
19.53 ±0.20	4.541 ±0.046	24
19.71 ±0.20	4.501 ±0.045	16
20.14 ±0.20	4.405 ± 0.043	9
20.38 ±0.20	4354 ±0.042	31

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2# O	rf-spacing (Â)	Intensity (%)
20.73 ±0.20	4.280 ±0.041	37
21.05 ±0.20	4.218 ±0.040	18
21.56 ±0.20	4.118 ±0.038	15
21.83 ±0.20	4.067 ± 0.037	81
22.16 ±0.20	4.008 ±0.036	38
23.14 ±0.20	3.841 ±0.033	38
24.06 ±0.20	3.695 ±0.030	35
24.54 ±0.20	3.624 ±0.029	12
24.77 ±0.20	3.591 ±0.029	31
25.75 ± 0.20	3.457 + 0.026	19
26.82 ±0.20	3.322 ± 0.024	16
27.71 ±0.20	3.217 ±0.023	7
27.94 ± 0.20	3.191 ±0.022	9
28.71 ±0.20	3.107 ±0.021	6
29.27 ± 0.20	3.049 ±0.020	11
29.85 ± 0.20	2.990 ± 0.020	6

[00340] The XRPD pattern of Compound 1 Mesylate Form A was successfully indexed, which indicates the material is composed of a single crystalline phase.

[00341] Unît cell data for Compound 1 Mesylate Form A

Bravais· l’ypc a [A| b |A| c |À| u |iieu| f [dc_?] 7 [d^J Volume [ V cell] Chiral CiHilenls?

AlÎÈKlion Symbol Space Croupis!

Primitive OrthiTh<*rnhit 63t>9 23.054 26.467

90

3.88ή 2

Achirai

P 2, 2t 2₅ P2,2,2. (19)

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[003421 Compound 1 Mesylate Form B

[00343] Compound 1 Mesylate Form B is a 1:1 sait, produced by mixing Compound 1 and methanesulfonic acid in hot chloroform. The material also includes about -1.5 moles of chloroform per mole of Compound 1.

[00344[ The XRPD pattern for Compound 1 Mesylate Form B is provided in Figure 30, and a list of peaks from the pattern is provided in Table 9 below,

[00345] Table 9: XRPD peaks of Compound 1 Mesylate Form B

20 0	d-spacing (Â)	Intensity (%)
5.14±0.20	17.169 ±0.667	16
6.62 ± 0.20	13.336 ±0.402	14
7.72 ± 0.20	11.441 ±0.296	16
7.89 ± 0.20	11.193 ± 0.283	10
10.33 ±0.20	8.556 ±0.165	12
10.73 ±0.20	8.240 ±0.153	8
12.74 ±0.20	6.945 ±0.109	26
13.31 ±0.20	6.646 ± 0.099	10
13,88 ±0.20	6.377 ± 0.091	8
14.23 ±0.20	6.220 ± 0.087	17
14.61 ±0.20	6.057 ± 0.082	35
15.21 ±0.20	5.822 ±0.076	44
15.52 ±0.20	5.704 ±0.073	24
15.87 ±0.20	5.580 ±0.070	12
16.17 ±0.20	5.477 ±0.067	38
17.18 ±0.20	5.157 ±0.060	78
17.41 ±0.20	5.090 ±0.058	42
17.88 ±0.20	4.956 ±0.055	12
18.15 ±0.20	4.883 ± 0.053	23
18.46 ±0.20	4.802 ±0.052	36
18.73 ±0.20	4.733 ±0.050	23
19.13 ±0.20	4.636 ±0.048	60

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20 0	rf-spacing (Â)	Intensity (%)
19.54 ±0.20	4.539 ±0.046	35
20.15 ±0.20	4.403 ±0.043	40
20.53 ± 0.20	4.323 ± 0.042	34
20.75 ± 0.20	4.278 ±0.041	75
20.98 ±0.20	4.230 ± 0.040	47
21.27 ±0.20	4.173 ±0.039	49
21.60 ±0.20	4.110±0.038	55
22.03 ± 0.20	4.032 ± 0.036	100
22.28 ± 0.20	3.986 ±0.035	27
23.07 ± 0.20	3.852 ±0.033	31
23.32 ±0.20	3.811 ±0.032	72
24.16 ±0.20	3.681 ±0.030	34
24.42 ± 0.20	3.642 ±0.029	50
24.87 ± 0.20	3.577 ±0.028	37
25.13 ±0.20	3.541 ±0.028	34
25.64 ±0.20	3.472 ±0.027	26
26.24 ±0.20	3.393 ±0.025	22
26.95 ± 0.20	3.306 ± 0.024	18
27.17 ±0.20	3.279 ±0.024	17
27.49 ± 0.20	3.242 ±0.023	21
27.77 ±0.20	3.210 ±0.023	17
28.42 ±0.20	3.138±0.022	19
29.54 ±0.20	3.022 ±0.020	30

[00346] The XRPD pattern of Compound 1 Mesylate Form B was successfully indexed, which indicates the material is composed of a single crystalline phase.

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[00347] Unît cell data for Compound 1 Mesylate Form B

	1Ί iaiLlivc
1 kiivais Type	ί ϊηΙΐιΌκνπΗίν
a |A|	6.472
b |Λ|	Γ4 r i p 1
e |A]	26.6 H?
U |dcü|	90
fl [dcg]	90
7	00
Volume |.V uell]	3 b K 44 0
Chiral Contents'?	Mî Spcciîicd
FxtitKlion mbol	F À 2, 2,
S puce <TH)upis>	1^2,2, (19)

[00348] Compound 1 Mesylate Form C (00349] Compound 1 Mesylate Form C is a 1:1 sait produced by mixing Compound 1 and methanesuIfonic acîd in hot methanol. The material also had ~0.1 molar équivalents of methanol.

[00350] The XRPD pattern for Compound 1 Mesylate Form C is provided in Figure 31, and a list of peaks from the pattern is provided in Table 10 below.

[00351] Table 10: XRPD peaks of Compound 1 Mesylate Form C

20 0	d-spacing (Â)	Intensity (%)
7.55 ± 0.20	11.702 ±0.310	22
9.53 ± 0.20	9.278 ±0.194	100
10.25 ±0.20	8.621 ±0.168	7
11.04 ±0.20	8.008 ±0.145	15
11.49 ±0.20	7.692 ±0.133	28
11.65 ±0.20	7.587 ±0.130	16
12.24 ±0.20	7.223±0.118	8
12.51 ±0.20	7.072±0.113	23
13.88 ±0.20	6.373 ± 0.091	23
14.44 ±0.20	6.129 ±0.084	25
15.36 ±0.20	5.765 ± 0.075	11
15.66 ±0.20	5.653 ± 0.072	9
16.29 ±0.20	5.437 ±0.066	14

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20 Q	0-spacing (Â)	Intensity (%)
16.58 + 0.20	5.342 + 0.064	23
17.16 + 0.20	5.164 + 0.060	8
17.54 + 0.20	5.053 +0.057	23
19.04+0.20	4.659 + 0.048	49
19.20 + 0.20	4.618 + 0.048	22
19.79 + 0.20	4.482 ± 0.045	20
20.54 + 0.20	4.322 + 0.042	47
21.12 + 0.20	4.203 ± 0.039	58
21.24 + 0.20	4.179 + 0.039	64
21.62 + 0.20	4.106 + 0.038	9
22.22 ± 0.20	3.998 + 0.036	24
23.15 + 0.20	3.839 + 0.033	78
23.57 + 0.20	3.772 + 0.032	39
23.99 + 0.20	3.706 + 0.030	35
24.61+0.20	3.615 + 0.029	15
24.77 ± 0.20	3.591 +0.029	18
25.22 + 0.20	3.528 + 0.028	37
25.61+0.20	3.475 ± 0.027	10
25.99 + 0.20	3.426 + 0.026	9
26.60 + 0.20	3.348 ± 0.025	10
26.89 + 0.20	3.312 + 0.024	11
27.29 + 0.20	3.265 ± 0.023	10
27.91 ± 0.20	3.194 + 0.022	28
29.03 + 0.20	3.074 + 0.021	16
29.29 ± 0.20	3.047 + 0.020	9

[00352] The XRPD pattern of Compound 1 Mesylate Form C was successfully indexed, which indicates the material is composed of a single crystalline phase.

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[00353] Unit cell data for Compound 1 Mesylate Form C

1 fravais Type	Ί nchnic
a |Λ[	8.884
l> |A|	1 1.922
U ]À]	15.312
U [dcp|	88.79
fi [dcj	81.08
7 [dcg]	7S.76
Vohiuic | A’ ccll]	1.573.6
Chiral Contents?	Not Speciûcd
Extinction 8} uibol	P-
Space Gioupis·	P1 (1). Pi i2j

[00354] The DSC thermogram for Compound 1 Mesylate Form C is provided in Figure 32 and shows a broad endotherm with a peak at about 69 °C, wherein the endotherm has a lower lirait of about 36 and an upper lirait of about 96 °C. The thermogram also shows another sharp endotherm with a peak at about 208 °C, wherein the endotherm has a lower lirait of about 169 and an upper limit of about 219 °C. TGA, Figure 33, indicates a -2.3% weight loss over the température range of 38-115 °C, corresponding to -0.08 molar équivalents of methanol.

[00355] The DVS isothenn (Figure 34) indicates gains/losses of about 5.1% weight through the sorption/desorption experiment (RH = 5% - 95%).

[00356] Compound 1 Oxalate Form A

[00357] Compound 1 Oxalate Form A is a 1:1 sait produced by adding oxalic acid in hot acetone to Compound l and forming a slurry.

[00358] The XRPD pattern for Compound 1 Oxalate Form A is provided in Figure 35, and a list of peaks from the pattern is provided in Table 11 below.

[00359] Table 11: XRPD peaks of Compound 1 Oxalate Form A

20 0	0-spacing (À)	Intensity (%)
4.90 ±0.20	18.008 ±0.734	62
5.25 ± 0.20	16.811 ±0.640	100
6.20 ± 0.20	14.248 ±0.459	5
8.05 ± 0.20	10.969 ±0.272	8
9.87 ± 0.20	8.951 ±0.181	24

20 0	d-spacing (Â)	Intensîty (%)
10.54 ±0.20	8.389 ±0.159	21
12.29 ±0.20	7.195±0.U7	41
14.79 ±0.20	5.985 ±0.080	7
15.35 ±0.20	5.768 ±0.075	28
15.84 ±0.20	5.589 ±0.070	9
16.49 ±0.20	5.371 ±0.065	12
16.89 ±0.20	5.246 ± 0.062	5
17.55 ± 0.20	5.049 ±0.057	7
18.27 ± 0.20	4.852 ± 0.053	5
18.67 ±0.20	4.750 ±0.050	32
19.12 ±0.20	4.638 ±0.048	12
19.40 ±0.20	4.572 ± 0.047	22
19.81 ±0.20	4.478 ±0.045	32
20.26 ±0.20	4.380 ±0.043	31
20.50 ±0.20	4.329 ±0.042	12
21.06 ±0.20	4.215 ±0.040	10
21.74 ±0.20	4.084 ±0.037	21
22.17 ±0.20	4.007 ±0.036	17
22.93 ± 0.20	3.876 ±0.033	46
23.26 ±0.20	3.822 ± 0.032	20
23.50 ±0.20	3.782 ±0.032	23
23.81 ±0.20	3.734 ±0.031	18
24.66 ± 0.20	3.607 ±0.029	30
25.06 ±0.20	3.550 ±0.028	11
25.95 ±0.20	3.431 ±0.026	20
26.90 ±0.20	3.312 ±0.024	7
27.82 ±0.20	3.204 ±0.023	9
28.24 ± 0.20	3.157 ±0.022	17

[00360] Compound 1 Oxalate Form B

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[00361] Compound 1 Oxalate Form B is a 1:1 sait produced by adding aqueous oxalic acid to Compound 1 in hot MEK and forming a slurry.

[00362] The XRPD pattern for Compound 1 Oxalate Form B is provided in Figure 36, and a list of peaks from the pattern is provided in Table 12 below.

[00363] Table 12: XRPD peaks of Compound 1 Oxalate Form B.

20 0	J-spacing (Â)	Tntensity (%)
4.20 ± 0.20	21.026 ± 1.001	34
7.59 ±0.20	11.640 ±0.306	100
8.02 ±0.20	11.013 ± 0.274	16
8.42 ± 0.20	10.496 ±0.249	15
10.53 ±0.20	8.391 ±0.159	90
12.36 ±0.20	7.154 ± 0.115	13
12.66 ±0.20	6.989 ±0.110	21
13.09 ±0.20	6.759 ±0.103	19
13.35 ±0.20	6.629 ±0.099	27
13.88 ±0.20	6.377 ±0.091	16
14.15 ±0.20	6.254 ±0.088	15
14.46 ±0.20	6.119±0.084	14
15.06 ±0.20	5.878 ±0.078	40
15.23 ±0.20	5.815 ±0.076	59
17.42 ±0.20	5.088 ±0.058	21
17.75 ±0.20	4.994 ±0.056	29
18.28 ±0.20	4.850 ±0.053	20
19.07 ± 0.20	4.649 ± 0.048	19
19.52 ±0.20	4.544 ± 0.046	32
20.33 ± 0.20	4.365 ± 0.042	19
21.18 ±0.20	4.190 ±0.039	44
21.43 ±0.20	4.143 ±0.038	37
21.74 ±0.20	4.085 ± 0.037	24
22.08 ± 0.20	4.022 ± 0.036	b9______________

20 0	rf-spacing (Â)	Lntensity (%)
22.59 ±0.20	3.932 ±0.034	43
23.53 ±0.20	3.778 ± 0.032	19
24.21 ± 0.20	3.673 ±0.030	37
24.52 ± 0.20	3.627 ± 0.029	28
24.71 ± 0.20	3.600 ± 0.029	25
25.24 ±0.20	3.525 ±0.027	19
25.85 ± 0.20	3.444 ±0.026	41
26.24 ± 0.20	3.393 ± 0.025	26
26.55 ± 0.20	3.355 ±0.025	30
26.90 ± 0.20	3.312 ±0.024	28
27.43 ± 0.20	3.249 ±0,023	24
28.56 ±0.20	3.123 ±0.021	29
29.30 ±0.20	3.045 ±0.020	17
29.51 ±0.20	3.024 ±0.020	A________j

[00364] Compound 1 Oxalate Form C

[00365] Compound 1 Oxalate Form C is a 1:1 sait produced by adding oxalic acid in hot TFE to Compound 1 and forming a slurry.

[00366] The XRPD pattern for Compound 1 Oxalate Form C is provided in Figure 37, and a list of peaks from the pattern is provided in Table 13 below.

[00367] Table 13: XRPD peaks of Compound 1 Oxalate Form C.

20 C)	rf-spacing (Â)	lntensity (%)
4.13 ±0,20	21.391 ± 1.036	30
7.70 ± 0.20	11.473 ±0.298	98
10.29 ±0.20	8.594 ± 0.167	34
10.59 ±0.20	8,351 ± 0.157	53
13.09 ± 0.20	6.760 ±0.103	51
13.70 ±0.20	6.459 ± 0.094	76
14.13 ±0.20	6.261 ±0.088	13
15.33 ±0.20	5.774 ±0.075	100

20 0	rf-spacïng (Â)	Intensity (%)
15.87 ±0.20	5.580 ±0.070	12
16.57 ±0.20	5.346 ±0.064	12
17.19 ±0.20	5.154 ±0.060	15
17.50 ±0.20	5.063 ±0.057	19
17.83 ±0.20	4.971 ±0.055	42
18.15 ±0.20	4.883 ±0.053	39
18.61 ±0.20	4.764 ±0.051	14
19.24 ±0.20	4.610 ±0.047	22
19.42 ±0.20	4.567 ±0.047	18
20.11 ±0.20	4.412 ±0.043	49
20.34 ± 0.20	4.362 ±0.042	34
20.64 ± 0.20	4.299 ±0.041	37
21.07 ±0.20	4.212 ±0.040	69
21.47 ±0.20	4.135 ±0.038	35
21.59 ±0.20	4.112 ± 0.038	36
21.91 ±0.20	4.053 ± 0.037	67
22.56 ± 0.20	3.937 ±0.034	69
22.92 ±0.20	3.877 ± 0.033	20
23.37 ±0.20	3.804 ±0.032	34
23.87 ±0.20	3.725 ±0.031	39
24.35 ± 0.20	3.653 ±0.030	18
25.35 ±0.20	3.511 ±0.027	33
25.91 ±0.20	3.436 ±0.026	33
26.47 ± 0.20	3.364 ±0.025	31
26.68 ± 0.20	3.338 ±0.025	36
27.74 ±0.20	3.213 ±0.023	32
28.47 ±0.20	3.132 ±0.022	27
29.14 ±0.20	3.062 ±0.021	25

[00368] Compound 1 Propionate Form A

[00369] Compound 1 Propionate Form A is a 1:1 sait produced by adding propionic acid to Compound 1 and slurrying in hot acetone. Compound 1 Propionate Form A was only formed as a minor part of a mixture with a free base form of Compound 1.

[Ü0370]

[00371]

[00372]

The XRPD pattern for Compound 1 Propionate Form A is provided in Figure 38.

Compound 1 Succinate Form A

Compound 1 Succinate Form A is a sait produced by adding one or two molar équivalent of succinic acid to Compound 1 and slurrying in hot acetone. Compound 1 Succinate Form A was only formed as a mixture with a free base form of Compound 1.

[00373]

[00374]

[00375]

The XRPD pattern for Compound 1 Succinate Form A is provided in Figure 39.

Compound 1 Sulfate Form A

Compound 1 Sulfate Form A is a 1:1 sait produced by adding one molar équivalents of sulfuric acid to Compound 1 in THF.

[00376] The XRPD pattern for Compound 1 Sulfate Form A is provided in Figure 40, and a list of peaks from the pattern is provided in Table 14 below.

[00377] Table 14: XRPD peaks of Compound 1 Sulfate Form A.

20 Q	d-spacing (Â)	Intensity (%)
4.74 ±0.20	18.617 ±0.785	100
5.85 ±0.20	15.104±0.516	14
9.47 ± 0.20	9.327 ±0.196	11
10.04 ±0.20	8.804 ±0.175	15
11.74 ±0.20	7.534 ±0.128	24
11.95 ±0.20	7.397 ±0.123	13
13.77 ±0.20	6.428 ±0.093	7
14.99 ± 0.20	5.905 ±0.078	12
15.42 ±0.20	5.742 ±0.074	7
15.71 ±0.20	5.637 ±0.071	7
16.48 ± 0.20	5.374 ±0.065	19
17.36 ±0.20	5.105 ±0.058	11
17.66 ±0.20	5.019 ±0.056	8
17.92 ±0.20	4.946 ± 0.055	8
18.59 ±0.20	4.768 ±0.051	11

2ΘΟ	J-spacing (Â)	Intensity (%)
18.95 ±0.20	4.680 ±0.049	12
19.36 ±0.20	4.581 ±0.047	18
19.74 ±0.20	4.493 ± 0.045	23
20.22 ±0.20	4.388 ±0.043	35
20.77 ± 0.20	4.272 ±0.041	25
21.38 ±0.20	4.153 ± 0.038	17
21.86 ±0.20	4.063 ±0.037	13
22.74 ±0.20	3.907 ±0.034	39
23.30 ±0.20	3.814 ± 0.032	15
23.70 ±0.20	3.751 ±0.031	12
24.33 ±0.20	3.655 ± 0.030	14
25.07 ±0.20	3.549 ±0.028	11
25.32 ±0.20	3.515 ±0.027	14
25.67 ±0.20	3.467 ±0.027	13
26.23 ± 0.20	3.395 ± 0.025	19
27.00 ±0.20	3.299 ±0.024	15

[00378] Compound 1 Sulfate Form B

[00379] Compound 1 Sulfate Form B is a 1:1 sait produced by adding one molar équivalent of sulfuric acid to Compound 1 in hot methanol.

[00380] The XRPD pattern for Compound 1 Sulfate Form B is provided in Figure 41, and a list of peaks from the pattern is provided in Table 15 below.

[00381] Table 15: XRPD peaks of Compound 1 Sulfate Form B.

20 0	0-spacing (Â)	Intensity (%)
4.27 ± 0.20	20.683 ±0.969	100
8.57 ±0.20	10.313 ±0.240	75
9.32 ±0.20	9.481 ±0.203	94
10.95 ±0.20	8.071 ±0.147	16
11.29 ±0.20	7.834 ±0.138	18
12.07 ±0.20	7.329 ±0.121	13

2Θ C)	rf-spacing (Â)	Intensity (%)
12.87 ±0.20	6.875 ±0.106	15
13.25 ±0.20	6.678 ±0.100	15
13.82 ±0.20	6.404 ± 0.092	21
14.13 ±0.20	6.264 ±0.088	25
14.67 ±0.20	6.032 ± 0.082	20
16.94 ±0.20	5.230 ±0.061	32
17.21 ±0.20	5.147 ±0.059	23
17.64 ±0.20	5.024 ±0.057	17
19.99 ±0.20	4.439 ± 0.044	48
20.26 ±0.20	4,380 ±0.043	26
21.03 ±0.20	4.221 ±0.040	67
21.44 ±0.20	4.141 ±0.038	41
22.00 ± 0.20	4.036 ±0.036	43
22.71 ±0.20	3.913 ±0.034	35
23.85 ± 0.20	3.728 ±0.031	30
25.20 ±0.20	3.531 ±0.028	27
26.02 ± 0.20	3.422 ±0.026	44

[00382] Compound 1 Sulfate Form C

[00383] Compound 1 Sulfate Form C is a 1:1 sait produced by adding one molar équivalent of sulfuric acid to Compound 1 in hot chloroform.

[00384] The XRPD pattern for Compound 1 Sulfate Form C is provided in Figure 42, and a list of peaks from the pattern is provided in Table 16 below.

[00385] Table 16: XRPD peaks of Compound 1 Sulfate Form B.

20 0	J-spacing (Â)	Intensity (%)
3.19 ±0.20	27.658 ± 1.733	23
5.35 ±0.20	16.519 ± 0.618	33
9.04 ± 0.20	9.776 ±0.216	12
9.62 ± 0.20	9.182 ±0.190	72
10.73 ±0.20	8.239 ±0.153	8

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20 f)	rf-spacing (Â)	Intensity (%)
11.31 ±0.20	7.820±0.138	8
11.60 ±0.20	7.619 ± 0.131	8
12.27 ±0.20	7.208 ±0.117	36
12.67 ±0.20	6.978 ±0.110	12
13.76 ±0.20	6.432 ± 0.093	22
14.31 ±0.20	6.183 ±0.086	10
14.65 ±0.20	6.040 ± 0.082	20
15.21 ±0.20	5.820 ± 0.076	21
15.63 ±0.20	5.664 ±0.072	21
16.11 ±0.20	5.498 ± 0.068	18
16.33 ±0.20	5.424 ±0.066	16
16.63 ±0.20	5.327 ±0.064	51
17.11 ±0.20	5.177 ±0.060	66
18.32 ±0.20	4.839 ±0.052	21
18.75 ±0.20	4.730 ± 0.050	42
18.99 ±0.20	4.670 ± 0.049	68
19.36 ±0.20	4.582 ± 0.047	32
19.47 ±0.20	4.555 ± 0.046	32
20.16 ±0.20	4.401 ±0.043	15
20.55 ± 0.20	4.318 ±0.042	39
21.01 ±0.20	4.224 ± 0.040	28
21.52 ±0.20	4.125 ±0.038	36
21.62 ±0.20	4.107 ±0.038	34
21.89 ±0.20	4.056 ±0.037	39
22.19 ±0.20	4.004 ±0.036	50
22.53 ± 0.20	3.943 ± 0.035	25
23.19 ±0.20	3.833 ±0.033	15
23.79 ± 0.20	3.737 ±0.031	47
24.23 ± 0.20	3.670 ±0.030	20

20 0	rf-spacing (Â)	Intensity (%)
24.81+0.20	3.586 + 0.028	37
25.07 ± 0.20	3.549 + 0.028	100
25.41+0.20	3.502 + 0.027	31
26.06 + 0.20	3.416 + 0.026	41
26.73 + 0.20	3.332 + 0.024	20
27.58 + 0.20	3.231 +0.023	21
28.16 + 0.20	3.167 + 0.022	13
28.63 + 0.20	3.116 + 0.021	13
28.90 ± 0.20	3.087 + 0.021	12
29.22 ± 0.20	3.054 + 0.020	16
29.47 ± 0.20	3.029 + 0.020	19
29.73 ± 0.20	3.003 + 0.020	21

[00386] Compound 1 Tartrate Form A

[00387] Compound 1 Tartrate Form A is a 1:1 sait produced by adding one molar équivalent of L-tartaric acid to Compound 1 in THF. Compound 1 Tartrate Form A was only formed as a mixture with a free base form of Compound 1.

[00388] The XRPD pattern for Compound 1 Tartrate Form A is provided in Figure 43.

[00389] Compound 1 Hemitartrate Form B

[00390] Compound 1 Hemitartrate Form B is a 2:1 sait produced by adding one molar équivalent of L-tartaric acid to Compound 1 in acetone. The material also contains about 0.7 molar équivalents of acetone.

[00391] The XRPD pattern for Compound 1 Hemitartrate Form B is provided in Figure 44 and a list of peaks from the pattern is provided in Table 17 beiow.

[00392] Table 17: XRPD peaks of Compound 1 Hemitartrate Form B

20 Q	rf-spacing (Â)	Intensity (%)
5.17 + 0.20	17.079 + 0.660	55
5.66 + 0.20 Π	15.592 + 0.550	24
7.22 + 0.20	12.229 + 0.338	18
9.27 ± 0.20	9.534 ± 0.205	11
10.10 + 0.20	8.752 + 0.173	26

I

I

20 0	d-spacing (Â)	Intensity (%)
10.40 ±0.20	8.503 ±0.163	23
11.37 ±0.20	7.776 ±0.136	26
11.55 ±0.20	7.659 ±0.132	37
12.77 ±0.20	6.929 ±0.108	8
13.94 ±0.20	6.346 ±0.091	19
14.51 ±0.20	6.100 ±0.084	31
15.60 ±0.20	5.676 ±0.072	8
16.06 ±0.20	5.514 ±0.068	17
16.48 ±0.20	5.374 ±0.065	14
17.09 ±0.20	5.184±0.060	53
17.69 ±0.20	5.011 ±0.056	12
17.90 ±0.20	4.951 ±0.055	12
18.27 ±0.20	4.851 ±0.053	15
18.94 ±0.20	4.681 ±0.049	11
19.15 ±0.20	4.630 ± 0.048	13
19.59 ±0.20	4.529 ±0.046	12
19.81 ±0.20	4.478 ± 0.045	15
20.06 ± 0.20	4.423 ±0.044	19
20.32 ±0.20	4.367 ± 0.043	19
21.23 ±0.20	4.182 ±0.039	48
21.83 ±0.20	4.068 ±0.037	48
22.34 ± 0.20	3.976 ±0.035	14
22.84 ±0.20	3.891 ±0.034	13
23.53 ±0.20	3.778 ±0.032	100
24.26 ± 0.20	3.666 ±0.030	45
24.70 ±0.20	3.601 ±0.029	11
25.26 ±0.20	3.523 ± 0.027	34
25.80 ±0.20	3.450 ± 0.026	13
26.78 ±0.20	3.326 ±0.024	59

I

20 (°)	d-spacing (Â)	Intensity (%)
27.29 ±0.20	3.266 ±0.023	16
27.90 ±0.20	3.195 ±0.022	30
29.04 ± 0.20	3.073 ±0.021	8
29.45 ± 0.20	3.030 ±0.020	17

[00393] The XRPD pattern of Compound 1 Hemitartrate Fonn B was successfully indexed, which indicates the material is composed of a single crystalline phase.

[00394] Unit cell data for Compound 1 Hemitartrate Fonn B

Bravais J’ypc a [AJ h I M c |À| a |(kg| iMdefl 7 |deg| Volume I V cell | Cl tirai Clhi1cii1s? FxtiiKlion Ssnihol Spauc GnUipfXj

Priiniiivç Muni idinic 5.356 34.062

17.503

92. H

3.191.0 Cl lirai P 1 2 1

P2, !-k

[00395] The DSC thermogram for Compound 1 Hemitartrate Form B is provided in Figure 45 and shows a broad endothenn at -111 °C, and another sharp endotherm at -148 °C. T GA, Figure 46, indicates a -7.4% weight loss over the température range of 39-157 °C, corresponding to 0.8 molar équivalents of acetone.

[00396] Compound 1 Tosvlate Form A

[00397] Compound 1 Tosylate Fonn A is a 1:1 sait produced by adding one molar équivalent of p-toluenesulfonic acid to Compound 1 in hot acetone. The material also contains about —0.2 molar équivalents of acetone.

[00398] The XRPD pattern for Compound 1 Tosylate Fonn A is provided in Figure 47 and a list of peaks from the pattern is provided in Table 18 below.

[00399] Table 18: XRPD peaks of Compound 1 Tosylate Form A (°) 1 rf-spacing^Â) Intensity (%)

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20 (°)	rf-spacing (Â)	Intensity (%)
5.81 ±0.20	15.205 ±0.523	10
7.05 ± 0.20	12.532 ±0.355	13
8.52 ±0.20	10.364 ±0.243	55
9.74 ± 0.20	9.076 ±0.186	100
10.40 ±0.20	8.497 ±0.163	5
10.99 ±0.20	8.042 ±0.146	21
11.26 ±0.20	7.849 ±0.139	12
11.66 ± 0.20	7.582 ±0.130	5
12.58 ±0.20	7.030 ±0.111	9
12.81 ±0.20	6.904 ±0.107	13
14.28 ±0.20	6.199 ±0.086	57
14.62 ±0.20	6.053 ±0.082	6
15.30 ±0.20	5.787 ±0.075	23
15.80 ±0.20	5.606 ±0.071	10
16.03 ±0.20	5.524 ±0.068	37
16.34 ±0.20	5.420 ±0.066	18
17,12 ±0.20	5.174 ± 0.060	6
17.55 ±0.20	5.050 ±0.057	49
18.03 ±0.20	4.917 ±0.054	7
18.94 ±0.20	4.682 ± 0.049	39
19.26 ± 0.20	4.605 ±0.047	34
19.67 ±0.20	4.509 ±0.045	23
20.31 ±0.20	4.370 ±0.043	84
20.65 ±0.20	4.297 ±0.041	20
21.02 ±0.20	4.222 ± 0.040	58
21.43 ±0.20	4.143 ±0.038	64
22.11 ±0.20	4.018 ±0.036	52
22.44 ± 0.20	3.960 ±0.035	43
22.66 ± 0.20	3.921 ±0.034	41

I I 1 I I I

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20 Q	rf-spacing (Â)	Intensity (%)
22.94 ± 0.20	3.874 ±0.033	29
23.07 ± 0.20	3.851 ±0.033	35
23.54 ±0.20	3.776 ±0.032	14
23.79 ± 0.20	3.737 ±0.031	20
24.55 ±0.20	3.623 ±0.029	35
24.88 ± 0.20	3.576 ±0.028	9
25.42 ±0.20	3.501 ±0.027	11
25.83 ±0.20	3.446 ±0.026	9
26.10 ±0.20	3.412 ±0.026	6
26.53 ± 0.20	3.357 ±0.025	12
27.70 ±0.20	3.218 ±0.023	39
28.11 ±0.20	3.172 ±0.022	7
28.62 ±0.20	3.116 ± 0.021	5
29.18 ±0.20	3.058 ±0.021	8
29.40 ± 0.20	3.036 ±0.020	7
29.66 + 0.20	3.010 ±0.020	9
29.83 ± 0.20	2.993 ±0.020	9

[00400] The XRPD pattern of Compound 1 Tosylate Form A was successfully indexed, which indicates the material is composed of a single crystalline phase.

[00401] Unit cell data for Compound 1 Tosylate Form A

I I 1

I I I I 1 I I

I I

I I I I I

Bravais Type	Iriclink
« |A|	8.821
b l-M	13/110
e |À|	15.364
et|deü|	96.93
[î [aer J	95.1'2
7 [d^]	103.96
Volume f A’cell]	1,688.2
Chiral Coutcnis?	Not Spccificd
1 Àtinction Symbol	P-
Space Groupts}	P1 (1k Pi 12j

[00402] The DSC thermogram for Compound 1 Tosylate Form A is provided in Figure 48 and shows a sharp endotherm with an onset at about 214 °C. TGA, Figure 49, indicates a —0.9% weight loss over the température range of 72-231 °C, corresponding to 0.1 molar équivalents of acetone.

[00403] Hot stage photomicrographs, shown in Figures 51A - 51D confirm the melting température of Compound 1 Tosylate Form A to be about 214 °C.

[00404] The DVS isotherm (Figure 50) indicates gains/losses of about 0.9% weight through the sorption/desorption experiment (RH = 5% - 95%).

[00405] Compound 1 Tosylate Form B

[00406] Compound 1 Tosylate Form B is a 1:1 sait produced during the scaled up procedure of Compound 1 Tosylate Form A.

[00407] The XRPD pattern for Compound 1 Tosylate Form B is provided in Figure 52 and a list of peaks from the pattern is provided in Table 19 below.

100408] Table 19: XRPD peaks of Compound 1 Tosylate Form B

20 0	0-spacing (Â)	Intensity (%)
4.61 ±0.20	19.171 ±0.832	47
8.69 ± 0.20	10.171 ±0.234	10
9.25 ± 0.20	9.550 ±0.206	25
10.68 ±0.20	8.274 ±0.154	23
12.44 ±0.20	7.107 ± 0.114	24
12.69 ±0.20	6.972 ±0.109	10
13.76 ±0.20	6.429 ±0.093	18

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20(°)	J-spacing (À)	Intensity (%)
14.42 ± 0.20	6.138 ±0.085	20
14.81 ±0.20	5.975 ±0.080	18
15.47 ±0.20	5.725 ±0.074	58
16.08 ±0.20	5.509 ±0.068	7
16.57 ±0.20	5.345 ± 0.064	7
17.45 ±0.20	5.078 ±0.058	15
17.76 ±0.20	4.991 ±0.056	59
18.44 ±0.20	4.808 ± 0.052	24
18.83 ±0.20	4.709 ±0.050	26
19.01 ±0.20	4.665 ± 0.049	51
19.35 ±0.20	4.584 ±0.047	100
20.42 ±0.20	4.345 ± 0.042	9
20.84 ±0.20	4.259 ± 0.040	26
21.15 ±0.20	4.198 ±0.039	16
21.69 ±0.20	4.095 ± 0.037	27
22.09 ± 0.20	4.021 ±0.036	12
22.86 ± 0.20	3.887 ±0.034	II
23.12 ±0.20	3.843 ±0.033	18
24.08 ± 0.20	3.692 ±0.030	6
24.53 ±0.20	3.626 ±0.029	10
24.86 ±0.20	3.579 ± 0.028	7
25.22 ± 0.20	3.528 ± 0.028	7
25.91 ±0.20	3.436 ±0.026	73
26.33 ± 0.20	3.382 ±0.025	34
26.82 ± 0.20	3.321 ±0.024	15
27.63 ± 0.20	3.226 ±0.023	35
28.61 ±0.20	3.118 ± 0.021	7
29.11 ±0.20	3.066 ±0.021	5
29.77 ± 0.20	2.999 ± 0.020	5

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[00409) The XRPD pattern of Compound 1 Tosylate Form B was successfully indexed, which indicates the material is composed of a single crystalline phase.

[00410]

Unit cell data for Compound 1 Tosylate Form B

Bravais; Type	Trielinii;
n L A)	8.5(11
b ) A|	H 393
0A|	19.667
u|dcg]	98.-16
3 A'gl	99.75
7 Ides']	97.34
Vu unie |.V wf]	1.673 3
Chaul Coiuuhn?	A ri lirai
Εχΐί'Ηΐίοιι Syndic	Ρ-
Spacc Group»	Pl 11 >_ PÎ (2)

[00411] The DSC thermogram for Compound 1 Tosylate Form B is provided in Figure 53 and shows a sharp endotherm at —183 °C. TGA, Figure 54, indicates a —0.7% weight loss over the température range of 39-214 °C.

[00412] Hot stage photomicrographs, shown in Figures 56A - 56F shows that Compound 1 Tosylate Form B begins to melt at -183 °C, is still melting at -194 °C, and is not completely melted until 200 °C.

[00413] The DVS isotherm (Figure 55) indicates gains/losses of about -0.9% weight through the sorption/desorption experiment (RH = 5% - 95%).

[00414] GENERAL ADMINISTRATION

[00415] Administration ofthe crystalline sait forms of Compound 1, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any ofthe accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aérosols, and the like, preferably in unit dosage forms suitable for simple administration of précisé dosages.

[00416] The compositions will include a conventional phannaceutical excipient and a crystalline sait form of Compound 1 as the/an active agent, and, in addition, may include other médicinal agents, pharmaceutical agents, adjuvants, etc. Compositions ofthe invention may be used in combination with antî cancer or other agents that are generally administered to a patient being treated for cancer. Adjuvants include preserving, wetting, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prévention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phénol, sorbic acid, and the like. It may also be désirable to include isotonie agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate, and gelatin. [00417] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan, monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc.

[00418] Compositions suitable for parentéral injection may comprise physiologically acceptable stérile aqueous or nonaqueous solutions, dispersions, suspensions or émulsions, and stérile powders for reconstitution into stérile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous excipients, diluents, solvents, or vehicles include water, éthanol, polyols (propyleneglycol, polyéthylèneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oîl), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[00419] One préférable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.

[00420] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient such as sodium citrate or dicalcium phosphate or (a) fïllers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silîcic acid, (b) binders, as for example, cellulose dérivatives, starch, alignâtes, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption acceierators, as for example, quatemary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnésium stéarate, and the like (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stéarate, magnésium stéarate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[00421] Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[00422] Liquid dosage forms for oral administration include pharmaceutically acceptable émulsions, solutions, suspensions, syrups, and élixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a crystalline sait form of Compound 1, and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, éthanol, and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, and dimethylformamîde; oils, in particular, cottonseed oil, groundnut oîl, corn genn oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a solution or suspension.

[00423] Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, or mixtures of these substances, and the like.

[00424] Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the présent invention with for example suitable non-irritating excipients or excipients such as cocoa butter, polyethyleneglycol, or a suppository wax, which are solid at ordinary températures but liquid at body température and therefore melt while in a suitable body cavity and release the active component therein.

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[00425] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under stérile conditions with a physiologically acceptable excipient and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

[00426] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1 % to about 99% by weight of a crystalline sait form of Compound 1, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a crystalline sait form of Compound 1, with the rest being suitable pharmaceutical excipients.

[00427] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 21^st Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006). The composition to be administered will, in any event, contain a therapeutically effective amount of a crystalline sait form of Compound 1, for treatment of a disease-state in accordance with the teachings of this invention.

[00428| The crystalline sait forms of Compound 1, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of Compound 1, the metabolic stability and length of action of Compound 1, the âge, body weight, general health, sex, diet, mode, and time of administration, rate of excrétion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The crystalline sait forms of Compound 1 can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The spécifie dosage used, however, can vary. For example, the dosage can dépend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The détermination of optimum dosages for a particular patient is well known to one of ordinary skill in the art.

[00429] Combination Therapy

[00430] A crystalline sait form of Compound 1 as disclosed herein can be administered as a single therapy or in combination (“co-administered”) with one or more additional thérapies for the treatment of a disease or disorder, for instance a disease or disorder associated with hyper prolifération such as cancer. Thérapies that may be used in combination with a compound disclosed herein include: (i) surgery; (ii) radiotherapy (for example, gamma radiation, neutron beam radiotherapy, électron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes); (iii) endocrine therapy; (iv) adjuvant therapy, immunotherapy, CAR T-cell therapy; and (v) other chemotherapeutic agents.

[004311 The term “co-administered” (“co-administering”) refers to either simultaneous administration, or any manner of separate sequential administration, of a crystalline sait form of Compound î as disclosed herein, and a further active pharmaceutical ingrédient or ingrédients, including cytotoxic agents and radiation treatment. If the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered topically and another compound may be administered orally.

[00432] Typically, any agent that has activity against a disease or condition being treated may be co-administered. Examples of such agents for cancer treatment can be found, for instance, at https://www.cancer.gov/about-cancer/treatment/drugs (last visited January 22, 2019) and in publically available sources such as Cancer Principles and Practice of Oncol ogy by V. T. Devita and S. Hellman (editors), 1 l^,h édition (2018), Lippincott Williams & Wilkins Publîshers. A person of ordînary skill in the art would be able to discem which combinations of agents would be usefol based on the particular characteristics of the drugs and the disease involved.

[00433] In one embodiment, the treatment method includes the co-administration of a crystalline sait form of Compound 1 as disclosed herein, and at least one immunotherapy. Immunotherapy (also called biological response modifier therapy, biologie therapy, biotherapy, immune therapy, or biological therapy) is a treatment that uses parts of the immune System to fight disease.

Immunotherapy can help the immune System recognîze cancer cells, or enhance a response against cancer cells. Immunothérapies include active and passive immunothérapies. Active immunothérapies stimulate the body's own immune System whîle passive immunothérapies generally use immune System components created outside of the body.

[00434] Examples of active immunothérapies include, but are not limited to vaccines including cancer vaccines, tumor cell vaccines (autologous or allogeneic), dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, DNA vaccines, viral vaccines, or Tumor-Infiltrating Lymphocyte (TIL) Vaccine with Interleukin-2 (IL-2) or Lymphokine-Activated Killer (LAK) Cell Therapy.

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[00435] Examples of passive immunothérapies include but are not limited to monoclonal antibodies and targeted thérapies containing toxins. Monoclonal antibodies include naked antibodies and conjugated monoclonal antibodies (also called tagged, labeled, or loaded antibodies). Naked monoclonal antibodies do not hâve a drug or radioactive material attached whereas conjugated monoclonal antibodies are joined to, for example, a chemotherapy drug (chemolabeled), a radioactive particle (radiolabeled), or atoxin (immunotoxin). Examples of these naked monoclonal antibody drugs include, but are not limited to Rituximab (Rituxan), an antibody against the CD20 antigen used to treat, for example, B cell non-Hodgkin lymphoma; Trastuzumab (Herceptin), an antibody against the HER2 protein used to treat, for example, advanced breast cancer; Alemtuzumab (Campath), an antibody against the CD52 antigen used to treat, for example, B cell chronic lymphocytic leukemia (B-CLL); Cetuximab (Erbitux), an antibody against the EGFR protein used, for example, in combination with irinotecan to treat, for example, advanced colorectal cancer and head and neck cancers; and Bevacizumab (Avastin) which is an antiangiogenesis therapy that works against the VEGF protein and is used, for example, in combination with chemotherapy to treat, for example, metastatic colorectal cancer. Examples of the conjugated monoclonal antibodies include, but are not limited to Radiolabeled antibody Ibritumomab tiuxetan (Zevalin) which delivers radioactivity directly to cancerous B lymphocytes and is used to treat, for example, B cell nonHodgkin lymphoma; radiolabeled antibody Tositumomab (Bexxar) which is used to treat, for example, certain types of non-Hodgkin lymphoma; and immunotoxin Gemtuzumab ozogamicin (Mylotarg) which contains calicheamicin and is used to treat, for example, acute myelogenous leukemia (AML). BL22 is a conjugated monoclonal antibody for treating, for example, hairy cell leukemia, immunotoxins for treating, for example, leukemias, lymphomas, and brain tumors, and radiolabeled antibodies such as OncoScînt for example, for colorectal and ovarian cancers and ProstaScint for example, for prostate cancers.

[00436] Further examples of therapeutic antibodies that can be used include, but are not limited to, HERCEPTIN™ (Trastuzumab) (Genentech, Calif.) which is a humanized anti-HER2 monoclonal antibody for the treatment of patients with metastatic breast cancer; REOPRO.RTM. (abciximab) (Centocor) which is an anti-glycoprotein Hb/IIIa receptor on the platelets for the prévention of clôt formation; ZENAPAX™ (daclizumab) (Roche Pharmaceuticals, Switzerland) which is an immunosuppressive, humanized anti-CD25 monoclonal antibody for the prévention of acute rénal allograft rejection; PANOREX™ which is a murine anti-17-IA cell surface antigen IgG2a antibody (Glaxo Welicome/Centocor); BEC2 which is a murine anti-idiotype (GD3epitope) IgG antibody (ImClone System); IMC-C225 which is a chimeric anti-EGFR IgG antibody (ImClone System); VITAXIN™ which is a humanized anti-alpha V beta 3 integrin antibody (Applied Molecular Evolution/Medlmmune); Campath 1H/LDP-03 which is a humanized anti CD52 IgGl antibody (Leukosite); Smart M195 which is a humanized anti-CD33 IgG antibody (Protein Design Lab/Kanebo); RITUXAN™ which is a chimeric anti-CD20 IgGl antibody (IDEC Pharm/Genentech, Roche/Zettyaku); LYMPHOC1DE™ which is a humanized anti-CD22 IgG antibody (Immunomedics); LYMPHOCIDE™ Y-90 (Immunomedics); Lymphoscan (Tc-99mlabeled; radioimaging; Immunomedics); Nuvion (against CD3; Protein Design Labs); CM3 is a humanized anti-ICAM3 antibody (ICOS Pharm); IDEC-114 is a primatized anti-CD80 antibody (IDEC Pharm/Mitsubishi); ZEVALIN™ is a radiolabelled murine anti-CD20 antibody (IDEC/Schering AG); 1DEC-131 is a humanized anti-CD40L antibody (IDEC/Eisai); IDEC-151 is a primatized anti-CD4 antibody (IDEC); IDEC-152 is a primatized anti-CD23 antibody (IDEC/Seikagaku); SMART anti-CD3 is a humanized anti-CD3 IgG (Protein Design Lab); 5G1.1 is a humanized anti-complement factor 5 (C5) antibody (Alexion Pharm); D2E7 is a humanized antiTNF-alpha antibody (CAT/BASF); CDP870 is a humanized anti-TNF-alpha. Fab fragment (Celltech); IDEC-151 is a primatized anti-CD4 IgGl antibody (IDEC Pharm/SmithKline Beecham); MDX-CD4 is a human anti-CD4 IgG antibody (Medarex/Eisai/Genmab); CD20-sreptdavidin (+biotin-yttrium 90; NeoRx); CDP571 is a humanized anti-TNF-alpha. IgG4 antibody (Celltech); LDP-02 is a humanized anti-alpha4 beta7 antibody (LeukoSîte/Genentech); OrthoClone OKT4A is a humanized anti-CD4 IgG antibody (Ortho Biotech); ANTOVA™ is a humanized anti-CD40L IgG antibody (Biogen); ANTEGREN™ is a humanized anti-VLA-4 IgG antibody (Elan); and CAT-152 is a human anti-TGF-beta₂ antibody (Cambridge Ab Tech). Others are provided in later paragraphs. [00437] Immunothérapies that can be used in combination with a crystalline sait form of Compound 1 as disclosed herein include adjuvant immunothérapies. Examples include cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-l-alpha, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factors (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); Bacille Calmette-Guerin (BCG); Keyhole limpet hemocyanin (KLH); Incomplète Freund's adjuvant (IFA); QS-21; DETOX; Levamisole; and Dînitrophenyl (DNP), and combinations thereof, such as combinations of interleukins, for example IL-2 with other cytokines, such as IFN-alpha.

(00438] In various embodiments, a crystalline sait form of Compound 1 can be combined with an immunological therapy and/or an immunological therapeutic agent. In various embodiments, an immunological therapy and/or an immunological therapeutic agent can include, one or more of the following: an adoptive cell transfer, an angiogenesis inhibitor, Bacillus Cahnette-Guerin therapy, biochemotherapy, a cancer vaccine, a chimeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, an immunoconjugate, a radioconjugate, an oncolytic virus therapy, or a targeted drug therapy. The immunological therapy or immunological therapeutic agent, is collectively referred to herein as an “immunotherapeutic agent”.

[00439] The présent disclosure provides a method for preventing, treating, reducing, inhibiting or controlling a neoplasia, a tumor or a cancer in a subject in need thereof, involving administering a therapeutically effective amount of a crystalline sait form of Compound 1 in combination with an immunotherapeutic agent. In one non-limiting embodiment, the method comprises administering a therapeutically effective amount of a combination comprising a crystalline sait form of Compound 1 in combination with an immunotherapeutic agent. In various embodiments, the combination provides a cooperative effect, an additive effect, or a synergistic effect in reducing the number of cancer cells when treated with the combination as compared to each treatment alone. In some embodiments, administration of a therapeutically effective amount of a combination comprising a crystalline sait form of Compound 1 and an immunotherapeutic agent, results in synergistic antitumor activity and/or antitumor activity that is more potent than the additive effect of administration of a crystalline sait form of Compound 1 or immunotherapeutic agent alone.

[00440] Human cancers harbor numerous genetîc and epigenetic alterations, generating neoantigens potentially recognizable by the immune System (Sjoblom et al. (2006) Science 314:268-74). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens. Further, the immune system demonstrates considérable plasticity and a memory component. The successful hamessing of ail these attributes of the adaptive immune system would make immunotherapy unique among ail cancer treatment modalities.

[00441] The présent disclosure provides a combination of a crystalline sait form of Compound 1 and an immunotherapeutic agent. These exemplified combinations can be used to treat a subject with a cancer. In various embodiments, immunotherapeutic agents that fmd utility in the présent compositions, formulations, and methods can include one or more agents or thérapies, including: an adoptive cell transfer, an angiogenesis inhibitor, Bacillus Calmette-Guerin therapy, bîochemotherapy, a cancer vaccine, a chîmeric antigen receptor (CAR) T-cell therapy, a cytokine therapy, gene therapy, an immune checkpoint modulator, for example an immune checkpoint inhibitor, an immunoconjugate, a radioconjugate, an oncolytic virus therapy, or a targeted drug therapy.

[00442] In certain embodiments of the présent dîsclosure, a therapeutically effective combination comprises a crystalline sait form of Compound 1 and an immunotherapeutic agent. In various related embodiments, the crystalline sait form of Compound 1 enhances the activity of the immunotherapeutic agent.

[00443] In certain embodiments of each of the aforementioned aspects, as well as other aspects and embodiments described elsewhere herein, the immunotherapeutic agent enhances the activity of the crystalline sait form of Compound 1 of the présent invention.

[00444] In certain embodiments of each of the aforementioned aspects, as well as other aspects and embodiments described elsewhere herein, the crystalline sait form of Compound 1 and the immunotherapeutic agent act synergistically. In various embodiments described herein, an exemplary immunotherapeutic agent is an immune cell (e.g. T-cell, dendritic cell, a natural killer cell and the like) modulator chosen from an agonist or an activator of a costimulatory molécule, wherein the modulator is a monoclonal antîbody, a bîspecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody/fusion protein/construct known in the art. In some embodiments, the immunotherapeutic agent can be an antibody that modulâtes a costimulatory molécule, bind to an antigen on the surface of an immune cell, or a cancer cell. In each of these different embodiments, the antibody modulator can be a monoclonal antibody, a polyclonal antibody, a bîspecific antibody, a trispecific or multîspecific format antibody, a fusion protein, or a fragment thereof, for example, a Diabody, a Single-chain (sc)-diabody (scFv)2, a Miniantibody, a Minibody, a Bamase-barstar, a scFv-Fc, a sc(Fab)2, a Trimeric antibody construct, a Triabody antibody construct, a Trimerbody antibody construct, a Tribody antibody construct, a Collabody antibody construct, a (scFv-TNFa)3, or a F(ab)3/DNL antibody construct.

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[00445] In certain embodiments of each of the aforementioned aspects, as well as other aspects and embodiments described elsewhere herein, the immunotherapeutic agent is an agent that modulâtes immune responses, for example, a checkpoint inhibitor or a checkpoint agonist. In some embodiments, the immunotherapeutic agent is an agent that enhances anti-tumor immune responses. In some embodiments, the immunotherapeutic agent is an agent that increases cell-mediated immunity. In some embodiments, the immunotherapeutic agent is an agent that increases T-cell activity. In some embodiments, the immunotherapeutic agent is an agent that increases cytolytic Tcell (CTL) activity.

[00446] In some embodiments, the present methods of treatment may include administering a crystalline sait form of Compound 1 together in combination with a molécule, for example, a binding agent, for example, an antibody or functional fragment thereof that modulâtes (activâtes or inhibits) a checkpoint protein. A checkpoint inhibitor can be any molécule, agent, treatment and/or method of inhibiting an immune checkpoint, and/or promoting an inhibitor of an immune checkpoint, e.g., by promoting an intrinsic immune checkpoint inhibitor; inhibiting a transcription factor involved in the expression of an immune checkpoint; and/or by acting in concert with some additional extrinsic factor. For example, a checkpoint inhibitor could include a treatment that inhibits transcription factors involved in the expression of immune checkpoint genes, or promotes the expression of transcription factors for tumor-suppressor genes, e.g., BACH2 (Luan et al., (2016). Transcription Factors and Checkpoint Inhibitor Expression with Age: Markers of Immunosenescence. Blood, 128(22), 5983). Moreover, a checkpoint inhibitor can inhibit the transcription of immune checkpoint genes; the modification and/or processing of immune checkpoint mRNA; the translation of immune checkpoint proteins; and/or molécules involved in immunity or the immune checkpoint pathway, e.g., PD-1 transcription factors such as HIF-1, STAT3, NF-κΒ, and AP-1, or the activation of common oncogenic pathways such as JAK/STAT, RASÆRK, or PI3K/AKT/mTOR (Zerdes et al., Genetic, transcriptional and post-transiational régulation of the programmed death protein ligand 1 in cancer: biology and clinical corrélations, Oncogene volume 37, pages 4639^-661 (2018), the dîsclosure of which is incorporated herein by référencé in its entirety).

[00447] Checkpoint inhibitors can include treatments, molécules, agents, and/or methods that regulate immune checkpoints at the transcriptional level, e.g., using the RNA-interference pathway co-suppression, and/or post-transcriptional gene silencing (PTGS) (e.g., microRNAs, miRNA;

silencing-RNA, small-interfering-RNA, or short-interfering-RNA (siRNA). Transcriptional régulation ofcheckpoint molécules has been shown to involve mir-16, which has been shown to target the 3'UTR of the checkpoint mRNAs CDSO, CD274 (PD-L1) and CD4Û (Leibowitz et al., Post-transcriptional régulation of immune checkpoint genes by mir-16 in melanoma, Annals of Oncology (2017) 28; v428-v448). Mir-33a has also been shown to be involved in regulating the expression of PD-1 in cases of lung adenocarcinoma (Boldîni et al.. Rôle of microRNA-33a in regulating the expression of PD-1 in lung adenocarcinoma, Cancer Cell Int. 2017; 17: 105, the disclosure of which is incorporated herein by reference in its entirety).

[00448] T-cell-spécifie aptamer-siRNA chimeras hâve been suggested as a hîghly spécifie method of inhibiting molécules in the immune checkpoint pathway (Hossain et ai., The aptamer-siRNA conjugates: reprogrammîng T cells for cancer therapy, Ther. Deliv. 2015 Jan; 6(1): 1-4, the disclosure of which is incorporated herein by reference in its entirety).

[00449] Altematively, members of the immune checkpoint pathway can be inhibited using treatments that affect associated pathways, e.g., metabolism. For example, oversupplying the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulatory factor 1 (BMP4/p-SMADl/5/IRFl) signaling pathway. Accordingly, implementing treatments that modulate the metabolic pathway can resuit in subséquent modulation of the immunoinhîbitory PD1/PD-L1 checkpoint pathway (Watanabe et al., Pyruvate Controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity, J Clin Invest. 2017 Jun 30; 127(7): 2725-2738).

[00450] Checkpoint immunity can be regulated via oncolytic viruses that selectively replicate within tumor cells and induce acute immune responses in the tumor-micro-environment, i.e., by acting as genetic vectors that cany spécifie agents (e.g., antibodies, miRNA, siRNA, and the like) to cancer cells and effecting their oncolysîs and sécrétion of cytokines and chemokines to synergize with immune checkpoint inhibition (Shi et al., Cancer Immunotherapy: A Focus on the Régulation of Immune Checkpoints, Int J Mol Sci. 2018 May; 19(5): 1389). Currently, there are clinical trials underway that utilize the following viruses as checkpoint inhibitors: poliovirus, measles virus, adenoviruses, poxvirases, herpes simplex virus (HSV), coxsackievi ruses, reovirus, Newcastle disease virus (NDV), T-VEC (a herpes virus encoded with GM-CSF (granulocyte-macrophage colony stimulating factor)), and Fil01 (Shi et al., supra).

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[00451] Checkpoint inhibitors can operate at the translational level of checkpoint immunity. The translation of mRNA into protein represents a key event in the régulation of gene expression, thus inhibition of immune checkpoint translation is a method in which the immune checkpoint pathway can be inhibited.

[00452] Inhibition of the immune checkpoint pathway can occur at any stage of the immune checkpoint translational process. For example, drugs, molécules, agents, treatments, and/or methods can inhibit the initiation process (whereby the 40S ribosomai subunit is recruited to the 5’ end of the mRNA and scans the 5’UTR of the mRNA toward its 3’ end. Inhibition can occur by targeting the anticodon of the initiator methionyl-transfer RNA (tRNA) (Met-tRNAi), its base-pairing with the start codon, or the recruitment of the 60S subunit to begin élongation and sequential addition of amino acids in the translation of immune-checkpoînt-specific genes. Altematively, a checkpoint inhibitor can inhibit checkpoints at the translational level by preventing the formation of the temary complex (TC), i.e., eukaryotic initiation factor (eIF)2 (or one or more of its α, β, and γ subunits); GTP; and Met-tRNAi.

[00453] Checkpoint inhibition can occur via destabilization of eIF2a by precluding its phosphorylation via protein kinase R (PKR), PERK, GCN2, or HRI, or by precluding TCs from associating with the 40S ribosome and/or other initiation factors, thus preventing the preinitiation complex (PIC) from forming; inhibiting the eIF4F complex and/or its cap-binding protein eIF4E, the scaffolding protein eIF4G, or eIF4A helicase. Methods discussing the translational control of cancer are discussed in Truitt et al., New frontiers in translational control of the cancer genome, Nat Rev Cancer. 2016 Apr 26; 16(5): 288-304, the disclosure of which is incorporated herein by reference in its entirety.

[00454] Checkpoint inhibitors can also include treatments, molécules, agents, and/or methods that regulate immune checkpoints at the cellular and/or protein level, e.g., by inhibiting an immune checkpoint receptor. Inhibition of checkpoints can occur via the use of antibodies, antibody fragments, antigen-binding fragments, small-molecules, and/or other drugs, agents, treatments,

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[00455] Immune checkpoints refer to inhibitory pathways in the immune system that are responsible for maintaining self-tolerance and modulating the degree of immune System response to minimize peripheral tissue damage. However, tumor cells can also activate immune system checkpoints to decrease the effectiveness of immune response ('block' the immune response)

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I I I I against tumor tissues. In contrast to the majority of anti-cancer agents, checkpoint inhibitors do not target tumor cells directly, but rather target lymphocyte receptors or their ligands in order to enhance the endogenous antitumor activity of the immune system. (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[00456] In some embodiments, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-IBB activity, an modulator of 0X40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a cytokine, a chemokine, an interferon, an înterleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide. In some embodiments, the immune checkpoint modulator, î.e. is an inhibitor or antagonist, or is an activator or agonist, for example, a CD28 modulator, a 4-1BB modulator, an OX40 modulator, a CD27 modulator, a CD80 modulator, a CD86 modulator, a CD40 modulator, or a GITR modulator, a Lag-3 modulator, a 41BB modulator, a LIGHT modulator, a CD4Û modulator, a GITR modulator, a TGF-beta modulator, a TIM-3 modulator, a SIRP-alpha modulator, a TIGIT modulator, a VSIG8 modulator, a BTLA modulator, a SIGLEC7 modulator, a SIGLEC9 modulator, a ICO S modulator, a B7H3 modulator, a B7H4 modulator, a F AS modulator, and/or a BTNL2 modulator. In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator as described above (e.g., an immune checkpoint modulator antibody, which can be in the form of a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody/fusion protein/construct known in the art).

[00457] In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of PD-1. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of PD-L1 and/or PD-L2. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of CTLA-4. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of CD 80 and/or CD86. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of TIGIT. In some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of KIR, In some embodiments, the immunotherapeutîc agent is an agent that enhances or stimulâtes the activity of activaiing immune checkpoint receptors.

[00458J PD-] (also known as Programmed Death 1, CD279, PDCD1) is a cell surface receptor with a critical rôle in regulating the balance between stîmulatory and inhibitory signais in the immune System and maintaining peripheral tolérance (Ishida, Y et al. 1992 EMBO J. 11 3887; Kier, Mary E et al. 2008 Annu Rev Immunol 26 677-704; Okazaki, Taku et al. 2007 International Immunology 19 813-824). PD-1 is an inhibitory member of the immunoglobulin super-family with homology to CD28. The structure of PD-1 is a monomeric type l transmembrane protein, consîsting of one immunoglobulin variable-like extracellular domain and a cytoplasmic domain containing an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Expression of PD-1 is inducible on T cells, B cells, natural killer (NK) cells and monocytes, for example upon lymphocyte activation via T cell receptor (TCR) or B cell receptor (BCR) signalling (Kier, Mary E et al. 2008 Annu Rev Immunol 26 677-704; Agata, Y et al 1996 Int Immunol 8 765-72). PD-1 is a receptor for the ligands CD80, CD86, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), which are cell surface expressed members of the B7 family (Freeman, Gordon et al. 2000 J Exp Med 192 1027; Latchman, Y et al. 2001 Nat Immunol 2: 261). Upon ligand engagement, PD-1 recruits phosphatases such as SHP-1 and SHP-2 to its intracellular tyrosine motifs which subsequently dephosphorylate effector molécules activated by TCR or BCR signalling (Chemnitz, J et al. 2004 J Immunol 173: 945-954; Riley, James L 2009 Immunological Reviews 229: 114-125) In this way, PD-1 transduces inhibitory signais into T and B cells only when it is engaged simultaneously with the TCR or BCR.

[00459] PD-1 has been demonstrated to down-regulate effector T cell responses via both cellintrinsîc and cell-extrinsic fiinctional mechanisms. Inhibitory signaling through PD-1 induces a State of unresponsiveness in T cells, resulting in the cells being unable to clonally expand or produce optimal levels of effector cytokines. PD-1 may also induce apoptosis in T cells via its abîlity to inhibit survival signais from co-stimulation, which leads to reduced expression of key anti-apoptotic molécules such as Bcl-XL (Kier, Mary E et al. 2008 Annu Rev Immunol 26: 677-704). In addition to these direct effects, recent publications hâve împlicated PD-1 as being involved in the suppression of effector cells by promoting the induction and maintenance of regulatory T cells (TREG). For example, PD-L1 expressed on dendritic cells was shown to act in synergy with TGF-β to promote the induction of CD4+ FoxP3+TREG with enhanced suppressor function (Francisco, Loise M et al. 2009 J Exp Med 206: 3015-3029).

[00460] TIM-3 (also known as T-ceil immunoglobulin and mucin-domain containing-3, TIM-3, Hepatitis A virus cellular receptor 2, HAVCR2, HAVcr-2, KIM-3, TIMD-3, TIMD3, Tim-3, and CD366) is a ~33.4-kDa single-pass type 1 membrane protein involved in immune responses (Sanchez-Fueyo et al., Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promûtes immunological tolérance, Nat. Immunol. 4: 1093-1101(2003)).

[00461] TIM-3 is selectively expressed on Th 1-cells, and phagocytic cells (e.g., macrophages and dendritic cells). The use of siRNA or a blocking antibody to reduce the expression of human TIM-3 resulted in increased sécrétion of interferon γ (IFN-γ) from CD4 positive T-cells, implicating the inhibitory rôle of TIM-3 in human T cells. Analysis of clinical samples from autoimmune disease patients showed no expression of TIM-3 in CD4 positive cells. In particular, expression Ievel of TIM-3 is lower and sécrétion of IFN-γ is higher in T cell clones derived from the cerebrospinal fluid of patients with multiple scierosis than those in clones derived from normal healthy persons (Koguchi K et al., J Exp Med. 203: 1413-8. (2006)).

[00462] TIM-3 is the receptor for the ligand Galectin-9, which is a member of galectin family, molécules ubiquitously expressed on a variety of cell types and which binds β-galactoside;

Phospatidyl serine (PtdSer) (DeKryff et al., T cell/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and médiate phagocytosis of apoptotic cells, J Immunol. 2010 Feb 15; 184(4): 1918-30); High Mobility Group Protein 1 (also known as HMGB1, HMG1, HMG3, SBP-1, HMG-1, and high mobility group box 1) Chiba et al., Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1, Nat Immunol. 2012 Sep; 13(9); 832-42); and Carcinoembryonic Antigen Related Cell Adhesion Molécule 1 (also known as CEACAM1, BGP, BGP1, BGPI, carcinoembryonic antigen related cell adhesion molécule 1) (Huang et al., CEACAM1 régulâtes TIM-3-mediated tolérance and exhaustion, Nature. 2015 Jan 15; 517(7534): 386-90).

[00463] BTLA (also known as B- and T-lymphocyte attenuator, BTLA1, CD272, and B and T lymphocyte associated) is a ~27.3-kDa single-pass type I membrane protein involved in lymphocyte inhibition during immune response. BTLA is constitutively expressed in both B and T cells. BTLA interacts with HVEM (herpes virus-entry mediator), a member of the tumor-necrosis factor receptor (TNFR) family (Gonzalez et al., Proc. Natl. Acad. Sci. USA, 2005, 102: 1116-21). The interaction

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I I I of BTLA, which belongs to the CD28 family of the immunoglobulin superfamily, and HVEM, a costimulatory tumor-necrosis factor (TNF) receptor (TNFR), is unique in that it defmes a cross talk between these two families of receptors. BTLA contains a membrane proximal immunoreceptor tyrosine-based inhibitory motif (ITIM) and membrane distal immunoreceptor tyrosine-based switch motif (ITSM). Disruption of either the ITIM or 1TSM abrogated the ability of BTLA to recruit either SHP1 or SHP2, suggesting that BTLA recruits SHP1 and SHP2 in amanner distinct from PD-1 and both tyrosine motifs are required to block T cell activation. The BTLA cytoplasmic tail also contains a thîrd conserved tyrosine-containing motif within the cytoplasmic domain, similar in sequence to a Grb-2 recruitment site (YXN). Also, a phosphorylated peptide containing this BTLA N-terminal tyrosine motif can interact with GRB2 and the p85 subunit of PI3K in vitro, although the functional effects of this interaction remain unexplored in vivo (Gavrieli et al., Bioochem. Biophysi Res Commun, 2003, 312, 1236-43). BTLA is the receptor for the ligands PTPN6/SHP-1; PTPN1I/SHP2; TNFRSF14/HVEM; and B7H4.

[00464] VISTA (also known as V-domain Ig suppressor of T cell activation VSIR, B7-H5, B7H5, GI24, PP2135, SISP1, DDlalpha, VISTA, C10orf54, chromosome 10 open reading frame 54, PD1H, and V-set immunoregulatory receptor) is a ~33.9-kDa single-pass type I membrane protein involved in T-cell inhibitory response, embryonic stem cells différentiation via BMP4 signaling inhibition, and MMPI4-mediated MMP2 activation (Yoon et al., Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53, Science. 2015 Jul 31; 349(6247): 1261669). VISTA interacts with the ligand VSIG-3 (Wang et al., VSIG-3 as a ligand of VISTA inhibits human T-cell fonction, Immunology. 2019 J an; 156(1): 74-85)

[00465] LAG-3 (also known as Lymphocyte-activation gene 3, LAG3, CD223, and lymphocyte activating 3) is a -57.4-kDa single-pass type I membrane protein involved in lymphocyte activation that also binds to HLA class-II antigens. LAG-3 is a member of the immunoglobulin supergene family, and is expressed on activated T cells (Huard et al., 1994, Immunogenetics 39: 213), NK cells (Triebel et al., 1990, J. Exp. Med. 171: 1393-1405), regulatory T cells (Huang et al., 2004, Immunity 21: 503-513; Camisaschi et al., 2010, J Immunol. 184: 6545-6551; Gaglianî et al., 2013, Nat Med 19: 739-746), and plasmacytoid dendritic cells (DCs) (Workman et al., 2009, J Immunol 182: 1885-1891). LAG-3 is a membrane protein encoded by a gene located on chromosome 12, and is structurally and genetically related to CD4. Similar to CD4, LAG-3 can interact with MHC class Il molécules on the cell surface (Baixeras et al., 1992, J. Exp. Med. 176: 327-337; Huard et al.,

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1996, Eur. J. Immunol. 26: 1180-1186). It has been suggested that the direct binding of LAG-3 to MHC class II plays a rôle in down-regulating antigen-dependent stimulation of CD4+ T lymphocytes (Huard et al., 1994, Eur. J. Immunol. 24: 3216-3221) and LAG-3 blockade has also been shown to reinvigorate CD8+ lymphocytes in both tumor or self-antigen (Gross et al., 2007, J Clin Invest. 117: 3383-3392) and viral models (Blackbum et al., 2009, Nat. Immunol. 10: 29-37). Further, the intra-cytoplasmic région of LAG-3 can interact with LAP (LAG-3-associated protein), which is a signal transduction molécule involved in the downregulation of the CD3/TCR activation pathway (louzalen et al., 2001, Eur. J. Immunol. 31: 2885-2891). Moreover, CD4+CD25+ regulatory T cells (Treg) hâve been shown to express LAG-3 upon activation, which contri butes to the suppressor activîty of Treg cells (Huang, C. et al., 2004, Immunity 21: 503-513). LAG-3 can also negatively regulate T cell homeostasis by Treg cells in both T cell-dependent and independent mechanîsms (Workman, C. J. and Vignali, D. A., 2005, J. Immunol. 174: 688-695).

[00466] LAG-3 has been shown to interact with MHC class II molécules (Huard et al., CD4/major histocompatibility complex class II interaction analyzed with CD4- and lymphocyte activation gene3 (LAG-3)-Ig fusion proteins, Eur J Immunol. 1995 Sep; 25(9): 2718-21).

[00467] Additionally, several kinases are known to be checkpoint inhîbitors. For example, CHEKl,CHEK-2, and A2aR.

[00468] CHEK-1 (also known as CHK l kinase, CHK1, and checkpoint kinase i) is a -54.4-kDa serine/threonine-proteîn kinase that is involved with checkpoint-mediated cell cycle arrest, and the activation of DNA repair in response to the DNA damage and/or unreplîcated DNA.

[00469] CHEK-2 (also known as CHK2 kinase, CDS1, CHK2, HuCdsl, LFS2, PP 1425, RAD53, hCdsl, and checkpoint kinase 2) is a ~60.9-kDa. serine/threonine-protein kinase involved in checkpoint-mediated cell cycle airest, DNA-repair activation, and double-strand break-mediated apoptosis.

[00470] A2aR (also known as adenosine A2A receptor, ADORA2A, adenosine A2a receptor, A2aR, ADORA2, and RDC8) îs a ~44.7-kDa multi-pass membrane receptor for adenosine and other ligands.

[00471] In some embodiments, illustrative immunotherapeutic agents can include one or more antibody modulators that target PD-1, PD-L1, PD-L2, CEACAM (e.g., CEACAM-1, -3 and/or -5), CTLA-4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, TGF beta, OX40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS,

B7H3, B7H4, FAS, and/or BTNL2 among others known in the art,. In some embodiments, the immunotherapeutic agent is an agent that increases natural killer (NK) cell activity. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppression of an immune response. In some embodiments, the immunotherapeutic agent is an agent that inhibits suppressor cells or suppressor cell activity. In some embodiments, the immunotherapeutic agent is an agent or therapy that inhibits Treg activity. in some embodiments, the immunotherapeutic agent is an agent that inhibits the activity of inhibitory immune checkpoint receptors.

[00472] In some embodiments, the combination of the présent disclosure comprises a crystalline sait form of Compound 1 and an immunotherapeutic agent, wherein the immunotherapeutic agent includes a T cell modulator chosen from an agonist or an activator of a costimulatory molécule. In one embodiment, the agonist of the costimulatory molécule is chosen from an agonist (e.g., an agonistîc antibody or antigen-binding fragment thereof, or a soluble fusion) of GITR, 0X40, SLAM (e.g., SLAMF7), HVEM, LIGHT, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CD1 la/CDl 8), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, CD7, NKG2C, NKpSO, CD160, B7-H3, or CD83 ligand. In other embodiments, the effector cell combination includes a bispecific T cell engager (e.g., a bispecific antibody molécule that binds to CD3 and a tumor antîgen (e.g., EGFR, P SCA, PSMA, EpCAM, HER2 among others).

[00473] In some embodiments, the immunotherapeutic agent is a modulator of PD-1 activity, a modulator ofPD-Ll activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD 86 activity, a modulator of 4-IBB activity, an modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a modulator of SIRP-alpha activity, a modulator of TIGIT activity, a modulator of VSIG8 activity, a modulator of BTLA activity, a modulator of SIGLEC7 activity, a modulator of SIGLEC9 activity, a modulator of ICOS activity, a modulator of B7H3 activity, a modulator of B7H4 activity, a modulator of FAS activity, a modulator of BTNL2 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (TNF) family, or an immunostimulatory oligonucleotide.

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[00474] In some embodiments, the immunotherapeutic agent is an immune checkpoint modulator (e.g., an immune checkpoint inhibitor e.g. an inhibitor of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4, or a CD40 agonist (e.g., an antiCD40 antîbody molécule), (xi) an 0X40 agonist (e.g., an anti-OX40 antibody molécule), or (xîî) a CD27 agonist (e.g., an anti-CD27 antibody molécule). In one embodiment, the immunotherapeutic agent is an inhibitor of: PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or -5), VISTA, BTLA, TIGIT, LAIRI, CD 160, 2B4 and/or TGF beta, Galectin 9, CD69, Galectin-1, CD113, GPR56, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4. In one embodiment, the inhibitor of an immune checkpoint molécule inhibits PD-1, PD-L1, LAG-3, TIM3, CEACAM (e.g., CEACAM-1, -3 and/or -5), CTLA-4, or any combination thereof.

[00475] In one embodiment, the immunotherapeutic agent is an agonist of a protein that stimulâtes T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, G1TR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[00476] In some embodiments, the immunotherapeutic agent used in the combinations disclosed herein (e.g., in combination with a crystalline sait form of Compound 1 of the présent invention) is an actîvator or agonist of a costimulatory moiecule. In one embodiment, the agonist of the costimulatory moiecule is chosen from an agonist (e.g., an agonistic antibody or antigen-binding fragment thereof, or a soluble fusion) of CD2, CD28, CDS, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), 4-IBB (CD 137), GITR, CD30, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD 160, B7-H3, or CD83 ligand.

[00477] Inhibition of an inhibitory moiecule can be performed at the DNA, RNA or protein level. In embodiments, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA), can be used to inhibit expression of an inhibitory moiecule. In other embodiments, the inhibitor of an inhibitory signal is, a polypeptide e.g., a soluble ligand (e.g., PD-1-Ig or CTLA-4 Ig), or an antibody or antigen-binding fragment thereof, for example, a monoclonal antibody, a bispecific antibody comprising one or more immune checkpoint antigen binding moieties, a trispecific antibody, or an immune cell-engaging multivalent antibody/fusion protein/construct known in the art that bînds to the inhibitory moiecule; e.g., an antibody or fragment thereof (also referred to herein as an antibody moiecule) thatbinds to PD-1, PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, -3 and/or -5), VISTA, BTLA, TIGIT, LAIR1, CD 160, 2B4 and/or TGF beta, Galectin

9, CD69, Galectin-1, CD113, GPR56, CD48, GARP, PD1H, LAIR1, TIM-1, ΤΊΜ-4, or a

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[00478] In some embodiments, where the combination comprises a crystalline sait form of Compound 1 and an immunotherapeutic agent, wherein the immunotherapeutic agent is a monoclonal antibody or a bispecifîc antibody. For example, the monoclonal or bispecific antibody may specifically bind a member of the c-Met pathway and/or an immune checkpoint modulator (e.g., the bispecific antibody binds to both a hépatocyte growth factor receptor (HGFR) and an immune checkpoint modulator described herein, such as an antibody that binds PD-1, PD-L1, PDL2, or CTLA-4, LAG-3, 0X40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2 or CD27). In partîcular embodiments, the bispecific antibody specifically binds a human HGFR proteîn and one of PD-1, PD-L 1, and CTLA-4.

[00479] In some of the embodiments of the methods described herein, the immunotherapeutic agent is a PD-1 antagonist, a PD-L1 antagonist, a PD-L2 antagonist, a CTLA-4 antagonist, a CD80 antagonist, a CD86 antagonist, a KIR antagonist, a Tim-3 antagonist, a LAG3 antagonist, a TIGIT antagonist, a CD20 antagonist, a CD96 antagonist, or an IDO1 antagonist.

[00480] lu some embodiments, the PD-1 antagonist is an antibody that specifically binds PD-1. In some embodiments, the antibody that binds PD-1 is pembrolizumab (KEYTRUDA®, MK-3475; Merck), pidilizumab (CT-011; Curetech Ltd.), nivolumab (OPDIVO®, BMS-936558, MDX-1106; Bristol Myer Squibb), MEDI0680 (AMP-514; AstraZenenca/Medïmmune), REGN2810 (Regeneron Pharmaceuticals), BGB-A317 (BeiGene Ltd.), PDR-001 (Novartis), or STI-A1110 (Sorrento Therapeutics). In some embodiments, the antibody that binds PD-1 is described in PCT Publication WO 2014/179664, for example, an antibody identified as APE2058, APE 1922, ΑΡΕΙ923, APE 1924, APE 1950, or APE 1963 (Anaptysbio), or an antibody containing the CDR régions of any of these antibodîes. In other embodiments, the PD-1 antagonist is a fusion proteîn that includes the extracellular domain of PD-L1 or PD-L2, for example, AMP-224 (AstraZeneca/Medlmmune). In other embodiments, the PD-1 antagonist is a peptide inhibitor, for example, AUNP-12 (Aurigene). [00481] In some embodiments, the PD-L1 antagonist is an antibody that specifically binds PD-L1. In some embodiments, the antibody that binds PD-L1 is atezolizumab (RG7446, MPDL3280A; Genentech), MEDI4736 (AstraZeneca/Medlmmune), BMS-936559 (MDX-1105; Bristol Myers Squibb), avelumab (MSB0010718C; Merck KGaA), KDO33 (Kadmon), the antibody portion of

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KD033, or STI-A1014 (Sorrento Therapeutics). In some embodiments, the antibody that binds PDL1 is described in PCT Publication WO 2014/055897, for example, Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, or Ab-55, or an antibody that contains the CDR régions of any of these antibodies, the disclosure of which is incorporated herein by reference in its entirety.

[00482] In some embodiments, the CTLA-4 antagonist is an antibody that specificaliy binds CTLA-4. In some embodiments, the antibody that binds CTLA-4 is ipilimumab (YERVOY®; Bristol Myer Squibb) or tremelimumab (CP-675, 206; Pfizer). In some embodiments, the CTLA-4 antagonist a CTLA-4 fusion protein or soluble CTLA-4 receptor, for example, KARR-102 (Kahr Medical Ltd.).

[00483] In some embodiments, the LAG3 antagonist is an antibody that specifically binds LAG3. In some embodiments, the antibody that binds LAG3 is IMP701 (Prima BîoMed), IMP731 (Prima BioMed/GlaxoSmithKline), BMS-986016 (Bristol Myer Squibb), LAG525 (Novartis), and GSK2831781 (GlaxoSmithKline). In some embodiments, the LAG3 antagonist includes a soluble LAG3 receptor, for example, IMP321 (Prima BioMed).

[00484] In some embodiments, the KIR antagonist is an antibody that specifically binds KIR. In some embodiments, the antibody that binds KIR is lirilumab (Bristol Myer Squibb/Innate Pharma). [00485] In some embodiments, the immunotherapeutic agent is a cytokine, for example, a chemokine, an interferon, an interleukin, lymphokine, or a member of the tumor necrosis factor family. In some embodiments, the cytokine is IL-2, IL15, or interferon-gamma.

[00486] In some embodiments of any of the above aspects or those described elsewhere herein, the cancer is selected from the group consisting of lung cancer (e.g., a non-small cell lung cancer (NSCLC)), a kidney cancer (e.g., a kidney urothélial carcinoma), a bladder cancer (e.g., a bladder urothélial (transitional cell) carcinoma), a breast cancer, a colorectal cancer (e.g., a colon adenocarcinoma), an ovarian cancer, a pancreatic cancer, a gastric carcinoma, an esophageal cancer, a mesothelioma, a melanoma (e.g., a skin melanoma), a head and neck cancer (e.g., a head and neck squamous cell carcinoma (HNSCC)), a thyroîd cancer, a sarcoma (e.g., a soft-tissue sarcoma, a fïbrosarcoma, a myxosarcoma, a liposarcoma, an ostéogénie sarcoma, an osteosarcoma, a chondrosarcoma, an angîosarcoma, an endotheiiosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a leiomyosarcoma, or a rhabdomyosarcoma), a prostate cancer, a glioblastoma, a cervical cancer, a thymie carcinoma, a leukemia (e.g., an acute lymphocytic leukemia (ALL), an acute myelocytic leukemia (AML), a chronic myelocytic leukemia (CML), a

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I I I I I I chronic éosinophilie leukemia, or a chronic lymphocytic leukemia (CLL)), a lymphoma (e.g., a Hodgkin lymphoma or a non-Hodgkin lymphoma (NHL)), a myeloma (e.g., a multiple myeloma (MM)), a mycoses fungoides, a merkel cell cancer, a hématologie malignancy, a cancer of hematological tîssues, a B cell cancer, a bronchus cancer, a stomach cancer, a brain or central nervous system cancer, a peripheral nervous System cancer, a uterine or endométrial cancer, a cancer of the oral cavity or pharynx, a liver cancer, a testicular cancer, a biliary tract cancer, a small bowel or appendix cancer, a salivary gland cancer, an adrenal gland cancer, adrenal cortex carcinoma, an adenocarcinoma, an inflammatory myofibroblastic tumor, a gastrointestinal stromal tumor (GIST), a colon cancer, a myelodysplastic syndrome (MDS), a myeloproliferative disorder (MPD), a polycythemia Vera, a chordoma, a synovioma, an Ewîng's tumor, a squamous cell carcinoma, a basal cell carcinoma, an adenocarcinoma, a sweat gland carcinoma, a sebaceous gland carcinoma, a papillary carcinoma, a papillary adenocarcinoma, a medullary carcinoma, a bronchogenic carcinoma, a rénal cell carcinoma, a hepatoma, a bile duct carcinoma, a choriocarcinoma, a seminoma, an embryonal carcinoma, a Wilms' tumor, a bladder carcinoma, an épithélial carcinoma, a glioma, anaplastic astrocytoma, an astrocytoma, a medulloblastoma, a craniopharyngioma, an ependymoma, a pinealoma, a hemangioblastoma, an acoustic neuroma, an oligodendroglioma, a meningioma, a neuroblastoma, a retinoblastoma, a follicular lymphoma, a diffuse large B-cell lymphoma, a mantle cell lymphoma, a hepatocellular carcinoma, a thyroid cancer, a small cell cancer, an essentiai thrombocythemîa, an agnogenic myeloid metaplasia, a hyperéosinophilie syndrome, a systemic mastocytosis, a familiar hypereosinophilia, a neuroendocrine cancer, or a carcinoid tumor.

[00487] In some embodiments of any of the above aspects or those described elsewhere herein, the subject's cancer or tumor does not respond to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or PD-L1 antagonîst) or the subject's cancer or tumor has progressed following an initial response to immune checkpoint inhibition (e.g., to any immune checkpoint inhibitor described herein, such as a PD-1 antagonist or PD-LI antagonist).

[00488] In various embodiments, the immunotherapeutic agent can comprise an antibody or an antigen binding fragment thereof. Within this définition, immune checkpoint inhibitors include bîspecific antibodies and immune cell-engaging multivalent antibody/fusion protein/constructs known in the art. In some embodiments, immunotherapeutic agents which comprise bîspecific

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I I I I antibodies may include bispecific antibodies that are bivalent and bind either the same epitope of the immune checkpoint molécule, two different epitopes of the same immune checkpoint molécule or different epitopes of two different immune checkpoints.

[00489] Persons of ordinary ski 11 in the art can implement several bispecific antibody formats known in the field to target one or more of CTLA4, PDI, PD-L1 TTM-3, LAG-3, various B-7 ligands, B7H3, B7H4, CHK 1 and CHK2 kinases, BTLA, A2aR, 0X40, 41BB, LIGHT, CD40, GITR, TGF-beta, SIRP-alpha, TIGIT, VSIG8, SIGLEC7, SIGLEC9, ICOS, FAS, BTNL2 and other for use in the combination described herein.

[00490] In various embodiments, the immunotherapeutic agent can include am immune cellengaging multivalent antibody/fusion protein/construct.

[00491] In an embodiment of the disclosure, the checkpoint inhibitor, in combination with a crystalline sait form of Compound 1, is used to reduce or inhibit metastasis of a prîmary tumor or cancer to other sites, or the formation or establishment of metastatic tumors or cancers at other sites distal from the prîmary tumor or cancer thereby inhibiting or reducing tumor or cancer relapse or tumor or cancer progression.

[004921 In a further embodiment of the disclosure, provided herein îs a combination therapy for treating cancer, which comprises a crystalline sait form of Compound 1 and a checkpoint inhibitor with the potential to elicit potent and durable immune responses with enhanced therapeutic benefit and more manageable toxicity.

[00493] In a further embodiment of the disclosure, provided herein îs a combination therapy for treating cancer, which comprises a crystalline sait form of Compound 1 and an immune checkpoint inhibitor. In an embodiment of the disclosure provided herein is a method for treating cancer and/or preventing the establishment of métastasés by employing a crystalline sait form of Compound 1 of the présent invention, which acts synergistically with a checkpoint inhibitor.

[00494] In further embodiments, the disclosure provides methods for one or more of the following: 1) reducing or inhibiting growth, prolifération, mobility or invasiveness of tumor or cancer cells that potentially or do develop métastasés, 2) reducing or inhibiting formation or establishment of métastasés arising from a prîmary tumor or cancer to one or more other sites, locations or régions distinct from the prîmary tumor or cancer; 3) reducing or inhibiting growth or prolifération of a metastasis at one or more other sites, locations or régions distinct from the prîmary tumor or cancer after a metastasis has formed or has been established, 4) reducing or inhibiting formation or establishment of additional metastasis after the metastasis has been formed or established, 5) prolonged overall survival, 6) prolonged progression free suivi val, or 7) disease stabilization. The methods include administering to a subject in need thereof a crystalline sait form of Compound 1 of the présent invention, in combination with a check point inhibitor as described herein.

[00495] In an embodiment of the disclosure, administration of a crystalline sait form of Compound 1 in combination with the immunotherapeutic agent, provides a détectable or measurable improvement in a condition of a given subject, such as alleviating or ameliorating one or more adverse (physical) symptoms or conséquences associated with the presence of a cell proliférative or cellular hyperproliferatîve disorder, neoplasia, tumor or cancer, or metastasis, i.e., a therapeutic benefit or a bénéficiai effect.

[00496] A therapeutic benefit or bénéficiai effect is any objective or subjective, transient, temporary, or long-term improvement in the condition or pathology, or a réduction in onset, severity, duration or frequency of adverse symptom associated with or caused by cell prolifération or a cellular hyperproliferatîve disorder such as a neoplasia, tumor or cancer, or metastasis. It may lead to improved survival. A satisfactory clinical endpoint of a treatment method in accordance with the disclosure is achieved, for example, when there is an incrémental or a partial réduction in severity, duration or frequency of one or more associated pathologies, adverse symptoms or complications, or inhibition or reversai of one or more of the physiological, biochemical or cellular manifestations or characterisiics of cell prolifération or a cellular hyperproliferatîve disorder such as a neoplasia, tumor or cancer, or metastasis. A therapeutic benefit or improvement therefore may be, but is not limited to destruction of target proliferating cells (e.g., neoplasia, tumor or cancer, or metastasis) or ablation of one or more, most or ail pathologies, adverse symptoms or complications associated with or caused by cell prolifération or the cellular hyperproliferatîve disorder such as a neoplasia, tumor or cancer, or metastasis. However, a therapeutic benefit or improvement need not be a cure or complété destruction of ail target proliferating cells (e.g., neoplasia, tumor or cancer, or metastasis) or ablation of ail pathologies, adverse symptoms or complications associated with or caused by cell prolifération or the cellular hyperproliferatîve disorder such as a neoplasia, tumor or cancer, or metastasis. For example, partial destruction of a tumor or cancer cell mass, or a stabilization of the tumor or cancer mass, size or cell numbers by inhibiting progression or worsening of the tumor or cancer, can reduce mortality and prolong lifespan even if only for a few days, weeks or months, even though a portion or the bulk of the tumor or cancer mass, size or cells remain.

[00497] Spécifie non-limiting examples of therapeutic benefit include a réduction in neoplasîa, tumor or cancer, or metastasîs volume (size or cell mass) or numbers of cells; inhibiting or preventing an increase in neoplasia, tumor or cancer volume (e.g., stabilizing); slowing or inhibiting neoplasîa, tumor or cancer progression, worsening or metastasîs; or inhibiting neoplasia, tumor or cancer prolifération, growth or metastasîs.

[00498] In an embodiment of the disclosure, administration of the îmmuno therapeutic agent, in combination therapy with a crystalline sait form of Compound 1, provides a détectable or measurable improvement or overall response according to the îrRC (as derived from time-point response assessments and hased on tumor burden), including one of more of the foilowing: (i) irCR-complete disappearance of ail lésions, whether measurable or not, and no new lésions (confirmation by a repeat, consecutive assessment no less than 4 weeks from the date first documented), (ii) irPR— decrease in tumor burden >50% relative to baseline (confirmed by a consecutive assessment at least 4 weeks after first documentation).

[00499] Optionally, any method described herein may not take effect immediately. For example, treatment may be followed by an increase in the neoplasia, tumor or cancer cell numbers or mass, but over time eventual stabilization or réduction in tumor cell mass, size or numbers of cells in a given subject may subsequently occur.

[00500] Additional adverse symptoms and complications associated with neoplasia, tumor, cancer and metastasîs that can be inhibited, reduced, decreased, delayed or prevented include, for example, nausea, lack of appetite, lethargy, pain and discomfort. Thus, a partial or complété decrease or réduction in the severity, duration or frequency of adverse symptom or complication associated with or caused by a cellular hyperproliferative disorder, an improvement in the subject’s quality of life and/or well-being, such as increased energy, appetite, psychologîcal well-being, are ail particular non-limiting examples of therapeutic benefit.

[00501] A therapeutic benefit or improvement therefore can also include a subjective improvement in the quality of life of a treated subject. In an additional embodiment, a method prolongs or extends lifespan (survivai) of the subject. In a further embodiment, a method improves the quality of life of the subject.

[00502] In one embodiment, administration of the immunotherapeutic agent, in combination therapy with a crystalline sait form of Compound 1, results in a clinically relevant improvement in one or more markers of disease status and progression selected from one or more of the following: (i) overall survival, (ii) progression-free survival, (iii) overall response rate, (iv) réduction in metastatic disease, (v) circulating levels of tumor antigens such as carbohydrate antigen 19.9 (CA 19.9) and carcinembryonic antigen (CEA) or others dependîng on tumor, (vii) nutritional status (weight, appetite, sérum albumin), (viii) pain control or analgésie use, and (ix) CRP/albumin ratio. [00503] Treatment with a crystalline sait form of Compound 1 in combination with an immunotherapeutic agent gives rise to more complex immunity including not only the development of innate immunity and type-1 immunity, but also immunoregulation which more efficiently restores appropriate immune functions.

[00504] In various exemplary methods, a checkpoint inhibitor antibody (monoclonal or polyclonal, bispecific, trispecifîc, or an immune cell-engaging multivalent antibody/fusion protein/construct) directed to a checkpoint molécule of interest (e.g., PD4) may be sequenced and the polynucleotide sequence may then be cloned into a vector for expression or propagation. The sequence encoding the antibody or antigen-binding fragment thereof of interest may be maintained in vector in a host cell and the host cell can then be expanded and frozen for future use. Production of recombinant monoclonal antibodies in cell culture can be carried out through cloning of antibody genes from B cells by means known in the art. See, e.g. Tiller et al., 2008, J. Immunol. Methods 329: 112; U.S. Pat. No. 7,314,622.

[00505] Pharmaceutical compositions containing a crystalline sait form of Compound 1 according to the présent disclosure will comprise an effective amount of a crystalline sait form of Compound 1, an immunotherapeutic agent, and/or both, typically dispersed in a pharmaceutically acceptable excipient. The phrases pharmaceutically or pharmacologically acceptable refers to molecular entities and compositions that do not produce adverse, allergie or other untoward reaction when administered to animal, such as, for example, a human, as appropriate. The préparation of an pharmaceutical composition that contains a crystalline sait form of Compound 1 will be known to those of skill in the art in light of the présent disclosure, as exemplified by Remington’s Pharmaceutical Sciences, 21^st Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006). Moreover, for animal (e.g., human) administration, it will be understood that préparations should meet sterility, pyrogenicity, general safety and purity standards. A spécifie example of a

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I pharmacologically acceptable excipient for a combination composition, containing a crystalline sait fonn of Compound 1 in admixture with an i mmunotherapeutic agent as described herein is borate buffer or stérile saline solution (0.9% NaCl).

[00506] Formulations of the an immunotherapeutic agent, for example an immune checkpoint modulator antibody used in accordance with the présent disclosure can be prepared for storage by mixing an antibody having the desired degree of purity with optional phannaceutically acceptable excipients or stabîlizers as amply described and illustrated in Remington’s Phannaceutical Sciences 21^st Ed., (Lippincott, Williams and Wilkins Philadelphia, PA, 2006), in the form of lyophilized formulations or aqueous solutions and/or suspensions. Acceptable excipients, buffers or stabîlizers are nontoxic to récipients ai the dosages and concentrations employed, and include suitable aqueous and/or non-aqueous excipients that may be employed in the pharmaceutical compositions of the disclosure, for example, water, éthanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the iike), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants, buffers such as phosphate, citrate, and other organic acids. Antioxidants may be included, for example, (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oilsolubie antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) métal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartane acid, phosphoric acid, and the like; preservatives (such as octade-cyldimethylbenzyl ammonium chloride; hexaméthonium chloride; benzalkonium chloride, benzéthonium chloride; phénol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyciohexanol; 3pentanol; and m-cresol); low molecular weight (less than about 10 residues). Other exemplary pharmaceutically acceptable excipients may include polypeptides; proteins, such as sérum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrîns; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; métal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

[00507] ïn one illustrative embodiment, the pharmaceutical compositions can optionally contaîn pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjustîng and buffering agents and toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate. In some embodiments, the checkpoint inhibitor antibodies or antigen-binding fragments thereof of the present dîsclosure are formulated for and can be lyophilized for storage and reconstituted in a suitabie excipient prior to use according to art-known lyophîlization and reconstitution techniques. In one exemplary pharmaceutical composition containing one or more checkpoint inhibitor antibodies or antigen-binding fragment thereof, the composition is formulated as a stérile, preservative-free solution of one or more checkpoint inhibitor antibodies or antigen-binding fragment thereof for intravenous or subcutaneous administration. The formulation can be supplied as either a single-use, prefilled pen, as a single-use, for example containing about 1 mL prefilled glass syringe, or as a single-use institutional use vial. Preferably, the pharmaceutical composition containing the checkpoint inhibitor antibody or antigen-binding fragment thereof is clear and colorless, with a pH of about 6.9-5.0, preferably a pH of 6.5-5.0, and even more preferably a pH ranging from about 6.0 to about 5.0. In various embodiments, the formulations comprising the pharmaceutical compositions can contaîn from about 500 mg to about 10 mg, or from about 400 mg to about 20 mg, or from about 300 mg to about 30 mg or from about 200 mg to about 50 mg of the checkpoint inhibitor antibody or antigen-binding fragment thereof per mL of solution when reconstituted and administered to the subject. Exemplary injection or infusion excipients can include mannitol, citric acid monohydrate, dibasic sodium phosphate dihydrate, monobasîc sodium phosphate dihydrate, polysorbate 80, sodium chloride, sodium citrate and water for parentéral administration, for example, intravenously, intramuscularly, intraperitoneally, or subcutaneous administration.

[00508] In another exemplary embodiment, one or more immunotherapeutic agents, or an antigenbinding fragment thereof is formulated for intravenous or subcutaneous administration as a stérile aqueous solution containing 1-75 mg/mL, or more preferably, about 5-60 mg/mL, or yet more preferably, about 10-50 mg/mL, or even more preferably, about 10-40 mg/mL of antibody, with sodium acetate, polysorbate 80, and sodium chloride at a pH ranging from about 5 to 6. Preferably,

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I the intravenous or subcutaneous formulation is a stérile aqueous solution containing 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg/mL ofthe immunotherapeutic agent, for example, an immune checkpoint inhibitor antibody or an antigen-binding fragment thereof, with 20 mM sodium acetate, 0.2 mg/mL polysorbate 80, and 140 mM sodium chloride at pH 5.5. Further, a solution comprising a checkpoint inhibitor antibody or an antigen-binding fragment thereof, can comprise, among many other compounds, histidine, mannitol, sucrose, trehalose, glycine, poly(ethylene)glycol, EDTA, méthionine, and any combination thereof, and many other compounds known in the relevant art. [00509] In one embodiment, a pharmaceutical composition of the présent disclosure comprises the following components: 5-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof ofthe présent disclosure, 10 mM histidine, 5% sucrose, and 0.01% polysorbate 80 at pH 5.8, with a crystalline sait form of Compound 1. This composition may be provided as a lyophilized powder. When the powder is reconstituted at full volume, the composition retains the same formulation. Altematively, the powder may be reconstituted at half volume, in which case the composition comprises 10-500 mg of an immunotherapeutic agent or antigen-binding fragment thereof ofthe présent disclosure, 20 mM histidine, 10% sucrose, and 0.02% polysorbate 80 at pH 5.8.

[00510] In one embodiment, part of the dose is administered by an intravenous bolus and the rest by infusion of the immunotherapeutic agent formulation. For example, from about 0.001 to about 200 mg/kg, for example, from about 0.001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 50 mg/kg, or from about 0.001 mg/kg to about 10 mg/kg intravenous injection ofthe immunotherapeutic agent, or antigen-binding fragment thereof, may be given as a bolus, and the rest of the antibody dose may be administered by intravenous injection. A predetermined dose of the immunotherapeutic agent, or antigen-binding fragment thereof, may be administered, for example, over a period of an hour to two hours to five hours.

[00511] In a further embodiment, part of the dose is administered by a subcutaneous injection and/or infusion in the form of a bolus and the rest by infusion of the immunotherapeutic agent formulation. In some exemplary doses, the immunotherapeutic agent formulation can be administered subcutaneously in a dose ranging from about 0.001 to about 200 mg/kg, for example, from about 0.001 mg/kg to about 100 mg/kg, or from about 0.001 mg/kg to about 50 mg/kg, or from about 0.001 mg/kg to about 10 mg/kg intravenous injection of the immunotherapeutic agent, or antigen-binding fragment thereof. In some embodiments the dose may be given as a bolus, and the

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I rest of the immunotherapeutic agent dose may be administered by subcutaneous or intravenous injection. A predetermined dose of the immunotherapeutic agent, or antigen-binding fragment thereof, may be administered, for example, over a period of an hour to two hours to five hours. [00512] The formulation herein may also contain more than one active compound as necessary for the parti cul ar indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be désirable to provide one or more immunotherapeutic agents with other specificities. Altematively, or in addition, the composition may comprise an anti-inflammatory agent, a chemotherapeutic agent, a cytotoxic agent, a cytokine, a growth inhibitory agent and/or a small molécule antagonist. Such molécules are suitably présent in combination in amounts that are effective for the purpose intended.

[00513] The formulations to be used for in vivo administration should be stérile, or nearly so. This is readily accomplished by filtration through stérile filtration membranes.

[0Û514] In various embodiments, illustrative formulations of the pharmaceutical compositions described herein can be prepared using methods widely known in the field of pharmaceutical formulations. In general, such preparatory methods can include the step of bringing the active ingrédient into association with a excipient or one or more other accessory ingrédients, and then, if désirable, packaging the product into a desired single-or multi-dose unit.

[00515] In some embodiments, the composition comprising a crystalline sait form of Compound 1 can be also delivered in a vesîcle, and the immunotherapeutic agent can be delivered in the same liposome formulation, or in a separate formulation that is compatible with the liposomal formulation containing the crystalline sait fonn of Compound 1. In some illustrative examples, a liposome containing one or more liposomal surface moieties for example, poiyethylene glycol, antibodies and antibody fragments thereof that target a desired tumor surface antigen, receptor, growth factor, glycoprotein, glycolipid or neoantigen, which are selectively transported into spécifie cells or organs, thus enhance targeted drug delivery.

[00516] In another embodiment, a crystalline sait form of Compound 1 can be delivered in a vesicle, in particular a liposome (see Langer, Science 249: 1527-1533 (1990); Treat et al., in LIPOSOMES IN THE THERAPY OF INFECTIOUS DISEASE AND CANCER, Lopez-Berestein and Fidler (eds.), Liss, N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid.).

[00517] In yet another embodiment, a crystalline sait form of Compound 1, or the composition containing the combination, or a composition contaîning the immunotherapeutic agent, can be delivered in a controlled release System. In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed. Eng. 14: 201 (1987); Buchwald et al., Surgery 88: 507 (1980);

Saudek et al., N. Engl. J. Med. 321: 574 (1989)). In another embodiment, controlled release ofthe crystalline sait form of Compound 1 can comprise polymeric materials to provide sustained, intermediate, pulsatile, or altemate release (see MEDICAL APPLICATIONS OF CONTROLLED RELEASE, Langer and Wise (eds.), CRC Près., Boca Raton, Fia. (1974); CONTROLLED DRUG BIOAVAILABILITY, DRUG PRODUCT DESIGN AND PERFORMANCE, Smolen and Bail (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23: 61 (1983); see also Levy et al., Science 228: 190 (1985); During et al., Ann. Neurol. 25: 351(1989); Howard et al., J. Neurosurg. 71: 105 (1989)). Other controiled-release Systems discussed in the review by Langer (Science 249: 1527-1533 (1990)) can be used.

[00518] The optimum concentration of the active ingredient(s) in the chosen medium can be determined empirically, according to procedures well known to the ski lied artisan, and will dépend on the ultimate pharmaceutical formulation desired and the use to be employed.

[00519] The présent disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingrédients of the pharmaceutical compositions of the disclosure, which at minimum will include a crystalline sait form of Compound 1 and one or more checkpoint inhibitor antibodies or antigen-binding fragment thereof as described herein. In other embodiments, the kit may contain one or more further containers providing a pharmaceutically acceptable excipient, for example a diluent. In one embodiment a kit may comprise at least one container, wherein the container can include a crystalline sait form of Compound 1, a checkpoint inhibitor antibody or an antigen-binding fragment thereof of the présent disclosure. The kit may also include a set of instructions for preparing and administering the final pharmaceutical composition to the subject in need thereof, for the treatment of a checkpoint molecule-mediated disease or disorder.

[00520] In some embodiments of the présent disclosure, the immunotherapeutic agent is a population of immune cells, which can be administered in combination with a crystalline sait form of Compound 1 to treat a subject with cancer. In some embodiments, the immunotherapeutic agent is a population of immune cells, such as leukocytes (nucleated white blood cells), comprising (e.g., expressing) a receptor that binds to an antigen of interest. A leukocyte of the présent disclosure may

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I be, for example, a neutrophii, eosinophil, basophil, lymphocyte or a monocyte. In some embodiments, a leukocyte is a lymphocyte. Examples of lymphocytes include T cells, B cells, Natural Killer (NK) cells or NKT cells. In some embodiments, a T-cell is a CD4+ Th (T helper) cell, a CD8+ cytotoxic T cell, a γδΤ cell or a regulatory (suppressor) T cell. In some embodiments, an immune cell is a dendritic cell.

[00521] Immune cells of the present disclosure, in some embodiments, are genetically engineered to express an antigen-binding receptor. A cell is considered engineered if it contains an engineered (exogenous) nucleic acid. Engineered nucleic acids of the present disclosure may be introduced into a cell by any known (e.g., conventional) method. For exampie, an engineered nucleic acid may be introduced into a cell by electroporation (see, e.g., Fleiser W. C. Transcription Factor Protocols: Methods in Molecular Biology.TM. 2000; 130: 117-134), Chemical (e.g., calcium phosphate or lipid), transfection (see, e.g., Lewis W. H., et al., Somatic Cell Genet. 1980 May; 6(3): 333-47; Chen C., et al., Mol Cell Biol. 1987 August; 7(8): 2745-2752), fusion with bacterial protoplasts containing recombinant plasmids (see, e.g., Schaffher W. Proc Natl Acad Sci USA. 1980 April; 77(4): 2163-7), microinjection of purified DNA directly into the nucléus of the cell (see, e.g., Capecchi M. R. Cell. 1980 November; 22(2 Pt 2): 479-88), or retrovirus transduction.

[00522] Some aspects of the present disclosure provide an adoptive cell approach, which involves isolating immune cells (e.g., T-cells) from a subject with cancer, genetically engineering the immune cells (e.g., to express an antigen-binding receptor, such as a chimeric antigen receptor), expanding the cells ex vivo, and then re-introducing the immune cells into the subject. This method results in a greater number of engineered immune cells in the subject relative to what could be achîeved by conventional gene delivery and vaccination methods. In some embodiments, immune cells are isolated from a subject, expanded ex vivo without genetic modification, and then reintroduced into the subject.

[00523] Immune cells of the present disclosure comprise receptors that bind to antigens, such as an antigen encoded by an exogenously delivered nucleic acid, as provided herein. In some embodiments, a leukocyte is modified (e.g., genetically modified) to express a receptor that binds to an antigen. The receptor may be, in some embodiments, a naturally-occurring antigen receptor (normally expressed on the immune cell), recombinant antigen receptor (not nomially expressed on the immune cell) or a chimeric antigen receptor (CAR). Naturally-occurring and recombinant antigen receptors encompassed by the présent disclosure include T cell receptors, B cell receptors,

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NK cell receptors, NKT cell receptors and dendritic cell receptors. A chimeric antigen receptor refers to an artificial immune cell receptor that is engineered to recognize and bind to an antigen expressed by tumor cells. Generally, a CAR is desîgned for a T cell and is a chimera of a signaling domain of the T-ceII receptor (TcR) complex and an antigen-recognizing domain (e.g., a single chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8): 498-505), the disclosure of which is incorporated herein by reference in its entirety.

[00524] In some embodiments, an antigen binding receptor is a chimeric antigen receptor (CAR). A T cell that expresses a CAR is referred to as a CAR T cell. A CAR T cell receptor, in some embodiments, comprises a signaling domain of the T-cell receptor (TcR) complex and an antigenrecognizing domain (e.g., a single chain fragment (scFv) of an antibody) (Enblad et al., Human Gene Therapy. 2015; 26(8): 498-505) the disclosure of which is incorporated herein by reference in its entirety.

[00525] There are four générations of CARs, each of which contains different components. First génération CARs join an antibody-derived scFv to the CD3zeta (zêta, or z) intracellular signaling domain of the T-cell receptor through hinge and transmembrane domains. Second génération CARs incorporate an additional domain, e.g., CD28, 4-1BB (41BB), or ICOS, to supply a costimulatory signal. Third-generation CARs contain two costimulatory domains fused with the TcR CD3-zeta chain. Third-generation costimulatory domains may include, e.g., a combination of CD3z, CD27, CD28, 4-IBB, ICOS, or OX40. CARs, in some embodiments, contain an ectodomain (e.g., CD3), commonly derived from a single chain variable fragment (scFv), a hinge, a transmembrane domain, and an endodomain with one (first génération), two (second génération), or three (third génération) signaling domains derived from CD3Z and/or co-stimulatory molécules (Maude et al., Blood. 2015; 125(26): 4017-4023; Kakarla and Gottschalk, Cancer J. 2014; 20(2): 151-155) the disclosure of which is incorporated herein by reference in its entirety.

[00526] In some embodiments, the chimeric antigen receptor (CAR) îs a T-cell redirected for universal cytokine killing (TRUCK), also known as a fourth génération CAR. TRUCKs are CARredirected T-cells used as vehicles to produce and release a transgenic cytokine that accumulâtes in the targeted tissue, e.g., a targeted tumor tissue. The transgenic cytokine is released upon CAR engagement of the target. TRUCK cells may deposit a variety of therapeutic cytokines in the target. This may resuît in therapeutic concentrations at the targeted site and avoid systemic toxicîty.

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[00527] CARs typically differ in their fonctional properties. The CD3zeta signaling domain of the T-cell receptor, when engaged, will activate and induce prolifération of T-cells but can lead to anergy (a lack of reaction by the body's defense mechanisms, resulting in direct induction of peripheral lymphocyte tolérance). Lymphocytes are considered anergie when they fail to respond to a spécifie antigen. The addition of a costimulatory domain in second-generation CARs improved réplicative capacity and persistence of modified T-cells. Similar antitumor effects are observed in vitro with CD28 or 4-IBB CARs, but preclinical in vivo studies suggest that 4-1BB CARs may produce superior prolifération and/or persistence. Clinical trials suggest that both of these secondgeneration CARs are capable of inducing substantial T-cell prolifération in vivo, but CARs containing the 4-1BB costimulatory domain appear to persist longer. Third génération CARs combine multiple signaling domains (costimulatory) to augment potency. Fourth génération CARs are additionally modified with a constitutive or inducible expression cassette for a transgenic cytokine, which is released by the CAR T-cell to modulate the T-cell response. See, for example, Enblad et al., Human Gene Therapy. 2015; 26(8); 498-505; Chmielewski and Hinrich, Expert Opinion on Biological Therapy. 2015; 15(8): 1145-1154 the disclosures of which are incorporated herein by reference in their entireties.

[00528] In some embodiments, an illustrative immunotherapeutic agent is a first génération chimeric antigen receptor CAR. In some embodiments, a chîmeric antigen receptor is a second génération CAR. In some embodiments, a chimeric antigen receptor is a third génération CAR. In some embodiments, the chimeric antigen receptor is a fourth génération CAR or a T-cell redirected for universal cytokine killing (TRUCK).

[00529] In some embodiments, a chimeric antigen receptor (CAR) comprises an extracelluiar domain comprising an antigen binding domain, a transmembrane domain, and a cytoplasmic domain. In some embodiments, a CAR is fully human. In some embodiments, the antigen binding domain of a CAR is spécifie for one or more antigens. In some embodiments, a spacer domain or hinge domain is located between an extracelluiar domain (comprising the antigen binding domain) and a transmembrane domain of a CAR, or between a cytoplasmic domain and a transmembrane domain of the CAR. A spacer domain refers to any oligopeptide or polypeptide that fonctions to link the transmembrane domain to the extracelluiar domain and/or the cytoplasmic domain in the polypeptide chain. A hinge domain refers to any oligopeptide or polypeptide that fonctions to provide flexibî 1 ity to the CAR, or domains thereof, or to prevent steric hindrance of the CAR, or

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I I domains thereof. In some embodiments, a spacer domain or hinge domain may comprise up to 300 amino acids (e.g., 10 to 100 amino acids, or 5 to 20 amino acids). In some embodiments, one or more spacer domain(s) may be included in other régions of a CAR.

[00530] In some embodiments, a CAR of the disclosure comprises an antigen bînding domain, such as a single chain Fv (scFv) spécifie for a tumor antigen. The choice of binding domain dépends upon the type and number of ligands that define the surface of a target cell. For example, the antigen bînding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease State, such as cancer or an autoimmune disease. Thus, examples of cell surface markers that may act as ligands for the antigen binding domain in the CAR of the présent disclosure include those associated with cancer cells and/or other forms of diseased cells. In some embodiments, a CAR is engineered to target a tumor antigen of interest by way of engineering a desired antigen binding domain that specifically binds to an antigen on a tumor cell encoded by an engineered nucleic acid, as provided herein.

[00531] An antigen binding domain (e.g., an scFv) that specifically binds to a target or an epitope is a term understood in the art, and methods to détermine such spécifie binding are also known in the art. A molécule is said to exhibit spécifie binding if it reacts or associâtes more frequently, more rapidly, with greater duration and/or with greater affinity with a particular target antigen than it does with alternative targets. An antigen binding domain (e.g., an scFv) that specifically binds to a first target antigen may or may not specifically bind to a second target antigen. As such, spécifie binding does not necessarily require (although it can include) exclusive binding.

[00532] In some embodiments, immune cells expressing a CAR are genetically modified to recognize multiple targets or antigens, which permits the récognition of unique target or antigen expression patterns on tumor cells. Examples of CARs that can bind multiple targets include: split signal CARs, which limit complété immune cell activation to tumors expressing multiple antigens; tandem CARs (TanCARs), which contaîn ectodomains having two scFvs; and universal ectodomain CARs, which încorporate avidin or a fluorescein îsothiocyanate (FITC)-specific scFv to recognize tumor cells that hâve been incubated with tagged monoclonal antibodies (Mabs).

[00533] A CAR is considered bispecific if it recognizes two distinct antigens (has two distinct antigen récognition domains). In some embodiments, a bispecific CAR is comprised of two distinct antigen récognition domains présent in tandem on a single transgenic receptor (referred to as a TanCAR; see, e.g., Grada Z et al. Molecular Therapy Nucleic Acids 2013; 2: el05, incorporated

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I herein by reference in its entirety). Thus, methods, in some embodiments, comprise delivering to a tumor a combination comprising a crystalline sait form of Compound 1 and an immunotherapeutic agent, wherein the immunotherapeutic agent is an engineered nucleic acid that encodes an antigen, or delivering to a tumor an engineered nucleic acid that induces expression of a self-antigen, and delivering to the tumor an immune cell expressing a bispecific CAR that binds to two antigens, one of which is encoded by the engineered nucleic acid.

[00534] In some embodiments, a CAR is an antigen-specific inhibitory CAR (iCAR), which may be used, for example, to avoid off-tumor toxicity (Fedorov, V D et al. S ci. Transi. Med. published online Dec. 11, 2013, incorporated herein by reference in its entirety). iCARs contain an antigenspecific inhibitory receptor, for example, to block nonspecifîc immunosuppression, which may resuit from extra tumor target expression. iCARs may be based, for example, on inhibitory molécules CTLA-4 or PD-1. In some embodiments, these iCARs block T cell responses from T cells activated by either their endogenous T cell receptor or an activating CAR. In some embodiments, this inhibiting effect is temporary.

[00535] In some embodiments, CARs may be used in adoptive cell transfer, wherein immune cells are removed from a subject and modified so that they express receptors spécifie to an antigen, e.g., a tumor-specific antigen. The modified immune cells, which may then recognize and kill the cancer cells, are reintroduced into the subject (Pule, et al., Cytotherapy. 2003; 5(3): 211-226; Mande et al., Blood. 2015; 125(26): 4017-4023, each of which is incorporated herein by reference in their entireties).

[00536] According to other aspects of the disclosure, the tumor antigenic component in the vaccine of the invention is any natural or synthetic tumor-associated protein or peptide or combination of tumor-associated proteins and/or peptides or glycoproteins or glycopeptides. In still yet other aspects, the antigenic component can be patient-specific or common to many or most patients with a particular type of cancer. According to one aspect, the antigenic component consists of a cell lysate derived from tumor tissue removed from the patient being treated. In another aspect, the lysate can be engineered or synthesized from exosomes derived from tumor tissue. In yet another aspect, the antigenic component consists of a cell lysate derived from tumor tissue extracted from one or more unrelated individuals or from tumor-cell fines.

[00537] In various embodiments, an illustrative immunotherapeutic agent comprises one or more cancer vaccines, for use in combination with a crystalline sait form of Compound 1. The tumor

103 associated antigen component of the vaccine may be manufactured by any of a variety of wellknown techniques. For indîvidual protein components, the antigenic protein is isolated from tumor tissue or a tumor-cell line by standard chromatographie means such as high-pressure liquid chromatography or affinîty chromatography or, altematively, it is synthesized by standard recombinant DNA technology in a suitable expression system, such as E. coli, yeast or plants. The tumor-assocîated antigenic protein is then purified from the expression system by standard chromatographie means. In the case of peptide antigenic components, these are generally prepared by standard automated synthesis. Proteins and peptides can be modified by addition of amino acids, lipids and other agents to improve their incorporation into the delivery system of the vaccine (such as a multilamellar liposome). For a tumor-associated antigenic component derived from the patient's own tumor, or tumors from other individuals, or cell lines, the tumor tissue, or a single cell suspension derived from the tumor tissue, is typically homogenîzed in a suitable buffer. The homogenate can also be fractionated, such as by centrifugation, to isolate particular cellular components such as cell membranes or soluble material. The tumor material can be used directly or tumor-associated antigens can be extracted for incorporation in the vaccine using a buffer containing a low concentration of a suitable agent such as a detergent. An example of a suitable detergent for extracting antigenic proteins from tumor tissue, tumor cells, and tumor-cell membranes is diheptanoyl phosphatidylcholine. Exosomes derived from tumor tissue or tumor cells, whether autologous or heterologous to the patient, can be used for the antigenic component for incorporation in the vaccine or as a starting material for extraction of tumor-associated antigens.

[00538] In some embodiments of the présent disclosure, a combination therapy comprises a crystalline sait form of Compound l in combination with a cancer vaccine immunotherapeutic agent. In various examples, the cancer vaccine includes at least one tumor-associated antigen, at least one immunostimulant, and optionally, at least one cell-based immunotherapeutic agent. In some embodiments, the immunostimulant component in the cancer vaccine ofthe disclosure is any Biological Response Modifier (BRM) with the ability to enhance the therapeutic cancer vaccine's effectiveness to induce humoral and cellular immune responses against cancer cells in a patient. According to one aspect, the immunostimulant is a cytokine or combination of cytokines. Examples of such cytokines include the interferons, such as IFN-gamma, the interleukins, such as IL-2, IL-15 and IL-23, the colony stimulating factors, such as M-CSF and GM-CSF, and tumor necrosis factor. According to another aspect, the immunostimulant component of the disclosed cancer vaccine

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I I includes one or more adjuvant-type immunostimulatory agents such as APC Toll-like Receptor agonists or costimulatory/cell adhesion membrane proteins, with or without immunostimulatory cytokines. Examples of Toll-like Receptor agonists include lipid A and CpG, and costimulatory/adhesion proteins such as CD80, CD86, and ICAM-1.

[00539] In some embodiments, the immunostimulant is selected from the group consisting of IFNgamma (IFN-γ), IL-2, IL-15, IL-23, M-CSF, GM-CSF, tumor necrosis factor, lipid A, CpG, CD80, CD86, and ICAM-1, or combinations thereof. Accordîng to other aspects, the cell-based immunotherapeutic agent is selected from the group consisting of dendritic cells, tumor-infiltratîng T lymphocytes, chimeric antigen receptor-modified T effector cells directed to the patient's tumor type, B lymphocytes, naturel killer cells, bone marrow cells, and any other cell of a patient's immune system, or combinations thereof. In one aspect, the cancer vaccine immunostimulant includes one or more cytokines, such as interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-γ), one or more Toll-like Receptor agonists and/or adjuvants, such as monophosphoryl lipid A, lipid A, muramyl dipeptide (MDP) lipid conjugate and double stranded RNA, or one or more costimulatory membrane proteins and/or cell adhesion proteins, such CD80, CD86 and ICAM-1, or any combination of the above. In one aspect, the cancer vaccine includes an immunostimulant that is a cytokine selected from the group consisting of interleukin 2 (IL-2), GM-CSF, M-CSF, and interferon-gamma (IFN-γ). In another aspect, the cancer vaccine includes an immunostimulant that is a Toll-like Receptor agonist and/or adjuvant selected from the group consisting of monophosphoryl lipid A, lipid A, and muramyl dipeptide (MDP) lipid conjugate and double stranded RNA, In yet another aspect, the cancer vaccine includes an immunostimulant that is a costimulatory membrane protein and/or cell adhesion protein selected from the group consisting of CD80, CD86, and ICAM-1.

[00540] In varions embodiments, an immunotherapeutic agent can include a cancer vaccine, wherein the cancer vaccine incorporâtes any tumor antigen that can be potentially used to construct a fusion protein accordîng to the invention and particulariy the following: (a) cancer-testis antigens including NY-ESO-1, SSX2, SCP1 as well as RAGE, BAGE, GAGE and MAGE family polypeptides, for example, GAGE-1, GAGE-2, MAGE-1 MAGE-2, MAGE-3, MAGE-4, MAGE-5, MAGE-6, and MAGE-12, which can be used, for example, to address melanoma, lung, head and neck, NSCLC, breast, gastrointestinal, and bladder tumors; (b) mutated antigens, including p53, associated with varions solid tumors, e.g., colorectal, lung, head and neck cancer; p21/Ras

105 associated with, e.g., melanoma, pancreatic cancer and colorectal cancer; CDK4, associated with, e.g., melanoma; MUM1 associated with, e.g., melanoma; caspase-8 associated with, e.g., head and neck cancer; CIA 0205 associated with, e.g., bladder cancer; HLA-A2-R17Û1, beta catenin associated with, e.g., melanoma; TCR associated with, e.g., T-cell non-Hodgkin lymphoma; BCRabl associated with, e.g., chronic myelogenous leukemia; triosephosphate isomerase; KIA 0205; CDC-27, and LDLR-FUT; (c) over-expressed antigens, including, Galectin 4 associated with, e.g., colorectal cancer; Galectin 9 associated with, e.g., Hodgkin's disease; protéinase 3 associated with, e.g., chronic myelogenous leukemia; WT 1 associated with, e.g., various leukemias; carbonic anhydrase associated with, e.g., rénal cancer; aldolase A associated with, e.g., lung cancer; PRAME associated with, e.g., melanoma; HER-2/neu associated with, e.g., breast, colon, lung and ovarian cancer; mammaglobin, alpha-fetoprotein associated with, e.g., hepatoma; KSA associated with, e.g., colorectal cancer; gastrin associated with, e.g., pancreatic and gastric cancer; telomerase catalytic protein, MUC-1 associated with, e.g., breast and ovarian cancer; G-250 associated with, e.g., rénal cell carcinoma; p53 associated with, e.g., breast, colon cancer; and carcinoembryonic antigen associated with, e.g., breast cancer, lung cancer, and cancers of the gastrointestinal tract such as colorectal cancer; (d) shared antigens, including melanoma-mélanocyte différentiation antigens such as MART-l/Melan A; gplOO; MC1R; melanocyte-stimulating hormone receptor; tyrosinase;

tyrosinase related protein-1/TRP 1 and tyrosinase related protein-2/TRP2 associated with, e.g., melanoma; (e) prostate associated antigens including PAP, PSA, PSMA, PSH-P1, PSM-P1, PSMP2, associated with e.g., prostate cancer; (f) immunoglobulin idiotypes associated with myeloma and B cell lymphomas. In certain embodiments, the one or more TAA can be selected from pi 5, Hom/Mel-40, H-Ras, E2A-PRL, H4-RET, IGH-1GK, MYL-RAR, Epstein Barr virus antigens, EBNA, human papillomavirus (HPV) antigens, including E6 and E7, hepatitis B and C virus antigens, human T-cell lymphotropic virus antigens, TSP-180, pl85erbB2, pl 80erbB-3, c-met, mn23H1, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, pi 6, TAGE, PSCA, CT7, 43-9F, 5T4, 791 Tgp72, beta-HCG, BCA225, BTAA, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, CD68\KP1, CO-029, FGF-5, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV 18, NB/70K, NY-CO-1, RCAS1, SDCCAG16, TA-90 (Mac-2 binding proteîn/cyclophilin C-associated protein), TAAL6, TAG72, TLP, TPS or any combinations thereof.

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I (00541] In some embodiments, the présent disclosure provides a crystalline sait form of Compound 1 for use in combination with a cancer vaccine which can include a tumor antigen comprising the entire amino acid sequence, a portion of it, or spécifie immunogenic epitopes of a human protein. [00542] In various embodiments, an illustrative immunotherapeutic agent may include an mRNA opérable to encode any one or more of the aforementioned cancer antigens usefiil for synthesizing a cancer vaccine. In some illustrative embodiments, the mRNA based cancer vaccine may hâve one or more of the following properties: a) the mRNA encoding each cancer antigen is interspersed by cleavage sensitive sites; b) the mRNA encoding each cancer antigen is linked directly to one another without a linker; c) the mRNA encoding each cancer antigen is linked to one another with a single nucléotide linker; d) each cancer antigen comprises a 20-40 amino acids and includes a centrally located SNP mutation; e) at least 40% of the cancer antigens hâve a highest affinity for class I MHC molécules from the subject; f) at least 40% of the cancer antigens hâve a highest affinity for class II MHC molécules from the subject; g) at least 40% of the cancer antigens hâve a predicted binding affinity of IC>500 nM for HLA-A, HLA-B and/or DRB1; h) the mRNA encodes 1 to 15 cancer antigens; i) 10-60% of the cancer anti gens hâve a binding affinity for class I MHC and 10-60% of the cancer antigens hâve a binding affinity for class II MHC; and/or j) the mRNA encoding the cancer antigens is arranged such that the cancer antigens are ordered to minimîze pseudo-epitopes.

[00543] In various embodiments, the combination comprising a crystalline sait form of Compound 1 and a cancer vaccine immunotherapeutic agent as disclosed herein can be used to illicit an immune response in a subject against a cancer antigen. The method involves administering to the subject a RNA vaccine comprising at least one RNA polynucleotide having an open reading frame encoding at least one antigenic polypeptide or an immunogenic fragment thereof, thereby inducing in the subject an immune response spécifie to the antigenic polypeptide or an immunogenic fragment thereof, in combination with administering a crystalline sait form of Compound 1 either in the same composition or a separate composition, administered at the same time, or sequentially dosed, wherein the anti-antigenic polypeptide antibody titer in the subject is increased following vaccination relative to anti-antigenic polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a traditional vaccine against the cancer. An anti-antigenic polypeptide antibody is a sérum antibody the binds specifically to the antigenic polypeptide.

[00544] A prophylactically effective dose is a therapeutically effective dose that prevents advancement of cancer at a clinically acceptable level. In some embodiments the therapeutically

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I effective dose is a dose listed in a package insert for the vaccine. A traditional vaccine, as used herein, refers to a vaccine other than the mRNA vaccines of the invention. For instance, a traditional vaccine includes but is not limited to live microorganism vaccines, killed mîcroorganism vaccines, subunit vaccines, proteîn antigen vaccines, DNA vaccines, and the like. In exemplary embodiments, a traditional vaccine is a vaccine that has achieved regulatory approval and/or is registered by a national drug regulatory body, for example the Food and Drug Administration (FDA) in the United States or the European Medicines Agency (EMA.)

[00545] In some embodiments the anti-antigenic polypeptide antibody titer in the subject is încreased 1 log to 10 log following vaccination relative to anti-antigenic polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a traditional vaccine against the cancer. In some embodiments the anti-antigenic polypeptide antibody titer in the subject is încreased 1 log following vaccination relative to anti-antigenic polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a traditional vaccine against the cancer. In some embodiments the anti-antigenic polypeptide antibody titer in the subject is încreased 2 log following vaccination relative to anti-antigenic polypeptide antibody titer in a subject vaccinated with a prophylactically effective dose of a traditional vaccine against the cancer.

[00546] Aspects of the invention provide nucleic acid vaccines comprising one or more RNA polynucleotîdes having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucieotide is présent in the formulation for in vivo administration to a host, which confers an antibody titer superior to the criterion for sero-protection for the first antigen for an acceptable percentage of human subjects. In some embodiments, the antibody titer produced by the mRNA vaccines of the invention is a neutralizing antibody titer. In some embodiments the neutralizing antibody titer is greater than a proteîn vaccine. In other embodiments the neutralizing antibody titer produced by the mRNA vaccines of the invention is greater than an adjuvanted proteîn vaccine. In y et other embodiments the neutralizing antibody titer produced by the mRNA vaccines of the invention is 1,000-10,000, 1,200-10,000, 1,400-10,000, 1,500-10,000, 1,000-5,000, 1,000-4,000, 1,800-10,000, 2000-10,000, 2,000-5,000, 2,000-3,000, 2,000-4,000, 3,000-5,000, 3,000-4,000, or 2,000-2,500. A neutralization titer is typically expressed as the highest sérum dilution required to achieve a 50% réduction in the number of plaques.

[00547] In preferred aspects, RNA vaccine immunotherapeutic agents of the présent disclosure (e.g., mRNA vaccines) produce prophylactically- and/or therapeutically-efficacious levels,

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I I concentrations and/or titers of antigen-specific antibodies in the blood or sérum of a vaccinated subject. As defined herein, the tenu antibody titer refers to the amount of antigen-specific antibody produced in a subject, e.g., a human subject. In exemplary embodiments, antibody titer is expressed as the inverse of the greatest dilution (in a serial dilution) that still gives a positive resuit. In exemplary embodiments, antibody titer is determined or measured by enzyme-linked îmmunosorbent assay (ELISA). In exemplary embodiments, antibody titer is determined or measured by neutralization assay, e.g., by microneutralization assay. In certain aspects, antibody titer measurement is expressed as a ratio, such as 1:40, 1:100, and the lîke.

[00548] In exemplary embodiments of the invention, an efficacious vaccine produces an antibody titer of greater than 1:40, greater that 1:100, greater than 1:400, greater than 1:1000, greater than 1:2000, greater than 1:3000, greater than 1:4000, greater than 1:500, greater than 1:6000, greater than 1:7500, greater than 1:10000. In exemplary embodiments, the antibody titer is produced or reached by 10 days following vaccination, by 20 days following vaccination, by 30 days following vaccination, by 40 days following vaccination, or by 50 or more days following vaccination. In exemplary embodiments, the titer is produced or reached following a single dose of vaccine administered to the subject. In other embodiments, the titer is produced or reached following multiple doses, e.g., following a first and a second dose (e.g., a booster dose.) In exemplary aspects of the invention, antigen-specific antibodies are measured in units of g/ml or are measured in units of IU/L (International Units per liter) or mlU/ml (milli International Units per ml). In exemplary embodiments of the invention, an efficacious vaccine produces >0.5 pg/mL, >0.1 pg/mL, >0.2 pg/mL, >0.35 pg/mL, >0.5 pg/mL, >1 pg/mL, >2 pg/mL, >5 pg/mL or >10 pg/mL. In exemplary embodiments of the invention, an efficacious vaccine produces >10 mlU/ mL, >20 mlU/ mL, >50 mlU/ mL, >100 mlU/ mL, >200 mlU/ mL, >500 mlU/ml or >1000 mlU/ml. In exemplary embodiments, the antibody level or concentration is produced or reached by 10 days following vaccination, by 20 days following vaccination, by 30 days following vaccination, by 40 days following vaccination, or by 50 or more days following vaccination. In exemplary embodiments, the level or concentration is produced or reached following a single dose of vaccine administered to the subject. In other embodiments, the level or concentration is produced or reached following multiple doses, e.g., following a first and a second dose (e.g., a booster dose.) In exemplary embodiments, antibody level or concentration is determined or measured by enzyme-linked îmmunosorbent assay (ELISA). In exemplary embodiments, antibody level or concentration is determined or measured by

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I I I I I I I neutralization assay, e.g., by microneutralization assay. Also provided are nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, wherein the RNA polynucleotide is présent in a formulation for in vivo administration to a host for eliciting a longer lasting high antibody titer than an antibody titer elicited by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to produce neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from a cationic peptide and an îmmunostimulatory nucleic acid. In some embodiments, the cationic peptide is protamine. [00549] Immunotherapeutic agents comprising a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame comprising at least one Chemical modification or optionally no nucléotide modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, wherein the RNA polynucleotide is présent in the formulation for in vivo administration to a host such that the level of antigen expression in the host significantly exceeds a level of antigen expression produced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide. [00550] Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame comprising at least one Chemical modification or optionally no nucléotide modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, wherein the vaccine has at least 10 fold less RNA polynucleotide than is required for an unmodîfied mRNA vaccine to produce an équivalent antibody titer. In some embodiments, the RNA polynucleotide is présent in a dosage of 25-100 micrograms.

[00551] Aspects of the invention also provide a unit of use vaccine, comprising between 10 pg and 400 μ g of one or more RNA polynucleotides having an open reading frame comprising at least one Chemical modification or optionally no nucléotide modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, and a pharmaceutically acceptable excipient, formulated for delivery to a human subject. In some embodiments, the vaccine further comprises a cationic lipid nanoparticle.

[00552] Aspects of the invention provide methods of creatîng, maintaining or restoring antigenic memory to a tumor in an individual or population of individuals comprising administering to said individual or population an antigenic memory booster nucleic acid vaccine comprising (a) at least

110 one RNA polynucleotide, said polynucleotide comprising at least one Chemical modification or optionally no nucléotide modification and two or more codon-optimized open reading frames, said open reading trames encoding a set of reference antigenic polypeptides, and (b) optionally a pharmaceutically acceptable excipient. In some embodiments, the vaccine is administered to the indivîdual via a route selected from the group consîsting of intramuscular administration, intradermal administration and subcutaneous administration. In some embodiments, the administering step comprises contacting a muscle tissue ofthe subject with a device suitable for injection of the composition. In some embodiments, the administering step comprises contacting a muscle tissue of the subject with a device suitable for injection of the composition in combination with electroporation.

[00553] Aspects of the invention provide methods of vaccinating a subject comprising administering to the subject a single dosage of between 25 pg /kg and 400 pg /kg of a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide in an effective amount to vaccînate the subject.

[00554] Other aspects provide nucleic acid vaccines comprising one or more RNA polynucleotides having an open reading frame comprising at least one Chemical modification, the open reading frame encoding a first antigenic polypeptide or a concatemeric polypeptide, wherein the vaccine has at least 10 fold less RNA polynucleotide than is required for an unmodified mRNA vaccine to produce an équivalent antibody titer. In some embodiments, the RNA polynucleotide is présent in a dosage of25-I00 micrograms.

[00555] In some embodiments, a crystalline sait form of Compound 1 can be used in combination with a bispecific antibody immunotherapeutic agent. The bispecific antibody can include a protein construct having a first antigen binding moiety and a second antigen binding site that binds to a cytotoxic immune cell. The first antigen binding site can bind to a tumor antigen that is specifically being treated with the combination of the présent invention. For example, the first antigen binding moiety may bind to a non-limiting example of tumor antigens selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD133, CEA, gpA33, Mucins, TAG-72, CIX, PSMA, folate-binding protein, GD2, GD3, GM2, VEGF. VEGFR, Integrin αΥβ3, Integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRA1LR1, TRAILR2, RANKL, FAP and Tenascin among others. In some embodiments, the first antigen binding moiety has specificity to a protein or a

111 peptide that is overexpressed on a tumor ceil as compared to a corresponding non-tumor cell. In some embodiments, the first antigen binding moiety has specificity to a protein that is overexpressed on a tumor cell as compared to a corresponding non-tumor cell. A corresponding non-tumor cell as used here, refers to a non-tumor cell that is of the same cell type as the origin of the tumor cell. It is noted that such proteins are not necessarily different from tumor antigens. Non-limiting exampies include carcinoembryonic antigen (CEA), which is overexpressed in most colon, rectum, breast, lung, pancréas and gastrointestinal tract carcinomas; heregulin receptors (HER-2, neu or c-erbB-2), which is frequently overexpressed in breast, ovarian, colon, lung, prostate and cervical cancers; epidermal growth factor receptor (EGFR), which is highly expressed in a range of solid tumors including those of the breast, head and neck, non-small cell lung and prostate; asialoglycoprotein receptor; transferrin receptor; serpin enzyme complex receptor, which is expressed on hépatocytes; fîbroblast growth factor receptor (FGFR), which is overexpressed on pancreatic ductal adenocarcinoma cells; vascular endothélial growth factor receptor (VEGFR), for anti-angiogenesis gene therapy; folate receptor, which is selectively overexpressed in 90% of nonmucinous ovarian carcinomas; cell surface glycocalyx; carbohydrate receptors; and poiymeric immunoglobulin receptor.

[00556] The second antîgen-binding moiety is any molécule that specifically binds to an antigen or protein or polypeptide expressed on the surface of a cytotoxic immune cell (a CIK cell). Exemplary non-limiting antigens expressed on the surface of the cytotoxic immune cells suitable for use with the présent dîsclosure may include CD2, CD3, CD4, CD5, CD8, CD1 la, CD11 b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, the Fc receptor, LFA, LFA-1, TCRap, CCR7, macrophage inflammatory protein la, perform, PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, 0X40, 41BB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27 and Fas ligand. In some embodiments, the second antigen binding moiety binds to CD3 of the cytotoxic immune cell, e.g., CIK cell. In some embodiments, the second antigen binding moiety binds to CD56 of the cytotoxic immune cell. In some embodiments, the second antigen binding moiety binds to the Fc receptor of the cytotoxic immune cell. In some embodiments, the Fc région of the bîspecific antibody binds to the Fc receptor of the cytotoxic immune cell. In some embodiments, a second antigen-binding moiety is any molécule that specifically binds to an antigen expressed on the surface of a cytotoxic immune cell (e.g., a CIK cell). The second antigen binding moiety is spécifie for an antigen on a cytotoxic

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I immune cell. Exemplary cytotoxic immune cells include, but are not limited to CIK cells, T-cells, CD8+ T cells, activated T-cells, monocytes, natural killer (NK) cells, NK T cells, lymphokineactivated killer (LAK) cells, macrophages, and dendritic cells. The second antigen binding moîety specifically binds to an antigen expressed on the surface of a cytotoxic immune cell. Exemplary non-limiting antigens expressed on the surface of the cytotoxic immune cells suitable for modulation with the présent disclosure may include CD2, CD3, CD4, CD5, CD8, CD1 la, CD11 b, CD14, CD16a, CD27, CD28, CD45, CD45RA, CD56, CD62L, the Fc receptor, LFA, LFA-1, TCRap, CCR7, macrophage inflammatory protein la, perforin, PD-1, PD-L1, PD-L2, or CTLA-4, LAG-3, 0X40, 4IBB, LIGHT, CD40, GITR, TGF-beta, TIM-3, SIRP-alpha, TIGIT, VSIG8, BTLA, SIGLEC7, SIGLEC9, ICOS, B7H3, B7H4, FAS, BTNL2, CD27 and Fas ligand. In other embodiments, the bispecific antibody modulator is an activator of a costimulatory molécule (e.g., an 0X40 agonist). In one embodiment, the 0X40 agonist is a bispecific antibody molécule to 0X40 and another tumor antigen or a costimulatory antigen. The 0X40 agonist can be administered alone, or in combination with other immunomodulators, e.g., in combination with an inhibîtor (for example an antibody construct) of PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and/or -5), TIM3 or LAG-3. In some embodiments, the anti-OX40 antibody molécule is a bispecific antibody that binds to GITR and PD-1, PD-L1, CTLA-4, CEACAM (e.g., CEACAM-1, -3 and/or -5), TIM-3 or LAG-3. In one exemplary embodiment, an 0X40 antibody molécule is administered in combination with an anti-PD-1 antibody molécule (e.g., an anti-PD-1 molécule as described herein). The 0X40 antibody molécule and the anti-PD-I antibody molécule may be in the form of separate antibody composition, or as a bispecific antibody molécule. In other embodiments, the 0X40 agonist can be administered in combination with other costimulatory molécule, e.g., an agonist of GITR, CD2, CD27, CD28, CDS, ICAM-1, LFA-1 (CDlla/CD18), ICOS (CD278), 4-1BB (CD137), CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CDI60, B7-H3, or CD83 ligand. In some embodiments, the second antigen binding moiety binds to the Fc receptor on the cytotoxic immune cell, e.g., CIK cell.

[005571 In some embodiments, the bispecific antibody immunotherapeutic agent has specificities for a tumor antigen and a CIK cell, which brings the tumor antigen expressing tumor cell in close proximity of the CIK cell, leadîng to the élimination of the tumor cell through anti-tumor cytotoxicity of CIK cell. In some embodiments, the bispecific antibody has specificity for a tumor antigen but does not hâve specificity for a CIK cell, however, the Fc région of the bispecific

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I antibody can bind to the Fc receptor of the CIK cell, which in tum brings the tumor cell in close proximity of the CIK cell, leading to the élimination of the tumor cell through anti-tumor cytotoxicity of CIK cell. In some embodiments, the bispecific antibody has specificity for a CIK cell but does not hâve specificity for tumor cell, however, the Fc région of the bispecific antibody can bind to the Fc receptor of the tumor cell, which in tum brings the tumor cell in close proximity of the CIK cell, leading to the élimination of the tumor cell through anti-tumor cytotoxicity of CIK cell.

[00558] In some embodiments, a crystalline sait form of Compound I can be used in combination with an immune cell-engaging multivalent antibody/fusion protein/construct immunotherapeutic agent. In various embodiments, an exemplary immunotherapeutic agent can include immune cellengaging multivalent antibody/fusion protein/construct which may comprise a recombinant structure, for example, ail engineered antibodies that do not imitate the original IgG structure. Here, different strategies to multimerize antibody fragments are utilized. For example, shortening the peptide linker between the V domains forces the scFv to self-associate into a dimer (diabody; 55 kDa). Bispecific diabodies are formed by the noncovalent association of two VHA-VLB and VHBVLA fragments expressed in the same cell. This leads to the formation of heterodimers with two different binding sites. Single-chain diabodies (sc-diabodies) are bispecific molécules where the VHA-VLB and VHB-VLA fragments are linked together by an additional third linker. Tandemdiabodies (Tandabs) are tetravalent bispecific antibodies generated by two scDiabodies.

[00559] Also included are the di-diabodies known in the art. This 130-kDa molécule is formed by the fusion of a diabody to the N-terminus of the CH3 domain of an IgG, resulting in an IgG-like structure. Further diabody dérivatives are the triabody and the tetra-body, which fold into trimeric and tetrameric fragments by shortening the linker to <5 or 0-2 residues. Also exemplified are (scFv)2 constructs known as ‘bispecific T cell engager’ (BITE). BITEs are bispecific single-chain antibodies consisting of two scFv antibody fragments, joined via a flexible linker, that are directed against a surface antigen on target cells and CD3 on T cells. Also exemplified are bivalent (Fab)2 and tri valent (Fab)3 antibody formats. Also exemplified are minibodies and trimerbodies generated from scFvs. Exemplary constructs useful to target tumor antigens as can include one or more of; Diabody, Single-chain (sc)-diabody (scFv)2, Miniantibody, Minibody, Bamase-barstar, scFv-Fc, sc(Fab)2, Trimeric antibody constructs, Triabody antibody constructs, Trimerbody antibody constructs, Tribody antibody constructs, Collabody antibody constructs, (scFv-TNFa)3,

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F(ab)3/DNL. Exemplary cytotoxic immune cells include, but are not limited to C1K cells, T-cells, CD8+ T cells, activâted T-cells, monocytes, natural killer (NK) cells, NK T cells, lymphokineactivated killer (LAK) cells, macrophages, and dendritic cells.

[00560] In some embodiments, a crystalline sait form of Compound 1 can be used in combination with a radioconjugate immunotherapeutic agent.

[00561] In various embodiments, a radioconjugate is a small molécule or large molécule (herein referred to as a “cell targeting agent”), for example and polypeptide, an antibody or an antibody fragment thereof, that is coupled to or otherwise affixed to a radionuclide, or a plurality of radionuclides, such that the binding of the radioconjugate to its target (a protein or molécule on or in a cancer cell), will lead to the death or morbidity of said cancer cell. In various embodiments, the radioconjugate can be a cell targeting agent labelled with a radionuclide, or the cell targeting agent may be coupled or otherwise affixed to a particle, or microparticle, or nanoparticle containing a plurality of radionuclides, wherein the radionuclides are the same or different. Methods for synthesizing radioconjugates are known in the art, and may include the class of immunoglobulin or antigen binding parts thereof, that are conjugated to a toxic radionuclide.

100562] In some embodiments, the molécule that binds to the cancer cell can be known as a “cell targeting agent”. As used herein, an exemplary cell targeting agent can allow the drug-containing nanoparticles or radionuclide to target the spécifie types of cells of interest. Examples of cell targeting agents include, but are not limited to, small molécules (e.g., folate, adenosine, purine) and large molécule (e.g., peptide or antibody) that bind to or target a tumor associated antigen. Examples of tumor associated antigens include, but are not limited to, adenosine receptors, alpha v beta 3, aminopeptidase P, alpha fetoproteîn, cancer antigen 125, carcinoembryonic antigen, cCaveolin-1, chemokine receptors, clusterin, oncofetal antigens, CD20, épithélial tumor antigen, melanoma associated antigen, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate spécifie antigen, purine receptors, radiation-induced cell surface receptor, serpin B3, serpin B4, squamous cell carcînoma antigens, thrombospondin, tumor antigen 4, tumor-associated glycoprotein 72, tyosinase, and tyrosine kinases. In some embodiments, the cell targeting agent is folate or a folate dérivative that binds specifically to folate receptors (FRs). In some embodiments, the cell targeting agent is an antibody, a bispecific antibody, a tri spécifie antibody or an antigen binding construct thereof, that specifically binds to a cancer antigen selected from: EGFR, HGFR, Her2, Ep-CAM, CD20, CD30, CD33, CD47, CD52, CD 133, CEA, gpA33,

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Mucins, TAG-72, CIX, PSMA, folate-binding protein, GD2, GD3, GM2, VEGF. VEGFR, Integrin «Vp3, Integrin α5β1, MUC1, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRA1LR2, RANKL, FAP and Tenascin among others.

[00563] The use of folate as a targeting agent in the radioconjugate also aliow both tumor cells and regulatory T (Treg) cells to be targeted for destruction. It is well accepted that high numbers of Treg cells suppress tumor immunity. Specifically, Treg cells suppress (foreign and self) reactive T cells without killing them through contact-dependent or cytokine (e.g., IL-10, TGF-beta., and the like) sécrétion. FR4 is selectively upregulated on Treg cells. It has been shown that antibody blockade of FR4 depleted Treg cells and provoked tumor immunity in tumor-bearmg mice. Thus, folate-coated PBM nanoparticles carrying a cytotoxic agent would take FR-expressing cells for their destruction, which would both directly (i.e., BrCa ce 11) and indirectly (i.e., breast tumor assocîated and peripheral Treg cells) inhibit tumor progression.

[00564] In another further embodiment, the targeting agent is an antibody or peptide, or immune ceii-engaging multivalent antibody/fiision protein/constructs capable of binding tumor assocîated antigens consisting of but not limited to: adenosine receptors, alpha v beta 3, aminopeptidase P, alpha fetoprotein, cancer antigen 125, carcinoembryonic antigen, caveolin-l, chemokine receptors, clusterin, oncofetal antigens, CD20, Human Growth Factor Receptor (HGFR), épithélial tumor antigen, meianoma assocîated antigen, MUC1, Ras, p53, Her2/Neu, ErbB2, ErbB3, ErbB4, folate receptor, prostate-specific membrane antigen, prostate spécifie antigen, purine receptors, radiationinduced cell surface receptor, serpin B3, serpin B4, squamous cell carcinoma antigens, thrombospondin, tumor antigen 4, tumor-associated glycoprotein 72, tyrosinase, tyrosine kinases, and the like.

[00565] In some embodiments, a crystalline sait form of Compound 1 as described herein can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, a crystalline sait form of Compound 1 as described herein can be used in combination with an immunotherapeutic agent such as a vaccine. In various embodiments, exemplary vaccines include those used to stimulate the immune response to cancer antigens.

[00566] The amount of both the crystalline sait form of Compound 1 as disclosed herein and the additional one or more additional therapeutic agents (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with excipient materials to produce a single dosage form will vary depending upon the host treated and the particular mode of

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I administration. In certain embodiments, compositions of this invention are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of an inventive can be administered.

[00567] The additional therapeutic agent and the crystalline sait form of Compound 1 as disclosed herein may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions may be less than that required in a monotherapy utilizing only that therapeutic agent, or there may be fewer side effects for the patient gîven that a lower dose is used. In certain embodiments, in such compositions a dosage of between 0.01-10,000 pg/kg body weight/day of the additional therapeutic agent can be administered.

[00568] In some embodiments, the crystalline sait forms of compound 1 as disclosed herein can be combined with one or more inhibitors of the following kinases for the treatment of a disease disclosed herein such as cancer: Aktl, Akt2, Akt3, TGF-pR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, 1NS-R, IGF1R, IR-R, PDGFaR, PDGFp/R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphAl, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYR, FRK, J AK, ABL, ALK, CDK7, CDK12, CDK13, KRAS, and B-Raf. In some embodiments, the crystalline forms or sait forms of compound 1 as disclosed herein can be combined with one or more inhibitors of CD47 and MALT1 proteins for the treatment of cancer.

[00569] In some embodiments, the crystalline sait forms of compound 1 as disclosed herein can be used in combination with one or more Poly ADP ribose polymerase (PARE) inhibitors for the treatment of a disease disclosed herein such as cancer. Exemplary PARP inhibitors include, but are not limited to, olaparib (Lynparza®), rucaprib (Rubraca®) niraparib (Zejula®), talzoparib (Talzenna®) and TPST-1120.

[00570] In some embodiments, the crystalline sait forms of compound 1 as disclosed herein can be used in combination therapy with any of the kinase inhibitors disclosed herein for the treatment of diseases such as cancer. Exemplary kinase inhibitors include imatinib, baricitinib gefitinib, erlotinib, sorafenib, dasatinib, sunitinib, lapatinib, nilotinib, pirfenidone, zanubrutinib, updacitinib, fedratinib, entrectinib, alpelisib, pazopanib, crizotinib, vemurafenib, vandetanib, ruxolitinib, axitinib, bosutinib, regorafenib, tofacitinîb, cabozantinib, ponatinib, trametinib, dabrafenib, afatinib, ibrutinib, ceritinib, idelalisib, nintedanib, palbociclib, lenvatinib, cobimetinîb, abemaciclib, acalabrutinib, alectinib, binimetinib, brigatinib, encorafenib, erdafitinib, everolimus, fostamatinib, gilter, larotrectinib,

117 lorlatinib, netarsudil, osimertinib, pexidartinib, ribociclib, temsirolimus, XL-147, XL-765, XL-499, and XL-880. In some embodiments, a compound as described herein can be used in combination with a HSP90 inhibitor (e.g., XL888), liver X receptor (LXR) modulators, retinoid-related orphan receptor gamma (RORy) modulators, a CK1 inhibitor, a CKl-a inhibitor, a Wnt pathway inhibitor (e.g., SST-215), or a mineralocorticoid receptor inhibitor, (e.g., esaxerenone or XL- 550) for the treatment of a disease disclosed herein such as cancer.

[00571] In some embodiments, the crystalline sait forms of compound 1 as disclosed herein can be used in combination with polatuzumab vedotin for the treatment of a disease disclosed herein such as cancer.

Labeled Compounds and Assay Methods

[00572] Another aspect relates to labeled crystalline sait forms of Compound 1 (radîo-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating TAM kinases in tissue samples, including human, and for identifying TAM kinase ligands by inhibition binding of a labeled compound. Accordingly, the présent invention includes TAM kinase assays that contain such labeled compounds.

[00573] The présent invention further includes isotopicaliy-iabeled crystalline sait forms of Compound 1. An “isotopically” or “radio-labeled” compound is a crystalline sait form of Compound 1 where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). Suitable radionuclides that may be incorporated in compounds of the présent invention include but are not limited to ²H (also written as D for deuterium), ³ H (also written as T for tritium), ^,!C, ^,3C, ¹⁴C, ¹³N, ^1SN, ¹⁵O, ¹⁷O, ^1SO, ^,8F, ³⁵S, ³⁶C1, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁱ²³I, ¹²⁴I, ¹²⁵I, and ^l3lI. The radionuclide that is incorporated in the instant radio-labeled compounds will dépend on the spécifie application of that radio-labeled compound. For example, for in vitro metalloprotease labeling and compétition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵S will generally be most useful. For radio-imaging applications ¹ ’C, ¹⁸F, ^l25I, ¹²³I, ^l24I, ^13lï, ⁷⁵Br, ⁷⁶Br, or ⁷⁷Br will generally be most useful. In some embodiments, the crystalline forms or crystalline sait forms described herein in which one or more hydrogens is/are replaced by deuterium, such as hydrogen bonded to a carbon atom. Such compounds exhibit increased résistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human.

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[00574] It is understood that a “radio-label ed” or “labeled compound” is a compound that has incorporated at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of ³H, ^l4C, ¹²⁵I, ³⁵S, and ⁸²Br.

[00575] The present invention can further include synthetic methods for incorporating radioisotopes into crystalline sait forms of Compound 1. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art, and a person of ordinary skill in the art will readîly recognize the methods applicable for the compounds of invention.

[00576] A labeled crystalline sait form of Compound 1 can be used in a screening assay to identîfy/evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a TAM by monitoring its concentration variation when contacting with the TAM kinases, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a TAM kinase (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the TAM kinase directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled, and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the compétition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.

[00577] PREPARATIONS AND EXAMPLES

[00578] General Experimental Techniques |00579] Aqueous Slurry Experiments: Salts of Compound 1 that were determined to hâve aqueous solubility less than 1 mg/mL were slurried in 20 mL of water at ambient température for 1 day.

Solids were then coilected by vacuum filtration and analyzed by XRPD.

[00580] Crash Cooling (CC): Concentrated solutions of Compound 1 and various counterions were prepared in MeOH at elevated température with stirring. Capped vials contaîning hot solutions were transferred to the freezer (—20 °C) and rapidly cooled. Solids that were formed were coilected. If no solids were present, additional crystallization techniques were employed.

[00581] Crash Précipitation (CP): Clear solutions of Compound 1 and coformer were prepared in various solvents at RT. Alîquots of various anti-solvents were added to the solution, slowly, with

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(00582] Fast Cooling (FC): Concentrated solutions of Compound 1 and various counterions were prepared in acetone or MeOH at elevated température with stirring. Capped vials containing bot solutions were transferred to the bench top at ambient température. Solids that were formed were collected. If no solids were présent, additional crystallization techniques were employed.

[00583] Fast Evaporation (FE): Clear solutions of Compound 1 and coformer were prepared in various solvents. Vials were left uncapped and solvent evaporated at ambient conditions.

[00584] Interconversion Slurry: A slurry of Compound 1 Form A was prepared by adding enough solids to a given solvent System at ambient conditions so that undissolved solids were présent. The mixture was then agitated for an extended period of time to ensure saturation. Solids of the forms of interest were then added to an aliquot of the saturated solution (filtered through a 0.2-pm nylon filter) so that undissolved solids were présent. The mixture was then agitated at ambient température for an extended period of time, and the solids were isolated.

[00585] Isolation Techniques: In general, isolation was do ne quickly after removîng non-ambient samples from their respective température control devices to minîmize équilibration to ambient température prior to isolation of the solids.

[00586] Decanting Liquid Phase: Some of the solids isolated from solution-based crystallization techniques were collected by centrifuging the suspension (if needed) and discarding the liquid phase, leaving behind damp solids. Solids were dried briefly (e.g. air dried or under nitrogen) unless specified as “analyzed damp” herein.

[00587] Poitive-Pressure Filtration: Solids were collected on 0.2-μιη nylon or PTFE filters by pressing a slurry through a syringe and Swinnex filter holder assembly. In general, solids were dried briefly by blowing a 20-mL syringe of air over the filter. If desîgnated as “analyzed damp” herein, solids were left damp with mother liquor. Some samples were additionally dried briefly under a gentle stream of nitrogen gas prior to analysis.

[00588] Vacuum Filtration: Solids were collected on paper or nylon filters by vacuum filtration and air dried on the filters under reduced pressure briefly before transferring to a vial.

[00589] Reaction Crystallization (RC): A mixture of Compound 1 and various coformers were combined in an elevated température, acetone slurry, such that the molarity of coformer was 2-fold

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I greater than the API. The solution stirred for a given period of time. Additional crystallization techniques were employed when clear solutions were observed.

[00590] Stability Testing: Various Compound 1 salts were placed in open vials within a 75% RH chamber (saturated sodium chloride solutiona). The RH chamber was placed in a 40 °C oven for 1516 days. Sampies were analyzed by PLM and XRPD upon the end of the duration.

[00591] Slow Cooling (SC)'. Concentrated solutions of Compound 1 and various cofonners were prepared in a variety of solvents at elevated températures with stirring. Vials were capped in the heated sample block and the hot plate was tumed off, allowing the vials to graduai]y cool to ambient température in the heated vial block. Clear solutions, upon cooling to ambient, were further cooled in the refrigerator (5 to 7 °C) and/or the freezer (—20 °C). If no solids were présent, additional crystallization techniques were employed.

[00592] Slow Evaporation: Solutions were prepared in various solvents with agitation and, typically, fdtered through a 0.2-pm nylon or PTFE filter. Each solution was allowed to evaporate from a covered vial (such as loosely capped or covered with perforated aluminum foil) at ambient conditions, unless otherwîse stated. Solutions were allowed to evaporate to dryness unless designated as partial évaporations (solid présent with a small amount of solvent remaining), in which case solids were isolated as described herein.

[00593] Solubility Estimation: Aliquots of various solvents were added to measured amounts of Compound 1 with agitation (typically sonication) at stated températures until complété dissolution was achieved, as judged by visual observation. If dissolution occurred after the addition of the first aliquot, values are reported as If dissolution did not occur, values are reported as <.”

[00594] Aqueous Solubility Estimation: Aliquots of water were added to measured amounts of various Compound 1 salts with sonication.

[00595] Slurry Experiments: Saturated solutions of Compound 1 and various cofonners were prepared in a variety of solvents and solvent mixtures. Mixtures were stirred at ambient and elevated températures for the noted duration of time. Solids were collected by the stated technique and additional crystallization techniques were employed where approprîate.

[00596] Vacuum Oven Desolvation: Salts of Compound 1 that were determined to be solvatés by various analytical methods underwent an attempted desolvation. Sampies were placed in a vacuum oven at températures ranging from ambient to 80 °C for a given period of time. Sampies were analyzed by XRPD and/or TGA for détermination of desolvation success.

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[00597] Vapor Diffusion: Concentrated solutions were prepared in various solvents and, typically, filtered through a 0.2-pm nylon or PTFE filter. The filtered solution was dispensed into a small vial, which was then placed inside a larger vial containing anti-solvent. The small vial was left uncapped and the larger vial was capped to allow vapor diffusion to occur. Any solids présent were isolated as described herein.

[00598] Vapor Stressing: Select solids were transferred to a small vial, which was then placed inside a larger vial containing solvent. The small vial was left uncapped and the larger vial was capped to allow vapor stressing to occur at the stated température.

[00599] Coformer means one or more pharmaceutically acceptable bases and/or pharmaceutically acceptable acids disclosed herein in association with Compound 1. Exemplary coformers as used herein include benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, HBr, lactic acid, malic acid, maleic acid, methanesulfonic acid, oxalic acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, and toluenesulfonic acid.

[00600] Instrumental Techniques

[00601] Differential Scanning Calorimetry (DSC): DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimeter. Température calibration was performed using adamantane, phenyl salicylate, indium, tin, and zinc. The sample was placed into a hennetically sealed or an open aluminum DSC pan, and the weight was accurately recorded. A weighed aluminum pan configured as the sample pan was placed on the reference side of the cell. The samples were analyzed from -30 to 250 °C at a ramp rate of 10 °C/min. Although thermograms are plotted by reference température (x-axis), results are reported according to sample températures.

[00602] Dynamic Vapor Sorpiion (DVS)

[00603] a. VTI: Automated vapor sorption (VS) data were collected on a VTI SGA-100 Vapor Sorption Analyzer. NaCl and P VP were used as calibration standards. Samples were dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH incréments under a nitrogen purge. The equilibrium criterion used for analysis was less than 0.0100% weight change in 5 minutes with a maximum équilibration time of 3 hours. Data were not corrected for the initial moisture content of the samples.

[00604] b. Intrinsic: Automated vapor sorption (VS) data were collected on a Surface Measurement System DVS Intrinsic instrument. Samples were not dried prior to analysis. Sorption and desorption data were collected over a range from 5% to 95% RH at 10% RH incréments under a

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[00605] Hot stage Microscopy (HSM): Hot stage microscopy was performed using a Linkam hot stage (FT1R 600) mounted on a Leica DM LP microscope equipped with a SPOT Insight™ color digital caméra. Température calibrations were performed using US P melting point standards.

Samples were placed on a cover glass, and a second cover glass was placed on top of the sample. As the stage was heated, each sample was visually observed using a 20x objective with crossed polarizers and a first order red compensator. Images were captured using SPOT software (v. 4.5.9). [00606] Optical Microscopy. Samples were observed under a Motic or Wolfe optical microscope with crossed polarizers or under a Leica stereomîcroscope with a first order red compensator with crossed polarizers.

[00607] pKa and logP Détermination'. pKa and logP détermination were performed by Pion Inc./Sirius Analytical Instruments Ltd. in East Sussex, United Kingdom.

[00608] Solution Proton Nuclear Magnetic Résonance Spectroscopy (¹HNMRf. The solution ^lH NMR spectra were acquired by Spectral Data Services of Champaign, IL. The samples were prepared by dissolving approximately 5-10 mg of sample in DMSO-d(,. The data acquisition parameters are displayed on the first page of each spectrum in the Data section of this report.

[00609] Thermogravimetric Analysis (TGA)·. Thermo gravimétrie analyses were performed using a Mettler Toledo TGA/DSC3+ analyzer. Température calibration was performed using phenyl salicylate, indium, tin, and zinc. The sample was placed in an aluminum pan. The open pan was inserted into the TG fumace. The fumace was heated under nitrogen. Each sample was heated from ambient température to 350 °C, at ramp rates of 2, 5, or 10 °C/min. Although thermograms are plotted by reference température (x-axis), results are reported according to sample températures.

[00610] X-ray Polder Diffraction (XRPD)

[00611] a. Reflection'. XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu Ka radiation produced using a long, fme-focus source and a nickel filter at room température (298 Kelvin). The diffractometer was configured using the symmetric Bragg-Brentano geometry. Prior to the analysis, a Silicon specimen (NIST SRM 640e) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen of the sample was packed in a well. Antiscatter slits (SS) were used to

123 minimize the background generated by air. Seller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collecter software v. 2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence sût (DS) and the incident-beam SS. [00612] b. Transmission: XRPD patterns were collected with a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optîx long, fîne-focus source at room température (298 Kelvin). An elliptically graded multilayer mirror was used to focus Cu Ka X-rays through the specimen and onto the detector. Prier to the analysis, a Silicon specimen (NIST SRM 64Üe) was analyzed to verify the observed position of the Si 111 peak is consistent with the NIST-certified position. A specimen ofthe sample was sandwiched between 3-pm-thick films and analyzed in transmission geometry. A beam-stop, short antiscatter extension, antiscatter knife edge, were used to minimize the background generated by air. Soller slits for the incident and diffracted beams were used to minimize broadening from axial divergence. Diffraction patterns were collected using a scanning position-sensitive detector (X’Celerator) located 240 mm from the specimen and Data Collecter software v. 2.2b. The data acquisition parameters for each pattern are displayed above the image in the Data section of this report including the divergence slit (DS) before the mirror.

[00613] XRPD Indexing

[00614] Indexing and structure refinement are computational studies. Within the figure referenced for a given indexed XRPD pattern, agreement between the allowed peak positions, marked with bars, and the observed peaks indicates a consistent unit cell détermination. Successful indexing of a pattern indicates that the sample is composed primarily of a single crystalline phase unless otherwise stated. Space groups consistent with the assigned extinction symbol, unit cell parameters, and derived quantities are tabulated.

[00615] Examples

[00616] Préparative Example 1: Synthesis of Compound 1

[00617] STEP 1: N-(4-Fluorophenyl)-N-(4-hydroxyphenyl)cyclopropane-l,l-dicarboxamide (4):

EDCI *

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[00618] To a solution of Compound 2 (10 g, 44.80 mmol, 1 eq.) and Compound 3 (5.87 g, 53.8 mmol, 1.2 eq.) in dimethyl acetamide (DMA) (60 mL) was added 3-(ethyliminomethyleneamino)N,N-dimethyl-propan-l-amine hydrochloride (EDCI) (10.31 g, 53.8 mmol, 1.2 eq.). The mixture was stirred vigorously at 20 °C until the reaction was complété. The mixture was poured into aqueous (aq) saturated NaHCO₃ (400 mL) and extracted with EtOAc (4 x 100 mL). The combined organic phases were washed with aqueous saturated NaCI (100 mL), dried over anhydrous (anhyd) Na₂SO4, and concentrated. Compound 4 (21 g, crude) (50% purity) was obtained. ^lH NMR (400 MHz, DMSO-rfe) δ 10.16 (br s, 1H), 9.72 (br s, 1H), 7.61 (dd, 2H), 7.34 (d, 2H), 7.13 (t, 2H) 6.68 (d, 2H), 1.42 (s, 4H); MS (El) for C_i7Hi5FN₂O₃, found 314.9 (MH+).

[00619] STEP 2: Methyl 4-[4-[[l-r(4-fluorophenyl)carbamovi]cvclopropanecarbonyl]amino]phenoxy]-7-methoxyquinoÎine-6-carboxvlate (6): o ci Ό

HO

H N

^F Pd(OAc)₂

TrixiePhos, Anisole, 110 °C

[00620] A mixture of Compound 4 (5.99 g, 9.5 mmol, 1.2 eq.), Compound 5 (2 g, 8.0 mmol, 1.0 eq.), Pd(OAc)₂ (89 mg, 397.4 μιηοΐ, 0.05 eq.), rac-2-(Di-fer/-butylphosphino)-l,l'-binaphthyl (TrixiePhos, 316.71 mg, 794.7 μmol, 0.1 eq.), and K3PO4 (2.53 g, 11.9 mmol, 1.5 eq.) in anisole (50 mL) was stirred at 110 °C for 2 hours (h) under an atmosphère of nitrogen. The mixture was filtered, and the fïltrate was concentrated. The residue was purified by flash silica gel chromatography (1:1 Petroleum ether:EtOAc to 20:1 EtOAc:MeOH). Compound 6 was obtained (2.6 g, 61.8% yield). 'H NMR (400 MHz, CDCh) δ 9.38 (s, IH), 8.80 (s, 1H), 8.63 (d, 2H), 7.64 (d, 2H), 7.54-7.41 (m, 3H), 7.18 (d, 2H), 7.09-7.01 (m, 2H), 6.43 (d, 1H), 4.05 (s, 3H), 3.97 (s, 3H), 1.78-1.72 (m, 2H), 1.691.63 (m, 2H); MS (El) for C₂9H34FN3O6, found 530.0 (MH+).

[00621] STEP 3: 4-[4-[[1 -r(4-Fluorophenyr)carbamovl]cvclopropane-carbonvl1amino]phenoxvlTmiefljqvyqumqhnetoz^^

F

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[00622] To a solution of Compound 6 (1.8 g, 3.4 mmol, 1 eq.) in tetrahydrofuran (THF) (15 mL) and MeOH (15 mL) was added 2 M aqueous NaOH (7 mL, 4.1 eq.). The mixture was stirred at 6-13 °C for 4 hours. The mixture was adjusted to a pH of approximately 8 with 1 M aqueous HCl and concentrated to remove solvent. Water (50 mL) was added, and the mixture was adjusted to a pH of approximately 6 with I M aqueous HCl. The resulting precipitate was filtered, washed with water (2 x 10 mL), and dried under vacuum. Compound 7 was obtained (1.7 g, 97.0% yield). 'H NMR (400 MHz, DMSO-dô) δ 10.22 (s, 1H), 10.08 (s, IH), 8.65 (d, 1H), 8.48 (s, 1H), 7.77 (d, 2H), 7.64 (dd, 2H) 7.47 (s, 1H), 7.25 (d, 2H), 7.15 (t, 2H), 6.45 (d, 1H), 3.96 (s, 3H), 1.47 (s, 4H); MS (El) for C2sH22FN₃O₆, found 516.1 (MH+).

[00623] STEP 4: 1 -N'-(4-FIuoronhenyl)-l-N-[4-[7-methoxv-6-|methylcarbamovl)quinolm-4ylloxyphenvllcyclopropane-l.l-dicarboxamide (1)

[00624] A solution of Compound 7 (300 mg, 582.0 pmol, 1 eq.), HATU (332 mg, 873.2 pmol,

1.5 eq.), and DIEA (301 mg, 2.3 mmol, 406 pL, 4 eq.) in DMF (10 mL) was stirred at 6-10 °C for 1 hour. Methanamine hydrochloride (79 mg, 1.2 mmol, 2.0 eq.) was added, and the mixture was stirred at 6-10 °C for 17 hours. The mixture was filtered, and the resulting filtrate purified by prep HPLC (Column: Waters Xbridge 150 mm*25 mm*5 pm, gradient: 33-63% of acetonitrile in 10 mM aqueous NH4HCO3, flow rate: 25 mL/min). Compound 1 was obtained (105.4 mg, 34.3% yield). 'H NMR (400 MHz, DMSO-Æ) δ 10.20 (s, 1H), 10.06 (s, 1H), 8.65 (d, 1H), 8.61 (s, 1H), 8.42-8.33 (m, 1H), 7.77 (d, 2H), 7.68-7.61 (m, 2H), 7.51 (s, 1H), 7.25 (d, 2H), 7.19-7.11 (m, 2H), 6.46 (d, 1H), 4.02 (s, 3H), 2.84 (d, 3H) 1.47 (s, 4H); MS (El) for C29H25FN4O5, found 529.1 (MH+).

[00625] Example 1: Préparation of Compound 1 Besylate Form A

[00626] One molar équivalent of benzenesulfonic acid in hot acetone was added to Compound 1. The resulting slurry was then stirred at —50 °C for 3 days. Solids were collected by positive pressure filtration.

[00627] Example 2: Préparation of Compound 1 Besylate Form B

[00628] Compound 1 Besylate Form A was placed in a vacuum at 80 °C for 1 day to provide a mixture of Compound 1 Besylate Form A and Compound 1 Besylate Form B.

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[00629] Example 3: Préparation of Compound 1 Benzoate Form A

[00630] To one molar équivalent ofbenzoic acid and Compound 1 was added hot methanol. The resulting solution was stirred for 20 minutes at -60 °C. The solution was then crash cooled to -20 °C and let stand for 1 day. The solids were filtered by vacuum filtration.

[00631] Example 4: Préparation of Compound 1 Camsylate Form A

[00632] One molar équivalent of camphorsulfonic acid in hot acetone was added to Compound 1.

The resulting solution was then stirred at -50 °C for 3 days. Solids were collected by positive pressure filtration.

[00633] Example 5: Préparation of Compound 1 Camsylate Form B

[00634] Compound 1 Camsylate Form A was placed in a vacuum at 80 °C for 1 day to provide Compound 1 Camsylate Form B.

[00635] Example 6: Préparation of Compound 1 Citrate Form A

[00636] One molar équivalent of citric acid in acetone was added to Compound 1. The resulting solution was then stirred at -50 °C for 4 days. The mixture was then slow cooled to room température over 2 hours, and 3 mL acetone was added and the solution was stirred for an additional day at room température. Solids were collected by positive pressure filtration.

[00637] Example 7: Préparation of Compound 1 Citrate Form B

[00638] Two molar équivalents of citric acid in acetone was added to Compound 1. The resulting solution was then stirred at -50 °C for 6 days. Solids were collected by positive pressure filtration of the hot solution.

[00639] Example 8: Préparation of Compound 1 Esylate Form A

[00640] One molar équivalent of ethanesulfonic acid in hot acetone was added to Compound 1.

The resulting solution was then stirred at -50 °C for 3 days. Solids were collected by positive pressure filtration.

[00641] Example 9: Préparation of Compound 1 Esylate Form B

[00642] Compound 1 Esylate Form A was placed in a vacuum at 80 °C for 1 day to provide Compound 1 Esylate Form B.

[00643] Example 10: Préparation of Compound 1 HBr Form A

[00644] One molar équivalent of hydrobromic acid was added to a slurry of Compound 1 in hot acetone. The resulting solution was then stirred at -50 °C for 3 days. Solids were collected by positive pressure filtration.

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[00645] Example 11: Préparation of Compound 1 HBr Form B

[00646] One molar équivalent of hydrobromic acid was added to a slurry of Compound 1 in hot MEK. The resulting solution was then stirred at ~55 °C for 1 day. Solution was then slow cooled.

[00647] Example 12: Préparation of Compound 1 Lactate Form A

[00648] One molar équivalent of lactic acid was added to a slurry of Compound 1 in hot acetone. The resulting solution was then stirred at -50 °C for 3 days. Solids were collected by positive pressure filtration.

[00649] Example 13A: Préparation of Compound 1 Malate Form A

[00650] One molar équivalent of malîc acid in acetone was added to Compound 1. The resulting solution was then stirred at -50 °C for 4 days, slow cooled to room température over 2 hours, diluted with 3 mL acetone, and stirred at room température for 1 day. Solids were collected by positive pressure filtration.

[00651] Example 13B: Préparation of Compound 1 Malate Form A

[00652] Two molar équivalents of malic acid in acetone was added to Compound 1. The resulting solution was then stirred at -50 °C for 6 days. Solids were collected by positive pressure filtration of the hot solution.

100653] Example 14A: Préparation of Compound 1 Maleate Form A

[00654] One molar équivalent of aqueous maleic acid was added to a slurry of Compound 1 in MEK, as to provide a resulting solution of 1:7 water/MEK. The resulting solution was then stirred at —55 °C for 5 minutes to 1 day, slow cooled, and the solvent partially evaporated (FE).

[00655] Example 14B: Préparation of Compound 1 Maleate Form A

[00656] Two molar équivalents of maleic acid in hot acetone were added to Compound 1. The resulting solution was then stirred at -50 °C for 1 day, and then the solution was fast cooled to room température. Solids were collected by positive pressure filtration of the hot solution.

[00657] Example 15: Préparation of Compound 1 Maleate Form B

[00658] (scale up) Two molar équivalents of maleic acid and Compound 1 were slurried in hot acetone ai -50 °C, with seed crystals 2 days. Solids were collected by vacuum filtration to provide a mixture of Compound 1 Maleate Forms A and B.

[00659] Example 16: Préparation of Compound 1 Mesylate Form A

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[00660] One molar équivalent of methanesulfonic acid was added to a sluny of Compound 1 in THF at room température. The sluny was stirred at room température for 3 days, and the solids were collected by positive pressure filtration.

[00661] Example 17: Préparation of Compound 1 Mesylate Form B

[00662] One molar équivalent of methanesulfonic acid was added to a sluny of Compound 1 in chloroform. The slurry was then stirred at -50 °C for 3 days. The solution was then slow cooled to room température. Heptane was added so that the final solution was about S: 1 chloroform to heptane, and the solution was stirred for 5 hours. The solids were collected by positive pressure filtration.

[00663] Example 18: Préparation of Compound 1 Mesylate Form C

[00664] One molar équivalent of methanesulfonic acid was added to a solution of Compound 1 in methanol at ~60 °C. The solution was then crash cooled to -20 °C, and let stand for 2 days. The solvent was partially evaporated and MTBE was added so that the final solution was about 2:5 methanol to MTBE, and the solution was stirred for 5 hours. The solids were collected by positive pressure filtration.

[00665] Example 19: Préparation of Compound 1 Oxylate Form A

[00666] One molar équivalent of oxalic acid in hot acetone was added to Compound 1. The resulting solution was then stirred at -50 °C for 3 days. Solids were collected by positive pressure filtration.

[00667] Example 20: Préparation of Compound 1 Oxylate Form B

[00668] One molar équivalent of aqueous oxalic acid at 55 °C was added to a slurry of Compound 1 in MEK, as to provide a resulting solution of 1:7 water/MEK. The resulting solution was then stirred at -55 °C for 1 day, slow cooled, and the solvent partially evaporated (FE).

100669] Example 21 : Préparation of Compound 1 Oxylate Form C

[00670] One molar équivalent of oxalic acid in TFE at 55 °C was added to Compound i. The resulting solution was then slow cooled to room température for 1 day, placed in the refrigerator at 2-8 °C for 2 hours, and then placed in the freezer at -20 °C for 6 days. The solution was then crash precipitated with 1 volume of MTBE, stirred at room température for 1 day, and filtered by positive pressure filtration.

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[00671J Example 22: Préparation of Compound 1 Propionate Form A

[00672] One molar équivalent of propionic acid was added to Compound 1 in hot acetone. The resulting solution was then stirred at -50 °C for 3 days. Solids were collected by positive pressure filtration.

[00673] Example 23A: Préparation of Compound 1 Succinate Form A

[00674] One molar équivalent of succinic acid was added to Compound 1 in acetone. The resulting solution was then stirred at -50 °C for 4 days, then slow cooled to room température and stirred for another day. Solids were collected by positive pressure filtration.

[00675] Example 23B: Préparation of Compound 1 Succinate Form A

[00676] Two molar équivalents of succinic acid was added to Compound 1 in acetone. The resulting solution was then stirred at -50 °C for 6 days. Solids were collected by positive pressure filtration.

[00677] Example 24; Préparation of Compound 1 Sulfate Form A

[00678] One molar équivalent of sulfurie acid was added to a slurry of Compound 1 in THF. The resulting solution was then stirred at room température for 3 days. Solids were collected by positive pressure filtration.

[00679] Example 25: Préparation of Compound 1 Sulfate Form B

[00680] One molar équivalent of sulfuric acid was added to Compound 1 in methanol at -60 °C.

The resulting solution was then crash cooled to -20 °C and let stand for 2 days. The solvent was then evaporated (FE) to provide the title form.

[00681] Example 26: Préparation of Compound 1 Sulfate Form C

[00682] One molar équivalent of sulfuric acid was added to Compound 1 in cliloroform, and the resulting solution was stirred at -50 °C for 3 days. The resulting solution was then slow cooled to room température and let stand for 1 day. Solids were collected by positive pressure filtration.

[00683] Example 27: Préparation of Compound 1 Tartrate Form A

[00684] One molar équivalent of L-tartaric acid was added to Compound 1 in THF, and the resulting solution was stirred at room température for 3 days. Solids were collected by positive pressure filtration.

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[00685] Example 28: Préparation of Compound 1 Hemitartrate Form B

[00686] One molar équivalent of L-tartaric acid was added to Compound 1 in acetone, and the resulting solution was stirred at -50 °C for 34days. The resulting solution was then slow cooled to room température and let stand for 1 day. Solids were coilected by positive pressure filtration.

[00687] Example 29: Préparation of Compound 1 Tosylate Form A

[00688] One molar équivalent of p-toluenesulfonic acid was added to Compound 1 in acetone, and the resulting solution was stirred at -50 °C for 3 days. Solids were coilected by positive pressure filtration.

[00689] Example 30: Préparation of Compound 1 Tosylate Form B

[00690] (scale up) One molar équivalent of p-toluenesulfonîc acid in hot acetone was added to Compound 1 in acetone at -50 °C. Seed crystals were then added, and the resulting solution was stirred at -50 °C for 2 days.

Other Embodiments

[00691] The foregoing disclosure has been described in some detail by way of illustration and example, for purposes of clarity and understanding. The invention has been described with reference to various spécifie and preferred embodiments and techniques. However, it should be understood that many variations and modifications can be made while remainîng within the spirit and scope of the invention. It will be obvious to one of skill in the art that changes and modifications can be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive.

[00692] The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the fiill scope of équivalents to which such claims are entitled.

Claims (13)

1. A crystalline sait form of Compound 1

Compound 1 selected from the group consisting of Compound 1 Besylate Form A, Compound 1 Besylate Form B, Compound 1 Benzoate Form A, Compound 1 Camsylate Form A, Compound 1 Camsylate Form B, Compound 1 Citrate Form A, Compound 1 Citrate Form B, Compound 1 Esylate Form A, Compound 1 Esylate Form B, Compound 1 HBrForm A, Compound 1 HBrForm B, Compound 1 Lactate Form A, Compound 1 Malate Form A, Compound 1 Maleate Form A, Compound 1 Maieate Form B, Compound 1 Mesylate Form A, Compound 1 Mesylate Form B, Compound 1 Mesylate Form C, Compound 1 Oxalate Form A, Compound 1 Oxalate Form B, Compound 1 Oxalate Form C, Compound 1 Propionate Form A, Compound 1 Succinate Form A, Compound 1 Sulfate Form A, Compound 1 Sulfate Form B, Compound 1 Sulfate Form C, Compound 1 Tartrate Form A, Compound 1 Hemitartrate Form B, Compound 1 Tartrate Form C, Compound i Tosylate Form A, and Compound 1 Tosylate Form B.

2. The crystalline sait form of claim 1, wherein:

Compound 1 Besylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.78, 7.56, 10.08, 10.42, 1 ] .70, 11.78, 12.00, 12.71, 13.20, 13.92, 14.06, 14.44, 14.93, 15.18, 15.96, 16.21, 16.40, 16.73, 16.86, 17.38, 18.32, 19.07,20.07, 20.26, 20.51, 20.94, 21.45, 21.60, 22.30, 22.90, 23.05, 23.28, 23.71, 24.28, 24.97, 25.30, 25.69, 26.33, 26.71,27.29, 27.65, 28.07, 29.22, and 29.50

Compound 1 Besylate Form B is characterized by an XRPD pattern substantially identical to Figure 4;

Compound 1 Benzoate Form A is characterized by an XRPD pattern substantially identical to Figure 5;

Compound 1 Camsylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.55, 7.90, 8.25, 8.38, 9.55, 9.87, 10.26,

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11.12, 11.34, 12.50, 12.94, 13.40, 13.65, 14.79, 15.83, 16.16, 16.41, 16.54, 16.82, 17.10, 17.69, 18.02, 18.22, 18.47, 18.91, 19.10, 19.47, 20.04, 20.87, 21.05, 22.16, 22.36, 22.93, 23.71, 24.55, 25.33, 26.02, 26.40, 27.09, 27.33, 27.97, 28.32, 28.68, and 28.98;

Compound 1 Camsylate Fonn B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.25, 8.32, 8.51, 8.76, 9.05, 9.58, 9.88, 10.00, 10.52, 10.80, 11.06, 11.96, 12.24, 12.58, 13.98, 15.62, 15.81, 16.15, 16.70, 17.12, 17.42, 17.71, 18.41, 19.37, 19.55, 20.63, 21.13, 21.56, 21.89, 22.50, 23.04, 24.43, 26.08, 27.07, 27.97, 28.22, and 28.73;

Compound 1 Citrate Fonn A is characterized by an XRPD pattern substantially identical to Figure 10;

Compound 1 Citrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.58, 5.95, 7.61, 8.88, 9.19, 9.94, 11.93, 13.26, 13.79, 14.29, 14.68, 15.26, 15.95, 16.64, 17.11, 17.87, 18.21, 18.43, 18.90, 19.36, 19.67, 20.14, 20.57, 21.47, 22.30, 22.64, 23.06, 23.80, 24.25, 24.55, 24.81, 25.10, 25.45, 25.54, 25.85, 26.35, 26.51, 26.83, 27.16, 27.57, 27.85, 28.08, and 28.47;

Compound 1 Esylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.97, 7,95, 9.89, 10.62, 10.92, 11.03, 11.34, 11.77, 12.03, 12.53, 12.71, 13.27, 14,00, 14.70, 15.08, 15.94, 16.17, 16.92, 17.01, 17.19, 17.35, 17.61, 18.15, 18.76, 19.03, 19.66, 19.89,20.26,20.65,20.78,21.44,22.08,23.14, 23.27, 23.99, 24.32, 25.43, 25.66, 25.85, 26.52, 26.87, 27.61, 27.96, 28.18, 28.40, and 28.91;

Compound 1 Esylate Form B is characterized by an XRPD pattern substantially identical to Figure 18;

Compound 1 HBr Form A is characterized by an XRPD pattern substantially identical to Figure 19; Compound 1 HBr Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.26, 8.29, 9.75, 9.91, 10.56, 10.72, 12.25, 12.50, 12.75, 13.31, 13.54, 14.11, 14.72, 14.89, 15.87, 16.29, 16.50, 17.36, 17.78, 18.09, 18.44, 18.75, 19.12, 19.24, 19.56, 19.92, 20.40, 20.55, 20.69, 21.18, 22.09, 22.64, 23.24, 24.56, 25.80, 26.52, 27.23, 27.43, 28.13, 28.46, 28.76, 29.08, 29.66, and 30.07;

Compound 1 Lactate Fonn A is characterized by an XRPD pattern substantially identical to Figure 21;

Compound 1 Malate Form A is characterized by an XRPD pattern substantially identical to Figure 22;

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Compound 1 Maleate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 7.58, 8.34, 10.92, 12.38, 12.87, 14.17, 15.13, 15.78,16.43, 16.91, 17.51,18.09,18.71,20.30,21.60,21.99, 22.30, 22.49,23.32,23.56, 23.92, 24.79, 26.04, 26.41, 26.92, 27.62, 28.18, 28.54, and 29.01;

Compound 1 Maleate Form B is characterized by an XRPD pattern substantially identical to Figure 28.

Compound 1 Mesylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.06, 6.65, 7.66, 8.35, 10.16, 10.72, 11.98, 12.62, 13.32, 14.41, 14.79, 15.42, 15.72, 15.89, 16.23, 16.77, 17.20, 17.59, 18.08, 18.40, 18.81, 19.33, 19.53, 19.71,20.14,20.38, 20.73,21.05,21.56,21.83,22.16,23.14, 24.06,24.54, 24.77, 25.75, 26.82, 27.71, 27.94, 28.71, 29.27, and 29.85;

Compound 1 Mesylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.14, 6.62, 7.72, 7.89, 10.33, 10.73,

12.74, 13.31, 13.88, 14.23, 14.61, 15.21, 15.52, 15.87, 16.17, 17.18, 17.41, 17.88, 18.15, 18.46,

18.73, 19.13, 19.54, 20.15, 20.53, 20.75, 20.98, 21.27, 21.60, 22.03, 22.28, 23.07, 23.32, 24.16,

24.42, 24.87, 25.13, 25.64, 26.24, 26.95, 27.17, 27.49, 27.77, 28.42, and 29.54;

Compound 1 Mesylate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 7.55, 9.53, 10.25, 11.04, 11.49, 11.65, 12.24, 12.51, 13.88, 14.44, 15.36, 15.66, 16.29, 16.58, 17.16, 17.54, 19.04, 19.20, 19.79, 20.54, 21.12, 21.24, 21.62, 22.22, 23.15, 23.57, 23.99, 24.61, 24.77, 25.22, 25.61,25.99, 26.60, 26.89, 27.29, 27.91, 29.03, and 29.29;

Compound 1 Oxalate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.90, 5.25, 6.20, 8.05, 9.87, 10.54, 12.29, 14.79, 15.35, 15.84, 16.49, 16.89, 17.55, 18.27, 18.67, 19.12, 19.40, 19.81,20.26, 20.50, 21.06, 21.74, 22.17, 22.93, 23.26, 23.50, 23.81, 24.66, 25.06, 25.95, 26.90, 27.82, and 28.24;

Compound 1 Oxalate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.20, 7.59, 8.02, 8.42, 10.53, 12.36, 12.66, 13.09, 13.35, 13.88, 14.15, 14.46, 15.06, 15.23, 17.42, 17.75, 18.28, 19.07, 19.52, 20.33, 21.18, 21.43, 21.74, 22.08, 22.59, 23.53, 24.21, 24.52, 24.71, 25.24, 25.85, 26.24, 26.55, 26.90, 27.43, 28.56, 29.30, and 29.51;

Compound 1 Oxalate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.13, 7.70, 10.29, 10.59, 13.09, 13.70, 14.13, 15.33, 15.87, 16.57, 17.19, 17.50, 17.83, 18.15, 18.61, 19.24, 19.42,20.11,20.34,20.64,

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21.07, 21.47, 21.59, 21.91, 22.56, 22.92, 23.37, 23.87, 24.35, 25.35, 25.91, 26.47, 26.68, 27.74, 28.47, and 29.14;

Compound 1 Propionate Form A is characterized by an XRPD pattern substantially identical to Figure 38;

Compound 1 Succinate Form A is characterized by an XRPD pattern substantially identical to Figure 39;

Compound 1 Sulfate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.74, 5.85, 9.47, 10.04, 11.74, 11.95, 13.77, 14.99, 15.42, 15.71, 16.48, 17.36, 17.66, 17.92, 18.59, 18.95, 19.36, 19.74,20.22,20.77, 21.38, 21.86, 22.74, 23.30, 23.70, 24.33, 25.07, 25.32, 25.67, 26.23, and 27.00;

Compound 1 Sulfate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks îs selected from 4.27, 8.57, 9.32, 10.95, 11.29, 12.07, 12.87, 13.25, 13.82, 14.13, 14.67, 16.94, 17.21, 17.64, 19.99, 20.26, 21.03, 21.44, 22.00, 22.71, 23.85, 25.20, and 26.02;

Compound 1 Sulfate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected front 3.19, 5.35, 9.04, 9.62, 10.73, 11.31, 11.60, 12.27, 12.67, 13.76, 14.31, 14.65, 15.21, 15.63, 16.11, 16.33, 16.63, 17.11, 18.32, 18.75, 18.99, 19.36, 19.47, 20.16, 20.55, 21.01, 21.52,21.62,21.89,22.19, 22.53, 23.19, 23.79, 24.23, 24.81, 25.07, 25.41,26.06, 26.73, 27.58, 28.16, 28.63, 28.90, 29.22, 29.47, and 29.73;

Compound 1 Tartrate Form A is characterized by an XRPD pattern substantially identical to Figure 43;

Compound 1 Hemitartrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.17, 5.66, 7.22, 9.27, 10.10, 10.40, 11.37, 11.55, 12.77, 13.94, 14.51, 15.60, 16.06, 16.48, 17.09, 17.69, 17.90, 18.27, 18.94, 19.15, 19.59, 19.81, 20.06, 20.32, 21.23, 21.83, 22.34, 22.84, 23.53, 24.26, 24.70, 25.26, 25.80, 26.78, 27.29, 27.90, 29.04, and 29.45;

Compound 1 Tartrate Form C is characterized by an XRPD pattern substantially identical to Figure 69;

Compound 1 Tosylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks îs selected from 5.81, 7.05, 8.52, 9.74, 10.40, 10.99, 11.26, 11.66, 12.58, 12.81, 14.28, 14.62, 15.30, 15.80, 16.03, 16.34, 17.12, 17.55, 18.03, 18.94, 19.26, 19.67, 20.31, 20.65, 21.02, 21.43, 22.11, 22.44, 22.66, 22.94, 23.07, 23.54, 23.79, 24.55, 24.88, 25.42, 25.83, 26.10, 26.53, 27.70, 28.11,28.62, 29.18, 29.40, 29.66, and 29.83; and

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Compound 1 Tosylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.61, 8.69, 9.25, 10,68, 12.44, 12.69, 13.76, 14.42, 14.81, 15.47, 16.08, 16.57, 17.45, 17.76, 18.44, 18.83, 19.01, 19.35,20.42,20.84, 21.15, 21.69, 22.09, 22.86, 23.12, 24.08, 24.53, 24.86, 25.22, 25.91, 26.33, 26.82, 27.63, 28.61, 29.11, and 29.77.

3. The crystalline sait form of claim 1 or 2, wherein

Compound 1 Besylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.78, 7.56, 10.42,20.51, 20.94, 21.60, and 25.30;

Compound 1 Camsylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.55, 9.87, 10.26, 16.16, 16.82, 20.87, 22.36, and 23.71;

Compound 1 Camsylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.25, 10.52, 16.15, 21.13, 21.56, and 21.89;

Compound 1 Citrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.58, 5.95, 8.88, 11.93, 13.79, 14.29, 16.64, 18.90, 21.47, 23.80, 24.25, and 25.85;

Compound 1 Esylate Fonn A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.97, 7.95, 9.89, 10.62, 13.27, 15.08, 16.17, 16.92, 17.01, 20.65, 20.78, 21.44, 22.08, 23.99, 25.43, and 26.52;

Compound 1 HBr Fonn B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.26, 9.91, 10.72, 20.55, 20.69, 21.18, 22.09, 23.24, 24.56, and 25.80;

Compound 1 Maleate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 10.92, 15.13, 15.78, 16.43, 18.09, 18.71, 20.30, 21.99, 22.30, 22.49, 23.32, 23.56, 24.79, 26.41,26.92, and 29.01;

Compound 1 Mesylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.06, 7.66, 14.79, 15.42, 16.23, 17.20, 17.59, 18.40, 19.33, 19.53,20.38,20.73,21.83,22.16, 23.14, 24.06, and 24.77;

Compound 1 Mesylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 14.61, 15.21, 16.17, 17.18, 17.41,

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18.46, 19.13, 19.54, 20.15, 20.53, 20.75, 20.98, 21.27, 21.60, 22.03, 23.32, 24.16, 24.42, 24.87, and 25.13;

Compound 1 Mesylate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks îs selected from 7.55, 9.53, 11.49, 12.51, 14.44, 19.04, 20.54, 21.12, 21.24, and 23.15;

Compound 1 Oxalate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.90, 5.25, 9.87, 10.54, 12.29, 15.35, 18.67, 19.40, 19.81, 20.26, 22.93, and 24.66;

Compound 1 Oxalate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.20, 7.59, 10.53, 15.06, 15.23, 19.52, 21.18, 21.43, 22.59, 24.21, and 25.85;

Compound 1 Oxalate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 7.70, 10.29, 10.59, 13.09, 13.70, 15.33, 17.83, 18.15, 20.11, 21.07, 21.91, and 22.56;

Compound 1 Sulfate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.74, 5.85, 9.47, 10.04, 11.74, 11.95, 16.48, 20.22, and 22.74;

Compound 1 Sulfate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.27, 8.57, 9.32, 16.94, 19.99, 21.03, 21.44, 22.00, and 26.02;

Compound 1 Sulfate Form C is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 3.19, 5.35, 9.62, 12.27, 16.33, 17.11, 18.75, 18.99, 19.36, 19.47, 20.55, 21.01,21.52, 21.62, 21.89, 22.19, 23.79, 25.07, and 26.06;

Compound 1 Hemitartrate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 5.17, 5.66, 10.10, 10.40, 11.37, 11.55, 14.51, 17.09, 21.23, 21.83, 23.53, 24.26, 25.26, and 26.78;

Compound 1 Tosylate Form A is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 8.52, 9.74, 14.28, 16.03, 17.55, 18.94, 19.26, 20.31, 21.02, 21.43, 22.11, 22.44, 22.66, 23.07, 24.55, and 27.70; and

Compound 1 Tosylate Form B is characterized by one or more peaks in an XRPD pattern on a 2 Thêta scale, wherein the one or more peaks is selected from 4.61, 9.25, 12.44, 15.47, 17.76, 19.01, 19.35, 25.91,26.33, and 27.63.

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4. The crystalline sait form of any one of daims 1-3, wherein the Compound 1 Besylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.78, 7.56, 10.42, 20.51, 20.94, 21.60, and 25.30;

Compound 1 Camsylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.55, 9.87, 10.26, 16.16, 16.82, 20.87, 22.36, and 23.71;

Compound 1 Camsylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.25, 10.52, 16.15, 21.13, 21.56, and 21.89;

Compound 1 Citrate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.58, 5.95, 8.88, 11.93, 13.79, 14.29, 16.64, 18.90,21.47,23.80, 24.25, and 25.85;

Compound 1 Esylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.97, 7.95, 9.89, 10.62, 13.27, 15.08, 16.17, 16.92, 17.01,20.65, 20.78, 21.44, 22.08, 23.99, 25.43, and 26.52;

Compound 1 HBr Fonn B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.26, 9.91, 10.72, 20.55,20.69,21.18, 22.09, 23.24, 24.56, and 25.80;

Compound 1 Maleate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 10.92, 15.13, 15.78, 16.43, 18.09, 18.71,20.30,21.99, 22.30, 22.49, 23.32, 23.56, 24.79, 26.41, 26.92, and 29.01;

Compound 1 Mesylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.06, 7.66, 14.79, 15.42, 16.23, 17.20, 17.59, 18.40, 19.33, 19.53, 20.38, 20.73, 21.83, 22.16, 23.14, 24.06, and 24.77;

Compound 1 Mesylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 14.61, 15.21, 16.17, 17.18, 17.41, 18.46, 19.13, 19.54, 20.15,20.53, 20.75, 20.98, 21.27, 21.60, 22.03, 23.32, 24.16, 24.42, 24.87, and 25.13;

Compound 1 Mesylate Form C is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 7.55, 9.53, 11.49, 12.51, 14.44, 19.04, 20.54,21.12, 21.24, and 23.15; Compound 1 Oxalate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.90, 5.25, 9.87, 10.54, 12.29, 15.35, 18.67, 19.40, 19.81, 20.26, 22.93, and 24.66;

Compound 1 Oxalate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.20, 7.59, 10.53, 15.06, 15.23, 19.52,21.18,21.43,22.59, 24.21, and 25.85;

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I Compound 1 Oxalate Fonn C is characterized by ah of the following peaks in an XRPD pattern on a

2 Thêta scale, selected from 7.70, 10,29, 10.59,13.09, 13.70, 15.33, 17.83, 18.15,20.11,21.07,

I 21.91, and 22,56;

_ Compound 1 Sulfate Form A is characterized by ail of the following peaks in an XRPD pattern on a

I 2 Thêta scale, selected from 4.74, 5.85, 9.47, 10.04, i 1.74, i 1.95, 16.48, 20.22, and 22.74;

Compound 1 Sulfate Form B is characterized by ail of the following peaks in an XRPD pattern on a I 2 Thêta scale, selected from 4.27, 8.57, 9.32, 16.94, 19.99, 21.03, 21.44, 22.00, and 26.02;

Compound 1 Sulfate Form C is characterized by ail of the following peaks in an XRPD pattern on a I 2 Thêta scale, selected from 3.19, 5.35, 9.62, 12.27, 16.33, 17.11, 18.75, 18.99, 19.36, 19.47, 20.55, 21.01, 21.52, 21.62, 21.89, 22.19, 23.79, 25.07, and 26.06;

| Compound 1 Hemitartrate Form B is characterized by ail of the following peaks in an XRPD pattern on a2 Thêta scale, selected from 5.17, 5.66, 10.10, 10.40, 11.37, 11.55, 14.5i, 17,09,21.23,21.83, I 23.53, 24.26, 25.26, and 26.78;

Compound ï Tosylate Form A is characterized by ail of the following peaks in an XRPD pattern on | a 2 Thêta scale, selected from 8.52, 9.74, 14.28, 16.03, 17.55, 18.94, 19.26, 20.31, 21.02, 21.43, 22.11, 22,44, 22.66, 23.07, 24.55, and 27.70; and | Compound 1 Tosylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.61, 9.25, 12.44, 15.47, 17.76, 19.01, 19.35, 25.91, 26.33, and 27.63.

I

5. The crystalline sait form of any one of daims 1-4, wherein the Compound 1 Besylate Fonn | A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.78, 7.56, 10.08, 10.42, 11.70, 11.78, 12.00, 12.71, 13.20, 13.92, 14.06, 14.44, 14.93, 15.18, | 15.96, 16.21, 16.40, 16.73, 16.86, 17.38, 18.32, 19.07, 20.07, 20.26, 20.51, 20.94, 21.45, 21.60,

2 2.30, 22.90, 23.05, 23.28, 23.71, 24.28, 24.97, 25.30, 25.69, 26.33, 26.71, 27.29, 27.65, 28.07, | 29.22, and 29.50;

Compound 1 Camsylate Form A is characterized by ail of the following peaks in an XRPD pattern | on a 2 Thêta scale, selected from 5.55, 7.90, 8.25, 8.38, 9.55, 9.87, 10.26, 11.12, 11.34, 12.50, 12.94, 13.40, 13.65, 14.79, 15.83, 16.16, 16.41, 16.54, 16.82, 17.10, 17.69, 18.02, 18.22, 18.47, | 18.91, 19.10, 19.47, 20.04, 20.87, 21.05, 22.16, 22.36, 22.93, 23.71, 24.55, 25.33, 26.02, 26.40,

27 .09, 27.33, 27.97, 28.32, 28.68, and 28.98;

| Compound 1 Camsylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.25, 8.32, 8.51, 8.76, 9.05, 9.58, 9.88, 10.00, 10.52, 10.80, 11.06,

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11.96, 12.24, 12.58, 13.98, 15.62, 15.81, 16.15, 16.70, 17.12, 17.42, 17.71, 18.41, 19.37, 19.55, 20.63, 21.13, 21.56, 21.89, 22.50, 23.04, 24.43, 26.08, 27.07, 27.97, 28.22, and 28.73;

Compound 1 Citrate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.58, 5.95, 7.61, 8.88,9.19,9.94, 11.93, 13.26, 13.79, 14.29, 14.68, 15.26, 15.95,16.64, 17.11, 17.87, 18.21, 18.43, 18.90, 19.36, 19.67, 20.14,20.57,21.47,22.30, 22.64, 23.06, 23.80, 24.25, 24.55, 24.81, 25.10, 25.45, 25.54, 25.85, 26.35, 26.51, 26.83, 27.16, 27.57, 27.85, 28.08, and 28.47;

Compound 1 Esylate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.97, 7.95, 9.89, 10.62, 10.92, 11.03, 11.34, 11.77, 12.03, 12.53, 12.71, 13.27, 14.00, 14.70, 15.08, 15.94, 16.17, 16.92, 17.01, 17.19, 17.35, 17.61, 18.15, 18.76, 19.03, 19.66, 19.89, 20.26, 20.65, 20.78, 21.44, 22.08, 23.14, 23.27, 23.99, 24.32, 25.43, 25.66, 25.85, 26.52, 26.87, 27.61, 27.96, 28.18, 28.40, and 28.91;

Compound 1 HBr Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.26, 8.29, 9.75, 9.91, 10.56, 10.72, 12.25, 12.50, 12.75, 13.31, 13.54, 14.11, 14.72, 14.89, 15.87, 16.29, 16.50, 17.36, 17.78, 18.09, 18.44, 18.75, 19.12, 19.24, 19.56, 19.92, 20.40, 20.55, 20.69, 21.18, 22.09, 22.64, 23.24, 24.56, 25.80, 26.52, 27.23, 27.43, 28.13, 28.46, 28.76, 29.08, 29.66, and 30.07;

Compound 1 Maleate Form A is characterized by ali of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 7.58, 8.34, 10.92, 12.38, 12.87, 14.17, 15.13, 15.78, 16.43, 16.91, 17.51, 18.09, 18.71, 20.30, 21.60, 21.99, 22.30, 22.49, 23.32, 23.56, 23.92, 24.79, 26.04, 26.41, 26.92, 27.62, 28.18, 28.54, and 29.01 ;

Compound 1 Mesylate Fonn A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.06, 6.65, 7.66, 8.35, 10.16, 10.72, 11.98, 12.62, 13.32, 14.41, 14.79, 15.42, 15.72, 15.89, 16.23, 16.77, 17.20, 17.59, 18.08, 18.40, 18.81, 19.33, 19.53, 19.71, 20.14, 20.38, 20.73, 21.05, 21.56, 21.83, 22.16, 23.14, 24.06, 24.54, 24.77, 25.75, 26.82, 27.71, 27.94, 28.71,29.27, and 29.85;

Compound 1 Mesylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.14, 6.62,7.72,7.89, 10.33, 10.73, 12.74, 13.31, 13.88, 14.23, 14.61, 15.21, 15.52, 15.87, 16.17, 17.18, 17.41, 17.88, 18.15, 18.46, 18.73, 19.13, 19.54,20.15,20.53, 20.75, 20.98, 21.27, 21.60, 22.03, 22.28, 23.07, 23.32, 24.16, 24.42, 24.87, 25.13, 25.64, 26.24, 26.95, 27.17, 27.49, 27.77, 28.42, and 29.54;

Compound 1 Mesylate Fonn C is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 7.55, 9.53, 10.25, 11.04, 11.49, 11.65, 12.24, 12.51, 13.88, 14.44,

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15.36, 15.66, 16.29, 16.58, 17.16, 17.54, 19.04, 19.20, 19.79,20.54,21.12,21.24,21.62, 22.22, 23.15, 23.57, 23.99, 24.61, 24.77, 25.22, 25.61, 25.99, 26.60, 26.89, 27.29, 27.91, 29.03, and 29.29; Compound 1 Oxalate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.90, 5.25, 6.20, 8.05, 9.87, 10.54, 12.29, 14.79, 15.35, 15.84, 16.49, 16.89, 17.55, 18.27, 18.67, 19.12, 19.40, 19.81, 20.26, 20.50, 21.06, 21.74, 22.17, 22.93, 23.26, 23.50, 23.81, 24.66, 25.06, 25.95, 26.90, 27.82, and 28.24;

Compound 1 Oxalate Form B is characterized by ail ofthe following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.20, 7.59,8.02, 8.42, 10.53, 12.36, 12.66, 13.09, 13.35, 13.88, 14.15, 14.46, 15.06, 15.23, 17.42, 17.75, 18.28, 19.07, 19.52,20.33,21.18,21.43,21.74, 22.08, 22.59, 23.53, 24.21, 24.52, 24.71, 25.24, 25.85, 26.24, 26.55, 26.90, 27.43, 28.56, 29.30, and 29.51;

Compound 1 Oxalate Form C is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.13, 7.70, 10.29, 10.59, 13.09, 13.70, 14.13, 15.33, 15.87, 16.57, 17.19, 17.50, 17.83, 18.15, 18.61, 19.24, 19.42, 20.11,20.34, 20.64,21.07,21.47,21.59,21.91, 22.56, 22.92, 23.37, 23.87, 24.35, 25.35, 25.91, 26.47, 26.68, 27.74, 28.47, and 29.14;

Compound 1 Sulfate Form A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.74, 5.85, 9.47, 10.04, 11.74, 11.95, 13.77, 14.99, 15.42, 15.71, 16.48, 17.36, 17.66, 17.92, 18.59, 18.95, 19.36, 19.74, 20.22,20.77,21.38,21.86,22.74,23.30, 23.70, 24.33, 25.07, 25.32, 25.67, 26.23, and 27.00;

Compound 1 Sulfate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.27, 8.57, 9.32, 10.95, 11.29, 12.07, 12.87, 13.25, 13.82, 14.13, 14.67, 16.94, 17.21, 17.64, 19.99, 20.26, 21.03, 21.44, 22.00, 22.71, 23.85, 25.20, and 26.02;

Compound 1 Sulfate Form C is characterized by ail ofthe following peaks in an XRPD pattern on a 2 Thêta scale, selected from 3.19, 5.35, 9.04, 9.62, 10.73, 11.31, 11.60, 12.27, 12.67, 13.76, 14.31, 14.65, 15.21, 15.63, 16.11, 16.33, 16.63, 17.11, 18.32, 18.75, 18.99, 19.36, 19.47,20.16,20.55, 21.01, 21.52, 21.62, 21.89, 22.19, 22.53, 23.19, 23.79, 24.23, 24.81, 25.07, 25.41, 26.06, 26.73, 27.58, 28.16, 28.63, 28.90, 29.22, 29.47, and 29.73;

Compound 1 Hemitartrate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.17, 5.66, 7.22, 9.27, 10.10, 10.40, 11.37, 11.55, 12.77, 13.94, 14.51, 15.60, 16.06, 16.48, 17.09, 17.69, 17.90, 18.27, 18.94, 19.15, 19.59, 19.81,20.06, 20.32, 21.23, 21.83, 22.34, 22.84, 23.53, 24.26, 24.70, 25.26, 25.80, 26.78, 27.29, 27.90, 29.04, and 29.45; Compound 1 Tosylate Fonn A is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 5.81, 7.05, 8.52,9.74, 10.40, 10.99, 11.26, 11.66, 12.58, 12.81, 14.28, 14.62, 15.30, 15.80, 16.03, 16.34, 17.12, 17.55, 18.03, 18.94, 19.26, 19.67, 20.31, 20.65, 21.02,

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21.43, 22.11, 22.44, 22.66, 22.94,23.07, 23.54, 23.79, 24.55, 24.88, 25.42, 25.83, 26.10, 26.53, 27.70, 28.11, 28.62, 29.18, 29.40, 29.66, and 29.83; and

Compound 1 Tosylate Form B is characterized by ail of the following peaks in an XRPD pattern on a 2 Thêta scale, selected from 4.61, 8.69, 9.25, 10.68, 12.44, 12.69, 13.76, 14.42, 14.81, 15.47, 16.08, 16.57, 17.45, 17.76, 18.44, 18.83, 19.01, 19.35, 20.42, 20.84, 21.15, 21.69, 22.09, 22.86, 23.12, 24.08, 24.53, 24.86, 25.22, 25.91, 26.33, 26.82, 27.63, 28.61, 29.11, and 29.77.

6. The crystalline sait form of any one of claims 1-5, wherein the Compound 1 Besylate Form A is characterized by a first endotherm at a température of about 144 °C and a second endotherm at a température of about 170 °C in a DSC thermogram;

Compound 1 Camsylate Form A is characterized by a first endotherm at a température of about 110 °C and a second endotherm at a température of about 174 °C in a DSC thermogram;

Compound 1 Citrate Form B is characterized by an endotherm with an onset température at about 175 °C in a DSC thermogram;

Compound 1 Esylate Form A is characterized by a first endotherm at a température of about 69 °C, a second endotherm at about 156 °C, and a third endotherm at a température of about 190 °C, in a DSC thermogram;

Compound 1 Maleate Form A is characterized by an endotherm at a température of about 117 °C in a DSC thermogram;

Compound 1 Mesylate Form C îs characterized by a first endotherm with a peak at a température of about 69 °C, wherein the first endotherm has a lower limit of about 36 and an upper limit of a température of about 96 °C, and a second endotherm with a peak at a température of about 208 °C, wherein the second endotherm has a lower limit of a température of about 169 and an upper limit of a température of about 219 °C;

Compound 1 Hemitartrate Form B is characterized by a first endotherm at a température of about 111 °C, and a second endotherm at a température of about 148 °C in a DSC thermogram;

Compound 1 Tosylate Form A is characterized by an endotherm with an onset température at about 214 °C in a DSC thermogram; and

Compound l Tosylate Form B is characterized by a sharp endotherm with an onset température at -183 °C in a DSC thermogram.

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7. The crystalline sait form of any one of claims 1-6, wherein the Compound 1 Besylate Form A is characterized by a weight loss of about 7,9% over a température range of 39-177 °C in a TGA thermogram;

Compound 1 Camsylate Form A is characterized by a weight loss of about 5.9% over a température range of 38-170 °C in a TGA thermogram;

Compound 1 Citrate Form B is characterized by a weight loss beginning at a température of about 159 °C and ending at about 220 °C in a TGA thermogram;

Compound 1 Esylate Form A is characterized by a weight loss of about 8.5 wt% over a température range of 38-188 °C in a TGA thermogram;

Compound 1 Maleate Form A is characterized by a weight loss of about 3.1 wt% in the température range of 42-146 °C in a TGA thermogram;

Compound 1 Mesylate Form C is characterized by a weight loss of from 0.5 to 3.0 wt% in the température range of 36-130 °C in a TGA thermogram;

Compound 1 Hemitartrate Form B is characterized by a weight loss of about 7.4 wt% in the température range of 39-157 °C in a TGA thermogram;

Compound 1 Tosylate Form A is characterized by a weight loss of about 0.9 wt% in the température range of 72-231 °C in a TGA thermogram; and

Compound 1 Tosylate Form B is characterized by a weight loss of about 0.7 wt% in the température range of 39-214 °C in a TGA thermogram.

8. The crystalline sait form of any one of claims 1-7, wherein the Compound 1 Citrate Form B is characterized by about a 4.1 wi% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity;

Compound 1 Maleate Form A is characterized by about a 2.5 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity;

Compound 1 Mesylate Form C is characterized by about a 5.1 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity;

Compound 1 Tosylate Form A is characterized by about a 0.9 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity; and

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Compound 1 Tosylate Fonn B is characterized by about a 0.9 wt% increase, as measured by DVS, when taken from an environment of 5% relative humidity to an environment of 95% relative humidity.

9. A pharmaceutical composition comprising a crystalline sait form of any one of daims 1-8 and a pharmaceutically acceptable excipient.

10. A method of treating a disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase, comprising administering to a subject in need thereof a crystalline sali form of any one of daims 1-8, or a pharmaceutical composition of daim 9.

11. The method of daim 10, wherein the disease, disorder, or syndrome mediated at least in part by modulating in vivo activity of a protein kinase is cancer.

12. A method for inhibiting a protein kinase, the method comprising contacting the protein kinase with a crystalline sait form of any one of daims 1-8.

13. The method of any of daims 10-12, wherein the protein kinase is Axl, Mer, c-Met, KD R, or a combination thereof.