Solid-state forms of (( s)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-1 h-pyrrolo[2,3-c]-pyridin-1-YL)-5-fluoro- n,n-diisopropylbenzamide salts

Abstract

Solid-state forms of (S)-2-(3-(1-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-1-yl)-5-fluoro-N,N-diisopropylbenzamide, Atropisomer A-2; corresponding pharmaceutical compositions; uses to treat and / or prevent Menin- mediated conditions; kits; and methods of preparation.

Description

SOLID-STATE FORMS OF (($-2-(3-(l-(5,5-DIMETHYLPYRROLIDINE-2- CARBONYL)PIPERIDINE-4-CARBONYL)-2-METHYL-lH-PYRROLO[2,3-c]- PYRIDIN-l-YL)-5-FLUORO-A^V-DIISOPROPYLBENZAMIDE SALTSFIELD

[0001] The present disclosure relates generally to solid-state forms of f5)-2-(3-(l-(5,5- dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-lJ / -pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-7V,7V-diisopropylbenzamide salts, including the amorphous hydrochloride, amorphous besylate, and crystalline orotate salts of f5J-2-(3-(l-(5,5-dimethylpyrrolidine-2- carbonyl)piperidine-4-carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V- diisopropylbenzamide, Atropisomer 2. The present disclosure further relates to pharmaceutical compositions comprising a solid-state form of an f£J-2-(3-(l-(5,5-dimethylpyrrolidine-2- carbonyl)piperidine-4-carbonyl)-2-methyl-lJ / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V- diisopropylbenzamide salt; use of a pharmaceutical composition comprising a solid-state form of an f5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2-methyl-lJ / - pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide salt to treat and / or prevent Menin-mediated conditions; kits comprising a pharmaceutical composition comprising a solid- state form of an (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4-carbonyl)-2- methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,A-diisopropylbenzamide salt; and methods for preparing a solid-state form of an f£)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-lJ / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,7V-diisopropyl- benzamide salt.BACKGROUND

[0002] MLL1 is a histone methyltransferase encoded by the mixed-lineage leukemia 1 (MI.I.l) gene (also known as the KMT2A gene) on chromosome 1 lq23. MLL1 is a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. Multiple chromosomal translocations involving ^XQ MLLI gene are the cause of certain acute myeloid leukemias (AML) and acute lymphoid leukemias (ALL). These chromosomal translocations have the downstream effect of upregulating H0XA9 and A / AZS' / gene expression critical to leukemogenesis. H0XA9 and MEIS1 then contribute toenhanced proliferation and blockage of hematopoietic differentiation ultimately leading to acute leukemias. A / / . / . / -rearranged (MLLl- ) leukemias are associated with resistance to standard therapies and higher rates of relapse. Patients with MLLl- leukemias generally have an unfavorable prognosis and respond poorly to available treatments relative to patients with non- MI.I.l-v leukemias.

[0003] MLL1 normally associates with a cohort of highly conserved cofactors to form a macromolecular complex. One of these cofactors is Menin, a product of the AffiTW tumor suppressor gene. Menin is an essential cofactor necessary for binding of ^XQ MLLI complex to promoters of target genes. The Menin binding site on MLL1 is located on the N-terminus and preserved throughout MLL 1 fusion proteins resulting from the chromosomal rearrangements.

[0004] Current treatments for MLLl- leukemias are conventional chemotherapeutics that non- selectively kill all rapidly proliferating cells including normal stem / progenitor cells in the bone marrow and other organs including the intestines. Such treatments can cause severe toxicities, side effects, and even secondary cancers. Targeted pharmacologic inhibition of Menin-MLLl binding is a presently unexploited therapeutic approach for treating leukemias and other diseases associated with Menin activity. No approved pharmacological agents that inhibit Menin activity generally, or that inhibit Menin activity specifically, are currently available. Accordingly, there is a need for Menin inhibitors, particularly Menin inhibitors having pharmacologically appropriate properties (such as selectivity, bioavailability, etc.) that are suitable for administration to a subject in need of such treatment.

[0005] The present disclosure addresses this large unmet need by providing solid-state salt forms of the Menin inhibitor, 5 -2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)piperidine-4- carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer 2, together with corresponding pharmaceutical compositions, that are suitable for treating and / or preventing Menin-mediated conditions such as MLLl-r leukemias and other Menin-mediated cancers.SUMMARY

[0006] In one aspect, the present disclosure provides a solid-state salt form of (5)-2-(3-(l - (5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l 7-pyrrolo[2,3-c]- pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide, Atropisomer A-2.

[0007] In another aspect, the present disclosure provides amorphous salts of (5)-2-(3-(l -(5,5- di methyl pyrrol i di ne-2-carbonyl)-pi peri dine-4-carbonyl)-2-methyl - I / / -pyrrol o[2, 3 -c]pyri di n- l - yl)-5-fluoro-7V,7V-diisopropylbenzamide, Atropisomer A-2. In one aspect, the amorphous salt is a hydrochloride salt. In another aspect, the amorphous salt is a besylate salt.

[0008] In another aspect, the present disclosure provides crystalline salts of (5)-2-(3-(l -(5,5- dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-7V,7V-diisopropylbenzamide, Atropisomer A-2. In one aspect, the crystalline salt is an orotate salt.

[0009] In another aspect, the present disclosure provides pharmaceutical compositions comprising an amorphous or crystalline salt of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2- carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V- diisopropylbenzamide, Atropisomer A-2, and one or more pharmaceutically acceptable excipients. In one aspect, the pharmaceutical composition comprises an amorphous hydrochloride salt. In another aspect, the pharmaceutical composition comprises an amorphous besylate salt. In another aspect, the pharmaceutical composition comprises a crystalline orotate salt.

[0010] In another aspect, the present disclosure provides methods of treating and / or preventing a Menin-mediated condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of an amorphous or crystalline salt of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2- methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide, Atropisomer A-2, and one or more pharmaceutically acceptable excipients. In one aspect, the pharmaceutical composition comprises an amorphous hydrochloride salt. In another aspect, the pharmaceutical composition comprises an amorphous besylate salt. In another aspect, the pharmaceutical composition comprises a crystalline orotate salt.

[0011] In another aspect, the present disclosure provides use of a pharmaceutical composition comprising an amorphous or crystalline salt of (5)-2-(3-(l-(5,5-dimethyl- pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl- l / / -pyrrolo[2,3-c]pyridin- l-yl)-5- fluoro-A,A-diisopropylbenzamide, Atropisomer A-2, for treating and / or preventing a Menin- mediated condition. In one aspect, the pharmaceutical composition comprises an amorphous hydrochloride salt. In another aspect, the pharmaceutical composition comprises an amorphous besylate salt. In another aspect, the pharmaceutical composition comprises a crystalline orotate salt.

[0012] In another aspect, the present disclosure provides use of an amorphous or crystalline salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2, for the manufacture of a medicament for treating and / or preventing a Menin-mediated condition. In one aspect, the salt is an amorphous hydrochloride salt. In another aspect, the salt is an amorphous besylate salt. In another aspect, the salt is a crystalline orotate salt.

[0013] In another aspect, the present disclosure provides kits comprising a pharmaceutical composition comprising an amorphous or crystalline salt of (5)-2-(3-(l-(5,5-dimethyl- pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5- fluoro-A,A-diisopropylbenzamide, Atropisomer A-2. In one aspect, the pharmaceutical composition comprises an amorphous hydrochloride salt. In another aspect, the pharmaceutical composition comprises an amorphous besylate salt. In another aspect, the pharmaceutical composition comprises a crystalline orotate salt.

[0014] In another aspect, the present disclosure provides methods for preparing an amorphous or crystalline salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2. In one aspect, the salt is an amorphous hydrochloride salt. In another aspect, the salt is an amorphous besylate salt. In another aspect, the salt is a crystalline orotate salt.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG. l is a representative X-ray powder diffraction (XRPD) pattern for crystalline Form A of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,7V-diisopropylbenzamide, Atropisomer A-2.

[0016] FIG. 2 is a representative differential scanning calorimetry (DSC) curve for crystalline Form A of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,7V-diisopropyl- benzamide, Atropisomer A-2.

[0017] FIG. 3 is a representative thermogravimetric analysis (TGA) thermogram for crystalline Form A of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-17 / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V- diisopropylbenzamide, Atropisomer A-2.

[0018] FIG. 4 is a representative gravimetric vapor sorption (GVS) plot for crystalline Form A of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,7V-diisopropylbenzamide, Atropisomer A-2.

[0019] FIG. 5 is a representative X-ray powder diffraction (XRPD) pattern for crystalline Form B of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,7V-diisopropylbenzamide, Atropisomer A-2.

[0020] FIG. 6 is a representative differential scanning calorimetry (DSC) curve for crystalline Form B of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,7V-diisopropyl- benzamide, Atropisomer A-2.

[0021] FIG. 7 is a representative thermogravimetric analysis (TGA) thermogram for crystalline Form B of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,7V-diisopropyl-benzamide, Atropisomer A-2.

[0022] FIG. 8 is a representative X-ray powder diffraction (XRPD) pattern for crystalline Form C of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2.

[0023] FIG. 9 is a representative differential scanning calorimetry (DSC) curve for crystalline Form C of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropyl- benzamide, Atropisomer A-2.

[0024] FIG. 10 is a representative thermogravimetric analysis (TGA) thermogram for crystalline Form C of the orotate salt of (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropyl- benzamide, Atropisomer A-2.

[0025] FIG. 11 illustrates the temperature profile for thermocycling experiments in a Crystall6™ reactor with (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2.

[0026] FIG. 12 illustrates the effect of treatment with (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine- 2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A- diisopropylbenzamide, Atropisomer A-2, on tumor volume in MLLr AML Xenograft Model MV-4-11.

[0027] FIGS. 13A and 13B illustrate the effect of treatment with (5)-2-(3-(l-(5,5-dimethyl- pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5- fluoro-A,A-diisopropylbenzamide, Atropisomer A-2, on tumor volume in MLLr AML Xenograft Model MOLM-13.

[0028] FIGS. 14-A, 14-B, and 14-C illustrate the effect of treatment with (5)-2-(3-(l-(5,5- dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2, on survival in MLLr AML PatientDerived Disseminated Xenograft Mouse Models CBAM-68552 (FIG. 14-A), CB AM-44728 (FIG. 14-B), and DFAL-49600 (FIG. 14-C).

[0029] FIG. 15 illustrates the effect of treatment with (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine- 2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A- diisopropylbenzamide, Atropisomer A-2, on survival in NPM1 mutant AML Patient Derived Disseminated Xenograft Model DFAM-16835.

[0030] FIG. 16 illustrates a combination signal heatmap (% inhibition of growth signal) for MOLM-13 cells after treatment with (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropyl- benzamide, Atropisomer A-2, a BCL-2 inhibitor (venetoclax), or a combination of a (5)-2-(3-(l- (5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3- c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2, and a BCL-2 inhibitor (venetoclax).

[0031] FIG. 17 illustrates the effect of treatment with a combination of (5)-2-(3-(l -(5,5- dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2, a BCL-2 inhibitor (venetoclax), and 5-azacytadine on human CD45 levels in NPM1 mutant AML Patient Derived Disseminated Xenograft Model DFAM-16835.

[0032] FIGS. 18-A, 18-B, and 18-C illustrate the effect of treatment with (5)-2-(3-(l-(5,5- dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2, on Menin protein levels in an MV-4- 11 cell line. FIG. 18-A shows treatment with a DMSO control. FIG. 18-B shows treatment with a (5)-2-(3-(l-(5,5-dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2. FIG. 18-C shows total Menin protein (“heavy” and “light”) signal normalized to DMSO.

[0033] Compound 56-2 referenced in FIG. 12 through FIG. 18-C is (5)-2-(3-(l-(5,5- dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2.DETAILED DESCRIPTION

[0034] Many embodiments are detailed throughout the specification and will be apparent to a reader skilled in the art. Such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments may be employed in practicing the invention.I. Definitions

[0035] With respect to the embodiments disclosed in this specification, the following terms have the meanings set forth below:

[0036] Reference to “a” or “an” means “one or more.” Throughout, the plural and singular should be treated as interchangeable, other than the indication of number.

[0037] When ranges are used herein to describe, for example, physical or chemical properties, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term “about” or “approximately” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range.

[0038] Unless the context requires otherwise, the words "comprise" or "comprises" or “comprising" are used on the basis and clear understanding that they are to be interpreted inclusively, rather than exclusively, and that Applicant intends each of those words to be so interpreted in construing this patent, including the claims below.

[0039] The term “amorphous form” refers to a form of a compound that lacks long range crystalline order.

[0040] The term “atropisomers” refers to stereoisomers resulting from hindered rotation about one or more single bonds, where the energy barrier to rotation is high enough to allow for the isolation of the conformers. Atropisomers are depicted in the chemical structures of the present disclosure by wedged bonds (solid or broken (hashed)) in aromatic rings in which the wedged bond is connected to the o-bond around which axial rotation is hindered. Thecompound f5 -2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl- lH-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide has two atropisomeric forms (Atropisomer A-l and Atropisomer A-2) that are shown below:Atropisomer A-l of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2- methyl-lH-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide and Atropisomer A- 2 of (A)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lH- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide are referred to throughout this specification as Atropisomer A-l and Atropisomer A-2, respectively.

[0041] The terms “co-administration,” “co-administering,” “administered in combination with,” and “administering in combination with” as used herein, encompass administration of two or more agents to a subject so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more agents are present.

[0042] The term “crystalline form” is intended to include all crystalline forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), and conformational polymorphs, as well as mixtures thereof, unless reference is to a particular crystalline form.

[0043] The term “therapeutically effective amount” of a pharmacological agent is an amountthat is sufficient to effect beneficial or desired results, including clinical results, and, as such, will depend upon the situation in which it is being administered. Where the pharmacological agent is being administered to treat a cancer, for example, a therapeutically effective amount of the agent is an amount of the agent that is sufficient, either alone or in combination with additional therapies, to provide an anti-cancer effect in a subject as compared to the response obtained without administration of the agent.

[0044] The term “pharmaceutically acceptable” is used adjectivally in this specification to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product. For example, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is intended to include any and all carriers or excipients that are suitable for use in mammals, particularly humans.

[0045] The terms “reflection” or “reflection mode,” when used in conjunction with X-ray powder diffraction, refers to the reflection (also known as Bragg-Brentano) sampling mode.

[0046] The terms “preventing” or “prevention” are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the condition and secondary prophylaxis whereby the condition has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the condition.

[0047] The term “solvate” refers to a crystalline phase of a compound in physical association with one or more molecules of a solvent. The crystalline phase of a compound in physical association with one or more molecules of water is referred to as a “hydrate.”

[0048] The terms “transmission” or “transmission mode,” when used in conjunction with X- ray powder diffraction, refers to the transmission (also known as Debye-Scherrer) sampling mode.

[0049] The terms "treating” or “treatment” are readily understood by an ordinarily skilled physician and, with respect to treatment of a particular condition, can include (1) diminishing the extent or cause of the condition being treated, and / or (2) alleviating or ameliorating one ormore symptoms associated with that condition. Treatment of cancer, for example, can include stabilizing (z.e., not worsening), delaying, or slowing the spread or progression of the cancer; prolonging survival as compared to expected survival if not receiving treatment; and / or otherwise ameliorating or palliating the cancer or the severity of the cancer, in whole or in part.II. Amorphous and Crystalline Salts of Atropisomer A-2

[0050] A compound that is an active pharmaceutical ingredient in a drug product potentially can exist in different solid-state forms exhibiting different physical properties. These physical property differences can impact the manufacturing and formulation of the drug product. Such physical properties can include, but are not limited to: (1) packing properties such as molar volume, density, and hygroscopicity; (2) thermodynamic properties such as melting temperature, vapor pressure, and solubility; (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions); (4) surface properties such as surface area, wettability, interfacial tension, and shape; (5) mechanical properties such as hardness, tensile strength, compressibility, compactibility, handling, flow and blend; and (6) filtration properties. Accordingly, solid-state forms of a compound, particularly crystalline forms of the compound, that provide an improvement in one or more of these physical properties relative to other solid-state forms of the compound are desirable. The discovery of a new solid-state form of a pharmaceutically useful compound therefore provides a potential opportunity to improve the performance characteristics of the corresponding drug product and related manufacturing process.

[0051] Efforts to identify a solid-state form of Atropisomer A-2 having pharmacologically appropriate properties and suitable for administration to a human subject have been challenging. Examples 2 to 12 report extensive efforts to identify solid-state forms of Atropisomer A-2. Initial efforts focused on identifying a suitable crystalline free base form, but such efforts were unsuccessful. No crystalline free base form was isolated. Further, the amorphous free base form isolated generally had issues with chemical instability and solvent retention.

[0052] Efforts then focused on identifying crystalline salt forms of Atropisomer A-2 having pharmacologically appropriate properties and suitable for administration to a human subject. Such efforts to identify a suitable crystalline salt form likewise were unsuccessful. Later efforts,however, finally resulted in the identification of the crystalline orotate salt forms reported in Example 12.

[0053] After initial efforts to identify a suitable crystalline salt form were unsuccessful, efforts then focused on identifying amorphous salt forms of Atropisomer A-2 having pharmacologically appropriate properties and suitable for administration to a human subject. Although several amorphous salt forms were identified, those amorphous salt forms generally had pharmacological properties that potentially could present formulation development challenges (e.g., stability, hygroscopicity, etc.).

[0054] Given the difficulty in identifying a suitable solid-state form of Atropisomer A-2, initial formulation development was carried out with the amorphous hydrochloride salt and subsequently shifted to the amorphous besylate salt. The recent discovery of the crystalline orotate salt, however, provides another potential formulation development approach for Atropisomer A-2.

[0055] Accordingly, the present disclosure provides solid-state salt forms of Atropisomer A- 2:In one aspect, the solid-state salt form possesses one or more of the above-described advantageous properties relative to one or more of the other solid-state salt forms of the compound. In another aspect, the solid-state salt form is substantially pure. As used in the present specification, the term "substantially pure" means that the solid-state salt formcomprises at least about 90 weight % of the desired solid-state salt form relative to any other solid-state salt form of Atropisomer A-2. In another aspect, the solid-state salt form comprises at least about 95 weight % of the desired solid-state salt form relative to any other solid-state salt form of Atropisomer A-2. In another aspect, the solid-state salt form comprises at least about 96 weight % of the desired solid-state salt form relative to any other solid-state salt form of Atropisomer A-2. In another aspect, the solid-state salt form comprises at least about 97 weight % of the desired solid-state salt form relative to any other solid-state salt form of Atropisomer A-2. In another aspect, the solid-state salt form comprises at least about 98 weight % of the desired solid-state salt form relative to any other solid-state salt form of Atropisomer A-2. In another aspect, the solid-state salt form comprises at least about 99 weight % of the desired solid-state salt form relative to any other solid-state salt form of Atropisomer A-2.

[0056] In some embodiments, the present disclosure provides amorphous salts of (5)-2-(3-(l - (5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3- c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2:

[0057] In some embodiments, the present disclosure provides an amorphous hydrochloride salt of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2:

[0058] In some embodiments, the present disclosure provides an amorphous besylate salt of(5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lJT- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide, Atropisomer A-2:The amorphous besylate salt of Atropisomer A-2 exhibits properties that collectively are advantageous relative to other amorphous salts of Atropisomer A-2. For example, the amorphous besylate salt has an acceptable level of hygroscopicity and retains, at most, an acceptable level of solvent from processing. The amorphous besylate salt also has 1 : 1 stoichiometry which is beneficial for process robustness in a scaled-up process. Further, a scalable precipitation and isolation process can be employed to provide the amorphous besylate salt.

[0059] In some embodiments, the present disclosure provides a crystalline orotate salt of (S)- 2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lJ / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2:In one aspect, the crystalline orotate salt is crystalline Form A. In another aspect, the crystalline orotate salt is crystalline Form B. In another aspect, the crystalline orotate salt is crystalline Form C.CRYSTALLINE FORM A

[0060] In some embodiments, the crystalline orotate salt is characterized by an X-Ray powder diffraction (XRPD) pattern that comprises at least one peak selected from the group consisting of 5.2 ± 0.2° 26, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 26, and 15.4 ± 0.2° 29. In one aspect, the X-ray powder diffraction pattern comprises at least two, three, or four peaks selected from the group consisting of 5.2 ± 0.2° 29, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern comprises peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern further comprises one or two peaks selected from the group consisting of 19.1 ± 0.2° 26 and 21.7 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern further comprises peaks at 19.1 ± 0.2° 29 and 21.7 ± 0.2° 29. In another aspect, the X- ray powder diffraction pattern further comprises at least one, two, three, or four peaks selected from the group consisting of 13.4 ± 6.2° 29, 17.3 ± 6.2 °29, 19.1 ± 0.2° 29, 21.7 ± 0.2° 26, and 23.3 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern further comprises peaks at 13.4 ± 0.2° 29, 17.3 ± 0.2 °29, 19.1 ± 0.2° 29, 21.7 ± 0.2° 29, and 23.3 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern comprises peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 26, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, 13.4 ± 0.2° 29, 15.4 ± 0.2° 29, 17.3 ± 0.2 °29, 19.1 ± 0.2° 29, 21.7 ±0.2° 29, and 23.3 ± 0.2° 29. In another aspect, the X-ray powder diffraction is reflection X-ray powder diffraction. In another aspect, the X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern of FIG. 1.

[0061] In some embodiments, the crystalline orotate salt is characterized by a differential scanning calorimetry (DSC) curve comprising a melting endotherm having an onset temperature of about 165 °C ± 5 °C. In another aspect, the endotherm has a peak at about 171 °C ± 5 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 165 °C ± 5 °C and a peak at about 171 °C ± 5 °C. In another aspect, the endotherm has an onset temperature of about 165 °C ± 2 °C. In another aspect, the endotherm has a peak at about 171 °C ± 2 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 165 °C ± 2 °C and a peak at about 171 °C ± 2 °C. In another aspect, the endotherm has an onset temperature of about 165 °C. In another aspect, the endotherm has a peak at about 171 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 165 °C and a peak at about 171 °C. In another aspect, the differential scanning calorimetry curve is substantially the same as the differential scanning calorimetry curve of FIG. 2.

[0062] In some embodiments, the crystalline orotate salt is characterized by a thermogravimetric analysis (TGA) thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C. In one aspect, the weight loss is less than about 8 weight %. In another aspect, the weight loss is less than about 6 weight %. In another aspect, the weight loss is less than about 4 weight %. In another aspect, the thermogravimetric analysis thermogram is substantially the same as the thermogravimetric analysis thermogram of FIG. 3.

[0063] In some embodiments, the crystalline orotate salt is characterized by a gravimetric vapor sorption (GVS) plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C. In one aspect, the reversible moisture uptake is less than about 9 weight %. In another aspect, the reversible moisture uptake is less than about 8 weight %. In another aspect, the gravimetric vapor sorption plot is substantially the same as the gravimetric vapor sorptionplot of FIG. 4.

[0064] In some embodiments, crystalline Form A is characterized by at least two of the above-described physical characterization embodiments (X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and / or gravimetric vapor sorption).

[0065] In some embodiments, crystalline Form A is characterized by at least three of the above-described physical characterization embodiments (X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and / or gravimetric vapor sorption).

[0066] In some embodiments, crystalline Form A is characterized by at least four of the above-described physical characterization embodiments (X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, and gravimetric vapor sorption).

[0067] In some embodiments, crystalline Form A is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29,9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29; and a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165 °C ± 5 °C.

[0068] In some embodiments, crystalline Form A is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29,9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29; and a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C.

[0069] In some embodiments, crystalline Form A is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29,9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29; and a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C.

[0070] In some embodiments, crystalline Form A is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29,9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29; a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165 °C ± 5 °C; and a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C.

[0071] In some embodiments, crystalline Form A is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29,9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29; a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165 °C ± 5 °C; a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C.

[0072] In some embodiments, crystalline Form A is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29,9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29; a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C; and a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C.

[0073] In some embodiments, crystalline Form A is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29,9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29;a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165 °C ± 5 °C; a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C; and a gravimetric vapor sorption plot wherein the crystalline form exhibits a reversible moisture uptake of less than about 10_ weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C.

[0074] In some embodiments, crystalline Form A is a crystalline solvate. In one aspect, the crystalline orotate salt is a crystalline hydrate.CRYSTALLINE FORM B

[0075] In some embodiments, crystalline Form B is characterized by an X-Ray powder diffraction (XRPD) pattern that comprises at least one peak selected from the group consisting of 4.6 ± 0.2° 20, 7.9 ± 0.2° 20, 8.9 ± 0.2° 20, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29. In one aspect, the X-ray powder diffraction pattern comprises at least two, three, or four peaks selected from the group consisting of 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern comprises peaks at 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern further comprises at least one, two, three, or four peaks selected from the group consisting of 18.2 ± 0.2 °29, 19.2 ± 0.2° 29, 20.6 ± 0.2° 29, 27.2 ± 0.2° 29, and 35.6 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern further comprises peaks at 18.2 ± 0.2 °20, 19.2 ± 0.2° 20, 20.6 ± 0.2° 29, 27.2 ± 0.2° 29, and 35.6 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern comprises peaks at 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, 12.5 ± 0.2° 29, 18.2 ± 0.2 °29, 19.2 ± 0.2° 29, 20.6 ± 0.2° 29, 27.2 ± 0.2° 29, and 35.6 ± 0.2° 29. In another aspect, the X-ray powder diffraction is reflection X-ray powder diffraction. In another aspect, the X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern of FIG. 5.

[0076] In some embodiments, crystalline Form B is characterized by a differential scanning calorimetry (DSC) curve comprising a melting endotherm having an onset temperature of about150 °C ± 5 °C. In another aspect, the endotherm has a peak at about 168 °C ± 5 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 150 °C ± 5 °C and a peak at about 168 °C ± 5 °C. In another aspect, the endotherm has an onset temperature of about 150 °C ± 2 °C. In another aspect, the endotherm has a peak at about 168 °C ± 2 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 150 °C ± 2 °C and a peak at about 168 °C ± 2 °C. In another aspect, the endotherm has an onset temperature of about 150 °C. In another aspect, the endotherm has a peak at about 168 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 150 °C and a peak at about 168 °C. In another aspect, the differential scanning calorimetry curve is substantially the same as the differential scanning calorimetry curve of FIG. 6.

[0077] In some embodiments, crystalline Form B is characterized by a thermogravimetric analysis (TGA) thermogram wherein the crystalline form exhibits a weight loss of less than about 15 weight % from about 25 °C to about 175 °C. In one aspect, the weight loss is less than about 13 weight %. In another aspect, the weight loss is less than about 11 weight %. In another aspect, the thermogravimetric analysis thermogram is substantially the same as the thermogravimetric analysis thermogram of FIG. 7.

[0078] In some embodiments, crystalline Form B is characterized by at least two of the above-described physical characterization embodiments (X-ray powder diffraction, differential scanning calorimetry, and / or thermogravimetric analysis).

[0079] In some embodiments, crystalline Form B is characterized by three of the abovedescribed physical characterization embodiments (X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis).

[0080] In some embodiments, crystalline Form B is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 12.5 ± 0.2° 29, and 11.7 ± 0.2 °29; and a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 150 °C ± 5 °C.

[0081] In some embodiments, crystalline Form B is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 12.5 ± 0.2° 29, and 11.7 ± 0.2 °29; and a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 15 weight % from about 25 °C to about 175 °C.

[0082] In some embodiments, crystalline Form B is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 12.5 ± 0.2° 29, and 11.7 ± 0.2 °29; a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 150 °C ± 5 °C; and a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 15 weight % from about 25 °C to about 175 °C.

[0083] In some embodiments, crystalline Form B is a crystalline solvate.CRYSTALLINE FORM C

[0084] In some embodiments, crystalline Form C is characterized by an X-Ray powder diffraction (XRPD) pattern that comprises at least one peak selected from the group consisting of 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29. In one aspect, the X-ray powder diffraction pattern comprises at least two, three, or four peaks selected from the group consisting of 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29. In another aspect, the X-ray powder diffraction pattern comprises peaks at 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29. In another aspect, the X-ray powder diffraction pattern further comprises at least one, two, three, or four peaks selected from the group consisting of 10.7 ± 0.2° 29, 13.0 ± 0.2° 29, 14.7 ± 0.2° 29, 17.9 ± 0.2 °29, and 21.3 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern further comprises peaks at 10.7 ± 0.2° 29, 13.0 ± 0.2° 29, 14.7 ± 0.2° 29, 17.9 ± 0.2 °29, and 21.3 ± 0.2° 29. In another aspect, the X-ray powder diffraction pattern comprises peaks at 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, 10.7 ± 0.2° 29, 13.0 ± 0.2° 29, 14.7 ± 0.2° 29, 17.9 ± 0.2 °29, 21.3 ± 0.2° 29,and 24.3 ± 0.2 °29. In another aspect, the X-ray powder diffraction is reflection X-ray powder diffraction. In another aspect, the X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern of FIG. 8.

[0085] In some embodiments, crystalline Form C is characterized by a differential scanning calorimetry (DSC) curve comprising a melting endotherm having an onset temperature of about 157 °C ± 5 °C. In another aspect, the endotherm has a peak at about 174 °C ± 5 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 157 °C ± 5 °C and a peak at about 174 °C ± 5 °C. In another aspect, the endotherm has an onset temperature of about 157 °C ± 2 °C. In another aspect, the endotherm has a peak at about 174 °C ± 2 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 157 °C ± 2 °C and a peak at about 174 °C ± 2 °C. In another aspect, the endotherm has an onset temperature of about 157 °C. In another aspect, the endotherm has a peak at about 174 °C. In one aspect, the endotherm comprises a melting endotherm having an onset temperature of about 157 °C and a peak at about 174 °C. In another aspect, the differential scanning calorimetry curve is substantially the same as the differential scanning calorimetry curve of FIG. 9.

[0086] In some embodiments, crystalline Form C is characterized by a thermogravimetric analysis (TGA) thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 150 °C. In one aspect, the weight loss is less than about 8 weight %. In another aspect, the weight loss is less than about 6 weight %. In another aspect, the thermogravimetric analysis thermogram is substantially the same as the thermogravimetric analysis thermogram of FIG. 10.

[0087] In some embodiments, crystalline Form C is characterized by at least two of the above-described physical characterization embodiments (X-ray powder diffraction, differential scanning calorimetry, and / or thermogravimetric analysis).

[0088] In some embodiments, crystalline Form C is characterized by three of the abovedescribed physical characterization embodiments (X-ray powder diffraction, differential scanning calorimetry, and thermogravimetric analysis).

[0089] In some embodiments, crystalline Form C is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 4.9 ± 0.2° 29, 8.5 ± 0.2° 29,9.1 ± 0.2° 26, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29; and a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 157 °C ± 5 °C.

[0090] In some embodiments, crystalline Form C is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 4.9 ± 0.2° 29, 8.5 ± 0.2° 26,9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29; and a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 150 °C.

[0091] In some embodiments, crystalline Form C is characterized by the following: an X-Ray powder diffraction pattern comprising peaks at 4.9 ± 0.2° 29, 8.5 ± 0.2° 29,9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29; a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 157 °C ± 5 °C; and a thermogravimetric analysis thermogram wherein the crystalline form exhibits a weight loss of less than about 10 weight % from about 25 °C to about 150 °C.

[0092] In some embodiments, crystalline Form C is a crystalline solvate. In one aspect, crystalline Form C is a crystalline hydrate.

[0093] In some embodiments, the crystalline orotate salt is substantially pure. In one aspect, the crystalline orotate salt comprises less than 10 weight % of any other crystalline freebase or salt form of Atropisomer A-2. In another aspect, the crystalline orotate salt comprises less than 5 weight % of any other crystalline freebase or salt form of Atropisomer A-2. In another aspect, the crystalline orotate salt comprises less than 4 weight % of any other crystalline freebase or salt form of Atropisomer A-2. In another aspect, the crystalline orotate salt comprises less than 3 weight % of any other crystalline freebase or salt form Atropisomer A-2. In another aspect, the crystalline orotate salt comprises less than 2 weight % of any other crystalline freebase or salt form of Atropisomer A-2. In another aspect, the crystalline orotate salt comprises less than 1 weight % of any other crystalline freebase or salt form of Atropisomer A-2. In another aspect,the crystalline orotate salt does not comprise any other crystalline freebase or salt form of Atropisomer A-2 as determined by XRPD analysis.III. Methods of Use

[0094] Atropisomer A-2, and pharmaceutically acceptable salts thereof, are inhibitors of Menin activity.

[0095] In some embodiments, therefore, the present disclosure provides a method for treating and / or preventing a Menin-mediated condition in a subject in need thereof by administering to the subject a therapeutically effective amount of an amorphous or crystalline salt of Atropisomer A-2.

[0096] In some embodiments, the present disclosure provides a method for treating and / or preventing a condition characterized by overexpression of Menin in a subject in need thereof by administering to the subject a therapeutically effective amount of an amorphous or crystalline salt of Atropisomer A-2.

[0097] In some embodiments, the present disclosure provides a method for treating and / or preventing a cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of an amorphous or crystalline salt of Atropisomer A-2. In one aspect, the cancer is a hematological malignancy. In another aspect, the cancer is a solid tumor cancer.

[0098] In some embodiments, the present disclosure provides a method for treating and / or preventing a hematological malignancy in a subject in need thereof by administering to the subject a therapeutically effective amount of an amorphous or crystalline salt of Atropisomer A- 2 wherein the hematological malignancy is selected from the group consisting of leukemias, myeloma, Non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), myeloproliferative neoplasm (MPN), and myelodysplastic syndrome (MDS). In one aspect, the hematological malignancy is a leukemia. In another aspect, the hematological malignancy is mixed-lineage leukemia (MLL)-rearranged leukemia. In another aspect, the hematological malignancy is multiple myeloma. In another aspect, the hematological malignancy is NonHodgkin lymphoma. In another aspect, the hematological malignancy is diffuse large B-cell lymphoma (DLBCL). In another aspect, the hematological malignancy is myeloproliferativeneoplasm. In another aspect, the hematological malignancy is myelodysplastic syndrome (MDS).

[0099] In some embodiments, the present disclosure provides a method for treating and / or preventing a leukemia in a subject in need thereof by administering to the subject a therapeutically effective amount of an amorphous or crystalline salt of Atropisomer A-2 wherein the leukemia is selected from the group consisting of acute leukemia, chronic leukemia, myeloid leukemia, myelogeneous leukemia, lymphoblastic leukemia, lymphocytic leukemia, acute myelogeneous leukemia (AML), chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), T cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, hairy cell leukemia (HCL), mixed- lineage leukemia (MLL)-rearranged leukemia, mixed lineage leukemia-partial tandem duplication (MLL-PTD) leukemia, MLL-amplified leukemias, MLL-positive leukemias, NPM1- mutant acute myelogeneous leukemia (AML), NUP98-rearranged acute myelogeneous leukemia (AML), SETD2 / RUNX1 mutant leukemia, and leukemia exhibiting an HOX / MEIS1 gene expression signature. In aspect, the leukemia is acute myeloid leukemia (AML). In another aspect, the leukemia is NPMl-mutant acute myeloid leukemia (AML). In another aspect, the leukemia is NUP98-rearranged acute myelogeneous leukemia (AML). In another aspect, the leukemia is acute lymphoblastic leukemia (ALL).

[0100] In some embodiments, the present disclosure provides a method for treating and / or preventing a solid tumor cancer in a subject in need thereof by administering to the subject a therapeutically effective amount of an amorphous or crystalline salt of Atropisomer A-2 wherein the solid tumor cancer is selected from the group consisting of ovarian cancer, head and neck cancer, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, liver cancer, melanoma, glioblastoma, and sarcoma cancers. In one aspect, the solid tumor cancer is ovarian cancer. In another aspect, the solid tumor cancer is head and neck cancer. In another aspect, the solid tumor cancer is prostate cancer. In another aspect, the solid tumor cancer is lung cancer. In another aspect, the solid tumor cancer is breast cancer. In another aspect, the solid tumor cancer is pancreatic cancer. In another aspect, the solid tumor cancer is colorectal cancer. In another aspect, the solid tumor cancer is liver cancer. In another aspect,the solid tumor cancer is melanoma. In another aspect, the solid tumor cancer is glioblastoma. In another aspect, the solid tumor cancer is a sarcoma cancer.

[0101] In some embodiments, the amorphous or crystalline salt form of the present disclosure is administered as first line therapy.

[0102] In some embodiments, the amorphous or crystalline salt form of the present disclosure is administered as second line (or later) therapy.

[0103] In some embodiments, the subject to whom a therapeutically effective amount of an amorphous or crystalline salt form of the present disclosure is administered exhibits a partial response (PR) in response to such treatment.

[0104] In some embodiments, the subject to whom a therapeutically effective amount of an amorphous or crystalline salt form of the present disclosure is administered exhibits a complete response (CR) in response to such treatment.

[0105] In some embodiments, the subject to whom a therapeutically effective amount of an amorphous or crystalline salt form of the present disclosure is administered exhibits an improved progression free survival (PFS) in response to such treatment.

[0106] In some embodiments, the subject to whom a therapeutically effective amount of an amorphous or crystalline salt form of the present disclosure is administered exhibits an improved overall survival (OR) in response to such treatment.

[0107] The subject treated typically will be a human or non-human mammal, particularly a human. Suitable subjects can also include domestic or wild animals; companion animals (including dogs, cats, and the like); livestock (including horses, cows and other ruminants, pigs, poultry, rabbits, and the like); primates (including monkeys such as rhesus monkeys, cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets, tamarins, chimpanzees, macaques, and the like); and rodents (including rats, mice, gerbils, guinea pigs, and the like).

[0108] In some embodiments, the present disclosure provides an amorphous or crystalline salt of Atropisomer A-2 for use as a medicament.

[0109] In some embodiments, the present disclosure provides for the use of an amorphous or crystalline salt of Atropisomer A-2 for treating and / or preventing a Menin-mediated condition as discussed above.

[0110] In some embodiments, the present disclosure provides for the use of an amorphous or crystalline salt of Atropisomer A-2 for the manufacture of a medicament for treating and / or preventing a Menin-mediated condition as discussed above.IV. Combination Therapies and Fixed-Dose Combinations

[0111] The amorphous and crystalline salts of Atropisomer A-2 may be used in the methods described above as either as single pharmacological agents or in combination with other pharmacological agents or techniques. Such combination therapies may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment. These combination therapies (and corresponding combination products) employ the amorphous and crystalline salts of Atropisomer A-2 within the dosage ranges described in this application and the other pharmacological agent(s) typically within its approved dosage range(s).

[0112] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and chemotherapy. In one aspect, the chemotherapy is induction chemotherapy. In another aspect, the chemotherapy is consolidation chemotherapy. In another aspect, the chemotherapy comprises administration of cytarabine. In another aspect, the chemotherapy comprises administration of cytarabine and an anthracy cline. In another aspect, the chemotherapy comprises administration of cytarabine and an anthracycline selected from daunorubicin and idarubicin. In another aspect, the chemotherapy comprises administration of azacitidine. In another aspect, the chemotherapy comprises administration of all-trans-retinoic acid (ATRA) and arsenic trioxide or an anthracycline. In another aspect, the chemotherapy comprises administration of all-trans- retinoic acid (ATRA) and arsenic trioxide or an anthracycline selected from daunorubicin and idarubicin. In another aspect, the chemotherapy comprises administration of two or more agents selected from the group consisting of vincristine, cyclophosphamide, cytarabine, daunorubicin, etoposide, thioguanine, mercaptopurine. In another aspect, the chemotherapy further comprisesadministration of methotrexate and / or a steroid selected from the group consisting of prednisolone, dexamethasone, and hydrocortisone.

[0113] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and radiation therapy.

[0114] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and allogenic stem cell transplantation.

[0115] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and CAR- T therapy.

[0116] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and an epigenetic modulator. In one aspect, the epigenetic modulator is selected from the group consisting of ivosidenib and enasidenib.

[0117] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and a tyrosine kinase inhibitor. In one aspect, the tyrosine kinase inhibitor is selected from the group consisting of adavosertib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, and sunitinib.

[0118] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt Atropisomer A-2 and a Bruton kinaseinhibitor. In one aspect, the tyrosine kinase inhibitor is selected from the group consisting of acalabrutinib, ibrutinib, nemtabrutinib, orelabrutinib, pirtobrutinib, remibrutinib, tolebrutinib, and zanubrutinib.

[0119] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and a BCL2 inhibitor. In one aspect, the BCL2 inhibitor is venetoclax.

[0120] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and a CDK4 / 6 kinase inhibitor. In one aspect, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, riboci clib, lerociclib (G1T38), trilaciclib (G1T28), dalpiciclib (SHR- 6390), and BPI-16350. In another aspect, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, abemaciclib, ribociclib, and dalpiciclib.

[0121] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt Atropisomer A-2 and an isocitrate dehydrogenase- 1 (IDH1) inhibitor. In one aspect, the IDH1 inhibitor is olutasidenib (Rezlidhia™).

[0122] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and a bi-specific T- cell engager. In one aspect, the bi-specific T-cell engager is blinatumomab.

[0123] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and a FLT3 inhibitor. In one aspect, the FLT3 inhibitor is gilteritinib.

[0124] In some embodiments, the present disclosure provides a combination suitable for usein the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and an XPO inhibitor.

[0125] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt of Atropisomer A-2 and a chromatin regulator.

[0126] In some embodiments, the present disclosure provides a combination suitable for use in the treatment of a condition selected from the previously discussed conditions, wherein the combination comprises an amorphous or crystalline salt Atropisomer A-2 and an immunomodulatory agent from the class of IMids.V. Pharmaceutical Compositions

[0127] The amorphous or crystalline salt of Atropisomer A-2 may be administered as a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients. Therefore, in some embodiments the present disclosure provides pharmaceutical compositions comprising an amorphous or crystalline salt of Atropisomer A-2 and at least one pharmaceutically acceptable excipient.

[0128] The excipient(s) selected for inclusion in a particular composition will depend on factors such as the mode of administration and the form of the composition provided. Suitable pharmaceutically acceptable excipients are well known to persons skilled in the art and are described, for example, in the Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn, Marian.Pharmaceutically acceptable excipients may function as, for example, adjuvants, diluents, carriers, stabilisers, flavourings, colorants, fillers, binders, disintegrants, lubricants, glidants, thickening agents and coating agents. As persons skilled in the art will appreciate, certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the composition and what other excipients are present in the composition.

[0129] The compositions may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing), or as a suppository for rectal dosing. Compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0130] The total daily dose will necessarily be varied depending upon the subject treated, the route of administration, any therapies being co-administered, and the severity of the illness being treated, and may include single or multiple doses. Specific dosages can be adjusted, for example, depending upon the condition being treated; the age, body weight, general health condition, sex, and diet of the subject; administration routes; dose intervals; excretion rate; and other drugs being co-administered to the subject. The amorphous or crystalline salt of Atropisomer A-2 typically will be administered to a warm-blooded animal at a unit dose within the range 2.5 to 5000 mg / m2body area of the animal, or approximately 0.05 to 100 mg / kg, and this normally provides a therapeutically effective dose.

[0131] In some embodiments, the present disclosure provides pharmaceutical compositions for use in therapy, comprising an amorphous or crystalline salt of Atropisomer A-2 and at least one pharmaceutically acceptable excipient.

[0132] In some embodiments, the present disclosure provides pharmaceutical compositions for use in the treatment of Menin-mediated conditions, comprising an amorphous or crystalline salt of Atropisomer A-2 and at least one pharmaceutically acceptable excipient. In one aspect, the Menin-mediated condition is a hematological malignancy. In another aspect, Menin- mediated condition is a solid tumor cancer.

[0133] In some embodiments, the present disclosure provides pharmaceutical compositions comprising an amorphous or crystalline salt of Atropisomer A-2 and one or more pharmaceutically acceptable excipients; wherein if Atropisomer A-l is present in thepharmaceutical composition as an impurity, the amount of Atropisomer A-l is less than about 5 weight % relative to the Atropisomer A-2 present in the pharmaceutical composition. In another aspect, the amount of Atropisomer A-l is less than about 4 weight % relative to Atropisomer A- 2. In another aspect, the amount of Atropisomer A-l is less than about 3 weight % relative to Atropisomer A-2. In another aspect, the amount of Atropisomer A-l is less than about 2 weight % relative to Atropisomer A-2. In another aspect, the amount of Atropisomer A-l is less than about 1 weight % relative to Atropisomer A-2. In another aspect, the amount of Atropisomer A- 1 is less than about 0.5 weight % relative to Atropisomer A-2.

[0134] In some embodiments, the present disclosure provides pharmaceutical compositions comprising an amorphous or crystalline salt of Atropisomer A-2 and one or more pharmaceutically acceptable excipients; wherein the pharmaceutical composition comprises at least 90 weight % of the amorphous or crystalline salt form relative to any other solid-state form of Atropisomer A-2. In another aspect, the pharmaceutical composition comprises at least 95 weight % of the amorphous or crystalline salt form relative to any other solid-state form of Atropisomer A-2. In another aspect, the pharmaceutical composition comprises at least 96 weight % of the amorphous or crystalline salt form relative to any other solid-state form of Atropisomer A-2. In another aspect, the pharmaceutical composition comprises at least 97 weight % of the amorphous or crystalline salt form relative to any other solid-state form of Atropisomer A-2. In another aspect, the pharmaceutical composition comprises at least 98 weight % of the amorphous or crystalline salt form relative to any other solid-state form of Atropisomer A-2. In another aspect, the pharmaceutical composition comprises at least 99 weight % of the amorphous or crystalline salt form relative to any other solid-state form of Atropisomer A-2.VI. Kits

[0135] The present disclosure further provides kits comprising a unit dosage form comprising an amorphous or crystalline salt of Atropisomer A-2 contained within a packaging material and a label or package insert which indicates that the unit dosage form can be used for treating one or more of the previously described conditions.

[0136] In some embodiments, the kit comprises a unit dosage form comprising anamorphous or crystalline salt of Atropisomer A-2 contained within a packaging material and a label or package insert which indicates that the pharmaceutical composition can be used for treating a Menin-mediated condition. In one aspect, the Menin-mediated condition is a hematological malignancy. In another aspect, the Menin-mediated condition is a solid tumor cancer.

[0137] In some embodiments, kit comprises: (a) a first unit dosage form comprising an amorphous or crystalline salt of Atropisomer A-2; (b) a second unit dosage form comprising a pharmacological agent selected from the group consisting of chemotherapeutic agents, epigenetic modulators, tyrosine kinases, Bruton kinase inhibitors, BCL2 inhibitors, CDK4 / 6 kinase inhibitors, isocitrate dehydrogenase- 1 (IDH1) inhibitors, FLT3 inhibitors, XPO inhibitors, chromatin regulators, and EGFR inhibitors; (c) a container means for containing said first and second dosage forms; and (d) a label or package insert which indicates that the first unit dosage form and second unit dosage form can be used for treating an FAP-mediated condition.VII. Method of Preparation

[0138] As discussed further in Example 12-B, four stereoisomers of 2-(3-(l-(5,5-dimethyl- pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lH-pyrrolo[2,3-c]pyridin-l-yl)-5- fluoro-N,N-diisopropylbenzamide have been identified. The desired stereoisomer is Atropisomer A-2, but the other stereoisomers (Atropisomers A-l, A-3, and / or A-4) may be present as impurities depending upon the method of synthesis. It has been found that first preparing an orotate salt (particularly a crystalline orotate salt such as Form A) from the Atropisomer A-2 starting material and then converting the orotate salt to the desired alternative Atropisomer A-2 salt (for example, an Atropisomer A-2 besylate salt) can improve the Atropisomer A-2 stereoisomeric purity in the final salt product relative to converting the Atropisomer A-2 starting material directly to the alternative Atropisomer A-2 salt without proceeding through the Atropisomer A-2 orotate salt.

[0139] In some embodiments, the present disclosure provides a method for preparing a final salt of Atropisomer A-2, wherein the method comprises: preparing an orotate salt of Atropisomer A-2 from a starting material comprising Atropisomer A-2; andconverting the orotate salt of Atropisomer A-2 into the final salt of Atropisomer A-2.

[0140] In some embodiments, the present disclosure provides a method for preparing a besylate salt of Atropisomer A-2, wherein the method comprises: preparing an orotate salt of Atropisomer A-2 from a starting material comprising Atropisomer A-2; and converting the orotate salt of Atropisomer A-2 into a besylate salt of Atropisomer A-2.In one aspect, the Atropisomer A-2 orotate salt is a crystalline Atropisomer A-2 orotate salt. In another aspect, the crystalline Atropisomer A-2 orotate salt is Form A. In another aspect, the crystalline Atropisomer A-2 orotate salt is Form B. In another aspect, the crystalline Atropisomer A-2 orotate salt is Form C. In another aspect, the Atropisomer A-2 besylate salt is an amorphous salt.

[0141] In some embodiments, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 95% by weight. As used in the present specification, stereoisomeric purity of at least 95% by weight means that at least 95% by weight of the compound (z.e,, 2-(3-(l-(5,5- dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lH-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-N,N-diisopropylbenzamide) is present as the Atropisomer A-2 stereoisomer relative to other stereoisomers (z.e., Atropisomers A-l, A-3, and A-4). Stated alternatively, the Atropisomer A-2 besylate comprises less than 5 weight % of any other stereoisomers of the compound. In one aspect, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 96% by weight. In another aspect, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 97% by weight. In another aspect, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 98% by weight. In another aspect, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 99% by weight. In another aspect, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 99.5% by weight. In another aspect, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 99.3% by weight. In another aspect, the Atropisomer A-2 besylate has a stereoisomeric purity of at least 99.1% by weight.

[0142] In some embodiments, the Atropisomer A-2 orotate has a stereoisomeric purity of at least 95% by weight. In one aspect, the Atropisomer A-2 orotate has a stereoisomeric purity ofat least 96% by weight. In another aspect, the Atropisomer A-2 orotate has a stereoisomeric purity of at least 97% by weight. In another aspect, the Atropisomer A-2 orotate has a stereoisomeric purity of at least 98% by weight. In another aspect, the Atropisomer A-2 orotate has a stereoisomeric purity of at least 99% by weight. In another aspect, the Atropisomer A-2 orotate has a stereoisomeric purity of at least 99.5% by weight. In another aspect, the Atropisomer A-2 orotate has a stereoisomeric purity of at least 99.3% by weight. In another aspect, the Atropisomer A-2 orotate has a stereoisomeric purity of at least 99.1% by weight.

[0143] In one aspect, stereoisomeric purity by weight is estimated using High-Performance Liquid Chromatography (HPLC) trace coupled with mass spectrometry.VIII. Examples

[0144] The following descriptions of experiments, procedures, examples, and intermediates are intended to exemplify embodiments of the disclosure. They are in no way intended to be limiting. Other embodiments of this disclosure may be prepared using the methods illustrated in these examples, either alone or in combination with techniques generally known in the art.

[0145] Unless otherwise stated, the following abbreviations have been used in the Examples: aq. = aqueous;ATP = adenosine triphosphate;C = Celsius;CDCh = deuterated chloroform;CHO = Chinese hamster ovary;CO2 = carbon dioxide;CS2CO3 = cesium carbonate;CuO = copper(II) oxide;DCM = dichloromethane;DIPEA = N,N-diisopropylethylamine;DMSO = dimethylsulfoxide;DMSO-de = deuterated dimethylsulfoxide;EDC = N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide;EDTA = ethylenediaminetetraacetic acid;EGTA = ethylene glycol-bis(P-aminoethyl ether)-N,N,N',N'-tetraacetic acid;ES = electrospray;EtOAc = ethyl acetate; g = gram; h = hour(s);HBSS = Hepes-buffered saline solution;HEPES = (4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid); hERG = human Ether-a-go-go-Related Gene;HOBt = 1 -hydroxybenzotriazole;IC50 = half-maximum inhibitory concentration;ID = inner diameter;KC1 = potassium chloride;KF = potassium fluoride;LCMS = liquid chromatography-mass spectrometry;M = molar;MeOH = methanol;2Me-THF = 2-methyltetrahydrofuran;Mg = magnesium; mg = milligram;MHz = megahertz; min = minute(s); mL = milliliter; mmol = millimole;MS = mass spectrometry; m / z = mass spectrometry peak(s);NaCl = sodium chloride;NaH = sodium hydride;NaHCCh = sodium bicarbonate;Na2SO4 = sodium sulfate;NH3 = ammonia;NH4CI = ammonium chloride;NMDG = N-methyl-d-glucamine;NMR = nuclear magnetic resonance;Pd2dba3.CHCh = tris(dibenzylideneacetone)dipalladium-chloroform adduct; rt = room temperature; sat = saturated;SFC = supercritical fluid chromatography;TFA = trifluoroacetic acid; th. = theoretical;THF = tetrahydrofuran;T3P = 2,4,6-tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide; pL = microliter; pm = micrometer; andXantphos = (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane).Example 1: Preparation of (S)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lH-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-N,N- diisopropylbenzamide separated Atropisomers A-l and A-2)

[0146] (lS)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl- lH-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide can be prepared as described below:A. Preparation of tert-butyl 4-(3-oxobutanoyl)piperidine-l-carboxylate (Intermediate 1):

[0147] NaH (3.52 g, 88.0 mmol, 60% dispersion in mineral oil) was added to a cooled solution of tert-butyl 4-acetylpiperidine-l -carboxylate (9.50 mL, 44.0 mmol) in THF (100 mL) at 0°C under N2. The reaction mixture was allowed to reach rt and stirred for 1 h before EtOAc (8.59 mL, 88.0 mmol) was added. The resulting mixture was stirred at 40°C for 3 h. The reaction mixture was poured into water (150 mL) and sat. aq. NH4Q (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by straight phase flash chromatography on silica (gradient: 0-40% EtOAc in heptane) to give the title compound (8.50g, 72%) as a beige solid; MS m / z (ES+) [M+H- / Bu] = 213.9;XH NMR (400 MHz, CDCh, 22°C) 5 1.45 - 1.47 (9H, m), 1.57 (2H, m), 1.81 (2H, d), 2.07 (3H, s), 2.33 (1H, tt), 2.69 - 2.82 (2H, m), 4.05 - 4.23 (2H, m), 5.53 (1H, s), 15.54 (1H, br s).B. Preparation of 5-niioro-2-iodo-\,\-diisopropylbenzaniide (Intermediate 2):

[0148] T3P (198 mL, 338 mmol, 50% in DCM) was added to a stirred solution of 5-fluoro-2- iodobenzoic acid (75.0 g, 282 mmol) and diisopropylamine (199 mL, 1.41 mol) in DCM (450 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was washed sequentially with sat. aq. NaHCCh and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in EtOAc, filtered through a short plug of silica and rinsed with EtOAc. The filtrate was concentrated under reduced pressure to give the crude title compound (40.0 g) as a beige solid. The silica plug was rinsed with DCM:MeOH (3: 1) and the filtrate was concentrated under reduced pressure to give the crude title compound (63.0 g) as a brown solid; MS m / z (ES+) [M+H]+= 350.0; 'H NMR (400 MHz, DMSO-t / e, 22°C) 5 1.06 (3H, d), 1.21 (3H, d), 1.46 (6H, t), 3.41 (1H, p), 3.57 (1H, p), 7.03 (1H, td), 7.20 (1H, dd), 7.87 (1H, dd).C. Preparation of 2-((4-bromopyridin-3-yl)amino)-5-fluoro-AkV-diisopropyl- benzamide (Intermediate 3)

[0149] Pd2dba3 CHCh (5.34 g, 10.3 mmol) was added to a deoxygenated mixture of Intermediate 2 (36.0 g, 103 mmol, th.), 4-bromopyri din-3 -amine (21.4 g, 124 mmol), XantPhos (5.97 g, 10.3 mmol) and CS2CO3 (101 g, 309 mmol) in 2-MeTHF (360 mL). The mixture was purged with N2 for additional 5 minutes and stirred at 80°C overnight. The reaction mixture wasfiltered over Celite® and the Celite was rinsed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by straight phase flash chromatography on silica (gradient: 0-100% EtOAc in heptane). Appropriate fractions were combined and concentrated under reduced pressure. The residue was dissolved in DCM and washed sequentially with aq. N- acetyl-cysteine (2%) and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (23.6 g, 58%) as a yellow solid; MS m / z (ES+) [M+H]+= 394.0 / 396.0; 'H NMR (400 MHz, DMSO-t / e, 22°C) 5 0.80 - 1.50 (12H, m), 3.67 (2H, s), 7.00 (1H, s), 7.19 (1H, dd), 7.26 (1H, td), 7.35 (1H, dd), 7.62 (1H, d), 7.88 (1H, d), 8.06 (1H, s).D. Preparation of tert-butyl 4-(l-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-2- methyl-lH-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-l-carboxylate (Intermediate 4, mixture of atropisomers)

[0150] CuO (171 mg, 2.16 mmol) was added to a deoxygenated mixture of Intermediate 1 (1.37 g, 5.07 mmol), Intermediate 3 (1.00 g, 2.54 mmol) and CS2CO3 (1.16 g, 3.55 mmol) in DMSO (18 mL). The resulting mixture was purged with N2 for additional 10 minutes and was stirred at 110°C for 6 h. Above procedure was carried out 16 times. The reaction mixtures were combined, diluted with EtOAc (500 mL) and water (500 mL) and filtered. The organic layer of the filtrate was separated and washed with water (300 mL) and brine (500 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by straight phase flash chromatography on silica (gradient: 20-100% EtOAc in heptane) to give the title compound (17.9 g, 78%) as a brown foam; MS m / z (ES+) [M+H]+= 565.3; 'HNMR (400 MHz, DMSO-t / e, 27°C) 5 0.41 (3H, br s), 0.53 - 0.77 (3H, m), 0.98 - 1.13(3H, m), 1.26 (3H, d), 1.41 (11H, s), 1.73 - 1.89 (2H, m), 3.02 (2H, br s), 3.13 - 3.27 (1H, m), 3.38 - 3.54 (1H, m), 3.68 (1H, br s), 3.87 - 4.01 (2H, m), 7.16 - 9.27 (6H, m).E. Preparation of 5-nuoro-\.\-diisopropyl-2-(2-methyl-3-(piperidine-4-carbonyl)- lH-pyrrolo[2,3-c]pyridin-l-yl)benzamide (Intermediate 5, mixture of atropisomers)

[0151] TFA (25 mL) was added to a solution of Intermediate 4 (17.0 g, 30.2 mmol) in DCM (95 mL). The resulting mixture was stirred at rt for 4 h. The mixture was diluted with DCM (400 mL) and quenched with sat. aq. NaHCCh (200 mL). The organic layer was separated, and the water layer extracted with DCM (200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound in a quantitative yield (14.9 g) as a beige foam; MS m / z (ES+) [M+H]+= 465.3; 'H NMR (400 MHz, DMSO-t / e, 22°C) 5 0.41 (3H, d), 0.50 - 0.75 (3H, m), 0.95 - 1.17 (3H, m), 1.26 (3H, d), 1.57 - 1.83 (2H, m), 1.90 (2H, br s), 2.94 - 3.11 (2H, m), 3.12 - 3.26 (3H, m), 3.43 - 3.58 (2H, m), 3.61 - 3.78 (1H, m), 7.46 - 7.63 (2H, m), 7.65 - 7.79 (1H, m), 7.83 - 8.00 (1H, m), 8.32 (2H, s).E. Preparation of tert-Butyl (S)-5-(4-(l-(2-(diisopropylcarbamoyl)-4-fluorophenyl)-2-methyl- / / / -pyrrolo|2.3-c|pyridine-3-carbonyl)piperidine-l-carbonyl)-2.2- dimethylpyrrolidine-l-carboxylate (Intermediate 6, mixture of atropisomers)

[0152] Intermediate 5 (11.2 g, 24.0 mmol th.) was added to a solution of (S)-l-(tert- butoxycarbonyl)-5,5-dimethylpyrrolidine-2-carboxylic acid (5.90 g, 24.2 mmol), EDC (5.53 g, 28.8 mmol), HOBt (4.41 g, 28.8 mmol) and DIPEA (8.39 mL, 48.0 mmol) in DCM (120 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (200 mL) and washed sequentially with sat. aq. NaHCCh (300 mL) and brine (300 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by straight phase flash chromatography on silica (gradient: 0-10% MeOH in DCM) to give the title compound (14.2 g, 86%) as a beige foam; MS m / z (ES+) [M+H]+= 690.3; 'H NMR (400 MHz, DMSO-t / e, 22°C) 5 0.34 - 0.49 (3H, m), 0.52 - 0.76 (3H, m), 0.99 - 1.13 (3H, m), 1.21 - 1.35 (12H, m), 1.37 - 1.48 (7H, m), 1.52 - 1.93 (6H, m), 2.14 (1H, br s), 2.51 (3H, s), 2.79 - 3.01 (1H, m), 3.12 - 3.32 (2H, m), 3.41 - 3.61 (1H, m), 3.63 - 3.74 (1H, m), 3.98 (1H, d), 4.23 - 4.47 (1H, m), 4.64 - 4.78 (1H, m), 7.46 - 7.62 (2H, m), 7.67 - 7.80 (1H, m), 7.83 - 7.97 (1H, m), 8.26 - 8.39 (2H, m).F. Preparation of (5)-2-(3-(l-(5,5-Dimethylpyrrolidine-2-carbonyl)piperidine-4- carbonyl)-2-inetliyl-l / / -pyrrolo|2.3-c|pyridin-l-yl)-5-nuoro-\.\-diisopropylbenzainide(separated atropisomer) (Atropisomers A-l and A-2)

[0153] TFA (15 mL) was added to a solution of tert-butyl (5)-5-(4-(l-(2-(diisopropyl- carbamoyl)-4-fluorophenyl)-2-methyl-lJH-pyrrolo[2,3-c]pyridine-3-carbonyl)piperidine-l- carbonyl)-2,2-dimethylpyrrolidine-l -carboxylate (Intermediate 6) (14.1 g, 20.5 mmol) in DCM (90 mL). The reaction mixture was stirred at rt for 2 h. The mixture was quenched with sat. aq. NaHCCh (800 mL) and extracted with DCM (2 x 400 mL). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified straight phase flash chromatography on silica (gradient: 0- 15% 0.7 M NH3 in MeOH in DCM). The residue was purified by preparative SFC on a IK column (5 pm, 250x20 mm ID) using MeOH with 0.1% NH3 in CO2 as mobile phase to give Atropisomer A-l as first eluting product (4.82 g, 40%); MS m / z (ES+) [M+H]+= 590.3;1H NMR (500 MHz, DMSO-t / e, 27°C) 5 0.33 - 0.48 (3H, m), 0.56 - 0.76 (3H, m), 1.04 (3H, s), 1.08 (3H, d), 1.18 (3H, s), 1.27 (3H, d), 1.30 - 1.70 (5H, m), 1.80 - 1.95 (2H, m), 2.10 - 2.25 (1H, m), 2.27 - 2.37 (1H, m), 2.53 (3H, s), 2.89 - 3.03 (1H, m), 3.18 - 3.29 (2H, m), 3.43 - 3.61 (1H, m), 3.63 - 3.75 (1H, m), 3.92 - 4.04 (2H, m), 4.28 - 4.44 (1H, m), 7.48 - 7.62 (2H, m), 7.66 - 7.79 (1H, m), 7.83 - 7.96 (1H, m), 8.26 - 8.41 (2H, m);“36-3(c°-223- MeOH). and Atropisomer A-2 as second eluting product (4.42 g, 37%) as an off-white solid; MS m / z (ES+) [M+H]+= 590.4; 'H (500 MHz, DMSO-t / e, 27°C) 5 0.42 (3H, d), 0.56 - 0.77 (3H, m), 1.02 - 1.11 (6H, m), 1.20 (3H, d), 1.27 (3H, d), 1.33 - 1.73 (5H, m), 1.82 - 1.94 (2H, m), 2.13 - 2.27 (1H, m), 2.53 (3H, s), 2.96 (1H, q), 3.14 - 3.28 (2H, m), 3.46 - 3.61 (1H, m), 3.69 (1H, p), 3.91 - 4.06 (2H, m), 4.28 - 4.42 (1H, m), 7.48 - 7.60 (2H, m), 7.67 - 7.78 (1H, m), 7.83 - 7.95(1H, m), 8.25 - 8.40Example 2: Free Base Crystallization Study

[0154] The following crystallization experiments were conducted using the free base form of Atropisomer A-2 as the starting material for the experiments. No crystalline freebase material, however, was obtained in these experiments.A. Methyl Tert-Butyl Ether / Cyclohexane

[0155] Amorphous Atropisomer A-2 (10 mg) was dissolved in methyl tert-butyl ether (0.20 mL) resulting in a clear colorless solution. Cyclohexane (0.50 mL) was added dropwise and a white solid started to precipitate. The solid converted to a gel within a few minutes. The suspension was stirred at the room temperature for 3 days. No crystalline material was obtained. The suspension was evaporated to dryness resulting in a mixture of white solid and gel.B. Cyclopentyl Methyl Ether / Cyclohexane

[0156] Amorphous Atropisomer A-2 (10 mg) was dissolved in cyclopentyl methyl ether (0.20 mL) resulting in a clear colorless solution. Cyclohexane (0.50 mL) was added dropwise and a white solid started to precipitate. The solid converted to a gel within a few minutes. The suspension was stirred at the room temperature for 3 days. No crystalline material was obtained. The suspension was evaporated to dryness resulting in a mixture of white solid and gel.C. Polycarbonate / Cyclohexane

[0157] Amorphous Atropisomer A-2 (10 mg) was dissolved in polycarbonate (0.20 mL) resulting in a clear colorless solution. Cyclohexane (0.50 mL) was added dropwise resulting in a bi-layer solution.D. Cyclohexane

[0158] Amorphous Atropisomer A-2 (10 mg) was suspended in cyclohexane (0.20 mL). The resulting slurry was stirred at the room temperature for 3 days. No crystalline material wasobtained. White amorphous solid was obtained after the slurry was dried in vacuum (GeneVac).E. Fumaric Acid

[0159] Amorphous Atropisomer A-2 (30 mg, 0.050 mmol) and fumaric acid (6 mg, 0.050 mmol) were suspended in acetonitrile (0.20 mL), and methanol (0.40 mL) was added resulting in a clear solution. The solution was evaporated to dryness resulting in a white gel. The white gel was suspended in methyl tert-butyl ether (0.20 mL), and ethyl acetate (0.40 mL) was added resulting in some glass-like material. The solution was stirred at room temperature over weekend resulting in gel-like material retains. The solvent was removed in GeneVac and a white solid (with a small amount of gel) was obtained. The solid was stirred in heptane (0.40 mL) for one day resulting in a homogenous slurry. The slurry was dried in vacuum (GeneVac) resulting in an amorphous white solid.F. Trans-Cinnamic Acid

[0160] Amorphous Atropisomer A-2 (30 mg, 0.050 mmol) and trans-cinnamic acid (7 mg, 0.050 mmol) were dissolved in acetonitrile (0.20 mL). The solution was evaporated to dryness resulting in a white gel. The white gel was suspended in methyl tert-butyl ether (0.20 mL), and ethyl acetate (0.20 mL) was added resulting in a clear solution. The solution was stirred at 5°C over the weekend. No solid precipitates were observed. The solvent was removed in GeneVac resulting in a gel-like solid. The solid was stirred in heptane (0.40 mL) for one day resulting in a homogenous slurry. The slurry was dried in vacuum (GeneVac) resulting in an amorphous white solid.G. Aqueous HC1

[0161] Amorphous Atropisomer A-2 (30 mg, 0.050 mmol) was dissolved in acetone (0.50 mL). IN HC1 aqueous solution (105 pL) was added to the solution. The solution was dried in vacuum. The resulting solid was stirred in methyl tert-butyl ether at the room temperature for one day resulting in a homogenous slurry. The slurry was dried in vacuum (GeneVac) resulting in an amorphous white solid.H. Methanesulfonic Acid

[0162] Amorphous Atropisomer A-2 (30 mg, 0.050 mmol) was dissolved in acetone (0.50 mL). IN methanesulfonic acid aqueous solution (105 pL) was added to the solution. The solution was dried in vacuum. The resulting solid was stirred in methyl tert-butyl ether at the room temperature for one day resulting in a suspension with the solid stuck to the wall. The suspension was dried in vacuum (GeneVac) resulting in an amorphous white solid.Example 3: Solubility Study

[0163] The solubility of 5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-lH-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide, Atropisomer A-2 was quantitatively determined in a set of 20 solvents. A first aliquot of 50 or 100 pL of solvent was added to approximately 20 mg of amorphous Atropisomer A-2. The amorphous Atropisomer A-2 completely dissolved in all solvents except dibutyl ether, water, cyclohexane, n-heptane, and hexane. The dibutyl ether, water, cyclohexane, n-heptane, and hexane suspensions were equilibrated at room temperature under continuous stirring for 24 hours. Upon completion of the incubation time, an aliquot of mother liquor was taken from the five suspensions, filtered, and analyzed by UPLC to determine the Atropisomer A-2 concentration in solution. The solubility of Atropisomer A-2 in each of the solvent systems tested after 24 hours at room temperature is reported in Table 1. The solubility classification is indicated according to the US Pharmacopoeia: freely soluble (solubility > 100 mg / mL); slightly soluble (solubility 1-10 mg / mL); and very slightly soluble (solubility 0.1-1 mg / mL).Atropisomer A-2 was highly soluble in the organic polar solvents tested and slightly or very slightly soluble in the apolar solvents tested.TABLE 1Example 4: Free Base Crystallization Study

[0164] A crystallization screen was conducted at Ardena Oss BV employing different solvent / antisolvent systems using the following crystallization methodologies:• Solvent equilibration at room temperature for 2 weeks in organic solvent / water mixtures;• Solvent equilibration at 5°C for 2 weeks in organic solvents and organic solvent / water mixtures;• Solvent equilibration at 40°C for one week; and• Thermocycling.The starting material employed in all experiments was amorphous freebase of (S)-2-(3-(l -(5,5- dimethyl-pyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lH-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-N,N-diisopropylbenzamide, Atropisomer A-2.A. Solvent Equilibration at Room Temperature for Solubility Determination

[0165] Suspensions were prepared by adding solvent aliquots to amorphous Atropisomer A- 2. The suspensions were equilibrated at room temperature under continuous stirring. After 24 hours incubation, an aliquot of the mother liquor was taken from the suspensions, filtered, and analyzed by UPLC to determine the Atropisomer A-2 concentration in solution. The same suspensions were allowed to equilibrate for 2 weeks to remeasure the Atropisomer A-2 concentration in solution. After 2-weeks incubation, the vials were centrifuged and an aliquot of mother liquor was taken, filtered, and analyzed by UPLC to determine the Atropisomer A-2 concentration in solution. The solubility of Atropisomer A-2 was calculated against a calibration line determined from two independently prepared stock solutions of Atropisomer A-2. Additionally, solids recovered after 2-weeks equilibration were analyzed by UPLC and HT- XRPD. Table 2 reports the experimental details and results of the solubility determination.

[0166] If a solution was obtained after the initial addition of solvent, it was allowed to equilibrate 24 hours at RT and 3 days at 5°C. If no precipitation occurred, antisolvent (either water or n-heptane, depending on miscibility) was added to the solutions to attempt precipitation. Aliquots of 10% of antisolvent were added and solutions were allowed to stir at 5°C overnight. The same procedure was repeated until a solvent:antisolvent ratio of 1 : 1 was reached. Results are reported in Table 2.B. Solvent Equilibration Experiments

[0167] Given the high solubility of Atropisomer A-2 in most type of solvents tested, antisolvent was initially added to the amorphous material and then aliquots of the good solvent were added until a suitable suspension was obtained. The resulting suspensions were then: (i) equilibrated at room temperature for 2 weeks (organic solvent mixtures and organic solvent / water mixtures), (ii) equilibrated at 5 °C for 2 weeks (pure organic solvents, water, organic solvent mixtures, and organic solvent / water mixtures), or (iii) equilibrated at 40°C for one week (pure organic solvents, water, and organic solvent mixtures). After the incubation time, the vials were centrifuged and analyzed by HT-XRPD as ambient solids and vacuum dried solids. The liquid phases (mother liquors and solutions) recovered from the solvent equilibration at both room temperature and 5°C were used for the evaporative experiments. Theliquid phases (mother liquors and solutions) recovered from the solvent equilibration at 40°C were used for the cooling experiments. In the evaporative experiments, solvents were left evaporating initially at ambient conditions. Samples that were still solutions after 3 days were dried under vacuum at 25°C. The solids obtained were then analyzed by XRPD. For the cooling experiments, the solutions at 40°C were slowly cooled to 5°C and aged at this temperature for 3 days. If precipitation did not occur, the liquid phases were evaporated at 10 mbar / RT. The experimental details and results of the solvent equilibration experiments are reported in Tables 3, 4, 5, 6, 7, and 8. Notations: “AS” = antisolvent; AAC = accelerated aging conditions; “Amb.” = ambient-dried sample; “Evap:” = solid sample recovered by evaporation; “Vac.” = vacuum-dried sample; “ly” = low yield;= low yield / no solid; “Am” = “amorphous”.

[0168] Table 3 reports the experimental details and results of the solvent equilibration experiments in organic mixtures performed at 5°C for 2 weeks. The suspensions were equilibrated for 2 weeks at 5°C under continuous stirring. After 2 weeks, the solids were separated from the liquid phases, and analyzed by HT-XRPD as ambient- solids (Amb.) and vacuum-dried solids (Vac.). All liquid phases (mother liquors and solutions) were used for the evaporative experiments (Evap.). All solids were afterwards exposed to AAC (40°C / 75% RH) for 2 days and remeasured by HT-XRPD.

[0169] Table 4 reports the experimental details and results of the solvent equilibration experiments performed at 40°C for one week. The suspensions were equilibrated for one week at 40°C under continuous stirring. After one week, the solids were separated from the liquid phases, and analyzed by HT-XRPD as ambient-solids (Amb.) and vacuum-dried solids (Vac.). All liquid phases (mother liquors and solutions) were used for the cooling experiments (see Table 5). All solids were afterwards exposed to AAC (40°C / 75% RH) for 2 days and remeasured by HT-XRPD.

[0170] Table 6 reports the experimental details and results of the cooling for 3 days at 5°C of the mother liquors and solutions recovered from solvent equilibration experiments performed at 40°C for one week. The solids were separated from the liquid phases and analyzed by HT- XRPD as ambient-samples (Amb.). If precipitation did not occur, the liquid phases wereevaporated (Evap.). All solids were afterwards exposed to AAC (40°C / 75% RH) for 2 days and remeasured by HT-XRPD.

[0171] Table 7 reports the experimental details and results of the long-term equilibration experiments in organic solvent / water mixtures performed at 5°C for 2 weeks. The suspensions were subjected to 2 weeks stirring at 5°C. After 2 weeks, solids were collected by centrifugation and analyzed by HT-XRPD, as ambient-samples (Amb.) and vacuum-dried (Vac.) samples. The recovered mother liquors or solutions were evaporated (Evap.). Solids were exposed to 40°C / 75% RH (AAC) for 2 days and re-analyzed by HT-XRPD.

[0172] Table 8 reports the experimental details and results of the long-term equilibration experiments at room temperature. The suspensions were subjected to 2 weeks stirring at room temperature. After 2 weeks, solids were collected by centrifugation and analyzed by HT-XRPD, as ambient-samples (Amb.) and vacuum-dried (Vac.) samples. The recovered mother liquors were evaporated (Evap.). Solids were exposed to 40°C / 75% RH (AAC) for 2 days and reanalyzed by HT-XRPD.C. Thermocycling Experiments

[0173] Thermocycling experiments were performed in 10 neat organic solvents and solvent mixtures by adding the antisolvent first and then aliquots of the solvent until a suitable suspension was obtained. Samples were placed in a Crystal 16™ reactor and heated to 50°C and cooled to 5°C with a constant heating rate of 10°C / h and variable cooling rates of -20°C / h, - 10°C / h and -5°C / h from the first to the third cycle. FIG. 11 illustrates the temperature profile for the thermocycling experiments. After thermocycling was completed, the samples were aged at room temperature for 72 hours. Upon completion of the aging time, the solids were separated from the liquid phases by centrifugation and dried under ambient conditions and under vacuum before being analyzed by HT-XRPD. Solutions were evaporated and solids analyzed by HT- XRPD. Table 9 reports the experimental details and results.TABLE 3TABLE 4TABLESTABLE 6TABLE 7TABLE 8TABLE 9

[0174] No crystalline phases were identified among the solid samples recovered any of the above-described experiments in which different temperatures, solvent systems, and equilibration times were tested.Example 5: ENaCt Crystallization Study

[0175] Encapsulated nanodroplet crystallisation and co-crystallisation (ENaCt) studies were conducted at Indicatrix Crystallography Limited to obtain single crystal(s) of Atropisomer A-2 suitable for single crystal X-ray diffraction (SCXRD) analysis and confirmation of absolute stereochemistry together with supporting classical crystallisation experiments:• ENaCt experiments (24 x 96-well plates) were carried out using 96 organic solvents and four encapsulating oils. No crystals of Atropisomer A-2 were obtained from 2304 experiments (including replicates).• ENaCt co-crystallisation experiments (24 x 96-well plates) were carried out using four solvents (DMSO, DMF, EtOH, and DCE) and 12 acidic co-f ormers (oxalic acid, adipic acid, pamoic acid, 3 -nitrophthalic acid, 3,4-dihydroxybenzoic acid, 5-chlorosalicylic acid, 3,3 ’-di thiopropionic acid, tartaric acid, phenoxyacetic acid, salicylic acid, adipic acid, and 3-hydroxy-2-naphoic acid). Additional ENaCt co-crystallisation experiments (3 x 96-well plates) were then carried out with saccharin. No co-crystals of Atropisomer A-2 were obtained from 2304 experiments (including replicates).• ENaCt in situ derivatisation experiments (8 x 96-well plates) were carried out with four hydrazines (2-hydrazinebenzothiozole (2-HBT), 3 -bromophenylhydrazine hydrochloride (3-BPH.HC1), 3 -nitrophenylhydrazine hydrochloride (3-NPH.HC1), and 2-nitrophenyl- hydrazine (2-NPH)) and benzyl bromide (2 x 96-well plates). No crystals of Atropisomer A-2 derivatives were obtained from 960 experiments (including replicates).• ENaCt experiments (2 x 96-well plates) were carried out with a hydrochloride (HC1) salt of Atropisomer A-2 (prepared in CPME) using four solvents (DMSO, DMF, CPME, and 2-MeTHF) and two solvent mixtures (DMSO:CPME and DMF:CPME). No crystalline solids were observed. Further ENaCt in situ HC1 salt formation experiments (3 x 96-well plates) were carried out using HC1 in diethyl ether and in CPME. Again, no crystallinesolids were observed.• Supporting classical crystallisation experiments were carried out including (i) slow evaporation experiments with 96 solvents, (ii) in situ HCL salt formation via liquidliquid layered diffusion between Atroisomer A-2 and HC1 in diethyl ether and CPME, and (iii) in situ saccharin co-crystal formation. No crystals associated with Atropisomer A-2 were obtained from 108 classical crystallization experiments.

[0176] Unless otherwise statement, each of the ENaCt experiments described below evaluated each of the four oils listed in Table 10 as encapsulation oils for the solvents employed.TABLE 10

[0177] Despite carrying over 6,000 ENaCt experiments (3 x 96-well plates) and over 100 supporting classical crystallisation experiments, no crystals associated with Atropisomer A-2 were identified.

[0178] Further general background on ENaCt can be found, for example, at Tyler A.R., et al., “Encapsulated Nanodroplet Crystallization of Organic-Soluble Small Molecules,” Chem. 6(7), 1755-1765 (2020).A. ENaCt Crystallization: Single Solvents

[0179] Stock solutions were prepared as follows. Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added in 5 pL portions until the sample was fully dissolved, up to a maximum of 300 pL of solvent. Where the samples were not fully soluble, the supernatant was used. Table 11 reports the experimental details.TABLE 11

[0180] Although 2304 experiments were carried out [96 solvents x 4 oils x 6 replicates], no crystalline solids of Atropisomer A-2 were obtained.B. ENaCt Crystallization: Co-Crystallisation

[0181] ENaCt co-crystallisation experiments (24 x 96-well plates) were carried out using four solvents and 12 acidic co-formers. Atropisomer A-2 contains two basic nitrogen atoms which are capable of interm olecular hydrogen bonding to protons in acids. The 12 acidic coformers, therefore, were used to potentially allow intermolecular hydrogen bonding to Atropisomer A-2 with co-crystallisation as a result.

[0182] Stock solutions of Atropisomer A-2 in the four different solvents (DMSO, DMF, EtOH, and DCE) were prepared as follows. Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added in 12 pL portions until the sample was fully dissolved. Table 12 reports the experimental details.TABLE 12

[0183] Stock solutions of the co-formers in the four different solvents were prepared as follows. Co-formers were weighed in 2 mL screw-top vial (different masses were used based on known solubility) and solvents were added in 12 pL portions until the sample was fully dissolved, up to a maximum of 384 pL of solvent / mg material. Where the samples were not fully soluble, the supernatant was used. Table 13 reports the experimental details.TABLE 13

[0184] ENaCt crystallisation experiments were carried out with the stock solutions of Atropisomer A-2 and the stock solutions of co-former in same solvent at three differentAtropisomer A-2 / co-former ratios (2: 1; 1 : 1, and 1 :3) and in each of the four encapsulation oils. Although crystals were obtained in some experiments, all such crystals were associated with the co-former (as determined by unit cell analysis) and no co-crystals of Atropisomer A-2 were obtained. Although 2304 experiments were carried out [4 solvents x 12 co-formers x 3 Atropisomer A-2 / co-former ratios x 4 oils x 4 replicates], no crystalline solids of Atropisomer A-2 were obtained.C. ENaCt Crystallization: In Situ Derivatization with Hydrazines

[0185] ENaCt crystallisation experiments (24 x 96-well plates) were carried out using in situ derivatisation with hydrazines. Atropisomer A-2 contains a carbonyl functional group capable of undergoing a condensation reaction with an added hydrazine containing molecule to give a hydrazone. It was hypothesized that the hydrazine would be more crystalline than the parent molecule and potentially allow crystallisation of the Atropisomer A-2-hydrazine adduct. Such a molecule could then be analyzed by SCXRD to allow structural and stereochemical determination.

[0186] Stock solutions of Atropisomer A-2 were prepared as follows. Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added until the sample was fully dissolved.

[0187] Stock solutions of hydrazine were prepared by dissolving the hydrazine in the appropriate solvents to give same concentrations as the stock solution of Atropisomer A-2 where possible. Where the samples were not fully soluble, the supernatant was used.

[0188] Tables 14, 15, 16, 17, and 18 report the experimental details.TABLE 14Atropisomer A-2 with 2-Hydrazinebenzothiozole (2-BHT)TABLE 15Atropisomer A-2 with 3 -Bromophenylhydrazine Hydrochloride (3-BPH.HC1)TABLE 16Atropisomer A-2 with 3 -Nitrophenylhydrazine Hydrochloride (3-NPH.HC1)TABLE 17Atropisomer A-2 with 2-Nitrophenylhydrazine (2-NPH))No crystalline solids of Atropisomer A-2 derivatives were obtained.D. ENaCt Crystallization: In Situ Derivatization with Benzyl Bromide

[0189] ENaCt crystallisation experiments (2 x 96-well plates) were carried out using in situ derivatisation with benzyl bromide to improve crystallinity of an Atropisomer A-2 derivative. It was hypothesized that the nucleophilic nitrogen atoms in Atropisomer A-2 would react with benzyl bromide to give benzylic substituted Atropisomer A-2 in which the added aromatic ring would improve crystallinity.

[0190] Stock solutions of Atropisomer A-2 and benzyl bromide were prepared in four solvents (DMSO, DMF, EtOH, and DCE) as follows. Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added until the sample was fully dissolved. Stock solutions of benzyl bromide were prepared by dissolving benzyl bromide in theappropriate solvents to give the same concentrations as the stock solution of Atropisomer A-2.

[0191] Table 18 reports the experimental details.TABLE 18No crystalline solids of Atropisomer A-2 were obtained.E. ENaCt Crystallization: In Situ Salt Formation with HC1

[0192] ENaCt crystallisation experiments (2 x 96-well plates) were carried out using in situ salt formation of Atropisomer A-2 with HC1. Solutions of Atropisomer A-2 were combined with HC1 in an organic solvent (either cyclopentyl methyl ether (CPME) or diethyl ether (DEE)) at four different molar ratios (Atropisomer A-2 and HC1 in CPME: 1 :3.5, 1 :7, 1 : 10.5, and 1 : 14; and Atropisomer A-2 and HC1 in DEE: 1 :3.3; 1 :6.6; 1:9.9; and 1: 13.3).

[0193] Stock solutions of Atropisomer A-2 were prepared as follows. Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added until the sample was fully dissolved. Table 19 reports the experimental details.TABLE 19

[0194] Commercially available solutions of HC1 in CPME (3 M) and HC1 in DEE (1 M) were used. Table 20 reports the experimental details for the molar ratios of Atropisomer A-2 to HC1 employed.TABLE 20

[0195] No crystalline solids were observed and no crystalline Atropisomer A-2 was obtained.F. ENaCt Crystallization: Co-Crystallisation with Saccharin

[0196] ENaCt co-crystallisation experiments (1 x 96-well plate) were carried out using Atropisomer A-2 and saccharin in CPME. Observations were made at three different time points (0 minutes, 7 days, and 14 days).

[0197] Stock solutions of Atropisomer A-2 in the CPME were prepared as follows.Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added until the sample was fully dissolved. Saccharin solutions were prepared in the same way. Where the samples were not fully soluble, the supernatant was used. Table 21 reports the experimental details.TABLE 21No crystalline solids were observed and no crystalline Atropisomer A-2 was obtained.G. ENaCt Crystallization: Co-Crystallisation with Saccharin

[0198] ENaCt co-crystallisation experiments (2 x 96-well plate) were carried out using Atropisomer A-2 and saccharin in acetone at different ratios of Atropisomer A-2 and saccharin as well as using diluted saccharin solutions (80% and 60%).

[0199] Stock solutions of Atropisomer A-2 in the acetone were prepared as follows. Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvent was added until the sample was fully dissolved. Saccharin solutions were prepared in the same way. Table 22 reports the experimental details.TABLE 22

[0200] Although some crystalline material was observed, SCXRD analysis could not be carried out because the crystals were too small for analysis.H. Layered Diffusion with HC1 or Saccharin

[0201] Salt formation of Atropisomer A-2 with HC1 and co-crystallisation of Atropisomer A- 2 with saccharin were evaluated using classical crystallisation methods (layered diffusion).1. Layered Diffusion with HC1

[0202] Stock solutions were prepared as follows. Amorphous Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added until the sample was fully dissolved. HC1 in CPME (3 M) and HC1 in DEE (1 M) were diluted to match the concentration of HC1 to that of Atropisomer A-2 in solution. Table 23 reports the experimental details.TABLE 23

[0203] Layered diffusion between Atropisomer A-2 and HC1 was carried out at three different ratios (100 pL:300 pL; 200 pL:200 pL; and 300 pL: 100 pL) in 750 pL vial inserts, kept within a larger 3 mL vial, in two different solvents CPME and DEE. The vials were then stored at room temperature and checked visually over time. Layered diffusion of Atropisomer A-2 with HC1 in CPME and DEE resulted in glassy amorphous solids which did not rotate polarised light, and which were not suitable for SCXRD analysis.2. Layered Diffusion with Saccharin

[0204] Stock solutions were prepared as follows. Atropisomer A-2 was weighed in 2 mL screw-top vials and solvents were added until the sample was fully dissolved. Saccharin was weighed in 2 mL screw-top vials and solvents were added to match the concentration of Atropisomer A-2 in solution. Table 24 reports the experimental details.TABLE 24

[0205] Layered diffusion between Atropisomer A-2 and saccharin was carried out at two different ratios (100 pL : 300 pL and 100 pL : 500 pL) in 750 pL vial inserts, kept within a larger 3 mL vial. The vials were then stored at room temperature and checked visually over time. Despite complete mixing of the layers, no solids were observed in layered diffusion experiments with Atropisomer A-2 with saccharin in acetone after 3 weeks.

[0206] No crystalline Atropisomer A-2 -HC1 or co-crystals of Atropisomer A-2 saccharinwere obtained.I. Methods1. Standard Method

[0207] Using a STP Labtech Mosquito Liquid-Handling Robot, 200 nL of one of four oils (PDMSO, FC-40, FY, and mineral oil) or secondary solvents were dispensed onto 96-well SWISSCI LCP plate with a 100-micron spacer. 50 nL of stock solution, containing the compound of interest, was collected from the parent plate and dispensed into the oil droplets within the wells. The plates were sealed with a glass cover slip and were stored in the dark at room temperature. After 2 weeks, evaluation of crystals growth was carried out visually by a cross-polarised optical microscopy.2. High Boiling Solvent Method

[0208] Using a STP Labtech Mosquito Liquid-Handling Robot, 250 nL of one of 48 high boiling solvents were dispensed onto 2x 96-well SWISSCI LCP plates with a 100-micron spacer. 50 nL of stock solution, containing the compound of interest, was collected from the parent plate and dispensed into the high boiling solvent droplets within the wells. The plates were sealed with a glass cover slip and were stored in the dark at room temperature. After 2 weeks, evaluation of crystals growth was carried out visually by a cross-polarised optical microscopy.3. Multi-Aspirate Method

[0209] Using a STP Labtech Mosquito Liquid-Handling Robot, 200 nL of one of four oils (PDMSO, FC-40, FY, and mineral oil) were dispensed onto a 96-well SWISSCI LCP plate with a 100-micron spacer. Following which an appropriate volume of each stock solution, containing the compound of interest, and an appropriate volume of a second solvent(s) were collected from the parent plate and were simultaneously dispensed into the oil droplets within the wells. The plates were sealed with a glass cover slip and were stored in the dark at room temperature and after 2 weeks, evaluation of crystals growth was carried out visually by a cross-polarised optical microscopy.4. End-Point Observations of ENaCt Experiments

[0210] After 14 days, the 96 well plates were examined by cross-polarised optical microscopy, and the results of the ENaCt experiments in each well were classified as: F: Fail; 1: remains in solution; 2: oiled-out or non-crystalline solid; 3: micro-crystalline solid; 4: crystals suitable for X-ray diffraction analysis.J. Additional AbbreviationsExample 6: Counterion Study

[0211] A counterion study was conducted for amorphous Atropisomer A-2 with the 48 counterions listed in Table 25 and five different solvents (methanol, ethyl acetate, tetrahydrofuran, acetonitrile, and ethanol / water (50 / 50)). The screen was repeated using amorphous Atropisomer A-2 that had been further purified by column chromatography.

[0212] An Atropisomer A-2 stock solution was prepared by dissolving 50.63 mg of Atropisomer A-2 in 6 mL of methanol to provide a 0.0143 M solution. A stock solution for each counterion was prepared by dissolving the counterion in an amount of methanol sufficient to provide a 0.025 M counterion solution. lOOpL of the Atropisomer A-2 stock solution was added to 48 wells of a 98 well plate. 57pL of the appropriate counterion stock solution was added to the corresponding wells to allow the salt formation. The methanol solvent was then allowed to evaporate in a slow and controlled manner (24 hours) to help induce crystallization. The resulting plate was then analyzed by polarized light microcopy (PLM) to determine whether there was any evidence of crystalline material by birefringence.

[0213] Ethyl acetate (lOOpL) was added to each well plate and vortexed at 400 RPM for 2 minutes to aid dissolution. The ethyl acetate solvent was then allowed to evaporate over 24hours and the plate was screened via PLM as previously described. The process was then repeated with each of the tetrahydrofuran (THF), acetonitrile, and ethanol / water (50 / 50) solvents.

[0214] No clear hits with strong birefringence or crystalline morphology were observed.TABLE 25Example 7: Counterion Study

[0215] A counterion study was conducted for amorphous Atropisomer A-2 with the counterions listed in Table 26 using methanol, acetone, and methyl tert-butyl ether (TBME) as solvents. Amorphous Atropisomer A-2 (353 mg) was dissolved in methanol (12 mL) to provide 0.05 M solution of Atropisomer A-2 (“Atropisomer Solution”). 0.05 M solutions of each counterion were prepared in methanol (“Counterion Solution”). Where a counterion was not fully soluble in methanol, a sufficient amount of water was added to the solution to solubilize the counterion. A 24-well plate was used to hold 24 4-mL vials for the screening.A. Reaction in Methanol (or Methanol / Water)

[0216] 0.5 mL of the 0.05 M Atropisomer Solution was mixed with 0.05 M of each Counterion Solution in a 4-mLl vial. The resulting solution was evaporated in the hood under ambient conditions. The resulting solid was then dried in vacuum (GeneVac).B. Crystallization in Acetone

[0217] The material in each vial from the methanol reaction was dissolved in acetone. The resulting solution was evaporated in the hood under ambient conditions. The resulting solid was then dried in vacuum (GeneVac).C. Crystallization in TBME

[0218] The material in each vial from the acetone crystallization was suspended or dissolved in TBME. The resulting solution was evaporated in the hood under ambient conditions. The resulting solid was then dried in vacuum (GeneVac).

[0219] Results are shown in Tables 26, 27, and 28 below.TABLE 26 (Methanol)TABLE 27 (Acetone)TABLE 28 (TBME)D. Hygroscopicity Study at 75% RH (Sodium Chloride (NaCl) Saturated Solution)

[0220] The powder material (non-gelling) in each vial from the TBME crystallization was placed into container with an NaCl saturated solution (75%RH). After one day, the deliquesce samples were removed. After 5 days, the deliquesce samples were removed leaving a total of seven samples remaining. The seven samples were dried in vacuum at 40°C for 3 hours and analyzed by DSC (Tg) and TGA (weight loss). Results are reported in Table 29.TABLE 29

[0221] No crystalline free form or crystalline salt of Atropisomer A-2 was obtained. With respect to the seven amorphous salts obtained, four salts (3-HO-benzoate, gentisate, saccharine and N-acetyl-L-tyrosine) showed better hygroscopicity than the amorphous free form and three salts (sulfate, besylate, tosylate) showed similar hygroscopicity to the amorphous free form.Example 8: Co-Crystal Study

[0222] Atropisomer A-2 (approximately 10 mg) and a 1 :1 stoichiometric amount of conformer were added to an HPLC vial together with four small balls per vial. The amount of Atropisomer A-2 and conformer added to each vial are reported in Table 30 below. The vialswere placed in a planetary mill (Fitsch Mill Pulverisette 6, Gawsworth Fl), dry-milled at 600 rpm for about 30 minutes, and then analyzed by XRPD. Cyclohexane (5pL) of was added to each vial. The vials were milled (liquid assisting grinding) at 600 rpm for an additional 30 minutes and then analyzed by XRPD again. No crystalline material was detected at either of the time points.TABLE 30Example 9: Preparation of Atropisomer A-2 SaltsA. Preparation of 3-Hydroxybenzoate Salt

[0223] Amorphous Atropisomer A-2 (125 mg, 0.21 mmol) and 3 -hydroxybenzoic acid (28 mg, 0.20 mmol) were dissolved in 0.5 ml of methanol. The clear solution was stirred at room temperature for one hour, and then the solution was concentrated to dryness in vacuum by GeneVac. The gel-like material was suspended in 1.0 mL of TBME, and the gel-like material solidified after stirring at the room temperature for one day. The slurry with some amounts of gel material was evaporated to dryness. The white solid was suspended in 1.0 mL of TBME and stirred at the room temperature for one day. The white slurry was filtered and dried at 40°C in vacuum for 20 hours. A white powder (102 mg) was obtained. The white powder was confirmed to be an amorphous 3 -hydroxybenzoate salt of Atropisomer A-2.B. Preparation of 3-Hydroxybenzoate Salt

[0224] 3 -Hydroxybenzoic acid (24 mg, 0.20 mmol) was dissolved in EtOAc (0.5 mL) resulting in a clear solution. Amorphous Atroisomer A-2 (118 mg, 0.20 mmol) was added to the solution resulting in a high-viscosity solution with some gel on the wall. TBME (1.50 mL) was added slowly to the solution and white solid started to precipitate. After addition, the resulting slurry was stirred at room temperature for one day. The homogenous slurry was filtered and the solid was dried in vacuum for 2 hours. A white solid (85 mg) was obtained. The white powder was confirmed to be an amorphous 3 -hydroxybenzoate salt of Atropisomer A-2.C. Preparation of Hydrochloride Salt

[0225] Amorphous Atropisomer A-2 (15 mg, 0.025 mmol) was dissolved in methanol (0.50 mL) resulting in a clear solution. IN HC1 aqueous solution (25 pL) was added. The solution was stirred at the room temperature for one hour and then concentrated to dryness in vacuum. A gel material was obtained. Acetone (0.5 mL) was added to the white gel resulting in a clear solution. Heptane (0.5 mL) was added, but no solid was obtained. The clear solution was then concentrated to dryness in vacuum. The resulting solid was suspended in TBME (0.5 mL) and the slurry was stirred at the room temperature for 3 days. No crystalline material was obtained. The solution was evaporated to dryness (GeneVac) to yield a white powder. The white powder was confirmed to be an amorphous hydrochloride salt of Atropisomer A-2.D. Preparation of Methanesulfonate Salt

[0226] Amorphous Atropisomer A-2 (15 mg, 0.025 mmol) was dissolved in methanol (0.50 mL) resulting in a clear solution. IN methanesulfonic acid (MSA) aqueous solution (25 pL) was added. The solution was stirred at the room temperature for one hour and then concentrated to dryness in vacuum. A gel material was obtained. Acetone (0.5 mL) was added to the white gel resulting in a clear solution. Heptane (0.5 mL) was added, but no solid was obtained. The clear solution was concentrated to dryness in vacuum and the resulting solid was suspended in TBME (0.5 mL). The slurry was stirred at the room temperature for 3 days. No crystalline material was obtained. The solution was evaporated to dryness (GeneVac) to yield a white powder. The white powder was confirmed to be an amorphous methansulfonate salt ofAtropisomer A-2E. Preparation of Hydrochloride Salt

[0227] Amorphous Atropisomer A-2 (236 mg, 0.40 mmol) was dissolved in acetone (1.0 mL) resulting in a clear solution. 2. ON HC1 aqueous solution (0.21 mL) was added. The solution was stirred at room temperature for one hour and then concentrated to dryness in vacuum. A white solid with was obtained. TBME (2.0 mL) was added to the white solid and the solution was stirred at room temperature for one hour until a homogenous slurry was obtained. A white solid (240 mg) was isolated by filtration and dried in vacuum at 40°C for 2 hours. The white powder was confirmed to be an amorphous hydrochloride salt of Atropisomer A-2.F. Preparation of l-Hydroxy-2-Naphthoic Acid Salt

[0228] Amorphous Atropisomer A-2 (104.277 mg, 0.18 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. 1 -Hydroxy -2-naphthoic acid (36.84 mg, 0.20 mmol) in tBME (0.5mL) was added resulting in a precipitate forming. An off-white solid (a 1 -hydroxy-2 - naphthoic acid salt of Atropisomer A-2) was isolated via filtration under vacuum. The off-white solid was analyzed by XRPD which confirmed that the 1 -hydroxy -2-naphthoic acid salt was amorphous. Further analysis determined a hygroscopic weight change of 19% between 0% RH to 80% RH at 25°C.G. Preparation of 3-Hydroxybenzoic Acid Salt

[0229] Amorphous Atropisomer A-2 (105.824 mg, 0.18 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. 3-Hydroxybenzoic acid (23.827 mg, 0.17 mmol) in tBME (0.5mL) was added which resulted in a precipitate forming. An off-white solid (a 3- hydroxybenzoic acid salt of Atropisomer A-2) was isolated via filtration under vacuum. The off- white solid was analyzed by XRPD which confirmed that the 3 -hydroxybenzoic acid salt was amorphous. Further analysis determined a hygroscopic weight change of 9% between 0% RH to 80% RH at 25°C.H. Preparation of (15)-(+)-10-Camphorsulfonic Acid Salt

[0230] Amorphous Atropisomer A-2 (102.747 mg, 0.17 mmol) was dissolved in tBME (1.0mL) resulting in a clear solution. (15)-(+)-10-Camphorsulfonic acid (41.517 mg, 0.18 mmol) in tBME (0.5mL) was added as a suspension which resulted in a precipitate forming. An off-white solid (a (lS)-(+)-10-camphorsulfonic acid salt of Atropisomer A-2) was isolated via filtration under vacuum. The off-white solid was analyzed by XRPD which confirmed that the (lS)-(+)- 10-camphorsulfonic acid salt was amorphous. The amorphous salt was shown to deliquesce when stored over saturated NaCl / water solution (75% RH) for around 2 weeks.I. Preparation of Citric Acid Salt

[0231] Amorphous Atropisomer A-2 (97.368 mg, 0.17 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. Citric acid (38.641 mg, 0.18 mmol) in tBME (0.5mL) was added as a suspension which resulted in a precipitate forming. An off-white solid (a citric acid salt of Atropisomer A-2) was isolated via filtration under vacuum. The off-white solid was analyzed by XRPD which confirmed that the citric acid salt was amorphous. Further analysis determined a hygroscopic weight change of 12% between 0% RH to 80% RH at 25°C.J. Preparation of Fumaric Acid Salt

[0232] Amorphous Atropisomer A-2 (99.521 mg, 0.17 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. Fumaric acid (20.482 mg, 0.18 mmol) in tBME (0.5mL) was added as a suspension which resulted in a precipitate forming. An off-white solid (a fumaric acid salt of Atropisomer A-2) was isolated via filtration under vacuum. The off-white solid was analyzed by XRPD which confirmed that the fumaric acid salt was amorphous. Further analysis determined a hygroscopic weight change of 12% between 0% RH to 80% RH at 25°C.K. Preparation of Gallic Acid Salt

[0233] Amorphous Atropisomer A-2 (97.140 mg, 0.17 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. Gallic acid (29.549 mg, 0.17 mmol) in tBME (0.5mL) was added as a suspension which resulted in a precipitate forming. An off-white solid (a gallic acid salt of Atropisomer A-2) was isolated via filtration under vacuum. The off-white solid was analyzed by XRPD which confirmed that the gallic acid salt was amorphous. Further analysis determined a hygroscopic weight change of 5% between 0% RH to 80% RH at 25°C.L. Preparation of Oxalic Acid Salt

[0234] Amorphous Atropisomer A-2 (99.871 mg, 0.17 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. Oxalic acid (15.26 mg, 0.18 mmol) in tBME (0.5mL) was added as a suspension which resulted in a precipitate forming. An off-white solid (a oxalic acid salt of Atropisomer A-2) was isolated via filtration under vacuum. The off-white solid was analyzed by XRPD which confirmed that the oxalic acid salt was amorphous. Further analysis determined a hygroscopic weight change of 18% between 0% RH to 80% RH at 25°C.M. Preparation of Saccharin Salt

[0235] Amorphous Atropisomer A-2 (42.36 mg, 0.07 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. Saccharin (15.53 mg, 0.08 mmol) in tBME (0.5mL) was added which resulted in a precipitate forming. An off-white solid (a saccharin salt of Atropisomer A-2) was isolated via filtration under vacuum. The off-white solid was analyzed by XRPD which confirmed that the saccharin salt was amorphous. Further analysis determined a hygroscopic weight change of 18% between 0% RH to 80% RH at 25°C.N. Preparation of Succinic Acid Salt

[0236] Amorphous Atropisomer A-2 (99.615 mg, 0.17 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. Succinic acid (20.308 mg, 0.17 mmol) in tBME (0.5mL) was added as a suspension which resulted in a precipitate forming. A sticky solid (a succinic acid salt of Atropisomer A-2) was isolated via filtration under vacuum.Example 10: Preparation of Hydrochloride Salt of Atropisomer A-2

[0237] Amorphous Atropisomer A-2 (48.2mg, 0.08 mmol) was dissolved in tBME (0.5 mL) resulting in a clear solution. 3.0 M HCL in CPME (30 pL) was added, resulting in a precipitate forming. The solvent was allowed to evaporate to dryness over the weekend. A white solid (a hydrochloride salt of Atropisomer A-2) was obtained. The white powder was analyzed by XRPD which confirmed that the hydrochloride salt was amorphous. Further analysis confirmed that the amorphous hydrochloride salt had a glass transition of 147°C (dry) and a hygroscopic weight change of 19.2% between 0% RH - 80% RH at 25°C.Example 11: Preparation of Besylate Salt of Atropisomer A-2

[0238] Amorphous Atropisomer A-2 (107.158 mg, 0.18 mmol) was dissolved in tBME (1.0 mL) resulting in a clear solution. Benzene sulphonic acid (63.907 mg) in tBME (0.5 mL) was added resulting in a precipitate forming. The solid was isolated via filtration under vacuum to yield an off-white solid (a besylate salt of Atropisomer A-2). The off-white solid was analyzed by XRPD which confirmed that the besylate salt was amorphous. Further analysis determined a hygroscopic weight change of 10.2% between 0% RH - 80% RH at 25°C. No obvious glass transition was detected.Example 12-A: Orotate SaltA. Preparation of Crystalline Orotate Salt1. Preparation in THF (Form A)

[0239] Amorphous Atropisomer A-2 (59 mg, 0.10 mmol) and orotic acid (17 mg) were dissolved in THF (1.0 mL) resulting in a clear solution. The solution was evaporated at room temperature and a white solid with gel was obtained. The solid was slurried in TBME for one day, but no crystalline form was obtained. The slurry was dissolved in THF / acetone and then evaporated at room temperature. A white material was obtained. XRPD analysis confirmed that the white material was the crystalline Form A of the orotate salt of Atropisomer A-2.2. Preparation in MeOH / EtOAc / TBME (Form B)

[0240] Amorphous Atropisomer A-2 (59 mg, 0.10 mmol) and orotic acid (17 mg, 0.10 mmol) were dissolved in MeOHZEtOAc (1 : 1) (1.0 mL) resulting in a clear solution. The solution was evaporated at the room temperature and a white gel was obtained. The gel-like material was stirred in TBME (1.0 mL) at room temperature for one day and a homogenous slurry was obtained. A white amorphous solid was obtained after drying by evaporation. Ethyl acetate (0.40 mL) was added to the solid and a wet-cake was obtained. TBME (0.80 mL) was added to get a slurry and the slurry was stirred at room temperature for one day. A partially crystalline material was obtained after drying. XRPD analysis confirmed that the crystalline portion of the isolated material was the Form B of the orotate salt of Atropisomer A-23. Preparation in THF / TBME (Form B)

[0241] Amorphous Atropisomer A-2 (59 mg, 0.10 mmol) and orotic acid (17 mg, 0.10 mmol) were suspended in THF (0.50 mL) and stirred for 2 hours resulting in a clear light yellow solution. TBME (1.0 mL) was slowly added to the solution, some gel was formed, and a white solid started to precipitate. The gel hardened after stirring for one hour and was disrupted into the slurry from the wall of the vial. The slurry was stirred at room temperature for 2 days. A white solid (70 mg) was filtered from the slurry and and air-dried. XRPD analysis confirmed that the white solid was the crystalline Form B of the orotate salt of Atropisomer A-2.4. Preparation in Acetone / TBME (Form B)

[0242] Amorphous Atropisomer A-2 (59 mg, 0.10 mmol) and orotic acid (17 mg, 0.10 mmol) were suspended in acetone (0.50 mL) and stirred for 0.5 hours resulting in a clear light yellow solution. TBME (1.0 mL) was slowly added to the solution and a gel was formed. The suspension was stirred at room tmeprature and white solid started to precipitate. The gel hardened after stirred for one hour and was disrupted into the slurry from the wall of the vial. The wet-cake / slurry was stirred at room temperature. Additional TBME was added to get a slurry and the slurry was stirred for 2 days. XRPD analysis confirmed that the white solid was the crystalline Form B of the orotate salt of Atropisomer A-2.5. Preparation in TBME / EtOAc (Form B)

[0243] Amorphous Atropisomer A-2 (59 mg, 0.10 mmol) and orotic acid (17 mg, 0.10 mmol) were suspended in TBME (0.50 mL). The Atropisomer A-2 dissolved resulting in a light yellow solution and the orotic acid was suspended in the solution. The suspension was stirred at room temperature for 2 days and a hemi-crystalline material containing the orotic acid was obtained. Ethyl acetate (1.0 mL) was added to the slurry and the slurry was stirred at room temperature for 3 days. XRPD analysis confirmed that the crystalline Form B of the orotate salt of Atropisomer A-2 was forming but that the counterion still retained.6. Preparation in Acetone (Form A)

[0244] Amorphous Atropisomer A-2 (125 mg, 0.21 mmol) and orotic acid (35 mg, 0.20 mmol) were suspended in acetone (1.0 mL) and stirred at room temperture. The Atropisomer A-2 solid was dissolved immediately and the white crystalline solid of orotic acid was dissolved slowly. After about 15 to 30 minutes, most of orotic acid was dissolved and a white solid started to precipitate. A wet cake was formed after about one hour. Acetone (1.0 mL) was added and the resulting slurry was stirred at room temperature for one day. A white solid (118 mg) was isolated by filtration and dried in vaccum for 2 hours. XRPD analysis confirmed that the white solid was the crystalline Form A of the orotate salt of Atropisomer A-2.7. Preparation in THF / Heptane / Acetone (Form A)

[0245] Amorphous Atropisomer A-2 (60 mg, 0.10 mmol) and orotic acid (17 mg, 0.10 mmol) were suspended in THF (1.0 mL) and stirred at room temperture. The Atropisomer A-2 solid was dissolved immediately and the white crystalline solid of orotic acid was dissolved slowly. The light brown solution was filtered. Form A seeds (2 to 3 mg) of were added and heptane (0.50 mL) was added slowly. The suspension was stirred at room temperature for one day. More heptane (0.50 mL) was added and the soup-like slurry remained. Acetone (0.5 mL) was added, and a homogenous slurry was formed. A white solid (46 mg) was isolated by filtration and dried in vaccum for 2 hours. XRPD analysis confirmed that the white solid was the crystalline Form A of the orotate salt of Atropisomer A-2.8. Form A Slurry in TBME

[0246] Crystalline Form A of the orotate salt of Atropisomer A-2 (approximately 10 mg) was suspended in TBME (0.5 mL) and stirred for 3 days. The crystalline Form A of the orotate salt converted to the crystalline Form B of the orotate salt of Atropisomer A-2.9. Form B Slurry in Acetone

[0247] Crystalline Form B of the orotate salt of Atropisomer A-2 (approximately 10 mg) was suspended in acetone (0.5 mL) and stirred for 3 days. The crystalline Form B of the orotate salt converted to the crystalline Form A of the orotate salt of Atropisomer A-2. The slurry was heated to 50°C for 2 hours and Form A was retained.10. Form B Slurry in Ethyl Acetate

[0248] Crystalline Form B of the orotate salt of Atropisomer A-2 (approximately 10 mg) wassuspended in ethyl acetate (0.5 mL) and stirred for 3 days. Form B was retained. The slurry was heated to 50°C for 2 hours and Form B was retained.11. Evaporation from Acetonitrile (Form C)

[0249] Crystalline Form B of the orotate salt of Atropisomer A-2 (approximately 10 mg) was dissolved in acetonitrile (2.0 mL). The solution was filtered and evaporated in a hood. A needle-like crystalline material was obtained. XRPD analysis confirmed that the white solid was the crystalline Form C orotate salt of Atropisomer A-2.12. Evaporation of TBME into EtOAc / DCM / MeOH Solution

[0250] Crystalline Form B of the orotate salt of Atropisomer A-2 (approximately 10 mg) was dissolved in ethyl acetate / dichloromethane / methanol (1 : 1 : 1) (1.5 mL) and TBME (2.0 mL) was slowly evaporated into the solution. A white solid started to precipitate. The solution was evaporated, and a white solid was obtained. XRPD analysis confirmed that the white solid was the crystalline Form B of the orotate salt of Atropisomer A-2.

[0251] Initial observations from the above-described orotate salt crystallization study can be summarized as follows:• Three crystalline orotate salts of Atropisomer A-2 were isolated: Forms A, B, and C.• Form A contained approximately 3% of solvent residue. No form change was observed after heating to 125°C and no form change was observed after the GVS study.• Form B contained more than 10% of solvent residue and may be a TBME solvate. No form change was observed after heating to 150°C.• Form A converted to Form B in TBME.• Form B converted to Form A in acetone.• Form C was obtained from evaporation of acetonitrile. Form C contains about 5% of solvent residue and may be an acetonitrile solvate.B. Characterization of Crystalline Orotate Salt1. Form A

[0252] Characterization of crystalline Form A of the orotate salt of Atropisomer A-2 wascarried out using various techniques including X-ray powder diffraction (XRPD) (FIG. 1), differential scanning calorimetry (DSC) (FIG. 2), thermogravimetic analysis (TGA) (FIG. 3), and gravimetric vapor sorption (GVS) (FIG. 4). a. XRPD

[0253] FIG. 1 shows a representative XRPD pattern for crystalline Form A measured using reflection geometry. The XRPD pattern of FIG. 1 confirms that Form A of the orotate salt is crystalline. Table 31 below lists selected peaks identified in the XRPD pattern of FIG. 1.TABLE 31The following definitions have been used for the relative intensity (%): 25% - 100%, vs (very strong); 10% - 25%, s (strong); 3% - 10%, m (medium); 1% - 3%, w (weak).

[0254] Crystalline Form A shows characteristic peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29. Crystalline Form A shows further characteristic peaks at 19.1 ± 0.2° 29 and 21.7 ± 0.2° 29. Crystalline Form A shows further peaks at 13.4 ± 0.2° 29, 17.3 ± 0.2 °29, and 23.3 ± 0.2° 29. b. DSC

[0255] FIG. 2 shows a representative differential scanning calorimetry (DSC) thermogram for crystalline Form A. Exothermic events are plotted in the upward direction. The thermal event shown in FIG. 2 has an onset temperature of about 25°C and a heat enthalpy of approximately 75.8 J / g for the de-solvated endotherm, followed by an onset temperature of about 165°C and a heat enthalpy of approximately 16.7 J / g for the melting endotherm. The DSC values obtained can vary by as much as ± 5°C depending upon the instrument used, how samples are prepared, and differences between batches. c. TGA

[0256] FIG. 3 shows a representative thermogravimetic analysis (TGA) thermogram for crystalline Form A. Crystalline Form A exhibited a weight loss of about 3.3 weight % upon heating from about 25°C to 100°C, which confirms that crystalline Form A is a crystalline solvate / hydrate. d. GVS

[0257] FIG. 4 shows a representative gravimetric vapor sorption (GVS) plot for crystalline Form A. Crystalline Form A exhibited a reversible moisture uptake of about 6.0 weight % between 0% relative humidity and 80% relative humidity at 25°C ±0.1°C. The desorption curve indicates that crystalline Form A lost moisture at a similar rate to the moisture gained during sorption, with limited hysteresis. No form change was observed by XRPD after the GVS experiment.2. Form B

[0258] Characterization of crystalline Form B was carried out using various techniques including X-ray powder diffraction (XRPD) (FIG. 5), differential scanning calorimetry (DSC)(FIG. 6), and thermogravimetic analysis (TGA) (FIG. 7). a. XRPD

[0259] FIG. 5 shows a representative XRPD pattern for crystalline Form B measured using reflection geometry. The XRPD pattern of FIG. 5 confirms that Form B of the orotate salt is crystalline. Table 32 below lists selected peaks identified in the XRPD pattern of FIG. 5.TABLE 32The following definitions have been used for the relative intensity (%): 25% - 100%, vs (very strong); 10% - 25%, s (strong); 3% - 10%, m (medium); 1% - 3%, w (weak).

[0260] Crystalline Form B shows characteristic peaks at 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29. Crystalline Form B shows further characteristic peaks at 18.2 ± 0.2 °29, 19.2 ± 0.2° 29, 20.6 ± 0.2° 29, 27.2 ± 0.2° 29, and 35.6 ± 0.2° 29.b. DSC

[0261] FIG. 6 shows a representative differential scanning calorimetry (DSC) thermogram for crystalline Form B. Exothermic events are plotted in the upward direction. The thermal event shown in FIG. 6 has an onset temperature of about 32°C and a heat enthalpy of approximately 66.4 J / g for the de-solvated endotherm, followed by an onset temperature of about 150°C and a heat enthalpy of approximately 10.7 J / g for the melting endotherm. The DSC values obtained can vary by as much as ± 5°C depending upon the instrument used, how samples are prepared, and differences between batches. c. TGA

[0262] FIG. 7 shows a representative thermogravimetic analysis (TGA) thermogram for crystalline Form B. Crystalline Form B exhibited a weight loss of about 10.1 weight % upon heating from about 25°C to 175°C, which confirms that the crystalline Form B is a crystalline solvate / hydrate.3. Form C

[0263] Characterization of crystalline Form C was carried out using various techniques including X-ray powder diffraction (XRPD) (FIG. 8), differential scanning calorimetry (DSC) (FIG. 9), and thermogravimetic analysis (TGA) (FIG. 10). a. XRPD

[0264] FIG. 8 shows a representative XRPD pattern for crystalline Form C measured using reflection geometry. The XRPD pattern of FIG. 8 confirms that Form C of the orotate salt is crystalline. Table 33 below lists selected peaks identified in the XRPD pattern of FIG. 8.TABLE 33The following definitions have been used for the relative intensity (%): 25% - 100%, vs (very strong); 10% - 25%, s (strong); 3% - 10%, m (medium); 1% - 3%, w (weak).

[0265] Crystalline Form C shows characteristic peaks at 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29. Crystalline Form C shows further characteristic peaks at 10.7 ± 0.2° 29, 13.0 ± 0.2° 29, 14.7 ± 0.2° 29, 17.9 ± 0.2 °29, and 21.3 ± 0.2° 29. b. DSC

[0266] FIG. 9 shows a representative differential scanning calorimetry (DSC) thermogram for crystalline Form C. Exothermic events are plotted in the upward direction. The thermal event shown in FIG. 9 has an onset temperature of about 27°C and a heat enthalpy of approximately 88.8 J / g for the de-solvated endotherm, followed by an onset temperature ofabout 157°C and a heat enthalpy of approximately 14.4 J / g for the melting endotherm. The DSC values obtained can vary by as much as ± 5°C depending upon the instrument used, how samples are prepared, and differences between batches. c. TGA

[0267] FIG. 10 shows a representative thermogravimetic analysis (TGA) thermogram for crystalline Form C. Crystalline Form C exhibited a weight loss of about 4.8 weight % upon heating from about 25°C to 150°C, which confirms that crystalline Form C of the orotate salt is a crystalline solvate / hydrate.C. Analytical Methods

[0268] Unless otherwise stated, the following analytical methods were used to characterize the crystalline orotate salts described in this Example:1. Reflection X-Ray Powder Diffraction

[0269] The X-ray diffraction analysis is performed according to standard methods, which can be found, for example, in Kitaigorodsky, A.I. (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; or Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York.

[0270] The X-ray powder diffraction (XRPD) pattern is determined by mounting a sample on a zero-background holder, single silicon crystal, and spreading out the sample into a thin layer. The XRPD is recorded with a Theta-Theta Rigaku MiniFlex (wavelength of X-rays 1.5418 A nickel-filtered Cu radiation, Voltage 40 kV, filament emission 15 mA). Variable divergence and anti-scatter slits and incident and diffracted seller slit 0.04° are used. The samples are rotated during measurement. Samples are scanned from 3 to 40°26 using a 0.013° step width and a 115.770 s count time together with a PIXcellD detector (active length 3.35°20). The XRPD patterns are obtained in Bragg-Brentano geometry.

[0271] One of skill in the art will recognize that a XRPD pattern may be obtained which has one or more measurement errors depending on measurement conditions, such as equipment ormachine used (Jenkins, R & Snyder, R.L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons 1996; Bunn, C.W. (1948), Chemical Crystallography, Clarendon Press, London; Klug, H. P. & Alexander, L. E. (1974), X-Ray Diffraction Procedures). Those skilled in the art of X-ray powder diffraction will further recognize that the relative intensity of peaks can be affected by, for example, grains above 30 microns in size and non-unitary aspect ratios that may affect analysis of samples. Those skilled in the art would further understand that intensities might fluctuate depending on experimental conditions and sample preparation (e.g., preferred orientation). The following definitions have been used for the relative intensity (%): 25% - 100%, vs (very strong); 10% - 25%, s (strong); 3% - 10%, m (medium); 1% - 3%, w (weak).

[0272] One of skill in the art will also recognize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence the diffraction pattern data presented are not to be taken as absolute values. Generally, a measurement error of a diffraction angle in a powder X-ray diffractogram may be approximately plus or minus 0.2°26, and such a degree of a measurement error should be taken into account when considering the XRPD data.

[0273] The reflection mode XRPD pattern may be compared to the transmission mode XRPD pattern, although those skilled in the art will realize that the diffraction patterns may vary, particularly with respect to peak intensities.2. Differential Scanning Calorimetry (DSC)

[0274] The melting point temperature onset (Tm) is determined by Differential Scanning Calorimetry using a TA Instruments DSC, model Discovery Q2500. A sample (approximately 1-3 mg) is weighed into an aluminum sample pan. The sample is packed to the bottom of the sample pan and a lid with a pin hole is used. The instrument is purged with nitrogen at 50 mL / min and data collected between 22°C and 300°C, using a heating rate of 10°C / minute.3. Thermogravimetric Analysis (TGA)

[0275] Thermal gravimetric analysis is performed using a TA Instruments TGA, Discovery Q5500. A sample (approximately 10 mg) is transferred to a tared sample holder. The instrumentis purged with nitrogen, oven 60 mL / min and balance 40 mL / min, and data are collected between room temperature and 300°C, using a heating rate of 10°C / min. During heating, the buoyancy effect will result in an observed weight increase. This effect can be reduced by using more than 15 mg of material or performing a baseline subtraction on the sample curve.4. Gravimetric Vapor Sorption (GVS)

[0276] Gravimetric vapor sorption analysis is performed using a TA Instruments TGA, model Discovery SA. A sample (approximately 5-10 mg) is transferred to a tared sample holder. The instrument is purged with nitrogen, chamber 200 mL / min and balance 10 mL / min at 25°C and data are collected at different relative humidity (%RH). Starting at 40% relative humidity (RH) and going stepwise up to 90%RH, down stepwise to 0%RH, and eventually a second cycle going up to 90%RH and back to 40%RH. The equilibrium criteria for moving to next %RH is reached when the drift criteria (dm / dt) is below 0.002 for 10 min.

[0277] Hygroscopicity can be assessed, for example, according to the European Pharmacopoeia (EP) classification: non-hygroscopic: < 0.2%; slightly hygroscopic: > 0.2% and < 2%; hygroscopic: > 2% and < 15%; very hygroscopic: > 15%; deliquescent: sufficient water is absorbed to form a liquid; all values measured as weight increase at 80% RH and 25°C).Example 12-B: Initial Preparation as Orotate SaltA. Stereoisomeric Forms

[0278] Four stereoisomers of 2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide have been identified and are shown in Table 33-A below. The desired stereoisomer is Atropisomer A-2, but the other stereoisomers (Atropisomers A-l, A-3, and / or A-4) may be present as impurities depending upon the method of synthesis. It has been found that first preparing an orotate salt (particularly a crystalline orotate salt such as Form A) from the 5-2-(3-(l-(5,5- dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-lH-pyrrolo[2,3-c]pyridin-l- yl)-5-fluoro-N,N-diisopropylbenzamide starting material and then converting the orotate salt into a besylate salt can improve the Atropisomer A-2 stereoisomeric purity in the final besylate salt product relative to preparing the besylate salt directly from the Atropisomer A-2 startingmaterial without proceeding through the Atropisomer A-2 orotate salt.TABLE 33-A

[0279] Benzenesulfonic acid (7.71 g, 48.7 mmol) was dissolved in 2-methyltetrahydrofuran (23 mL) and added over 2.5 hours to a solution of Atropisomer A-2 (30.01 g, 48.85 mmol, 96 mass % purity) in 2-methyltetrahydrofuran (345 mL) at 20°C. The Atropisomer A-2 starting material included Atropisomer A-l (0.12 area %) and Atropisomer A-4 (1.43 area %) as impurities. 2-Methyltetrahydrofuran (8 mL) was charged as a line wash. Heptane (375 mL) was added to a separate vessel and the solution of Atropisomer A-2 besylate was added over more than 1 hour at 20°C. The resulting slurry was stirred overnight (approximately 16 hours) before the slurry was filtered, washed with heptane (3x150 mL), and dried under vacuum to yield Atropisomer A-2 besylate as an off-white solid (37.07 g, 46.59 mmol, 94 mass %). Chiral analysis indicated that the besylate salt product also contained Atropisomer A-l (0.94 area %) and Atropisomer A-4 (1.43 area %). The increase in Atropisomer A-l content may have been due to the age of the Atropisomer A-2 starting material rather than the process itself, but the overall results confirm that the Atropisomer A-l and A-4 impurities in the Atropisomer A-2 starting material were retained in the final Atropisomer A-2 besylate salt product.C. Preparation of Besylate Salt (Orotate Salt Isolation)

[0280] Atropisomer A-2 (25.41g, 41.36 mmol, 96 mass %) was dissolved in acetone (250 mL) and orotic acid (6.457 g, 41.37 mmol) was added. The Atropisomer A-2 starting material included Atropisomer A-l (0.12 area %) and Atropisomer A-4 (1.43 area %) as impurities. The suspension was stirred for 10 days then filtered under vacuum, washed with acetone (150 mL), and dried under vacuum to yield Atropisomer A-2 orotate (25.25 g, 33.85 mmol). TheAtropisomer A-2 orotate was determined to be crystalline orotate Form A. Atropisomer A-l was non-detected in the Atropisomer A-2 orotate. Atropisomer A-4 content was not measured.

[0281] A portion of Atropisomer A-2 orotate (12.5 g, 16.8 mmol) was slurried in 2- methyltetrahydrofuran (125mL). IM NaOH (125 mL) was added and the solids dissolved. The aqueous phase was removed and the organic phase washed with water (3x62.5 mL). The organic phase was concentrated under vacuum and azeodried with 2-methyltetrahydrofuran (500 mL). The resulting Atropisomer A-2 concentrate was diluted with further 2- methyltetrahydrofuran to make the final volume 107 mL. To this was added a solution of benzenesulfonic acid (2.35 g, 14.9 mmol) in 2-methyltetrahydrofuran (7 mL) over 2 hours. The resulting solution was added to heptane (120 mL) and the resulting slurry filtered under vacuum and washed with heptane (3x50 mL). The collected solids were dried under vacuum to yield Atropisomer A-2 besylate (10.34 g, 13.73 mmol, 99.31 mass %). Atropisomer A-l was nondetected in the final Atropisomer A-2 besylate salt product. Atropisomer A-4 content was not measured.D. Preparation of Atropisomer A-2 Orotate from Atropisomer A-l / A-2 Mixture

[0282] To a 1 : 1 mixture of Atropisomer A-l / Atropisomer A-2 (1.0 g, 1.475 mmol, 87 mass %) was added orotic acid (230 mg, 1.47 mmol) followed by acetone (15mL) and the mixture stirred for 9 days. The slurry was then filtered under vacuum and washed with acetone (2x2.5 mL) to yield Atropisomer A-2 orotate (370 mg, 0.490 mmol (98.9 mass%)). The Atropisomer content of the recovered product was 0.21 area % Atropisomer A-l and 99.79 area % Atropisomer A-2.Example 13: Menin / MLL Fluorescence Polarization (FP) Assay

[0283] Compounds were tested in a biochemical binding assay using Menin protein at 2 nM (N6his-tev-Menin_4i80, PB-20-1459) and the substrate cRhol 10-Ahx-MBMl / MBM2 peptide (UbiQ, UbiQ-Q20201030; cRhl 10-Ahx-SCRWRFPARPGTTGGGGGGGRRGLGGAPR- QRVPALLLPPG-NH2) at 1 nM.

[0284] 384 Low volume black plates (Corning #4514) were used. 5 pL / well compound or 3% DMSO was added at 10-fold serial dilutions in DMSO from 10 pM. 5 pL / well cRhol 10-Ahx-MBM1 / MBM2 peptide or binding buffer (50 mM Tris pH 7.5, 50 mM NaCl, 1 mM TCEP, 0.01% BGG, 0.01% Brij-35) was added to all wells. 5 pL / well Menin protein or binding buffer (50 mM Tris pH 7.5, 50 mM NaCl, 1 mM TCEP, 0.01% BGG, 0.01% Brij-35) was added to all wells. Plates were read on an EnVision plate reader (Perkin Elmer) with excitation at 480 nm and emission at 535 nm P+S, and measured every 5 minutes for 180 minutes.

[0285] Data were analyzed in Genedata Screener®. ICso values were determined by plotting % inhibition versus log compound concentration and using a one site dose response model. Raw data signals were normalized using 1% DMSO no Menin as 100% inhibitor control and 1% DMSO with Menin and no inhibitor as 0% inhibitor control. Data are reported in Table 34 for Atropisomers A-l and A-2.TABLE 341ICso is reported after a single measurement (n=l) or as an average for multiple measurements (n>l).Example 14: Proliferation Assay

[0286] The anti-proliferative effect of compounds was tested in human leukaemia cell lines. The cell lines MOLM-3 and MV4; 11 each harbor an MLL translocation expressing the MLL fusion proteins MLL-AF9 and MLL-AF4, respectively. Each also express the wildtype protein from the second allele. OCI-AML3 cells carrying the NPMlc gene mutation were also tested. EEL cells which do not carry MLL1 translocation or NPMlc mutations were used as a control cell line to exclude compounds that displayed general cytotoxic effects.

[0287] MOLM-13 and EEL cells were cultured in RPMI 1640 (Gibco) supplemented with 10% FBS (Gibco) and 1% Pen / Strep (Gibco). MV4;11 cells were cultured in IMDM (Gibco) supplemented with 10% FBS (Gibco) and 1% Pen / Strep (Gibco). OCI-AML3 cells were cultured in MEMa (Gibco) supplemented with 20% FBS (Gibco) and 1% Pen / Strep (Gibco).

[0288] To assess proliferative effects, 125 MOLM-13 cells, 300 MV4;11 cells, 75 OCI- AML3 cells, and 200 EEL cells were seeded in 40 pL media per well in 384-well ViewPlates(Perkin Elmer, 6007480). Cell seeding numbers were chosen based on growth curves to ensure linear growth throughout the experiments. Test compounds were added at 3.16-fold serial dilutions in DMSO from 10 pM and DMSO content was normalized to 0.1%. Cells were incubated for 7 days at 37°C and 5% CO2. A day 0 plate was seeded for each cell line and used as a standard control.

[0289] To measure cell viability, CellTiter-Glo 2.0 (Promega, G9242) luminescent growth indicator was used. 10 pL CellTiter-Glo reagent was added per well. Plates were placed on a plate shaker for 2 minutes in the dark and left to incubate off the shaker for another 8 minutes in the dark, for a total of 10 minutes. Plates were read using an EnVision plate reader (Perkin Elmer) using the Luminescence aperture and a measurement time of 0.1 second.

[0290] Data were analyzed in Genedata Screener®. IC50 values were determined by plotting % inhibition versus log compound concentration and using a one site dose response model. Raw data signals were normalized using 0.1% DMSO media only as background control, 0.1% DMSO with cells no compound as 100% viability (maximum signal), and day 0 0.1% DMSO with cells no compound as 0% viability (minimum signal). Data are reported in Table 35 for Atropisomers A-l and A-2.TABLE 351IC50 is reported after a single measurement (n=l) or as an average for multiple measurements (n>l).Example 15: hERG AssaysA. hERG Assay 1 (Standard)

[0291] Experiments were performed on the SyncroPatch 384PE (Nanion Technologies) high throughput patch clamp platform at room temperature and used medium resistance chips with 4 patch holes per site. hERG-expressing Chinese hamster ovary KI (CHO) cell line was used in assay-ready format and kept in liquid nitrogen until use. 2 vials of cells (10 x 10A6 cells pervial) were thawed and added to 20 ml Hepes-buffered saline solution (HBSS). HBSS comprised 140 mM NaCl, 4mM KC1, lOmM HEPES and 5mM Glucose (pH 7.4). The internal patch clamp solution was KF 120 mM, KC1 20 mM, HEPES 10 mM, EGTA 10 mM, and 25 pM Escin (pH 7.2). After the initial sealing process was complete, a seal enhancer solution comprising HBSS supplemented with 10 mM CaCh and ImM MgCh was applied to cells. The external solution was then exchanged (4 times) for external patch clamp solution comprising NaCl 80 mM, KC1 4 mM, HEPES 10 mM, CaCh 2 mM, MgCh 1 mM, glucose 5 mM, and NMDG 60 mM (pH7.4). All compounds were dispensed from initial 10 mM DMSO stocks. An industry standard +60 / - 40 mV voltage protocol was applied every 15 seconds. Compounds were tested in a 6-point cumulative assay (final DMSO concentration 0.33%), with a concentration range of 139 nM to 40 uM. Data were analyzed in Genedata Screener®. ICso values were determined by plotting % inhibition versus log compound concentration and using a one site dose response model. Only wells that passed acceptance criteria for this platform were used in this analysis (30 MegaOhm seal resistance, Z prime >0.4 and current size >0.2 nA). Data are reported in Table 36 for Atropisomers A-l and A-2.B. hERG Assay l

[0292] Experiments were performed on the QPatch II 48X (Sophion Biosciences) high throughput patch clamp platform at room temperature and used single hole Qplates. hERG DUO cell line (BSys) was used. The internal patch clamp solution was KF 60 mM, KC1 70 mM, HEPES 10 mM, EGTA 10 mM, and 5 mM Mg ATP (pH7.2). After sealing and whole cell access was gained the external solution (NaCl 140 mM, KC1 4 mM, HEPES 10 mM, CaCh 2 mM, MgCh 1 mM, glucose 5 mM (pH 7.4) was applied twice to establish stable baseline currents. An industry standard +40 / -40 mV voltage protocol was applied every 15 seconds. All compounds were tested in a 6-point cumulative assay (final DMSO concentration 0.4-2 % depending on stock concentration of compounds). Compounds were dispensed from initial 10 mM or 50 mM DMSO stocks after which DMSO dilutions were undertaken with a top concentration of 200 pM tested. Solvent controls were run in all experiments in line with the DMSO % required. Only wells that passed acceptance criteria for this platform were used in this analysis (500 MegaOhm seal resistance and current size >0.2 nA). Analysis was completed inPrism Graphpad to complete a composite IC50, by plotting % inhibition versus log compound concentration and using a log(inhibitor) vs. response — Variable slope. Data are reported in Table 36 for Atropisomer A-2.C. hERG Assay 3

[0293] Experiments were performed on the QPatchll 48X(Sophion Biosciences) high throughput patch clamp platform at 30 degrees Celsius using single holes QChips (Sophion Bioscience). Chinese hamster ovary KI (CHO) cell lines over-expressing the hERG ion channel were used from live culture. All compounds were dispensed as solid stocks in glass vials. Compounds were solubilised to 10 or 50 mM DMSO stocks on the day of experiments, after which dilutions in DMSO we undertaken. Stamps of DMSO stocks were made into an MTP plate using glass vials, after which extracellular solution was backfilled creating testing concentrations with a highest concentration of 40 and 200 pM, respectively. The internal patch clamp solution was KF 60 mM, KC1 70 mM, HEPES 10 mM, EGTA 10 mM, and 5mM Mg ATP (pH7.2). After sealing and whole cell access was gained the external solution (NaCl 140 mM, KC1 4 mM, HEPES 10 mM, CaCh 2 mM, MgCh 1 mM, glucose 5 mM (pH7.4) supplemented with 0.4% DMSO was applied twice to establish stable baseline currents. An industry standard +40 / -40 mV voltage protocol was applied every 15 seconds. Cells were then applied with a single concentration of compound for a minimum of 15 minutes (a bolus addition every 3 minutes). Analysis was completed in Prism Graphpad to complete a composite IC50, by plotting % inhibition versus log compound concentration and using a log(inhibitor) vs. response — Variable slope Only wells that passed previously agreed acceptance criteria for this platform were used in this analysis (500 MegaOhm seal resistance and current size >0.2 nA). Data are reported in Table 36 for Atropisomer A-2.TABLE 361IC50 is reported after a single measurement (n=l) or as an average for multiple measurements (n>l).Example 16: Muscarinic M2 Receptor Assay

[0294] Cell membrane homogenates (60 pg protein) were incubated for 60 minutes at 22°C with 2 nM [3H]AF-DX 384 in the absence or presence of the test compound in a buffer containing 50 mM Tris-HCl (pH 7.4), 120 mM NaCl, 5 mM KC1, 5 mM MgCh, and 1 mM EDTA. Nonspecific binding was determined in the presence of 1 pM atropine. Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters (GF / B, Packard) presoaked with 0.3% PEI and rinsed several times with ice-cold 50 mM Tris-HCl using a 96-sample cell harvester (Unifilter, Packard). The filters were dried then counted for radioactivity in a scintillation counter (Topcount, Packard) using a scintillation cocktail (Microscint 0, Packard). The results were expressed as a percent inhibition of the control radioligand specific binding, from which the Ki was calculated. Data were analyzed using software developed at Cerep (Hill software) and validated by comparison with data generated by the commercial software SigmaPlot®4.0 for Windows® (© 1997 by SPSS Inc.). The inhibition constant, Ki, was calculated using the Cheng Prusoff equation:Ki = ICso / (1+L / Kd) where L = concentration of ligand in the assay, and Kd = affinity of the ligand for the receptor.

[0295] The standard reference compound was methoctramine, which was tested in each experiment at several concentrations to obtain a competition curve from which its IC50 was calculated. Data are reported in Table 37 for Atropisomers A-l and A-2.TABLE 371IC50 is reported after a single measurement (n=l) or as an average for multiple measurements (n>l).Example 17: Metabolic Stability AssaysA. Human Liver Microsomes (HLMs) Intrinsic Clearance AssayMaterial and Reagents

[0296] Human liver microsomes (HLMs) were obtained from Coming (UltraPool 150 donors) at a concentration of 20 mg / mL protein. HLMs were stored at -80°C until use and prior to use, thawed in a 37°C water bath and then stored on wet ice. DMSO and NADPH were sourced from Solarbio S&T Co Ltd.Performing the HLM Intrinsic Clearance AssayPreparation of Stock Solutions

[0297] 2 mL of 10 mM DMSO stock solutions of test compound were added to 198 mL acetonitrile to produce 100 mmol / L concentration. 1325 mL of 20 mg / mL HLM were added to 22260 mL of phosphate buffer to produce the HLM mixture. An 8.334 mg / mL solution of NADPH was prepared in 100 mmol / L pH 7.4 phosphate buffer.HLM Incubation

[0298] 222.5 mL of the HLM mixture and 25 mL of the lOmM NADPH were added into the incubation plates (1 mL 96 well deep well plate from Thermo). The mixture was vortexed for 10 seconds at 1000 rpm. The incubation plate was pre-warmed in a water bath at 37°C for 8 minutes. 2.5 mL of the 100 mM stocks of test compound was added to initiate the reaction. The mix was vortexed for 12 seconds at 1000 rpm and incubated at 37°C. The incubation mixture (250 mL) contained 1 mg / mL HLM, 1 mmol / L NADPH and 1 mM test compound.

[0299] The reaction was quenched by transferring 20 mL of the incubation mixture at 0.5, 5, 10, 15, 20 and 30 minutes into the quenching plate containing 100 mL of cold stop solution (acetonitrile containing internal standards). The plate was vortexed at 800 rpm for 2 minutes.

[0300] The quenching plates were centrifuged for 20 minutes at 4000 rpm and 4°C. 40 mL of the supernatant was transferred into a 96-well analysis plate containing 160 mL of water. The analysis plate was shaken at 1000 rpm for 2 minutes and the samples analysed by LC-MS / MS.Calculation of HLM CLint

[0301] Peak areas were determined from extracted ion chromatograms. Percent parent remaining was calculated from peak area of test compound. The slope value, k, was determined by linear regression of the natural logarithm of percent parent remaining versus incubation time.

[0302] The in vitro half-life (ti / 2) was determined from the slope value by the equation:in vitro ti / 2 = - (0.693 / k)Conversion of the in vitro half-life (min) into in vitro CLint (mL / min / mg proteins) was completed using the equation:0.693 volume of incubation (pL) in vitro CLlnt= ( - ) * ( - )(ti / z) amount of proteins (mg)Data are reported in Table 38 for Atropisomers A-l and A-2.B. Human Hepatocyte Intrinsic Clearance AssayMaterial and Reagents

[0303] Human hepatocytes (LiverPool™ 10-Donor Human hepatocytes (Mixed Gender, PEG-free, Product No. S01205, 5 million cells per vial) were obtained from BioreclamationIVT. DMSO was sourced from Solarbio S&T Co Ltd. Leibovitz’s L-15 Medium, Williams’ Medium E, GlutaMAX™-l (100*), HEPES, DPBS (10*) and Human Recombinant Insulin Solution were purchased from Gibco. Isotonic Percoll Solution was purchased from GE Healthcare. Fetal Bovine Serum (FBS) was purchased from Coming.Performing the Human Hepatocyte Intrinsic Clearance Assay Preparation of Thawing Medium

[0304] lOmM dexamethasone stock solution was prepared by dissolving 3.9 mg dexamethasone in 1 mL of DMSO. An Isotonic Percoll Solution was prepared by dilution of Percoll with DPBS (lOx). 15 mL of Isotonic Percoll Solution (90% Percoll / 10% DPBS) was added to 31.25mL William’s E medium containing 500 mL of GlutaMAX™-l (lOOx), 750 mL of IM HEPES, 2.5 mL of 5% FBS, 50mL of 4mg / mL Human Recombinant Insulin Solution and 5 mL of the 10 mM dexamethasone stock.Preparation of Stock Solutions

[0305] 2 mL of 10 mM DMSO stock solutions of test compound were added to 198 mL acetonitrile to produce 100 mmol / L concentration.Human Hepatocyte Incubation

[0306] The human hepatocyte vial was thawed at 37°C in a waterbath. Once thawed,contents were poured into a 50mL conical tube and centrifuged at 100 g for 10 minutes. The thawing medium was poured out and 4mL L-15 medium was added. The tube was gently shaken to resuspend the hepatocytes and cells were counted with an appropriate cell counter.247.5 mL of the hepatocyte suspension was transferred into each well of the plate and prewarmed at 600 rpm and 50°C to enable the temperature to rise to 37°C.

[0307] 2.5 mL of the 100 mmol / L test compound solution was added to initiate the reaction (final concentration 1 mM) and incubated at 37°C with shaking at 900 rpm. At 0.5, 5, 15, 30, 45, 60, 80, 100 and 120 minutes, 20mL was taken into a quenching solution of acetonitrile containing internal standards. The mix was vortexed at 800 rpm for 2 minutes followed by centrifugation for 20 minutes at 4000 rpm at 4°C. 40 mL of supernatant was transferred into a 96 well analysis plate containing 160 mL of water in each well. The analysis plate was shaken at 100 rpm for 2 minutes prior to analysis by LC-MS / MS.Calculation of Human Hepatocyte CLint

[0308] Peak areas were determined from extracted ion chromatograms. Percent parent remaining was calculated from peak area of test compound. The slope value, k, was determined by linear regression of the natural logarithm of percent parent remaining versus incubation time. The in vitro intrinsic clearance (in vitro CLint in mL / min / 106cells) was determined from the slope value using the following equation: in vitro Clj„t= kV / N where V is the incubation volume (0.25 mL) and N is the number of hepatocytes per well (0.25 x 106cells). Data are reported in Table 38 for Atropisomers A-l and A-2.TABLE 381ICso is reported after a single measurement (n=l) or as an average for multiple measurements (n>l).Example 18: Intrinsic Intestinal Caco-2 Cell Monolayers Cell Permeation Assay in thePresence of Efflux InhibitorsMaterial and Reagents

[0309] Caco-2 cells were obtained from American Type Culture Collection (ATCC). HEPES, penicillin, streptomycin, bovine serum albumin (BSA) were obtained from Beijing Xinjingke Biotechnology Co, Ltd. Fetal bovine serum, Hank’s balanced salt solution (HBSS) and non-essential amino acids (NEAA) were purchased from Gibco. Dulbecco’s Modified Eagle’s Medium (DMEM) was purchased from Corning and MES from Sigma. HTS Transwell- 24 permeable supports were purchased from Corning. Zosuquidar and Ko- 143 were obtained from MedChemExpress and Benzbromarone from Sigma.Preparation for Cell Seeding

[0310] The Caco-2 cell culture medium consisted of DMEM with high glucose and L- glutamine supplemented with 10% FBS, 0.1 mg / mL streptomycin, 100 units of penicillin, 0.6 mg / mL kanamycin sulfate and 1 x NEAA. 100 mL culture medium was added to each Transwell insert with 800 mL added to each well of the reservoir. After incubation at 37°C in 5% CO2 for one hour, the plates were ready for seeding.

[0311] The cells were cultivated in T-75 flasks at 37°C, 5% CO2, 95% relative humidity. At 80 to 90% confluence, cells were treated with trypsin / EDTA treatment until they became detached. The trypsin / EDTA was inactivated by adding excess serum containing medium. The cell suspension was centrifuged at 120 g for 10 minutes followed by resuspension of the cell pellet in seeding medium at a cell density of 7.92 x 105cells / mL.Seeding and Feeding of Caco-2 Cells into Transwell Plates

[0312] 100 mL of the resulting cell suspension was added to each well of the Transwell plate and incubated for 14 to 18 days, with medium replaced every other day. After incubation for 14 to 18 days, the cells should have reached confluence and should be tested for electrical resistance using a Millicel Epithelial Volt-Ohm measuring system (Millipore).Performing the Drug Transport Assay

[0313] The cell monolayers were washed twice with pre-warmed HBSS and incubated at 37°C for 30 minutes under gentle shaking (480rpm).

[0314] The compound under test was presented as a 10 mM DMSO stock solution. 2 mL of the 10 mM stock was added to 8 mL DMSO to produce a 2 mM stock. 2 mL was added to 398 mL of HBSS containing 10 mM Zosuquidar, 30 mM Benzbromarone and 2 mM KO-143 to make a lOmM drug stock solution.

[0315] 210 mL of the test compound solution was added to the apical compartment of the Transwell plate, with a 10 mL sample taken to act as the time 0 sample. The wells of the receiver (basolateral) compartment were filled with 800 mL HBSS (containing the efflux inhibitors). The plates were incubated at 37°C with shaking at 480 rpm for 120 minutes with sampling at 45 and 120 minutes.

[0316] At each sampling time (0, 45 and 120 minutes) 10 mL was removed from the apical compartment and add to 90 mL (HBSS containing the efflux inhibitors). 100 mL was removed from each basolateral compartment. 3 volumes of cold acetonitrile containing internal standard was added to each sample and vortex mixed for 10 minutes at 100 rpm. Samples were then centrifuged at 400 rpm for 20 minutes. 50 mL of the supernatant was taken for LC / MS / MS analysis to determine compound concentration.Calculation of Apparent Permeability and Recovery

[0317] The apparent permeability (Papp), in units of centimetre per second, were calculated for Caco-2 drug transport using the following equation:where CR is the concentration of compound in the receiver side at the respective time point, CD is the concentration of compound in the donor side at the respective timepoint. Area is the surface area of the membrane and time is 4500 seconds (75 x 60 seconds).

[0318] The recovery rate (0-120 minutes) was determined using the following equation:where VR IS the volume (in mL) in the acceptor well and VD is the volume (in mL) in the donorwell. Data are reported in Table 39 for Atropisomers A-l and A-2.TABLE 391ICso is reported after a single measurement (n=l) or as an average for multiple measurements (n>l).Example 19: Anti-Tumor Effect in MLLr AML Xenograft Model MV-4-11

[0319] A study was conducted to evaluate the in vivo efficacy of monotherapy with a Menin inhibitor in a human MLLr AML xenograft model.A. Materials

[0320] MV-4-11 cells were grown in RPM1 1640 (Gibco, #21875091) supplemented with 10% FBS (Gibco; #10091-148) and 1% Pen / Strep (Gibco; #15140-122). Cells were harvested and resuspended in PBS / Matrigel (Corning; # CLS354234) (50 / 50). Atropisomer A-2 was formulated in water at pH 4.5-5 using 1 M MSA as pH-adjusting agent at the concentrations up to 100 mg / mL to achieve a uniform suspension and dosed twice daily by oral gavage 10 mL / kg.B. Procedure

[0321] 10 million human MV-4-11 AML cells were implanted subcutaneously in the right flank of female CB17 SCID mice. Mice were randomized into groups of 5 when average tumor volume reached approximately 160 mm3. Mice were treated for 14 days with vehicle (water at pH 4.5-5 using IM MSA) or Atropisomer A-2 at 30, 100, or 200 mg / kg. Atropisomer A-2 was dosed orally twice daily 8 / 16 hours apart. The group administered Atropisomer A-2 at 30, 100, 200 mg / kg were monitored for regrowth for 6 weeks. Atropisomer A-2 at 100 mg / kg and 200 mg / kg resulted in no tumor regrowth compared to Atropisomer A-2 at 30 mg / kg. FIG. 12 illustrates the effect of treatment with Atropisomer A-2 on tumor volume in this MLLr MV-4- 11 human AML cancer xenograft mouse model. Data are reported in Table 40 for Atropisomer A-2.TABLE 40Example 20: Anti-Tumor Effect in MLLr AML Xenograft Model MOLM-13

[0322] A study was conducted to evaluate the in vivo efficacy of a Menin inhibitor in a human MLLr AML xenograft model.A. Materials

[0323] MOLM-13 cells were grown in RPM1 1640 (Gibco, #21875091) supplemented with 10% FBS (Gibco; #10091-148) and 1% Pen / Strep (Gibco; #15140-122). Cells were harvested and resuspended in PBS / Matrigel (Corning; # CLS354234) (50 / 50). Atropisomer A-2 was formulated in water at pH 4.5-5 using 1 M MSA as pH-adjusting agent at the concentrations up to 100 mg / mL to achieve a uniform suspension and dosed twice daily by oral gavage 10 mL / kg.B. Procedure

[0324] 1 million human MOLM-13 AML cells were implanted subcutaneously in the right flank of female CB17 SCID mice. Mice were randomized into groups of 5 when average tumor volume reached approximately 160 mm3. Mice were treated for 21 days with vehicle (water at pH 4.5-5 using 1 M MSA) or Atropisomer A-2 at 30, 100, or 200 mg / kg. Test compound was dosed orally twice daily 8 / 16 hours apart. The group administered Atropisomer A-2 at 30, 100, 200 mg / kg were monitored for regrowth for 3 weeks. Atropisomer A-2 at 100 mg / kg and 200 mg / kg resulted in complete tumor regressions at the end of treatment and tumors regrew 3 weeks after stopping treatment compared to 30 mg / kg which outgrew after treatment end. FIG. 13-A illustrates the effect of treatment with Atropisomer A-2 on tumor volume in this MLLr MOLM-13 human AML cancer xenograft mouse model. Data are reported in Table 41 A for Atropisomer A-2.TABLE 41A

[0325] In a second cohort of mice, MOLM-13 AML cells were implanted and randomized as described above. Mice were treated until tumor outgrowth with vehicle (water at pH 4.5-5 using 1 M MSA) or Atropisomer A-2 at 30 mg / kg or 150 mg / kg. Test compound was dosed orally twice daily 8 / 16 hours apart. The group administered Atropisomer A-2 at 30 mg / kg were dosed for a total of 41 days or less and all animals outgrew treatment. The group administered Atropisomer A-2 at 150 mg / kg were dosed for a total of 90 days and monitored for regrowth for an additional 70 days and resulted in complete tumor regression at the end of treatment. FIG. 13-B illustrates the effect of treatment with Atropisomer A-2 on tumor volume in this MLLr MOLM-13 human AML cancer xenograft mouse model. Data are reported in Table 41B for Atropisomer A-2.TABLE 41BExample 21: Anti-Tumor Effect in MLLr AML Patient Derived Disseminated Xenograft Models CBAM-68552, CBAM-44728, and DFAL-49600

[0326] A study was conducted to evaluate the in vivo efficacy of monotherapy with a Menin inhibitor in three human MLLr AML Patient Derived Disseminated Xenograft Models.A. Materials

[0327] Viably frozen A. CBAM-68552, B. CBAM-44728, and C. DFAL-49600 single cell suspensions from spleens of donor mice were prepared into frozen stock. Flow cytometry antibodies for Teri 19 (Miltenyi 130-112-914), mouse CD45 (Miltenyi 130-110-665), and human CD45 (Miltenyi 130-110-634) and Fixable Live Dead Stain (ThermoFisher; # L34963)for disease evaluation via flow cytometry on MACSQuant (Miltenyi). Atropisomer A-2 was formulated in water at pH 4.5-5 using IM MSA as pH-adjusting agent at concentrations up to 100 mg / mL to achieve a uniform suspension and dosed twice daily by oral gavage 10 mL / kg.B. Procedure

[0328] A. CBAM-68552, B. CBAM-44728, and C. DFAL-49600 cells were thawed and 1 million cells implanted via the tail vein in to female NSG mice. Mice were randomized into groups of 5 when human CD45 levels reached average of A. CBAM-68552 6.5%, B. CBAM- 44728 4.8%, and C. DFAL-49600 12.4% in the bone marrow of satellite animals. Mice were treated for 21 days with vehicle (water at pH 4.5-5 using 1 M MSA) or Atropisomer A-2 at 150 mg / kg. Atropisomer A-2 was dosed orally twice daily 8 / 16 hours apart and mice were monitored for overall survival. Figs. 14-A, 14-B, and 14-C further illustrate the effect of treatment with Atropisomer A-2 in human MLLr AML Patient Derived Disseminated Xenograft Models A. CBAM-68552, B. CBAM-44728, and C. DFAL-49600, respectively. Data are reported in Table 42 for Atropisomer A-2.TABLE 42Example 22: Anti-Tumor Effect in NPM1 Mutant AML Patient Derived Disseminated Xenograft Model DFAM-16835

[0329] A study was conducted to evaluate the in vivo efficacy of monotherapy with a Menin inhibitor in human NPM1 mutant AML Patient Derived Disseminated Xenograft Model DF AM- 16835.A. Materials

[0330] Viably frozen DFAM-16835 single cell suspensions from spleens of donor mice were prepared into frozen stock. Flow cytometry antibodies for Teri 19 (Miltenyi 130-112-914), mouse CD45 (Miltenyi 130-110-665), and human CD45 (Miltenyi 130-110-634) and Fixable Live Dead Stain (ThermoFisher; # L34963) for disease evaluation via flow cytometry onMACSQuant (Miltenyi). Atropisomer A-2 was formulated in water at pH 4.5-5 using 1 M MSA as pH-adjusting agent at the concentrations up to 100 mg / mL to achieve a uniform suspension and dosed twice daily by oral gavage 10 mL / kg.B. Procedure

[0331] DFAM-16835 cells were thawed and 1 million cells implanted via the tail vein into female NSG mice. Mice were randomized into groups of 10 when human CD45 levels reached average of 22.3% in the bone marrow of satellite animals. Mice were treated for 21 days with vehicle (water at pH4.5-5 using IM MSA) or Atropisomer A-2 at 30 and 150 mg / kg.Atropisomer A-2 was dosed orally twice daily 8 / 16 hours apart. An increase in overall survival was observed with Atropisomer A-2 extending latency from 59 days to 73 days (30 mg / kg) and 94 days (150 mg / kg). FIG. 15 further illustrates the effect of treatment with Atropisomer A-2 in human NPM1 mutant AML Patient Derived Disseminated Xenograft Model DFAM-16835. Data are reported in Table 43 for Atropisomer A-2.TABLE 43Example 23: Enhanced Cell Death in MOLM-13 Cell Line with Atropisomer A-2 and BCL2 Inhibitor (Venetoclax)

[0332] Induction of cell death was assessed in a human MOLM-13 AML MLLr cell line treated with Atropisomer A-2 alone or in combination with a BCL2 inhibitor (venetoclax).

[0333] Test compound was dispensed using a Tecan compound dispenser into 384-well plates (Microplate 384-well, polypropylene, F-bottom; Greiner Bio-One, #781201) in a ten-by- ten response matrix to assess the combination effects of Menin inhibition (Atropisomer A-2) together with BCL-2 inhibition (venetoclax) at the following concentrations after subsequent cell seeding in 40 pL of growth media: 10 pM, 3.16 pM, 1 pM, 0.316 pM, 0.1 pM, 0.0316 pM, 0.01 pM, 0.00316 pM, 0.001 pM, and vehicle (DMSO; Sigma-Aldrich, D2650). Cells were seeded at 1000 cells per well and incubated at 37°C and 5% CO2. MOLM-13 cells were grown in RPM1 1640 (Gibco, #21875091) supplemented with 10% FBS (Gibco; #10091-148) and 1%Pen / Strep (Gibco; #15140-122). After 4 days of compound treatment, plates were placed at room temperature for 15 minutes. 10 pL CellTiter- Gio reagent (Promega, #G9242) was added to the cells and incubated for 10 minutes in the dark on a plate shaker at room temperature. A backseal (Perkin Elmer; #6005199) was added to the plates and luminescence was measured at 0.1 sec / well in an Envision (Perkin Elmer). Data were normalized for each plate so that the average of control wells (DMSO) was set to 0%, and the maximum observed value across the plate was set as 100%. Data fitting was performed using Graphpad Prism and combination effect was assessed using SynergyFinder.

[0334] In vitro combination benefit was seen in the MOLM-13 cells and cell viability loss was induced with both agents as a monotherapy. FIG. 16 illustrates a combination signal heatmap (% viability) for the MLLr MOLM-13 cells after treatment with Atropisomer A-2, venetoclax, or Atropisomer A-2 in combination with venetoclax.Example 24: Anti-Tumor Effect in NPM1 Mutant AML Patient Derived Disseminated Xenograft Model DFAM-16835 (Atropisomer A-2 in Combination with Venetoclax)

[0335] A study was conducted to evaluate the in vivo efficacy of monotherapy with a Menin inhibitor (Atropisomer A-2) and combination therapy with a BCL2 inhibitor (venetoclax) and 5- azacytidine in a human NPM1 mutant AML Patient Derived Disseminated Xenograft Model.A. Materials

[0336] Viably frozen DFAM-16835 single cell suspensions from spleens of donor mice were prepared into frozen stock. Flow cytometry antibodies for Teri 19 (Miltenyi 130-112-914), mouse CD45 (Miltenyi 130-110-665), and human CD45 (Miltenyi 130-110-634) and Fixable Live Dead Stain (ThermoFisher; # L34963) for disease evaluation via flow cytometry on MACSQuant (Miltenyi). Atropisomer A-2 was formulated in water at pH 4.5-5 using IM MSA as pH-adjusting agent at the concentrations up to 100 mg / mL to achieve a uniform suspension and dosed twice daily by oral gavage lOmL / kg. 5-Azacytidine was formulated in saline at 0.2mg / mL and dosed twice daily by intraperitoneal injection 5ml / kg on days 1-5 of treatment. Venetoclax was formulated in 10% ethanol plus 60% Phosal 50 PG (Sigma, MO) plus 30% polyethylene glycol 400 at 5mg / mL and dosed once daily 2 hrs after Atropisomer A-2 in thecombination group. 5-Azacytidine was formulated in saline at 0.2mg / mL and dosed twice daily by intraperitoneal injection 5ml / kg.B. Procedure

[0337] 1 million DF AM-16835 cells were thawed and 1 million cells implanted via the tail vein. Mice were randomized into groups of 5 when human CD45 levels reached average of 64.2% in the bone marrow of satellite animals. Mice were treated for 21 days with (i) vehicle (water at pH 4.5-5 using IM MSA), (ii) Atropisomer A-2 at 150 mg / kg, (iii) venetoclax at lOOmg / kg in combination with 5-azacytidine at Img / kg, or (iv) the combination of Atropisomer A-2 and venetoclax with 5-azacytidine. Combination group (iv) was dosed as follows: (a) Days 1-5: AM dosing: Atropisomer A-2 was initially administered, 5-azacytidine was administered 15 minutes later, and venetoclax was administered 2 hours after Atropisomer A-2; and PM dosing: Atropisomer A-2 was initially administered and 5-azacytidine was administered 15 minutes later; and (b) Days 6-21 : AM dosing: Atropisomer A-2 was initially administered and venetoclax was administered 2 hours after Atropisomer A-2; and PM dosing: Atropisomer A-2 was administered. FIG. 17 further illustrates the effect of treatment with Atropisomer A-2 and venetoclax and 5-azacytidine in human NPM1 mutant AML Patient Derived Disseminated Xenograft Model DF AM-16835. Data are reported in Table 44.TABLE 44Example 25: Protein Degradation Effect in MV-4-11 Cell Line with Atropisomer A-2

[0338] Protein degradation was assessed in human MV-4-11 AML MLLr cell lines treated with Atropisomer A-2 alone.A. Materials

[0339] An MV-4-11 cell line was passaged at least eight times in SILAC-IMDM (ThermoFisher, #88367), which lacks L-lysine and L-arginine, and supplemented with 10%(v / v) dialyzed FBS (ThermoFisher, #A3382001), [13Ce,15N2]-L-lysine, and [13Ce,15N4]-L- arginine (Sigma #608041 and #608033) (100 pg / mL each) to achieve “heavy cell” status as determined by LC-MS / MS. Whenever thawed, the “heavy-labelled” cells were passaged at least three times before use in experiments. “Light” medium was prepared by supplementing SILAC- IMDM with 10% (v / v) dialyzed FBS and unlabeled L-arginine and L-lysine (Sigma, #A6969, #L8662). SILAC-IMDM was either supplemented with 300 nM of Atropisomer A-2 (10 mM solution in DMSO) or the equivalent amounts of DMSO as control. Cells were transferred to “light” media, incubated at 37 °C, 5% CO2, and collected at various time points (0 hrs, 1 hrs, 2 hrs, 4.25 hrs, 10.25 hrs, 20.75 hrs, 28.5 hrs, 47 hrs, 72 hrs) by two washes with ice cold PBS and pelleted by centrifugation.B. Procedure

[0340] Cell pellets (approximately 2xl05cells) were transferred to 96-well plate using cell lysis buffer (4% SDS, 50 mM HEPES pH 7.4, 5 mM TCEP, and 10 mM chloroacetamide) and heated to 95°C for 10 minutes. Lysed-samples were cleaned up using magnetic bead-assisted- SP3 protocol (Ref.) and the proteome was digested to peptides using LysC (Waco, #12505061) and trypsin enzymes (Promega, #V5111) overnight at 37°C. Peptides were eluted from SP3- beads, desalted (The Nest Group, #HNSS18V) and dried using speed vacuum (Fisher Scientific, #SPD140DDA) before for mass spectrometry analysis. Proteomics data were collected using nano-liquid chromatography and orbitrap® Exploris480 mass spectrometry system (ThermoFisher Scientific, #VNS10A01 and #BRE725533) coupled to a High-field asymmetric waveform IMS (FAIMS) interface (ThermoFisher Scientific, #OPTON-20068) and by employing parallel reaction monitoring (PRM) data acquisition targeting three unique peptides for Menin (121VSDVIWNSLSR131,368EFFEVANDVIPNLLK382,597VSTPSDYTLSFLK609). The PRM data were analyzed with Skyline (University of Washington, Seattle, WA., Ref.) using high-selectivity data extraction. Plots were constructed in GraphPad Prism™ using 1st order decay function to yield endogenous degradation and resysnthesis.

[0341] Figs. 18-A, 18-B, and 18-C further illustrate the effect of treatment on Menin protein in the human MLLr AML MV-4-11 SILAC cell line. Time is shown horizontally. The heavy and light Menin protein signals are shown vertically for A. DMSO (control) (FIG. 18-A), B.Atropisomer A-2 (FIG. 18-B), and C. Total Menin protein (“heavy” and “light”) signal normalized to DMSO (FIG. 18-C). Data for Atropisomer A-2 on Menin protein degradation in MLLr AML MV-4-11 SILAC cells is reported in Table 45. The rate at which a “heavy” Menin protein decreases represents its rate of degradation ( eg).TABLE 45

[0342] References:Pulse SILAC: Doherty MK, Hammond DE, Clague MJ, Gaskell SJ, Beynon RJ (2009) Turnover of the human proteome: determination of protein intracellular stability by dynamic SILAC. J Proteome Res 8: 104-112. doi: 10.1021 / pr800641v.SP3: Hughes, C.S., Moggridge, S., Muller, T. et al. Single-pot, solid-phase-enhanced sample preparation for proteomics experiments. Nat Protoc 14, 68-85 (2019). https: / / doi.org / 10.1038 / s41596-018-0082-xSkyline: MacLean, B. et al. Skyline: An open-source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 26(7), 966-968 (2010).IX. Embodiments

[0343] Embodiment 1 : An amorphous salt of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2- carbonyl)-piperidine-4-carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A- diisopropylbenzamide, Atropisomer A-2:

[0344] Embodiment 2: An amorphous hydrochloride salt of (5)-2-(3-(l-(5,5- di methyl pyrrol i di ne-2-carbonyl)-pi peri dine-4-carbonyl)-2-methyl - I / / -pyrrol o[2, 3 -c]pyri di n- l - yl)-5-fluoro-A,A-diisopropylbenzamide, Atropisomer A-2:

[0345] Embodiment 3: An amorphous besylate salt of (S)-2-(3-(l-(5,5-dimethylpyrrolidine- 2-carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A- diisopropyl-benzamide, Atropisomer A-2:

[0346] Embodiment 4: A crystalline orotate salt of (S)-2-(3-(l-(5,5-dimethylpyrrolidine-2- carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A- diisopropyl-benzamide, Atropisomer A-2:

[0347] Embodiment 5: The crystalline orotate salt of Embodiment 4, wherein the crystalline orotate salt is crystalline Form A.

[0348] Embodiment 6: The crystalline orotate salt of Embodiment 5, wherein the crystalline Form A is characterized by an X-Ray powder diffraction pattern comprising at least one peak selected from the group consisting of 5.2 ± 0.2° 29, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29.

[0349] Embodiment 7: The crystalline orotate salt of Embodiment 5, wherein the crystalline Form A is characterized by an X-Ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 5.2 ± 0.2° 29, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29.

[0350] Embodiment 8: The crystalline orotate salt of Embodiment 5, wherein the crystalline Form A is characterized by an X-Ray powder diffraction pattern comprising peaks at 5.2 ± 0.2° 29, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29.

[0351] Embodiment 9: The crystalline orotate salt of Embodiment 8, wherein the crystalline Form A is characterized by an X-Ray powder diffraction pattern further comprising at least one peak selected from the group consisting of 19.1 ± 0.2° 29 and 21.7 ± 0.2° 29.

[0352] Embodiment 10: The crystalline orotate salt of Embodiment 8, wherein the crystalline Form A is characterized by an X-Ray powder diffraction pattern further comprising peaks at 19.1 ± 0.2° 29 and 21.7 ± 0.2° 29.

[0353] Embodiment 11 : The crystalline orotate salt of any one of Embodiments 6 to 10, wherein X-ray powder diffraction is carried out using Cu radiation.

[0354] Embodiment 12: The crystalline orotate salt of any one of Embodiments 6 to 11, wherein X-ray powder diffraction is carried out using a Rigaku MiniFlex diffractometer operating in reflection geometry, a tube voltage of 40 kV, and filament emission of 15 mA.

[0355] Embodiment 13: The crystalline orotate salt of Embodiment 6, wherein the X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern of FIG. 1.

[0356] Embodiment 14: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165°C ± 5 °C.

[0357] Embodiment 15: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165°C ± 2 °C.

[0358] Embodiment 16: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 171°C ± 5 °C.

[0359] Embodiment 17: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 171°C ± 2 °C.

[0360] Embodiment 18: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165 °C ± 5 °C and a peak at about 171 °C ± 5 °C.

[0361] Embodiment 19: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165 °C ± 2 °C and a peak at about 171 °C ± 2 °C.

[0362] Embodiment 20: The crystalline orotate salt of any one of Embodiments 14 to 19, wherein differential scanning calorimetry is conducted on a TA Instruments Differential Scanning Calorimeter, model Discovery Q2500, with a sample placed in an aluminum pan and heated under nitrogen at a rate of 10°C / minute to a temperature of 300°C.

[0363] Embodiment 21 : The crystalline orotate salt of Embodiment 14, wherein the differential scanning calorimetry curve is substantially the same as the differential scanning calorimetry curve of FIG. 2.

[0364] Embodiment 22: The crystalline orotate salt of any one of Embodiments 6 to 21, wherein the crystalline Form A is further characterized by a thermogravimetric analysis thermogram wherein the crystalline Form A exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C.

[0365] Embodiment 23 : The crystalline orotate salt of Embodiment 22, wherein the weight loss is less than about 8 weight %.

[0366] Embodiment 24: The crystalline orotate salt of Embodiment 22, wherein the weight loss is less than about 6 weight %.

[0367] Embodiment 25: The crystalline orotate salt of Embodiment 22, wherein the thermogravimetric analysis thermogram is substantially the same as the thermogravimetric analysis thermogram of FIG. 3.

[0368] Embodiment 26: The crystalline orotate salt of any one of Embodiments 6 to 25, wherein the crystalline Form A is further characterized by a gravimetric vapor sorption plot wherein the crystalline Form A exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C.

[0369] Embodiment 27: The crystalline orotate salt of Embodiment 26, wherein the reversible moisture uptake is less than about 9 weight %.

[0370] Embodiment 28: The crystalline orotate salt of Embodiment 26, wherein the reversible moisture uptake is less than about 8 weight %.

[0371] Embodiment 29: The crystalline orotate salt of Embodiment 26, wherein the gravimetric vapor sorption plot is substantially the same as the gravimetric vapor sorption plot of FIG. 4.

[0372] Embodiment 30: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by the following: a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165°C ± 5°C; and a gravimetric vapor sorption plot wherein the crystalline Form A exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity toabout 80% relative humidity at 25 °C ± 0.1 °C.

[0373] Embodiment 31 : The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by the following: a thermogravimetric analysis thermogram wherein the crystalline Form A exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C; and a gravimetric vapor sorption plot wherein the crystalline Form A exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C.

[0374] Embodiment 32: The crystalline orotate salt of any one of Embodiments 6 to 13, wherein the crystalline Form A is further characterized by the following: a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 165°C ± 5°C; a thermogravimetric analysis thermogram wherein the crystalline Form A exhibits a weight loss of less than about 10 weight % from about 25 °C to about 100 °C; and a gravimetric vapor sorption plot wherein the crystalline Form A exhibits a reversible moisture uptake of less than about 10 weight % from about 0% relative humidity to about 80% relative humidity at 25 °C ± 0.1 °C.

[0375] Embodiment 33: The crystalline orotate salt of any one of Embodiments 5 to 32, wherein the crystalline Form A is a solvate.

[0376] Embodiment 34: The crystalline orotate salt of Embodiment 4, wherein the crystalline orotate salt is Form B.

[0377] Embodiment 35: The crystalline orotate salt of Embodiment 34, wherein the crystalline Form B is characterized by an X-Ray powder diffraction pattern comprising at least one peak selected from the group consisting of 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29.

[0378] Embodiment 36: The crystalline orotate salt of Embodiment 34, wherein the crystalline Form B is characterized by an X-Ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29.

[0379] Embodiment 37: The crystalline orotate salt of Embodiment 34, wherein the crystalline Form B is characterized by an X-Ray powder diffraction pattern comprising peaks at 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29.

[0380] Embodiment 38: The crystalline orotate salt of Embodiment 37, wherein the crystalline Form B is characterized by an X-Ray powder diffraction pattern further comprising at least one peak selected from the group consisting of 18.2 ± 0.2 °29, 19.2 ± 0.2° 29, 20.6 ± 0.2° 29, 27.2 ± 0.2° 29, and 35.6 ± 0.2° 29.

[0381] Embodiment 39: The crystalline orotate salt of Embodiment 37, wherein the crystalline Form B is characterized by an X-Ray powder diffraction pattern further comprising peaks at 18.2 ± 0.2 °29, 19.2 ± 0.2° 29, 20.6 ± 0.2° 29, 27.2 ± 0.2° 29, and 35.6 ± 0.2° 29.

[0382] Embodiment 40: The crystalline orotate salt of any one of Embodiments 35 to 39, wherein X-ray powder diffraction is carried out using Cu radiation.

[0383] Embodiment 41 : The crystalline orotate salt of any one of Embodiments 35 to 40, wherein X-ray powder diffraction is carried out using a Rigaku MiniFlex diffractometer operating in reflection geometry, a tube voltage of 40 kV, and filament emission of 15 mA.

[0384] Embodiment 42: The crystalline orotate salt of Embodiment 35, wherein the X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern of FIG. 5.

[0385] Embodiment 43: The crystalline orotate salt of any one of Embodiments 35 to 42, wherein the crystalline Form B is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 150°C ± 5 °C.

[0386] Embodiment 44: The crystalline orotate salt of any one of Embodiments 35 to 42, wherein the crystalline Form B is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 150°C ± 2 °C.

[0387] Embodiment 45: The crystalline orotate salt of any one of Embodiments 35 to 42, wherein the crystalline Form B is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 168°C ± 5 °C.

[0388] Embodiment 46: The crystalline orotate salt of any one of Embodiments 35 to 42, wherein the crystalline Form B is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 168°C ± 2 °C.

[0389] Embodiment 47: The crystalline orotate salt of any one of Embodiments 35 to 42, wherein the crystalline Form B is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 150 °C ± 5 °C anda peak at about 168 °C ± 5 °C.

[0390] Embodiment 48: The crystalline orotate salt of any one of Embodiments 35 to 42, wherein the crystalline Form B is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 150 °C ± 2 °C and a peak at about 168 °C ± 2 °C.

[0391] Embodiment 49: The crystalline orotate salt of any one of Embodiments 43 to 48 wherein differential scanning calorimetry is conducted on a TA Instruments Differential Scanning Calorimeter, model Discovery Q2500, with a sample placed in an aluminum pan and heated under nitrogen at a rate of 10°C / minute to a temperature of 300°C.

[0392] Embodiment 50: The crystalline orotate salt of Embodiment 43, wherein the differential scanning calorimetry curve is substantially the same as the differential scanning calorimetry curve of FIG. 6.

[0393] Embodiment 51 : The crystalline orotate salt of any one of Embodiments 35 to 50, wherein the crystalline Form B is further characterized by a thermogravimetric analysis thermogram wherein the crystalline Form B exhibits a weight loss of less than about 15 weight % from about 25 °C to about 175 °C.

[0394] Embodiment 52: The crystalline orotate salt of Embodiment 51, wherein the weight loss is less than about 13 weight %.

[0395] Embodiment 53: The crystalline orotate salt of Embodiment 51, wherein the weight loss is less than about 11 weight %.

[0396] Embodiment 54: The crystalline orotate salt of Embodiment 51, wherein the thermogravimetric analysis thermogram is substantially the same as the thermogravimetric analysis thermogram of FIG. 7.

[0397] Embodiment 55: The crystalline orotate salt of any one of Embodiments 35 to 54, wherein the crystalline Form B is further characterized by the following: a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 150°C ± 5°C; and a thermogravimetric analysis thermogram wherein the crystalline Form B exhibits a weight loss of less than about 15 weight % from about 25 °C to about 175 °C.

[0398] Embodiment 56: The crystalline orotate salt of any one of Embodiments 34 to 55, wherein the crystalline Form B is a solvate.

[0399] Embodiment 57: The crystalline orotate salt of Embodiment 4, wherein the crystalline orotate salt is Form C.

[0400] Embodiment 58: The crystalline orotate salt of Embodiment 57, wherein the crystalline Form C is characterized by an X-Ray powder diffraction pattern comprising at least one peak selected from the group consisting of 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29.

[0401] Embodiment 59: The crystalline orotate salt of Embodiment 57, wherein the crystalline Form C is characterized by an X-Ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29.

[0402] Embodiment 60: The crystalline orotate salt of Embodiment 57, wherein the crystalline Form C is characterized by an X-Ray powder diffraction pattern comprising peaks at 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29.

[0403] Embodiment 61 : The crystalline orotate salt of Embodiment 60, wherein the crystalline Form C is characterized by an X-Ray powder diffraction pattern further comprising at least one peak selected from the group consisting of 10.7 ± 0.2° 29, 13.0 ± 0.2° 29, 14.7 ± 0.2° 29, 17.9 ± 0.2 °29, and 21.3 ± 0.2° 29.

[0404] Embodiment 62: The crystalline orotate salt of Embodiment 60, wherein the crystalline Form C is characterized by an X-Ray powder diffraction pattern further comprising peaks at 10.7 ± 0.2° 29, 13.0 ± 0.2° 29, 14.7 ± 0.2° 29, 17.9 ± 0.2 °29, and 21.3 ± 0.2° 29.

[0405] Embodiment 63: The crystalline orotate salt of any one of Embodiments 58 to 62, wherein X-ray powder diffraction is carried out using Cu radiation.

[0406] Embodiment 64: The crystalline orotate salt of any one of Embodiments 58 to 63, wherein X-ray powder diffraction is carried out using a Rigaku MiniFlex diffractometer operating in reflection geometry, a tube voltage of 40 kV, and filament emission of 15 mA.

[0407] Embodiment 65: The crystalline orotate salt of Embodiment 58, wherein the X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern of FIG. 8.

[0408] Embodiment 66: The crystalline orotate salt of any one of Embodiments 58 to 65, wherein the crystalline Form C is further characterized by a differential scanning calorimetrycurve comprising a melting endotherm having an onset temperature of about 157°C ± 5 °C.

[0409] Embodiment 67: The crystalline orotate salt of any one of Embodiments 58 to 65, wherein the crystalline Form C is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 157°C ± 2 °C.

[0410] Embodiment 68: The crystalline orotate salt of any one of Embodiments 58 to 65, wherein the crystalline Form C is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 174°C ± 5 °C.

[0411] Embodiment 69: The crystalline orotate salt of any one of Embodiments 58 to 65, wherein the crystalline Form C is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having a peak at about 174°C ± 2 °C.

[0412] Embodiment 70: The crystalline orotate salt of any one of Embodiments 58 to 65, wherein the crystalline Form C is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 157 °C ± 5 °C and a peak at about 174 °C ± 5 °C.

[0413] Embodiment 71 : The crystalline orotate salt of any one of Embodiments 58 to 65, wherein the crystalline Form C is further characterized by a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 157 °C ± 2 °C and a peak at about 174 °C ± 2 °C.

[0414] Embodiment 72: The crystalline orotate salt of any one of Embodiments 66 to 71, wherein differential scanning calorimetry is conducted on a TA Instruments Differential Scanning Calorimeter, model Discovery Q2500, with a sample placed in an aluminum pan and heated under nitrogen at a rate of 10°C / minute to a temperature of 300°C.

[0415] Embodiment 73: The crystalline orotate salt of Embodiment 58, wherein the differential scanning calorimetry curve is substantially the same as the differential scanning calorimetry curve of FIG. 9.

[0416] Embodiment 74: The crystalline orotate salt of any one of Embodiments 58 to 73, wherein the crystalline Form C is further characterized by a thermogravimetric analysis thermogram wherein the crystalline Form C exhibits a weight loss of less than about 10 weight % from about 25 °C to about 150 °C.

[0417] Embodiment 75: The crystalline orotate salt of Embodiment 74, wherein the weightloss is less than about 8 weight %.

[0418] Embodiment 76: The crystalline orotate salt of Embodiment 74, wherein the weight loss is less than about 6 weight %.

[0419] Embodiment 77: The crystalline orotate salt of Embodiment 74, wherein the thermogravimetric analysis thermogram is substantially the same as the thermogravimetric analysis thermogram of FIG. 10.

[0420] Embodiment 78: The crystalline orotate salt of any one of Embodiments 58 to 77, wherein the crystalline Form C is further characterized by the following: a differential scanning calorimetry curve comprising a melting endotherm having an onset temperature of about 157°C ± 5°C; and a thermogravimetric analysis thermogram wherein the crystalline Form C exhibits a weight loss of less than about 10 weight % from about 25 °C to about 150 °C.

[0421] Embodiment 79: The crystalline orotate salt of any one of Embodiments 57 to 78, wherein the crystalline Form C is a solvate.

[0422] Embodiment 80: The crystalline orotate salt of any one of Embodiments 5 to 33, wherein the crystalline orotate salt comprises less than 5 weight % of any one other crystalline form of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-17T- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide.

[0423] Embodiment 81 : The crystalline orotate salt of any one of Embodiments 34 to 56, wherein the crystalline orotate salt comprises less than 5 weight % of any one other crystalline form of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-17T- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide.

[0424] Embodiment 82: The crystalline orotate salt of any one of Embodiments 57 to 79, wherein the crystalline orotate salt comprises less than 5 weight % of any one other crystalline form of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-17T- pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropylbenzamide.

[0425] Embodiment 83: A pharmaceutical composition comprising the amorphous hydrochloride salt of Embodiment 2, and one or more pharmaceutically acceptable excipients.

[0426] Embodiment 84: A pharmaceutical composition comprising the amorphous besylate salt of Embodiment 3, and one or more pharmaceutically acceptable excipients.

[0427] Embodiment 85: A pharmaceutical composition comprising the crystalline orotatesalt of any one of Embodiments 4 to 82, and one or more pharmaceutically acceptable excipients.

[0428] Embodiment 86: A method of treating or preventing a Menin-mediated condition in a subject suffering from or susceptible to the Menin-mediated condition, the method comprising administering to the subject a therapeutically effective amount of the salt of any one of Embodiments 1 to 82.

[0429] Embodiment 87: The method of Embodiment 86, wherein the Menin-mediated condition is a hematological malignancy.

[0430] Embodiment 88: The method of Embodiment 86, wherein the Menin-mediated condition is selected from the group consisting of leukemias, myeloma, Non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), myeloproliferative neoplasm (MPN), and myelodysplastic syndrome (MDS).

[0431] Embodiment 89: The method of Embodiment 86, wherein the Menin-mediated condition is a solid tumor cancer.

[0432] Embodiment 90: The method of Embodiment 86, wherein the Menin-mediated condition is selected from the group consisting of ovarian cancer, head and neck cancer, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, liver cancer, melanoma, glioblastoma, and sarcoma cancers.

[0433] Embodiment 91 : Use of a salt of any one of Embodiments 1 to 82, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a Menin-mediated condition.

[0434] Embodiment 92: A kit comprising a unit dosage form comprising a salt of any one of Embodiments 1 to 82 contained within a packaging material, and a label or package insert which indicates that the unit dosage form can be used for treating a Menin-mediated condition.

[0435] Although specific embodiments and examples have been described above, these embodiments and examples are only illustrative and do not limit the scope of the disclosure. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the disclosure in its broader aspects as defined in the following claims. Forexample, any embodiment described herein can be combined with any other suitable embodiment described herein to provide additional embodiments.

Claims

What is claimed is:

1. An amorphous salt of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)-piperidine-4- carbonyl)-2-methyl-l -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-7V,7V-diisopropylbenzamide, Atropisomer A-2:

2. The amorphous salt of claim 1, wherein the amorphous salt is a besylate salt.

3. The amorphous besylate salt of claim 2, wherein the amorphous besylate salt comprises less than 5 weight % of any other stereoisomer of 2-(3-(l-(5,5-dimethylpyrrolidine-2- carbonyl)-piperidine-4-carbonyl)-2-methyl-17 / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A- dii sopropy lb enzami de .

4. A crystalline orotate salt of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2-carbonyl)- piperidine-4-carbonyl)-2-methyl-17 / -pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A-diisopropyl- benzamide, Atropisomer A-2:

5. The crystalline orotate salt of claim 4, wherein the crystalline orotate salt is crystalline Form A.

6. The crystalline orotate salt of claim 5, wherein the crystalline Form A is characterized by an X-Ray powder diffraction pattern comprising at least one peak selected from the group consisting of 5.2 ± 0.2° 26, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 19.8 ± 0.2° 26, and 15.4 ± 0.2° 29.

7. The crystalline orotate salt of claim 5, wherein the crystalline Form A is characterized by an X-Ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 5.2 ± 0.2° 29, 8.1 ± 0.2° 29, 9.2 ± 0.2° 29, 10.8 ± 0.2° 29, and 15.4 ± 0.2° 29.

8. The crystalline orotate salt of claim 4, wherein the crystalline orotate salt is Form B.

9. The crystalline orotate salt of claim 8, wherein the crystalline Form B is characterized by an X-Ray powder diffraction pattern comprising at least one peak selected from the group consisting of 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29.

10. The crystalline orotate salt of claim 8, wherein the crystalline Form B is characterized by an X-Ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 4.6 ± 0.2° 29, 7.9 ± 0.2° 29, 8.9 ± 0.2° 29, 11.7 ± 0.2 °29, and 12.5 ± 0.2° 29.

11. The crystalline orotate salt of claim 4, wherein the crystalline orotate salt is Form C.

12. The crystalline orotate salt of claim 11, wherein the crystalline Form C is characterized by an X-Ray powder diffraction pattern comprising at least one peak selected from the group consisting of 4.9 ± 0.2° 26, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 19.9 ± 9.2° 26, and 24.3 ± 6.2 °29.

13. The crystalline orotate salt of claim 11, wherein the crystalline Form C is characterized by an X-Ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 4.9 ± 0.2° 29, 8.5 ± 0.2° 29, 9.1 ± 0.2° 29, 10.0 ± 0.2° 29, and 24.3 ± 0.2 °29.

14. The crystalline orotate salt of any one of claims 4 to 13, wherein the crystalline orotate salt comprises less than 5 weight % of any other stereoisomer of 2-(3-(l-(5,5- dimethylpyrrolidine-2-carbonyl)-piperidine-4-carbonyl)-2-methyl-U / -pyrrolo[2,3-c]pyridin-l-yl)-5- fluoro-A,A-diisopropylbenzamide.

15. A pharmaceutical composition comprising the amorphous besylate salt of claim 2 or 3, and one or more pharmaceutically acceptable excipients.

16. A pharmaceutical composition comprising the crystalline orotate salt of any one of claims 4 to 14, and one or more pharmaceutically acceptable excipients.

17. A method of treating or preventing a Menin-mediated condition in a subject suffering from or susceptible to the Menin-mediated condition, the method comprising administering to the subject a therapeutically effective amount of the salt of any one of claims 1 to 14.

18. Use of a salt of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing a Menin-mediated condition.

19. A kit comprising a unit dosage form comprising a salt of any one of claims 1 to 14 contained within a packaging material, and a label or package insert which indicates that the unit dosage form can be used for treating a Menin-mediated condition.

20. A method for preparing a final salt of (5)-2-(3-(l-(5,5-dimethylpyrrolidine-2- carbonyl)-piperidine-4-carbonyl)-2-methyl-l / 7-pyrrolo[2,3-c]pyridin-l-yl)-5-fluoro-A,A- diisopropylbenzamide, Atropisomer A-2, wherein the method comprises: preparing an orotate salt of Atropisomer A-2 from a starting material comprising Atropisomer A-2; and converting the orotate salt of Atropisomer A-2 into the final salt of Atropisomer A-2.

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