IMPROVED SYNTHESIS OF KEY INTERMEDIATE OF KRAS G12C

INHIBITOR COMPOUND

FIELD OF THE INVENTION

The present invention relates to an improved, efficient, scalable process to prepare

intermediate compounds, such as compound 5M, having the structure
useful for the synthesis of compounds that inhibit KRAS G12C mutations.

BACKGROUND

KRAS gene mutations are common in pancreatic cancer, lung adenocarcinoma, colorectal cancer, gall bladder cancer, thyroid cancer, and bile duct cancer. KRAS mutations are also observed in about 25% of patients with NSCLC, and some studies have indicated that KRAS mutations are a negative prognostic factor in patients with NSCLC. Recently, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations have been found to confer resistance to epidermal growth factor receptor (EGFR) targeted therapies in colorectal cancer; accordingly, the mutational status of KRAS can provide important information prior to the prescription of TKI therapy. Taken together, there is a need for new medical treatments for patients with pancreatic cancer, lung adenocarcinoma, or colorectal cancer, especially those who have been diagnosed to have such cancers characterized by a KRAS mutation, and including those who have progressed after chemotherapy.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the crystal arrangement of composition 4a.

Figure 2-1 shows XRPD overlay of Dione racemate Type A~E.

Figure 2-2 shows XRPD overlay of (1S)-(-)-camphanic acid cocrystal.

Figure 2-3 shows XRPD overlay of (+)-2, 3-dibenzoyl-D-tartaric acid cocrystal.

Figure 2-4 shows XRPD overlay of D-(+)-malic acid cocrystal.

Figure 2-5 shows XRPD overlay of M-Dione cocrystal at different temperatures.

Figure 2-6 shows XRPD overlay of P-Dione cocrystal at different temperatures.

Figure 2-7 shows XRPD overlay of M-Dione cocrystal and P-Dione cocrystal mixture at different temperatures.

Figure 2-8 shows XRPD Overlay of Dione racemate at different temperatures (I/II). Figure 2-9 shows XRPD overlay of Dione racemate at different temperatures (II/II). Figure 2-10 shows Ternary Phase Diagram of M/P-Dione cocrystals.

Figure 2-11 shows Ternary phase diagram of M/P-Dione.

Figure 3-1 shows XRPD of Dione racemate Type A.

Figure 3-2 shows TGA/DSC overlay of Dione racemate Type A.

Figure 3-3 shows 1H NMR spectrum of Dione racemate Type A.

Figure 3-4 shows PLM image of Dione racemate Type A.

Figure 3-5 shows XRPD of Dione racemate Type B.

Figure 3-6 shows TGA/DSC overlay of Dione racemate Type B.

Figure 3-7 shows 1H NMR spectrum of Dione racemate Type B.

Figure 3-8 shows XRPD of Dione racemate Type C.

Figure 3-9 shows TGA/DSC overlay of Dione racemate Type C.

Figure 3-10 shows 1H NMR spectrum of Dione racemate Type C.

Figure 3-11 shows XRPD of Dione racemate Type D.

Figure 3-12 shows TGA/DSC overlay of Dione racemate Type D.

Figure 3-13 shows 1H NMR spectrum of Dione racemate Type D.

Figure 3-14 shows XRPD of Dione racemate Type E.

Figure 3-15 shows TGA/DSC overlay of Dione racemate Type E.

Figure 3-16 shows 1H NMR spectrum of Dione racemate Type E.

Figure 3-17 shows XRPD of M-Dione cocrystal Type A.

Figure 3-18 shows TGA/DSC overlay of M-Dione cocrystal Type A.

Figure 3-19 shows 1H NMR spectrum of M-Dione cocrystal Type A.

Figure 3-20 shows XRPD of P-Dione cocrystal Type A.

Figure 3-21 shows TGA/DSC overlay of P-Dione cocrystal Type A.

Figure 3-22 shows 1H NMR spectrum of P-Dione cocrystal Type A.

Figure 3-23 shows XRPD overlay of Dione racemate forms.

Figure 3-24 shows XRPD of competitive slurry samples.

Figure 3-25 shows XRPD overlay of prepared P-Dione cocrystal.

Figure 3-26 shows 1H NMR spectrum overlay of M/P-Dione cocrystals.

Figure 3-27 shows XRPD overlay of prepared P-Dione cocrystal.

Figure 4-1 shows Inter-conversion diagram of M-Dione DBTA Cocrystal crystal forms.

Figure 5-1 shows XRPD overlay of M-dione DBTA cocrystal crystal forms (Type A ~

E).

Figure 5-2 shows XRPD overlay of M-dione DBTA cocrystal crystal forms (Type F ~

K).

Figure 5-3 shows XRPD overlay of M-dione DBTA cocrystal crystal forms (Type L ~

Q).

Figure 5-4 shows XRPD pattern of Type A.

Figure 5-5 shows TGA/DSC curves of Type A.

Figure 5-6 shows 1H NMR of Type A.

Figure 5-7 shows XRPD overlay of Type B.

Figure 5-8 shows TGA/DSC curves of Type B.

Figure 5-9 shows 1H NMR of Type B.

Figure 5-10 shows XRPD pattern of Type C.

Figure 5-11 shows TGA/DSC curves of Type C.

Figure 5-12 shows 1H NMR of Type C.

Figure 5-13 shows XRPD pattern of Type D.

Figure 5-14 shows TGA/DSC curves of Type D.

Figure 5-15 shows 1H NMR of Type D.

Figure 5-16 shows XRPD pattern of Type E.

Figure 5-17 shows TGA/DSC curves of Type E.

Figure 5-18 shows 1H NMR of Type E.

Figure 5-19 shows XRPD pattern of Type F.

Figure 5-20 shows TGA/DSC curves of Type F.

Figure 5-21 shows 1H NMR of Type F.

Figure 5-22 shows XRPD pattern of Type G.

Figure 5-23 shows TGA/DSC curves of Type G.

Figure 5-24 shows 1H NMR of Type G.

Figure 5-25 shows XRPD pattern of Type H.

Figure 5-26 shows TGA/DSC curves of Type H.

Figure 5-27 shows 1H NMR of Type H.

Figure 5-28 shows XRPD pattern of Type I.

Figure 5-29 shows TGA/DSC curves of Type I.

Figure 5-30 shows 1H NMR of Type I.

Figure 5-31 shows XRPD pattern of Type J.

Figure 5-32 shows TGA/DSC curves of Type J.

Figure 5-33 shows 1H NMR of Type J.

Figure 5-34 shows XRPD patern of Type K.

Figure 5-35 shows TGA/DSC curves of Type K.

Figure 5-36 shows 1H NMR of Type K.

Figure 5-37 shows XRPD patern of Type L.

Figure 5-38 shows TGA/DSC curves of Type L.

Figure 5-39 shows 1H NMR of Type L.

Figure 5-40 shows XRPD patern of Type M.

Figure 5-41 shows TGA/DSC curves of Type M.

Figure 5-42 shows 1H NMR of Type M.

Figure 5-43 shows XRPD patern of Type N.

Figure 5-44 shows TGA/DSC curves of Type N.

Figure 5-45 shows 1H NMR of Type N.

Figure 5-46 shows XRPD patern of Type O.

Figure 5-47 shows TGA/DSC curves of Type O.

Figure 5-48 shows 1H NMR of Type O.

Figure 5-49 shows XRPD patern of Type P.

Figure 5-50 shows TGA/DSC curves of Type P.

Figure 5-51 shows 1H NMR of Type P.

Figure 5-52 shows XRPD patern of Type Q.

Figure 5-53 shows TGA/DSC curves of Type Q.

Figure 5-54 shows 1H NMR of Type Q.

Figure 6-1 shows HPLC of M-5 from resolution with l,3-diphenyl-3-oxopropanesulfonic acid.

Figure 6-2 shows HPLC of 5 (P-atropisomer excess) from resolution with 1,3-diphenyl-3-oxopropanesulfonic acid.

SUMMARY

The present invention relates to improved preparation of a compound having the following chemical structure:

and key intermediates thereof, i.e., compositions and compounds comprising the following chemical structures:

The present invention additional relates to a method of preparing Compound 5M having the following chemical structure

The present invention additional relates to a composition comprising a structure

DETAILED DESCRIPTION

Definitions

Abbreviations: The following abbreviations may be used herein:

The use of the terms “a,” “an,” “the,” and similar referents in the context of describing the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated. Recitation of ranges of values herein merely are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to better illustrate the invention and is not a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

As used herein, the term “alkyl” refers to straight chained and branched C1-C8 hydrocarbon groups, including but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethybutyl. The term Cm-n means the alkyl group has “m” to “n” carbon atoms. The term “alkylene” refers to an alkyl group having a substituent. An alkyl (e.g., methyl), or alkylene (e.g., -CH2-), group can be substituted with one or more, and typically one to three, of independently selected, for example, halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, C1-8alkyl. C2-8alkenyl. C2- 8alkynyl, -NC, amino, -CO2H, -CO2C1-C8alkyl, -OCOC1-C8alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C5-C10aryl, and C5-C10 heteroaryl. The term “haloalkyl” specifically refers to an alkyl group wherein at least one, e.g., one to six, or all of the hydrogens of the alkyl group are substituted with halo atoms.

The terms “alkenyl” and “alkynyl” indicate an alkyl group that further includes a double bond or a triple bond, respectively.

As used herein, the term “halo” refers to fluoro, chloro, bromo, and iodo. The term “alkoxy” is defined as -OR, wherein R is alkyl.

As used herein, the term “amino” or “amine” interchangeably refers to a -NR2 group, wherein each R is, e.g., H or a substituent. In some embodiments, the amino group is further substituted to form an ammonium ion, e.g., NR3+. Ammonium moieties are specifically included in the definition of “amino” or “amine.” Substituents can be, for example, an alkyl, alkoxy, cycloalkyl, heterocycloalkyl, amide, or carboxylate. An R group may be further substituted, for example, with one or more, e.g., one to four, groups selected from halo, cyano, alkenyl, alkynyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, urea, carbonyl, carboxylate, amine, and amide. An “amide” or “amido” group interchangeably refers to a group similar to an amine or amino group but further including a C(O), e.g., -C(O)NR2.

As used herein, the term “aryl” refers to a C6-14 monocyclic or polycyclic aromatic group, preferably a C6-10 monocyclic or bicyclic aromatic group, or C10-14 polycyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to C10-14 bicyclic and tricyclic carbon rings, where one ring is aromatic and the others are saturated, partially unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl, or

tetrahydronaphthyl (tetralinyl). Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four, groups independently selected from, for example, halo, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, -CF3, -OCF3, -NO2, -CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C8alkyl, -OCOC1-C8alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C5-C10aryl, and C5-C10 heteroaryl.

As used herein, the term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic carbocyclic ring, where the polycyclic ring can be fused, bridged, or spiro. The carbocyclic ring can have 3 to 10 carbon ring atoms. Contemplated carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.

As used herein, the term “heterocycloalkyl” means a monocyclic or polycyclic (e.g., bicyclic), saturated or partially unsaturated, ring system containing 3 or more (e.g., 3 to 12, 4 to 10, 4 to 8, or 5 to 7) total atoms, of which one to five (e.g., 1, 2, 3, 4, or 5) of the atoms are independently selected from nitrogen, oxygen, and sulfur. Nonlimiting examples of heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolyl, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, and diazacycloheptyl.

Unless otherwise indicated, a cycloalkyl or heterocycloalkyl group can be unsubstituted or substituted with one or more, and in particular one to four, groups. Some contemplated substituents include halo, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, -CF3, -OCF3, -NO2, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C8alkyl, -OCOC1-C8alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C5-C10aryl, and C5-C10 heteroaryl.

As used herein, the term “heteroaryl” refers to a monocyclic or polycyclic ring system (for example, bicyclic) containing one to three aromatic rings and containing one to four (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in an aromatic ring. In certain embodiments, the heteroaryl group has from 5 to 20, from 5 to 15, from 5 to 10 ring, or from 5 to 7 atoms. Heteroaryl also refers to C10-14 bicyclic and tricyclic rings, where one ring is aromatic and the others are saturated, partially unsaturated, or aromatic. Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, triazolyl, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quiazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Unless otherwise indicated, a heteroaryl group can be unsubstituted or substituted with one or more, and in particular one to four or one or two, substituents. Contemplated substituents include halo, C1 -8alkyl. C2-8alkenyl. C2-8alkynyl, -OCF3, -NO2, - CN, -NC, -OH, alkoxy, amino, -CO2H, -CO2C1-C8alkyl, -OCOC1-C8alkyl, C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, C5-C10aryl, and C5-C10 heteroaryl.

As used herein, the term Boc refers to the structure

EMBODIMENTS

Embodiment 1

In one embodiment of the invention, the present invention comprises a composition, the composition comprising a compound of Formula 4:

and a compound of Formula B:

Embodiment 2

In another embodiment of the present invention, the present invention comprises the composition of embodiment 1, wherein the compound of Formula 4 is a compound of Formula 5M:

Embodiment 3

In another embodiment of the present invention, the present invention comprises the composition of embodiment 1, wherein the compound of Formula 4 is a compound of Formula 5P:

Embodiment 4

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 1-3, wherein the compound of Formula B is a compound of formula Bl :

Embodiment 5

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 1-3, wherein the compound of Formula B is a compound of formula B2:

Embodiment 6

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 1-5, wherein the composition comprises a 2 to 1 ratio of the compound of Formula 4 to the compound of Formula B.

Embodiment 7

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 1-6, wherein the composition further comprises 2- methyltetrahydrofuran having the formula:

Embodiment 8

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 1-7, wherein the ratio of the 2-methyltetrahydrofuran to the compound of formula B is 2 to 1.

Embodiment 9

In another embodiment of the present invention, the present invention comprises the composition of embodiment 1, wherein the composition has the formula:

Embodiment 10

In another embodiment of the present invention, the present invention comprises the composition of embodiment 9, wherein the composition has the formula:

Embodiment 11

In another embodiment of the present invention, the present invention comprises the composition of embodiment 9, wherein the composition has the formula:

Embodiment 12

In another embodiment of the present invention, the present invention comprises the composition of embodiment 9, wherein the composition has the formula:

Embodiment 13

In another embodiment of the present invention, the present invention comprises the composition of embodiment 9, wherein the composition has the formula:

Embodiment 14

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 1-13, wherein the composition is in a crystalline state.

Embodiment 15

In another embodiment of the present invention, the present invention comprises a method of making a composition of formula 4a, the method comprising reacting a compound 4, having the following chemical structure:

4, with a compound Bl, having the formula:

in the presence of 2-methyltetrahydrofuran to form the composition of formula 4a,

having the structure:

Embodiment 16

In another embodiment of the present invention, the present invention comprises a method of obtaining a compound of formula 5M, having the following chemical structure:

the method comprising:

a) reacting a compound 4, having the following chemical structure:

4, with a compound B1, having the formula:

in the presence of 2-methyltetrahydrofuran to form a composition of formula 4a, having the

structure:
4a as crystals;

b) isolating composition 4a, and

c) treating the isolated composition 4a with a base to produce the compound of formula 5M.

Embodiment 17

In another embodiment of the present invention, the present invention comprises the method according to Embodiment 16, wherein the base is Na2HPO4.

Embodiment 18

In another embodiment of the present invention, the present invention comprises the method according to Embodiment 16, wherein the base is NaHCO3.

Embodiment 19

In another embodiment of the present invention, the present invention comprises the composition, the composition comprising a compound of Formula 4:

and a compound of Formula 11 :

Embodiment 20

In another embodiment of the present invention, the present invention comprises the composition of embodiment 19, wherein the compound of Formula 4 is a compound of Formula 5M:

Embodiment 21

In another embodiment of the present invention, the present invention comprises the composition of embodiment 19, wherein the compound of Formula 4 is a compound of Formula 5P:

Embodiment 22

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 19-21, wherein the compound of Formula 11 is a compound of formula 11a:

Embodiment 23

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 19-21, wherein the compound of Formula 11 is a compound of formula lib

Embodiment 24

In another embodiment of the present invention, the present invention comprises the composition of embodiment 19, wherein the composition has the formula:

Embodiment 25

In another embodiment of the present invention, the present invention comprises the composition of embodiment 19, wherein the composition has the formula:

Embodiment 26

In another embodiment of the present invention, the present invention comprises the composition of embodiment 19, wherein the composition has the formula:

Embodiment 27

In another embodiment of the present invention, the present invention comprises the composition of embodiment 19, wherein the composition has the formula:

Embodiment 28

In another embodiment of the present invention, the present invention comprises the composition of any one of embodiments 19-27, wherein the composition comprises a 1 to 1 ratio of the compound of Formula 4 to the compound of Formula 11.

Embodiment 29

In another embodiment of the present invention, the present invention comprises the the method of embodiment 16, wherein the compound of formula 5M is used to generate a

compound having the Formula 9:

Embodiment 30

The method of embodiment 29, wherein the method further comprises mixing the compound of Formula 9 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.

Compounds of the disclosure

Provided herein are KRAS inhibitors having structures discussed in more detail below.

The compounds disclosed herein include all pharmaceutically acceptable isotopically-labeled compounds wherein one or more atoms of the compounds disclosed herein are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2H, 1H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I, respectively. These radiolabelled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labeled compounds of the disclosure, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence are preferred in some circumstances.

Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of structure (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Isotopically-labeled compounds as disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and schemes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

Certain of the compounds as disclosed herein may exist as stereoisomers (i.e., isomers that differ only in the spatial arrangement of atoms) including optical isomers and conformational isomers (or conformers). The compounds disclosed herein include all stereoisomers, both as pure individual stereoisomer preparations and enriched preparations of each, and both the racemic mixtures of such stereoisomers as well as the individual diastereomers and enantiomers that may be separated according to methods that are known to those skilled in the art. Additionally, the compounds disclosed herein include all tautomeric forms of the compounds.

Certain of the compounds disclosed herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, both as pure individual atropisomer preparations, enriched preparations of each, or a non-specific mixture of each. Where the rotational barrier about the single bond is high enough, and interconversion between conformations is slow enough, separation and isolation of the isomeric species may be

permitted. For example, groups such as, but not limited to, the following groups

may exhibit restricted rotation.

The term “monohydrate” means a salt of Compound 9 having about one associated water molecule. Those skilled in the art appreciate that the exact number of the associated water molecules may vary slightly at any time with variable temperature, pressure, and other environmental influence. All slight variations of the number of the associated water molecules are contemplated to be within the scope of the present invention.

The term “dihydrate” means a salt of Compound 9 having about two associated water molecules. Those skilled in the art appreciate that the exact number of the associated water molecules may vary slightly at any time with variable temperature, pressure, and other environmental influence. All slight variations of the number of the associated water molecules are contemplated to be within the scope of the present invention.

The term “co-crystal” means a crystalline material comprising two or more compounds at ambient temperature (20 °C to 25 °C., preferably 20 °C.), of which at least two are held

together by weak interaction, wherein at least one of the compounds is a co-crystal former and the other is Compound 5. Weak interaction is being defined as an interaction which is neither ionic nor covalent and includes for example: hydrogen bonds, van der Waals forces, and p-p interactions.

The term "amorphous form" or "amorphous" means a material that lacks long range order and as such does not show distinct X-ray diffraction peaks, i.e. a Bragg diffraction peak. The XRPD pattern of an amorphous material is characterized by one or more amorphous halos.

The term "amorphous halo" is an approximately bell-shaped maximum in the X-ray powder pattern of an amorphous substance.

The term “substantially pure” refers to a solid form of Compound 9 having purity greater than about 95%, specifically greater than about 99.5%, more specifically greater than about 99.8% and still more specifically greater than about 99.9%.

The term "patient" means animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are mammals. The term patient includes males and females.

The terms "treating", "treat" or "treatment" and the like include preventative (e.g., prophylactic) and palliative treatment.

The term “excipient” means any pharmaceutically acceptable additive, carrier, diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration to a patient.

Pharmaceutical compositions, dosing, and routes of administration

Also provided herein are pharmaceutical compositions that include a compound as disclosed herein, together with a pharmaceutically acceptable excipient, such as, for example, a diluent or carrier. Compounds and pharmaceutical compositions suitable for use in the present invention include those wherein the compound can be administered in an effective amount to achieve its intended purpose. Administration of the compound described in more detail below.

Suitable pharmaceutical formulations can be determined by the skilled artisan depending on the route of administration and the desired dosage. See, e.g., Remington’s Pharmaceutical Sciences, 1435-712 (18th ed., Mack Publishing Co, Easton, Pennsylvania, 1990). Formulations may influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of the administered agents. Depending on the route of administration, a suitable dose may be calculated according to body weight, body surface areas or organ size. Further refinement of the calculations necessary to determine the appropriate treatment dose is routinely made by those of ordinary skill in the art without undue experimentation, especially in light of the dosage information and assays disclosed herein as well as the pharmacokinetic data obtainable through animal or human clinical trials.

CLAIMS

What is claimed is:

1. A composition, the composition comprising a compound of Formula 4:

and a compound of Formula B:

2. The composition of claim 1, wherein the compound of Formula 4 is a compound of Formula 5M:

3. The composition of claim 1, wherein the compound of Formula 4 is a compound of Formula 5P:

4. The composition of any one of claims 1-3, wherein the compound of Formula B is a compound of formula B1 :

5. The composition of any one of claims 1-3, wherein the compound of Formula B is a compound of formula B2:

6. The composition of any one of claims 1-3, wherein the composition comprises a 2 to 1 ratio of the compound of Formula 4 to the compound of Formula B.

7. The composition of any one of claims 1-3, wherein the composition further comprises 2-methyltetrahydrofuran having the formula:

8. The composition of any one of claims 1-3, wherein the ratio of the 2-methyltetrahydrofuran to the compound of formula B is 2 to 1.

9. The composition of claim 1, wherein the composition has the formula:

10. The composition of claim 9, wherein the composition has the formula:

11. The composition of claim 9, wherein the composition has the formula:

12. The composition of claim 9, wherein the composition has the formula:

13. The composition of claim 9, wherein the composition has the formula:

14. The composition of any one of claims 1-13, wherein the composition is in a crystalline state.

15. A method of making a composition of formula 4a, the method comprising reacting a compound 4, having the following chemical structure:

4, with a compound B1, having the formula:

in the presence of 2-methyltetrahydrofuran to form the composition of formula 4a,

having the structure:

16. A method of obtaining a compound of formula 5M, having the following chemical structure:

the method comprising:

a) reacting a compound 4, having the following chemical structure:

4, with a compound B1, having the formula:

in the presence of 2-methyltetrahydrofuran to form a composition of formula 4a, having

the structure: 4a as crystals;

b) isolating composition 4a, and

c) treating the isolated composition 4a with a base to produce the compound of formula 5M.

17. The method according to Claim 16, wherein the base is Na2HPO4.

18. The method according to Claim 16, wherein the base is NaHCO3.

19. A composition, the composition comprising a compound of Formula 4:

and a compound of Formula 11 :

20. The composition of claim 19, wherein the compound of Formula 4 is a compound of Formula 5M:

21. The composition of claim 19, wherein the compound of Formula 4 is a compound of Formula 5P:

22. The composition of any one of claims 19-21, wherein the compound of Formula 11 is a compound of formula 11a:

23. The composition of any one of claims 19-21, wherein the compound of Formula 11 is a compound of formula lib:

24. The composition of claim 19, wherein the composition has the formula:

25. The composition of claim 19, wherein the composition has the formula:

26. The composition of claim 19, wherein the composition has the formula:

27. The composition of claim 19, wherein the composition has the formula:

28. The composition of any one of claims 19-27, wherein the composition comprises a 1 to 1 ratio of the compound of Formula 4 to the compound of Formula 11.

29. The method of claim 16, wherein the compound of formula 5M is used to

generate a compound having the Formula 9:

30. The method of claim 29, wherein the method further comprises mixing the compound of Formula 9 with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.