WO2022036033A4

WO2022036033A4 - Solid state forms of an organic compound

Info

Publication number: WO2022036033A4
Application number: PCT/US2021/045656
Authority: WO
Inventors: Jose Luis RIOS LIZARRAGA; Kristopher Depew; Louis Grenier; Benjamin S. Lane; Eric Simone; Jacob Paul SIZEMORE
Original assignee: Servier Pharmaceuticals LLC
Current assignee: Servier Pharmaceuticals LLC
Priority date: 2020-08-12
Filing date: 2021-08-12
Publication date: 2022-06-23
Anticipated expiration: 2023-02-12
Also published as: AR123228A1; WO2022036033A3; TW202227446A; WO2022036033A2

Abstract

Provided herein are various solid state forms, including salts as well as various crystalline and amorphous forms, of Compound I which is represented by the structural formula: Also provided are pharmaceutical compositions comprising these materials, methods for their manufacture, uses thereof for treating conditions, including but not limited to conditions that would benefit from inhibition of methionine adenosyltransferase 2a (MAT2A).

Claims

AMENDED CLAIMS received by the International Bureau on 13 May 2022 (13.05.2022)WHAT IS CLAIMED IS:

1. An anhydrous solid state form of Compound I that is represented by the formula:

Compound I.

2. The solid state form of claim 1 that is crystalline Form D that is characterized by two or more X-ray powder diffraction peaks at 20 angles (± 0.2°) chosen from 7.6°, 10.7°, 19.0° and 23.7°.

3. The solid state form of claim 2 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 1.

4. The solid state form of claim 1 that is crystalline Form K-C that is characterized by two or more X-ray powder diffraction peaks at 20 angles (± 0.2°) chosen from 5.2°, 10.4°, 11.7°, and 26.3°.

5. The solid state form of claim 4 characterized by an X-ray powder diffraction pattern substantially similar to FIG. 55.

6. A solid state form of a basic salt of Compound I, wherein Compound I is represented by the formula:

AMENDED SHEET (ARTICLE 19)

salt, a lithium salt, or a calcium salt. The solid state form of claim 6 or 7, wherein the salt is crystalline or amorphous. A solid state form of a hydrate of Compound I, wherein Compound I is represented by the formula:

The solid state form of any one of claims 1-9, wherein the solid state form is at least 60 wt.% a single crystalline form, at least 70 wt.% a single crystalline form, at least 80 wt.% a single crystalline form, at least 90 wt.% a single crystalline form, at least 95 wt.% a single crystalline form, or at least 99 wt.% a single crystalline form. The solid state form of any one of claims 1-9, wherein solid state form has a chemical purity of at least 60 wt.%, at least 70 wt.%, at least 80 wt.%, at least 90 wt.%, at least 95 wt.%, or at least 99 wt.%, as measured by HPLC. A solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula:

152

AMENDED SHEET (ARTICLE 19)

A spray-dried solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula:

A pharmaceutical composition comprising a solid dispersion comprising a compound that is 3-(cyclohex-l-en-l-yl)-6-(4-methoxyphenyl)-2-phenyl-5-(pyridin-2- ylamino)pyrazolo[l,5-a]pyrimidin-7(4H)-one (Compound I) and a pharmaceutically acceptable excipient. The pharmaceutical composition of claim 14, wherein the solid dispersion further comprises a polymer. The pharmaceutical composition of claim 15, wherein the polymer is a water soluble polymer. The pharmaceutical composition of any one of claims 15-16, wherein the polymer is a cellulosic polymer.

153

AMENDED SHEET (ARTICLE 19) The pharmaceutical composition of claim 14 or 15, wherein the solid dispersion comprises a polymer selected from cellulose ethers, cellulose esters, cellulose co- carboxyesters, cellulose phthalates, cellulose succinates, or mixtures thereof. The pharmaceutical composition of claim 14 or 15, wherein the solid dispersion comprises a polymer selected from methylcellulose (MC); ethylcellulose (EC); hydroxyethylcellulose (HEC); hydroxypropyl methyl cellulose (HPMC) such as HPMC 606 or HPMC E5; hydroxypropyl cellulose (HPC); carboxymethyl ethyl cellulose (CMEC); hydroxypropyl methyl cellulose acetosuccinate (HPMCAS) such as HPMCAS/SLS, HPMCAS AS-MF, HPMCAS-HF, HPMCAS-H, HPMCAS-L, HPMCAS-M, HPMCAS 912 HP, HPMCAS 912, or HPMCAS HP-55; hydroxypropyl methyl cellulose phthalate (HPMCP); cellulose acetate phthalate (CAP); cellulose acetate groups having at least a half of cellulose acetate in hydrolyzed form; polyvinylpyrrolidone such as PVP K-12, PVPVA, PVP K 29/32, or PVPVA 64; polyoxyethylene-polyoxypropylene copolymers; polyvinylacetate (PVAc); polypvinyl pyridine) (P2VP), TPGS, copovidone; cellulose acetate (CA); cellulose acetate butyrate (CAB); 5 -carboxypentyl hydroxypropyl cellulose (CHC); polyacrylic acid (PAA); carboxymethylcellulose derivatives such as carboxymethyl cellulose (CMC) or carboxymethyl cellulose acetate butyrate (CMCAB); hydroxypropylmethylphthalate (HPMP); hydroxypropylmethylphthalate acetate succinate (HPMPAS); Eudragit EPO; Eudragit E-100; cellulose acetate adipate (CAAdP); cellulose acetate suberate (CASub); methylcellulose adipate (MCAd); cellulose acetate butyrate sebacate (CAB Seb); cellulose acetate butyrate suberate (CAB Sub); cellulose acetate sebacate (CASeb); cellulose acetate phthalate (CAPhth); cellulose succinate (CS); cellulose acetate butyrate suberate (CABSu); HPCPenlO6- AA-H-hydroxypropyl pent-4-enyl cellulose; HPC-SSL; HP- -CD; or mixtures thereof. The pharmaceutical composition of any one of claims 15-19, wherein the molar ratio of Compound I to the polymer is about 25:75 to about 50:50, or optionally about 25:75, or optionally about 35:65, or optionally about 50:50. The pharmaceutical composition of any one of claims 14-20, wherein the solid dispersion comprises HPMCAS.

154

AMENDED SHEET (ARTICLE 19) The pharmaceutical composition of any one of claims 14-21, wherein the solid dispersion comprises HPMCAS, microcrystalline cellulose, croscarmellose sodium, and sodium stearyl fumarate. The pharmaceutical composition of any one of claims 14-22, wherein the solid dispersion is a spray dried dispersion or spray-precipitated dispersion, preferably a spray dried dispersion. The pharmaceutical composition of any one of claims 14-23, wherein Compound I is present in a substantially amorphous solid state form in the solid dispersion. A method of treating cancer in a subject, comprising administering to the subject an effective amount of the solid state form of any one of claims 1-11 or the pharmaceutical composition of any one of claims 14-24. The method of claim 25, wherein the cancer comprises a solid tumor. The method of claim 25, wherein the cancer is selected from lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma. The method of any one of claims 25-27, further comprising administering a therapeutically effective amount of an additional therapeutic agent. The method of claim 28, wherein the additional therapeutic agent is a taxane such as docetaxel, paclitaxel, or nab-paclitaxel. The method of claim 28, wherein the additional therapeutic agent is a platinum-based chemotherapeutic such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetra nitrate, phenanthriplatin, picoplatin, or satraplatin. The method of claim 28, wherein the additional therapeutic agent is a DNA synthesis inhibitor such as gemcitabine. The method of claim 28, wherein the additional therapeutic agent is nab-paclitaxel and gemcitabine. The method of claim 32, wherein the cancer is pancreatic cancer.

155

AMENDED SHEET (ARTICLE 19) The method of any one of claims 28-33, wherein the solid state form and the additional therapeutic agent are administered concurrently. The method of any one of claims 28-33, wherein the solid state form and the additional therapeutic agent are administered sequentially. Use of a solid state form of any one of claims 1-11 or the pharmaceutical composition of any one of claims 14-24 for the manufacture of a medicament for treating cancer. The use of claim 36, wherein the cancer comprises a solid tumor. The use of claim 36, wherein the cancer is lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma. The solid state form of Compound I of any one of claims 1-11 or the pharmaceutical composition of any one of claims 14-24 for treating cancer, wherein the solid state form or the pharmaceutical composition is optionally used in combination with an additional therapeutic agent. The solid state form of Compound I or pharmaceutical composition of claim 39, wherein the cancer comprises a solid tumor. The solid state form of Compound I or pharmaceutical composition of claim 39 or 40, wherein the cancer is selected from lung cancer, pancreatic cancer, cancer of the esophagus, lymphoma, or mesothelioma. The solid state form of Compound I or pharmaceutical composition of any one of claims 39-41, wherein the additional therapeutic agent is a taxane such as docetaxel, paclitaxel, or nab-paclitaxel. The solid state form of Compound I or pharmaceutical composition of any one of claims 39-42, wherein the additional therapeutic agent is a platinum-based chemotherapeutic such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetra nitrate, phenanthriplatin, picoplatin, or satraplatin. The solid state form of Compound I of any one of claims or the pharmaceutical composition of claim 39 or 40, wherein the additional therapeutic agent is a DNA synthesis inhibitor such as gemcitabine.

156

AMENDED SHEET (ARTICLE 19) A method of treating disease in a subject wherein the disease is responsive to inhibition of methionine adenosyltransferase 2A (MAT2A) comprising administering to the subject an effective amount of a solid state form of Compound I of any one of claims 1-11 or the pharmaceutical composition of any one of claims 14-24. A process for preparing a solid dispersion of Compound I comprising combining a solid state form of any one of claims 1-11 with a polymer and a solvent to form a mixture; and spray-drying or spray-precipitating the mixture to produce the solid dispersion; wherein the solid dispersion comprises Compound I in a substantially amorphous form. The process of claim 46, wherein the mixture is an emulsion, solution, or suspension. A product produced by the process of claim 46 or 47. A process for preparing the amorphous solid state form of Compound I, comprising dissolving a crystalline form of Compound I of any one of claims 1-11 in a solvent to form a solution and producing the solid state form that is amorphous Compound I from the solution. The process of claim 49, wherein the solvent is benzyl alcohol. The process of claim 49 or 50, comprising precipitating the amorphous form from the solution. The process of claim 51, wherein the solution is heated to a temperature that is above 20 °C, such as about 50-70°C. The process of claim 51 or 52, wherein the precipitation is performed at a solution temperature that is about room temperature or lower, such as a temperature of about - 20-15°C.

157

AMENDED SHEET (ARTICLE 19) A process for preparing Compound I of the following structure:

the process comprising:

• converting compound INT-15 to ketenimine compound INT-15K of the following structure:

• reacting compound INT-15K with compound INT- 12 to form compound INT-

12A;

• deprotecting compound INT - 12A to form compound INT - 12B ;

• cyclizing compound INT-12B to form Compound I. The process of claim 54, wherein compound INT-15K is prepared by reacting compound INT-15 with triphenylphosphine chloride or triphenylphosphine bromide, followed by a base.

158

AMENDED SHEET (ARTICLE 19) The process of claim 55, comprising reacting triphenylphosphine oxide and oxalyl chloride to form the triphenylphosphine chloride. The process of claim 56, wherein triphenylphosphine oxide and oxalyl chloride are combined before contacting with compound INT-15. The process of any one of claims 55 to 57, wherein the temperature is a reduced temperature, such as about -10 to about 20°C, optionally about 10°C. The process of any one of claims 55 to 58, wherein the base is an amine base such as N-methyhnorpholine, triethyl amine, 2,6-lutidine, pyridine, 4-dimethylaminopyridine, N,N-diisopropylethylamine, or l,4-diazabicyclo[2.2.2]octane. The process of any one of claims 55 to 59, comprising an excess of the base, or optionally about more than 1 equivalents, or optionally at least about 1.5 equivalents, or optionally at least about 3 equivalents. The process of any one of claims 54 to 60, wherein compound INT-12 is reacted with compound INT-15K at a reduced temperature, such as about -25 to about 20°C, optionally about 0°C. The process of claim 61, wherein the temperature is raised to an elevated temperature, such as about 25 to about 45 °C, optionally about 35 °C. The process of any one of claims 54 to 62, comprising a molar excess of compound INT-15K relative to compound INT-12. The process of any one of claims 54 to 63, comprising at least 1.1 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.2 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.25 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.3 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12, or optionally at least 1.5 equivalents of compound INT-15 relative to 1 equivalent of compound INT-12 The process of any one of claims 54 to 64, wherein the deprotecting is performed using an acid or a base.

159

AMENDED SHEET (ARTICLE 19) The method of claim 65, wherein the acid is a strong acid, such as HC1 or methane sulfonic acid, preferably HC1. The method of claim 65, wherein the base is potassium tert-butoxide. The process of any one of claims 54 to 67, wherein the deprotecting is performed at a reduced temperature, such as about -25 to about 20°C, optionally about 0°C. The process of any one of claims 54 to 68, wherein the deprotecting is performed in an aqueous organic solvent, optionally an ether such as dioxane or cyclopentyl methyl ether, an alcohol such as isopropyl alcohol, or ethyl acetate, or preferably dioxane. The process of any one of claims 54 to 69, wherein the cyclizing is performed at elevated temperatures, such as about 30 to about 50°C, optionally about 25 to about 45°C. The process of any one of claims 54 to 70, further comprising coupling compound INT-14 with 2-aminopyridine to form compound INT-15:

14. The process of claim 71, wherein the coupling is performed using a coupling agent such as l,l'-carbonyldiimidazole (CDI), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC), 2,2-dichloro-5-(2-phenylethyl)-4- (trimethylsilyl)-3 -furanone (DPTF), 4-(4,6-dimethoxy- l,3,5-triazin-2-yl)-4-methyl- morpholin-4-ium chloride (DMT-MM), (l-cyano-2-ethoxy-2- oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), or N,N’-diisopropylcarbodiimide (DIC), optionally CDI. The process of claim 71 or 72, wherein the coupling is performed at a reduced temperature, such as about -25 to about 20°C, optionally about 0°C. The process of any one of claims 71 to 73, wherein compound INT-14 is added to a solution comprising the coupling compound.

160

AMENDED SHEET (ARTICLE 19) The process of any one of claims 71 to 74, further comprising carboxylating methyl 4- methoxyphenylacetate (INT-13) to form compound INT-14

13. The process of claim 75, wherein the carboxylation is performed using carbon dioxide, such as a carbon dioxide gas or solid carbon dioxide. The process of claim 75 or 76, further comprising a base such as a strong non- nucleophilic base such as sodium hexamethyldisilazide, lithium hexamethyldisilazide, or potassium hexamethyldisilazide. The process of any one of claims 75 to 77, that is performed at a reduced temperature, such as about -100 to about 0°C, or optionally about -90 to about -50°C, or optionally about -50 to about -70°C. The process of any one of claims 75 to 78, further comprising one or more warming steps. The process of claim 79, wherein at least one warming step comprises warming to a temperature of about -35 to about -15°C, or optionally about -30 to about -20°, or optionally -25 °C. The process of claim 80, wherein a second warming step comprises warming to about -15 to about 5°C, or optionally about -5°C. The process of claim 81, wherein a third warming step comprises warming to about room temperature. The process of any one of claims 77 to 82, wherein an excess of the base is utilized, such as at least about 1 to about 4 equivalents, or optionally about 1.1 to about 3.5 equivalents, or optionally about 1.1 to about 3.3 equivalents, or optionally 1.5 equivalents. The process of any one of claims 54 to 83, further comprising reacting compound INT-25 with methane sulfonic acid to prepare compound INT-15

161

AMENDED SHEET (ARTICLE 19)

The process of claim 84, that is performed at an elevated temperature, such as about

50 to about 80°C, optionally about 60 to about 70°C, or optionally about 65 to about 70°C. The process of any one of claims 54 to 85, further comprising reacting compound INT-2 with 2-aminopyridine to provide compound INT-15, compound INT-25, or a combination thereof

25. The process of claim 86, that is performed in an organic solvent such as an organic solvent with a high boiling point, or optionally toluene. The process of claim 86 or 87, that is performed at an elevated temperature, such as about 90 to about 120°C, optionally about 100 to about 110°C, or optionally about 110°C. The process of any one of claims 54 to 88, further comprising reacting compound INT-11 with cyclohexanone to provide compound INT-12

The process of claim 89, that is performed at a reduced temperature, such as about 0 to about 20°C, optionally about 15°C. The process of claim 89 or 90, comprising an excess of cyclohexanone, such as at least about 1.5 equivalents, at least about 2 equivalents, or at least about 2.5 equivalents. The process of any one of claims 89 to 91, that is performed in the presence of a strong organic acid, such as p-toluenesulfonic acid.

162

AMENDED SHEET (ARTICLE 19) The process of claim 92, comprising a catalytic amount of the strong organic acid, such as about 0.01 to about 0.1 equivalents, optionally about 0.03 to about 0.07 equivalents, or optionally about 0.04 equivalents. The process of any one of claims 89 to 93, further comprising protecting the pyrazole group of compound INT-10 to provide compound INT-11

10. The process of claim 94, wherein the pyrazole is protected with a pivalyl group. The process of claim 94 or 95, wherein the protecting is performed using pivalic anhydride or pivalic chloride. The process of any one of claims 94 to 96, wherein the protecting further comprises an alkali t-butoxide, such as lithium t-butoxide, sodium t-butoxide, or potassium t- butoxide, optionally lithium t-butoxide. The process of claim 96 or 97, wherein portions of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof are added to compound INT-10. The process of claim 98, wherein the first portion comprises at least about 0.50 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0.50 equivalents. . The process of claim 99, wherein the second portion comprises at least about 0.30 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0.35 equivalents. . The process of claim 100, wherein the third portion comprises at least about 0.20 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0.1 equivalents. . The process of claim 101, wherein the fourth portion comprises at least about 0.10 equivalents of the pivalic anhydride or pivalic chloride, alkali t-butoxide, or a combination thereof, optionally about 0.05 equivalents.

163

AMENDED SHEET (ARTICLE 19)

. The process of any one of claims 94 to 102, wherein the protecting further comprises a base such as an alkali hydroxide, such as sodium hydroxide, lithium hydroxide, or potassium hydroxide, optionally potassium hydroxide, or an amine such as triethylamine. . The process of any one of claims 54-103, that lacks a palladium reagent.. A spray-precipitated solid dispersion comprising an amorphous solid state form of Compound I that is represented by the formula:

Compound I.

164

AMENDED SHEET (ARTICLE 19)