Tosylate salt form of a maturation inhibitor for treatment of HIV

Abstract

The present invention relates to a tosylate salt of compound A, and a crystalline form thereof, and their use in treating or preventing infection with human immunodeficiency virus (HIV), and to pharmaceutical compositions containing same, as well as to methods for their preparation and use, thereof.

Description

[0001] TOSYLATE SALT FORM OF A MATURATION INHIBITOR FOR TREATMENT OF HIV

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a tosylate salt of a maturation inhibitor, a crystalline form of the compound thereof, and their uses in treating infection with human immunodeficiency virus (HIV), pharmaceutical compositions containing same, as well as to methods for their preparation and use.

[0004] BACKGROUND OF THE INVENTION

[0005] An emerging class of compounds for the treatment of HIV are called HIV maturation inhibitors. Maturation is the last of as many as 10 or more steps in HIV replication or the HIV life cycle, in which HIV becomes infectious as a consequence of several HIV protease- mediated cleavage events in the gag protein that ultimately results in release of the capsid (CA) protein. Maturation inhibitors prevent the HIV capsid from properly assembling and maturing, from forming a protective outer coat, or from emerging from human cells. Instead, non-infectious viruses are produced, preventing subsequent cycles of HIV infection.

[0006] International Application No. PCT / IB2020 / 17050568, filed February 2, 2017 (WO 2017 / 134596 A1 , published August 10, 2017, claiming priority from U.S. Provisional Application 62 / 291 ,298, filed February 4, 2016), describes a series of compounds which are indicated as having HIV maturation inhibitory activity. Specifically disclosed is the compound (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)- 3a-((2-(1 ,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2- yl)-2,3,3a,4,5,5a,5b,6,7,7a,8, 11 , 11 a, 11 b, 12, 13, 13a, 13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid (free base). Identification of a developable salt form and a unique crystalline form of such compound with suitable properties for oral administration would be highly desirable for the treatment of infection with HIV.

[0007] SUMMARY OF THE INVENTION

[0008] In one aspect, this invention provides a tosylate salt of (S)-1-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1 - dioxidothiomorpholino)ethyl)-amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2, 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8,11 ,11a, 11b, 12, 13,13a,13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid. In particular, the free base compound is hereinafter referred to as Compound A, with the structure below:

[0009] In one embodiment, this invention provides the tosylate salt of Compound A in a solid form.

[0010] In one embodiment, this invention provides an anhydrous tosylate salt of Compound

[0011] A, which is (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

[0012] ((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 ,1- dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,11 ,11a,11b,12,13,13a,13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid, tosylate salt, anhydrate. In one embodiment, this invention provides the anhydrous tosylate salt of Compound A in solid form.

[0013] In one aspect, this invention provides novel crystalline forms of the tosylate salt of Compound A. In one embodiment, a crystalline form of the anhydrous tosylate salt of Compound A is (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1- dioxidothiomorpholino)ethyl)amino) -5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2, 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 11 , 11 a, 11 b, 12, 13, 13a, 13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid, tosylate salt, anhydrate.

[0014] In a particular embodiment, the crystalline form of the anhydrous tosylate salt of Compound A is Form 1 (hereinafter “Compound A - Form 1”). In another aspect, this invention provides a pharmaceutical composition comprising the tosylate salt of Compound A, and one or more pharmaceutically acceptable excipients. In one embodiment, the pharmaceutical composition comprises the anhydrous tosylate salt of Compound A, and one or more pharmaceutically acceptable excipients. In another embodiment, the pharmaceutical composition comprises Compound A - Form 1 , and one or more pharmaceutically acceptable excipients. In one embodiment, the invention provides the pharmaceutical compositions described herein, comprising one or more additional therapeutic agents.

[0015] In one aspect, this invention provides a method for preparing a pharmaceutical composition comprising the tosylate salt of Compound A, by combining the tosylate salt of Compound A and one or more pharmaceutically acceptable excipients to provide the pharmaceutical composition. In one embodiment, this invention provides a method for preparing a pharmaceutical composition comprising the anhydrous tosylate salt of Compound A, by combining the anhydrous tosylate salt of Compound A and one or more pharmaceutically acceptable excipients to provide the pharmaceutical composition. In one embodiment, this invention provides a method for preparing a pharmaceutical composition comprising Compound A - Form 1, by combining Compound A - Form 1 and one or more pharmaceutically acceptable excipients to provide the pharmaceutical composition.

[0016] In another aspect, this invention relates to the use of the tosylate salt of Compound A in the manufacture of a medicament for the treatment of infection with HIV. In one embodiment, the invention relates to the use of the anhydrous tosylate salt of Compound A, in the manufacture of a medicament for the treatment of infection with HIV. In yet another embodiment, the invention relates to the use of Compound A - Form 1, in the manufacture of a medicament for the treatment of infection with HIV.

[0017] In another aspect, the invention provides the tosylate salt of (S)-1-(((3-cyanopyridin- 2-yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 ,1- dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid, for use in therapy. In one embodiment, the invention provides the anhydrous tosylate salt of Compound A, for use in therapy. In another embodiment, the invention provides Compound A - Form 1 for use in therapy.

[0018] In a further aspect, this invention provides a method of treating or preventing infection with HIV comprising administering to a subject in need thereof, a therapeutically effective amount of a tosylate salt of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1-dioxidothiomorpholino) ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8, 11 , 11 a, 11b, 12, 13,13a, 13b-octadecahydro-1 H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 - carboxylic acid. In one embodiment, the invention provides a method of treating or preventing infection with HIV comprising administering to a subject in need thereof, a therapeutically effective amount of the anhydrous tosylate salt of Compound A. In one embodiment, the invention provides a method of treating or preventing infection with HIV comprising administering to a subject in need thereof, a therapeutically effective amount of Compound A - Form 1. In one embodiment, the invention provides a method of treating or preventing infection with HIV comprising administering to a subject in need thereof, a pharmaceutically acceptable composition comprising a therapeutically effective amount of Compound A - Form 1 . In yet a further embodiment, this invention provides a method of treating or preventing infection with HIV comprising administering to a subject in need thereof, a therapeutically effective amount of Compound A - Form 1 and one or more additional therapeutic agents.

[0019] In one embodiment, the invention provides the use of Compound A - Form 1 for the prophylactic or therapeutic treatment of infection with HIV. In another embodiment, this invention provides the use of Compound A - Form 1 to treat infection with HIV.

[0020] Other aspects and advantages of the present invention are described further in the following detailed description of the embodiments thereof.

[0021] Brief Description of the Figures

[0022] FIG. 1 depicts a X-Ray Powder Diffraction pattern (XRPD) of a crystalline form of the anhydrous tosylate salt of Compound A, specifically Compound A - Form 1.

[0023] FIG. 2 depicts Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) curves of a crystalline form of the anhydrous tosylate salt of Compound A, specifically Compound A - Form 1.

[0024] FIG. 3 depicts the characterization scans of a crystalline form of the hydrated sulfate salt of Compound A. FIG. 3A depicts an X-Ray Powder Diffraction pattern of the crystalline form of the hydrated sulfate salt form of Compound A. FIG. 3B depicts the Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) curves of the crystalline form of the hydrated sulfate salt of Compound A. FIG. 4 depicts the characterization scans of a crystalline form of a hydrate of Compound A. FIG. 4A depicts an X-Ray Powder Diffraction pattern of the crystalline form of a hydrate of Compound A. FIG. 4B depicts the Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA) curves of the crystalline form of a hydrate of Compound A.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] “Compounds of the invention” means a tosylate salt of (S)-1-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1- dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2, 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 11 , 11a, 11 b, 12, 13,13a,13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid (“the tosylate salt of Compound A”); the anhydrous tosylate salt of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

[0027] ((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1-dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11 ,11a,- 11 b, 12, 13, 13a, 13b-octadecahydro- 1 H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 - carboxylic acid (“the anhydrous tosylate salt of Compound A”); and in some embodiments, specifically, the crystalline form of the anhydrous tosylate salt of (S)- 1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR,11aS,11bR, 13aR,13bR)-3a- ((2-(1 ,1-dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2, 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 11 , 11a, 11 b, 12, 13,13a,13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid (“Compound A - Form 1”).

[0028] As used herein, the terms X-ray powder diffraction (XRPD) and Powder X-ray diffraction (PXRD) are used interchangeably to mean a technique to analyze the crystal structure and phase of solids.

[0029] In one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least nine diffraction angles, when measured using Cu Karadiation, selected from a group consisting of about: 5.2±0.3, 5.7±0.3, 9.0±0.3, 9.3±0.3, 10.2±0.3, 10.7±0.3, 10.8±0.3, 11.0±0.3, 11.2±0.3, 11.4±0.3, 12.5±0.3, 12.6±0.3, 13.2±0.3, 13.5±0.3, 13.8±0.3, 14.4±0.3, 15.0±0.3, 15.2±0.3, 15.7±0.3, 16.0±0.3, 16.5±0.3, 16.8±0.3, 17.2±0.3, 17.4±0.3, 17.7±0.3, 18.0±0.3, 18.7±0.3, 19.1±0.3, 19.9±0.3, 20.4±0.3, 20.9±0.3, 21.3±0.3, 21.6±0.3, 22.0±0.3, 22.4±0.3, 22.6±0.3, 22.9±0.3, 23.3±0.3, 23.6±0.3, 24.2±0.3, 24.7±0.3, 25.1±0.3, 25.5±0.3, 26.2±0.3, 26.9±0.3, 27.7±0.3, 28.0±0.3, 28.3±0.3, 28.9±0.3, 29.3±0.3, 29.6±0.3, 31.1±0.3, 32.0±0.3, 32.3±0.3, 33.6±0.3, 33.8±0.3, 34.7±0.3, 36.2±0.3, 37.1±0.3, 38.3±0.3, and 38.9±0.3 degrees 20.

[0030] In other embodiments, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least eight diffraction angles or at least seven diffraction angles or at least six diffraction angles or at least five diffraction angles or at least four diffraction angles, when measured using Cu Ka radiation, selected from a group consisting of about: 5.2±0.3, 5.7±0.3, 9.0±0.3, 9.3±0.3, 10.2±0.3, 10.7±0.3, 10.8±0.3, 11.0±0.3, 11.2±0.3, 11.4±0.3, 12.5±0.3, 12.6±0.3, 13.2±0.3, 13.5±0.3, 13.8±0.3, 14.4±0.3, 15.0±0.3, 15.2±0.3, 15.7±0.3, 16.0±0.3, 16.5±0.3, 16.8±0.3, 17.2±0.3, 17.4±0.3, 17.7±0.3, 18.0±0.3, 18.7±0.3, 19.1±0.3, 19.9±0.3, 20.4±0.3, 20.9±0.3, 21.3±0.3, 21.6±0.3, 22.0±0.3, 22.4±0.3, 22.6±0.3, 22.9±0.3, 23.3±0.3, 23.6±0.3, 24.2±0.3, 24.7±0.3, 25.1±0.3, 25.5±0.3, 26.2±0.3, 26.9±0.3, 27.7±0.3, 28.0±0.3, 28.3±0.3, 28.9±0.3, 29.3±0.3, 29.6±0.3, 31.1±0.3, 32.0±0.3, 32.3±0.3, 33.6±0.3, 33.8±0.3, 34.7±0.3, 36.2±0.3, 37.1±0.3, 38.3±0.3, and 38.9±0.3 degrees 20.

[0031] In one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu Karadiation, selected from a group consisting of about: 5.2±0.3, 5.7±0.3, 9.0±0.3, 9.3±0.3, 10.2±0.3, 10.7±0.3, 10.8±0.3, 11.0±0.3, 11.2±0.3, 11.4±0.3, 12.5±0.3, 12.6±0.3, 13.2±0.3, 13.5±0.3, 13.8±0.3, 14.4±0.3, 15.0±0.3, 15.2±0.3, 15.7±0.3, 16.0±0.3, 16.5±0.3, 16.8±0.3, 17.2±0.3, 17.4±0.3, 17.7±0.3, 18.0±0.3, 18.7±0.3, 19.1±0.3, 19.9±0.3, 20.4±0.3, 20.9±0.3, 21.3±0.3, 21.6±0.3, 22.0±0.3, 22.4±0.3, 22.6±0.3, 22.9±0.3, 23.3±0.3, 23.6±0.3, 24.2±0.3, 24.7±0.3, 25.1±0.3, 25.5±0.3, 26.2±0.3, 26.9±0.3, 27.7±0.3, 28.0±0.3, 28.3±0.3, 28.9±0.3, 29.3±0.3, 29.6±0.3, 31.1±0.3, 32.0±0.3, 32.3±0.3, 33.6±0.3, 33.8±0.3, 34.7±0.3, 36.2±0.3, 37.1±0.3, 38.3±0.3, and 38.9±0.3 degrees 20.

[0032] In one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu Ka radiation, selected from a group consisting of about: 5.2, 5.7, 9.0, 9.3, 10.2, 10.7, 10.8, 11.0, 11.2, 11.4, 12.5, 12.6, 13.2, 13.5, 13.8, 14.4, 15.0, 15.2, 15.7, 16.0, 16.5, 16.8,

[0033] 17.2, 17.4, 17.7, 18.0, 18.7, 19.1 , 19.9, 20.4, 20.9, 21.3, 21.6, 22.0, 22.4, 22.6, 22.9, 23.3,

[0034] 23.6, 24.2, 24.7, 25.1 , 25.5, 26.2, 26.9, 27.7, 28.0, 28.3, 28.9, 29.3, 29.6, 31.1 , 32.0, 32.3,

[0035] 33.6, 33.8, 34.7, 36.2, 37.1 , 38.3, and 38.9 degrees 20.

[0036] In one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu Karadiation, selected from a group consisting of about: 5.2±0.3, 9.0±0.3, 14.4±0.3, 18.7±0.3 and 19.9±0.3 degrees 20.

[0037] In one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu Karadiation, selected from a group consisting of about: 5.2, 9.0, 14.4, 18.7 and 19.9 degrees 20.

[0038] In one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu Ka radiation, of about: 5.2±0.3, 9.0±0.3, 14.4±0.3, 18.7±0.3 and 19.9±0.3 degrees 20.

[0039] In further embodiments, Compound A - Form 1 is characterized by a differential scanning calorimetry trace substantially in accordance with FIG. 2. A person skilled in the art would recognize that the onset temperature of the endotherm may vary depending on the experimental conditions.

[0040] In one embodiment, the temperature at which the crystalline Compound A - Form 1 , begins to melt is determined by differential scanning calorimetry (“DSC”) and is referred to as the “melting onset temperature”. In another embodiment, the melting onset temperature of crystalline Compound A - Form 1 , is 224.39 °C followed by a single exotherm with an onset temperature of about 227.7 °C. In another embodiment, the melting onset temperature of crystalline Compound A - Form 1 is a temperature range from about 211 °C to about 230 °C. In another embodiment, the melting onset temperature of crystalline Compound - A Form 1 is selected from (about 211 , 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229 and about 230 °C. In another embodiment, the melting onset temperature of crystalline Compound A - Form 1 is 224.4± 5 °C.

[0041] In still further embodiments, as a person having ordinary skill in the art will understand, Compound A - Form 1 is characterized by any combination of the analytical date characterizing the aforementioned embodiments. For example, in one embodiment, Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1 and a differential scanning calorimetry trace substantially in accordance with FIG. 2.

[0042] In one embodiment, crystalline Compound A - Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu Ka radiation, of about: 5.2±0.3, 9.0±0.3, 14.4±0.3, 18.7±0.3 and 19.9±0.3 degrees 20 and a differential scanning calorimetry trace substantially in accordance with FIG. 2.

[0043] An XRPD pattern will be understood to comprise a diffraction angle (expressed in degrees 20) of “about” a value specified herein when the XRPD pattern comprises a diffraction angle within ± 0.3 degrees 20 of the specified value. Further, it is well known and understood to those skilled in the art that the apparatus employed, humidity, temperature, orientation of the powder crystals, and other parameters involved in obtaining an X-ray powder diffraction (XRPD) pattern may cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern. An X-ray powder diffraction pattern that is “substantially in accordance” with that of FIG. 1 provided herein, is an XRPD pattern that would be considered by one skilled in the art to represent a compound possessing the same crystal form as the compound that provided the XRPD pattern of FIG. 1 . That is, the XRPD pattern may be identical to that of FIG. 1 , or more likely it may be somewhat different. Such an XRPD pattern may not necessarily show each of the lines of any one of the diffraction patterns presented herein, and / or may show a slight change in appearance, intensity, or a shift in position of said lines resulting from differences in the conditions involved in obtaining the data. A person skilled in the art is capable of determining if a sample of a crystalline compound has the same form as, or a different form from, a form disclosed herein by comparison of their XRPD patterns. For example, one skilled in the art can overlay an XRPD pattern of a sample of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

[0044] ((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1-dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11 ,11a,- 11 b, 12, 13, 13a, 13b-octadecahydro-1 H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene- 1 - carboxylic acid, tosylate salt, anhydrate with FIG. 1 and, using expertise and knowledge in the art, readily determine whether the XRPD pattern of the sample is substantially in accordance with the XRPD pattern of Compound A - Form 1 . If the XRPD pattern is substantially in accordance with FIG. 1 , the sample form can be readily and accurately identified as having the same form as Compound A - Form 1.

[0045] The instant invention also includes isotopically-labelled salts and forms, which are identical to those recited in the tosylate salt of Compound A, the anhydrous tosylate salt of Compound A, and Compound A - Form 1 , but for the fact that one or more atoms are replaced by an atom having 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 compounds of the invention and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as2H,3H,11C,13C,14C,15N,17O,180,31P,32P,35S,18F,36CI,123l and125l.

[0046] Compounds of the present invention containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. I sotopically- labelled compounds of the present invention, for example those into which radioactive isotopes such as3H,14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability.11C and18F isotopes are particularly useful in PET (positron emission tomography), and125l isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of this invention can generally be prepared by carrying out the procedures disclosed in the Examples below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

[0047] In one aspect, the invention provides a method of making a crystalline anhydrous tosylate of Compound A comprising the steps of:

[0048] (i) dissolving the free base form in a first solvent;

[0049] (iii) crystallizing the crystalline Form I.

[0050] Suitably, the first solvent is a combination of methanol and ethyl acetate. Suitably, the second solvent is n-heptane. Suitably, the reaction mixture is aged for 3 hours at 50 °C, n-heptane added over 9 hours and aged another 2 hours at 50 °C and then cooled to 20 °C over 3 hours, and then held at 20 °C for 6 hours, after which the solid is isolated by filtration, and then washed with methanokethyl acetate: n-heptane in a 1 :2:4 volume ratio. Suitably, the resulting solid is crystalline.

[0051] The invention includes a therapeutic method for treating or preventing infection with HIV in a subject in need thereof comprising administering to a subject in need thereof an antiviral effective amount of a compound of the invention or a composition comprising an effective amount of a compound of the invention and an optional pharmaceutically acceptable carrier.

[0052] In one aspect, this invention relates to a compound of the invention for use in the treatment of infection with HIV. In another aspect, the invention includes the use of a compound of the invention in the manufacture of a medicament for use in the treatment or prevention of HIV infection. In one embodiment, the invention includes the use of a compound of the invention in the manufacture of a medicament for use in the treatment of HIV infection.

[0053] In another aspect, the invention includes the use of a compound of the invention in therapy. The invention further includes the use of a compound of the invention as an active therapeutic substance in treating infection with HIV.

[0054] As used herein, "HIV" or "Human Immunodeficiency Virus" refers to HIV-1 and / or HIV-2.

[0055] As used herein, the terms “subject” or “patient” are used interchangeably to mean a human.

[0056] As used herein, the terms “treatment of infection with HIV” and "treatment of HIV infection" are used interchangeably to mean the treatment of a subject being infected with HIV.

[0057] The term "treatment of HIV associated diseases" relates to the treatment of diseases associated with HIV infection, for example AIDS, or other conditions associated with HIV infection including thrombocytopenia, Kaposi's sarcoma and infection of the central nervous system characterized by progressive demyelination, resulting in dementia and symptoms such as, progressive dysarthria, ataxia and disorientation, and further conditions where HIV infection has also been associated with, such as peripheral neuropathy, progressive generalized lymphadenopathy (PGL), and AIDS-related complex (ARC).

[0058] It will be understood that treatment refers to a means by which the viral load of HIV (represented as the number of copies of viral RNA in a specified volume of serum) is reduced. The more effective the treatment, the lower the viral load. In one embodiment, the viral load should be reduced to as low levels as possible, e.g., below about 200 copies / ml, in particular below about 100 copies / ml, more in particular below 50 copies / ml, if possible, below the detection limit of the virus. Reductions of viral load of one, two or even three orders of magnitude are an indication of the effectiveness of the treatment. Another parameter to measure effectiveness of anti-HIV treatment is the CD4 count, which in normal adults ranges from 500 to 1500 cells per pl. Lowered CD4 counts are an indication of HIV infection and once below about 200 cells per pl, AIDS may develop. An increase of CD4 count, e.g., with about 50, 100, 200 or more cells per pl, is also an indication of the effectiveness of anti-HIV treatment. The CD4 count in particular should be increased to a level above about 200 cells per pl, or above about 350 cells per pl. Viral load or CD4 count, or both, can be used to diagnose the degree of HIV infection.

[0059] The term "prevention of HIV infection" relates to the prevention or avoidance of a subject becoming infected with HIV. The source of infection can be various, a material containing HIV, in particular a body fluid that contains HIV such as blood or sperm, or another subject who is infected with HIV. Prevention of HIV infection relates to the prevention of the transmission of the virus from the material containing HIV or from the HIV infected individual to an uninfected person or relates to the prevention of the virus from entering the body from an uninfected person. Transmission of the HIV virus can be by any known cause of HIV transfer such as by sexual transmission or by contact with blood of an infected subject, e.g., medical staff providing care to infected subjects. Transfer of HIV can also occur by contact with HIV infected blood, e.g., when handling blood samples or with blood transfusion. It can also be by contact with infected cells, e.g., when carrying out laboratory experiments with HIV infected cells.

[0060] In another aspect, the present invention discloses methods of preventing HIV infection in a patient or reducing the risk of infection, comprising administering a pharmaceutical composition of the invention. “Pre-exposure prophylaxis” (or PrEP) is when people at risk for HIV infection take HIV antiretroviral medicine to lower their chances of acquiring HIV infection. PrEP has been shown to be effective in reducing the risk of infection. In one embodiment, the invention provides a pharmaceutical composition comprising Compound A - Form 1 and one or more pharmaceutically acceptable excipients, for PrEP of HIV infection.

[0061] The terms "effective treatment of HIV" and similar terms refer to that treatment that lowers the viral load, or increases CD4 count, or both, as described above. The terms "effective prevention of HIV" and similar terms refer to that situation where there is a decrease in the relative number of newly infected subjects in a population in contact with a source of HIV infection such as a material containing HIV, or a HIV infected subject. Effective prevention can be measured, for example, by measuring in a mixed population of HIV infected and non-infected individuals, if there is a decrease of the relative number of newly infected individuals, when comparing non-infected individuals treated with a pharmaceutical composition of the invention, and non-treated non-infected individuals. This decrease can be measured by statistical analysis of the numbers of infected and non-infected individuals in a given population over time.

[0062] As used herein, the terms "effective amount" and “antiviral effective amount” means any amount of a drug or pharmaceutical agent, as described herein, that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Further, as compared to a corresponding subject who has not received such amount of the drug or pharmaceutical agent, as described herein, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a compound of the invention, as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition. Suitably, an effective amount can be the amount of the compound of the invention that result in efficacious blood plasma levels. As used herein, “efficacious blood plasma levels” is meant those blood plasma levels of the compound of the invention that provide effective treatment or effective prevention of HIV infection.

[0063] As used herein, the term “pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from pharmaceutically acceptable counterions. Suitable salts include those described in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002.

[0064] Administration methods include administering an effective amount of a compound or composition of the invention at different times during the course of therapy or concurrently in a combination form. The methods of the invention include all known therapeutic treatment regimens.

[0065] Because the compounds of this invention are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the purer forms used in the pharmaceutical compositions.

[0066] It is understood that samples of the compounds of the invention may contain as a weight percentage small quantities of other molecules, including small quantities of stereoisomers of the tosylate salt of Compound A, the anhydrous tosylate salt of Compound A or Compound A - Form 1. In certain embodiments, this invention relates to a pharmaceutical composition comprising the tosylate salt of Compound A. In certain embodiments, this invention relates to a pharmaceutical composition comprising the anhydrous tosylate salt of Compound A. In another embodiment, this invention relates to a pharmaceutical composition comprising the the anhydrous tosylate salt of Compound A wherein at least 10 % by weight of the the anhydrous tosylate salt of Compound A is present as Compound A - Form 1. In another embodiment, this invention relates to a pharmaceutical composition comprising the the anhydrous tosylate salt of Compound A wherein at least 20 % by weight, or at least 30 % by weight, or at least 40 % by weight, or at least 50 % by weight, or at least 60 % by weight, or at least 70 % by weight, or at least 80 % by weight, or at least 90 % by weight of the the anhydrous tosylate salt of Compound A is present as Compound A - Form 1. In another embodiment, this invention relates to a pharmaceutical composition comprising the the anhydrous tosylate salt of Compound A wherein at least 95 % by weight, or at least 96 % by weight, or at least 97 % by weight, or at least 98 % by weight, or at least 99 % by weight, or at least 99.5 % by weight, or at least 99.8 % by weight, or at least 99.9 % by weight of the the anhydrous tosylate salt of Compound A is present as Compound A - Form 1.

[0067] Suitably, pharmaceutical compositions of this invention may be applied in the longterm treatment or the long-term prevention of HIV infection, or in other words they may be used in the treatment of HIV infection, or in the prevention of HIV infection, during a prolonged period of time. The compositions of the invention are effective in anti-HIV therapy or in the prevention of HIV infection for a prolonged period of time, for example for at least about one week or longer, or for about 1 month or longer. Suitably, a prolonged period of time for treating HIV infection may be in the range of one week up to one year or up to two years, or longer, such as five or ten years. In particular in the case of treatment of HIV infection, such terms will be long, in the order of one to several years. Such terms may also be relatively short, in particular in the case of prevention. Shorter terms are those of several days, e.g., 7, 10 or 12 days, or several weeks, e.g., 2, 3 or 4 weeks, or one month, or several months, e.g., 2, 3, 4, 5 or six months or even longer, e.g., 7, 8, 9 or 12 months.

[0068] The compounds of the invention will normally, but not necessarily, be formulated into pharmaceutical compositions prior to administration to a patient. Accordingly, in one aspect, the invention is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically-acceptable excipients.

[0069] As used herein, "pharmaceutically-acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle involved in giving form or consistency to the pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically-acceptable.

[0070] A compound of the invention and the pharmaceutically-acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. For example, dosage forms include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, including by intramuscular injection, subcutaneous injection, intravenously, intrasternal injection or infusion technique such as sterile solutions, suspensions, or powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as dry powders, aerosols, suspensions, and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels. One or more adjuvants may also be included.

[0071] Suitable pharmaceutically-acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically-acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their ability to facilitate the carrying or transporting of the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically-acceptable excipients may be chosen for their ability to enhance patient compliance.

[0072] Suitable pharmaceutically-acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anticaking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that 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 formulation and what other ingredients are present in the formulation. Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically-acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically-acceptable excipients and may be useful in selecting suitable pharmaceutically-acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

[0073] The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).

[0074] In one aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule. Suitable pharmaceutically acceptable excipients for oral administration of a compound of the invention, include a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g., corn starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g., microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g., corn starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g., microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmellose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

[0075] In one embodiment, the invention provides a pharmaceutical composition comprising the tosylate salt of Compound A and one or more pharmaceutically acceptable excipients, which composition is administered as an oral dosage form. In one embodiment, the oral dosage form is a tablet. In another embodiment, the oral dosage form is a capsule.

[0076] In another embodiment, the invention provides a pharmaceutical composition comprising the anhydrous tosylate salt of Compound A and one or more pharmaceutically acceptable excipients, which composition is administered as an oral dosage form. In one embodiment, the oral dosage form is a tablet. In another embodiment, the oral dosage form is a capsule. In another embodiment, the invention provides a pharmaceutical composition comprising Compound A - Form 1 and one or more pharmaceutically acceptable excipients, which composition is administered as an oral dosage form. In one embodiment, the oral dosage form is a tablet. In another embodiment, the oral dosage form is a capsule.

[0077] In another aspect, the invention is directed to a dosage form adapted for administration to a subject parenterally including subcutaneous, intramuscular, intravenous or intradermal. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

[0078] In one embodiment, the invention provides a pharmaceutical composition comprising the tosylate salt of Compound A and one or more pharmaceutically acceptable excipients, which composition is adapted to being administered as an injectable dosage form. In one embodiment, the injectable dosage form is adapted to being administered subcutaneously. In one embodiment, the injectable dosage form is adapted to being administered intramuscularly.

[0079] In one embodiment, the invention provides a pharmaceutical composition comprising the anhydrous tosylate salt of Compound A and one or more pharmaceutically acceptable excipients, which composition is adapted to being administered as an injectable dosage form. In one embodiment, the injectable dosage form is adapted to being administered subcutaneously. In one embodiment, the injectable dosage form is adapted to being administered intramuscularly.

[0080] In one embodiment, the invention provides a pharmaceutical composition comprising Compound A - Form 1 and one or more pharmaceutically acceptable excipients, which composition is adapted to being administered as an injectable dosage form. In one embodiment, the injectable dosage form is adapted to being administered subcutaneously. In one embodiment, the injectable dosage form is adapted to being administered intramuscularly. In one embodiment, the injectable dosage form comprising a compound of the invention is adapted to being administered in the long-term treatment of HIV infection. In one embodiment, the injectable dosage form comprising a compound of the invention is adapted to being administered in the long-term prevention of HIV infection.

[0081] Administration methods include administering an effective amount of a compound or composition of the invention at different times during the course of therapy or concurrently in a combination form. The methods of the invention include all known therapeutic treatment regimens.

[0082] The compounds and compositions of the present invention can be combined with other compounds and compositions having related utilities to prevent and treat the condition or disease of interest, such as infection with HIV. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of infection with HIV. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects. In certain embodiments, a compound or composition provided herein is administered in combination with one or more additional therapeutically active agents that improve its bioavailability, reduce and / or modify its metabolism, inhibit its excretion, and / or modify its distribution within the body.

[0083] Combination therapy includes co-administration of a compound of the invention and said other agent, sequential administration of a compound of the invention and the other agent, administration of a composition containing a compound of the invention and the other agent, or simultaneous administration of separate compositions containing a compound of the invention and the other agent.

[0084] Exemplary additional therapeutically active agents include, but are not limited to, at least one other agent used for treatment of AIDS or HIV infection selected from the group consisting of nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, HIV capsid inhibitors and HIV integrase inhibitors.

[0085] In one embodiment, the invention provides a pharmaceutical composition comprising the tosylate salt of Compound A and one or more other therapeutic agents. In one embodiment, the invention provides a pharmaceutical composition comprising the anhydrous tosylate salt Compound A and one or more other therapeutic agents. In one embodiment, the invention provides a pharmaceutical composition comprising Compound A - Form 1 and one or more other therapeutic agents. Suitable other agents are selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK4004280, GSK4011499, indinavir, islatravir, lamivudine, lopinavir, lenacapavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S- 648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.

[0086] In one aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, for example, the tosylate salt of Compound A, or the anhydrous tosylate salt of Compound A or Compound A - Form 1 , and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK4004280, GSK4011499, indinavir, islatravir, lamivudine, lopinavir, lenacapavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.

[0087] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK4004280, GSK4011499, indinavir, islatravir, lamivudine, lopinavir, lenacapavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.

[0088] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK4004280, GSK4011499, indinavir, islatravir, lamivudine, lenacapavir, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598. In another embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, darunavir, delavirdine, didanosine, dideoxyinosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, etavirine, fosamprenavir, fostemsavir, GSK3640254, GSK4004280, GSK4011499, indinavir, islatravir, lamivudine, lenacapavir, lopinavir, maraviroc, N6LS, nelfinavir, nevirapine, raltegravir, rilpiverine, ritonavir, S-648414, saquinavir, stavudine, tipranavir, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, zalcitabine, zidovudine, and S-365598.

[0089] Suitably, the other therapeutic agent is selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, lenacapavir, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, GSK4004280, GSK4011499, N6LS, and S-365598.

[0090] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, lenacapavir, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, GSK4004280, GSK4011499, N6LS, and S-365598.

[0091] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, lenacapavir, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, GSK4004280, GSK4011499, N6LS, and S-365598.

[0092] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, lenacapavir, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, GSK4004280, GSK4011499, N6LS, and S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of abacavir, atazanavir, bictegravir, cabotegravir, dolutegravir, fostemsavir, lamivudine, lenacapavir, maraviroc, rilpiverine, tenofovir disoproxil, tenofovir, tenofovir afenamide, islatravir, doravirine, preziata, S-648414, GSK3640254, GSK4004280, GSK4011499, N6LS, and S- 365598.

[0093] Suitably, the other agent is selected from the group consisting of, dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK4000422 / VH4000422, GSK4004280, GSK4011499, and S-365598.

[0094] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK4000422 / VH4000422, GSK4004280, GSK4011499, and S-365598.

[0095] In one embodiment, the invention provides a pharmaceutical composition comprising the tosylate salt of Compound A and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK4000422 / VH4000422, GSK4004280, GSK4011499, and S-365598.

[0096] In one embodiment, the invention provides a pharmaceutical composition comprising the anhydrous tosylate salt of Compound A and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK4000422 / VH4000422, GSK4004280, GSK4011499, and S-365598.

[0097] In one embodiment, the invention provides a pharmaceutical composition comprising Compound A - Form 1 and another therapeutic agent selected from the group consisting of dolutegravir, lamivudine, fostemsavir, cabotegravir, N6LS, GSK4000422 / VH4000422, GSK4004280, GSK4011499, and S-365598.

[0098] Suitably, the other agent is selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0099] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir. In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0100] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0101] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, islatravir, lamivudine, fostemsavir, S-365598, and cabotegravir.

[0102] Suitably, the other agent is selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0103] In one embodiment, the invention provides a pharmaceutical composition comprising compound of the invention and another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0104] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0105] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0106] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent selected from the group consisting of dolutegravir, bictegravir, S-365598, and cabotegravir.

[0107] In one embodiment, the other agent is dolutegravir. In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent is which is dolutegravir.

[0108] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is dolutegravir.

[0109] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is dolutegravir.

[0110] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent is which is dolutegravir.

[0111] In one embodiment, the other agent is cabotegravir.

[0112] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent which is cabotegravir.

[0113] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is cabotegravir.

[0114] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is cabotegravir.

[0115] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent is which is cabotegravir.

[0116] In one embodiment, the other agent is S-365598.

[0117] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent which is S-365598.

[0118] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is S-365598. In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is S-365598.

[0119] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent is which is S-365598.

[0120] In one embodiment, the other agent is a capsid inhibitor. In one embodiment, the capsid inhibitor is selected from lenacapavir, GSK4004280 or GSK4011499.

[0121] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another therapeutic agent which is selected from lenacapavir, GSK4004280 or GSK4011499.

[0122] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is selected from lenacapavir, GSK4004280 or GSK4011499.

[0123] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of the anhydrous tosylate salt of Compound A, and a therapeutically effective amount of another therapeutic agent is which is selected from lenacapavir, GSK4004280 or GSK4011499.

[0124] In one embodiment, the invention provides a pharmaceutical composition comprising therapeutically effective amount of Compound A - Form 1, and a therapeutically effective amount of another therapeutic agent is selected from lenacapavir, GSK4004280 or GSK4011499.

[0125] It will be understood that GSK3640254 is a compound as described in Dicker I, Jeffrey JL, Protack T, et al.; GSK3640254 Is a Novel HIV-1 Maturation Inhibitor with an Optimized Virology Profile’ Antimicrob Agents Chemother. 2022;66(1):e0187621. doi:10.1128 / AAC.01876-21 ; N6LS: also known as VRC-HIVMAB091-00-AB, is a human monoclonal antibody and the compound of clinical trial NCT03538626; S-365598: is a third- generation HIV integrase strand-transfer inhibitor (INSTI) discovered by Shionogi; GSK4004280 and GSK4011499: are capsid inhibitors and the compounds in clinical trial 218307; and S-648414 is the compound of clinical trial NCT04147715. The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein a therapeutically effective amount of a compound of the invention can be extracted and then given to the patient such as with powders or syrups. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form wherein each physically discrete unit contains a therapeutically effective amount of a compound of the invention. When prepared in unit dosage form, the pharmaceutical compositions of the invention typically contain from 1 mg to 1000 mg. Therefore, in one aspect, the invention provides a pharmaceutical composition comprising 1-1000 mg of a compound of the invention.

[0126] The pharmaceutical compositions of the invention typically contain a compound of the invention. However, the pharmaceutical compositions of the invention may optionally further comprise one or more additional pharmaceutically active compounds as described above.

[0127] When identifying a developable salt or crystalline form of a compound for pharmaceutical use, properties such as biopharmaceutics, physical and / or solid state properties, including solid state stability and manufacturability are considered. Generally, there are risks involved with developing solvates and hydrates. One of skill in the art would understand that it is difficult to control the drying of a solvated or hydrated compound during manufacturing, in particular, to avoid over drying, i.e. , controlling the level of the solvent or water at the end point of drying. Also, when developing a solvate or hydrate, on storage, there is a risk of desolvation or dehydration, which is a stability risk potentially leading to a shorter shelf life).

[0128] EXAMPLES

[0129] The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention. Unless otherwise noted, reagents are commercially available or are prepared according to procedures in the literature. The symbols and conventions used in the descriptions of processes, schemes, and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. The naming program used was ChemBioDraw® Ultra 12.0.

[0130] All temperatures are given in degrees Celsius; all solvents are highest available purity and all reactions run under anhydrous conditions in an argon (Ar) or nitrogen (N2) atmosphere where necessary.

[0131] As used herein, “PLM” refers to Polarized-light Microscopy. The photomicrographs were collected using Olympus BX60 polarized-light microscope equipped with Olympus DP70 camera.

[0132] As used herein, “XRPD” refers to “X-Ray Powder Diffraction” and may be measured by the skilled person using methods known in the art, for example, an X-ray diffractometer such as a Bruker D8 advance X-Ray Diffractometer using Cu (40 kV / 40 mA) radiation, K- Alpha 1 (A of 1.54060 A); scan step size of 0.02 °20 ; a LynxEye Detector = (1 D mode), PSD opening: 2.9, Coupled 20 / 0; Scan range / scope = 2.0 to 40.0 degrees 20; Scan mode: Continuous PSD fast; Measurement time: not less than 10 minutes; Step size: 0.02 degrees; Time per step: 0.325 seconds. Incident beam optics: fixed incident beam optics, primary soller slit: 2.5 degrees, secondary soller slit: 2.5 degrees, divergence slit: 0.60 mm; slit: fixed.

[0133] As used herein, “Differential Scanning Calorimetry” (DSC) refers to a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference is measured as a function of temperature. The skilled person is aware of the methods and instruments to conduct such measurements, for example a TA Instruments Q 20 differential scanning calorimeter with a heating range of 30 °C to 300 °C at a ramp (heating) rate of 10 °C / minute. 1.51 mg of samples were transferred into an aluminium Tzero DSC pan, and covered the Tzero lid, then placed it into a mould and sealed by a crimper. An empty Tzero DSC pan was used as a reference.

[0134] Analytical HPLC was run using an Agilent system, Shimadzu / Sciex LCMS with variable wavelength UV detection using reverse phase chromatography with a CH3CN and water gradient with a 0.02 or 0.1% TFA modifier (added to each solvent). LC-MS was determined using either a PE Sciex Single Quadrupole 150EX LC-MS, or Waters ZQ Single Quadrupole LC-MS or Agilent 1200 series SL (detectors: Agilent 6140 single quadrupole and Agilent 1200 MWD SL) instruments. The compound is analyzed using a reverse phase column, e.g., Thermo Hypersil Gold C18, eluted using a gradient of CH3CN and water with a low percentage of an acid modifier such as 0.02% TFA or 0.1 % formic acid or a base modifier such as 5mM ammonium bicarbonate (adjusted to pH 10 with aqueous ammonia). When specified “acid method” refers to 0.1 % formic acid in water and CH3CN gradient (1.8 min. 0.9 mL / min flow) with a Waters Acquity UPLC HSS C18; 1.8 .; 2.1x50mm at 50 °C; “basic method” refers to 95:5 H2O+0.1% NH OHLCHsCN (pH = 9.4) and water gradient (1.8 min. 0.9 mL / min flow) with a Waters Acquity LIPLC BEH C18; 1.7 .; 2.1x50mm at 50 °C and “overnight basic method” refers to 95:5 H2O+0.1% NH4OH:CHsCN (pH = 9.4) and water gradient (16 min. 0.8 mL / min flow) with a Waters Acquity LIPLC BEH C18; 1.7 .; 2.1x50mm at 50 °C.

[0135] Compound A, (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-

[0136] ((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1-dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-

[0137] 2, 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 11 , 11a, 11 b, 12 ,13,13a,13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid, can be prepared in accordance with Example 25 on page 164, of WO 2017 / 134596.

[0138] Table of Abbreviations

[0139] Example 1

[0140] Preparation of Compound A - Form 1 Seed

[0141] Aqueous 3M tosic acid (403 pL) was added to (S)-1-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1 - dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2, 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 11 , 11a, 11 b, 12,13,13a,13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid (1.0 g) and MEK (5.72 mL) in a 50 mL round vessel equipped with a magnetic stirrer at room temperature. The reaction was stirred at room temperature to give a solution. The solution was concentrated under vacuum to give an amorphous solid. The amorphous solid was transferred to a 100 mL jacketed vessel equipped with overhead stirrer. MEK (8.57 mL) was added. The reaction was heated to 50 °C and stirred for 10 minutes to give a clear solution. TBME (42.86 mL) was added over 15 hours. The reaction was stirred for 4 hours at 50 °C, cooled to 20 °C over 3 hours, and stirred for 1 hour at 20 °C. The solid was isolated by filtration, dried under vacuum for 19 hours at 40 °C to give the title compound as a white crystalline solid (0.94 g, Karl Fisher: 0.65% w / w, Purity: 98.3%)

[0142] Example 2

[0143] Preparation of Crystalline (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4- ((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(1,1-dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12, 13,13a,13b-octadecahydro-1H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid, tosylate salt, anhydrate (Compound A - Form 1)

[0144] (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)- 3a-((2-(1 ,1-dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2- yl)-2,3,3a,4,5,5a,5b,6,7,7a,8, 11 , 11 a, 11 b, 12, 13, 13a, 13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid (20 kg) and tosylic acid monohydrate (4.6 kg) were dissolved in a solution of 1v:2v of methanokethyl acetate (95 kg) at 50 °C under nitrogen. n-Heptane (27 kg, 2 vol) was added. 0.5% w / w seeds (made according to the seed preparation described herein, 100 g) suspended in n-heptane (3 kg) was added followed by n-heptane rinse (2 kg). The resulting mixture was aged for 3 hours at 50 °C. n-Heptane (55.8 kg) was added over 9 hours. The reaction mixture was aged for 2 hours at 50 °C, cooled to 20 °C over 3 hours, then held for 6 hours at 20 °C. The solid was isolated by filtration, washed with a mixture of 1v:2v:3.375v methanokethyl acetatem- heptane (43 kg) followed by n-heptane (34 kg). The solid was dried under vacuum at 40-50 °C for 16-24 hours under nitrogen to give the title compound as a white crystalline solid (21.08 kg, 87% yield). The XRPD of this material is shown in FIG. 1 and the corresponding diffraction data is provided in Table 1.

[0145] Table 1:

[0146] FIG. 2 represents the DSC thermogram of Compound A - Form 1 - anhydrate made in Example 2. There is a melting onset of about 224.39 °C and a DSC peak of 227.7 °C. Example 3

[0147] Solubility measurement and chemical stability study of (S)-1-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((1R,3aS,5aR,5bR,7aR,11aS,-11bR,13aR,13bR)-3a-((2-(1,1- dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1 -(prop-1 -en-2-yl)- 2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid (free base)

[0148] Solubility of the free base compound was measured in different solvents at different temperatures by the gravimetric method and the results are shown Table 2. Table 2: Solubility study of free base in single solvents at different temperatures (by gravimetric method)

[0149] Chemical stability of the free base was studied in different solvent systems (as a solution of corresponding solvents) as shown in Table 3.

[0150] Table 3: Solution state chemical stability of free base

[0151] It was concluded that the compound degraded slightly in EtOAc and THF at 55°C for 24h. However, the compound was stable at 55°C in 2-MeTHF, MEK / EA, 2-MeTHF / EA, and THF / EtOAc for 24h.

[0152] Example 4

[0153] Solubility measurement and chemical stability study of Compound A - Form 1 Solubility of Compound A - Form 1 was measured in different solvents at different temperatures by the gravimetric method. The results are summarised in Table 4. Chemical stability of Compound A - Form 1 was studied in different solvent systems (as a solution of corresponding solvents) as shown in Table 5. Solid state stability of Compound A - Form 1 iwas tested at 55°C and 75°C, and the results are shown in Table 6.

[0154] Table 4: Solubility study of Compound A - Form 1 in single solvents at different temperatures

[0155] Data indicated that Compound A - Form 1 had low solubility in most of the solvents, moderate solubility in acetone and MEK, and high solubility in THF.

[0156] Table 5: Solution / chemical stability of Compound A- Form 1

[0157] It was concluded that Compound A - Form 1 was stable at 55°C in THF and THF / EtOAc for 24h, but it showed slight degradation in MEK and MEK / EA at 55°C for 24h. A drying stability study of Compound A - Form 1 was carried out. The solid was dried under vacuum at 55°C and 75°C in the oven, and XRPD and purity were tracked. The results are shown in Table 6. Table 6: Solid state stability of Compound A - Form 1 at 55°C and 75°C

[0158] It was concluded that Compound A - Form 1 was both chemically and physically (form) stable for 120h at 55°C but showed slight degradation during drying at 75°C.

[0159] Example 5

[0160] Version screening of free base

[0161] Salt screening studies involved screening 15 counterions in six solvents. In addition, crystallization experiments to find a developable crystalline parent were attempted in six solvents.

[0162] The free base has an acidic site (pKa = 2.5) and a basic site (pKa = 10.6) suitable for salt formation. 15 counterions were selected. One equivalent of counterion was dosed in all experiments.

[0163] The following six solvents were selected based on their ability to solubilize the free base and were utilized in the salt screening studies: acetone, MeCN, IPA, EtOAc, MIBK and 1,4-dioxane.

[0164] Modes of Crystallization

[0165] 1. The solutions / suspensions were stirred while cycling the temperature between 40°C and 5°C for up to three days

[0166] 2. The gums / amorphous suspensions were stirred while cycling the temperature between 50°C and 5°C for up to three days

[0167] 3. The solutions were cooled from 23°C to 4°C and hold at 4°C for up to three days

[0168] 4. Fast evaporation of solvents from experiments that did not yield crystalline product 5. Addition of cosolvent to amorphous suspensions, gums or oils at 50°C followed by cycling the temperature between 50°C and 5°C for up to three days

[0169] 6. Addition of antisolvents to solutions at 50°C followed by cooling from 50°C to 5°C and holding at 5°C for a day 7. Slow evaporation of solvents at RT for up to 10 days

[0170] All samples were examined by PLM to assess the crystallinity of the material. All crystalline samples were isolated by vacuum filtration. All crystalline hits isolated from the version screen were found to be hydrated or found to contain mixture of crystallization solvent and water. Of the hydrated hits analyzed, the sulfate salt was found to have suitable crystallinity, thermal properties and could be isolated from a variety of solvents. The results from the screening study are summarized in Table 7.

[0171] Table 7: Results from version screening experiments

[0172] Parent A represents a crystalline form of a hydrate of Compound A. The other boxes labelled “Parent” were unsuitable / unstable crystalline versions of Compound A. PC is poorly crystalline

[0173] Crystalline salt hits were isolated from six out of 16 counterions utilized: sulfate, phosphate, fumarate, citrate, sodium and potassium. In addition, crystalline parent forms were also observed. All crystalline hits isolated from the version screen were found to be hydrated or found to contain mixture of crystallization solvent and water. Of the hydrated hits analyzed, only the crystalline form of the hydrated sulfate salt of Compound A and the Parent A, crystalline form of a hydrate of Compound A were found to have suitable crystallinity, thermal properties and could be isolated from a variety of solvents.

[0174] Example 6

[0175] Preparation of a crystalline form of a hydrated sulfate salt of Compound A

[0176] Acetone (21 mL) was added to amorphous (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)- 4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1 -dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8, 11 a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8, 11 , 11 a, 11 b, 12,13,13a,13b-octadecahydro-1 H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1-carboxylic acid (349.1 mg). The partial suspension was heated to 50°C which led to a clear solution. To the solution, sulfuric acid (2.5M solution in water, 1 equivalent) was added along with seeds of sulfate salt which led to a cloudy solution. The cloudy solution was stirred at 50°C for three hours, cooled slowly (0.1°C / min) to 20°C and stirred at 20°C for -16 hours. The crystalline sulfate salt was isolated via vacuum filtration, air-dried for an hour and dried in a vacuum oven at 50°C for four hours. The yield of crystalline sulfate salt was -92% (360 mg).

[0177] The XRPD of this material is shown in FIG. 3A and the DSC / TGA traces of this material are shown in FIG. 3B. The DSC data shows a small dehydration endotherm between 29°C-61 °C followed by a melt at 216.2°C. TGA-IR analysis shows loss of ~1.5%wt. loss of water between 18°C-57°C (1 equivalent of water is 1.9%) indicating the sulfate salt is a hydrate. TGA data, which was obtained on the dried material, suggests the hydrated form of the sulfate salt is stable and can readily rehydrate at RT as the weight loss starts at the onset of the TGA run. PXRD pattern of freshly isolated sample and after drying at 50°C did not show any change in the crystal-form.

[0178] Example 7

[0179] Preparation of a crystalline form of a hydrate of Compound A (Parent A)

[0180] Acetone (18 mL) was added to the amorphous (S)-1-(((3-cyanopyridin-2- yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1 - dioxidothiomorpholino)ethyl) amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)- 2, 3, 3a, 4, 5, 5a, 5b, 6, 7, 7a, 8, 11 , 11 a, 11 b, 12, 13, 13a, 13b-octadecahydro-1 H- cyclopenta[a]chrysen-9-yl)cyclohex-3-ene-1 -carboxylic acid (302 mg). The partial suspension was heated to 50°C which led to a clear solution. To the clear solution, seeds of crystalline parent (~1mg) were added which led to slow precipitation of a white suspension. The suspension was stirred at 50°C for 3 hours, cooled slowly (0.1°C / min) to 20°C and stirred at 20°C for ~16 hours. The solids were isolated via vacuum filtration, air-dried for an hour and dried in a vacuum oven at 50°C for four hours. The weight of the product was 245 mg.

[0181] The XRPD of this material is shown in FIG. 4A and the DSC / TGA traces of this material are shown in FIG. 4B. The DSC data shows a broad dehydration endotherm between 29°C-87°C followed by a melt at 173.8°C. TGA-IR analysis shows loss of ~1.7%wt. loss of water between 30°C-42°C (1 equivalent of water is 2.1%) indicating that material is a hydrate. TGA data, which was obtained on the dried material, suggests the hydrated form of crystalline parent is stable and can readily rehydrate at RT as the weight loss starts at the onset of the TGA run. The PXRD pattern of freshly isolated sample and after drying at 50°C did not show any change in the crystal form; however, loss in crystallinity was observed for the dried sample.

[0182] Based upon the physical characteristics of Compound A - Form 1, i.e. , the crystalline anhydrous tosylate salt of Compound A, and the physical characteristics of the crystalline form of a hydrated sulfate salt of Compound A, the tosylate salt has preferred characteristics. The crystalline anhydrate of Compound A - Form 1 was identified as the most stable polymorphic form, which enables a simpler polymorphic landscape. There is <1% moisture sorption at 70% RH.

[0183] In contrast, the sulfate salt has the non-preferred characteristics of being a variable hydrate (this crystalline form was identified as the most stable form) which picks up water based on the humidity. A variable hydrate may create a complex polymorphic landscape wherein before achieving the stable solid-state form, there may be combinations of forms, which may be difficult to separate / isolate, creating a gum-like slurry instead of a crystalline product. This can be problematic given the scale of manufacturing an active for pharmaceutical use. In addition, the sulfate salt, crystalline variable hydrrate forms agglomerates of acicular primary particles which create unstable systems.

[0184] Further, the crystalline tosylate salt has favorable manufacturability characteristics; a wide range of available solvents with which to develop the crystallization process; evidence of low levels of amorphous formation at high energy micronization conditions. In contrast, the crystalline sulfate salt has poor manufacturability characteristics; limited choice for crystallisation solvent and control of particle; variation in solvent / water content observed for sulfate lab batches; difficult to micronize (blockage, poor flow, static, low yields); melt point suppression and an amorphous film observed during compaction experiments.

Claims

ClaimsWhat is claimed is:

1. A tosylate salt of (S)-1-(((3-cyanopyridin-2-yl)oxy)methyl)-4-((1 R,3aS,5aR,5bR,7aR, 11 aS, 11 bR, 13aR, 13bR)-3a-((2-(1 , 1-dioxidothiomorpholino) ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11 , 11 a, 11b, 12, 13,13a, 13b-octadecahydro- 1 H-cyclopenta[a]chrysen-9-yl)cyclohex-3-ene- 1 - carboxylic acid.

2. The tosylate salt according to claim 1 , wherein the tosylate salt is anhydrous.

3. A crystalline form of a tosylate salt according to claim 1 or claim 2 .

4. The crystalline form according to claim 3, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu Karadiation, selected from a group consisting of about 5.2±0.3, 5.7±0.3, 9.0±0.3, 9.3±0.3, 10.2±0.3, 10.7±0.3, 10.8±0.3, 11.0±0.3, 11.2±0.3, 11.4±0.3, 12.5±0.3, 12.6±0.3, 13.2±0.3, 13.5±0.3, 13.8±0.3, 14.4±0.3, 15.0±0.3, 15.2±0.3, 15.7±0.3, 16.0±0.3, 16.5±0.3, 16.8±0.3, 17.2±0.3, 17.4±0.3, 17.7±0.3, 18.0±0.3, 18.7±0.3, 19.1±0.3, 19.9±0.3, 20.4±0.3, 20.9±0.3, 21.3±0.3, 21.6±0.3, 22.0±0.3, 22.4±0.3, 22.6±0.3, 22.9±0.3, 23.3±0.3, 23.6±0.3, 24.2±0.3, 24.7±0.3, 25.1±0.3, 25.5±0.3, 26.2±0.3, 26.9±0.3, 27.7±0.3, 28.0±0.3, 28.3±0.3, 28.9±0.3, 29.3±0.3, 29.6±0.3, 31.1±0.3, 32.0±0.3, 32.3±0.3, 33.6±0.3, 33.8±0.3, 34.7±0.3, 36.2±0.3, 37.1 ±0.3, 38.3±0.3, and 38.9±0.3 degrees 26.

5. The crystalline form according to claim 3, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three diffraction angles, when measured using Cu Karadiation, selected from a group consisting of about 5.2±0.3, 9.0±0.3, 14.4±0.3, 18.7±0.3 and 19.9±0.3 degrees 20.

6. The crystalline form according to claim 3, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction angles, when measured using Cu Karadiation, of about 5.2±0.3, 9.0±0.3, 14.4±0.3, 18.7±0.3 and 19.9±0.3 degrees 20.

7. The crystalline form according to any one of claims 3-6, wherein the crystalline form is characterized by an X-ray powder diffraction (XRPD) pattern substantially in accordance with FIG. 1.

8. A pharmaceutical composition comprising the crystalline form according to any one of claims 3-7, and one or more pharmaceutically acceptable excipients.

9. The pharmaceutical composition according to claim 8 wherein the composition is adapted for oral administration.

10. The pharmaceutical composition according to claim 9 wherein the composition is in the form of a tablet or capsule.

11. The pharmaceutical composition according to claim 8 wherein the composition is adapted for administration by injection.

12. The pharmaceutical composition according to claim 11 wherein the composition is in the form of a subcutaneous injection.

13. The pharmaceutical composition according to claim 11 wherein the composition is in the form of an intramuscular injection.

14. A method of treating or preventing infection with HIV in a human in need thereof comprising administering to said human an effective amount of the crystalline form according to any one of claims 3-7.

15. A method of treating or preventing infection with HIV in a human in need thereof comprising administering to said human an effective amount of the pharmaceutical composition according to any one of claims 8-13.

16. The crystalline form according to any of claims 3-13 for use in therapy.

17. The crystalline form according to any of claims 3-13 for use in treating or preventing infection with HIV.

18. The use of a crystalline form according to any of claims 3-13 in the manufacture of a medicament for the treatment or prevention of infection with HIV.

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