Advantageous Form of AT-527 Hemisulfate

Abstract

An advantageous isolated Form III of the hemisulfate salt of AT-527, which exhibits a faster dissolution rate than the amorphous form resulting in increased bioavailability and therefore efficacy for therapeutic administration in a solid dosage form to treat viral indications, and methods for its preparation.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 141,789, filed January 26, 2021, the entirety of which is incorporated by reference herein for all purposes.

[0002] The present invention provides an advantageous isolated form of isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate hemisulfate salt (AT-527), which can be used in pharmaceutical compositions in solid dosage form or as a manufacturing intermediate for pharmaceutical compositions, including spray dried dosage forms. [Background technology]

[0003] Nos. 5,233, 5,363, 5,491, 5,523, 5,603, 5,711, 5,816, 5,922, 6,103, 6,112, 6,121, 6,136, 6,143, 6,151, 6,166, 6,171, 6,182, 6,191, 7,203, 7,211, 7,221, 7,236, 7,241, 7,252, 7,261, 7,271, 7,282, 7,316, 7,321, 7,332, 7,411, 7,421, 7,522, 7,532, 7,611, 7,292, 8,293, 8,294, 9,295, 9,296, 10,297, 11,203, 12,204, and 13,342, 7,212, 14,211, 15,221, 16,232, 17,241, 18,251, 19,361, 19,372, 19,402, 19,522, 19,602, 19,712, 19,822, 19,9 ... [ka]

[0004] Patent application 14 to Atea Pharmaceuticals describes the use of Compound A and Compound B to treat SARS-CoV-2, the virus that causes COVID-19. Surprisingly, Compound A was discovered to be potent against SARS-CoV-2. Compound A, an orally administered drug, is being studied in an international Phase 2 trial for moderate COVID-19. Oral administration is particularly advantageous for facilitating broad patient access and compliance. Compound A, alone or in combination with other active agents, could be an advancement in the global fight against COVID-19.

[0005] Compound A and Compound B also have activity against HCV (see, for example, Patent Document 15). Compound A has completed Phase 2 clinical trials in patients infected with HCV. A multipart study evaluated the effects of single and multiple doses of Compound A in healthy subjects, non-cirrhotic HCV-infected patients, and cirrhotic HCV-infected patients. Compound A induced significant antiviral reduction when administered to all HCV-infected cohorts tested (Non-Patent Document 1).

[0006] Compound A and Compound B have also been shown to be active against positive-stranded RNA viruses (see, for example, US Pat. No. 5,399,633).

[0007] Given the importance of Compound A for the therapeutic treatment of humans infected with or at risk of infection with viruses susceptible to Compound A, such as positive-stranded RNA viral diseases, including SARS-CoV-2 and HCV, it would be useful to identify improved pharmaceutical formulations and methods for their manufacture. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] U.S. Patent No. 9,828,410 [Patent Document 2] U.S. Patent No. 10,000,523 [Patent Document 3] U.S. Patent No. 10,005,811 [Patent Document 4] U.S. Patent No. 10,239,911 [Patent Document 5] U.S. Patent No. 10,519,186 [Patent Document 6] U.S. Patent No. 10,815,266 [Patent Document 7] U.S. Patent No. 10,870,672 [Patent Document 8] U.S. Patent No. 10,870,673 [Patent Document 9] U.S. Patent No. 10,875,885 [Patent Document 10] International Application No. PCT / US16 / 21276 (International Publication No. WO 2016 / 144918) [Patent Document 11] International Application No. PCT / US2017 / 50323 (International Publication No. PCT / 048937) [Patent Document 12] International Application No. PCT / US18 / 16301 (International Publication No. WO 2018 / 144640) [Patent Document 13] International Application No. PCT / US2019 / 26837 (International Publication No. 2019 / 200005) [Patent Document 14] U.S. Patent No. 10,874,687 [Patent Document 15] U.S. Patent No. 10,906,928 [Patent Document 16] U.S. Patent No. 10,946,033 [Non-patent literature]

[0009] [Non-Patent Document 1] Good et al. PLoS ONE 15(1): e0227104 Summary of the Invention

[0010] It has been discovered that compound A (isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate hemisulfate salt (also known as AT-527) can be prepared in a highly purified and advantageous form. [ka]

[0011] This highly purified advantageous form is referred to as "Form III". Form III is a form of Compound A that exhibits superior crystallinity compared to other forms. Importantly, Form III of Compound A has a high dissolution rate compared to amorphous Compound A. The dissolution rates described herein were evaluated in vitro according to the method described in Example 5 using dilute (0.1 N) HCl.

[0012] As a non-limiting example, Example 5 shows that tablets made with spray-dried amorphous Compound A took 60 minutes to reach about 99% dissolution of Compound A, whereas tablets made with superior Form III reached about 99% dissolution of Compound A within 20 minutes. Clinical results suggest that faster dissolution rates lead to higher exposure and clinical efficacy. It is unusual for highly crystalline Compound A Form III to show a higher dissolution rate than the amorphous form. This unique feature results in improved pharmaceutical compositions for drug therapy, such as antiviral therapy, for hosts such as humans in need thereof.

[0013] Thus, the present invention includes solid dosage forms and pharmaceutical compositions with superior properties incorporating an effective amount of Compound A Form III, optionally in combination with one or more excipients and / or one or more other ingredients, which may or may not be pharma- ceutical active. In certain non-limiting embodiments, an effective amount of Compound A Form III is used in a solid dosage form for administration to a host, such as a human, in need thereof. Solid dosage forms containing Compound A Form III exhibit unexpectedly high dissolution rates compared to amorphous or spray-dried Compound A.

[0014] In another embodiment, Compound A Form III can be used as a high purity manufacturing intermediate for pharmaceutical solid dosage forms, including spray-dried dispersions. The purity, crystallinity, and stability of Form III are advantageous for manufacturing. Compound A Form III showed little or no loss in chemical purity after one year under ambient conditions, as measured by XRPD and HPLC-UV. No loss in purity or impurity generation was measured after three months when stored under conditions that accelerate decomposition (40° C. and 75% RH).

[0015] In certain non-limiting embodiments, Form III of Compound A can be produced on a large scale using, for example, the procedures of Example 3 or Example 4. As a non-limiting example, large scale production can include, in embodiments, slurrying the hemisulfate salt AT-527 in acetone, removing the acetone, slurrying in heptane, and then drying. These have been found to be excellent conditions for producing Form III of Compound A. When Compound A is slurried in acetone, it decomposes and partially solubilizes in preparation, forming crystals. Acetone is a good solvent for preparing Compound A for crystallization, but it is removed too quickly for good crystallization to occur. Therefore, the acetone is removed to form a cake, to which heptane is added. Heptane has been found to be an excellent solvent for crystallizing Compound A, as it comes off slowly, facilitating solvent removal and allowing optimal crystallization to Form III over time.

[0016] More specifically, the hemisulfate salt can be slurried in hot acetone, cooled, and filtered to obtain a wet cake, which is then slurried in cooled heptane, filtered, and dried. In an alternative embodiment, the heptane is replaced with another non-polar solvent having similar properties. Non-limiting examples of non-polar solvents include, but are not limited to, heptane (which may be n-heptane or mixed heptanes), cyclohexane, hexane (which may be n-hexane or a mixture of hexanes), petroleum ether, octane, diethyl ether, methyl tert-butyl ether, dibutyl ether, or other dialkyl ethers.

[0017] In another non-limiting embodiment, Form III of Compound A is produced by crystallization of Compound A in methanol and acetone, as also described in more detail herein. In certain non-limiting embodiments, Form III of Compound A is produced by crystallizing Compound A in a mixture of methanol and acetone. A non-limiting embodiment of this process can be found in Example 2. In certain non-limiting embodiments, Compound A is dissolved in methanol, then acetone is slowly added and the mixture is heated. This is followed by cooling and filtration to isolate Form III.

[0018] In addition to Form III, Forms I and II, as well as Forms IV and V of Compound A have also been prepared and are provided herein. Forms I and II, as well as Forms IV and V, have more amorphous characteristics compared to Form III (Example 2).

[0019] In one aspect, Form III of Compound A is characterized by an XRPD pattern substantially similar to that depicted in Figure 2. In certain non-limiting embodiments, Form III of Compound A is characterized by an XRPD pattern that includes at least 5, 6, 7, 8, 9, or 10 2-theta values ​​selected from Table 2. In some aspects, Form III of Compound A is characterized by an XRPD pattern that includes 2-theta values ​​of at least 3, 4, 5, 6, or all 7 peaks selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 13.6±0.2°, 17.0±0.2°, 19.9±0.2°, and 21.8±0.2°. For example, Form III of Compound A can be characterized by an XRPD pattern comprising 2-theta values ​​of at least 5.2±0.2°, 8.9±0.2°, 13.6±0.2°, 19.9±0.2°, and 21.8±0.2°, or selected from among these. In another embodiment, Form III is characterized by an XRPD pattern comprising 2-theta values ​​of at least 5.2±0.2°, 8.9±0.2°, 19.9±0.2°, and 21.8±0.2°, or selected from these. In another non-limiting embodiment, Form III of Compound A is characterized by an XRPD pattern comprising 2-theta values ​​of at least 5.2±0.2° and 21.8±0.2°. In another embodiment, Form III of Compound A is characterized by an XRPD pattern comprising 2-theta values ​​of at least 5.2±0.2°. In another embodiment, the standard deviation is ±0.3° 2-theta or ±0.4° 2-theta.

[0020] Accordingly, the present invention provides isolated Form III of Compound A, pharmaceutical compositions comprising such forms, including solid dosage forms, and methods of treating infections with viruses susceptible to Form III of Compound A, such as positive-stranded RNA viruses (including viruses from the Flaviviridae family, such as SARS-CoV-2 and HCV, Dengue virus, West Nile virus, Yellow fever virus, and Zika virus), comprising administering an effective amount of Form III to treat a host, such as a human in need thereof.

[0021] Form III of compound A is advantageously provided in a solid pharmaceutical formulation. In certain embodiments, the formulation contains at least about 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, or 700 mg of Form III of compound A (when both nucleotide and hemisulfate are included in the weight calculation). In certain embodiments, the formulation contains about 500 mg to about 1200 mg of compound A. In certain embodiments, the formulation contains about 300 mg to about 1200 mg of compound A. In certain embodiments, the formulation contains about 400 mg to about 800 mg of compound A. In certain embodiments, the formulation contains about 500 mg to about 700 mg of compound A. In certain embodiments, the formulation contains at least about 600 mg of compound A. When a dosage form is referred to herein in milligram weight doses, it refers to the amount of compound A (i.e., the weight of the hemisulfate and the nucleotide), unless otherwise specified to the contrary. For example, approximately 600 mg of Compound A is equivalent to approximately 550 mg of Compound B.

[0022] In specific embodiments, the formulation is suitable for oral delivery, e.g., a solid dosage form. In certain embodiments, the solid dosage form comprising Compound A Form III is at least approximately 70%, 75%, 80%, 85% or 90% dissolved in aqueous medium (as used herein, refers to dilute HCl, e.g., 0.1N HCl) within 30 minutes. In certain embodiments, the solid dosage form comprising Compound A Form III is more than 90% dissolved in aqueous medium within 20 minutes. In certain embodiments, the solid dosage form comprising Compound A Form III is approximately 99% or more dissolved in aqueous medium within 30 minutes. It is believed that the high dissolution rate and high solubility of the solid dosage form lead to increased efficacy through increased bioavailability.

[0023] In other embodiments, Compound A Form III material is used in the preparation of pharmaceutical compositions, for example as a spray-dried solid dispersion or a granulo layered solid dispersion, due to its high purity and stability.

[0024] In another aspect of the invention, an effective amount of Compound A Form III is administered to a host in need thereof to treat Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) or Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV). In another embodiment, an effective amount of Compound A Form III is administered to a host in need thereof infected with a Flaviviridae virus, including Hepatitis C virus, Dengue virus, West Nile virus, Zika virus, Yellow fever virus, or Japanese encephalitis virus.

[0025] Thus, the present invention includes at least the following features: (a) Isolated Crystalline Form III of Compound A: [ka] (b) Form III of Compound A of (a), characterized by an XRPD pattern comprising 2-theta values ​​selected from 5.2±0.4°, 7.3±0.4°, 8.9±0.4°, 13.6±0.4°, 17.0±0.4°, 19.9±0.4°, and 21.8±0.4°; (c) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least six 2-theta values ​​selected from 5.2±0.4°, 7.3±0.4°, 8.9±0.4°, 13.6±0.4°, 17.0±0.4°, 19.9±0.4°, and 21.8±0.4°; (d) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least five 2-theta values ​​selected from 5.2±0.4°, 7.3±0.4°, 8.9±0.4°, 13.6±0.4°, 17.0±0.4°, 19.9±0.4°, and 21.8±0.4°; (e) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least four 2-theta values ​​selected from 5.2±0.4°, 7.3±0.4°, 8.9±0.4°, 13.6±0.4°, 17.0±0.4°, 19.9±0.4°, and 21.8±0.4°; (f) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least three 2-theta values ​​selected from 5.2±0.4°, 7.3±0.4°, 8.9±0.4°, 13.6±0.4°, 17.0±0.4°, 19.9±0.4°, and 21.8±0.4°; (g) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least two 2-theta values ​​selected from 5.2±0.4°, 7.3±0.4°, 8.9±0.4°, 13.6±0.4°, 17.0±0.4°, 19.9±0.4°, and 21.8±0.4°; (h) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least one 2-theta value selected from 5.2±0.4°, 7.3±0.4°, 8.9±0.4°, 13.6±0.4°, 17.0±0.4°, 19.9±0.4°, and 21.8±0.4°; (i) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least two 2-theta values ​​selected from 5.2±0.4°, 8.9±0.4°, 19.9±0.4°, and 21.8±0.4°; (j) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least one 2-theta value selected from 5.2±0.4°, 8.9±0.4°, 19.9±0.4°, and 21.8±0.4°; (k) Form III of Compound A of (a), characterized by an XRPD pattern comprising at least 2-theta values ​​of 5.2±0.4° and 21.8±0.4°; (l) Form III of Compound A of (a), characterized by an XRPD pattern comprising a 2-theta value of at least 5.2±0.4°; (m) embodiments (b)-(l) in which the standard deviation is ±0.3° 2-theta; (n) embodiments (b)-(l) in which the standard deviation is ±0.2° 2-theta; (o) a pharmaceutical composition comprising Form III of Compound A of any one of embodiments (a)-(l) and a pharma- ceutically acceptable carrier; (p) the pharmaceutical composition of (o), which is a solid dosage form suitable for oral administration; (q) the pharmaceutical composition of (o) or (p), wherein the solid dosage form is a tablet; (r) the pharmaceutical composition of (o) or (p), wherein the solid dosage form is a capsule; (s) a pharmaceutical composition of (o) to (r) delivering from about 600 mg to about 1200 mg of Form III of Compound A; (t) a pharmaceutical composition of (o)-(r) delivering from about 400 mg to about 1000 mg of Form III of Compound A; (u) a pharmaceutical composition of (o)-(r) delivering about 500 mg to about 800 mg of Compound A Form III; (v) a pharmaceutical composition of (o)-(r), delivering at least about 900 mg to about 1200 mg of Form IIII of Compound A; (w) a pharmaceutical composition of (o)-(r), delivering at least about 500 mg of Form IIII of Compound A; (x) a pharmaceutical composition of (o)-(r), which delivers at least about 600 mg of Form IIII of Compound A; (y) a pharmaceutical composition of (o)-(r), delivering at least about 700 mg or about 800 mg of Form IIII of Compound A; (z) a pharmaceutical composition of (o) to (y) administered once daily; (aa) a pharmaceutical composition of (o) to (y) administered twice daily; (bb) a pharmaceutical composition of (o) to (y) administered three times a day; (cc) a pharmaceutical composition of (o) to (aa) prepared using Form III of Compound A; (dd) The pharmaceutical composition of (o)-(aa), wherein at least about 90% of Form III of Compound A dissolves in an aqueous solvent within 30 minutes. (ee) The pharmaceutical composition of any of embodiments (o)-(aa), wherein the dosage form comprising Compound A Form III is at least about 98% dissolved within 20 minutes. (ff) The pharmaceutical composition of any of embodiments (o)-(aa), wherein the dosage form comprising Compound A Form III is at least about 99% dissolved within 20 minutes. (gg) A pharmaceutical composition comprising Form III of Compound A of any of embodiments (o)-(ff), which remains at least about 90% pure for one year at ambient temperature. (hh) A pharmaceutical composition comprising Form III of Compound A of any of embodiments (o)-(ff), which remains at least about 98% pure for one year at ambient temperature. (ii) A pharmaceutical composition comprising Form III of Compound A of any of embodiments (o)-(ff), which remains at least about 99% pure for one year at ambient temperature. (jj) A pharmaceutical composition comprising Form III of Compound A of any of embodiments (o)-(ii), which does not require refrigerated storage. (kk) a spray-dried solid dispersion prepared using Form III of Compound A; (ll) granular layered solid dispersions prepared using Form III of Compound A; (mm) a method of treating a coronavirus, such as SARS-CoV-2, comprising administering to a host in need thereof an effective amount of Form III of compound A of any one of embodiments (a) to (n), a pharmaceutical composition of embodiments (o) to (jj), or a solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier; (nn) a method of treating HCV comprising administering to a host in need thereof an effective amount of Form III of Compound A of any one of embodiments (a)-(n), a pharmaceutical composition of embodiments (o)-(jj), or a solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier; (oo) a method for treating a virus of the Flaviviridae family, comprising administering to a host in need thereof an effective amount of Form III of compound A of any one of embodiments (a)-(n), a pharmaceutical composition of embodiments (o)-(jj), or a solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier; (pp) the method of embodiment (mm) or (oo), wherein Form III of Compound A is administered in a dosage form suitable for oral administration; (qq) the method of any one of embodiments (mm)-(pp), wherein the host is a human; (rr) Form III of Compound A of any one of embodiments (a)-(n), the pharmaceutical composition of embodiments (o)-(jj), or the solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier, for use in treating SARS-CoV-2 or SARS-CoV in a host in need thereof; (ss) Form III of Compound A of any one of embodiments (a)-(n), the pharmaceutical composition of embodiments (o)-(jj), or the solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier, for use in treating HCV in a host in need thereof; (tt) Form III of Compound A of any one of embodiments (a)-(n), the pharmaceutical composition of embodiments (o)-(jj), or the solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier, for use in treating a Flaviviridae virus in a host in need thereof; (uu) Form III or a solid dispersion of Compound A of any one of embodiments (rr)-(tt), wherein the host is a human. (vv) use of Form III of Compound A of any one of embodiments (a) to (n), a pharmaceutical composition of embodiments (o) to (jj), or a solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier, in the manufacture of a medicament for treating SARS-CoV-2 or SARS-CoV in a host in need thereof; (ww) use of Form III of Compound A of any one of embodiments (a)-(n), a pharmaceutical composition of embodiments (o)-(jj), or a solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier, in the manufacture of a medicament for treating HCV in a host in need thereof; (xx) use of Form III of Compound A of any one of embodiments (a)-(n), a pharmaceutical composition of embodiments (o)-(jj), or a solid dispersion of embodiment (kk) or (ll), optionally in a pharma- ceutical acceptable carrier, in the manufacture of a medicament for treating a Flaviviridae virus in a host in need thereof; (yy) Use of (vv) to (xx) where the host is a human; (zz) Preparation of Form III of Compound A comprising the steps of slurrying hemisulfate salt AT-527 in acetone, removing the acetone, slurrying in heptane, and then drying. (aaa) Preparation of Form III of Compound A comprising slurrying in hot acetone, cooling and filtering to obtain a wet cake which is then slurried in chilled heptane, filtered and dried. (bbb) Preparation of Form III of Compound A comprising crystallization in methanol and acetone. (ccc) Preparation of Form III of Compound A by dissolving in methanol and then slowly adding acetone, followed by heating, cooling and then filtration. (ddd) A pharmaceutical composition comprising Form III of Compound A and one or more excipients. (eee) A pharmaceutical composition of (ddd), comprising mannitol. (fff) A pharmaceutical composition of (ddd) or (eee) comprising microcrystalline cellulose. (ggg) A pharmaceutical composition comprising silicified microcrystalline cellulose (ddd) to (fff). (hhh) A pharmaceutical composition comprising colloidal silicon dioxide (ddd) to (ggg). (iii) A pharmaceutical composition of any one of (ddd) to (hhh) containing croscarmellose sodium. (jjj) A pharmaceutical composition of (ddd) to (iii) containing magnesium stearate. (kkk) A pharmaceutical composition of (ddd) to (jjj) comprising microcrystalline cellulose as an intragranular excipient. (lll) A pharmaceutical composition of (ddd) to (kkk) comprising microcrystalline cellulose as an extragranular excipient. (mmm) A pharmaceutical composition of (ddd) to (lll), comprising silicified microcrystalline cellulose as an intragranular excipient. (nnn) A pharmaceutical composition of (ddd) to (mmm) comprising silicified microcrystalline cellulose as an extragranular excipient. (ooo) A pharmaceutical composition of (ddd) to (nnn) comprising croscarmellose sodium as an intragranular excipient. (ppp) A pharmaceutical composition of (ddd) to (ooo) comprising croscarmellose sodium as an extragranular excipient. (qqq) A pharmaceutical composition of (ddd) to (ppp) comprising magnesium stearate as an intragranular excipient. (rrr) A pharmaceutical composition of (ddd) to (qqq) containing magnesium stearate as an extragranular excipient. (sss) A pharmaceutical composition comprising anhydrous dibasic calcium hydrogen phosphate (ddd) to (rrr). (ttt) A solid dosage form comprising Form III of Compound A and one or more excipients. (uuu) A solid dosage form of (ttt), comprising mannitol. (vvv) A solid dosage form of (ttt) or (uuu) comprising microcrystalline cellulose. (www) A solid dosage form of (ttt) to (vvv) comprising silicified microcrystalline cellulose. (xxx) A solid dosage form of (ttt) to (www) comprising colloidal silicon dioxide. (yyy) A solid dosage form of (ttt) to (xxx) comprising croscarmellose sodium. (zzz) A solid dosage form of (ttt) to (yyy), comprising magnesium stearate. (aaaa) A solid dosage form of (ttt) to (zzz) comprising microcrystalline cellulose as an intragranular excipient. (bbbb) A solid dosage form of (ttt) to (aaaa) containing microcrystalline cellulose as an extragranular excipient. (cccc) A solid dosage form of (ttt) to (bbbb) comprising silicified microcrystalline cellulose as an intragranular excipient. (dddd) A solid dosage form of (ttt) to (cccc) containing silicified microcrystalline cellulose as an extragranular excipient. (eeee) A solid dosage form of (ttt) to (dddd) containing croscarmellose sodium as an intragranular excipient. (ffff) A solid dosage form of (ttt) to (eeee), comprising croscarmellose sodium as an extragranular excipient. (gggg) A solid dosage form of (ttt) to (ffff) comprising magnesium stearate as an intragranular excipient. (hhhh) A solid dosage form of (ttt) to (gggg) containing magnesium stearate as an extragranular excipient. (iiii) A solid dosage form of (ttt) to (hhhh) comprising anhydrous dibasic calcium hydrogen phosphate. (jjjj) A pharmaceutical composition prepared from Form III of Compound A and one or more excipients. (kkkk) A pharmaceutical composition of (jjjj), comprising mannitol. (llll) A pharmaceutical composition of (jjjj) or (kkkk) comprising microcrystalline cellulose. (mmmm) A pharmaceutical composition of (jjjj) to (llll) comprising silicified microcrystalline cellulose. (nnnn) A pharmaceutical composition of (jjjj) to (mmmm) comprising colloidal silicon dioxide. (oooo) Pharmaceutical compositions (jjjj) to (nnnn) containing croscarmellose sodium. (pppp) Pharmaceutical compositions (jjjj) to (oooo) containing magnesium stearate. (qqqq) A pharmaceutical composition of (jjjj) to (pppp) comprising microcrystalline cellulose as an intragranular excipient. (rrrr) Pharmaceutical compositions (jjjj) to (qqqq) comprising microcrystalline cellulose as an extragranular excipient. (ssss) A pharmaceutical composition of (jjjj) to (rrrr), comprising silicified microcrystalline cellulose as an intragranular excipient. (tttt) A pharmaceutical composition of (jjjj) to (ssss) comprising silicified microcrystalline cellulose as an extragranular excipient. (uuuu) Pharmaceutical compositions (jjjj) to (tttt) comprising croscarmellose sodium as an intragranular excipient. (vvvv) Pharmaceutical compositions (jjjj) to (uuuu) comprising croscarmellose sodium as an extragranular excipient. (wwww) A pharmaceutical composition of (jjjj) to (vvvv) comprising magnesium stearate as an intragranular excipient. (xxxx) A pharmaceutical composition of (jjjj) to (wwww) comprising magnesium stearate as an extragranular excipient. (yyyy) A pharmaceutical composition comprising anhydrous dibasic calcium hydrogen phosphate (jjjj) to (xxxx). [Brief description of the drawings]

[0026] [Figure 1] 1 is an XRPD pattern of wet Compound A Form III as described in Example 1. The labeled peaks correspond to those in Table 1. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Diagram 2] 1 is an XRPD pattern of dried Compound A Form III as described in Example 1. The labeled peaks correspond to those in Table 2. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Diagram 3] 1 is an overlay of XRPD patterns of Forms I, II, III, IV, and V of Compound A described in Example 2. Form III of Compound A is crystalline while Forms I and II, as well as Forms IV and V, are more amorphous in nature. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Figure 4] FIG. 1 is an XRPD pattern of dried Compound A Form I as described in Example 2. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Diagram 5] 1 is an XRPD pattern of dried Compound A Form II as described in Example 2. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Figure 6] FIG. 1 is an XRPD pattern of dried Form IV of Compound A as described in Example 2. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Figure 7] FIG. 1 is an XRPD pattern of dried Compound A Form V as described in Example 2. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Figure 8] FIG. 1 is an XRPD pattern of dried Compound A Form III as described in Example 3. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. [Figure 9] FIG. 1 is an XRPD pattern of dried Compound A Form III as described in Example 4. The x-axis is 2-theta measured in degrees and the y-axis is intensity measured in counts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] It is not possible to predict in advance whether a compound will exist in crystalline form or in more than one solid form, or in which solvate it will exist, or what the various properties of any solid form when one or more doses exist may be.It is also not possible to predict whether the properties of a particular form are advantageous for a therapeutic dosage form.As an example, the drug ritonavir is active in one form and inactive in another, and the inactive form is more stable.

[0028] I. Definition A "patient" or "host" or "subject" is a human or non-human animal in need of treatment. Typically, the host is a human. A "patient" or "host" or "subject" also refers to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, birds, etc.

[0029] The terms "prophylactic" or "preventative", when used, refer to the administration of an active compound to prevent or reduce the likelihood of the occurrence or recurrence of a viral infection as described herein, or to minimize new infections compared to infections occurring in the absence of such treatment. The present invention includes both treatment and prophylactic or preventative therapy. In certain non-limiting embodiments, the active compound is administered to a host that has been exposed to a viral infection and is therefore at risk of contracting it. In another alternative embodiment, a method of preventing transmission is provided that includes administering an effective amount of one of the compounds described herein to a human for a sufficient period of time (including, for example, up to 3, 5, 7, 10, 12, 14 or more days prior to a contagious situation) prior to exposure to potentially infectious crowds, including when traveling or at public events or meetings.

[0030] The terms "co-administer", "co-administration" or "combination" are used to describe the administration of Form III of Compound A in combination with at least one other antiviral active agent. The timing of co-administration is best determined by the specialist treating the patient. Sometimes it is preferred that the agents are administered simultaneously. Alternatively, the drugs selected for combination therapy may be administered to the patient at different times. Of course, when more than one virus or other infection or other condition is present, the compounds of the present invention may be combined with other agents to treat the other infections or conditions as necessary.

[0031] "Dosage form" means a unitary administration of an active agent. Non-limiting examples of dosage forms include tablets, capsules, and gelcaps.

[0032] "Carrier" refers to a diluent, excipient, or vehicle provided in a pharmaceutical composition.

[0033] By "pharmaceutical acceptable excipient" is meant an excipient that is useful in preparing a pharmaceutical composition / combination and is generally safe, sufficiently non-toxic and not biologically or otherwise undesirable.

[0034] As used herein, the term "isolated" refers to a material in substantially pure form. An isolated compound is free of other components that significantly affect the properties of the compound. In certain embodiments, the isolated form is at least 60%, 70%, 80%, 90%, 95%, 98%, or 99% pure.

[0035] As used herein, "positive strand RNA virus" refers to a virus that contains a single-stranded genome composed of ribonucleic acid, which is "positive strand" and allows the RNA to be translated directly into protein without the need for synthesis of a complementary strand. Non-limiting examples of positive strand RNA viruses include the order Nidoviridae (including the families Arteviridae, Coronaviridae, Mesoniviridae, and Roniviridae), the order Picornaviridae (including the families Dicistroviridae, Ifaviridae, Marnaviridae, Picornaviridae, and Secoviridae), the order Timovirales (including the families Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, and Tymoviridae), and the families Alphatetraviridae, Alvernaviridae, Astroviridae, Barnaviridae, Beniviridae, Bromoviridae, Caliciviridae, Carmotetraviridae, Closteroviridae, Flaviviridae, Fusariviridae, Hepeviridae, Leviviridae, Luteoviridae, Narnaviridae, Nodaviridae, Permtotetraviridae, Potyviridae, Togaviridae, Tombusviridae, and Virugaviridae.

[0036] II. Compound A and Compound B Compound A has previously been disclosed in U.S. Patent No. 5,399,433; U.S. Patent No. 10,894,804; and U.S. Patent No. 5,399,433; and PCT applications No. 5,399,433; and WO 2020 / 117966, all of which are assigned to Atea Pharmaceuticals. Compound A is the hemisulfate salt of Compound B.

[0037] Compound B is (isopropyl ((S)-(((2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphoryl)-L-alaninate). The preparation of Compound B has been previously described in U.S. Pat. No. 5,399,433; U.S. Pat. No. 5,499,623; U.S. Pat. No. 5,523,366; U.S. Pat. No. 5,633,633; U.S. Pat. No. 5,711,363; and U.S. Pat. No. 5,711,363, assigned to Atea Pharmaceuticals, as well as PCT applications U.S. Pat. No. 5,399,363; and WO 2020 / 117966.

[0038] Provided herein is Form III, an advantageous crystalline stable form of Compound A. Four other forms, Form I and Form II, as well as Form IV and Form V, are also provided and can be used in place of Form III for any of the treatment methods described herein. Form III of Compound A exhibits superior solubility to amorphous Compound A. In certain embodiments, tablets made from Form III of Compound A dissolve at least about 99% within 20 minutes, while spray-dried amorphous material takes about 60 minutes or more to dissolve 99% (see Example 5). This improved solubility leads to higher exposure and clinical efficacy.

[0039] In another embodiment, Compound A Form III is used as a high purity manufacturing intermediate. Compound A Form III is advantageous as a manufacturing intermediate because it has been shown to be surprisingly stable. Stability testing under ambient conditions shows no measurable loss of purity over a 12 month period.

[0040] In certain embodiments, Form III of Compound A is stable at 40° C.±2° C. and 75% RH±5% RH over the course of at least one month.

[0041] In certain embodiments, Form III of Compound A is stable at 40° C.±2° C. and 75% RH±5% RH over the course of at least two months.

[0042] In certain embodiments, Form III of Compound A is stable at 40° C.±2° C. and 75% RH±5% RH over the course of at least 3 months.

[0043] In certain embodiments, Compound A Form III is at least about 90% or greater pure by HPLC-UV after storage at 40° C.±2° C., 75% RH±5% RH for at least 3 months.

[0044] In certain embodiments, Compound A Form III has at least 0.05% or less impurities after storage at 40° C.±2° C. and 75% RH±5% RH for 3 months.

[0045] In certain embodiments, Compound A Form III contains 1.1% or less water after storage at 40° C.±2° C. and 75% RH±5% RH for at least 3 months.

[0046] In certain embodiments, Form III of Compound A is stable over the course of at least one year under ambient conditions.

[0047] In certain embodiments, Form III of Compound A is stable at 25° C.±2° C. and 60% RH±5% RH over the course of at least one month.

[0048] In certain embodiments, Form III of Compound A is stable at 25° C.±2° C. and 60% RH±5% RH over the course of at least two months.

[0049] In certain embodiments, Form III of Compound A is stable at 25° C.±2° C. and 60% RH±5% RH over the course of at least 3 months.

[0050] In certain embodiments, Compound A Form III is at least about 90% or greater pure by HPLC-UV after storage at 25° C.±2° C., 60% RH±5% RH for at least 3 months.

[0051] In certain embodiments, Compound A Form III has 0.05% or less impurities after storage at 25° C.±2° C. and 60% RH±5% RH for at least 3 months.

[0052] In certain embodiments, Compound A Form III contains 1.0% or less water after storage at 25° C.±2° C. and 60% RH±5% RH for at least 3 months.

[0053] One embodiment of the present invention is isolated Form III of Compound A: [ka]

[0054] In certain non-limiting embodiments, Form III of Compound A is characterized by an XRPD pattern substantially similar to that depicted in Figure 2. In certain non-limiting embodiments, Form III of Compound A is characterized by an XRPD pattern comprising at least 5, 6, 7, 8, 9, or 10 2-theta values ​​selected from Table 2. In certain non-limiting embodiments, Form III of Compound A is characterized by an XRPD pattern comprising: (a) a 2-theta value that is, or is selected from, at least 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (b) at least nine 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (c) at least eight 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (d) at least seven 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (e) at least six 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (f) at least five 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (g) at least three 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (h) at least two 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (i) at least one 2-theta value selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (j) a 2-theta value of at least 5.2±0.2°, 8.9±0.2°, 13.6±0.2°, 19.9±0.2°, and 21.8±0.2°, or selected therefrom; (k) at least four 2-theta values ​​including at least 5.2±0.2°, 8.9±0.2°, 13.6±0.2°, 19.9±0.2°, and 21.8±0.2°, or selected therefrom; (l) at least three 2-theta values ​​including at least 5.2±0.2°, 8.9±0.2°, 13.6±0.2°, 19.9±0.2°, and 21.8±0.2°, or selected therefrom; (m) at least one 2-theta value selected from 5.2±0.2°, 8.9±0.2°, 13.6±0.2°, 19.9±0.2°, and 21.8±0.2°; (n) at least one 2-theta value selected from 5.2±0.2°, 8.9±0.2°, 19.9±0.2°, and 21.8±0.2°; (o) at least one 2-theta value selected from 5.2±0.2°, 8.9±0.2°, and 21.8±0.2°; (p) at least one 2-theta value selected from 5.2±0.2° and 21.8±0.2°; (q) a 2-theta value of at least 5.2 ± 0.2°; (r) any one of embodiments (a)-(q), wherein the standard deviation is ±0.3° 2 theta; and (s) Any one of embodiments (a)-(q), wherein the standard deviation is ±0.4 degrees two theta.

[0055] In an alternative embodiment, Form III of Compound A is wet and is characterized by an XRPD pattern substantially similar to that depicted in Figure 1. In certain non-limiting embodiments, wet Form III of Compound A is characterized by an XRPD pattern comprising at least 5, 6, 7, 8, 9, or 10 2-theta values ​​selected from Table 1. In certain non-limiting embodiments, Form III of Compound A is characterized by an XRPD pattern comprising: (a) a 2-theta value that is, or is selected from, at least 5.2±0.2°, 7.0±0.2°, 7.3±0.2°, 8.7±0.2°, 10.3±0.2°, 13.6±0.2°, 16.8±0.2°, 19.9±0.2°, 21.8±0.2°, and 24.7±0.2°; (b) at least two, three, or four 2-theta values ​​selected from 5.2±0.2°, 7.0±0.2°, 7.3±0.2°, 8.7±0.2°, 10.3±0.2°, 13.6±0.2°, 16.8±0.2°, 19.9±0.2°, 21.8±0.2°, and 24.7±0.2°; (c) at least five, six, or seven 2-theta values ​​selected from 5.2±0.2°, 7.0±0.2°, 7.3±0.2°, 8.7±0.2°, 10.3±0.2°, 13.6±0.2°, 16.8±0.2°, 19.9±0.2°, 21.8±0.2°, and 24.7±0.2°; (d) at least eight, nine, or ten 2-theta values ​​selected from 5.2±0.2°, 7.0±0.2°, 7.3±0.2°, 8.7±0.2°, 10.3±0.2°, 13.6±0.2°, 16.8±0.2°, 19.9±0.2°, 21.8±0.2°, and 24.7±0.2°; (e) a 2-theta value of at least 5.2±0.2°, 8.7±0.2°, 13.6±0.2°, 19.9±0.2°, and 21.8±0.2°, or selected therefrom; (f) at least one 2-theta value selected from 5.2±0.2°, 19.9±0.2°, and 21.8±0.2°; (g) 2-theta value of 5.2 ± 0.2°; (h) Any one of embodiments (a)-(g), wherein the standard deviation is ±0.3° 2 theta; and (i) Any one of embodiments (a)-(g), wherein the standard deviation is ±0.4°2 theta.

[0056] In certain non-limiting embodiments, the crystalline form of Compound A is Form I.

[0057] In certain non-limiting embodiments, the crystalline form of Compound A is Form II.

[0058] In certain non-limiting embodiments, the crystalline form of Compound A is Form III.

[0059] In certain non-limiting embodiments, the crystalline form of Compound A is Form IV.

[0060] In certain non-limiting embodiments, the crystalline form of Compound A is Form V.

[0061] The synthesis of compound A is described in US Pat. No. 5,399,804, and US Pat. No. 5,433,663. One non-limiting exemplary process for the preparation of compound A is (i) a first step of dissolving compound B in an organic solvent, such as acetone, ethyl acetate, methanol, acetonitrile, or ether, in a flask or container; (iii) adding H2SO4 dropwise to the solution of compound B from step (i) at ambient temperature or at a slightly elevated or reduced temperature (e.g., 23°C to 35°C); (iv) stirring the reactants of step (iii), for example at ambient temperature or at a slightly elevated or reduced temperature, until a precipitate of compound A is formed; (v) optionally filtering and washing the precipitate resulting from step (iv) with an organic solvent; (vi) optionally drying the obtained compound A under vacuum, optionally at elevated temperature, for example 55° C., 56° C., 57° C., 58° C., 59° C., or 60° C.; Includes.

[0062] In certain non-limiting embodiments, the solvent in step (i) is acetone.

[0063] US Patent No. 5,999,633, also assigned to Atea Pharmaceuticals, describes the use of Compound B and Compound A for the treatment of SARS-CoV-2. Compound A, an orally administered drug, is currently being studied in a Phase 2 trial in hospitalized patients with moderate COVID-19.

[0064] The metabolic pathway of compound B is described in Good et al. (2020) Preclinical evaluation of AT-527, a novel guanosine nucleotide prodrug with potent, pan-genotypic activity against hepatitis C virus. PLoS ONE 15(1): e0227104 (Scheme 1 below) and involves initial deesterification of a phosphoramidate (compound B) to form metabolite 1-1, which spontaneously degrades to metabolite 1-2. Metabolite 1-2 then degrades to N 6 -methyl-2,6-diaminopurine-5'-monophosphate derivatives (metabolites 1-3), which are then converted to the free 5'-hydroxyl-N 6-methyl-2,6-diaminopurine nucleoside (Metabolite 1-8), and as the 5'-monophosphate ((2R,3R,4R,5R)-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methyl dihydrogen phosphate (Metabolite 1-4). Metabolite 1-4 is assimilated to the corresponding diphosphate (Metabolite 1-5) and then to the active triphosphate derivative (Metabolite 1-6). The 5'-triphosphate can be further metabolized to produce 2-amino-9-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one (1-7). Metabolites 1-7 are measurable in plasma and therefore are surrogates for the active triphosphate (1-6), which cannot be measured in plasma. [ka]

[0065] III. Process for Making Form III of Compound A In certain non-limiting embodiments, Form III of Compound A is, for example, 1. Slurrying compound A in a polar aprotic solvent at an elevated temperature, optionally below the boiling point of the solvent; 2. Optionally, cooling; 3. Optionally, collecting the solids by filtration; 4. Slurrying the resulting solid in a non-polar solvent at room temperature or, optionally, at a reduced temperature; 5. Filtering the solids; 6. Drying and crystallization; It can be synthesized on a large scale by

[0066] Examples of polar aprotic solvents (e.g., those that act as a solvent or partial solvent for compound A) include, but are not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanone, acetonitrile, tetrahydrofuran, propionitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, 1,4-dioxane, ethyl acetate, dichloromethane, tetrachloroethane, dichloroethane, dimethylsulfoxide, methyl carbonate, propylene carbonate, methyl n-propyl ketone, chloroform, methyl isoamyl ketone, nitromethane, pyridine, or methyl acetate.

[0067] Examples of non-polar solvents include, but are not limited to, pentane (n-pentane or mixture of isomers), hexane (n-hexane or mixture of isomers), cyclohexane, heptane (n-heptane or mixture of isomers), petroleum ether, octane, diethyl ether, methyl tert-butyl ether, dibutyl ether, n-butyl chloride, toluene, benzene, xylene, chlorobenzene, tetrachloroethane, cyclopentane, and carbon disulfide.

[0068] In certain non-limiting embodiments of step 1, compound A is slurried in a solvent selected from acetone, methyl ethyl ketone, and methyl acetate.

[0069] In certain non-limiting embodiments of step 1, compound A is slurried in acetone.

[0070] In certain non-limiting embodiments of step 1, compound A is slurried at a temperature from about room temperature to just below the boiling point of the solvent.

[0071] In certain non-limiting embodiments of step 1, compound A is slurried at a temperature from about room temperature to about 10° C. or less below the boiling point of the solvent.

[0072] In certain non-limiting embodiments of step 1, compound A is slurried at a temperature from about room temperature to about 15° C. or less below the boiling point of the solvent.

[0073] In certain non-limiting embodiments of step 1, compound A is slurried at a temperature of about 55° C. to about 58° C. and the solvent is acetone.

[0074] In certain non-limiting embodiments of step 1, compound A is slurried until the solution is saturated or long enough to decompose the compound as much as possible in order to prepare it for crystallization.

[0075] In certain non-limiting embodiments of step 1, compound A is slurried for a period ranging from one hour to several hours.

[0076] In certain non-limiting embodiments of step 1, compound A is slurried for 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours or more.

[0077] In certain non-limiting embodiments of step 2, the suspension is allowed to cool before collecting the solids.

[0078] In certain non-limiting embodiments of step 2, the suspension is allowed to cool.

[0079] In certain non-limiting embodiments of step 2, the suspension is allowed to cool to room temperature.

[0080] In certain non-limiting embodiments of step 3, the solids are collected by filtration.

[0081] In certain non-limiting embodiments of step 3, the solids are collected by vacuum filtration.

[0082] In certain non-limiting embodiments of step 3, the filtration is carried out under ambient conditions.

[0083] In certain non-limiting embodiments of step 3, the filtration is performed with controlled humidity.

[0084] In certain non-limiting embodiments of step 3, the filtration is performed while controlling the humidity at or below 75% relative humidity.

[0085] In certain non-limiting embodiments of step 3, the filtration is performed while controlling the humidity at or below 50% relative humidity.

[0086] In certain non-limiting embodiments of step 3, the filtration is carried out while controlling the humidity at or below 40% relative humidity.

[0087] In certain non-limiting embodiments of step 3, the collected solids are washed with a polar aprotic solvent, including, but not limited to, acetone, methyl ethyl ketone, methyl isobutyl ketone, butanone, acetonitrile, tetrahydrofuran, propionitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, 1,4-dioxane, ethyl acetate, dichloromethane, tetrachloroethane, dichloroethane, dimethylsulfoxide, methyl carbonate, propylene carbonate, methyl n-propyl ketone, chloroform, methyl isoamyl ketone, nitromethane, pyridine, or methyl acetate.

[0088] In certain non-limiting embodiments of step 3, the collected solids are washed with the same solvent used for slurrying.

[0089] In certain non-limiting embodiments of step 3, the collected solids are washed with dichloromethane, acetone, methyl acetate, methyl ethyl ketone, or methyl isobutyl ketone.

[0090] In certain non-limiting embodiments of step 3, the collected solids are washed with acetone.

[0091] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried in a non-polar solvent (e.g., an anti-solvent), including, but not limited to, heptane, pentane, hexane, cyclohexane, petroleum ether, octane, diethyl ether, methyl tert-butyl ether, dibutyl ether, n-butyl chloride, toluene, benzene, xylene, chlorobenzene, tetrachloroethane, cyclopentane, and carbon disulfide.

[0092] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried in a non-polar solvent selected from heptane, pentane, hexane, cyclohexane, petroleum ether, octane, diethyl ether, methyl tert-butyl ether, dibutyl ether, toluene, xylene, or benzene.

[0093] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried in a non-polar solvent selected from heptane, pentane, hexane, cyclohexane, or petroleum ether.

[0094] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried in heptane.

[0095] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried at ambient temperature.

[0096] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried at low temperature.

[0097] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried at a temperature of about -20°C to about 25°C.

[0098] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried at a temperature of about -10°C to about 15°C.

[0099] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried at a temperature of about 0°C to about 10°C.

[0100] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried at a temperature of about 0°C to about 5°C.

[0101] In certain non-limiting embodiments of step 4, the solids collected in step 3 are slurried for a time sufficient to induce crystallization.

[0102] In certain non-limiting embodiments of step 5, the suspension of step 4 is filtered to collect the solids.

[0103] In certain non-limiting embodiments of step 5, the suspension of step 4 is filtered by vacuum filtration to collect the solids.

[0104] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried.

[0105] In certain non-limiting embodiments of step 6, the solid collected in step 5 is dried slowly enough to achieve good crystallization.

[0106] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried under vacuum.

[0107] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried under a pressure of 1 atmosphere.

[0108] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried at sequential temperatures.

[0109] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried under elevated temperature and reduced pressure.

[0110] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried under reduced pressure at a temperature between about 15°C and about 60°C.

[0111] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried under reduced pressure at a temperature of about 25°C to about 40°C.

[0112] In certain non-limiting embodiments of step 6, the solids collected in step 5 are dried until residual solvent has evaporated.

[0113] Selective Crystallization Form III of compound A can be prepared using selective crystallization. This process can be carried out by treating a solution containing a suitable solvent(s) and compound A in the presence of one or more seeds containing form III of compound A, optionally under conditions that result in the crystallization of form III of compound A. The selective crystallization can be carried out in any suitable organic solvent. For example, it can be carried out in an aprotic solvent, a protic solvent, or a mixture thereof.

[0114] Non-limiting examples of protic solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, butanol, dichloromethane, dioxane, tetrahydrofuran, and acetonitrile.

[0115] Non-limiting examples of aprotic solvents include acetone, dichloromethane, and dioxane.

[0116] In certain non-limiting embodiments, Form III of Compound A is crystallized from methanol and acetone.

[0117] In certain non-limiting embodiments, Form III of Compound A is crystallized from ethanol and acetone.

[0118] In certain non-limiting embodiments, Form III of Compound A is crystallized from n-propanol and acetone.

[0119] In certain non-limiting embodiments, Form III of Compound A is crystallized from i-propanol and acetone.

[0120] In certain non-limiting embodiments, Form III of Compound A is crystallized from methanol and dichloromethane.

[0121] In certain non-limiting embodiments, Form III of Compound A is crystallized from methanol and dioxane.

[0122] In certain non-limiting embodiments, Form III of Compound A is crystallized at a temperature between about room temperature and the boiling point of the solvent.

[0123] In certain non-limiting embodiments, the solution is seeded with crystals of Form III of Compound A.

[0124] In certain non-limiting embodiments, the solution is cooled to room temperature before filtering.

[0125] In certain non-limiting embodiments, the solids collected by filtration are dried under vacuum.

[0126] In certain non-limiting embodiments, the solids collected by filtration are dried under ambient pressure.

[0127] In certain non-limiting embodiments, compound B is dissolved in a solvent and sulfuric acid is added to obtain compound A, which is then crystallized to obtain Form III of compound A.

[0128] In certain non-limiting embodiments, Form III of Compound A is formed from the free base of Compound B using sulfuric acid, followed by crystallization in methanol and acetone.

[0129] In certain non-limiting embodiments, Form III of Compound A is formed from the free base of Compound B using sulfuric acid, followed by crystallization in acetone and heptane.

[0130] In certain non-limiting embodiments, Form III of Compound A can be synthesized from Compound B. Compound B is dissolved in acetone, sulfuric acid is added to cause gradual precipitation of a solid, which is filtered, and the solid is then dissolved in hot methanol, acetone is slowly added, stirred, then cooled, filtered, and dried.

[0131] In certain non-limiting embodiments, the selective crystallization can be carried out at a temperature ranging from about 20°C to about 50°C, from about 20°C to about 40°C, or from about 20°C to about 30°C, for example.

[0132] IV. Pharmaceutical Compositions and Dosage Forms The solid form of Compound A Form III isolated herein can be administered to a host in an effective amount to treat any of the disorders described herein using any suitable approach that achieves the desired therapeutic outcome. The amount and timing of Compound A Form III administration will depend on the host being treated, the instructions of the supervising medical professional, the time course of exposure, the method of administration, the pharmacokinetic properties of the particular active compound, and the judgment of the prescribing physician. Therefore, due to host-to-host variability, the dosages set forth below are guidelines, and the physician can adjust the dose of the compound to achieve the treatment he or she deems appropriate for the host. In considering the degree of treatment desired, the physician can balance various factors, such as the age and weight of the host, the presence of existing diseases, and the presence of other diseases.

[0133] The pharmaceutical composition can be formulated into any pharma- ceutical useful form, for example, pills, capsules, tablets, transdermal patches, subcutaneous patches, dry powders, inhalation formulations, formulations in medical devices, suppositories, buccal formulations, or sublingual formulations. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing an appropriate amount of the active ingredient, for example, an effective amount to achieve a desired purpose.

[0134] The therapeutically effective dosage of Compound A Form III described herein will be determined by a medical professional depending on the condition, size and age of the patient, and the route of delivery. In general, the therapeutically effective amount of Compound A Form III in a pharmaceutical dosage form ranges from about 0.1 mg per kg of patient to more than about 25 mg per kg of patient, or may be significantly more, one or more times per day, depending on the condition or infection being treated, the size of the patient, and the route of administration. For example, Compound A Form III may be administered in an amount ranging from about 0.1 mg per kg of patient to about 15 mg per kg of patient per day, depending on the pharmacokinetics of the agent in the patient. When a dosage form is referred to herein in milligram weight doses, it refers to the amount of Compound A (i.e., the weight of the hemisulfate and nucleotide), unless otherwise specified to the contrary. For example, approximately 600 mg of Compound A corresponds to approximately 550 mg of Compound B.

[0135] In certain non-limiting embodiments, Form III of Compound A can be administered in a solid dosage form in an amount ranging from about 250 micrograms to about 1200 milligrams or more at least once, twice, or three times daily. For example, at least about 5 milligrams, 10 milligrams, 20 milligrams, 25 milligrams, 50 milligrams, 75 milligrams, 100 milligrams, 150 milligrams, 200 milligrams, 250 milligrams, 300 milligrams, 350 milligrams, 400 milligrams, 450 milligrams, 500 milligrams, 550 milligrams, 600 milligrams, 650 milligrams, 700 milligrams, 750 milligrams, 800 milligrams, 850 milligrams, 900 milligrams, 950 milligrams, 1000 milligrams, 1050 milligrams, 1100 milligrams, 1150 milligrams, 1200 milligrams, 1300 milligrams, 1400 milligrams, 1500 milligrams or more once, twice, three times, or up to four times per day, as directed by a health care provider. Form III of Compound A is often administered orally, but may also be administered parenterally, topically, or in suppository form, and intranasally, as a nasal spray, or in other forms as described herein.More generally, Form III of Compound A may be administered in tablets, capsules, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalable forms, transdermal forms, buccal, sublingual, topical, gel, mucosal, etc.

[0136] In certain non-limiting embodiments, Form III of Compound A is administered in a dosage form that delivers at least about 600 mg. In certain non-limiting embodiments, Form III of Compound A is administered in a dosage form that delivers at least about 900 mg or 1200 mg. In certain non-limiting embodiments, Form III of Compound A is administered in a dosage form that delivers at least about 500 mg or 550 mg. In certain non-limiting embodiments, Form III of Compound A is administered in a dosage form that delivers at least about 700 mg. In certain non-limiting embodiments, Form III of Compound A is administered in a dosage form that delivers at least about 1200 mg.

[0137] In certain non-limiting embodiments, Form III of Compound A is administered once daily. In certain non-limiting embodiments, Form III of Compound A is administered twice daily. In certain non-limiting embodiments, Form III of Compound A is administered three, four or more times daily. In certain non-limiting embodiments, Form III of Compound A is administered in a dosage form that delivers at least about 600 mg once, twice or three times daily.

[0138] In certain embodiments, compound A form III is administered in a dosage form that delivers an initial dose (or loading dose) followed by a maintenance dose of at least about 500 mg, at least about 550 mg, at least about 600 mg, or at least about 750 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg, which is taken once, twice, or three times a day. In certain non-limiting embodiments, the loading dose is about 1.5 times greater, about 2 times greater, about 2.5 times greater, or about 3 times greater than the maintenance dose. In certain non-limiting embodiments, the loading dose is administered once, twice, three times, four times, or more times before the first maintenance dose. In certain non-limiting embodiments, compound A form III is administered twice a day at a loading dose of 1200 mg followed by a maintenance dose of 600 mg.

[0139] For example, the following dosing schedules are shown for the treatment of COVID-19 infection: In a first embodiment, compound A is provided once, twice, or three times a day for 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days or more. In certain embodiments, form III of compound A is administered at least twice a day for up to 12 days. In certain embodiments, form III of compound A is administered at least twice a day for up to 10 days. In certain embodiments, form III of compound A is administered at least twice a day for up to 8 days. In certain embodiments, form III of compound A is administered at least twice a day for up to 6 days. In certain embodiments, form III of compound A is administered at least twice a day for up to 5 days. In certain embodiments, Form III of Compound A is administered at least twice daily for up to 1 week, 2 weeks, or 3 weeks.

[0140] In the case of HCV infection or possibly other RNA virus infection, longer dosing schedules may be useful in the opinion of a medical professional. In certain embodiments, compound A form III is administered at least once a day for at least 3 or 4 weeks. In certain embodiments, compound A form III is administered at least once a day for at least 6 weeks. In certain embodiments, compound A form III is administered at least once a day for at least 8 weeks. In certain embodiments, compound A form III is administered at least once a day for at least 10 weeks. In certain embodiments, compound A form III is administered at least once a day for at least 12 weeks. In certain non-limiting embodiments, at least about 700 mg of compound A form III is administered at least once or twice a day for up to 6 weeks. In certain non-limiting embodiments, at least about 600 mg of compound A form III is administered at least once a day for up to 6 weeks. In certain non-limiting embodiments, at least about 500 mg of Compound A Form III is administered at least once a day for up to 6 weeks. In certain non-limiting embodiments, at least about 400 mg of Compound A Form III is administered at least once a day for up to 6 weeks. In certain non-limiting embodiments, at least 300 mg of Compound A Form III is administered at least once a day for up to 6 weeks. In certain non-limiting embodiments, at least 200 mg of Compound A Form III is administered at least once a day for up to 6 weeks. In certain non-limiting embodiments, at least 100 mg of Compound A Form III is administered at least once a day for up to 6 weeks.

[0141] Form III of Compound A may be administered orally, topically, parenterally, by inhalation or spray, sublingually, via an implant, transdermally, via buccal administration, rectally, intramuscularly, by inhalation, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous, nasal, sublingual, or rectally, or by other means in a dosage unit formulation containing a conventional pharma- ceutically acceptable carrier. Non-limiting examples of formulations of Form III of Compound A can be found in Examples 9-14.

[0142] According to the method of the present disclosure, the solid oral dosage form for administration can be any desired form in which compound A form III is stable as a solid.In certain embodiments, compound A form III is delivered in solid microparticles or nanoparticles.When administered via inhalation, isolated compound A form III can be in the form of a plurality of solid particles or droplets having any desired particle size.

[0143] Particles can be formed from Form III of Compound A described herein using a phase inversion method. In this method, Form III of Compound A is dissolved in a suitable solvent and the solution is poured into a strong non-solvent for the compound, and under favorable conditions, microparticles or nanoparticles are allowed to spontaneously form. This method can be used to produce nanoparticles of a wide range of sizes, typically with a narrow size distribution, including, for example, nanoparticles to microparticles.

[0144] In an alternative embodiment, Form III of Compound A is subjected to a milling process, including but not limited to hand milling, rotor milling, ball milling, and jet milling, to obtain microparticles and nanoparticles.

[0145] In certain non-limiting embodiments, the particles are between about 0.1 nm and about 10,000 nm, between about 1 nm and about 1000 nm, between about 10 nm and 1000 nm, between about 1 nm and 100 nm, between about 1 nm and 10 nm, between about 1 nm and 50 nm, between about 100 nm and 800 nm, between about 400 nm and 600 nm, or about 500 nm. In certain non-limiting embodiments, the microparticles are less than or equal to about 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100 nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600 nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm, 1250 nm, 1500 nm, 1750 nm, or 2000 nm.

[0146] The pharmaceutical formulation can include an active dosage form made from Form III of Compound A in any pharma- ceutically acceptable carrier.

[0147] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. Carriers may be inert or may themselves have medicinal properties. The amount of carrier used in conjunction with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

[0148] Classification of carriers includes, but is not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents and wetting agents.Some carriers may be listed in more than one category, for example, vegetable oils can be used as lubricants in some formulations and as diluents in other formulations.Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin; talc and vegetable oils.Any active agent that does not substantially interfere with the activity of the compound of the present invention may be included in the pharmaceutical composition.

[0149] When crystalline compound Form III of Compound A is used in a pharmaceutical formulation, depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid or semi-solid dosage form in which Form III of Compound A is stable, such as tablets, suppositories, pills, capsules, powders, etc., preferably in unit dosage forms suitable for single administration of precise dosage amounts. The composition will contain an effective amount of the selected drug in combination with a pharma- ceutically acceptable carrier, and may additionally include other medicinal agents, adjuvants, diluents, buffers, etc.

[0150] Thus, the compositions of the present disclosure can be administered as pharmaceutical formulations, including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal administration, or in a form suitable for administration by inhalation or insufflation. The preferred method of administration is oral administration, using a convenient daily dosing regimen that can be adjusted according to the degree of discomfort. For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.

[0151] In yet another embodiment, permeation enhancing excipients are used, including polymers such as polycations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethylchitosan, poly-acrylic acid); and thiolated polymers (carboxymethylcellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).

[0152] For oral administration, the composition generally takes the form of a tablet or capsule. Tablets and capsules are the preferred oral dosage forms. Oral tablets and capsules may contain one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. Typically, the compositions of the present disclosure can be combined with non-toxic pharma- ceutically acceptable inert carriers for oral use, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and the like. Furthermore, suitable binders, lubricants, disintegrating agents, and coloring agents may be incorporated into the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars, such as glucose or β-lactose, corn sweeteners, natural and synthetic gums, such as gum arabic, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, etc.

[0153] In addition to the active material made from Compound A Form III or Compound A Form III, the pharmaceutical formulation may contain other additives, such as pH adjusting additives. Particularly useful pH adjusting agents include acids such as hydrochloric acid, bases or buffers such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate or sodium gluconate. In addition, the formulation may contain an antimicrobial preservative. Useful antimicrobial preservatives include methylparaben, propylparaben and benzyl alcohol. Antimicrobial preservatives are typically used when the formulation is placed in a vial designed for multiple doses. The pharmaceutical formulations described herein can be lyophilized using techniques known in the art.

[0154] For oral administration, the pharmaceutical compositions can take the form of tablets, pills, capsules, powders, etc. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate can be used in conjunction with various disintegrants such as starch (e.g., potato or tapioca starch) and certain complex silicates, along with binders such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of similar types can also be employed as fillers in soft and hard gelatin capsules.

[0155] Also provided are pharmaceutical formulations that provide controlled release of the compounds described herein, including through the use of degradable polymers known in the art.

[0156] Formulations suitable for rectal administration are typically presented as unit-dose suppositories, which may be prepared by admixing the active compound disclosed herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.

[0157] Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol or oil that retains the stability of the isolated form.Carriers that can be used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.

[0158] Formulations suitable for transdermal administration can be provided as individual patches adapted to remain in intimate contact with the epidermis of the recipient for extended periods of time.In certain non-limiting embodiments, microneedle patches or devices provide drug delivery across or into biological tissue, particularly the skin.Microneedle patches or devices allow drug delivery across or into the skin or other tissue barrier at clinically relevant rates with little or no damage, pain or irritation to the tissue.

[0159] Formulations suitable for pulmonary administration can be delivered by a variety of passive respiratory and active power-driven single / multiple dose dry powder inhalers (DPIs). The most commonly used devices for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. Several types of nebulizers are available, including jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. The selection of an appropriate pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, the site of action, and the pathophysiology of the lungs.

[0160] V. Solid dosage form An embodiment of the invention is a solid dosage form comprising an effective amount of Form III of Compound A, optionally in a pharma- ceutically acceptable carrier.

[0161] In certain non-limiting embodiments, this solid dosage form prepared directly from Form III of Compound A may have faster dissolution and / or greater solubility than a dosage form produced by spray drying. A process for assessing dissolution rate is provided in Example 5 and generally uses a dilute acidic solution, such as 0.1 N HCl, in vitro.

[0162] In certain non-limiting embodiments, tablets formed from Form III of Compound A are at least approximately 90% dissolved within 30 minutes.

[0163] In certain non-limiting embodiments, tablets formed from Form III of Compound A are at least approximately 90% dissolved within 20 minutes.

[0164] In certain non-limiting embodiments, tablets formed from Form III of Compound A are at least approximately 95% dissolved within 30 minutes.

[0165] In certain non-limiting embodiments, tablets formed from Form III of Compound A are at least approximately 98% dissolved within 30 minutes.

[0166] In certain non-limiting embodiments, tablets formed from Form III of Compound A are at least approximately 99% dissolved within 30 minutes.

[0167] In certain non-limiting embodiments, Form III of Compound A described herein is used to make a spray-dried dispersion (SDD) that is administered to a patient in need thereof. In this method, Form III of Compound A is dissolved in an organic solvent, such as acetone, methylene chloride, or other organic solvent. The solution is pumped through an atomizing nozzle driven by a compressed gas flow, and the resulting aerosol is suspended in a cyclone of heated air, allowing the solvent to evaporate from the microdroplets to form particles. Using this method, microparticles and nanoparticles can be obtained.

[0168] In another embodiment, the spray-dried dispersion (SDD) prepared using Form III of Compound A also contains one or more pharma- ceutically acceptable excipients as defined herein. In another embodiment, the spray-dried dispersion (SDD) prepared using Form III of Compound A also contains an additional therapeutic agent. In a further embodiment, the spray-dried dispersion (SDD) prepared using Form III of Compound A also contains an additional therapeutic agent and one or more pharma- ceutically acceptable excipients. In another embodiment, any of the spray-dried dispersions described can be coated to form a coated tablet. In an alternative embodiment, the spray-dried dispersion is formulated into a tablet but is not coated. In certain non-limiting embodiments, Form III of Compound A described herein is used to make a granular layered solid dispersion.

[0169] In other embodiments, the solid dispersion also includes at least one excipient selected from copovidone, poloxamer, and HPMC-AS. In certain non-limiting embodiments, the poloxamer is poloxamer 407 or a mixture of poloxamers that may include poloxamer 407. In certain non-limiting embodiments, the HPMC-AS is HPMC-AS-L.

[0170] In yet another embodiment, the solid dosage form made from Form III of Compound A includes one or more of the following excipients: phosphoglycerides; phosphatidylcholine; dipalmitoylphosphatidylcholine (DPPC); dioleoylphosphatidylethanolamine (DOPE); dioleoyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine; cholesterol; cholesterol esters; diacylglycerol; diacylglycerol succinate; diphosphatidylglycerol. polyoxyethylene-9-lauryl ether; surfactant fatty acids such as palmitic acid or oleic acid; fatty acids; fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides; sorbitan trioleate (Span™ 85); glycocholate; sorbitan monolaurate (Span™ 20); polysorbate 20 (Tween™ 20); polysorbate 60 (Tween™ 60); polysorbate 65 (Tween™ 65); Polysorbate 80 (Tween™ 80); Polysorbate 85 (Tween™ 85); Polyoxyethylene monostearate; Surfactin; Poloxamer; Sorbitan fatty acid esters such as sorbitan trioleate; Lecithin; Lysolecithin; Phosphatidylserine; Phosphatidylinositol; Sphingomyelin; Phosphatidylethanolamine (cephalin); Cardiolipin; Phosphatidic acid; Cerebrosides; Dicetyl phosphate; Dipalmitoyl Phosphatidylglycerol;Stearylamine;Dodecylamine;Hexadecyl-amine;Acetyl palmitate;Glycerol ricinoleate;Hexadecyl stearate;Isopropyl myristate;Tyloxapol;Poly(ethylene glycol) 5000-phosphatidylethanolamine;Poly(ethylene glycol) 400-monostearate;Phospholipids;Synthetic and / or natural detergents with high surfactant properties;Deoxycholate;Cyclodextrin;Chaotropic salts;Ion pairing agents;Glucose, fructose, galactose, ribose, lactose, sucrose, maltose, trehalose, cellobiose, mannose, xylose, arabinose, glucuronic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine, and neuraminic acid;Pullulan, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran, glycogen, hydroxyethyl starch, carrageenan, glycon, amylose, chitosan, N,O-carboxymethyl chitosan, algin and alginic acid, starch, chitin, inulin, konjac, glucomannan, pastulan, heparin, hyaluronic acid, curdlan, and xanthan, mannitol, sorbitol, xylitol, erythritol, maltitol, and lactitol, Pluronic polymers, polyethylene, polycarbonates (e.g., poly(1,3-dioxane-2-one) )), polyanhydrides (e.g., poly(sebacic anhydride)), polypropyl fumarate, polyamides (e.g., polycaprolactam), polyacetals, polyethers, polyesters (e.g., polylactides, polyglycolides, polylactide-co-glycolides), polycaprolactones, polyhydroxy acids (e.g., poly((β-hydroxyalkanoates))), poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polyureas, polystyrenes, and polyamines, polylysine, polylysine-PEG copolymers, and poly(ethyleneimine), poly(ethyleneimine)-PEG copolymers, glycerol monocaprylocaprate, propylene glycol, vitamin E. TPGS (also known as d-α-tocopheryl polyethylene glycol 1000 succinate), gelatin, titanium dioxide, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (MC), block copolymers of ethylene oxide and propylene oxide (PEO / PPO), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), or hydroxypropyl methylcellulose acetate succinate (HPMCAS);

[0171] In other embodiments, the solid dosage form made from Compound A Form III also includes one or more of the following surfactants: polyoxyethylene glycol, polyoxypropylene glycol, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, glycerol alkyl esters, glyceryl laurate, cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, and poloxamer. Examples of poloxamers include poloxamers 188, 237, 338, and 407. These poloxamers are available under the trade name Pluronic™ (available from BASF, Mount Olive, NJ) and correspond to Pluronic™ F-68, F-87, F-108, and F-127, respectively. Poloxamer 188 (corresponding to Pluronic™ F-68) is a block copolymer having an average molecular weight of about 7000 Da to about 10000 Da, or about 8000 Da to about 9000 Da, or about 8400 Da. Poloxamer 237 (corresponding to Pluronic™ F-87) is a block copolymer having an average molecular weight of about 6000 Da to about 9000 Da, or about 6500 Da to about 8000 Da, or about 7700 Da. Poloxamer 338 (corresponding to Pluronic™ F-108) is a block copolymer having an average molecular weight of about 12000 Da to about 18000 Da, or about 13000 Da to about 15000 Da, or about 14600 Da. Poloxamer 407 (corresponding to Pluronic™ F-127) is a polyoxyethylene-polyoxypropylene triblock copolymer having an average molecular weight of about 10,000 Da to about 15,000 Da, or about 12,000 Da to about 14,000 Da, or about 12,000 Da to about 13,000 Da, or about 12,600 Da, in a ratio of about E101 P56 E101 to about E106 P70 E106, or about E101 P56 E101, or about E106 P70 E106.

[0172] In yet another embodiment, the solid dosage form made from Form III of Compound A comprises one or more of the following surfactants: polyvinyl acetate, sodium cholic acid salt, sodium dioctyl sulfosuccinate, hexadecyltrimethyl ammonium bromide, saponin, sugar esters, Triton. X series, sorbitan trioleate, sorbitan monooleate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, oleyl polyoxyethylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, corn oil, cottonseed oil and sunflower seed oil.

[0173] In an alternative embodiment, solid dosage forms made from Form III of Compound A are made by processes including solvent or dry granulation, optionally followed by compression or consolidation, spray drying, nanosuspension processing, hot melt extrusion, extrusion / spheronization, molding, spheronization, layering (e.g. spray layering suspension or solution), and the like. Examples of such techniques include direct compression using suitable punches and dies (e.g., where the punches and dies are fitted to a suitable tablet press); wet granulation using suitable granulation equipment such as a high shear granulator to form wet particles that are dried into granules; granulation followed by compression using suitable punches and dies (where the punches and dies are fitted to a suitable tablet press); extrusion of the wet mass to form a cylindrical extrudate that is cut to the desired length or broken to length under gravity and attrition; extrusion / spheronization (where the extrudate is rolled into spherical particles and densified by spheronization); spray layering of a suspension or solution onto an inert core using techniques such as a convention pan or Wurster column; injection or compression molding using a suitable mold fitted to the compression unit, etc.

[0174] Exemplary disintegrants include alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (sodium croscarmellose), powdered cellulose, chitosan, croscarmellose sodium, crospovidone, guar gum, low substituted hydroxypropyl cellulose, methylcellulose, microcrystalline cellulose, sodium alginate, sodium starch glycolate, partially pregelatinized starch, pregelatinized starch, starch, sodium carboxymethyl starch, and the like, or combinations thereof.

[0175] Exemplary lubricants include calcium stearate, magnesium stearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, light mineral oil, sodium lauryl sulfate, magnesium lauryl sulfate, sodium stearyl fumarate, stearic acid, zinc stearate, silicon dioxide, colloidal silicon dioxide, dimethyldichlorosilane treated with silica, talc, or combinations thereof.

[0176] The dosage cores described herein may be coated to provide coated tablets. The dosage cores may be coated with functional or non-functional coatings, or a combination of functional and non-functional coatings. "Functional coatings" include tablet coatings that modify the release characteristics of the overall composition, such as sustained or delayed release coatings. "Non-functional coatings" include coatings that are not functional, such as cosmetic coatings. Non-functional coatings may have some effect on the release of the active agent, such as initial dissolution, hydration, perforation of the coating, etc., but are not considered to be a significant deviation from the uncoated composition. Non-functional coatings may also mask the taste of the uncoated composition containing the pharma- ceutical active ingredient. The coating may include a light-blocking material, a light-absorbing material, or a light-blocking material and a light-absorbing material.

[0177] Exemplary polymethacrylates include copolymers of acrylic and methacrylic acid esters, such as: a. amino methacrylate copolymers USP / NF such as poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1 (e.g., EUDRAGIT E 100, EUDRAGIT EPO, and EUDRAGIT E 12.5; CAS No. 24938-16-7); b. poly(methacrylic acid, ethyl acrylate) 1:1 (e.g., EUDRAGIT L30 D-55, EUDRAGIT L100-55, EASTACRYL 30D, KOLLICOAT MAE 30D, and 30DP; CAS No. 25212-88-8); c. poly(methacrylic acid, methyl methacrylate) 1:1 (e.g., EUDRAGIT L 100, EUDRAGIT L 12.5, and 12.5P; also known as methacrylic acid copolymers, Type A NF; CAS number 25806-15-1; d. poly(methacrylic acid, methyl methacrylate) 1:2 (e.g. EUDRAGIT S 100, EUDRAGIT S 12.5 and 12.5P; CAS number 25086-15-1); e. poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 (e.g. Eudragit FS 30 D; CAS number 26936-24-3); f. poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2 or 1:2:0.1 (e.g. EUDRAGITS RL 100, RL PO, RL 30 D, RL 12.5, RS 100, RS PO, RS 30 D or RS 12.5; CAS No. 33434-24-1; g. Poly(ethyl acrylate, methyl methacrylate) 2:1 (e.g., EUDRAGIT NE 30 D, Eudragit NE 40D, Eudragit NM 30D; CAS No. 9010-88-2), and the like, or combinations thereof.

[0178] Suitable alkyl celluloses include, for example, methyl cellulose, ethyl cellulose, etc., or combinations thereof. Exemplary water-based ethyl cellulose coatings include AQUACOAT, a 30% dispersion that further includes sodium lauryl sulfate and cetyl alcohol, available from FMC, Philadelphia, PA; SURELEASE, a 25% dispersion that further includes stabilizers or other coating ingredients (e.g., ammonium oleate, dibutyl sebacate, colloidal anhydrous silica, medium chain triglycerides, etc.), available from Colorcon, West Point, PA; and Ethocel, available from Aqualon or Dow Chemical Co, Midland, MI. Those skilled in the art will appreciate that other cellulose polymers, including other alkyl cellulose polymers, can replace some or all of the ethyl cellulose.

[0179] Other suitable materials that can be used to make the functional coating include hydroxypropyl methylcellulose acetate succinate (HPMCAS); cellulose acetate phthalate (CAP); polyvinyl acetate phthalate; neutral or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl, or specifically cetostearyl alcohol), fatty acid esters, fatty acids including fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats and oils, hydrocarbons, regular waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic materials with a hydrocarbon backbone, or combinations thereof. Suitable waxes include beeswax, glycowax, castor wax, carnauba wax, microcrystalline wax, candelilla, and wax-like substances, such as materials that are normally solid at room temperature and have a melting point of about 30° C. to about 100° C., or combinations thereof.

[0180] In other embodiments, the functional coating comprises digestible long chain (e.g., C8-C 50 , specifically C 12 ~C 40) substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, waxes, or combinations thereof. Hydrocarbons having a melting point of about 25°C to about 90°C may be used. Specifically, fatty (aliphatic) alcohols, which are long-chain hydrocarbon materials, may be used.

[0181] The coating may optionally include additional pharma- ceutically acceptable excipients, such as plasticizers, stabilizers, water-soluble components (e.g., pore-forming agents), anti-tacking agents (e.g., talc), surfactants, and the like, or combinations thereof.

[0182] The functional coating may include a release modifier that affects the release characteristics of the functional coating. The release modifier may function, for example, as a pore former or matrix disintegrant. The release modifier may be organic or inorganic and includes materials that can be dissolved, extracted, or leached from the coating in the environment of use. The release modifier may include one or more hydrophilic polymers, including cellulose ethers and other cellulose compounds such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose acetate phthalate; povidone; polyvinyl alcohol; acrylic polymers such as gastrosoluble Eudragit FS 30D, pH sensitive Eudragit L30D 55, L 100, S 100, or L 100-55; or combinations thereof. Other exemplary release-modifying agents include povidone; saccharides (e.g., lactose, etc.); metal stearates; inorganic salts (e.g., dibasic calcium phosphate, sodium chloride, etc.); polyethylene glycols (e.g., polyethylene glycol (PEG) 1450, etc.); sugar alcohols (e.g., sorbitol, mannitol, etc.); alkali alkyl sulfates (e.g., sodium lauryl sulfate); polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates); or combinations thereof. Exemplary matrix disintegrants include water-insoluble organic or inorganic materials. Organic polymers, including but not limited to cellulose, cellulose ethers such as ethyl cellulose, cellulose esters such as cellulose acetate, cellulose acetate butyrate, and cellulose acetate propionate, and starch, can function as matrix disintegrants. Examples of inorganic disintegrants include many calcium salts, such as monocalcium phosphate, dicalcium phosphate, and tricalcium phosphate, silica, and talc.

[0183] The coating may optionally include a plasticizer to improve the physical properties of the coating. For example, since ethyl cellulose has a relatively high glass transition temperature and does not form a flexible film under normal coating conditions, it may be advantageous to add a plasticizer to the ethyl cellulose before use as a coating material. Generally, the amount of plasticizer included in the coating solution is based on the concentration of the polymer, and may be, for example, about 1% to about 200% depending on the polymer, but is often about 1% to about 100% by weight of the polymer. However, the concentration of the plasticizer can be determined by routine experimentation.

[0184] Examples of plasticizers for ethylcellulose and other celluloses include dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, triacetin, or combinations thereof, although other water insoluble plasticizers (acetylated monoglycerides, phthalates, castor oil, etc.) can be used.

[0185] Examples of plasticizers for acrylic polymers include citrate esters such as triethyl citrate NF, tributyl citrate, dibutyl phthalate, 1,2-propylene glycol, polyethylene glycol, propylene glycol, diethyl phthalate, castor oil, triacetin, or combinations thereof, although other plasticizers (acetylated monoglycerides, phthalates, castor oil, etc.) can be used.

[0186] The coating material can be applied to the surface of the dosage form core using any suitable method, including processes such as simple or complex coacervation, interfacial polymerization, submerged drying, thermal and ionic gelation, spray drying, spray chilling, fluidized bed coating, pan coating, or electrostatic deposition.

[0187] In certain embodiments, an optional intermediate coating is used between the dosage form core and the outer coating. Such intermediate coatings can be used to protect the active agent or other components of the core subunit from the material used in the outer coating or to provide other properties. Exemplary intermediate coatings typically include water-soluble film-forming polymers. Such intermediate coatings may include film-forming polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, gelatin, hydroxypropyl methyl cellulose, polyethylene glycol, polyethylene oxide, and the like, or combinations thereof, and plasticizers. Plasticizers can be used to reduce brittleness and increase tensile strength and elasticity. Exemplary plasticizers include polyethylene glycol propylene glycol and glycerin.

[0188] VI. How to treat SARS-CoV-2 virus infection In certain non-limiting embodiments, methods are provided that include administration of an effective amount of Form III of Compound A for treating or preventing infection with Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-2019.

[0189] Treatment of hosts infected with SARS-CoV-2 includes drug-resistant and multi-drug resistant forms of the virus and associated disease states, pathologies, or complications of viral infections, including pneumonia, such as 2019 novel coronavirus infection pneumonia (NCIP), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), etc. Additional non-limiting complications include hypoxemic respiratory failure, acute respiratory failure (ARF), acute liver injury, acute cardiac injury, acute kidney injury, septic shock, disseminated intravascular coagulation, thrombosis, multisystem inflammatory syndrome, chronic fatigue, rhabdomyolysis, and cytokine storm.

[0190] In certain non-limiting embodiments, administration of Form III of Compound A to a patient in need thereof results in a reduction in the incidence of progressive respiratory failure (PRI) as measured by an increase of one or more or even two or more tiers of respiratory support required to maintain satisfactory oxygen uptake (SpO2≧93%) using the six-tier hierarchical levels of respiratory support described below.

[0191] The scale of improvement in respiratory support level includes: Level 1: Normal oxygen uptake (SpO2 ≥ 93%) on room air, no need for supplemental O2 Level 2: Persistent hypoxemia (SpO2 ≥ 93) on room air requiring low-level O2 supplementation (up to 2 L / min) via nasal cannula or mask to maintain SpO2 ≥ 93%. Level 3: Higher levels of passive O2 supplementation (up to 2L / min) via nasal cannula or mask required to maintain SpO2 ≥ 93 Level 4: Requires oxygen intake via positive pressure devices, e.g., continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) or other non-invasive positive pressure respiratory support methods, to maintain satisfactory oxygen intake and / or ventilation. Level 5: Invasive respiratory support required (intubated mechanical ventilation or ECMO) Level 6: Death

[0192] In certain non-limiting embodiments, the PRI reduction is an increase from level 5 to level 3, from level 5 to level 2, or from level 5 to level 1. In certain non-limiting embodiments, the PRI reduction is an increase from level 4 to level 2, or from level 4 to level 1. In certain non-limiting embodiments, the PRI reduction is an increase from level 3 to level 1.

[0193] In certain non-limiting embodiments, administration of Form III of Compound A reduces the median time to clinical recovery (states 6, 7, or 8 on the NIAID Clinical Status Scale using an adapted National Institute of Allergy and Infectious Diseases (NIAID) ordinal scale of clinical status) by at least 3 days, 4 days, 5 days, or more. In certain non-limiting embodiments, administration of Form III of Compound A results in an improvement as measured by an adapted ordinal scale of clinical status.

[0194] From most severe disease to progressively less severe disease, stages on an adaptive ordinal scale of overall clinical status are defined as follows: 1.Death 2. Hospitalization, invasive mechanical ventilation or ECMO 3. Hospitalization, non-invasive ventilation or high-flow oxygen 4. Hospitalization and oxygen supplementation required 5. No hospitalization, no supplemental oxygen required, ongoing medical care required (COVID-19 related or otherwise) 6. No longer needing hospitalization, supplemental oxygen, or close medical care for COVID-19 7. Not hospitalized but has restricted activity and requires close outpatient care for COVID-19 symptoms 8. Not hospitalized, with no restrictions on activity, or need for ongoing close medical care

[0195] In certain non-limiting embodiments, administration of Form III of Compound A reduces the median time to clinical recovery (states 6, 7, or 8 on the National Institute of Allergy and Infectious Diseases (NIAID) Clinical Status Scale using an adapted NIAID ordinal scale of clinical status) by at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days.

[0196] In certain non-limiting embodiments, administration of Form III of Compound A reduces the length of hospital stay in patients infected with COVID-19.

[0197] In certain non-limiting embodiments, administration of Form III of Compound A shortens the time to persistence of undetectable SARS-CoV-2 virus in the nose and / or throat of patients infected with COVID-19.

[0198] In certain non-limiting embodiments, administration of Form III of Compound A reduces the proportion of SARS-CoV-2 positive patients in a hospital population after at least about 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days of treatment.

[0199] VII. How to Treat Hepatitis C (HCV) In another aspect, the present invention includes a method for preventing or preventing HCV infection or disease states, or disease states, conditions, or complications associated with HCV infection, including, inter alia, cirrhosis of the liver and associated liver toxicity, weakness, loss of appetite, weight loss, breast enlargement (especially in men), rashes (especially on the palms of the hands), blood clotting problems, spider veins in the skin, confusion, coma (encephalopathy), fluid accumulation in the abdominal cavity (ascites), esophageal varices, portal hypertension, renal failure, splenomegaly, low blood counts, anemia, thrombocytopenia, jaundice, and hepatocellular (liver) cancer, comprising administering to an at-risk patient an effective amount of Compound A Form II as described above in combination with a pharma- ceutically acceptable carrier, additive, or excipient, and optionally in combination with another anti-HCV agent. In another embodiment, the active compounds of the present invention can be administered to patients after hepatitis-related liver transplant to protect the new organ.

[0200] Form III of Compound A can also be used to treat a range of HCV genotypes. At least six different genotypes of HCV, each with multiple subtypes, have been identified worldwide. Genotypes 1-3 are prevalent worldwide, while genotypes 4, 5, and 6 are more geographically restricted. Genotype 4 is common in the Middle East and Africa. Genotype 5 is found primarily in South Africa. Genotype 6 is found primarily in Southeast Asia. The most common genotype in the United States is genotype 1, but defining the genotype and subtype can help with type and duration of treatment. For example, different genotypes respond differently to medications, and optimal treatment times vary depending on which genotype is infected. Subtypes within a genotype, such as genotype 1a and genotype 1b, also respond differently to treatment. Infection with one type of genotype does not preclude later infection with a different genotype.

[0201] In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 1, HCV genotype 2, HCV genotype 3, HCV genotype 4, HCV genotype 5, or HCV genotype 6. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 1a. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 1b. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 2a. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 2b. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 3a. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 4a. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 4d.

[0202] In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 5a. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotype 6a. In certain non-limiting embodiments, Form III of Compound A is used to treat HCV genotypes 6b, 6c, 6d, 6e, 6f, 6g, 6h, 6i, 6j, 6k, 6l, 6m, 6n, 6o, 6p, 6q, 6r, 6s, 6t, or 6u.

[0203] VIII. Methods of Treating Other RNA Viral Infections In one aspect of the present invention, compound A form III is administered in an effective amount to a host in need thereof for the treatment of RNA viruses. The present invention includes both treatment and prophylactic or preventative therapy of RNA viruses. In certain non-limiting embodiments, compound A form III is administered to a host that has been exposed to an RNA virus and is therefore at risk of infection or at risk of reinfection. Prophylactic treatment can be administered, for example, to a subject that has not yet been exposed to or infected with an RNA virus, but is susceptible to or otherwise at risk of exposure or infection by an RNA virus. In certain non-limiting embodiments, a host at risk of infection or reinfection is administered compound A form III indefinitely until the risk of exposure no longer exists.

[0204] In certain non-limiting embodiments, methods of preventing transmission are provided that include administering an effective amount of Form III of Compound A to a human for a sufficient period of time (including, for example, up to 3, 5, 7, 10, 12, 14, or more days prior to a contagious situation) prior to exposure to potentially contagious crowds, including when traveling or at public events or conferences, to prevent the human from becoming infected or in a contagious situation.

[0205] In certain non-limiting embodiments, Form III of Compound A is administered in an effective amount for at least 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months or more after infection.

[0206] The present invention relates to a method for the treatment or prevention of RNA viruses, including drug-resistant and multi-drug resistant forms of RNA viruses, as well as associated disease states, symptoms or complications of RNA virus infections, as well as other symptoms secondary to RNA virus infections, such as weakness, loss of appetite, weight loss, breast enlargement (especially in men), rashes (especially on the palms of the hands), blood clotting problems, spider veins in the skin, confusion, coma (encephalopathy), fluid accumulation in the abdominal cavity (ascites), esophageal varices, portal hypertension, renal failure, splenomegaly, decreased blood cells, anemia, thrombocytopenia, and jaundice, among others. The method comprises administering to a host in need thereof an effective amount of Compound A Form III, optionally in combination with at least one additional bioactive agent, such as an additional anti-RNA virus agent, and further in combination with a pharma- ceutically acceptable carrier, additive and / or excipient.

[0207] In yet another aspect, the invention is a method of preventing or preventing an RNA viral infection or disease state, or an associated or subsequent disease state, condition or complication of an RNA viral infection, including, inter alia, liver toxicity, weakness, loss of appetite, weight loss, breast enlargement (especially in men), rashes (especially on the palms of the hands), blood clotting problems, spider veins in the skin, confusion, coma (encephalopathy), fluid accumulation in the abdominal cavity (ascites), esophageal varices, portal hypertension, renal failure, splenomegaly, low blood counts, anemia, thrombocytopenia, jaundice, and hepatocellular (liver) cancer, comprising administering to an at-risk patient an effective amount of at least one compound according to the invention as described above in combination with a pharma- ceutically acceptable carrier, additive or excipient, and optionally in combination with another anti-RNA viral agent.

[0208] The Baltimore classification system categorizes viruses into groups labeled I-VII according to their genome. DNA viruses belong to groups I, II, and VII, while RNA viruses belong to groups III-VI. RNA viruses use ribonucleic acid as their genetic material. RNA viruses can have double-stranded (ds) RNA genomes or single-stranded RNA genomes. Viruses with single-stranded RNA genomes can have positive-stranded or negative-stranded genomes. Group III viruses are double-stranded RNA viruses. Groups IV and V are both single-stranded RNA viruses, but group IV viruses are positive-sense and group V are negative-sense. Group VI is a positive-sense single-stranded RNA virus that replicates through a DNA intermediate.

[0209] In certain non-limiting embodiments, Form III of Compound A is administered to a host infected with a double-stranded RNA virus.

[0210] In certain non-limiting embodiments, Form III of Compound A is administered to a host infected with a single-stranded RNA virus.

[0211] In certain non-limiting embodiments, Form III of Compound A is administered to a host infected with a positive stranded RNA virus.

[0212] In an alternative non-limiting embodiment, Form III of Compound A is administered to a host infected with a negative strand RNA virus.

[0213] In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including a human, to treat Group III dsRNA viruses selected from Amargaviridae, Birnaviridae, Chrysoviridae, Cystoviridae, Endornaviridae, Hypoviridae, Megabirnaviridae, Partitiviridae, Picobirnaviridae, Quadriviridae, Reoviridae, and Totiviridae.

[0214] In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including humans, to treat Group IV positive-sense ssRNA viruses. The order Nidoviridae includes the following families: Arteviridae, Coronaviridae, Mesoniviridae, and Roniviridae. The order Picornaviridae includes the following families: Dicistroviridae, Ifaviridae, Marnaviridae, Picornaviridae, and Secoviridae. The order Tymoviridae includes the following families: Alphaflexiviridae, Betaflexiviridae, Gammaflexiviridae, and Tymoviridae. The following positive-sense ssRNA viruses include viruses from the following unassigned families: Alphatetraviridae, Alvernaviridae, Astroviridae, Barnaviridae, Beniviridae, Bromoviridae, Caliciviridae, Carmotetraviridae, Closteroviridae, Flaviviridae, Fusariviridae, Hepeviridae, Leviviridae, Luteoviridae, Narnaviridae, Nodaviridae, Permtotetraviridae, Potyviridae, Togaviridae, Tombusviridae, and Virugaviridae.

[0215] In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including a human, to treat Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In other embodiments, Form III of Compound A is administered to a host in need thereof, including a human, to treat other Coronaviridae viral infections, including infections caused by viruses of the Alphacoronavirus, Betacoronavirus (including Severe Acute Respiratory Syndrome Coronavirus), Gammacoronavirus, and Deltacoronavirus genera. In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including a human, to treat Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV2).

[0216] In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including a human, to treat a Flaviviridae virus infection, including, but not limited to, infection with viruses of the genera Flavivirus, Hepacivirus, and Pestivirus. Flavivirus infections include dengue fever, Kyasanur Forest disease, Powassan disease, Wesselsbron disease, West Nile fever, yellow fever, Zika virus, Rio bravo, Rocio, Negishi, and encephalitis, including: Japanese encephalitis type B, Montana myositis leukoencephalitis virus, Central European encephalitis (tick-borne encephalitis), Irheus virus, Murray Valley encephalitis, St. Louis encephalitis, Louping disease, and Russian spring-rodents summer encephalitis.

[0217] Species in the Hepacivirus genus include Hepacivirus A through Hepacivirus N. Hepatitis C virus (HCV) is caused by Hepatovirus C, and in certain non-limiting embodiments, Form III of Compound A is administered to treat HCV.

[0218] Pestivirus infections primarily include livestock diseases including swine fever in pigs, BVDV (bovine viral diarrhea virus) infections in cattle, and Border disease virus infections.

[0219] In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including a human, to treat a picornavirus infection, including, but not limited to, Aphthovirus, Aquamavirus, Avipepatovirus, Cardiovirus, Cosavirus, Dysipivirus, Enterovirus, Erbovirus, Hepatovirus, Kobuvirus, Megrivirus, Parechovirus, Sarivirus, Sapelovirus, Senecavirus, Teschovirus, and Tremovirus.

[0220] In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including humans, to treat Togaviridae viruses. The Togaviridae family includes four genera: Alphavirus, Arterivirus, Rubivirus, and Pestivirus. The Alphavirus genus includes four viruses that cause encephalitis: Eastern equine encephalitis (EEE) virus, Venezuelan equine encephalitis (VEE) virus, Western equine encephalitis (WEE) virus, and Everglades virus. Additionally, the Alphavirus genus includes Chikungunya virus, Mayaro virus, Okerubo virus, Onion virus, Ross River virus, Semliki Forest virus, and Sindbis virus (SINV). The Arterivirus genus includes only one member, the Equine Arteritis virus. The genus Pestivirus contains three viruses of veterinary importance: Bovine viral diarrhea virus (BVDV), Classical hog fever virus and Border disease virus. The only member of the genus Rubivirus is the rubella virus.

[0221] In certain non-limiting embodiments, compound A form III is administered to a host in need thereof, including humans, to treat group V negative-sense ssRNA viruses, including but not limited to Mononegavirales. Mononegavirales include, but are not limited to, the following families and viruses: Borna disease virus of the Bornaviridae family; Ebola virus and Marburg virus of the Filoviridae family; Measles virus, Mumps virus, Nipah virus, Hendra virus, respiratory syncytial virus (RSV) and Newcastle disease virus (NDV) of the Paramyxoviridae family; Rabies virus of the Rhabdoviridae family, and Nyavirus of the Niamiviridae family. Unassigned families and viruses include, but are not limited to, Lassa virus of the Arenaviridae family; Hantavirus and Crimean-Congo hemorrhagic fever virus of the Bunyaviridae family; Influenza virus of the Ophioviridae and Orthomyxoviridae families.

[0222] In certain non-limiting embodiments, Form III of Compound A is administered to a host in need thereof, including humans, to treat Bunyaviridae viruses. The Bunyaviridae family includes over 200 named viruses, which are divided into five genera: Hantavirus, Nairovirus, Orthobunyavirus, Phlebovirus, and Tospovirus. The Hantavirus genus includes Hantaanvirus. The Nairovirus genus includes Crimean-Congo hemorrhagic fever virus and Djugbevirus. The Orthobunyavirus genus is composed of approximately 170 viruses divided into multiple serogroups. The serogroups include Anopheles A, Anopheles B, Bakau, Bunyamwera, Buwamba, California, Capim, Gamboa, Group C, Guama, Koongol, Maputta, Minatitlan, Nyando, Olifanstlei, Patois, Simbu, Tete, Turlock, Weomia, and unassigned. The Anopheles A serogroup includes Anopheles A virus, Takaiuma virus, Virgin River virus, Trombetas complex, Arumateua virus, Caraipe virus, Trombetas virus, and Tsukurui virus. The Anopheles B serogroup includes Anopheles B virus and Boraceia virus. The Bakau serogroup includes Bakau and Nora viruses. The Bunyamwera serogroup includes Birao, Bozo, Bunyamwera, Cache Valley, Fort Sherman, Germiston, Gualoa, Ilesha, Kaili, Main Drain, Northway, Prayas, Potosi, Shokwe, Stanfield, Tensaw, Xingu, Batai, Carbo, Chittor, Garissa, KV-141, and Ngari viruses. The Buwamba serogroup includes Buwamba and Pongola viruses.The California serogroup includes California encephalitis virus, Chatunga virus, Parakeet virus, Jamestown Canyon virus, Jerryslau virus, Keystone virus, Hatanga virus, La Crosse virus, Rambo virus, Maleo virus, Morro Bay virus, San Angelo virus, Serradonavio virus, Snowshoe hare virus, South River virus, Tahina virus, and Trivittatus virus. The Capim serogroup includes Akara virus, Benevides virus, and Capim virus. The Gamboa serogroup includes Alajuela virus, Gamboa virus, Pueblo Vieyo virus, and San Juan virus. Group C serogroups include, but are not limited to, Burcona virus, Ossa virus, Apiu virus, Brunconha virus, Carapal virus, Vinces virus, Madrid virus, Gambo limbo virus, Marituba virus, Murtsuk virus, Nepuyo virus, Lestan virus, Itaki virus, and Olivoca virus. The Guama serogroup includes, but is not limited to, Bertioga virus, Vimiti virus, Cananeia virus, Guama virus, Guaratuba virus, Itimirim virus, and Mirim virus. The Khongol serogroup includes, but is not limited to, Khongol virus and Wongal virus. The Maputta serogroup includes, but is not limited to, Buffalo Creek virus, Maputta virus, Mapric virus, Murrumbidgee virus, and Salt Ash virus. The Minatitlan serogroup includes, but is not limited to, Minatitlan virus and Palestina virus. The Nyando serogroup includes, but is not limited to, Eretomapodites virus and Nyando virus. The Olifants Stray serogroup includes, but is not limited to, Botanbi virus and Olifants Stray virus. The Patois serogroup includes, but is not limited to, Abla virus, Babaoyo virus, Pahayoqui virus, Patois virus, and Shark River virus.The Simbu serogroup includes, but is not limited to, Iquitos virus, Jatobal virus, Linier virus, Madre de Dio virus, Olopauche virus, Oya virus, Timiri virus, Akabane virus, Tinaroo virus, Douglas virus, Sashperi virus, Aino virus, Shuni virus, Peton virus, Chamonda virus, Schmallenberg virus, and Simbu virus. The Tete serogroup includes, but is not limited to, Batama virus and Tete virus. The Turlock serogroup includes, but is not limited to, Mpoko virus, Turlock virus, and Umbre virus. The Weomia serogroup includes, but is not limited to, Anhembi virus, Cachoeira Porteira virus, Iako virus, Macao virus, Sororoca virus, Taiasui virus, Chukanduba virus, and Weomia virus. Unassigned serogroups include, but are not limited to, Batama virus, Belmont virus, Enseada virus, Esteroreal virus, Urona virus, Kenkoi virus, and Kowanyama virus. The Phlebovirus genus includes, but is not limited to, Neapolitan and Sicilian types of sandfly fever virus, and Rift Valley fever virus. The genus Tospovirus includes, but is not limited to, the type species Tomato yellow dwarf virus, which includes the following species: Bean necrotic mosaic virus, Pepper chlorosis virus, Peanut bud necrosis virus, Peanut ring virus, Peanut yellow spot virus, Impatiens necrotic spot virus, Iris yellow spot virus, Melon yellow necrosis virus, Peanut bud necrosis virus, Peanut yellow spot virus, Soybean stem necrosis-associated virus, Tomato chlorosis virus, Tomato necrotic ring virus, Tomato yellow ring virus, Tomato ring virus, Watermelon bud necrosis virus, Watermelon gray white spot virus, and Zucchini lethal chlorosis virus.

[0223] Flaviviridae virus infections In one aspect of the invention, a method is provided that includes administering form III of compound A to a host, including a human, in need thereof for the treatment or prevention of an infection with a Flaviviridae virus. In certain non-limiting embodiments, the Flaviviridae virus is of the Flavivirus genus, including but not limited to dengue virus, yellow fever virus, Zika virus, and West Nile virus. In certain non-limiting embodiments, the Flavivirus virus is a dengue virus. In certain non-limiting embodiments, the dengue virus is a dengue 1 virus (DENV-1). In certain non-limiting embodiments, the dengue virus is a dengue 2 virus (DENV-2). In certain non-limiting embodiments, the dengue virus is a dengue 3 virus (DENV-3). In certain non-limiting embodiments, the dengue virus is a dengue 4 virus (DENV-4). In certain non-limiting embodiments, the Flavivirus genus virus is an encephalitis, including Central European encephalitis, Irvine virus encephalitis, Murray Valley encephalitis, St. Louis encephalitis, Japanese encephalitis type B, louping ill, and Russian spring rodent summer encephalitis. In certain non-limiting embodiments, the Flavivirus genus virus is a Japanese encephalitis type B virus.

[0224] In an alternative embodiment, the virus of the Flavivirus genus is selected from the group consisting of Apoivirus, Aroavirus, Bamagavirus, Bagazavirus, Banzivirus, Bubuivirus, Bukalasa bat virus, Cacipakoavirus, Carey Island virus, Cowbone Ridge virus, Dakar bat virus, Edge Hill virus, Entebbe bat virus, Gadget Gully virus, Israeli turkey meningoencephalomyelitis virus, Jugra virus, Jutiapa virus, Kadam virus, Kedougou virus, Kokobera virus, Koutango virus, Kyasanuru Forest disease virus, Langat virus, Meavan virus, Modoc virus, Montana myositis leukoencephalitis virus, Ntaya virus, virus), Omsk hemorrhagic fever virus, Phnom Penh bat virus, Powassan virus, Rio Bravo virus, Royal Farm virus, Savoya virus, Salvieja virus, San Perlita virus, Saumarese reef virus, Sepik virus, Tembusu virus, Tick-borne encephalitis virus, Tyureni virus, Uganda S virus, Ustu virus, Wesselsbron virus, Yaounde virus, and Yokose virus.

[0225] In certain non-limiting embodiments, the Flaviviridae virus is of the Pegivirus genus, hi certain non-limiting embodiments, the Pegivirus genus virus is selected from Pegivirus A, Pegivirus B, Pegivirus C, Pegivirus D, Pegivirus E, Pegivirus F, Pegivirus G, Pegivirus H, Pegivirus I, Pegivirus J, Pegivirus K, and Sifaka Pegivirus.

[0226] Pestivirus infections of the Flaviviridae family include diseases of livestock, primarily swine fever in pigs, BVDV (bovine viral diarrhea virus) infection in cattle, and Border disease virus infection.

[0227] IX. Combination and Alternation Therapy Form III of compound A described herein can be administered in addition to the current standard of care for the patient, or in combination or alternation with any other compound or therapy that the health care provider believes would be beneficial to the patient. The combination and / or alternation therapy can be therapeutic, adjunctive, or symptomatic.

[0228] It is well recognized that drug-resistant mutants of the virus may emerge after long-term treatment with antiviral agents. Drug resistance most typically occurs by mutations in genes that code for enzymes used in viral replication. The efficacy of a drug against an RNA virus infection may be extended, increased, or restored by administering the compound in combination or alternation with another (perhaps even two or three other) antiviral compound that induces different mutations than those of the primary drug or acts via a different pathway. Alternatively, the pharmacokinetics, biodistribution, half-life, or other parameters of the drug may be altered by such combination therapy (which may include alternation therapy, if it is considered to be coordinated). Since the disclosed purine nucleotides are polymerase inhibitors, it may be useful to administer the compound to a host in combination with, for example, (1) protease inhibitors, (2) Another polymerase inhibitor, (3) allosteric polymerase inhibitors, (4) interferon alpha-2a (which may be pegylated or otherwise modified), and / or ribavirin; (5) non-substrate inhibitors, (6) helicase inhibitors, (7) antisense oligodeoxynucleotide (S-ODN), (8) aptamers, (9) nuclease-resistant ribozymes, (10) iRNA, including microRNA and siRNA, (11) An antibody, partial antibody, or domain antibody against a virus, or (12) A viral antigen or partial antigen that induces a host antibody response.

[0229] SARS-CoV-2 Currently, there is only one approved vaccine (Comirnaty, Pfizer-BioNTech) and one approved drug (Veklury, remdesivir) for COVID-19, the disease caused by the SARS-CoV-2 virus. The FDA has issued emergency use authorizations for two other vaccines (manufactured by Janssen Pharmaceuticals and Moderna Therapeutics) and seven antiviral drugs, including molnupiravir, Paxlovid (nilmatreorvir copackaged with ritonavir), Evusheld (tixagevimab copackaged with silgavimab), Actemra (tocilizumab), sotroxivimab, bamlanivimab and etesevimab, and REGEN-COV (casirivimab and imdevimab). However, the spread of the omicron variant of the SARS-CoV-2 virus has led the FDA to restrict the authorization of bamlanivimab and etesevimab, as well as REGEN-COV. As new variants continue to evolve, many of the vaccines and drugs currently authorized for emergency use may become ineffective.

[0230] It has been observed that COVID-19 patients may go through various stages of the disease and standard treatment may differ depending on which stage of the disease the patient presents with or progresses through. COVID-19 has been noted for the occurrence of “crosstalk” between the immune and coagulation systems. As the disease progresses, patients may develop an overreaction by the immune system, which may lead to many serious effects including cytokine storms. Through crosstalk between the immune and coagulation systems, patients may initiate clotting in various areas of the body including the respiratory system, brain, heart, and other organs. Numerous blood clots have been observed throughout the body in COVID-19 patients, necessitating anticoagulant therapy. It is believed that these blood clots may cause long-term or even permanent damage if not treated to mitigate the disease.

[0231] More specifically, COVID-19 has been described as progressing through three general stages: stage 1 (early infection), stage 2 (pulmonary phase), and stage 3 (hyperinflammatory phase / cytokine storm).

[0232] Stage 1 is characterized by non-specific and often mild symptoms. Viral replication is occurring, and it is appropriate to immediately begin treatment with the compounds described herein, possibly in combination or alternation with another antiviral therapy. Interferon-β may also be administered to enhance the natural immune response to the virus. Thus, in certain non-limiting embodiments, Form III of Compound A is used in an effective amount in combination or alternation with interferon-β and / or additional antiviral drugs.

[0233] Stage 2 of COVID-19 is the pulmonary phase where patients may experience acute hypoxemic respiratory failure. In fact, the primary organ failure of COVID-19 is hypoxemic respiratory failure. It has been found that moderate immunosuppression via steroids, such as dexamethasone, may be beneficial for patients with acute hypoxemic respiratory failure and / or patients undergoing mechanical ventilation. In certain non-limiting embodiments, Form III of Compound A is used in an effective amount in combination with a corticosteroid, which may be a glucocorticoid. Non-limiting examples are budesonide (Entocort EC), besamethasone, (Celestone), prednisone (Prednisone Intensol), prednisolone (Orapred, Prelone), triamcinolone (Aristospan Intra-Articular, Aristospan Intralesional, Kenalog), methylprednisolone (Medrol, Depo-Medrol, Solu-Medrol), hydrocortisone, or dexamethasone (Dexamethasone Intensol, DexPak 10Day, DexPak 13Day, DexPak 6Day).

[0234] The final stage of the disease, stage 3, is characterized by progressive disseminated intravascular coagulation (DIC), a condition in which small clots develop throughout the bloodstream. This stage may also include multiple organ failure (e.g., vasodilatory shock, myocarditis). It has also been observed that many patients respond to this severe stage of COVID-19 infection with a "cytokine storm." There appears to be a bidirectional synergistic relationship between DIC and cytokine storm. To combat DIC, patients are often administered anticoagulants, which can be, for example, indirect thrombin inhibitors or direct oral anticoagulants ("DOACs"). Non-limiting examples are low molecular weight heparin, warfarin, bivalirudin (Angiomax), rivaroxaban (Xarelto), dabigatran (Pradaxa), apixaban (Eliquis), or edoxaban (Lixiana). In certain non-limiting embodiments, Form III of Compound A is administered in combination or alternation with anticoagulant therapy. In some severe cases of clotting in COVID patients, TPA (tissue plasminogen activator) can be administered.

[0235] High levels of the cytokine interleukin-6 (IL-6) have been observed to be a predictor of respiratory failure and death in COVID-19 patients. To treat this surge in immune responses that may constitute a cytokine storm, patients can be administered monoclonal antibodies targeting IL-6, pharmaceutical inhibitors, or protein degraders, such as bispecific compounds that bind to IL-6 and also proteins that mediate degradation. Examples of antibodies include tocilizumab, sarilumab, siltuximab, olokizumab, and clazakizumab. In certain non-limiting embodiments, Form III of Compound A is administered in combination or alternation with tocilizumab or sarilumab. Further non-limiting examples of immunosuppressants used to treat an over-reacting immune system include Janus kinase inhibitors (tofacitinib (Xeljanz)); calcineurin inhibitors (cyclosporine (Neoral, Sandimmune, SangCya)), tacrolimus (Astagraf XL, Envarsus XR, Prograf)); mTOR inhibitors (sirolimus (Rapamune), everolimus (Afinitor, Zortress)); and IMDH inhibitors (azathioprine (Azasan, Imuran), leflunomide (Arava), mycophenolic acid (CellCept, Myfortic)). Additional antibodies and biologics include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri), rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra), ustekinumab (Stelara), vedolizumab (Entyvio), basiliximab (Simulect), and daclizumab (Zinbryta).

[0236] IL-1 blocks the production of IL-6 and other proinflammatory cytokines. COVID patients may also be treated with anti-IL-1 therapy, such as intravenous administration of anakinra, to reduce the hyperinflammatory response. Anti-IL-1 therapy may generally be, for example, a targeted monoclonal antibody, a pharmaceutical inhibitor, or a protein degrader, such as a bispecific compound that binds to IL-1 and also to the protein that mediates degradation.

[0237] Patients with COVID often develop viral pneumonia, which can lead to bacterial pneumonia. Patients with severe COVID-19 may also be affected by sepsis or "septic shock." Treatment of bacterial pneumonia or sepsis secondary to COVID includes administration of antibiotics, such as macrolide antibiotics, including azithromycin, clarithromycin, erythromycin, or roxithromycin. Additional antibiotics include amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, or levofloxacin. In certain non-limiting embodiments, Form III of Compound A is thus administered in combination or alternation with an antibiotic, such as azithromycin. Some of these antibiotics, such as azithromycin, have independent anti-inflammatory properties. Such drugs are used as anti-inflammatory agents in COVID patients and may also have therapeutic effects against secondary bacterial infections.

[0238] A particular challenge in treating patients infected with COVID-19 is the need for relatively long-term sedation when the patient requires mechanical ventilation, which may last for 5, 10, or even 14 days or more. For ongoing pain during this treatment, analgesics can be added sequentially, and for ongoing anxiety, sedatives can be added sequentially. Non-limiting examples of analgesics include acetaminophen, ketamine, and PRN opioids (hydromorphone, fentanyl, and morphine). Non-limiting examples of sedatives include melatonin, atypical antipsychotics with predominantly sedative properties (olanzapine, quetiapine), propofol or dexmedetomidine, haloperidol, and phenobarbital. In certain non-limiting embodiments, Form III of Compound A is administered in combination or alternation with a pain reliever, such as acetaminophen, ketamine, hydromorphone, fentanyl, or morphine. In certain non-limiting embodiments, Form III of Compound A is administered in combination or alternation with a sedative, such as melatonin, olanzapine, quetiapine, propofol, dexmedetomidine, haloperidol, or phenobarbital.

[0239] Additional drugs that may be used to treat COVID patients include, but are not limited to, favipiravir, fingolimod (Gilenya), methylprednisolone, bevacizumab (Avastin), Actemra (tocilizumab), umifenovir, losartan, and the monoclonal antibody combinations REGN3048 and REGN3051 or ribavirin. Any of these drugs or vaccines may be used in combination or alternation with Form III of Compound A provided herein to treat such susceptible viral infections.

[0240] In certain non-limiting embodiments, Form III of Compound A is used in an effective amount in combination with an anti-coronavirus vaccine therapy, including, but not limited to, mRNA-1273 (Moderna, Inc.), AZD-1222 (AstraZeneca and University of Oxford), BNT162 (Pfizer and BioNTech), CoronaVac (Sinovac), NVX-CoV 2372 (NovoVax), SCB-2019 (Sanofi and GSK), ZyCoV-D (Zydus Cadila), CoVaxin (Bharat Biotech), and JNJ-78436735 (also known as Ad26.COV2.S, Janssen). In another embodiment, the compounds of the invention are used in an effective amount in combination with passive antibody therapy or convalescent plasma therapy.

[0241] Following entry into the host cell, the SARS-CoV-2 genome is translated by the host ribosome into long polypeptides that are then cleaved into viral proteins. Two proteases, the main protease (M Pro ) and papain-like protease (PL Pro ) performs this function. In certain non-limiting embodiments, Form III of Compound A is used in an effective amount in combination with a protease inhibitor. In certain non-limiting embodiments, Form III of Compound A inhibits SARS-CoV-2 M Pro Used in effective amounts in combination with a protease inhibitor. Pro Non-limiting examples of protease inhibitors include nilmatrervir (Paxlovid), GC376, MAC-5576, PF-07304814, and PF-00835231.

[0242] It may be advantageous to administer a CYP3A4 inhibitor in combination with a protease inhibitor to prevent presystemic metabolism of the protease inhibitor. In certain non-limiting embodiments, Form III of Compound A is used in an effective amount in combination with a protease inhibitor in addition to a CYP3A4 inhibitor, including, but not limited to, ritonavir, cobicistat, and ketoconazole.

[0243] SARS-CoV-2 is constantly mutating, which may increase its virulence and transmission rate. Drug-resistant variants of the virus may emerge after long-term treatment with antiviral drugs. Drug resistance may arise through mutations in genes that code for enzymes used in viral replication. The efficacy of a drug against an RNA virus infection in certain cases may be extended, increased, or restored by administering the compound in combination or alternation with another, and perhaps even two or three, other antiviral compounds that induce different mutations or act via different pathways than the primary drug.

[0244] HCV For the treatment of HCV, it may be useful to administer Form III of Compound A to the host in combination with, for example, the following: (1) Protease inhibitors such as NS3 / 4A protease inhibitors, (2) another NS5A inhibitor, (3) another NS5B polymerase inhibitor, (4) NS5B non-substrate inhibitors (5) interferon alpha-2a (which may be pegylated or otherwise modified), and / or ribavirin; (6) non-substrate inhibitors, (7) helicase inhibitors, (8) antisense oligodeoxynucleotide (S-ODN), (9) aptamer, (10) nuclease-resistant ribozymes, (11) iRNA, including microRNA and siRNA, (12) An antibody, partial antibody, or domain antibody against a virus, or (13) A viral antigen or partial antigen that induces a host antibody response.

[0245] Non-limiting examples of additional anti-HCV agents that may be further administered in combination or alternation with Form III of Compound A include: (i) protease inhibitors such as telaprevir (Incivek™), boceprevir (Victrelis™), simeprevir (Olysio™), paritaprevir (ABT-450), glecaprevir (ABT-493), ritonavir (Norvir), ACH-2684, AZD-7295, BMS-791325, danoprevir, filibusir, GS-9256, GS-9451, MK-5172, ruzasvir (MK-8408), setrobuvir, sovaprevir, tegobuvir, VX-135, VX-222, ALS-220, and voxilaprevir; (ii) NS5A inhibitors such as ACH-2928, ACH-3102, IDX-719, daclatasvir, redispasvir, velpatasvir (Epclusa), elbasvir (MK-8742), grazoprevir (MK-5172), and ombitasvir (ABT-267); (iii) NS5B inhibitors such as AZD-7295, clemizole, dasabuvir (Exviera), ITX-5061, PPI-461, PPI-688, sovosbuvir (Sovaldi™), MK-3682, and mericitabine; (iv) NS5B inhibitors such as ABT-333 and MBX-700, (v) antibodies such as GS-6624, (vi) Combination medications such as Harvoni (ledipasvir / sovosbuvir); Viekira Pak (ombitasvir / paritaprevir / ritonavir / dasabuvir); Viekirax (ombitasvir / paritaprevir / ritonavir); G / P (paritaprevir and glecaprevir); Technivie™ (ombitasvir / paritaprevir / ritonavir), Epclusa (sovosbuvir / velpatasvir), Zepatier (elbasvir and grazoprevir), Mavyret (glecaprevir and pibrentasvir), and Vosevi (sovosbuvir, velpatasvir, and voxilaprevir), Examples include:

[0246] When Form III of Compound A is administered to treat advanced Hepatitis C virus leading to liver cancer or cirrhosis, in certain non-limiting embodiments, Form III of Compound A can be administered in combination or alternation with another drug typically used to treat hepatocellular carcinoma (HCC), for example, as described by Andrew Zhu in "New Agents on the Horizon in Hepatocellular Carcinoma" Therapeutic Advances in Medical Oncology, V 5(1), January 2013, 41-50. Examples of compounds suitable for combination therapy when the host suffers from or is at risk of HCC include antiangiogenic agents, sunitinib, brivanib, linifanib, ramucirumab, bevacizumab, cediranib, pazopanib, TSU-68, lenvatinib, antibodies against EGFR, mTor inhibitors, MEK inhibitors, and histone deacetylase inhibitors, capecitabine, cisplatin, carboplatin, doxorubicin, 5-fluorouracil, gemcitabine, irinotecan, oxaliplatin, topotecan, and other topoisomerase. In certain non-limiting embodiments, form III of compound A is administered to a patient suffering from HCV infection in combination with ruzasvir (MK-8408).

[0247] In certain non-limiting embodiments, the aforementioned additional therapeutic agents are administered as pharma- ceutically acceptable salts, for example, the salts described below. The term "salts" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present disclosure. These salts can be prepared during the final isolation and purification of the compounds, or by separately reacting the purified compounds in their free base form with a suitable organic or inorganic acid and isolating the salt formed thereby. Basic compounds are capable of forming a wide variety of salts with various inorganic and organic acids. Acid addition salts of basic compounds are prepared in a conventional manner by contacting the free base form with a sufficient amount of the desired acid to produce a salt. The free base form can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base forms may differ from their respective salt forms in certain physical properties, such as solubility in polar solvents. Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, calcium, etc. Examples of suitable amines include, but are not limited to, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine. The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in a conventional manner. The free acid form can be regenerated by contacting the salt form with an acid in a conventional manner and isolating the free acid. The free acid forms may differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents.

[0248] Salts can be prepared from inorganic acids such as sulfate, pyrosulfate, bisulfate, sulfurous acid, bisulfite, nitric acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, etc. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, isethionate, and the like. Salts can also be prepared from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Salts of amino acids such as arginate, gluconate, galacturonate, etc. are also contemplated. See, e.g., Berge et al., J. Pharm. Sci., 1977, 66, 1-19, incorporated herein by reference.

[0249] Treatment for additional RNA viruses The drugs currently approved for influenza are amantadine, rimantadine, baloxavir marboxil (Xofluza™), oseltamivir phosphate (Tamiflu™), zanamivir (Relenza™), and peramivir (Rapivab™). Any of these drugs may be used in combination or alternation with the active compounds provided herein to treat such susceptible viral infections.

[0250] Currently, there is no approved drug for West Nile Virus. Doctors are recommended to provide intensive supportive care, which may include hospitalization, intravenous fluids, use of a ventilator to assist breathing, medication to control seizures, brain swelling, nausea and vomiting, and the use of antibiotics to prevent bacterial infections that further exacerbate the disease. This highlights the importance of this compound in viral medical therapy.

[0251] Additionally, there is no vaccine or specific treatment for Zika virus. Instead, the focus is on rest, hydration, and symptom relief, including acetaminophen for fever and pain.

[0252] There is no vaccine or specific treatment for dengue. Supportive care for infected individuals includes fluids and painkillers, along with acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs to treat fever and other symptoms.

[0253] Yellow fever vaccine (YF-Vax) is manufactured by Sanofi Pasteur, Inc. and is recommended for people 9 years of age and older traveling to high-risk areas, including South America and Africa. In certain non-limiting embodiments, Form III of Compound A is administered to the host in combination with YF-Vax. There is no cure for yellow fever, but the focus is on relieving fever, muscle pain, and dehydration. Aspirin and nonsteroidal drugs are not recommended due to the risk of internal bleeding. EXAMPLES

[0254] Example 1. Preparation of Form III of Compound A Compound B (150 g) was added to acetone (180 mL) and the mixture was stirred at 20°C-30°C to obtain a solution. Then, sulfuric acid (12.6 g, 0.5 equiv.) was added slowly at 15°C-20°C to gradually precipitate the solid. The mixture was stirred at 15°C-20°C for 30 min, then stirred at 40°C-45°C for 4-5 h. The mixture was cooled to 25°C-30°C, stirred at this temperature for 1 h, and the mixture was filtered. The resulting cake was rinsed with acetone (150 mL).

[0255] The wet material was dissolved in methanol (150 ml) at 30° C.-40° C., acetone (450 ml) was added, and then additional acetone was added slowly at 40° C.-45° C. The mixture was stirred at 40° C.-45° C. for 8-10 h, then cooled to 25° C.-30° C. The mixture was filtered and the resulting cake was rinsed with acetone (150 mL). The XRPD pattern of wet Compound A Form III is shown in FIG. 1, and the peaks are listed in Table 1. The peaks in the table correspond to the numbered peaks in FIG. 1.

[0256] The wet material was dried under vacuum at 30° C.-35° C. for 4-5 hours, then dried under vacuum at 50° C.-60° C. for about 15 hours to obtain dried Compound A Form III (130 g) in 87% yield. The XRPD pattern of Compound A Form III is shown in FIG. 2 and the peaks are listed in Table 2. The peaks in the table correspond to the numbered peaks in FIG. 2.

[0257] [Table 1]

[0258] [Table 2]

[0259] Alternatively, Compound A Form III was also prepared by placing Compound A (2 g) in a mixture of methanol (4 ml) and acetone (24 ml). The mixture was stirred at 30° C. for 20 hours. Following filtration, the wet material was dried at 60° C. for 20 hours without vacuum to obtain Compound A Form III (1.7 g, 85% yield).

[0260] Example 2. Preparation of additional Compound A forms In addition to Form III, four other forms of Compound A were prepared: Forms I and II, as well as Forms IV and V. The solvents and conditions for each form are shown in Table 3, and the analytical results for each form are shown in Table 4. The XRPD overlap of the five forms is shown in Figure 3. The preparation of each form is described below.

[0261] [Table 3]

[0262] [Table 4]

[0263] Form I Compound B (50 g) was placed in methanol (100 mL) and acetone (150 mL). The mixture was heated to about 50° C. to obtain a clear solution. Sulfuric acid (4 g) was added slowly and the mixture remained in solution. Acetone (600 mL) was slowly added at 50° C.-55° C., after which the mixture was cooled to 25° C.-30° C. and stirred at this temperature for 16-20 hours. A white solid started to precipitate at 36° C. The solid was then collected by suction and the cake was rinsed with a mixed solvent of methanol and acetone (10 mL+150 mL). The material was dried at 55° C. for 18 hours without vacuum to obtain 40 g of Compound A Form I in 75% yield. The XRPD pattern for Form I is shown in FIG. 4.

[0264] Alternatively, Form I was also prepared by adding Compound B (5 g) to acetone (60 mL). The mixture was stirred at 20°C-30°C to obtain a clear solution. Sulfuric acid (0.42 g, 0.5 equiv.) was added slowly at 15°C-20°C. Solids gradually precipitated during the addition. The mixture was stirred at 15°C-20°C for 30 min and then at 30°C-45°C for 2 h. The mixture was cooled to 25°C. Following filtration, the cake was rinsed with acetone (10 mL). The wet material was dried at 40°C for 2 h without vacuum and then at 60°C for 20 h without vacuum to obtain Form I of Compound A (4.8 g, 96% yield).

[0265] Form II Compound A (50 g) was placed in isopropanol (500 mL) and the mixture was heated to 50° C.-55° C. to obtain a clear solution. Isopropyl acetate (250 mL) was then added slowly and the mixture remained in solution. A seed of compound A (100 mg) was added. After stirring for 1 hour, some solids gradually precipitated and then isopropyl acetate (250 mL) was added slowly. The mixture was stirred at 45° C.-50° C. for 20 hours, after which the heating was stopped and the temperature was slowly reduced to about 25° C.-30° C. The solid was then filtered, washed with isopropyl acetate (50 mL) and dried in vacuum at 25° C.-30° C. for 4 hours. The material was then crushed and continued to dry in vacuum at 60° C. for 16 hours to obtain Form II of compound A (45 g, 90% yield). The XRPD pattern for Form II is shown in FIG. 5.

[0266] Form III Instead of the procedure described in Example 1, compound A (100 g) was placed in methanol (100 mL) and the mixture was heated to 50° C. to obtain a clear solution. Acetone (300 mL) was then added slowly at 45° C.-50° C. The system remained completely dissolved after cooling. Then 100 mg of compound A form III seeds were added. After stirring for 1 hour, the solid gradually precipitated. Acetone (300 mL) was added slowly with stirring at 45° C.-50° C. for 1 hour. After addition, the mixture was stirred at 40° C.-45° C. for 18 hours. Then, heating was stopped and the temperature was slowly lowered to about 25° C.-30° C. The solid was filtered, washed with acetone (100 mL), and dried in vacuum at 60° C. for 16 hours to obtain 90 g of compound A form III in 90% yield.

[0267] Form IV Compound A (120 g) was placed in methyl acetate (1200 mL) and the mixture was then slurried at about 55° C. for 20 hours. After that, the heating was stopped and the temperature was slowly lowered to about 25° C.-30° C. The solid was then filtered, washed with methyl acetate (100 mL) and dried in vacuum at 60° C. for 18 hours to obtain 105 g of Form IV of Compound A in 87.5% yield. The XRPD pattern for Form IV is shown in FIG. 6.

[0268] Form V Compound A (100 g) was placed in ethyl acetate (1000 mL) and the mixture was then slurried at about 78° C. for 20 hours. After that, heating was stopped and the temperature was slowly lowered to about 25° C.-30° C. The solid was then filtered, washed with ethyl acetate (100 mL) and dried in vacuum at 60° C. for 16 hours to obtain 96 g of Compound A Form V in 96% yield. The XRPD pattern for Form V is shown in FIG. 7.

[0269] In another method, compound B (75 g) was added to ethyl acetate (750 mL) and the mixture was heated to 60°C-65°C to obtain a clear solution. Sulfuric acid (6.45 g, 0.5 equiv.) was then added slowly undiluted at 60°C-65°C, during which the solid gradually precipitated. The resulting mixture was heated to about 78°C and then stirred at this temperature for 20 hours. The mixture was then cooled to 25°C-30°C and stirred at this temperature for 3 hours. The white solid was collected by suction and the cake was rinsed with ethyl acetate (100 mL). After drying at 60°C for 5 hours without vacuum, the material was ground using a blade mill. The material was dried again at 55°C for 16 hours without vacuum.

[0270] Example 3. Large scale preparation of Compound A Form III from Compound A A 5 L round bottom flask equipped with a mechanical stirrer was charged with acetone (3200 g, 4000 mL, 10V) at 20°C-30°C. Compound A (200 g) was then added to obtain a suspension. The mixture was then heated and stirred at 55°C-58°C for 1 h before a second charge of Compound A (200 g) was added over 5 min. The mixture was heated and stirred at 55°C-58°C for 16 h, then cooled to 20°C-25°C over 4 h, and stirred at 20°C-25°C for an additional 2 h. The solid was filtered (controlling environmental humidity below 40%) and then rinsed with acetone (400 mL, 1 volume) to obtain Compound A as a wet cake (980 g).

[0271] A 10 L four-neck glass flask was fitted with a thermometer and n-heptane (6000 ml) was charged to the flask at 10° C.-20° C. Compound A (980 g, wet cake) was charged in one portion at 10° C.-20° C. The mixture was stirred at 0° C.-5° C. for 2 hours. The solid was collected by filtration to obtain the wet cake as a white solid (1.1 kg). The wet cake was placed on two trays (30 cm×40 cm) and dried in a vacuum oven (−0.09 MPa) at 35° C. for 20 hours. Drying was continued at 55° C. under vacuum (−0.09 MPa) for 8 hours. Drying was continued at 55° C. under vacuum (−0.090 MPa) for 16 hours to obtain Compound A Form III in 90% yield. The XRPD pattern for the product of Example 3 is shown in FIG. 8.

[0272] Example 4. Large scale preparation of Form III of Compound A from Compound B Acetone (2000 g, 2500 mL, 10 V) was charged to a 5 L three-neck glass flask equipped with a mechanical stirrer, addition funnel, and thermometer at an internal temperature of 20°C-30°C. Compound B (250 g, 90% assay by titration) was charged in one portion with stirring. After stirring for approximately 5 minutes at 20°C-30°C, a clear solution was formed. Charcoal (7.5 g) was then charged to the solution and the resulting mixture was stirred for 30 minutes at 20°C-30°C. The charcoal was filtered and washed with acetone (200 g, 250 mL, 1 V).

[0273] The filtrate was added to a 5 L three-neck glass flask. Sulfuric acid (98% w / w, 19.3 g, 0.5 equiv.) was added dropwise to the solution over 2 h at 20°C-30°C. The suspension was aged at 20°C-25°C for 30 min, then heated to 55°C-58°C and aged for 16 h. The suspension was then cooled to 25°C within 3 h (cooling rate 5°C-10°C / h) and aged at 25°C for 1 h. The solid was filtered (humidity was kept below 40%). The wet cake was washed with acetone (400 g, 500 mL, 2 V) at room temperature to obtain Compound A wet cake (480 g).

[0274] A 10 L 4-neck glass flask equipped with a thermometer was charged with n-heptane (3750 ml) at 10° C.-20° C. Compound A wet cake (480 g) was added to the reactor in one portion at 10° C.-20° C. The mixture was stirred at 0° C.-5° C. for 2 hours. The solid was collected by filtration to obtain Compound A (450 g, wet cake) as an off-white solid. The wet cake was placed on a tray and dried in a vacuum oven (−0.09 MPa) at 35° C. for 20 hours. The oven temperature was increased to 50° C. and the compound was dried under vacuum (−0.09 MPa) for 8 hours. Drying was continued at 50° C. in vacuum (−0.09 MPa) for 16 hours to obtain Compound A Form III (85% yield). The XRPD pattern of the product of Example 4 is shown in FIG. 9.

[0275] Example 5. Dissolution Rates of Compound A Tablets Made with Amorphous API and Tablets Made from Form III API Dissolution is according to the United States Pharmacopoeia <711> The solubility was determined by a standardized solubility assay using a basket apparatus (USP Apparatus I). Compound A Form III and amorphous tablets of Compound A described above were dissolved in 0.1N HCl in USP Apparatus I. Samples were taken at various time points and analyzed by UHPLC-UV to quantify the amount of Compound A dissolved.

[0276] The conditions are as follows:

[0277] [Table 5]

[0278] Determination of UHPLC detection conditions and dissolution rate

[0279] [Table 6]

[0280] [Table 7]

[0281] [Table 8]

[0282] The tablets used in the dissolution rate study were prepared according to the following method:

[0283] [Table 9]

[0284] Granule preparation: Into a V blender, half of the SMCC, colloidal silicon dioxide, and half of the croscarmellose sodium were added. The mixture was then blended. Mannitol was added to the mixture, and the resulting mixture was blended and sieved. Magnesium stearate was sieved and then added to the blend and blended. The blend was then collected and granulated.

[0285] Tablet preparation: The granules were added to a V-blender followed by sieved Croscarmellose sodium and SMCC. The mixture was blended and then sieved Magnesium Stearate was added. The resulting mixture was blended and then compressed into tablets.

[0286] Example 6. Stability of a 5 kg lot of Form III at 25° C.±2° C. and 60% RH±5% RH

[0287] [Table 10]

[0288] As measured by HPLC-UV, Compound A Form III exhibits no measurable degradation over a period of 3 months when stored at about 25° C. and about 60% RH. This advantageous chemical stability is an improvement over amorphous forms of the compound, including spray-dried amorphous forms that require refrigerated storage. Compound A Form III also does not appreciably absorb water from the atmosphere or change density upon storage. These properties are advantageous for use in clinical trials or for clinical use of the compound.

[0289] Example 7. Stability of a 5 kg lot of Form III at 40° C.±2° C. and 75% RH±5% RH

[0290] [Table 11]

[0291] Further studies were conducted on the stability of Compound A Form III at elevated temperatures and humidity. These conditions are less desirable for storage of active pharmaceutical ingredients and can lead to accelerated degradation. However, even under these conditions, Compound A Form III showed no measurable degradation over a period of three months.

[0292] Example 8. Stability of 0.1 kg Lot of Form III

[0293] [Table 12]

[0294] Additional stability studies were performed on smaller lots of Compound A Form III. These studies were performed in stability chambers set at 25° C. and 60% RH, 40° C. and 75% RH for up to 8 weeks. In other embodiments, studies can be performed for up to 4 weeks, up to 2 weeks, and 1 week. Stability studies were also performed under ambient conditions at 15° C. to 25° C. without humidity control. The study was performed for 12 months with no measurable loss in purity of Compound A Form III.

[0295] [Table 13]

[0296] [Table 14]

[0297] Example 9. Pharmaceutical Composition 1 of Form III of Compound A

[0298] [Table 15]

[0299] Half of the Prosolv SMCC 90 LM was added to a V-blender and blended for 1 minute. To this was added Compound A Form III, Aerosil 200, Ac-Di-Sol SD-711, and the remaining half of the Prosolv SMCC 90 LM. The mixture was then blended for 3 minutes. Pearlitol 100 SD was added and the resulting mixture was blended for 3 minutes. The mixture was then sieved through a US 12 mesh screen. Ligamed MF-2V was then sieved through a US 20 mesh screen and added to the blend. The resulting mixture was blended for 2 minutes. The resulting mixture was double bagged with a desiccant pack inserted between the bags and sealed in a drum for storage.

[0300] The roller compactor was set up with smooth rollers, a micro hopper, a 1.0 mm screen, a 2 mm gap width, a compaction force of 5 kN / cm, and a roller speed of 1 revolution / min. Compound A blend was then added to the hopper and replenished as needed during processing. The material from the roller compactor was collected in a dry granulation bag.

[0301] The extragranular Ac-Di-Sol SD-711 and Prosolv SMCC 90 LM were sieved through a US 12 mesh screen and blended with the granulation materials for 3 minutes. Next, LIGAMED MF-2-V was sieved through a US 20 mesh screen and added to the blend. The resulting mixture was blended for 2 minutes.

[0302] Example 10. Pharmaceutical Composition 2 of Form III of Compound A

[0303] [Table 16]

[0304] Half of the Vivapur 105 was added to a V blender and blended for 1 minute. To this was added Compound A Form III, the remaining half of Vivapur 105, Aerosil 200, and Ac-Di-Sol SD-711 and blended for 3 minutes. Emcompress (anhydrous) was then added to the blend and blended for an additional 3 minutes. The blend was then sieved through a US 12 mesh screen. LIGAMED MF-2-V was then sieved through a US 20 mesh screen and added to the blend. The resulting mixture was blended for 2 minutes. The resulting mixture was double bagged with a desiccant pack inserted between the bags and sealed in a drum for storage.

[0305] The roller compactor was set up with smooth rollers, a micro hopper, a 1.0 mm screen, a 2 mm gap width, a compaction force of 5 kN / cm, and a roller speed of 1 revolution / min. Compound A blend was then added to the hopper and replenished as needed during processing. The material from the roller compactor was collected in a dry granulation bag.

[0306] The extragranular Ac-Di-Sol SD-711 and Prosolv SMCC 90 LM were sieved through a US 12 mesh screen and blended with the granulation materials for 3 minutes. Next, LIGAMED MF-2-V was sieved through a US 20 mesh screen and added to the blend. The resulting mixture was blended for 2 minutes and then collected in a bag.

[0307] Example 11. Pharmaceutical Composition 3 of Form III of Compound A In Examples 11-14, reference is made to tablets of 275 mg and 550 mg, this being the weight of nucleotide without hemisulfate.

[0308] [Table 17]

[0309] Pharmaceutical composition 3 of Form III of Compound A can be prepared according to the procedures described in Examples 9 and 10.

[0310] Example 12. Pharmaceutical Composition 4 of Form III of Compound A

[0311] [Table 18]

[0312] Pharmaceutical composition 4 of Form III of Compound A can be prepared according to the procedures described in Examples 9 and 10.

[0313] Example 13. Pharmaceutical Composition of Form III of Compound A

[0314] [Table 19]

[0315] Pharmaceutical composition 5 of Form III of Compound A can be prepared according to the procedures described in Examples 9 and 10.

[0316] Example 14. Pharmaceutical Composition 6 of Form III of Compound A

[0317] [Table 20]

[0318] Pharmaceutical composition 6 of Form III of Compound A can be prepared according to the procedures described in Examples 9 and 10.

[0319] The specification has been described with reference to embodiments of the present invention. However, those skilled in the art will appreciate that various modifications and changes can be made without departing from the scope of the present invention as set forth in the appended claims. Accordingly, the specification is to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of the present invention.

Claims

【Request 1】 【Chemistry 1】 and is characterized by an XRPD pattern comprising at least three 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°.

2. Compound A of form III described in claim 1, characterized by an XRPD pattern comprising at least four 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°.

3. 2. Form III of Compound A according to claim 1, characterized by an XRPD pattern comprising at least five 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°.

4. 2. Form III of Compound A according to claim 1, characterized by an XRPD pattern comprising at least six 2-theta values ​​selected from 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 10.4±0.2°, 13.6±0.2°, 14.7±0.2°, 17.0±0.2°, 18.2±0.2°, 19.9±0.2°, and 21.8±0.2°.

5. Compound A of form III as described in claim 1, characterized by an XRPD pattern including the following 2-theta values: 5.2±0.2°, 7.3±0.2°, 8.9±0.2°, 13.6±0.2°, 17.0±0.2°, 19.9±0.2°, and 21.8±0.2°.

6. A pharmaceutical composition comprising compound A in form III according to any one of claims 1 to 5 and a pharma- ceutically acceptable carrier.

7. The pharmaceutical composition of claim 6 , which is in a solid dosage form.

8. The pharmaceutical composition of claim 7 , wherein the solid dosage form is a tablet.

9. The pharmaceutical composition of claim 7 , wherein the solid dosage form is a capsule.

10. 10. The pharmaceutical composition of any one of claims 6 to 9, comprising at least about 300 mg of Form III of Compound A.

11. The pharmaceutical composition of claim 6, which is divided into unit dosage forms.

12. The pharmaceutical composition of claim 11, which is divided into two unit dosage forms.

13. 13. The pharmaceutical composition of any one of claims 6 to 12, comprising about 400 mg to about 1000 mg of Form III of Compound A.

14. 13. The pharmaceutical composition of any one of claims 6 to 12, comprising about 500 mg to about 800 mg of Form III of Compound A.

15. 13. The pharmaceutical composition of any one of claims 6 to 12, comprising about 600 mg of Form III of Compound A.

16. The pharmaceutical composition of claim 12, comprising approximately 600 mg of Compound A in Form III, divided into two unit dosage forms, each dosage form containing approximately 300 mg of Compound A in Form III.

17. A pharmaceutical composition for treating a human in need of treatment for HCV comprising compound A in form III of any one of claims 1 to 6 and a pharma- ceutically acceptable carrier.

18. The pharmaceutical composition of claim 17, which is a solid dosage form.

19. The pharmaceutical composition of claim 18, wherein the solid dosage form is a tablet.

20. The pharmaceutical composition of claim 18, wherein the solid dosage form is a capsule.

21. The pharmaceutical composition of any one of claims 17 to 20, comprising about 300 mg of Form III of Compound A.

22. The pharmaceutical composition of claim 17, wherein the composition is divided into unit dosage forms.

23. The composition of claim 22, separated into two unit dosage forms.

24. The pharmaceutical composition of any one of claims 17 to 23, comprising about 400 mg to about 1000 mg of Form III of Compound A.

25. The pharmaceutical composition of any one of claims 17 to 23, comprising about 500 mg to about 800 mg of Form III of Compound A.

26. The pharmaceutical composition of any one of claims 17 to 23, comprising about 600 mg of Form III of Compound A.

27. The pharmaceutical composition of claim 23, comprising approximately 600 mg of Compound A in Form III, divided into two unit dosage forms, each dosage form containing approximately 300 mg of Compound A in Form III.

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