Solid forms of a toll-like receptor modulator

1. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (Compound I):

characterized by an X-ray powder diffraction (XRPD) pattern comprising three or more peaks at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ(±0.2° 2θ), Form I.

2. The crystalline form of claim 1 , characterized by an XRPD pattern comprising four or more peaks at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ(±0.2° 2θ).

3. The crystalline form of claim 1 , characterized by an XRPD pattern comprising peaks at 15.5°, 21.4°, and 21.9° (±0.2° 2θ).

4. The crystalline form of claim 3 , wherein the XRPD pattern further comprises one or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9° 2θ(±0.2° 2θ).

5. The crystalline form of claim 3 , wherein the XRPD pattern further comprises two or more additional peaks at 10.9°, 11.5°, 13.2°, 14.7°, 23.2°, or 24.9° 2θ(±0.2° 2θ).

6. The crystalline form of claim 1 , characterized by an XRPD pattern comprising peaks at 10.9°, 13.2°, and 14.7° 2θ(±0.2° 2θ).

7. The crystalline form of claim 6 , wherein the XRPD pattern further comprises one or more additional peaks at 11.5°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ(±0.2° 2θ).

8. The crystalline form of claim 6 , wherein the XRPD pattern further comprises two or more additional peaks at 11.5°, 15.5°, 21.4°, 21.9°, 23.2°, or 24.9° 2θ(±0.2° 2θ).

9. The crystalline form of claim 1 , characterized by an XRPD pattern comprising peaks at 10.9°, 11.5°, 13.2°, 14.7°, 15.5°, 21.4°, 21.9°, 23.2°, and 24.9° 2θ(±0.2° 2θ).

10. The crystalline form of claim 1 , characterized by a unit cell as determined by single crystal X-ray crystallography of the following dimensions: a=8.0344 (2) Å; b=8.0344 (2) Å; c=23.7871 (7) Å; α=90°; β=90°; and γ=90°.

11. The crystalline form of claim 1 , characterized by an XRPD pattern substantially as shown in FIG. 1 .

12. The crystalline form of claim 1 , characterized by a differential scanning calorimetry (DSC) thermogram having an endotherm with an onset of about 164° C.

13. The crystalline form of claim 1 , characterized by a DSC thermogram substantially as shown in FIG. 2 .

14. A crystalline form of (R)-2-(2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hydrochloride:

characterized by an XRPD pattern comprising three or more peaks at 6.1°, 12.2°, 15.0°, 17.3°, 17.8°, 18.9°, 20.3°, 23.2°, or 24.1° 2θ(±0.2° 2θ), hydrochloride salt Form I.

15. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol hydrochloride:

characterized by an XRPD pattern comprising three or more peaks at 7.1°, 9.7°, 14.3°, 15.3°, 16.1°, 19.1°, 22.5°, 24.0°, or 26.0° 2θ(±0.2° 2θ), hydrochloride salt Form II.

16. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol tartaric acid:

characterized by an XRPD pattern comprising three or more peaks at 6.3°, 9.9°, 12.5°, 17.7°, 18.3°, 19.2°, 23.4°, 25.7°, or 28.1° 2θ(±0.2° 2θ), Compound I tartaric acid.

17. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol maleic acid:

characterized by an XRPD pattern comprising three or more peaks at 7.3°, 8.4°, 8.8°, 13.9°, 15.6°, 17.7°, 20.7°, 24.7°, or 27.4° 2θ(±0.2° 2θ), Compound I maleic acid.

18. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol fumaric acid:

characterized by an XRPD pattern comprising three or more peaks at 6.7°, 8.3°, 10.1°, 12.6°, 16.1°, 18.5°, 20.6°, 25.2° or 27.6° 2θ(±0.2° 2θ), Compound I fumaric acid.

19. A crystalline form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol methanesulfonic acid:

characterized by an XRPD pattern comprising three or more peaks at 5.4°, 10.4°, 10.8°, 15.8°, 17.3°, 18.1°, 20.5°, 20.8°, or 23.9° 2θ(±0.2° 2θ), Compound I methanesulfonic acid.

20. An amorphous solid form of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol:

21. A pharmaceutical composition comprising the crystalline form of claim 1 or the amorphous form of claim 20 and one or more pharmaceutically acceptable excipients.

22. The pharmaceutical composition of claim 21 , wherein the crystalline form is Form I.

23. A method of treating or preventing a hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the crystalline form of claim 1 , the amorphous form of claim 20 , or the pharmaceutical composition of claim 21 .

24. The method of claim 23 , further comprising administering a therapeutically effective amount of one or more additional therapeutic agents.

25. The method of claim 23 , wherein the one or more additional therapeutic agents are administered simultaneously with the crystalline form or the pharmaceutical composition.

26. The method of claim 23 , wherein the one or more additional therapeutic agents are selected from the group consisting of: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors, and other HBV drugs.

27. The method of claim 23 , wherein the one or more additional therapeutic agents are selected from the group consisting of: adefovir, tenofovir disoproxil fumarate+emtricitabine, tenofovir disoproxil fumarate entecavir, lamivudine, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine, emtricitabine, peginterferon alfa-2b interferon alpha interferon alpha 1b, interferon 2b, pegylated interferon alpha-2a, interferon alfa-n1, ribavirin, interferon beta-1a, Bioferon, Ingaron, Inmutag, Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b, Alfaferone, Feron, interferon-alpha 2, Bevac, Laferonum, Vipeg, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin 2, Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin.

28. The method of claim 23 , wherein the one or more additional therapeutic agents are selected from the group consisting of: entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine and lamivudine.

29. The method of claim 23 , wherein the one or more additional therapeutic agents are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate.