Choline salt forms of an HIV capsid inhibitor

1. A method of treating or preventing a human immunodeficiency virus (HIV) infection comprising administering a therapeutically effective amount of a pharmaceutically acceptable salt, which is N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide N,N,N-trimethylethanolammonium salt, or the crystalline form of the salt, to a subject in need thereof.

2. The method of claim 1 , wherein the method comprises administering the salt or crystalline form in combination with one, two, three, or four additional therapeutic agents.

3. The method of claim 2 , wherein the additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combinations thereof.

4. The method of claim 2 , wherein the additional therapeutic agents are selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combinations thereof.

5. The method of claim 2 , wherein the additional therapeutic agents are selected from the group consisting of 4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate.

6. The method of claim 2 , wherein the additional therapeutic agents are selected from the group consisting of 4′-ethynyl-2-fluoro-2′-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

7. The method of claim 1 , wherein the method comprises administering a therapeutically effective amount of N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide N,N,N-trimethylethanolammonium salt.

8. The method of claim 1 , wherein the method comprises administering a therapeutically effective amount of a crystalline form of the salt of claim 1 .

9. The method of claim 8 , wherein the crystalline form is crystalline Form I.

10. The method of claim 9 , wherein the crystalline Form I has at least three XRPD peaks, in terms of 2-theta±0.2°, selected from 5.5°, 7.5°, 7.9°, 14.9°, 15.7°, 16.8°, 17.6°, 19.3°, and 22.4°.

11. The method of claim 9 , wherein the crystalline Form I is characterized by an XRPD pattern substantially as shown in FIG. 4 .

12. The method of claim 9 , wherein the crystalline Form I is characterized by a DSC thermogram having a melting onset of about 157° C.

13. The method of claim 9 , wherein the crystalline Form I is characterized by a DSC thermogram substantially as shown in FIG. 5 .

14. The method of claim 8 , wherein the crystalline form is crystalline Form II.

15. The method of claim 14 , wherein the crystalline Form II has at least three XRPD peaks, in terms of 2-theta±0.2°, selected from 7.5°, 9.6°, 14.0°, 14.9°, 16.1°, 16.9°, 20.8°, 21.0°, and 26.5°.

16. The method of claim 14 , wherein the crystalline Form II is characterized by an XRPD pattern substantially as shown in FIG. 6 .

17. The method of claim 14 , wherein the crystalline Form II is characterized by a DSC thermogram having a melting onset of about 147° C.

18. The method of claim 14 , wherein the crystalline Form II is characterized by a DSC thermogram substantially as shown in FIG. 7 .

19. The method of claim 8 , wherein the crystalline form is crystalline Form III.

20. The method of claim 19 , wherein the crystalline Form III has at least three XRPD peaks, in terms of 2-theta±0.2°, selected from 7.8°, 8.1°, 8.3°, 15.0°, 15.7°, 16.7°, 20.0°, 21.1°, and 21.7°.

21. The method of claim 19 , wherein the crystalline Form III is characterized by an XRPD pattern substantially as shown in FIG. 8 .

22. The method of claim 19 , wherein the crystalline Form III is characterized by a DSC thermogram having a melting onset of about 144° C.

23. The method of claim 19 , wherein the crystalline Form III is characterized by a DSC thermogram substantially as shown in FIG. 9 .