Capsid inhibitors for treatment of HIV

Abstract

To provide capsid inhibitors for the treatment of HIV.SOLUTION: This disclosure relates to compounds of formula (Ia) and (Ib) useful in the treatment of HIV infections in a heavily treatment-experienced patient with multidrug resistant HIV infection, or to pharmaceutically acceptable salts thereof. In one embodiment, this disclosure relates to the use of the compound of formula (Ia) or formula (Ib), or the pharmaceutically acceptable salt thereof, in the treatment of infection caused by the HIV virus, comprising administering a therapeutically effective amount to a patient in need thereof, the patient being the heavily treatment-experienced patient with the multidrug-resistant HIV infection.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of U.S. Provisional Application No. 62 / 698,611, filed on Jul. 16, 2018, the entire content of which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to methods for the treatment of human immunodeficiency virus (HIV) infection in patients with a history of heavy treatment experience (e.g., patients with multidrug - resistant HIV infection).

Background Art

[0003] The viral capsid protein (CA) is essential at multiple stages of the HIV life cycle. During virus maturation after processing of the Gag polyprotein by HIV protease, CA self - assembles into the conical core that is characteristic of mature HIV - 1 virions. Contained within this capsid core are viral RNA, nucleocapsid, reverse transcriptase, and integrase. Failure to generate an appropriate core impedes infectivity. In addition, CA contributes to multiple major processes, including regulation of proper capsid core disassembly (uncoating) kinetics to ensure efficient and productive viral DNA synthesis via linked reverse transcription during the early stages of HIV replication, and contributes to the active transport of the pre - integration complex to the nuclear fraction to assist viral DNA integration into transcriptionally active loci. Defects in proper capsid function ultimately inhibit efficient nuclear import and integration of viral DNA into the host genome.

[0004] Currently, there are several antiretroviral drugs available for combating HIV infection. These drugs can be classified into classes based on the viral proteins they target or their mode of action. When used alone, these drugs are effective in reducing viral replication. However, the virus readily develops resistance to all known agents used as monotherapy, so the effect is only temporary. Combination therapy has proven to be very effective in reducing the virus and suppressing the emergence of resistance in several patients. In the United States, combination therapy is widely available and the number of HIV-related deaths has decreased dramatically (Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Furher, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D.; N. Engl. J. Med. 1998, 338:853-860).

[0005] Despite the success of antiretroviral combination therapies, a significant proportion of patients experience a loss of virological, immunological, or clinical benefits from their current regimens, leading to treatment failure and a rebound in the measurable amount of HIV in the blood. Initial studies have shown that approximately 30 - 50% of patients ultimately fail at least one drug in a suppressive combination. Treatment failure can be caused by the emergence of viral resistance. Viral resistance, on the other hand, can be caused by the replication rate of HIV-1 during the course of infection, which, combined with a relatively high viral mutation rate associated with the viral polymerase, and the failure of HIV-infected individuals to strictly adhere to taking these prescription drugs. Due to the structural similarities of drugs within the antiretroviral class, cross-resistance is commonly seen among other members of that class (for example, virological failure against a regimen containing a non-nucleoside reverse transcriptase inhibitor (NNRTI) will result in cross-resistance to other first-generation NNRTI agents). As patients repeatedly experience virological failure with antiretroviral combination therapies, these viruses develop broad multi-class antiretroviral drug resistance that limits the effectiveness of the next round of antiretroviral therapy. Many heavily treatment-experienced patients have viral resistance to several classes of antiretroviral drugs, and often there are not even two fully active drugs remaining to form the core of a new, effective antiretroviral drug regimen. Frequently, these patients have limited options for alternative treatment regimens and are at risk of serious morbidity and mortality.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

[0007] Therefore, there is a need for a safe and effective treatment for heavily treatment-experienced patients whose treatment options are limited due to antiretroviral drug resistance. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0008] The present disclosure relates to a method of treating human immunodeficiency virus (HIV) infection in heavily treatment-experienced patients. The method comprises administering to the patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib):

Chemical formula

[0009] In some embodiments, the HIV infection is an HIV-1 infection characterized by HIV-1 variant resistance to one or more antiretroviral drugs. In some embodiments, the HIV infection is an HIV-1 infection characterized by HIV-1 variant resistance to two or more antiretroviral drugs. In some embodiments, the HIV infection is an HIV-1 infection characterized by HIV-1 variant resistance to three or more antiretroviral drugs.

[0010] In some embodiments, the HIV-1 variant is resistant to a protease inhibitor (PI), a nucleoside or nucleotide reverse transcriptase inhibitor (NRTI), a non-nucleoside or non-nucleotide reverse transcriptase inhibitor (NNRTI), or an integrase strand transfer inhibitor (INSTI). In certain embodiments, the HIV-1 variant resistant to a protease inhibitor is selected from I50V, I84V / L90M, G48V / V82A / L90M, and G48V / V82S. In certain embodiments, the HIV-1 variant resistant to a nucleoside or nucleotide reverse transcriptase inhibitor is selected from K65R, M184V, and 6TAM. In certain embodiments, the HIV-1 variant resistant to a non-nucleoside or non-nucleotide reverse transcriptase inhibitor is selected from K103N, Y181C, Y188L, L100I / K103N, and K103N / Y181C. In certain embodiments, the HIV-1 variant resistant to an integrase strand transfer inhibitor is selected from Y143R, E138K / Q148K, G140S / Q148R, E92Q / N155H, N155H / Q148R, and R263K / M50I.

[0011] In some embodiments, the patient is infected with HIV-1 that is resistant to at least one antiretroviral drug. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs).

[0012] In some embodiments, the NRTI is selected from emtricitabine, lamivudine (3TC), zidovudine (azidothymidine (AZT)), didanosine (ddI), dideoxyinosine, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, stavudine (d4T), zalcitabine (dideoxycytidine, ddC), and abacavir.

[0013] In some embodiments, the NNRTI is selected from efavirenz, etravirine, rilpivirine, nevirapine, and delavirdine.

[0014] In some embodiments, the PI is selected from amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

[0015] In some embodiments, the INSTI is selected from raltegravir, elvitegravir, dolutegravir, and bictegravir.

[0016] In some embodiments of the method, the patient has been previously treated with at least one antiretroviral drug for at least 3 months, at least 6 months, at least 9 months, or at least 12 months.

[0017] In some embodiments, the patient has failed a previous HIV treatment regimen that included administration of at least one antiretroviral drug. In certain embodiments, the previous treatment regimen included administration of at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In certain embodiments, the previous treatment regimen included administration of at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs).

[0018] In certain embodiments of the present method, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered orally, subcutaneously, intramuscularly, or intravenously.

[0019] In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered orally at a concentration of about 20 mg / mL to about 100 mg / mL. In some embodiments, the compound of formula (Ia) or formula (Ib) is formulated as a hard gelatin capsule. In some embodiments, the compound of formula (Ia) or formula (Ib) is formulated as a soft gelatin capsule. In some embodiments, the compound of formula (Ia) or formula (Ib) is formulated as a tablet.

[0020] In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered subcutaneously. In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a concentration of about 50 mg / mL to about 500 mg / mL. In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is formulated as a solution preparation. In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is formulated as an aqueous suspension. In some embodiments, the compound of formula (Ia) is a sodium salt. In some embodiments, the compound of formula (Ib) is a trifluoroacetate salt.

[0021] In some embodiments of the method, the compound of formula (Ia) or formula (Ib) is formulated together with one or more other compounds selected from an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV nucleoside reverse transcriptase translocation inhibitor, and a pharmacokinetic activator. In some embodiments, the HIV nucleoside reverse transcriptase translocation inhibitor is 4'-ethynyl-2-fluoro-2'-deoxyadenosine triphosphate (MK-8591).

[0022] In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered once a week, once every two weeks, once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, once every twenty-four weeks, or once every forty-eight weeks.

[0023] In some embodiments of the method, the patient has a viral load of greater than about 200 copies / mL of HIV-1 RNA, greater than about 500 copies / mL of HIV-1 RNA, greater than about 750 copies / mL of HIV-1 RNA, greater than about 1000 copies / mL of HIV-1 RNA, or greater than about 2000 copies / mL of HIV-1 RNA at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the patient has failed an HIV treatment regimen that includes administration of at least one antiretroviral drug at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments of the method, administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, results in a reduction in the viral load in a patient. In some embodiments, the viral load is about 0.5 log 10 to about 2.5 log 10 lower compared to the viral load at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. In some embodiments, the viral load is about 0.5 log 10 , about 1 log 10 , about 1.5 log 10 , about 2 log 10 , or about 2.5 log 10 lower compared to the viral load at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks.

[0026] In some embodiments, the viral load of the patient is less than or equal to about 200 copies / mL of HIV-1 RNA after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. In some embodiments, the viral load of the patient is less than or equal to about 50 copies / mL of HIV-1 RNA after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks.

[0027] In some embodiments, the patient is co-treated with at least one additional antiretroviral drug. In some embodiments, the additional antiretroviral drug is selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), gp41 fusion inhibitors, CCR5 co-receptor antagonists, and combinations thereof.

[0028] In some embodiments, the NRTI is selected from emtricitabine, lamivudine (3TC), zidovudine (azidothymidine (AZT)), didanosine (ddI), dideoxyinosine, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, stavudine (d4T), zalcitabine (dideoxycytidine, ddC), and abacavir.

[0029] In some embodiments, the NNRTI is selected from efavirenz, etravirine, rilpivirine, nevirapine, and delavirdine.

[0030] In some embodiments, the PI is selected from amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir.

[0031] In some embodiments, the INSTI is selected from raltegravir, elvitegravir, dolutegravir, and bictegravir.

[0032] In some embodiments, the gp41 fusion inhibitor is selected from albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0033] In some embodiments, the CCR5 co-receptor antagonist is selected from apravirine, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavirin (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0034] Also provided herein is a method of treating human immunodeficiency virus-1 (HIV-1) infection in heavily treatment-experienced patients having multi-drug resistant HIV-1, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib):

Chemical formula

[0035] In some embodiments of the method, the multi-drug resistant HIV-1 is resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments of the method, the multi-drug resistant HIV-1 is resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs).

[0036] In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, the previous treatment regimen included administration of at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments, the previous treatment regimen included administration of at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs).

[0037] A method for treating human immunodeficiency virus type 1 (HIV-1) infection in heavily treatment-experienced patients having multi-drug resistant HIV-1, comprising administering to the patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib):

Chemical formula

[0038] A method for reducing the amount of virus associated with HIV infection in heavily treatment-experienced patients having multi-drug resistant HIV, comprising administering to the patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib):

Chemical formula

[0039] Additional embodiments of the present disclosure are disclosed herein. The present invention provides, for example, the following items. (Item 1) A method for treating human immunodeficiency virus (HIV) infection in heavily treatment-experienced patients, comprising administering to the patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib): [Chemical formula] A method comprising administering or a pharmaceutically acceptable salt thereof. (Item 2) The method according to item 1, wherein the HIV infection is an HIV-1 infection characterized by HIV-1 variant resistance to one or more antiretroviral drugs. (Item 3) The method according to item 1, wherein the HIV infection is an HIV-1 infection characterized by HIV-1 variant resistance to two or more antiretroviral drugs. (Item 4) The method according to item 1, wherein the HIV infection is an HIV-1 infection characterized by HIV-1 variant resistance to three or more antiretroviral drugs. (Item 5) The method according to any one of items 1 to 4, wherein the HIV-1 variant is resistant to a protease inhibitor (PI), a nucleoside or nucleotide reverse transcriptase inhibitor (NRTI), a non-nucleoside or non-nucleotide reverse transcriptase inhibitor (NNRTI), or an integrase strand transfer inhibitor (INSTI). (Item 6) The method according to item 5, wherein the HIV-1 variant resistant to a protease inhibitor is selected from I50V, I84V / L90M, G48V / V82A / L90M, and G48V / V82S. (Item 7) The method according to item 5, wherein the HIV-1 variant resistant to a nucleoside or nucleotide reverse transcriptase inhibitor is selected from K65R, M184V, and 6TAM. (Item 8) The method according to item 5, wherein the HIV-1 variant resistant to a non-nucleoside or non-nucleotide reverse transcriptase inhibitor is selected from K103N, Y181C, Y188L, L100I / K103N, and K103N / Y181C. (Item 9) The method according to item 5, wherein the HIV-1 variant resistant to the integrase strand transfer inhibitor is selected from Y143R, E138K / Q148K, G140S / Q148R, E92Q / N155H, N155H / Q148R, and R263K / M50I. (Item 10) The method according to any one of items 1 to 9, wherein the patient is infected with HIV-1 that is resistant to at least one antiretroviral drug. (Item 11) The method according to any one of items 1 to 10, wherein the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs, and the different classes of antiretroviral drugs are selected from nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). (Item 12) The method according to any one of items 1 to 10, wherein the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs, and the different classes of antiretroviral drugs are selected from nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). (Item 13) The method according to item 11 or item 12, wherein the different classes of antiretroviral drugs are selected from nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside or non-nucleotide reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). (Item 14) The method according to any one of items 11 to 13, wherein the NRTI is selected from emtricitabine, lamivudine (3TC), zidovudine (azidothymidine (AZT)), didanosine (ddI), dideoxyinosine, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, stavudine (d4T), zalcitabine (dideoxycytidine, ddC), and abacavir. (Item 15) The method according to any one of items 11 to 13, wherein the NNRTI is selected from efavirenz, etravirine, rilpivirine, nevirapine, and delavirdine. (Item 16) The method according to any one of items 11 to 13, wherein the PI is selected from amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir. (Item 17) The method according to any one of items 11 to 13, wherein the INSTI is selected from raltegravir, elvitegravir, dolutegravir, cabotegravir, and bictegravir. (Item 18) The method according to any one of items 10 to 17, wherein the patient has been previously treated with at least one antiretroviral drug for at least 3 months. (Item 19) The method according to any one of items 10 to 17, wherein the patient has been previously treated with at least one antiretroviral drug for at least 6 months. (Item 20) The method according to any one of items 10 to 17, wherein the patient has been previously treated with at least one antiretroviral drug for at least 9 months. (Item 21) The method according to any one of items 10 to 17, wherein the patient has been previously treated with at least one antiretroviral drug for at least 12 months. (Item 22) The method according to any one of items 10 to 21, wherein the patient has failed a previous HIV treatment regimen comprising administration of at least one antiretroviral drug. (Item 23) The method according to item 22, wherein the previous treatment regimen comprises administration of at least one antiretroviral drug from each of two different classes of antiretroviral drugs, and the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). (Item 24) The method according to item 22, wherein the previous treatment regimen comprises administration of at least one antiretroviral drug from each of three different classes of antiretroviral drugs, and the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). (Item 25) The method according to item 23 or item 24, wherein the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). (Item 26) The method according to any one of items 1 to 25, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered orally, subcutaneously, intramuscularly, or intravenously. (Item 27) The method according to item 26, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered orally. (Item 28) The method according to item 27, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered orally at a concentration of about 20 mg / mL to about 100 mg / mL. (Item 29) The method according to item 28, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered orally at a concentration of about 30 mg / mL. (Item 30) The method according to item 28, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered orally at a concentration of about 50 mg / mL. (Item 31) The method according to any one of items 27 to 30, wherein the compound of formula (Ia) or formula (Ib) is formulated as a hard gelatin capsule. (Item 32) The method according to any one of items 27 to 30, wherein the compound of formula (Ia) or formula (Ib) is formulated as a soft gelatin capsule. (Item 33) The method according to any one of items 27, wherein the compound of formula (Ia) or formula (Ib) is formulated as a tablet. (Item 34) The method according to item 26, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered subcutaneously. (Item 35) The method according to item 34, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a concentration of about 50 mg / mL to about 500 mg / mL. (Item 36) The method according to item 35, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a concentration of about 100 mg / mL. (Item 37) The method according to item 35, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a concentration of about 150 mg / mL. (Item 38) The method according to item 35, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered subcutaneously at a concentration of about 300 mg / mL. (Item 39) The method according to any one of items 34 to 38, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is formulated as a solution formulation. (Item 40) The method according to any one of items 34 to 38, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is formulated as an aqueous suspension. (Item 41) The method according to item 39 or item 40, wherein the compound of formula (Ia) is a sodium salt. (Item 42) The method according to item 39 or item 40, wherein the compound of formula (Ib) is a trifluoroacetate salt. (Item 43) The method according to any one of items 26 to 42, wherein the compound of formula (Ia) or formula (Ib) is formulated with one or more other compounds selected from an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV nucleoside reverse transcriptase translocation inhibitor, and a pharmacokinetic activator. (Item 44) The method according to item 43, wherein the compound of formula (Ia) or formula (Ib) is formulated with an HIV nucleoside reverse transcriptase translocation inhibitor. (Item 45) The method according to item 44, wherein the HIV nucleoside reverse transcriptase translocation inhibitor is 4'-ethynyl-2-fluoro-2'-deoxyadenosine triphosphate (MK-8591). (Item 46) The method according to any one of items 1 to 45, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered once daily. (Item 47) The method according to any one of items 1 to 45, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered once a week, once every two weeks, once every four weeks, once every eight weeks, once every twelve weeks, once every sixteen weeks, once every twenty weeks, once every twenty-four weeks, or once every forty-eight weeks. (Item 48) The method according to item 47, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered once every four weeks. (Item 49) The method according to item 47, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered once every eight weeks. (Item 50) The method according to item 47, wherein the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered once every twelve weeks. (Item 51) The method according to any one of items 1 to 50, wherein the patient has a viral load of more than about 200 copies / mL of HIV-1 RNA at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. (Item 52) The method according to any one of items 1 to 50, wherein the patient has a viral load of more than about 500 copies / mL of HIV-1 RNA at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. (Item 53) The method according to any one of items 1 to 50, wherein the patient has a viral load of more than about 750 copies / mL of HIV-1 RNA at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. (Item 54) The method according to any one of items 1 to 50, wherein the patient has a viral load of more than about 1000 copies / mL of HIV-1 RNA at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. (Item 55) The method according to any one of items 1 to 50, wherein the patient has a viral load exceeding about 2000 copies / mL of HIV-1 RNA at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. (Item 56) The method according to any one of items 1 to 50, wherein the patient has failed an HIV treatment regimen involving administration of at least one antiretroviral drug at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. (Item 57) The method according to any one of items 51 to 56, wherein administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, results in a reduction of the viral load in the patient. (Item 58) The viral load is about 0.5 log 10 ~ about 2.5 log 10 lowered as compared to the viral load at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. The method according to item 57. (Item 59) The viral load is about 0.5 log 10 lowered as compared to the viral load at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. The method according to item 57. (Item 60) The viral load is about 1 log 10 lowered as compared to the viral load at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. The method according to item 57. (Item 61) The amount of the virus is reduced by about 1.5 log compared to the amount of the virus at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. 10 The method according to item 57. (Item 62) The amount of the virus is reduced by about 2 log compared to the amount of the virus at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. 10 The method according to item 57. (Item 63) The amount of the virus is reduced by about 2.5 log compared to the amount of the virus at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. 10 The method according to item 57. (Item 64) The method according to item 57, wherein the amount of the virus in the patient is about 200 copies / mL or less of HIV-1 RNA after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. (Item 65) The method according to item 57, wherein the amount of the virus in the patient is about 50 copies / mL or less of HIV-1 RNA after administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. (Item 66) The method according to any one of items 1 to 65, wherein the patient is simultaneously treated with at least one additional antiretroviral drug. (Item 67) The method according to item 66, wherein the additional anti-retroviral drug is selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), gp41 fusion inhibitors, CCR5 co-receptor antagonists, and combinations thereof. (Item 68) The method according to item 67, wherein the NRTI is selected from emtricitabine, lamivudine (3TC), zidovudine (azidothymidine (AZT)), didanosine (ddI), dideoxyinosine, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, stavudine (d4T), zalcitabine (dideoxycytidine, ddC), and abacavir. (Item 69) The method according to item 67, wherein the NNRTI is selected from efavirenz, etravirine, rilpivirine, nevirapine, and delavirdine. (Item 70) The method according to item 67, wherein the PI is selected from amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir / ritonavir, nelfinavir, ritonavir, saquinavir, and tipranavir. (Item 71) The method according to item 67, wherein the INSTI is selected from raltegravir, elvitegravir, dolutegravir, and bictegravir. (Item 72) The method according to item 67, wherein the gp41 fusion inhibitor is selected from albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide. (Item 73) The method according to item 67, wherein the CCR5 co-receptor antagonist is selected from aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavire (RAP-101), nifeaviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). (Item 74) A method for treating human immunodeficiency virus-1 (HIV-1) infection in a heavily treatment-experienced patient having multi-drug resistant HIV-1, comprising administering to said patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein said patient has been previously treated with an HIV treatment regimen comprising administration of at least one antiretroviral drug and has failed said treatment regimen, and wherein administration of said compound results in a decrease in the amount of HIV virus in said patient. (Item 75) The method according to item 74, wherein said multi-drug resistant HIV-1 is resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs, and said different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). (Item 76) The method according to item 74, wherein said multi-drug resistant HIV-1 is resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs, and said different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). (Item 77) The method according to item 75 or item 76, wherein the different classes of anti-retroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). (Item 78) The method according to item 77, wherein the NRTI is selected from emtricitabine, lamivudine (3TC), zidovudine (azidothymidine (AZT)), didanosine (ddI), dideoxyinosine, tenofovir, tenofovir alafenamide, tenofovir disoproxil fumarate, stavudine (d4T), zalcitabine (dideoxycytidine, ddC), and abacavir. (Item 79) The method according to item 77, wherein the NNRTI is selected from efavirenz, etravirine, rilpivirine, nevirapine, and delavirdine. (Item 80) The method according to item 77, wherein the PI is selected from amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir / ritonavir, nelfinavir, ritonavir, saquinavir, and tipranavir. (Item 81) The method according to item 77, wherein the INSTI is selected from raltegravir, elvitegravir, dolutegravir, cabotegravir, and bictegravir. (Item 82) The method according to any one of items 74 to 81, wherein the patient has been previously treated with at least one anti-retroviral drug for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. (Item 83) The previous treatment regimen includes administration of at least one antiretroviral drug from each of two different classes of antiretroviral drugs, wherein the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs), the method according to any one of items 74 to 82. (Item 84) The previous treatment regimen includes administration of at least one antiretroviral drug from each of three different classes of antiretroviral drugs, wherein the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs), the method according to any one of items 74 to 82. (Item 85) The different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs), the method according to item 83 or item 84. (Item 86) A method for treating human immunodeficiency virus-1 (HIV-1) infection in a heavily treatment-experienced patient with multi-drug resistant HIV-1, comprising administering to the patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib):

Chemical formula

Chemical formula

Brief Description of the Drawings

[0040]

Figure 1

[0041]

Figure 2

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Figure 3

[0043]

Figure 4

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Figure 5

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Figure 6

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Figure 7

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Figure 8

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Figure 9

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Figure 10

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Figure 11

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Figure 12

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Figure 13

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Figure 14

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Figure 15

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Figure 16

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Figure 17

Best Mode for Carrying Out the Invention

[0057] The following description is made with the understanding that the present disclosure is considered to be illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout the present disclosure are provided for convenience only and should never be construed as limiting the claims. Embodiments illustrated under any heading can be combined with embodiments illustrated under any other heading.

[0058] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0059] When a trademark is used herein, it is intended to independently cover the trademarked product and the active pharmaceutical ingredient(s) of the trademarked product.

[0060] References herein to "about" a value or parameter include (and describe) embodiments that are directed to that value or parameter itself. In certain embodiments, the term "about" includes ±10% of the indicated amount. In other embodiments, the term "about" includes ±8% of the indicated amount. In other embodiments, the term "about" includes ±5% of the indicated amount. In other embodiments, the term "about" includes ±3% of the indicated amount. In certain other embodiments, the term "about" includes ±1% of the indicated amount. Also, the term "about X" includes the recitation of "X".

[0061] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, reference to "the assay" includes reference to one or more assays, and the like.

[0062] As an additional example, a reference to "pharmaceutically acceptable excipient(s)" includes both a single pharmaceutically acceptable excipient and plural pharmaceutically acceptable excipients.

[0063] As used herein, "HIV" or "human immunodeficiency virus" refers to HIV-1 and / or HIV-2.

[0064] As used herein, "treatment-experienced patient" refers to an HIV-infected patient whose treatment options are limited by multi-drug resistant HIV infection. For example, in some embodiments, a "treatment-experienced patient" is an HIV patient who has developed resistance to an antiretroviral drug from at least one class of antiretroviral drugs selected from the group consisting of NRTIs, NNRTIs, PIs, and INSTIs.

[0065] In some embodiments, "multi-drug resistant HIV infection" means resistance to an antiretroviral drug from at least one class of antiretroviral drugs selected from the group consisting of NRTIs, NNRTIs, PIs, and INSTIs. In some embodiments, "multi-drug resistant HIV infection" means resistance to at least one antiretroviral drug from two classes of antiretroviral drugs selected from the group consisting of NRTIs, NNRTIs, PIs, and INSTIs. In some embodiments, "multi-drug resistant HIV infection" means resistance to at least one antiretroviral drug from three classes of antiretroviral drugs selected from the group consisting of NRTIs, NNRTIs, PIs, and INSTIs. In some embodiments, "multi-drug resistant HIV infection" means resistance to at least one antiretroviral drug from each of four classes of antiretroviral drugs selected from the group consisting of NRTIs, NNRTIs, PIs, and INSTIs.

[0066] As used herein, the term "NRTI(s)" refers to nucleoside reverse transcriptase inhibitor(s) or nucleotide reverse transcriptase inhibitor(s).

[0067] As used herein, the term "NNRTI(s)" refers to non-nucleoside reverse transcriptase inhibitor(s) or non-nucleotide reverse transcriptase inhibitor(s).

[0068] As used herein, the term "PI(s)" refers to protease inhibitor(s).

[0069] As used herein, the term "INSTI(s)" refers to integrase strand transfer inhibitor(s).

[0070] As used herein, when referring to "failing" or "failed" in the context of HIV therapy or an HIV treatment regimen, it means a treatment outcome that precludes future use of the same agent or class in a patient with HIV. This can be due to an inadequate initial viral response due to pre-existing viral resistance, viral rebound due to emergent viral resistance, or the patient being unable to continue treatment due to intolerance or safety issues.

[0071] As used herein, the term "C max " refers to the observed maximum plasma / serum concentration of a drug.

[0072] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0073] "Pharmaceutically acceptable excipients" include, without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent approved by the U.S. Food and Drug Administration as acceptable for use in humans or food-producing animals.

[0074] "Pharmaceutically acceptable salts" refer to salts of compounds that are pharmaceutically acceptable and possess (or are convertible to a form that possesses) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, trimethylacetic acid, and salts formed when the acidic proton present in the parent compound is replaced by any of a metal ion, such as an alkali metal ion (e.g., sodium or potassium), an alkaline earth ion (e.g., calcium or magnesium), or an aluminum ion, or when an organic base such as, for example, diethanolamine, triethanolamine, N-methylglucamine, is coordinated. Ammonium and substituted or quaternized ammonium salts (e.g., quaternary ammonium salts containing the N,N,N-trimethylethanolammonium (choline) cation) are also included in this definition. A representative non-limiting list of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5 and both are hereby incorporated by reference into this specification.

[0075] "Patient(singular)" and "patient(plural)" refer to humans, domestic animals (e.g., dogs and cats), livestock (e.g., cows, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), etc.

[0076] As used herein, "treatment" or "treating" is a procedure for obtaining a beneficial or desired result. For the purposes of the present disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or reduction in the scope of symptoms and / or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" or "treating" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition and / or reducing the scope of the disease or condition); b) delaying or preventing the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition), and / or c) alleviating a disease or condition, e.g., causing regression of clinical symptoms, restoring the pathological state, delaying the progression of the disease, improving the quality of life, and / or prolonging life.

[0077] As used herein, the terms "therapeutically effective amount" or "effective amount" refer to an amount effective to elicit a desired biological or medical response, including an amount of a compound sufficient to effect such treatment of a disease when administered to a patient for treating the disease, or an amount effective to prevent the contraction or onset of a disease. The effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the patient to be treated. The effective amount can include a range of amounts. As is understood in the art, the effective amount can be a single or multiple doses, e.g., a single dose or multiple doses may be required to achieve the desired treatment result. The effective amount can be considered in relation to the administration of one or more therapeutic agents, and a single agent, alone or in combination with one or more other agents, can be considered to be administered in an effective amount if a desired or beneficial result is achieved, or can be achieved. The appropriate dosage of any co-administered compound can be decreased as necessary due to the combined action (e.g., additive or synergistic effect) of the compounds.

[0078] Unless otherwise expressly defined, this disclosure includes all tautomers of the compounds detailed herein, even if only one tautomer is explicitly represented (e.g., by presentation of one tautomeric form where a pair of two tautomers can exist, both tautomeric forms are intended and described). For example, when a compound containing an amide is referred to (e.g., by structure or chemical name), it is understood that the corresponding imidic acid tautomer is included in and described by this disclosure as if this amide were explicitly listed alone or together with the imidic acid. If more than two tautomers can exist, this disclosure includes all such tautomers even if only a single tautomeric form is indicated by chemical name and / or structure.

[0079] This disclosure also includes, at every atom, a higher proportion than the natural occurring isotope ratio, including but not limited to deuterium ( 2It is understood by those skilled in the art that any compound disclosed herein (e.g., a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof) may be enriched with one or more isotopes such as H or D).

[0080] Compounds are also disclosed in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D (where n is the number of hydrogen atoms in the molecule). As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and thus may be useful for increasing the half-life of a compound when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., Vol. 5 (No. 12): pp. 524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by utilizing starting materials in which one or more hydrogen atoms are replaced by deuterium.

[0081] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Positron-emitting isotopes, for example, 11 C, 18 F, 15 O and 13Substitution by N may be useful in positron emission tomography (PET) experiments for testing substrate receptor occupancy. Isotopically labeled compounds of formula (Ia) or formula (Ib), or pharmaceutically acceptable salts thereof, can generally be prepared by conventional techniques known to those skilled in the art or using appropriate isotopically labeled reagents in place of the unlabeled reagents previously utilized, by methods similar to those described in the examples presented below.

[0082] It should be understood that the compounds described herein can have chiral centers and / or geometric isomer centers (E and Z isomers), and all such optical isomers, enantiomers, diastereoisomers and geometric isomers are included. When the compounds are represented in these chiral forms, embodiments are understood to include, but are not limited to, specific diastereomers or enantiomer-enriched forms. Where chirality is not specified but is present, this embodiment is understood to be directed to either a specific diastereomer or enantiomer-enriched form, or a racemic or scalemic mixture of such compound(s).

[0083] Also provided herein are pharmaceutically acceptable hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein.

[0084] In one embodiment, the present disclosure relates to the use of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the treatment of an infection caused by the HIV virus, comprising administering a therapeutically effective amount to a patient in need thereof, wherein the patient is a heavily treatment-experienced patient with multi-drug resistant HIV infection.

[0085] The present disclosure relates to a compound of formula (Ia), 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, having the following structure: [Chemical Formula] or a pharmaceutically acceptable salt thereof, for use in treating HIV infection in heavily treatment-experienced patients having multi-drug resistant HIV infection.

[0086] The present disclosure also relates to a compound of formula (Ib), N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-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)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, having the following structure: [Chemical Formula] or a pharmaceutically acceptable salt thereof, for use in treating HIV infection in heavily treatment-experienced patients having multi-drug resistant HIV infection.

[0087] In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of formula (Ia) or formula (Ib). Non-limiting examples of pharmaceutically acceptable salts of the compounds of formula (Ia) and formula (Ib) include sodium salts and trifluoroacetate salts. In some embodiments, the compound of formula (Ia) is a sodium salt. In some embodiments, the compound of formula (Ib) is a trifluoroacetate salt.

[0088] The compounds used in the methods disclosed herein (e.g., a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof) are active against major HIV-1 variants selected by protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), and / or integrase inhibitors (INSTI). Method of treatment

[0089] administering to a patient a therapeutically effective amount of a compound of formula (Ia) or formula (Ib):

Chemical formula

[0090] In the disclosed method, heavily treatment-experienced patients are infected with multi-drug resistant HIV. In some embodiments, heavily treatment-experienced patients have multi-drug resistant HIV infection and have received an HIV treatment regimen with no expected success. In some embodiments, heavily treatment-experienced patients have a viral load of greater than about 1,000 copies / mL of HIV RNA.

[0091] In some embodiments, the HIV infection is an HIV-1 infection. In some embodiments, the HIV-1 infection is characterized by HIV-1 variant resistance to antiretroviral drugs, such as one, two, three, four or more classes of antiretroviral drugs (e.g., PI, NRTI, NNRTI, INSTI, etc.). In some embodiments, the HIV-1 infection is characterized by HIV-1 variant resistance to one or more classes of antiretroviral drugs. In some embodiments, the HIV-1 infection is characterized by HIV-1 variant resistance to two or more classes of antiretroviral drugs. In some embodiments, the HIV-1 infection is characterized by HIV-1 variant resistance to three or more classes of antiretroviral drugs. In some embodiments, the HIV-1 infection is characterized by HIV-1 variants including, but not limited to, the following: (a) HIV-1 variants resistant to PI (e.g., I50V, I84V / L90M, G48V / V82A / L90M, G48V / V82S, etc.); (b) HIV-1 variants resistant to NRTI (e.g., K65R, M184V, 6TAM, etc.); (c) HIV-1 variants resistant to NNRTI (e.g., K103N, Y181C, Y188L, L100I / K103N, K103N / Y181C, etc.); and / or (d) HIV-1 variants resistant to INSTI (Y143R, E138K / Q148K, G140S / Q148R, E92Q / N155H, N155H / Q148R, R263K / M50I, etc.).

[0092] In some embodiments, the patient is infected with HIV-1 that is resistant to at least one antiretroviral drug. In some embodiments, the patient is infected with multi-drug resistant HIV-1. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one, two, three, four, or more antiretroviral drugs. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). In some embodiments, the different classes of antiretroviral drugs are selected from NRTIs, NNRTIs, and PIs. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NRTI and at least one NNRTI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NRTI and at least one PI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NRTI and at least one INSTI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NNRTI and at least one PI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NNRTI and at least one INSTI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one PI and at least one INSTI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NRTI, at least one NNRTI, and at least one PI.In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NRTI, at least one NNRTI, and at least one INSTI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NRTI, at least one PI, and at least one INSTI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NNRTI, at least one PI, and at least one INSTI. In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one NRTI, at least one NNRTI, at least one PI, and at least one INSTI.

[0093] In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug that is an NRTI. Examples of NRTIs include, but are not limited to, emtricitabine (FTC; Emtriva®), lamivudine (3TC; Epivir®), zidovudine (azidothymidine (AZT); Retrovir®), didanosine (ddI; Videx-EC®), dideoxyinosine (Videx®), tenofovir, tenofovir alafenamide (Vemlidy®), tenofovir disoproxil fumarate (Viread®), stavudine (d4T; Zerit®), zalcitabine (dideoxycytidine, ddC; Hivid®), and abacavir (Ziagen®).

[0094] In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug that is an NNRTI. Examples of NNRTIs include, but are not limited to, efavirenz (Sustiva®), etravirine (Intelence®), rilpivirine (Edurant®), nevirapine (Viramune®), and delavirdine (Rescriptor®).

[0095] In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug that is a PI. Examples of PIs include, but are not limited to, amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Telzir®, Lexiva®), indinavir (Crixivan®), lopinavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Invirase®), and tipranavir (Aptivus®).

[0096] In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug that is an INSTI. Examples of INSTIs include, but are not limited to, raltegravir (Isentress®), elvitegravir (Vitekta®), dolutegravir (Tivicay®), cabotegravir, and bictegravir.

[0097] In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one antiretroviral drug that is a gp41 fusion inhibitor. Examples of gp41 fusion inhibitors include, but are not limited to, albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biosimilar, enfuvirtide biobetter, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0098] In some embodiments, the patient is infected with multi-drug resistant HIV-1 that is resistant to at least one anti-retroviral drug that is a CCR5 co-receptor antagonist. Examples of CCR5 co-receptor antagonists include, but are not limited to, apravirine, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavire (RAP-101), nevirapine (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0099] In some embodiments of the disclosed method, the patient has been previously treated with at least one antiretroviral drug before being treated with a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 3 months, such as at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, or at least 24 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 3 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 6 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 9 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 12 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 18 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 24 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 30 months. In some embodiments, the patient has been previously treated with at least one antiretroviral drug for at least 36 months.

[0100] In some embodiments of the disclosed method, the patient has failed or has no expected success with an HIV treatment regimen prior to treatment with a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the previous HIV treatment regimen included administration of at least one antiretroviral drug. In some embodiments, the patient infected with HIV has relapsed after an initial response to a previous HIV treatment regimen, e.g., antiretroviral therapy. In some embodiments, the patient has a viral load of greater than about 50 copies / mL of HIV RNA at about 48 weeks after a treatment regimen, e.g., antiretroviral therapy, prior to treatment with a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, the previous treatment regimen comprises administering at least one antiretroviral drug from each of two different classes of antiretroviral drugs. In some embodiments, the previous treatment regimen comprises administering at least one antiretroviral drug from each of three different classes of antiretroviral drugs. In some embodiments, the different classes of antiretroviral drugs are selected from nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs). In some embodiments, the different classes of antiretroviral drugs are selected from NRTIs, NNRTIs, and PIs. In some embodiments, the previous treatment regimen comprises administering at least one NRTI and at least one NNRTI. In some embodiments, the previous treatment regimen comprises administering at least one NRTI and at least one PI. In some embodiments, the previous treatment regimen comprises administering at least one NRTI and at least one INSTI. In some embodiments, the previous treatment regimen comprises administering at least one NNRTI and at least one PI. In some embodiments, the previous treatment regimen comprises administering at least one NNRTI and at least one INSTI. In some embodiments, the previous treatment regimen comprises administering at least one PI and at least one INSTI. In some embodiments, the previous treatment regimen comprises administering at least one NRTI, at least one NNRTI, and at least one PI. In some embodiments, the previous treatment regimen comprises administering at least one NRTI, at least one NNRTI, and at least one INSTI. In some embodiments, the previous treatment regimen comprises administering at least one NRTI, at least one PI, and at least one INSTI. In some embodiments, the previous treatment regimen comprises administering at least one NNRTI, at least one PI, and at least one INSTI.

[0102] In some embodiments, the previous treatment regimen comprises administering at least one anti-retroviral drug that is a gp41 fusion inhibitor.

[0103] In some embodiments, the previous treatment regimen comprises administering at least one anti-retroviral drug that is a CCR5 co-receptor antagonist.

[0104] In some embodiments, the previous treatment regimen comprises administering at least one anti-retroviral drug that is an NRTI. Examples of NRTIs include, but are not limited to, emtricitabine (FTC; Emtriva®), lamivudine (3TC; Epivir®), zidovudine (azidothymidine (AZT); Retrovir®), didanosine (ddI; Videx-EC®), dideoxyinosine (Videx®), tenofovir, tenofovir alafenamide (Vemlidy®), tenofovir disoproxil fumarate (Viread®), stavudine (d4T; Zerit®), zalcitabine (dideoxycytidine, ddC; Hivid®), and abacavir (Ziagen®).

[0105] In some embodiments, the previous treatment regimen comprises administering at least one anti-retroviral drug that is an NNRTI. Examples of NNRTIs include, but are not limited to, efavirenz (Sustiva®), etravirine (Intelence®), rilpivirine (Edurant®), nevirapine (Viramune®), and delavirdine (Rescriptor®).

[0106] In some embodiments, the previous treatment regimen includes administering at least one antiretroviral drug that is a PI. Examples of PIs include, but are not limited to, amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Telzir®, Lexiva®), indinavir (Crixivan®), lopinavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Invirase®), and tipranavir (Aptivus®).

[0107] In some embodiments, the previous treatment regimen includes administering at least one antiretroviral drug that is an INSTI. Examples of INSTIs include, but are not limited to, raltegravir (Isentress®), elvitegravir (Vitekta®), dolutegravir (Tivicay®), cabotegravir, and bictegravir.

[0108] In some embodiments, the previous treatment regimen includes administering at least one antiretroviral drug that is a gp41 fusion inhibitor. Examples of gp41 fusion inhibitors include, but are not limited to, albuvirtide, enfuvirtide, BMS-986197, enfuvirtide bio-better, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0109] In some embodiments, the previous treatment regimen includes administering at least one antiretroviral drug that is a CCR5 co-receptor antagonist. Examples of CCR5 co-receptor antagonists include, but are not limited to, apravirine, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavirin (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0110] In some embodiments of the disclosed method, severely treatment-experienced patients infected with HIV have an HIV-1 RNA viral load of about 200 copies / mL (c / mL) to about 1,000,000 c / mL, for example, about 200 c / mL to about 500,000 c / mL, about 200 c / mL to about 250,000 c / mL, about 200 c / mL to about 100,000 c / mL, about 200 c / mL to about 50,000 c / mL, about 200 c / mL to about 25,000 c / mL, about 200 c / mL to about 10,000 c / mL, about 200 c / mL to about 5,000 c / mL, about 200 c / mL to about 3,000 c / mL, about 200 c / mL to about 2,000 c / mL, about 200 c / mL to about 1,000 c / mL, about 200 c / mL to about 750 c / mL, about 200 c / mL to about 500 c / mL, about 500 c / mL to about 1,000,000 c / mL, about 500 c / mL to about 500,000 c / mL, about 500 c / mL to about 250,000 c / mL, about 500 c / mL to about 100,000 c / mL, about 500 c / mL to about 50,000 c / mL, about 500 c / mL to about 25,000 c / mL, about 500 c / mL to about 10,000 c / mL, about 500 c / mL to about 5,000 c / mL, about 500 c / mL to about 3,000 c / mL, about 500 c / mL to about 2,000 c / mL, about 500 c / mL to about 1,000 c / mL, about 500 c / mL to about 750 c / mL, about 750 c / mL to about 1,000,000 c / mL, about 750 c / mL to about 500,000 c / mL, about 750 c / mL to about 250,000 c / mL, about 750 c / mL to about 100,000 c / mL, about 750 c / mL to about 50,000 c / mL, about 750 c / mL to about 25,000 c / mL, about 750 c / mL to about 10,000 c / mL, about 750 c / mL to about 5,000 c / mL, about 750 c / mL to about 3,000 c / mL, about 750 c / mL to about 2,000 c / mL, about 750 c / mL to about 1,000 c / mL, about 1,000 c / mL to about 1,000,000 c / mL, about 1,000 c / mL to about 500,000 c / mL, about 1,000 c / mL to about 250,000 c / mL, about 1,000 c / mL to about 100,000 c / mL, about 1,000 c / mL to about 50,000 c / mL, about 1,000 c / mL to about 25,000 c / mL, about 1,000 c / mL to about 10,000 c / mL, about 1,000 c / mL to about 5,000 c / mL, about 1,000 c / mL to about 3,000 c / mL, about 1,000 c / mL to about 2,000 c / mL, about 2,000 c / mL to about 1,000,000 c / mL, about 2,000 c / mL to about 500,000 c / mL, about 2,000 c / mL to about 250,000 c / mL, about 2,000 c / mL to about 100,000 c / mL, about 2,000 c / mL to about 50,000 c / mL, about 2,000 c / mL to about 25,000 c / mL, about 2,000 c / mL to about 10,000 c / mL, about 2,000 c / mL to about 5,000 c / mL, about 3,000 c / mL to about 1,000,000 c / mL, about 3,000 c / mL to about 500,000 c / mL, about 3,000 c / mL to about 250,000 c / mL, about 3,000 c / mL to about 100,000 c / mL, about 3,000 c / mL to about 50,000 c / mL, about 3,000 c / mL to about 25,000 c / mL, about 3,000 c / mL to about 10,000 c / mL, about 3,000 c / mL to about 5,000 c / mL, about 5,000 c / mL to about 1,000,000 c / mL, about 5,000 c / mL to about 500,000 c / mL, about 5,000 c / mL to about 250,000 c / mL, about 5,000 c / mL to about 100,000 c / mL, about 5,000 c / mL to about 50,000 c / mL, about 5,000 c / mL to about 25,000 c / mL, about 5,000 c / mL to about 10,000 c / mL, about 10,000 c / mL to about 1,000,000 c / mL, about 10,000 c / mL to about 500,000 c / mL, about 10,000 c / mL to about 250,000 c / mL, about 10,000 c / mL to about 100,000 c / mL, about 10,000 c / mL to about 50,000 c / mL, about 10,000 c / mL to about 25,000 c / mL, about 25,000 c / mL to about 1,000,000 c / mL, about 25,000 c / mL to about 500,000 c / mL, about 25,000 c / mL to about 250,000 c / mL, about 25,000 c / mL to about 100,000 c / mL, about 25,000 c / mL to about 50,000 c / mL, about 50,000 c / mL to about 1,000,000 c / mL, about 50,000 c / mL to about 500,000 c / mL, about 50,It has a virus amount of 000 c / mL to approximately 250,000 c / mL, approximately 50,000 c / mL to approximately 100,000 c / mL, approximately 100,000 c / mL to approximately 1,000,000 c / mL, approximately 100,000 c / mL to approximately 500,000 c / mL, approximately 100,000 c / mL to approximately 250,000 c / mL, approximately 250,000 c / mL to approximately 1,000,000 c / mL, approximately 250,000 c / mL to approximately 500,000 c / mL, or approximately 500,000 c / mL to approximately 1,000,000 c / mL.,

[0111] In some embodiments, the patient has a viral load of greater than about 200 copies / mL (c / mL) of HIV-1 RNA, for example, greater than about 500 c / mL, greater than about 750 c / mL, greater than about 1,000 c / mL, greater than about 2,000 c / mL, greater than about 3,000 c / mL, greater than about 5,000 c / mL, greater than about 10,000 c / mL, greater than about 25,000 c / mL, greater than about 50,000 c / mL, greater than about 100,000 c / mL, greater than about 250,000 c / mL, greater than about 500,000 c / mL, or greater than about 1,000,000 c / mL at the start of administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load of greater than about 200 c / mL at the start of administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load of greater than about 500 c / mL at the start of administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load of greater than about 750 c / mL at the start of administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load of greater than about 1,000 c / mL at the start of administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the patient has a viral load of greater than about 2,000 c / mL at the start of administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof.

[0112] A compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, can be administered to a patient for a desired time or period, for example, for at least about 1 day, at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 12 months, or longer, according to an effective dosing regimen. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered daily or on an intermittent schedule. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered weekly. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered twice a month (i.e., every two weeks). In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered monthly. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every two months. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every three months. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every four months. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every five months. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every six months. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every five months. In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every twelve months.

[0113] In some embodiments, a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is administered every nine months.

[0114] In some embodiments of the disclosed method, administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, results in a reduction in the amount of virus in a patient. In some embodiments, the amount of virus is about 0.5 log 10 to about 2.5 log 10 reduction. For example, the amount of virus is about 0.5 log 10 , about 1 log 10 , about 1.5 log 10 , about 2 log 10 , or about 2.5 log 10 reduction after administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for a particular period of time, compared to the amount of virus at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of virus is about 0.5 log 10 reduction after administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks, compared to the amount of virus at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of virus is about 1 log 10 reduction after administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks, compared to the amount of virus at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of virus is about 1.5 log 10 reduction after administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks, compared to the amount of virus at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the amount of virus is about 2 log10 is reduced. In some embodiments, the viral load is about 2.5 log compared to the viral load at the start of administration of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, after administering the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks 10 is reduced.

[0115] In some embodiments of the disclosed methods, the viral load in a patient is about 200 c / mL or less, such as about 175 c / mL or less, about 150 c / mL or less, about 125 c / mL or less, about 100 c / mL or less, about 75 c / mL or less, or about 50 c / mL or less, after administering a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for a certain period of time. In some embodiments, the viral load in a patient is about 200 c / mL or less after administering a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. In some embodiments, the viral load in a patient is about 200 c / mL or less after administering a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. In some embodiments, the viral load in a patient is about 100 c / mL or less after administering a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks. In some embodiments, the viral load in a patient is about 50 c / mL or less after administering a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, for about 24 weeks.

[0116] In certain embodiments of the disclosed methods, heavily treatment-experienced patients are being concurrently treated with at least one additional antiretroviral drug. In some embodiments, the antiretroviral drug is selected from NRTIs, NNRTIs, PIs, INSTIs, gp41 fusion inhibitors, and CCR5 co-receptor antagonists.

[0117] In some embodiments, the patient is being concurrently treated with at least one NRTI. Examples of NRTIs include, but are not limited to, emtricitabine (FTC; Emtriva®), lamivudine (3TC; Epivir®), zidovudine (azidothymidine (AZT); Retrovir®), didanosine (ddI; Videx-EC®), dideoxyinosine (Videx®), tenofovir, tenofovir alafenamide (Vemlidy®), tenofovir disoproxil fumarate (Viread®), stavudine (d4T; Zerit®), zalcitabine (dideoxycytidine, ddC; Hivid®), and abacavir (Ziagen®).

[0118] In some embodiments, the patient is being concurrently treated with at least one NNRTI. Examples of NNRTIs include, but are not limited to, efavirenz (Sustiva®), etravirine (Intelence®), rilpivirine (Edurant®), nevirapine (Viramune®), and delavirdine (Rescriptor®).

[0119] In some embodiments, the patient is being concurrently treated with at least one PI. Examples of PIs include, but are not limited to, amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Telzir®, Lexiva®), indinavir (Crixivan®), lopinavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Invirase®), and tipranavir (Aptivus®).

[0120] In some embodiments, the patient is being treated simultaneously with at least one INSTI. Examples of INSTIs include, but are not limited to, raltegravir (Isentress®), elvitegravir (Vitekta®), dolutegravir (Tivicay®), cabotegravir, and bictegravir.

[0121] In some embodiments, the patient is being treated simultaneously with at least one gp41 fusion inhibitor. Examples of gp41 fusion inhibitors include, but are not limited to, albuvirtide, enfuvirtide, BMS-986197, enfuvirtide bio-better, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0122] In some embodiments, the patient is being treated simultaneously with at least one CCR5 co-receptor antagonist. Examples of CCR5 co-receptor antagonists include, but are not limited to, apravirine, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavirin (RAP-101), niverapine (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibody, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0123] A method for treating HIV-1 infection in heavily treatment-experienced patients with multi-drug resistant HIV-1, which comprises administering to a patient who has been previously treated with an HIV treatment regimen comprising administration of at least one anti-retroviral drug and has failed that treatment regimen, a therapeutically effective amount of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is also provided in the present disclosure. In some embodiments, the HIV treatment regimen comprises administration of at least one anti-retroviral drug such as those described herein. In some embodiments of the method, administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, results in a decrease in the amount of HIV virus in the patient.

[0124] A method for treating HIV-1 infection in heavily treatment-experienced patients with multi-drug resistant HIV-1, which comprises administering to a patient who has been previously treated with an HIV treatment regimen comprising administration of at least one anti-retroviral drug and has failed that treatment regimen, a therapeutically effective amount of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, wherein the multi-drug resistant HIV-1 is resistant to at least one anti-retroviral drug from each of two different classes of anti-retroviral drugs is also disclosed. In some embodiments, the different classes of anti-retroviral drugs are selected from NRTI, NNRTI, PI, and INSTI. In some embodiments, the patient has a viral load of greater than about 200 c / mL at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and administration of the compound results in a decrease in the amount of HIV virus in the patient.

[0125] In some embodiments, a method for treating HIV-1 infection in heavily treatment-experienced patients with multi-drug resistant HIV-1, which method comprises administering to a patient who has been previously treated with an HIV treatment regimen comprising administration of at least one antiretroviral drug and has failed that treatment regimen, a therapeutically effective amount of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, wherein the multi-drug resistant HIV-1 is resistant to at least one antiretroviral drug from each of three different classes of antiretroviral drugs, is disclosed. In some embodiments, the different classes of antiretroviral drugs are selected from NRTIs, NNRTIs, PIs, and INSTIs. In some embodiments, the patient has a viral load of greater than about 200 c / mL at the start of administration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and administration of the compound results in a decrease in the amount of HIV virus in the patient. Pharmaceutical composition

[0126] The pharmaceutical compositions disclosed herein contain a compound disclosed herein (e.g., a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof) together with one or more pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration.

[0127] Pharmaceutical compositions containing a compound disclosed herein (e.g., a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof) can be prepared using conventional carriers (e.g., inert ingredients or excipient materials) that can be selected according to ordinary practice. Tablets can contain excipients including glidants, fillers, binders, and the like. Aqueous compositions can be prepared in a sterile form and can generally be isotonic when intended for delivery other than by oral administration. All compositions contain excipients, e.g., Rowe et al., Handbook of Pharmaceutical Excipients, 5 thIt can contain, if necessary, those shown in the 1986 edition of the American Pharmacists Association. Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

[0128] In some embodiments, the tablets can contain excipients including glidants, fillers, binders, polymers, etc. Injection solutions and suspensions can be prepared in a sterile form and can generally be isotonic when intended for delivery other than oral administration. All compositions can, if necessary, contain excipients such as those shown in Rowe et al., Handbook of Pharmaceutical Excipients, 5 th edition, the 1986 edition of the American Pharmacists Association. Examples of excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc.

[0129] Although it is possible to administer the active ingredient (e.g., a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof) alone, it may be preferable to present the active ingredient as a pharmaceutical composition. Compositions for both veterinary use and human use contain at least a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, together with one or more acceptable carriers and optionally other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1 to 3, or 1 to 4) additional therapeutic agents as defined herein. In some embodiments, the pharmaceutical composition comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and one other therapeutic ingredient. The carrier(s) is / are "acceptable" in the sense of being compatible with the other ingredients of the composition and physiologically innocuous to its recipient.

[0130] In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide hemifumarate and bictegravir. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient and tenofovir alafenamide. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient and tenofovir alafenamide hemifumarate. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient and bictegravir.

[0131] In some embodiments, the pharmaceutical composition disclosed herein comprises a compound of formula (Ia) or formula (Ib), a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir. In some embodiments, the pharmaceutical composition disclosed herein comprises a compound of formula (Ia) or formula (Ib), a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide hemifumarate and bictegravir. In some embodiments, the pharmaceutical composition disclosed herein comprises a compound of formula (Ia) or formula (Ib), a pharmaceutically acceptable excipient and tenofovir alafenamide. In some embodiments, the pharmaceutical composition disclosed herein comprises a compound of formula (Ia) or formula (Ib), a pharmaceutically acceptable excipient and tenofovir alafenamide hemifumarate. In some embodiments, the pharmaceutical composition disclosed herein comprises a compound of formula (Ia) or formula (Ib), a pharmaceutically acceptable excipient and bictegravir.

[0132] In some embodiments, the pharmaceutical composition disclosed herein comprises a sodium salt of a compound of formula (Ia), a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir. In some embodiments, the pharmaceutical composition disclosed herein comprises a sodium salt of a compound of formula (Ia), a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide hemifumarate and bictegravir. In some embodiments, the pharmaceutical composition disclosed herein comprises a sodium salt of a compound of formula (Ia), a pharmaceutically acceptable excipient, and tenofovir alafenamide. In some embodiments, the pharmaceutical composition disclosed herein comprises a sodium salt of a compound of formula (Ia), a pharmaceutically acceptable excipient, and tenofovir alafenamide hemifumarate. In some embodiments, the pharmaceutical composition disclosed herein comprises a sodium salt of a compound of formula (Ia), a pharmaceutically acceptable excipient, and bictegravir.

[0133] In some embodiments, the pharmaceutical compositions disclosed herein comprise a trifluoroacetate salt of a compound of formula (Ib), a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir. In some embodiments, the pharmaceutical compositions disclosed herein comprise a trifluoroacetate salt of a compound of formula (Ib), a pharmaceutically acceptable excipient, and one other therapeutic agent selected from the group consisting of tenofovir alafenamide hemifumarate and bictegravir. In some embodiments, the pharmaceutical compositions disclosed herein comprise a trifluoroacetate salt of a compound of formula (Ib), a pharmaceutically acceptable excipient and tenofovir alafenamide. In some embodiments, the pharmaceutical compositions disclosed herein comprise a trifluoroacetate salt of a compound of formula (Ib), a pharmaceutically acceptable excipient and tenofovir alafenamide hemifumarate. In some embodiments, the pharmaceutical compositions disclosed herein comprise a trifluoroacetate salt of a compound of formula (Ib), a pharmaceutically acceptable excipient and bictegravir.

[0134] The compositions include those suitable for various routes of administration. The compositions can be conveniently presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (e.g., a compound of formula (Ia) or formula (Ib) or a pharmaceutically acceptable salt thereof) with one or more inactive ingredients (e.g., carriers, pharmaceutical excipients, etc.). The compositions can be prepared by uniformly and intimately bringing into association the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21 st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

[0135] The compositions described herein that are suitable for oral administration can be presented as separate units (unit dosage forms), including, but not limited to, capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.

[0136] When formulated for oral administration, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders, powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art of pharmaceutical composition manufacture. Such compositions can contain one or more agents, including sweetening agents, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be utilized alone or in combination with waxes.

[0137] In some embodiments, oral dosage forms (e.g., tablets) that can be prepared from hot melt extrusion or spray drying dispersion (SDD) techniques are disclosed herein.

[0138] In some embodiments, capsules filled with powders, beads, or granules containing an active ingredient, mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of hard or soft capsules, are disclosed herein. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. In some embodiments, the capsule is a hard capsule. In some embodiments, the capsule is a soft capsule.

[0139] In some embodiments, hard or soft capsules filled with a liquid or semi-solid mixture containing an active ingredient, mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of hard or soft capsules, are disclosed herein. These excipients may be, for example, solubilizing oils such as corn oil, sesame oil, or coconut oil; medium-chain triglycerides and related esters such as fractionated palm kernel oil or palm oil; self-emulsifying lipid systems (SEDDS or SMEDDS) such as triglyceride caprylate or polyethylene glycol esters of propylene glycol monocaprylate and medium-chain triglycerides; viscosity modifiers such as cetyl alcohol, steryl alcohol, glycerol stearate; a mixture of medium-chain monoglycerides and diglycerides; a mixture of monoglycerides, diglycerides, and triglycerides such as monoglycerides and diglycerides of caprylic / capric acid; and solubilizing agents and surfactants such as polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamer, or polysorbate. In some embodiments, the capsule is a hard capsule. In some embodiments, the capsule is a soft capsule.

[0140] In some embodiments, the hard or soft capsule formulation comprises a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In some embodiments, one or more pharmaceutically acceptable excipients of the hard or soft capsule formulations disclosed herein are water-soluble and / or water-insoluble. Examples of water-soluble excipients include, but are not limited to, dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), ethanol, N-methyl-2-pyrrolidone (NMP), PEG300, PEG400, PEG600, propylene glycol, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, glycerin, diethylene glycol monoethyl ether (e.g., Transcutol® HP), and phospholipids. Examples of phospholipids include, but are not limited to, hydrogenated soybean phosphatidylcholine (HSPC), distearoyl phosphatidylglycerol (DSPG), L-α-dimyristoyl phosphatidyl-choline (DMPC), and L-α-dimyristoyl phosphatidyl-glycerol (DMPG). Examples of water-insoluble excipients include, but are not limited to, beeswax, oleic acid, soybean fatty acid, vitamin E, corn oil mono-di-triglycerides, medium chain C 8~10 monoglycerides and medium chain C 8~10 diglycerides, propylene glycol dicaprylate / dicaprate, glyceryl monolaurate, glyceryl monooleate, long chain triglycerides, and medium chain triglycerides. Examples of long chain triglycerides include, but are not limited to, sesame oil, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, soybean oil, hydrogenated soybean oil, and hydrogenated vegetable oil. Examples of medium chain triglycerides include, but are not limited to, (caprylic acid / capric acid) triglycerides derived from coconut oil or palm kernel oil.

[0141] In some embodiments, one or more pharmaceutically acceptable excipients of the hard or soft capsules disclosed herein include one or more surfactants. Examples of surfactants include, but are not limited to, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), polysorbate 20, polysorbate 80, polyoxyl 35 castor oil (e.g., Cremophor® EL), polyoxyl 40 hydrogenated castor oil (e.g., Cremophor® RH40, Cremophor® RH60), Solutol® HS-15, sorbitan monooleate (e.g., Span® 20), PEG300 caprylic / capric glycerides (e.g., Softigen® 767), PEG400 caprylic / capric glycerides (e.g., Labrasol®), PEG300 oleic glycerides (e.g., Labrafil® M-1944CS), PEG300 linoleic glycerides (e.g., Labrafil® M-2125CS), PEG300 lauric glycerides (e.g., Labrafil® M2130CS), polyoxyl 8 stearate (e.g., PEG400 monosterate), polyoxyl 40 stearate (e.g., PEG1750 monosterate), povidone K-90, polyoxyl stearate, type I (e.g., Gelucire® 48 / 16), polyglyceryl-3 dioleate, propylene glycol monolaurate, type I, propylene glycol monolaurate, type II, propylene glycol monocaprylate, type II (e.g., Capryol™ 90), propylene glycol monocaprylate, type I (e.g., Capryol™ PGMC), lauroyl polyoxyl glycerides (e.g., Gelucire® 44 / 14), stearoyl polyoxyl glycerides (e.g., Gelucire® 50 / 13), poloxamer 124, poloxamer 188, and poloxamer 407.

[0142] The pharmaceutical composition of the present disclosure may be in the form of a sterile injectable preparation, for example, a solution or a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents described herein. The sterile injectable preparation may also be an injectable sterile solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol, or may be prepared as a lyophilized powder. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils can be conventionally used as solvents or suspending media. For this purpose, any non-irritating non-volatile oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can be similarly used in the preparation of injectables.

[0143] In some embodiments, the sterile injectable preparation disclosed herein may also be an injectable sterile solution or suspension prepared from a reconstituted lyophilized powder in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils can be conventionally used as solvents or suspending media. For this purpose, any non-irritating non-volatile oil containing synthetic monoglycerides or diglycerides can be used. In addition, fatty acids such as oleic acid can be similarly used in the preparation of injectables. Formulations suitable for parenteral administration may include aqueous and non-aqueous sterile injectables that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickening agents. In certain embodiments, the suspension is a micro-suspension. In certain embodiments, the suspension is a nano-suspension.

[0144] In some embodiments, the pharmaceutical composition of the present disclosure can be in the form of a solution formulation. In some embodiments, the solution comprises N-methyl-2-pyrrolidone (NMP), polyethylene glycol (PEG), water, and / or glycolic acid. In some embodiments, the solution comprises PEG200, ethanol, and water. In some embodiments, the solution comprises PEG300 and water. In some embodiments, the amount of water in the solution comprising PEG300 and water is about 25 w / w%, about 23 w / w%, about 20 w / w%, about 17 w / w%, about 15 w / w%, about 10 w / w%, about 9 w / w%, about 8 w / w%, or about 5 w / w%. In some embodiments, the amount of PEG300 in the solution comprising PEG300 and water is about 90 w / w%, about 85 w / w%, about 80 w / w%, about 75 w / w%, about 70 w / w%, about 65 w / w%, about 60 w / w%, about 55 w / w%, about 50 w / w%, or about 45 w / w%. In some embodiments, the solution comprising PEG300 and water comprises about 85 w / w% of PEG300 and about 15 w / w% of water. In some embodiments, the solution comprising PEG300 and water further comprises a base. In some embodiments, the solution comprising PEG300 and water further comprises an inorganic base. In some embodiments, the inorganic base is sodium hydroxide or sodium ethoxide. In some embodiments, sodium hydroxide or sodium ethoxide is present in an amount of about 3 w / w%, about 2 w / w%, about 1 w / w%, or about 0.5 w / w%.

[0145] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) comprise one or more excipients. The excipients should be compatible with the other components of the formulation and physiologically innocuous to its recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition 2009.

[0146] Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (e.g., polysorbate 20 or 80) and poloxamers (e.g., poloxamer 338, 188, or 207). In some embodiments, parenteral administration (e.g., SC or IM formulations) comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and a poloxamer are disclosed herein. In some embodiments, the poloxamer is poloxamer 338. In some embodiments, the poloxamer is poloxamer 188. In some embodiments, the amount of poloxamer in the parenteral administration disclosed herein is less than about 5%, e.g., less than about 3%, less than about 2%, less than about 1%, or less than about 0.5%.

[0147] In certain embodiments, excipients include N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide, polyethylene glycol and / or tetraglycol / glycofurol.

[0148] Generally, a poloxamer is a synthetic nonionic triblock linear copolymer having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic polypropylene oxides, and in certain cases, the weight ratio is 4:2:4. Thus, in certain embodiments, the compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and a block copolymer composed of one polyoxypropylene segment and two hydrophilic polypropylene oxide segments. In certain embodiments, the ratio of the polyoxypropylene segment to the two hydrophilic polypropylene oxide segments is 4:2:4 (hydrophilic polypropylene oxide: polyoxypropylene: hydrophilic polypropylene oxide). Poloxamers are generally understood to have the following structure:

Chemical formula

[0149] In some embodiments, the poloxamer is a synthetic non - ionic triblock of a linear copolymer having a central hydrophobic block of polypropylene oxide (PPO) adjacent to two hydrophilic chains of polyethylene oxide (PEO). In certain cases, the weight ratio is 4:2:4. Thus, in certain embodiments, the compositions disclosed herein include a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and a block copolymer composed of one PPO segment and two PEO segments. In certain embodiments, the ratio of the PPO segment to the two PEO segments is 4:2:4 (PEO:PPO:PEO). Poloxamers are generally understood to have the following structure: [Chemical formula] (Here, a and b are integers). For example, a is between about 2 and about 130, and b is between about 15 and about 67. Poloxamer 188 is understood to have a molecular weight of, for example, about 7680 to about 9510 Daltons (where a is about 80 and b is about 27) (see, for example, International Journal of PharmTech (See Research, Vol.1, No.2, pp 299-303, April-June 2009). In some cases, poloxamer 188 has an average molecular weight of about 8400 Daltons. Poloxamer 338 has a molecular weight in the range of about 12700 Da to about 17400 Da (where a is about 141 and b is about 44).

[0150] In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a poloxamer, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, poloxamer 188, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein do not comprise a poloxamer. In some embodiments, the pharmaceutical compositions disclosed herein do not comprise poloxamer 188. In some embodiments, the pharmaceutical compositions disclosed herein are solutions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein are solutions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a poloxamer, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein are solutions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, poloxamer 188, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein are solutions that do not comprise a poloxamer. In some embodiments, the pharmaceutical compositions disclosed herein are solutions that do not comprise poloxamer 188.

[0151] Examples of excipients in parenteral formulations (e.g., SC or IM formulations) include polyethylene glycol. Generally, polyethylene glycol (PEG) has the general formula H-(O-CH 2 -CH 2 ) nIt is a polyether having -OH. In certain embodiments, the PEG may be alkyl and "capped". In those embodiments, the capped PEG has the formula alkyl-(O-CH 2 -CH 2 ) n -O-alkyl (e.g., CH 3 -(O-CH 2 -CH 2 ) n -OCH 3 ). The pharmaceutical compositions of the present disclosure may contain PEG having an average molecular weight of about 100 to about 1000. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 100 to about 800. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 200 to about 600. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 400. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 300. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 200. In some embodiments of the pharmaceutical composition, by combining PEGs of different molecular weights, desired property(ies) (e.g., viscosity) can be obtained. Specific examples of PEGs include, but are not limited to, PEG100, PEG200, PEG300, PEG400, PEG500, and PEG600. PEG100 refers to polyethylene glycol having an average molecular weight of about 100, for example.

[0152] As described above, in some embodiments, the pharmaceutical compositions containing a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, disclosed herein are in solution form.

[0153] In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is from about 50 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is from about 75 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is from about 50 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is from about 75 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is from about 75 mg / ml to about 300 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, about 100 mg / ml, about 105 mg / ml, about 110 mg / ml, about 115 mg / ml, about 120 mg / ml, about 125 mg / ml, about 130 mg / ml, about 135 mg / ml, about 140 mg / ml, about 145 mg / ml, about 150 mg / ml, about 155 mg / ml, about 160 mg / ml, about 165 mg / ml, about 170 mg / ml, about 175 mg / ml, about 180 mg / ml, about 185 mg / ml, about 190 mg / ml, about 195 mg / ml, about 200 mg / ml, about 205 mg / ml, about 210 mg / ml, about 215 mg / ml, about 220 mg / ml, about 225 mg / ml, about 230 mg / ml, about 235 mg / ml, about 240 mg / ml, about 245 mg / ml, about 250 mg / ml, about 255 mg / ml, about 260 mg / ml, about 265 mg / ml, about 270 mg / ml, about 275 mg / ml, about 280 mg / ml, about 285 mg / ml, about 290 mg / ml, about 295 mg / ml, about 300 mg / ml, about 325 mg / ml, about 350 mg / ml, about 375 mg / ml, about 400 mg / ml, about 425 mg / ml, about 450 mg / ml, about 475 mg / ml, or about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 125 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 225 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 275 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 450 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the solution disclosed herein is about 500 mg / ml.

[0154] In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, PEG300, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, and water. In some embodiments, the solution disclosed herein comprises a sodium salt of a compound of formula (Ia), PEG300, and water. In some embodiments, the solution disclosed herein comprises a trifluoroacetate salt of a compound of formula (Ib), PEG300, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ib), PEG300, and water.

[0155] In some embodiments, the solution disclosed herein comprises a compound of formula (Ia), PEG300, and water. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is from about 50 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is from about 50 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 225 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, and water is about 275 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 500 mg / ml.

[0156] In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is from about 5 w / w% to about 15 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is from about 5 w / w% to about 10 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is from about 8 w / w% to about 12 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is from about 9 w / w% to about 10 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is about 8.0 w / w%, about 8.1 w / w%, about 8.2 w / w%, about 8.3 w / w%, about 8.4 w / w%, about 8.5 w / w%, about 8.6 w / w%, about 8.7 w / w%, about 8.8 w / w%, about 8.9 w / w%, about 9.0 w / w%, about 9.1 w / w%, about 9.2 w / w%, about 9.3 w / w%, about 9.4 w / w%, about 9.5 w / w%, about 9.6 w / w%, about 9.7 w / w%, about 9.8 w / w%, about 9.9 w / w%, about 10.0 w / w%, about 10.1 w / w%, about 10.2 w / w%, about 10.3 w / w%, about 10.4 w / w%, about 10.5 w / w%, about 10.6 w / w%, about 10.7 w / w%, about 10.8 w / w%, about 10.9 w / w%, about 11.0 w / w%, about 11.1 w / w%, about 11.2 w / w%, about 11.3 w / w%, about 11.4 w / w%, about 11.5 w / w%, about 11.6 w / w%, about 11.7 w / w%, about 11.8 w / w%, about 11.9 w / w%, or about 12.0 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is about 9.0 w / w%, about 9.1 w / w%, about 9.2 w / w%, about 9.3 w / w%, about 9.4 w / w%, about 9.5 w / w%, about 9.6 w / w%, about 9.7 w / w%, about 9.8 w / w%, about 9.9 w / w%, or about 10.0 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is about 9.5 w / w%, about 9.6 w / w%, about 9.7 w / w%, about 9.8 w / w%, about 9.9 w / w%, or about 10.0 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is about 9.8 w / w%.In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, and water is about 10 w / w%.

[0157] In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, and water is from about 50 w / w% to about 85 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, and water is from about 60 w / w% to about 80 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, and water is from about 60 w / w% to about 70 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, and water is about 50 w / w%, about 55 w / w%, about 60 w / w%, about 65 w / w%, about 70 w / w%, about 75 w / w%, about 80 w / w%, or about 85 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, and water is about 65 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, and water is about 65.0 w / w%.

[0158] In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is from about 15 w / w% to about 35 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is from about 20 w / w% to about 35 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is from about 24 w / w% to about 26 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, or about 25.5 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 25 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, and water is about 25.2 w / w%.

[0159] In some embodiments, the solution disclosed herein comprises from about 5 w / w% to about 15 w / w% water, from about 50 w / w% to about 85 w / w% PEG300, and from about 15 w / w% to about 35 w / w% of the compound of formula (Ia). In some embodiments, the solution comprises from about 5 w / w% to about 10 w / w% water, from about 60 w / w% to about 80 w / w% PEG300, and from about 20 w / w% to about 35 w / w% of the compound of formula (Ia). In some embodiments, the solution comprises from about 8 w / w% to about 12 w / w% water, from about 60 w / w% to about 70 w / w% PEG300, and from about 15 w / w% to about 35 w / w% of the compound of formula (Ia). In some embodiments, the solution comprises from about 9 w / w% to about 10 w / w% water, from about 60 w / w% to about 70 w / w% PEG300, and from about 24 w / w% to about 26 w / w% of the compound of formula (Ia). In some embodiments, the solution comprises about 9.8 w / w% water, about 65.0 w / w% PEG300, and about 25.2 w / w% of the compound of formula (Ia). In some embodiments, the solution comprises about 10 w / w% water, about 65.0 w / w% PEG300, and about 25 w / w% of the compound of formula (Ia).

[0160] In some embodiments, the solution disclosed herein comprises the sodium salt of the compound of formula (Ia), PEG300, and water. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 50 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 225 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 250 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 275 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 500 mg / ml.

[0161] In some embodiments, the amount of water in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 10 w / w% to about 40 w / w%. In some embodiments, the amount of water in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 15 w / w% to about 35 w / w%. In some embodiments, the amount of water in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 20 w / w% to about 30 w / w%. In some embodiments, the amount of water in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 21 w / w% to about 29 w / w%. In some embodiments, the amount of water in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 23.4 w / w% to about 27.5 w / w%. In some embodiments, the amount of water in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is from about 23.41 w / w% to about 27.47 w / w%.In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 22.0 w / w%, about 22.1 w / w%, about 22.2 w / w%, about 22.3 w / w%, about 22.4 w / w%, about 22.5 w / w%, about 22.6 w / w%, about 22.7 w / w%, about 22.8 w / w%, about 22.9 w / w%, about 23.0 w / w%, about 23.1 w / w%, about 23.2 w / w%, about 23.3 w / w%, about 23.4 w / w%, about 23.5 w / w%, about 23.6 w / w%, about 23.7 w / w%, about 23.8 w / w%, about 23.9 w / w%, about 24.0 w / w%, about 24.1 w / w%, about 24.2 w / w%, about 24.3 w / w%, about 24.4 w / w%, about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, about 25.5 w / w%, about 25.6 w / w%, about 25.7 w / w%, about 25.8 w / w%, about 25.9 w / w%, about 26.0 w / w%, about 26.1 w / w%, about 26.2 w / w%, about 26.3 w / w%, about 26.4 w / w%, about 26.5 w / w%, about 26.6 w / w%, about 26.7 w / w%, about 26.8 w / w%, about 26.9 w / w%, about 27.0 w / w%, about 27.1 w / w%, about 27.2 w / w%, about 27.3 w / w%, about 27.4 w / w%, about 27.5 w / w%, about 27.6 w / w%, about 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, about 28.0 w / w%, about 28.1 w / w%, about 28.2 w / w%, about 28.3 w / w%, about 28.4 w / w%, about 28.5 w / w%, about 28.6 w / w%, about 28.7 w / w%, about 28.8 w / w%, about 28.9 w / w%, or about 29.0 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 23.4 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 23.41 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 27.47 w / w%.In one embodiment, the amount of water in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, and water is about 27.5 w / w%.

[0162] In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 35 w / w% to about 75 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 45 w / w% to about 65 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 48 w / w% to about 60 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 50 w / w% to about 59 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 50.1 w / w% to about 58.8 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 50.13 w / w% to about 58.84 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 45 w / w%, about 46 w / w%, about 47 w / w%, about 48 w / w%, about 49 w / w%, about 50 w / w%, about 51 w / w%, about 52 w / w%, about 53 w / w%, about 54 w / w%, about 55 w / w%, about 56 w / w%, about 57 w / w%, about 58 w / w%, about 59 w / w%, about 60 w / w%, about 61 w / w%, about 62 w / w%, about 63 w / w%, about 64 w / w%, or about 65 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 50.1 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 50.13 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 58.8 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 58.84 w / w%.

[0163] In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 5 w / w% to about 35 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 10 w / w% to about 30 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 11 w / w% to about 28 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 13 w / w% to about 27 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 13.69 w / w% to about 26.46 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is from about 13.7 w / w% to about 26.5 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 13.0 w / w%, about 13.1 w / w%, about 13.2 w / w%, about 13.3 w / w%, about 13.4 w / w%, about 13.5 w / w%, about 13.6 w / w%, about 13.7 w / w%, about 13.8 w / w%, about 13.9 w / w%, about 14.0 w / w%, about 14.1 w / w%, about 14.2 w / w%, about 14.3 w / w%, about 14.4 w / w%, about 14.5 w / w%, about 14.6 w / w%, about 14.7 w / w%, about 14.8 w / w%, about 14.9 w / w%, about 15.0 w / w%, about 15.1 w / w%, about 15.2 w / w%, about 15.3 w / w%, about 15.4 w / w%, about 15.5 w / w%, about 15.6 w / w%, about 15.7 w / w%, about 15.8 w / w%, about 15.9 w / w%, about 16.0 w / w%, about 16.1 w / w%, about 16.2 w / w%, about 16.3 w / w%, about 16.4 w / w%, about 16.5 w / w%, about 16.6 w / w%, about 16.7 w / w%, about 16.8 w / w%, about 16.9 w / w%, about 17.0 w / w%, about 17.1 w / w%, about 17.2 w / w%, about 17.3 w / w%, about 17.4 w / w%, about 17.5 w / w%, about 17.6 w / w%, about 17.7 w / w%, about 17.8 w / w%, about 17.9 w / w%, about 18.0 w / w%, about 18.1 w / w%, about 18.2 w / w%, about 18.3 w / w%, about 18.4 w / w%, about 18.5 w / w%, about 18.6 w / w%, about 18.7 w / w%, about 18.8 w / w%, about 18.9 w / w%, about 19.0 w / w%, about 19.1 w / w%, about 19.2 w / w%, about 19.3 w / w%, about 19.4 w / w%, about 19.5 w / w%, about 19.6 w / w%, about 19.7 w / w%, about 19.8 w / w%, about 19.9 w / w%, about 20.0 w / w%, about 21.1 w / w%, about 21.2 w / w%, about 21.3 w / w%, about 21.4 w / w%, about 21.5 w / w%, about 21.6 w / w%, about 21.7 w / w%, about 21.8 w / w%, about 21.9 w / w%, about 22.0 w / w%, about 22.1 w / w%, about 22.2 w / w%, about 22.3 w / w%, about 22.4 w / w%, about 22.5 w / w%, about 22.6 w / w%, about 22.7 w / w%, about 22.8 w / w%, about 22.9 w / w%, about 23.0 w / w%, about 23.1 w / w%, about 23.2 w / w%, about 23.3 w / w%, about 23.4 w / w%, about 23.5 w / w%, about 23.6 w / w%, about 23.7 w / w%, about 23.8 w / w%, about 23.9 w / w%, about 24.0 w / w%, about 24.1 w / w%, about 24.2 w / w%, about 24.3 w / w%, about 24.4 w / w%, about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, about 25.5 w / w%, about 25.6 w / w%, about 25.7 w / w%, about 25.8 w / w%, about 25.9 w / w%, about 26.0 w / w%, about 26.1 w / w%, about 26.2 w / w%, about 26.3 w / w%, about 26.4 w / w%, about 26.5 w / w%, about 26.6 w / w%, about 26.7 w / w%, about 26.8 w / w%, about 26.9 w / w%, about 27.0 w / w%, about 27.1 w / w%, about 27.2 w / w%, about 27.3 w / w%, about 27.4 w / w%, about 27.5 w / w%, about 27.6 w / w%, about 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, about 28.0 w / w%, about 28.1 w / w%, about 28.It is 2 w / w%, about 28.3 w / w%, about 28.4 w / w%, about 28.5 w / w%, about 28.6 w / w%, about 28.7 w / w%, about 28.8 w / w%, about 28.9 w / w%, or about 29.0 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 13.69 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 13.7 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 26.46 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, and water is about 26.5 w / w%.

[0164] In some embodiments, the solution disclosed herein comprises from about 10 w / w% to about 40 w / w% water, from about 35 w / w% to about 75 w / w% PEG300, and from about 5 w / w% to about 35 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises from about 15 w / w% to about 35 w / w% water, from about 45 w / w% to about 65 w / w% PEG300, and from about 10 w / w% to about 30 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises from about 20 w / w% to about 30 w / w% water, from about 48 w / w% to about 60 w / w% PEG300, and from about 11 w / w% to about 28 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises from about 21 w / w% to about 29 w / w% water, from about 50 w / w% to about 59 w / w% PEG300, and from about 13 w / w% to about 27 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises from about 23.4 w / w% to about 27.5 w / w% water, from about 50.1 w / w% to about 58.8 w / w% PEG300, and from about 13.7 w / w% to about 26.5 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises from about 23.41 w / w% to about 27.47 w / w% water, from about 50.13 w / w% to about 58.84 w / w% PEG300, and from about 13.69 w / w% to about 26.46 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises about 27.5 w / w% water, about 58.8 w / w% PEG300, and about 13.7 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises about 27.47 w / w% water, about 58.84 w / w% PEG300, and about 13.69 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises about 23.4 w / w% water, about 50.1 w / w% PEG300, and about 26.5 w / w% sodium salt of the compound of formula (Ia). In some embodiments, the solution comprises about 23.41 w / w% water, about 50.13 w / w% PEG300, and about 26.46 w / w% sodium salt of the compound of formula (Ia).

[0165] In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, PEG300, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ia), PEG300, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a trifluoroacetate salt of a compound of formula (Ib), PEG300, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ib), PEG300, poloxamer 188, and water.

[0166] In some embodiments, the solution disclosed herein comprises the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 50 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 50 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 200 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 225 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 275 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 500 mg / ml.

[0167] In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 10 w / w% to about 45 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 15 w / w% to about 35 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 20 w / w% to about 35 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 20 w / w% to about 31 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 21.9 w / w% to about 30.1 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 21.87 w / w% to about 30.07 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 19.0 w / w%, about 19.1 w / w%, about 19.2 w / w%, about 19.3 w / w%, about 19.4 w / w%, about 19.5 w / w%, about 19.6 w / w%, about 19.7 w / w%, about 19.8 w / w%, about 19.9 w / w%, about 20.0 w / w%, about 20.1 w / w%, about 20.2 w / w%, about 20.3 w / w%, about 20.4 w / w%, about 20.5 w / w%, about 20.6 w / w%, about 20.7 w / w%, about 20.8 w / w%, about 20.9 w / w%, about 21.0 w / w%, about 21.1 w / w%, about 21.2 w / w%, about 21.3 w / w%, about 21.4 w / w%, about 21.5 w / w%, about 21.6 w / w%, about 21.7 w / w%, about 21.8 w / w%, about 21.9 w / w%, about 22.0 w / w%, about 22.1 w / w%, about 22.2 w / w%, about 22.3 w / w%, about 22.4 w / w%, about 22.5 w / w%, about 22.6 w / w%, about 22.7 w / w%, about 22.8 w / w%, about 22.9 w / w%, about 23.0 w / w%, about 23.1 w / w%, about 23.2 w / w%, about 23.3 w / w%, about 23.4 w / w%, about 23.5 w / w%, about 23.6 w / w%, about 23.7 w / w%, about 23.8 w / w%, about 23.9 w / w%, about 24.0 w / w%, about 24.1 w / w%, about 24.2 w / w%, about 24.3 w / w%, about 24.4 w / w%, about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, about 25.5 w / w%, about 25.6 w / w%, about 25.7 w / w%, about 25.8 w / w%, about 25.9 w / w%, about 26.0 w / w%, about 26.1 w / w%, about 26.2 w / w%, about 26.3 w / w%, about 26.4 w / w%, about 26.5 w / w%, about 26.6 w / w%, about 26.7 w / w%, about 26.8 w / w%, about 26.9 w / w%, about 27.0 w / w%, about 27.1 w / w%, about 27.2 w / w%, about 27.3 w / w%, about 27.4 w / w%, about 27.5 w / w%, about 27.6 w / w%, about 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, about 28.0 w / w%, about 28.1 w / w%, about 28.2 w / w%, about 28.3 w / w%, about 28.4 w / w%, about 28.5 w / w%, about 28.6 w / w%, about 28.7 w / w%, about 28.8 w / w%, about 28.9 w / w%, about 29.0 w / w%, about 29.1 w / w%, about 29.2 w / w%, about 29.3 w / w%, about 29.4 w / w%, about 29.5 w / w%, about 29.6 w / w%, about 29.7 w / w%, about 29.8 w / w%, about 29.9 w / w%, about 30.0 w / w%, about 30.1 w / w%, about 30.2 w / w%, about 30.3 w / w%, about 30.4 w / w%, about 30.5 w / w%, about 30.6 w / w%, about 30.7 w / w%, about 30.8 w / w%, about 30.9 w / w%, about 31.0 w / w%, about 31.1 w / w%, about 31.2 w / w%, about 31.3 w / w%, about 31.4 w / w%, about 31.5 w / w%, about 31.6 w / w%, about 31.7 w / w%, about 31.8 w / w%, about 31.9 w / w%, about 32.0 w / w%, about 32.1 w / w%, about 32.2 w / w%, about 32.3 w / w%, about 32.4 w / w%, about 32.5 w / w%, about 32.6 w / w%, about 32.7 w / w%, about 32.8 w / w%, about 32.9 w / w%, or about 33.It is 0 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 21.87 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 21.9 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 26.68 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 26.7 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 27.5 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 27.51 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 28.36 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 28.4 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 29.2 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 29.21 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 30.07 w / w%. In some embodiments, the amount of water in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 30.1 w / w%.

[0168] In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 30 w / w% to about 85 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 35 w / w% to about 75 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 40 w / w% to about 70 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 45 w / w% to about 68 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 46.8 w / w% to about 64.4 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 46.84 w / w% to about 64.40 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 40 w / w%, about 41 w / w%, about 42 w / w%, about 43 w / w%, about 44 w / w%, about 45 w / w%, about 46 w / w%, about 47 w / w%, about 48 w / w%, about 49 w / w%, about 50 w / w%, about 51 w / w%, about 52 w / w%, about 53 w / w%, about 54 w / w%, about 55 w / w%, about 56 w / w%, about 57 w / w%, about 58 w / w%, about 59 w / w%, about 60 w / w%, about 61 w / w%, about 62 w / w%, about 63 w / w%, about 64 w / w%, about 65 w / w%, about 66 w / w%, about 67 w / w%, about 68 w / w%, about 69 w / w%, or about 70 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 46.8 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 46.84 w / w%.In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 57.1 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 57.13 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 58.9 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 58.92 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 60.7 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 60.73 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 62.55 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 62.6 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 64.4 w / w%. In some embodiments, the amount of PEG300 in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 64.40 w / w%.

[0169] In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 0.5 w / w% to about 40 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 1 w / w% to about 35 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 1 w / w% to about 30 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 3 w / w% to about 28 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 4 w / w% to about 27 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 4.68 w / w% to about 26.47 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 4.7 w / w% to about 26.5 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 3.0 w / w%, about 3.1 w / w%, about 3.2 w / w%, about 3.3 w / w%, about 3.4 w / w%, about 3.5 w / w%, about 3.6 w / w%, about 3.7 w / w%, about 3.8 w / w%, about 3.9 w / w%, about 4.0 w / w%, about 4.1 w / w%, about 4.2 w / w%, about 4.3 w / w%, about 4.4 w / w%, about 4.5 w / w%, about 4.6 w / w%, about 4.7 w / w%, about 4.8 w / w%, about 4.9 w / w%, about 5.0 w / w%, about 5.1 w / w%, about 5.2 w / w%, about 5.3 w / w%, about 5.4 w / w%, about 5.5 w / w%, about 5.6 w / w%, about 5.7 w / w%, about 5.8 w / w%, about 5.9 w / w%, about 6.0 w / w%, about 6.1 w / w%, about 6.2 w / w%, about 6.3 w / w%, about 6.4 w / w%, about 6.5 w / w%, about 6.6 w / w%, about 6.7 w / w%, about 6.8 w / w%, about 6.9 w / w%, about 7.0 w / w%, about 7.1 w / w%, about 7.2 w / w%, about 7.3 w / w%, about 7.4 w / w%, about 7.5 w / w%, about 7.6 w / w%, about 7.7 w / w%, about 7.8 w / w%, about 7.9 w / w%, about 8.0 w / w%, about 8.1 w / w%, about 8.2 w / w%, about 8.3 w / w%, about 8.4 w / w%, about 8.5 w / w%, about 8.6 w / w%, about 8.7 w / w%, about 8.8 w / w%, about 8.9 w / w%, about 9.0 w / w%, about 9.1 w / w%, about 9.2 w / w%, about 9.3 w / w%, about 9.4 w / w%, about 9.5 w / w%, about 9.6 w / w%, about 9.7 w / w%, about 9.8 w / w%, about 9.9 w / w%, about 10.0 w / w%, about 10.1 w / w%, about 10.2 w / w%, about 10.3 w / w%, about 10.4 w / w%, about 10.5 w / w%, about 10.6 w / w%, about 10.7 w / w%, about 10.8 w / w%, about 10.9 w / w%, about 11.0 w / w%, about 11.1 w / w%, about 11.2 w / w%, about 11.3 w / w%, about 11.4 w / w%, about 11.5 w / w%, about 11.6 w / w%, about 11.7 w / w%, about 11.8 w / w%, about 11.9 w / w%, about 12.0 w / w%, about 12.1 w / w%, about 12.2 w / w%, about 12.3 w / w%, about 12.4 w / w%, about 12.5 w / w%, about 12.6 w / w%, about 12.7 w / w%, about 12.8 w / w%, about 12.9 w / w%, about 13.0 w / w%, about 13.1 w / w%, about 13.2 w / w%, about 13.3 w / w%, about 13.4 w / w%, about 13.5 w / w%, about 13.6 w / w%, about 13.7 w / w%, about 13.8 w / w%, about 13.9 w / w%, about 14.0 w / w%, about 14.1 w / w%, about 14.2 w / w%, about 14.3 w / w%, about 14.4 w / w%, about 14.5 w / w%, about 14.6 w / w%, about 14.7 w / w%, about 14.8 w / w%, about 14.9 w / w%, about 15.0 w / w%, about 15.1 w / w%, about 15.2 w / w%, about 15.3 w / w%, about 15.4 w / w%, about 15.5 w / w%, about 15.6 w / w%, about 15.7 w / w%, about 15.8 w / w%, about 15.9 w / w%, about 16.0 w / w%, about 16.1 w / w%, about 16.2 w / w%, about 16.3 w / w%, about 16.4 w / w%, about 16.5 w / w%, about 16.6 w / w%, about 16.7 w / w%, about 16.8 w / w%, about 16.9 w / w%, about 17.0 w / w%, about 17.1 w / w%, about 17.2 w / w%, about 17.3 w / w%, about 17.4 w / w%, about 17.5 w / w%, about 17.6 w / w%, about 17.7 w / w%, about 17.8 w / w%, about 17.9 w / w%, about 18.0 w / w%, about 18.1 w / w%, about 18.2 w / w%, about 18.3 w / w%, about 18.4 w / w%, about 18.5 w / w%, about 18.6 w / w%, about 18.7 w / w%, about 18.8 w / w%, about 18.9 w / w%, about 19.0 w / w%, about 19.1 w / w%, about 19.2 w / w%, about 19.3 w / w%, about 19.4 w / w%, about 19.5 w / w%, about 19.6 w / w%, about 19.7 w / w%, about 19.8 w / w%, about 19.9 w / w%, about 20.0 w / w%, about 20.1 w / w%, about 20.2 w / w%, about 20.3 w / w%, about 20.4 w / w%, about 20.5 w / w%, about 20.6 w / w%, about 20.7 w / w%, about 20.8 w / w%, about 20.9 w / w%, about 21.0 w / w%, about 21.1 w / w%, about 21.2 w / w%, about 21.3 w / w%, about 21.4 w / w%, about 21.5 w / w%, about 21.6 w / w%, about 21.7 w / w%, about 21.8 w / w%, about 21.9 w / w%, about 22.0 w / w%, about 22.1 w / w%, about 22.2 w / w%, about 22.3 w / w%, about 22.4 w / w%, about 22.5 w / w%, about 22.6 w / w%, about 22.7 w / w%, about 22.8 w / w%, about 22.9 w / w%, about 23.0 w / w%, about 23.1 w / w%, about 23.2 w / w%, about 23.3 w / w%, about 23.4 w / w%, about 23.5 w / w%, about 23.6 w / w%, about 23.7 w / w%, about 23.8 w / w%, about 23.9 w / w%, about 24.0 w / w%, about 24.1 w / w%, about 24.2 w / w%, about 24.3 w / w%, about 24.4 w / w%, about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, about 25.5 w / w%, about 25.6 w / w%, about 25.7 w / w%, about 25.8 w / w%, about 25.9 w / w%, about 26.0 w / w%, about 26.1 w / w%, about 26.2 w / w%, about 26.3 w / w%, about 26.4 w / w%, about 26.5 w / w%, about 26.6 w / w%, about 26.7 w / w%, about 26.8 w / w%, about 26.9 w / w%, about 27.0 w / w%, about 27.1 w / w%, about 27.2 w / w%, about 27.3 w / w%, about 27.4 w / w%, about 27.5 w / w%, about 27.6 w / w%, about 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, about 28.0 w / w%, about 28.1 w / w%, about 28.2 w / w%, about 28.3 w / w%, about 28.4 w / w%, about 28.5 w / w%, about 28.6 w / w%, about 28.7 w / w%, about 28.8 w / w%, about 28.9 w / w%, or about 29.0 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 4.68 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 4.7 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 6.97 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 7 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 9.2 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 9.23 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 11.48 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 11.It is 5 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 13.7 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 13.70 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 26.47 w / w%. In some embodiments, the amount of the sodium salt of the compound of formula (Ia) in a solution containing the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 26.5 w / w%.

[0170] In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 0.1 w / w% to about 10 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 0.3 w / w% to about 8 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 0.5 w / w% to about 7 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 0.6 w / w% to about 7 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 0.85 w / w% to about 4.82 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is from about 0.9 w / w% to about 4.8 w / w%.In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 0.5 w / w%, about 0.6 w / w%, about 0.7 w / w%, about 0.8 w / w%, about 0.9 w / w%, about 1.0 w / w%, about 1.1 w / w%, about 1.2 w / w%, about 1.3 w / w%, about 1.4 w / w%, about 1.5 w / w%, about 1.6 w / w%, about 1.7 w / w%, about 1.8 w / w%, about 1.9 w / w%, about 2.0 w / w%, about 2.1 w / w%, about 2.2 w / w%, about 2.3 w / w%, about 2.4 w / w%, about 2.5 w / w%, about 2.6 w / w%, about 2.7 w / w%, about 2.8 w / w%, about 2.9 w / w%, about 3.0 w / w%, about 3.1 w / w%, about 3.2 w / w%, about 3.3 w / w%, about 3.4 w / w%, about 3.5 w / w%, about 3.6 w / w%, about 3.7 w / w%, about 3.8 w / w%, about 3.9 w / w%, about 4.0 w / w%, about 4.1 w / w%, about 4.2 w / w%, about 4.3 w / w%, about 4.4 w / w%, about 4.5 w / w%, about 4.6 w / w%, about 4.7 w / w%, about 4.8 w / w%, about 4.9 w / w%, about 5.0 w / w%, about 5.1 w / w%, about 5.2 w / w%, about 5.3 w / w%, about 5.4 w / w%, about 5.5 w / w%, about 5.6 w / w%, about 5.7 w / w%, about 5.8 w / w%, about 5.9 w / w%, about 6.0 w / w%, about 6.1 w / w%, about 6.2 w / w%, about 6.3 w / w%, about 6.4 w / w%, about 6.5 w / w%, about 6.6 w / w%, about 6.7 w / w%, about 6.8 w / w%, about 6.9 w / w%, or about 7.0 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 0.85 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 0.9 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 1.27 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 1.3 w / w%.In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 1.68 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 1.7 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 2.09 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 2.1 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 2.49 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 2.5 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 4.8 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising the sodium salt of the compound of formula (Ia), PEG300, poloxamer 188, and water is about 4.82 w / w%.

[0171] In some embodiments, the solution disclosed herein comprises about 10 w / w% to about 45 w / w% water, about 30 w / w% to about 85 w / w% PEG300, about 0.5 w / w% to about 40 w / w% sodium salt of the compound of formula (Ia), and about 0.1 w / w% to about 10 w / w% poloxamer 188. In some embodiments, the solution comprises about 15 w / w% to about 35 w / w% water, about 35 w / w% to about 75 w / w% PEG300, about 1 w / w% to about 35 w / w% sodium salt of the compound of formula (Ia), and about 0.3 w / w% to about 8 w / w% poloxamer 188. In some embodiments, the solution comprises about 20 w / w% to about 35 w / w% water, about 40 w / w% to about 70 w / w% PEG300, about 1 w / w% to about 30 w / w% sodium salt of the compound of formula (Ia), and about 0.5 w / w% to about 7 w / w% poloxamer 188. In some embodiments, the solution comprises about 20 w / w% to about 31 w / w% water, about 45 w / w% to about 68 w / w% PEG300, about 3 w / w% to about 28 w / w% sodium salt of the compound of formula (Ia), and about 0.6 w / w% to about 7 w / w% poloxamer 188. In some embodiments, the solution comprises about 21.9 w / w% to about 30.1 w / w% water, about 46.8 w / w% to about 64.4 w / w% PEG300, about 4.7 w / w% to about 26.5 w / w% sodium salt of the compound of formula (Ia), and about 0.9 w / w% to about 4.8 w / w% poloxamer 188. In some embodiments, the solution comprises about 21.87 w / w% to about 30.07 w / w% water, about 46.84 w / w% to about 64.40 w / w% PEG300, about 4.68 w / w% to about 26.47 w / w% sodium salt of the compound of formula (Ia), and about 0.85 w / w% to about 4.82 w / w% poloxamer 188. In some embodiments, the solution comprises about 30.1 w / w% water, about 64.4 w / w% PEG300, about 4.7 w / w% sodium salt of the compound of formula (Ia), and about 0.9 w / w% poloxamer 188. In some embodiments, the solution comprises about 30.07 w / w% water, about 64.40 w / w% PEG300, about 4.68 w / w% sodium salt of the compound of formula (Ia), and about 0.85 w / w% poloxamer 188.In some embodiments, the solution comprises about 29.2 w / w% water, about 62.6 w / w% PEG300, about 7 w / w% sodium salt of the compound of formula (Ia), and about 1.3 w / w% poloxamer 188. In some embodiments, the solution comprises about 29.21 w / w% water, about 62.55 w / w% PEG300, about 6.97 w / w% sodium salt of the compound of formula (Ia), and about 1.27 w / w% poloxamer 188. In some embodiments, the solution comprises about 28.4 w / w% water, about 60.7 w / w% PEG300, about 9.2 w / w% sodium salt of the compound of formula (Ia), and about 1.7 w / w% poloxamer 188. In some embodiments, the solution comprises about 28.36 w / w% water, about 60.73 w / w% PEG300, about 9.23 w / w% sodium salt of the compound of formula (Ia), and about 1.68 w / w% poloxamer 188. In some embodiments, the solution comprises about 27.5 w / w% water, about 58.9 w / w% PEG300, about 11.5 w / w% sodium salt of the compound of formula (Ia), and about 2.1 w / w% poloxamer 188. In some embodiments, the solution comprises about 27.51 w / w% water, about 58.92 w / w% PEG300, about 11.48 w / w% sodium salt of the compound of formula (Ia), and about 2.09 w / w% poloxamer 188. In some embodiments, the solution comprises about 26.7 w / w% water, about 57.1 w / w% PEG300, about 13.7 w / w% sodium salt of the compound of formula (Ia), and about 2.5 w / w% poloxamer 188. In some embodiments, the solution comprises about 26.68 w / w% water, about 57.13 w / w% PEG300, about 13.70 w / w% sodium salt of the compound of formula (Ia), and about 2.49 w / w% poloxamer 188. In some embodiments, the solution comprises about 21.9 w / w% water, about 46.8 w / w% PEG300, about 26.5 w / w% sodium salt of the compound of formula (Ia), and about 4.8 w / w% poloxamer 188. In some embodiments, the solution comprises about 21.87 w / w% water, about 46.84 w / w% PEG300, about 26.47 w / w% sodium salt of the compound of formula (Ia), and about 4.82 w / w% poloxamer 188.

[0172] In some embodiments, the parenteral formulations (e.g., SC or IM formulations) disclosed herein are aqueous suspensions. In some embodiments, the parenteral formulations (e.g., SC or IM formulations) disclosed herein are aqueous suspensions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and saline. In some embodiments, the parenteral formulations (e.g., SC or IM formulations) disclosed herein are aqueous suspensions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, saline, and a suspending agent. In some embodiments, the parenteral formulations (e.g., SC or IM formulations) disclosed herein are aqueous suspensions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, saline, and a poloxamer (e.g., poloxamer 338, 188, or 207).

[0173] In some embodiments, suspensions are provided that comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in a poloxamer and saline. In some embodiments, the concentration of the poloxamer in the saline is from about 0.1% to about 20%. In some embodiments, the concentration of the poloxamer in the saline is from about 0.1% to about 10%. In some embodiments, the concentration of the poloxamer in the saline is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. In certain embodiments, the concentration of the poloxamer in the saline is about 2%. In certain embodiments, the poloxamer is poloxamer 188. In certain embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula (Ia). In certain embodiments, the compound is the sodium salt of a compound of formula (Ia). In certain embodiments, the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula (Ib). In certain embodiments, the compound is the trifluoroacetate salt of a compound of formula (Ib).

[0174] In some embodiments, a suspension is provided that comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in poloxamer and mannitol. In some embodiments, the concentration of poloxamer in mannitol is from about 0.1% to about 20%. In some embodiments, the concentration of poloxamer in mannitol is from about 0.1% to about 10%. In some embodiments, the concentration of poloxamer in mannitol is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. In certain embodiments, the concentration of poloxamer in mannitol is about 2%. In certain embodiments, the poloxamer is poloxamer 188. In certain embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula (Ia). In certain embodiments, the compound is the sodium salt of a compound of formula (Ia). In certain embodiments, the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula (Ib). In certain embodiments, the compound is the trifluoroacetate salt of a compound of formula (Ib).

[0175] In certain embodiments, the composition is formulated as a solid dosage form. In some embodiments, the solid dosage form is a solid injectable dosage form, such as a solid depot dosage form.

[0176] In certain embodiments, the active ingredient (e.g., a compound of formula (Ia) or formula (Ib)) is present as the free acid. In certain embodiments, the active ingredient (e.g., a compound of formula (Ia) or formula (Ib)) is present as the sodium salt. In certain embodiments, the active ingredient (e.g., a compound of formula (Ia) or formula (Ib)) is present as the trifluoroacetate salt. In some embodiments, the active ingredient is a compound of formula (Ia). In some embodiments, the active ingredient is a compound of formula (Ib).

[0177] In certain embodiments, the pharmaceutical compositions disclosed herein are parenteral formulations. In certain embodiments, the formulation is administered subcutaneously to a patient in need thereof. In certain embodiments, the formulation is administered intramuscularly to a patient in need thereof.

[0178] In certain embodiments, the parenteral formulation comprises N-methyl-2-pyrrolidone (NMP). In certain embodiments, the parenteral formulation consists essentially of N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation comprises dimethyl sulfoxide (DMSO). In some embodiments, the parenteral formulation comprises polyethylene glycol (PEG) or glycolfurole. In some embodiments, the solution comprises PEG200, ethanol, and water. In some embodiments, the solution comprises PEG300 and water. In some embodiments, the solution comprises poloxamer in saline. In some embodiments, the solution comprises 2% poloxamer 188 in physiological saline.

[0179] In certain embodiments, the parenteral formulation comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and water. In certain embodiments, the parenteral formulation comprises a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, and water. In certain embodiments, the parenteral formulation comprises a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, and water. In certain embodiments, the parenteral formulation further contains alcohol. In certain embodiments, the alcohol is ethanol. In certain embodiments, the parenteral formulation further contains polyethylene glycol. In certain embodiments, the polyethylene glycol has an average molecular weight of about 200 g / mol (e.g., polyethylene glycol 200). In certain embodiments, the parenteral formulation further contains an inorganic base. In certain embodiments, the inorganic base is sodium hydroxide (NaOH). In certain embodiments, the inorganic base is sodium ethoxide (NaOEt). In certain embodiments, the formulation contains from about 0.1 molar equivalents to about 1.5 molar equivalents of the inorganic base. In certain embodiments, the formulation contains from about 0.5 molar equivalents to about 1.5 molar equivalents of the inorganic base. In certain embodiments, the formulation contains from about 0.75 molar equivalents to about 1.2 molar equivalents of the inorganic base. In certain embodiments, the formulation contains about 1.0 molar equivalent of the inorganic base. In certain embodiments, the formulation contains about 1.2 molar equivalents of the inorganic base. In some embodiments, the inorganic base is NaOH or NaOEt.

[0180] In certain embodiments, the parenteral formulation comprises a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, water, and polyethylene glycol PEG300. In certain embodiments, the parenteral formulation comprises a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, water, and polyethylene glycol PEG300.

[0181] In certain embodiments, the parenteral formulation comprises a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, water, and polyethylene glycol PEG300 (polyethylene glycol having an average molecular weight of 300 g / mol), and NaOH. In certain embodiments, the parenteral formulation comprises a compound of formula (Ia), or a pharmaceutically acceptable salt thereof, water, and polyethylene glycol (PEG) 300, and NaOEt. In certain embodiments, the formulation comprises from about 0.1 molar equivalents to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises from about 0.5 molar equivalents to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises from about 0.75 molar equivalents to about 1.2 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises about 1.0 molar equivalent of NaOH or NaOEt. In certain embodiments, the formulation comprises about 1.2 molar equivalents of NaOH or NaOEt.

[0182] In certain embodiments, the parenteral formulation is a solution formulation comprising a mixture of ethanol, water, and polyethylene glycol. In certain embodiments, the parenteral formulation is a solution formulation comprising a mixture of ethanol, water, and PEG200. In certain embodiments, the solution formulation comprises from about 5% to about 20% ethanol, from about 5% to about 20% water, and from about 60% to about 90% PEG200. In certain embodiments, the solution formulation comprises from about 10% to about 15% ethanol, from about 10% to about 15% water, and from about 70% to about 80% PEG200. In certain embodiments, the solution formulation comprises about 10% ethanol, about 12% water, and about 78% PEG200. In certain embodiments, the solution formulation further comprises an inorganic base. In certain embodiments, the solution formulation comprises about 10% ethanol, about 13% water, and about 77% PEG200. In certain embodiments, the solution formulation further comprises an inorganic base. In certain embodiments, the formulation comprises from about 0.1 molar equivalent to about 1.5 molar equivalents of an inorganic base. In certain embodiments, the formulation comprises from about 0.5 molar equivalent to about 1.5 molar equivalents of an inorganic base. In certain embodiments, the formulation comprises from about 1.0 molar equivalent to about 1.2 molar equivalents of an inorganic base. In certain embodiments, the formulation comprises about 1.2 molar equivalents of an inorganic base. In certain embodiments, the inorganic base is sodium hydroxide or sodium ethoxide. In certain embodiments, the inorganic base is sodium hydroxide.

[0183] In certain embodiments, the parenteral formulation is a solution formulation comprising a mixture of water and polyethylene glycol. In certain embodiments, the parenteral formulation is a solution formulation comprising a mixture of water and PEG300. In certain embodiments, the solution formulation comprises from about 5% w / w to about 25% w / w water and from about 75% w / w to about 95% w / w PEG300. In some embodiments, the solution formulation further comprises an inorganic base. In certain embodiments, the formulation comprises from about 0.1 molar equivalents to about 1.5 molar equivalents of the inorganic base. In certain embodiments, the formulation comprises from about 0.5 molar equivalents to about 1.5 molar equivalents of the inorganic base. In certain embodiments, the formulation comprises from about 0.75 molar equivalents to about 1.2 molar equivalents of the inorganic base. In certain embodiments, the formulation comprises about 1.0 molar equivalent of the inorganic base. In certain embodiments, the formulation comprises about 1.2 molar equivalents of the inorganic base. In certain embodiments, the inorganic base is sodium hydroxide or sodium ethoxide. In certain embodiments, the inorganic base is sodium hydroxide.

[0184] In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, sodium hydroxide, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, PEG300, sodium hydroxide, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, sodium hydroxide, and water. In some embodiments, the solution disclosed herein comprises a sodium salt of a compound of formula (Ia), PEG300, sodium hydroxide, and water. In some embodiments, the solution disclosed herein comprises a trifluoroacetate salt of a compound of formula (Ib), PEG300, sodium hydroxide, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ib), PEG300, sodium hydroxide, and water.

[0185] In some embodiments, the solution disclosed herein comprises a compound of formula (Ia), PEG300, sodium hydroxide, and water. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 50 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 50 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 225 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 275 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 500 mg / ml.

[0186] In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 10 w / w% to about 40 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 15 w / w% to about 35 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 20 w / w% to about 30 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 21 w / w% to about 29 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 23.2 w / w% to about 27.9 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 23.2 w / w% to about 27.92 w / w%.In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 22.0 w / w%, about 22.1 w / w%, about 22.2 w / w%, about 22.3 w / w%, about 22.4 w / w%, about 22.5 w / w%, about 22.6 w / w%, about 22.7 w / w%, about 22.8 w / w%, about 22.9 w / w%, about 23.0 w / w%, about 23.1 w / w%, about 23.2 w / w%, about 23.3 w / w%, about 23.4 w / w%, about 23.5 w / w%, about 23.6 w / w%, about 23.7 w / w%, about 23.8 w / w%, about 23.9 w / w%, about 24.0 w / w%, about 24.1 w / w%, about 24.2 w / w%, about 24.3 w / w%, about 24.4 w / w%, about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, about 25.5 w / w%, about 25.6 w / w%, about 25.7 w / w%, about 25.8 w / w%, about 25.9 w / w%, about 26.0 w / w%, about 26.1 w / w%, about 26.2 w / w%, about 26.3 w / w%, about 26.4 w / w%, about 26.5 w / w%, about 26.6 w / w%, about 26.7 w / w%, about 26.8 w / w%, about 26.9 w / w%, about 27.0 w / w%, about 27.1 w / w%, about 27.2 w / w%, about 27.3 w / w%, about 27.4 w / w%, about 27.5 w / w%, about 27.6 w / w%, about 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, or about 29.0 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 23.2 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 27.9 w / w%. In some embodiments, the amount of water in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 27.92 w / w%.

[0187] In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 35 w / w% to about 75 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 45 w / w% to about 65 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 48 w / w% to about 60 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 49 w / w% to about 59 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 50.0 w / w% to about 58.0 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 50.0 w / w% to about 58.04 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 45 w / w%, about 46 w / w%, about 47 w / w%, about 48 w / w%, about 49 w / w%, about 50 w / w%, about 51 w / w%, about 52 w / w%, about 53 w / w%, about 54 w / w%, about 55 w / w%, about 56 w / w%, about 57 w / w%, about 58 w / w%, about 59 w / w%, about 60 w / w%, about 61 w / w%, about 62 w / w%, about 63 w / w%, about 64 w / w%, or about 65 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 50.0 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 58.0 w / w%. In some embodiments, the amount of PEG300 in a solution containing a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 58.04 w / w%.

[0188] In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 5 w / w% to about 35 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 10 w / w% to about 30 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 11 w / w% to about 28 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 13 w / w% to about 27 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 13.5 w / w% to about 25.7 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 13.47 w / w% to about 25.7 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 13.0 w / w%, about 13.1 w / w%, about 13.2 w / w%, about 13.3 w / w%, about 13.4 w / w%, about 13.5 w / w%, about 13.6 w / w%, about 13.7 w / w%, about 13.8 w / w%, about 13.9 w / w%, about 14.0 w / w%, about 14.1 w / w%, about 14.2 w / w%, about 14.3 w / w%, about 14.4 w / w%, about 14.5 w / w%, about 14.6 w / w%, about 14.7 w / w%, about 14.8 w / w%, about 14.9 w / w%, about 15.0 w / w%, about 15.1 w / w%, about 15.2 w / w%, about 15.3 w / w%, about 15.4 w / w%, about 15.5 w / w%, about 15.6 w / w%, about 15.7 w / w%, about 15.8 w / w%, about 15.9 w / w%, about 16.0 w / w%, about 16.1 w / w%, about 16.2 w / w%, about 16.3 w / w%, about 16.4 w / w%, about 16.5 w / w%, about 16.6 w / w%, about 16.7 w / w%, about 16.8 w / w%, about 16.9 w / w%, about 17.0 w / w%, about 17.1 w / w%, about 17.2 w / w%, about 17.3 w / w%, about 17.4 w / w%, about 17.5 w / w%, about 17.6 w / w%, about 17.7 w / w%, about 17.8 w / w%, about 17.9 w / w%, about 18.0 w / w%, about 18.1 w / w%, about 18.2 w / w%, about 18.3 w / w%, about 18.4 w / w%, about 18.5 w / w%, about 18.6 w / w%, about 18.7 w / w%, about 18.8 w / w%, about 18.9 w / w%, about 19.0 w / w%, about 19.1 w / w%, about 19.2 w / w%, about 19.3 w / w%, about 19.4 w / w%, about 19.5 w / w%, about 19.6 w / w%, about 19.7 w / w%, about 19.8 w / w%, about 19.9 w / w%, about 20.0 w / w%, about 21.1 w / w%, about 21.2 w / w%, about 21.3 w / w%, about 21.4 w / w%, about 21.5 w / w%, about 21.6 w / w%, about 21.7 w / w%, about 21.8 w / w%, about 21.9 w / w%, about 22.0 w / w%, about 22.1 w / w%, about 22.2 w / w%, about 22.3 w / w%, about 22.4 w / w%, about 22.5 w / w%, about 22.6 w / w%, about 22.7 w / w%, about 22.8 w / w%, about 22.9 w / w%, about 23.0 w / w%, about 23.1 w / w%, about 23.2 w / w%, about 23.3 w / w%, about 23.4 w / w%, about 23.5 w / w%, about 23.6 w / w%, about 23.7 w / w%, about 23.8 w / w%, about 23.9 w / w%, about 24.0 w / w%, about 24.1 w / w%, about 24.2 w / w%, about 24.3 w / w%, about 24.4 w / w%, about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, about 25.5 w / w%, about 25.6 w / w%, about 25.7 w / w%, about 25.8 w / w%, about 25.9 w / w%, about 26.0 w / w%, about 26.1 w / w%, about 26.2 w / w%, about 26.3 w / w%, about 26.4 w / w%, about 26.5 w / w%, about 26.6 w / w%, about 26.7 w / w%, about 26.8 w / w%, about 26.9 w / w%, about 27.0 w / w%, about 27.1 w / w%, about 27.2 w / w%, about 27.3 w / w%, about 27.4 w / w%, about 27.5 w / w%, about 27.6 w / w%, about 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, about 28.0 w / w%, about 28.1 w / w%, about 28.2 w / w%, about 28.3 w / w%, about 28.4 w / w%, about 28.5 w / w%, about 28.6 w / w%, about 28.7 w / w%, about 28.8 w / w%, about 28.9 w / w%, or about 29.0 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 13.47 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 13.5 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, and water is about 25.7 w / w%.

[0189] In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 0.05 w / w% to about 2 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 0.1 w / w% to about 1.5 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 0.3 w / w% to about 1.3 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 0.5 w / w% to about 1.2 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 0.6 w / w% to about 1.1 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is from about 0.58 w / w% to about 1.1 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 0.1 w / w%, about 0.2 w / w%, about 0.3 w / w%, about 0.4 w / w%, about 0.5 w / w%, about 0.6 w / w%, about 0.7 w / w%, about 0.8 w / w%, about 0.9 w / w%, about 1.0 w / w%, about 1.1 w / w%, about 1.2 w / w%, about 1.3 w / w%, about 1.4 w / w%, about 1.5 w / w%, about 1.6 w / w%, about 1.7 w / w%, about 1.8 w / w%, about 1.9 w / w%, or about 2.0 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 0.58 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 0.6 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, and water is about 1.1 w / w%.In some embodiments, the solution disclosed herein comprises about 10 w / w% to about 40 w / w% water, about 35 w / w% to about 75 w / w% PEG300, about 5 w / w% to about 35 w / w% of the compound of formula (Ia), and about 0.05 w / w% to about 2 w / w% sodium hydroxide. In some embodiments, the solution comprises about 15 w / w% to about 35 w / w% water, about 45 w / w% to about 65 w / w% PEG300, about 10 w / w% to about 30 w / w% of the compound of formula (Ia), and about 0.1 w / w% to about 1.5 w / w% sodium hydroxide. In some embodiments, the solution comprises about 20 w / w% to about 30 w / w% water, about 48 w / w% to about 60 w / w% PEG300, about 11 w / w% to about 28 w / w% of the compound of formula (Ia), and about 0.3 w / w% to about 1.3 w / w% sodium hydroxide. In some embodiments, the solution comprises about 21 w / w% to about 29 w / w% water, about 49 w / w% to about 59 w / w% PEG300, about 13 w / w% to about 27 w / w% of the compound of formula (Ia), and about 0.5 w / w% to about 1.2 w / w% sodium hydroxide. In some embodiments, the solution comprises about 23.2 w / w% to about 27.9 w / w% water, about 50 w / w% to about 58 w / w% PEG300, about 13.5 w / w% to about 25.7 w / w% of the compound of formula (Ia), and about 0.6 w / w% to about 1.1 w / w% sodium hydroxide. In some embodiments, the solution comprises about 23.2 w / w% to about 27.92 w / w% water, about 50.0 w / w% to about 58.04 w / w% PEG300, about 13.47 w / w% to about 25.7 w / w% of the compound of formula (Ia), and about 0.58 w / w% to about 1.1 w / w% sodium hydroxide. In some embodiments, the solution comprises about 27.9 w / w% water, about 58 w / w% PEG300, about 13.5 w / w% of the compound of formula (Ia), and about 0.6 w / w% sodium hydroxide. In some embodiments, the solution comprises about 27.92 w / w% water, about 58.04 w / w% PEG300, about 13.47 w / w% of the compound of formula (Ia), and about 0.58 w / w% sodium hydroxide. In some embodiments, the solution comprises about 23.2 w / w% water, about 50.0 w / w% PEG300, about 25.7 w / w% of the compound of formula (Ia), and about 1.1 w / w% sodium hydroxide.

[0190] In some embodiments, the compound of formula (Ia) ionizes in situ to the sodium salt of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water in the presence of sodium hydroxide. Thus, in some embodiments, the compound of formula (Ia) is present as the sodium salt of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, and water.

[0191] In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a poloxamer, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, poloxamer 188, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein are solutions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, a poloxamer, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions disclosed herein are solutions comprising a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, poloxamer 188, and a pharmaceutically acceptable excipient.

[0192] In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, sodium hydroxide, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, PEG300, sodium hydroxide, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, PEG300, sodium hydroxide, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a sodium salt of a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water. In some embodiments, the solution disclosed herein comprises a trifluoroacetate salt of a compound of formula (Ib), PEG300, sodium hydroxide, poloxamer 188, and water.

[0193] In some embodiments, the solution disclosed herein comprises a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 50 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 50 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 175 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 225 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 275 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 475 mg / ml.In one embodiment, the concentration of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 500 mg / ml.

[0194] In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 10 w / w% to about 45 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 15 w / w% to about 35 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 20 w / w% to about 35 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 20 w / w% to about 31 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 22 w / w% to about 30.1 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 21.97 w / w% to about 30.07 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 19.0 w / w%, about 19.1 w / w%, about 19.2 w / w%, about 19.3 w / w%, about 19.4 w / w%, about 19.5 w / w%, about 19.6 w / w%, about 19.7 w / w%, about 19.8 w / w%, about 19.9 w / w%, about 20.0 w / w%, about 20.1 w / w%, about 20.2 w / w%, about 20.3 w / w%, about 20.4 w / w%, about 20.5 w / w%, about 20.6 w / w%, about 20.7 w / w%, about 20.8 w / w%, about 20.9 w / w%, about 21.0 w / w%, about 21.1 w / w%, about 21.2 w / w%, about 21.3 w / w%, about 21.4 w / w%, about 21.5 w / w%, about 21.6 w / w%, about 21.7 w / w%, about 21.8 w / w%, about 21.9 w / w%, about 22.0 w / w%, about 22.1 w / w%, about 22.2 w / w%, about 22.3 w / w%, about 22.4 w / w%, about 22.5 w / w%, about 22.6 w / w%, about 22.7 w / w%, about 22.8 w / w%, about 22.9 w / w%, about 23.0 w / w%, about 23.1 w / w%, about 23.2 w / w%, about 23.3 w / w%, about 23.4 w / w%, about 23.5 w / w%, about 23.6 w / w%, about 23.7 w / w%, about 23.8 w / w%, about 23.9 w / w%, about 24.0 w / w%, about 24.1 w / w%, about 24.2 w / w%, about 24.3 w / w%, about 24.4 w / w%, about 24.5 w / w%, about 24.6 w / w%, about 24.7 w / w%, about 24.8 w / w%, about 24.9 w / w%, about 25.0 w / w%, about 25.1 w / w%, about 25.2 w / w%, about 25.3 w / w%, about 25.4 w / w%, about 25.5 w / w%, about 25.6 w / w%, about 25.7 w / w%, about 25.8 w / w%, about 25.9 w / w%, about 26.0 w / w%, about 26.1 w / w%, about 26.2 w / w%, about 26.3 w / w%, about 26.4 w / w%, about 26.5 w / w%, about 26.6 w / w%, about 26.7 w / w%, about 26.8 w / w%, about 26.9 w / w%, about 27.0 w / w%, about 27.1 w / w%, about 27.2 w / w%, about 27.3 w / w%, about 27.4 w / w%, about 27.5 w / w%, about 27.6 w / w%, about 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, about 28.0 w / w%, about 28.1 w / w%, about 28.2 w / w%, about 28.3 w / w%, about 28.4 w / w%, about 28.5 w / w%, about 28.6 w / w%, about 28.7 w / w%, about 28.8 w / w%, about 28.9 w / w%, about 29.0 w / w%, about 29.1 w / w%, about 29.2 w / w%, about 29.3 w / w%, about 29.4 w / w%, about 29.5 w / w%, about 29.6 w / w%, about 29.7 w / w%, about 29.8 w / w%, about 29.9 w / w%, about 30.0 w / w%, about 30.1 w / w%, about 30.2 w / w%, about 30.3 w / w%, about 30.4 w / w%, about 30.5 w / w%, about 30.6 w / w%, about 30.7 w / w%, about 30.8 w / w%, about 30.9 w / w%, about 31.0 w / w%, about 31.1 w / w%, about 31.2 w / w%, about 31.3 w / w%, about 31.4 w / w%, about 31.5 w / w%, about 31.6 w / w%, about 31.7 w / w%, about 31.8 w / w%, about 31.9 w / w%, about 32.0 w / w%, about 32.1 w / w%, about 32.2 w / w%, about 32.3 w / w%, about 32.4 w / w%, about 32.5 w / w%, about 32.6 w / w%, about 32.7 w / w%, about 32.8 w / w%, about 32.9 w / w%, or about 33It is 0 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 21.97 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 22 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 30.07 w / w%. In some embodiments, the amount of water in the solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 30.1 w / w%.

[0195] In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 30 w / w% to about 85 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 35 w / w% to about 75 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 40 w / w% to about 70 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 45 w / w% to about 68 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 47.1 w / w% to about 64.4 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 47.05 w / w% to about 64.41 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 40 w / w%, about 41 w / w%, about 42 w / w%, about 43 w / w%, about 44 w / w%, about 45 w / w%, about 46 w / w%, about 47 w / w%, about 48 w / w%, about 49 w / w%, about 50 w / w%, about 51 w / w%, about 52 w / w%, about 53 w / w%, about 54 w / w%, about 55 w / w%, about 56 w / w%, about 57 w / w%, about 58 w / w%, about 59 w / w%, about 60 w / w%, about 61 w / w%, about 62 w / w%, about 63 w / w%, about 64 w / w%, about 65 w / w%, about 66 w / w%, about 67 w / w%, about 68 w / w%, about 69 w / w%, or about 70 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 47.05 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 47.1 w / w%.In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 64.4 w / w%. In some embodiments, the amount of PEG300 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 64.41 w / w%.

[0196] In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.5 w / w% to about 40 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 1 w / w% to about 35 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 1 w / w% to about 30 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 3 w / w% to about 28 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 4 w / w% to about 26 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 4.6 w / w% to about 25.2 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 4.57 w / w% to about 25.21 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution containing the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 3.0 w / w%, about 3.1 w / w%, about 3.2 w / w%, about 3.3 w / w%, about 3.4 w / w%, about 3.5 w / w%, about 3.6 w / w%, about 3.7 w / w%, about 3.8 w / w%, about 3.9 w / w%, about 4.0 w / w%, about 4.1 w / w%, about 4.2 w / w%, about 4.3 w / w%, about 4.4 w / w%, about 4.5 w / w%, about 4.6 w / w%, about 4.7 w / w%, about 4.8 w / w%, about 4.9 w / w%, about 5.0 w / w%, about 5.1 w / w%, about 5.2 w / w%, about 5.3 w / w%, about 5.4 w / w%, about 5.5 w / w%, about 5.6 w / w%, about 5.7 w / w%, about 5.8 w / w%, about 5.9 w / w%, about 6.0 w / w%, about 6.1 w / w%, about 6.2 w / w%, about 6.3 w / w%, about 6.4 w / w%, about 6.5 w / w%, about 6.6 w / w%, about 6.7 w / w%, about 6.8 w / w%, about 6.9 w / w%, about 7.0 w / w%, about 7.1 w / w%, about 7.2 w / w%, about 7.3 w / w%, about 7.4 w / w%, about 7.5 w / w%, about 7.6 w / w%, about 7.7 w / w%, about 7.8 w / w%, about 7.9 w / w%, about 8.0 w / w%, about 8.1 w / w%, about 8.2 w / w%, about 8.3 w / w%, about 8.4 w / w%, about 8.5 w / w%, about 8.6 w / w%, about 8.7 w / w%, about 8.8 w / w%, about 8.9 w / w%, about 9.0 w / w%, about 9.1 w / w%, about 9.2 w / w%, about 9.3 w / w%, about 9.4 w / w%, about 9.5 w / w%, about 9.6 w / w%, about 9.7 w / w%, about 9.8 w / w%, about 9.9 w / w%, about 10.0 w / w%, about 10.1 w / w%, about 10.2 w / w%, about 10.3 w / w%, about 10.4 w / w%, about 10.5 w / w%, about 10.6 w / w%, about 10.7 w / w%, about 10.8 w / w%, about 10.9 w / w%, about 11.0 w / w%, about 11.1 w / w%, about 11.2 w / w%, about 11.3 w / w%, about 11.4 w / w%, about 11.5 w / w%, about 11.6 w / w%, about 11.7 w / w%, about 11.8 w / w%, about 11.9 w / w%, about 12.0 w / w%, about 12.1 w / w%, about 12.2 w / w%, about 12.3 w / w%, about 12.4 w / w%, about 12.5 w / w%, about 12.6 w / w%, about 12.7 w / w%, about 12.8 w / w%, about 12.9 w / w%, about 13.0 w / w%, about 13.1 w / w%, about 13.2 w / w%, about 13.3 w / w%, about 13.4 w / w%, about 13.5 w / w%, about 13.6 w / w%, about 13.7 w / w%, about 13.8 w / w%, about 13.9 w / w%, about 14.0 w / w%, about 14.1 w / w%, about 14.2 w / w%, about 14.3 w / w%, about 14.4 w / w%, about 14.5 w / w%, about 14.6 w / w%, about 14.7 w / w%, about 14.8 w / w%, about 14.9 w / w%, about 15.0 w / w%, about 15.1 w / w%, about 15.2 w / w%, about 15.3 w / w%, about 15.4 w / w%, about 15.5 w / w%, about 15.6 w / w%, about 15.7 w / w%, about 15.8 w / w%, about 15.9 w / w%, about 16.0 w / w%, about 16.1 w / w%, about 16.2 w / w%, about 16.3 w / w%, about 16.4 w / w%, about 16.5 w / w%, about 16.6 w / w%, about 16.7 w / w%, approximately 16.8 w / w%, approximately 16.9 w / w%, approximately 17.0 w / w%, approximately 17.1 w / w%, approximately 17.2 w / w%, approximately 17.3 w / w%, approximately 17.4 w / w%, approximately 17.5 w / w%, approximately 17.6 w / w%, approximately 17.7 w / w%, approximately 17.8 w / w%, approximately 17.9 w / w%, approximately 18.0 w / w%, approximately 18.1 w / w%, approximately 18.2 w / w%, approximately 18.3 w / w%, approximately 18.4 w / w%, approximately 18.5 w / w%, approximately 18.6 w / w%, approximately 18.7 w / w%, approximately 18.8 w / w%, approximately 18.9 w / w%, approximately 19.0 w / w%, approximately 19.1 w / w%, approximately 19.2 w / w%, approximately 19.3 w / w%, approximately 19.4 w / w%, approximately 19.5 w / w%, approximately 19.6 w / w%, approximately 19.7 w / w%, approximately 19.8 w / w%, approximately 19.9 w / w%, approximately 20.0 w / w%, approximately 21.1 w / w%, approximately 21.2 w / w%, approximately 21.3 w / w%, approximately 21.4 w / w%, approximately 21.5 w / w%, approximately 21.6 w / w%, approximately 21.7 w / w%, approximately 21.8 w / w%, approximately 21.9 w / w%, approximately 22.0 w / w%, approximately 22.1 w / w%, approximately 22.2 w / w%, approximately 22.3 w / w%, approximately 22.4 w / w%, approximately 22.5 w / w%, approximately 22.6 w / w%, approximately 22.7 w / w%, approximately 22.8 w / w%, approximately 22.9 w / w%, approximately 23.0 w / w%, approximately 23.1 w / w%, approximately 23.2 w / w%, approximately 23.3 w / w%, approximately 23.4 w / w%, approximately 23.5 w / w%, approximately 23.6 w / w%, approximately 23.7 w / w%, approximately 23.8 w / w%, approximately 23.9 w / w%, approximately 24.0 w / w%, approximately 24.1 w / w%, approximately 24.2 w / w%, approximately 24.3 w / w%, approximately 24.4 w / w%, approximately 24.5 w / w%, approximately 24.6 w / w%, approximately 24.7 w / w%, approximately 24.8 w / w%, approximately 24.9 w / w%, approximately 25.0 w / w%, approximately 25.1 w / w%, approximately 25.2 w / w%, approximately 25.3 w / w%, approximately 25.4 w / w%, approximately 25.5 w / w%, approximately 25.6 w / w%, approximately 25.7 w / w%, approximately 25.8 w / w%, approximately 25.9 w / w%, approximately 26.0 w / w%, approximately 26.1 w / w%, approximately 26.2 w / w%, approximately 26.3 w / w%, approximately 26.4 w / w%, approximately 26.5 w / w%, approximately 26.6 w / w%, approximately 26.7 w / w%, approximately 26.8 w / w%, approximately 26.9 w / w%, approximately 27.0 w / w%, approximately 27.1 w / w%, approximately 27.2 w / w%, approximately 27.3 w / w%, approximately 27.4 w / w%, approximately 27.5 w / w%, approximately 27.6 w / w%, approximately 27.7 w / w%, about 27.8 w / w%, about 27.9 w / w%, about 28.0 w / w%, about 28.1 w / w%, about 28.2 w / w%, about 28.3 w / w%, about 28.4 w / w%, about 28.5 w / w%, about 28.6 w / w%, about 28.7 w / w%, about 28.8 w / w%, about 28.9 w / w%, or about 29.0 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 4.57 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 4.6 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 25.2 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 25.21 w / w%.

[0197] In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.01 w / w% to about 3.0 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.01 w / w% to about 2.0 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.05 w / w% to about 1.5 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.05 w / w% to about 1.2 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.1 w / w% to about 1.1 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.10 w / w% to about 1.08 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 0.01 w / w%, about 0.02 w / w%, about 0.03 w / w%, about 0.04 w / w%, about 0.05 w / w%, about 0.06 w / w%, about 0.07 w / w%, about 0.08 w / w%, about 0.09 w / w%, about 0.1 w / w%, about 0.2 w / w%, about 0.3 w / w%, about 0.4 w / w%, about 0.5 w / w%, about 0.6 w / w%, about 0.7 w / w%, about 0.8 w / w%, about 0.9 w / w%, about 1.0 w / w%, about 1.1 w / w%, about 1.2 w / w%, about 1.3 w / w%, about 1.4 w / w%, about 1.5 w / w%, about 1.6 w / w%, about 1.7 w / w%, about 1.8 w / w%, about 1.9 w / w%, or about 2.0 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 0.1 w / w%.In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 0.10 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 1.08 w / w%. In some embodiments, the amount of sodium hydroxide in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 1.1 w / w%.

[0198] In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.1 w / w% to about 10 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.3 w / w% to about 8 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.5 w / w% to about 7 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.6 w / w% to about 7 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.85 w / w% to about 4.69 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is from about 0.9 w / w% to about 4.7 w / w%.In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 0.5 w / w%, about 0.6 w / w%, about 0.7 w / w%, about 0.8 w / w%, about 0.9 w / w%, about 1.0 w / w%, about 1.1 w / w%, about 1.2 w / w%, about 1.3 w / w%, about 1.4 w / w%, about 1.5 w / w%, about 1.6 w / w%, about 1.7 w / w%, about 1.8 w / w%, about 1.9 w / w%, about 2.0 w / w%, about 2.1 w / w%, about 2.2 w / w%, about 2.3 w / w%, about 2.4 w / w%, about 2.5 w / w%, about 2.6 w / w%, about 2.7 w / w%, about 2.8 w / w%, about 2.9 w / w%, about 3.0 w / w%, about 3.1 w / w%, about 3.2 w / w%, about 3.3 w / w%, about 3.4 w / w%, about 3.5 w / w%, about 3.6 w / w%, about 3.7 w / w%, about 3.8 w / w%, about 3.9 w / w%, about 4.0 w / w%, about 4.1 w / w%, about 4.2 w / w%, about 4.3 w / w%, about 4.4 w / w%, about 4.5 w / w%, about 4.6 w / w%, about 4.7 w / w%, about 4.8 w / w%, about 4.9 w / w%, about 5.0 w / w%, about 5.1 w / w%, about 5.2 w / w%, about 5.3 w / w%, about 5.4 w / w%, about 5.5 w / w%, about 5.6 w / w%, about 5.7 w / w%, about 5.8 w / w%, about 5.9 w / w%, about 6.0 w / w%, about 6.1 w / w%, about 6.2 w / w%, about 6.3 w / w%, about 6.4 w / w%, about 6.5 w / w%, about 6.6 w / w%, about 6.7 w / w%, about 6.8 w / w%, about 6.9 w / w%, or about 7.0 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 0.85 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 0.9 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 4.69 w / w%. In some embodiments, the amount of poloxamer 188 in a solution comprising a compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water is about 4.7 w / w%.

[0199] In some embodiments, the solution disclosed herein comprises from about 10 w / w% to about 45 w / w% water, from about 30 w / w% to about 85 w / w% PEG300, from about 0.5 w / w% to about 40 w / w% of the compound of formula (Ia), from about 0.01 w / w% to about 3.0 w / w% sodium hydroxide, and from about 0.1 w / w% to about 10 w / w% poloxamer 188. In some embodiments, the solution comprises from about 15 w / w% to about 35 w / w% water, from about 35 w / w% to about 75 w / w% PEG300, from about 1 w / w% to about 35 w / w% of the compound of formula (Ia), from about 0.01 w / w% to about 2.0 w / w% sodium hydroxide, and from about 0.3 w / w% to about 8 w / w% poloxamer 188. In some embodiments, the solution comprises from about 20 w / w% to about 35 w / w% water, from about 40 w / w% to about 70 w / w% PEG300, from about 1 w / w% to about 30 w / w% of the compound of formula (Ia), from about 0.05 w / w% to about 1.5 w / w% sodium hydroxide, and from about 0.5 w / w% to about 7 w / w% poloxamer 188. In some embodiments, the solution comprises from about 20 w / w% to about 31 w / w% water, from about 45 w / w% to about 68 w / w% PEG300, from about 3 w / w% to about 28 w / w% of the compound of formula (Ia), from about 0.05 w / w% to about 1.2 w / w% sodium hydroxide, and from about 0.6 w / w% to about 7 w / w% poloxamer 188.

[0200] In some embodiments, the solution comprises from about 22 w / w% to about 30.1 w / w% water, from about 47.1 w / w% to about 64.4 w / w% PEG300, from about 4.6 w / w% to about 25.2 w / w% of the compound of formula (Ia), from about 0.1 w / w% to about 1.1 w / w% sodium hydroxide, and from about 0.9 w / w% to about 4.7 w / w% poloxamer 188. In some embodiments, the solution comprises from about 21.97 w / w% to about 30.07 w / w% water, from about 47.05 w / w% to about 64.41 w / w% PEG300, from about 4.57 w / w% to about 25.21 w / w% of the compound of formula (Ia), from about 0.10 w / w% to about 1.08 w / w% sodium hydroxide, and from about 0.85 w / w% to about 4.69 w / w% poloxamer 188. In some embodiments, the solution comprises about 30.1 w / w% water, about 64.4 w / w% PEG300, about 4.6 w / w% of the compound of formula (Ia), about 0.1 w / w% sodium hydroxide, and about 0.9 w / w% poloxamer 188. In some embodiments, the solution comprises about 30.07 w / w% water, about 64.41 w / w% PEG300, about 4.57 w / w% of the compound of formula (Ia), about 0.10 w / w% sodium hydroxide, and about 0.85 w / w% poloxamer 188. In some embodiments, the solution comprises about 22 w / w% water, about 47.1 w / w% PEG300, about 25.2 w / w% of the compound of formula (Ia), about 1.1 w / w% sodium hydroxide, and about 4.7 w / w% poloxamer 188. In some embodiments, the solution comprises about 21.97 w / w% water, about 47.05 w / w% PEG300, about 25.21 w / w% of the compound of formula (Ia), about 1.08 w / w% sodium hydroxide, and about 4.69 w / w% poloxamer 188.

[0201] In some embodiments, the compound of formula (Ia) ionizes in situ to the sodium salt of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water, in the presence of sodium hydroxide. Thus, in some embodiments, the compound of formula (Ia) is present as the sodium salt of the compound of formula (Ia) in a solution comprising the compound of formula (Ia), PEG300, sodium hydroxide, poloxamer 188, and water.

[0202] In some embodiments, the solution formulation comprises from about 50 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 75 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 125 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 175 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 225 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 250 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 275 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 325 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 350 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 375 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof.

[0203] In some embodiments, the solution formulation comprises from about 100 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 150 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 200 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 300 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 400 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the solution formulation comprises from about 425 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 450 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 475 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the solution formulation comprises from about 500 mg / mL of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof.

[0205] In some embodiments, the solutions disclosed herein are administered via subcutaneous injection. In some embodiments, the solutions disclosed herein are administered via intramuscular injection.

[0206] In certain embodiments, an oral formulation of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and at least one excipient is provided. The excipient can include ethanol, medium-chain triglycerides, vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), glycerol monocaprylocaprate, glycerin, and / or a pharmaceutically acceptable oil. Examples of suitable medium-chain triglycerides include, but are not limited to, MIGLYOL 810, MIGLYOL 821, and MIGLYOL 840. Examples of suitable pharmaceutically acceptable oils include, but are not limited to, sesame oil, castor oil, safflower oil, vegetable oil, and soybean oil. The oral formulations disclosed herein can include any combination of one or more suitable excipients. The excipients, together, can be present in more than about 65% by weight of the total oral formulation, more than about 70% by weight of the total oral formulation, more than about 80% by weight of the total oral formulation, more than about 90% by weight of the total oral formulation, or more than about 95% by weight of the total oral formulation.

[0207] In some embodiments, an oral formulation of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and at least one excipient as disclosed herein is prepared as a hard or soft capsule. In some embodiments, the hard or soft capsule comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and one or more excipients selected from the group consisting of ethanol, propylene glycol, glycerin, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), polyoxyl 35 castor oil (e.g., Kolliphor® EL), glycerol monocaprylocaprate (e.g., Capmul® MCM), PEG400 glyceryl caprylate / caprate (e.g., Labrasol®), PEG400, diethylene glycol monoethyl ether (e.g., Transcutol®), propylene glycol monocaprylate, type II (e.g., Capryol® 90), glyceryl monooleate, type 40 (e.g., Peceol™), medium-chain triglycerides (e.g., Miglyol® 812N), glyceryl monolaurate (e.g., Maisine®), and polysorbate 80. In some embodiments, the hard or soft capsule comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and one or more excipients selected from the group consisting of ethanol, medium-chain triglycerides (e.g., Miglyol® 812N), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), glycerol monocaprylocaprate (e.g., Capmul® MCM), PEG400 glyceryl caprylate / caprate (e.g., Labrasol®), and PEG400.

[0208] In some embodiments, the hard or soft capsule further comprises a capsule shell. In some embodiments, the capsule shell comprises one or more pharmaceutically acceptable excipients. In some embodiments, one or more pharmaceutically acceptable excipients of the capsule shell are selected from the group consisting of a gelatin shell, a plasticizer, an opacifier, and a colorant. Plasticizers, opacifiers, and colorants are well known in the art. In some embodiments, the capsule shell comprises one or more pharmaceutically acceptable excipients selected from the group consisting of gelatin, glycerin, titanium dioxide, and iron oxide. In some embodiments, the iron oxide comprises iron oxide (yellow).

[0209] In some embodiments, an oral formulation of a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is provided. In certain embodiments, the oral formulation comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and glycerol monocaprylocaprate. In certain embodiments, the oral formulation comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, about 5% to about 20% ethanol, about 10% to about 30% vitamin E TPGS, and about 50% to about 85% MIGLYOL 812. In some embodiments, the oral formulation comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, about 8% to about 15% ethanol, about 15% to about 25% vitamin E TPGS, and about 60% to about 77% MIGLYOL 812. In certain embodiments, the oral formulation comprises a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in about 10% ethanol, about 20% vitamin E TPGS, and about 70% MIGLYOL 812. In certain embodiments, the oral formulation is prepared as a hard gelatin capsule. In certain embodiments, the oral formulation is prepared as a soft gelatin capsule.

[0210] In some embodiments, the hard gelatin or soft gelatin capsules disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient as disclosed herein. In some embodiments, the hard gelatin or soft gelatin capsules disclosed herein comprise a compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, and glycerol monocaprylocaprate. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is from about 10 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is from about 10 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is from about 50 mg / ml to about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is from about 50 mg / ml to about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 30 mg / ml, about 40 mg / ml, about 45 mg / ml, about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, about 100 mg / ml, about 105 mg / ml,About 110 mg / ml, about 115 mg / ml, about 120 mg / ml, about 125 mg / ml, about 130 mg / ml, about 135 mg / ml, about 140 mg / ml, about 145 mg / ml, about 150 mg / ml, about 155 mg / ml, about 160 mg / ml, about 165 mg / ml, about 170 mg / ml, about 175 mg / ml, about 180 mg / ml, about 185 mg / ml, about 190 mg / ml, about 195 mg / ml, about 200 mg / ml, 205 mg / ml, about 210 mg / ml, about 215 mg / ml, about 220 mg / ml, about 225 mg / ml, about 230 mg / ml, about 235 mg / ml, about 240 mg / ml, about 245 mg / ml, about 250 mg / ml, about 255 mg / ml, about 260 mg / ml, about 265 mg / ml, about 270 mg / ml, about 275 mg / ml, about 280 mg / ml, about 285 mg / ml, about 290 mg / ml, about 295 mg / ml, about 300 mg / ml, about 305 mg / ml, about 310 mg / ml, about 315 mg / ml, about 320 mg / ml, about 325 mg / ml, about 330 mg / ml, about 335 mg / ml, about 340 mg / ml, about 345 mg / ml, about 350 mg / ml, about 355 mg / ml, about 360 mg / ml, about 365 mg / ml, about 370 mg / ml, about 375 mg / ml, about 380 mg / ml, about 385 mg / ml, about 390 mg / ml, about 395 mg / ml, about 400 mg / ml, about 405 mg / ml, about 410 mg / ml, about 415 mg / ml, about 420 mg / ml, about 425 mg / ml, about 430 mg / ml, about 435 mg / ml, about 440 mg / ml, about 445 mg / ml, about 450 mg / ml, about 455 mg / ml, about 460 mg / ml, about 465 mg / ml, about 470 mg / ml, about 475 mg / ml, about 480 mg / ml, about 485 mg / ml, about 490 mg / ml, about 495 mg / ml, or about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 10 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 20 mg / ml. In some embodiments,The concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 30 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 40 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 225 mg / ml. In some embodiments, the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein,Alternatively, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 275 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) or formula (Ib), or a pharmaceutically acceptable salt thereof, in the hard gelatin or soft gelatin capsules disclosed herein is about 500 mg / ml.

[0211] In some embodiments, the hard or soft gelatin capsules disclosed herein contain a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, and glycerol monocaprylocaprate. In some embodiments, the hard or soft gelatin capsules disclosed herein contain a trifluoroacetate salt of a compound of formula (Ib) and glycerol monocaprylocaprate.

[0212] In some embodiments, the hard gelatin or soft gelatin capsules disclosed herein contain a compound of formula (Ia) and glycerol monocaprylocaprate. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 10 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 10 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 50 mg / ml to about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 50 mg / ml to about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 10 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 20 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard gelatin or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 30 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 40 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 50 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 225 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 275 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 500 mg / ml.

[0213] In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate is from about 30 w / w% to about 85 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate is from about 40 w / w% to about 80 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate is from about 50 w / w% to about 80 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate is from about 60 w / w% to about 70 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate is about 65.9 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate is about 65.94 w / w%.

[0214] In some embodiments, the amount of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 1 w / w% to about 40 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 1 w / w% to about 35 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 2 w / w% to about 30 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is from about 3 w / w% to about 28 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 3.4 w / w%. In some embodiments, the amount of the compound of formula (Ia) in a hard or soft gelatin capsule containing the compound of formula (Ia) and glycerol monocaprylocaprate is about 3.42 w / w%.

[0215] In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises a capsule shell. In some embodiments, the capsule shell comprises one or more pharmaceutically acceptable excipients. In some embodiments, one or more pharmaceutically acceptable excipients of the capsule shell are selected from the group consisting of a gelatin shell, a plasticizer, an opacifier, and a colorant. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of gelatin, glycerin, titanium dioxide, and iron oxide. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises gelatin. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises glycerin. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises titanium dioxide. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises iron oxide. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises gelatin and glycerin. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia) and glycerol monocaprylocaprate further comprises gelatin, glycerin, and titanium dioxide. In some embodiments, a hard gelatin or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide comprises iron oxide (yellow).

[0216] In some embodiments, the amount of gelatin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 10 w / w% to about 40 w / w%. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 10 w / w% to about 30 w / w%. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 15 w / w% to about 25 w / w%. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 18 w / w% to about 22 w / w%. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is about 19.6 w / w%. In some embodiments, the amount of gelatin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is about 19.60 w / w%.

[0217] In some embodiments, the amount of glycerin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 3 w / w% to about 25 w / w%. In some embodiments, the amount of glycerin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 5 w / w% to about 20 w / w%. In some embodiments, the amount of glycerin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 5 w / w% to about 15 w / w%. In some embodiments, the amount of glycerin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 8 w / w% to about 12 w / w%. In some embodiments, the amount of glycerin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is about 10.8 w / w%. In some embodiments, the amount of glycerin in a hard or soft gelatin capsule containing a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is about 10.80 w / w%.

[0218] In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 2 w / w%. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.05 w / w% to about 1.5 w / w%. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.1 w / w% to about 1.0 w / w%. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.1 w / w% to about 0.5 w / w%. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is about 0.2 w / w%. In some embodiments, the amount of titanium dioxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is about 0.22 w / w%.

[0219] In some embodiments, the amount of iron oxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 1 w / w%. In some embodiments, the amount of iron oxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.5 w / w%. In some embodiments, the amount of iron oxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.15 w / w%. In some embodiments, the amount of iron oxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is from about 0.01 w / w% to about 0.1 w / w%. In some embodiments, the amount of iron oxide in a hard or soft gelatin capsule comprising a compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide is about 0.02 w / w%.

[0220] In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 30 w / w% to about 85 w / w% glycerol monocaprylocaprate and from about 1 w / w% to about 40 w / w% of the compound of formula (Ia). In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 40 w / w% to about 80 w / w% glycerol monocaprylocaprate and from about 1 w / w% to about 35 w / w% of the compound of formula (Ia). In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 50 w / w% to about 80 w / w% glycerol monocaprylocaprate and from about 2 w / w% to about 30 w / w% of the compound of formula (Ia). In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 60 w / w% to about 70 w / w% glycerol monocaprylocaprate and from about 3 w / w% to about 28 w / w% of the compound of formula (Ia). In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise about 65.9 w / w% glycerol monocaprylocaprate and about 3.4 w / w% of the compound of formula (Ia). In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise about 65.94 w / w% glycerol monocaprylocaprate and about 3.42 w / w% of the compound of formula (Ia).

[0221] In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 30 w / w% to about 85 w / w% glycerol monocaprylocaprate, from about 1 w / w% to about 40 w / w% of the compound of formula (Ia), from about 10 w / w% to about 40 w / w% gelatin, from about 3 w / w% to about 25 w / w% glycerin, from about 0.01 w / w% to about 2 w / w% titanium dioxide, and from about 0.01 w / w% to about 1 w / w% iron oxide. In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 40 w / w% to about 80 w / w% glycerol monocaprylocaprate, from about 1 w / w% to about 35 w / w% of the compound of formula (Ia), from about 10 w / w% to about 30 w / w% gelatin, from about 5 w / w% to about 20 w / w% glycerin, from about 0.05 w / w% to about 1.5 w / w% titanium dioxide, and from about 0.01 w / w% to about 0.5 w / w% iron oxide. In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 50 w / w% to about 80 w / w% glycerol monocaprylocaprate, from about 2 w / w% to about 30 w / w% of the compound of formula (Ia), from about 15 w / w% to about 25 w / w% gelatin, from about 5 w / w% to about 15 w / w% glycerin, from about 0.1 w / w% to about 1.0 w / w% titanium dioxide, and from about 0.01 w / w% to about 0.15 w / w% iron oxide. In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise from about 60 w / w% to about 70 w / w% glycerol monocaprylocaprate, from about 3 w / w% to about 28 w / w% of the compound of formula (Ia), from about 18 w / w% to about 22 w / w% gelatin, from about 8 w / w% to about 12 w / w% glycerin, from about 0.1 w / w% to about 0.5 w / w% titanium dioxide, and from about 0.01 w / w% to about 0.1 w / w% iron oxide. In some embodiments, the hard gelatin or soft capsule agents disclosed herein comprise about 65.9 w / w% glycerol monocaprylocaprate, about 3.4 w / w% of the compound of formula (Ia), about 19.6 w / w% gelatin, about 10.8 w / w% glycerin, about 0.2 w / w% titanium dioxide, and about 0.02 w / w% iron oxide.In some embodiments, the hard gelatin or soft capsule disclosed herein comprises about 65.94 w / w% glycerol monocaprylocaprate, about 3.42 w / w% of the compound of formula (Ia), about 19.60 w / w% gelatin, about 10.80 w / w% glycerin, about 0.22 w / w% titanium dioxide, and about 0.02 w / w% iron oxide.

[0222] In some embodiments, the iron oxide in the hard gelatin or soft gelatin capsule comprising the compound of formula (Ia), glycerol monocaprylocaprate, gelatin, glycerin, titanium dioxide, and iron oxide comprises iron oxide (yellow). In some embodiments, the hard gelatin or soft capsule disclosed herein comprises about 65.9 w / w% glycerol monocaprylocaprate, about 3.4 w / w% of the compound of formula (Ia), about 19.6 w / w% gelatin, about 10.8 w / w% glycerin, about 0.2 w / w% titanium dioxide, and about 0.02 w / w% iron oxide (yellow). In some embodiments, the hard gelatin or soft capsule disclosed herein comprises about 65.94 w / w% glycerol monocaprylocaprate, about 3.42 w / w% of the compound of formula (Ia), about 19.60 w / w% gelatin, about 10.80 w / w% glycerin, about 0.22 w / w% titanium dioxide, and about 0.02 w / w% iron oxide (yellow).

[0223] In some embodiments, the hard or soft gelatin capsules disclosed herein contain the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 10 mg / ml to about 500 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 10 mg / ml to about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 50 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 75 mg / ml to about 300 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 10 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 20 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 30 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 40 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in the hard or soft gelatin capsules containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 50 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 75 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 100 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 125 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 150 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 175 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 200 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 225 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 250 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 275 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 300 mg / ml.In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 325 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 350 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 375 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 400 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 425 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 450 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 475 mg / ml. In some embodiments, the concentration of the compound of formula (Ia) in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 500 mg / ml.

[0224] In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 30 w / w% to about 99 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 50 w / w% to about 99 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 60 w / w% to about 99 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 75 w / w% to about 98 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 80.09 w / w% to about 94.85 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is from about 80.1 w / w% to about 94.9 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 80.09 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 80.1 w / w%. In some embodiments, the amount of glycerol monocaprylocaprate in a hard or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 94.85 w / w%.In some embodiments, the amount of glycerol monocaprylocaprate in a hard gelatin or soft gelatin capsule containing the sodium salt of the compound of formula (Ia) and glycerol monocaprylocaprate is about 94.9...

Claims

[Claim 1] The invention as depicted in the drawings.

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