Therapeutic compounds useful for prophylactic or therapeutic treatment of HIV virus infection

Abstract

To provide novel compounds for use in the treatment of a Retroviridae viral infection including an infection caused by the HIV virus.SOLUTION: The present disclosure relates to compounds of formulae (Ia), (Ib), (IIa), and (IIb), which are useful in the treatment of a Retroviridae viral infection including an infection caused by the HIV virus. The present disclosure relates to novel compounds. The present disclosure also relates to intermediates for its preparation and to pharmaceutical compositions containing the novel compound.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 377,312, filed August 19, 2016, and U.S. Provisional Application No. 62 / 457,555, filed February 10, 2017, the disclosures of which are incorporated by reference in their entireties.

[0002] The present disclosure relates to novel compounds for use in the treatment of Retroviridae viral infections, including those caused by the HIV virus. The disclosure also relates to intermediates for the preparation thereof and pharmaceutical compositions containing said novel compounds. [Background technology]

[0003] Positive single-stranded RNA viruses, including the family Retroviridae, include the subfamily Orthoretrovirinae and viruses of the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus, which cause many human and animal diseases. Among the Lentiviruses, HIV-1 infection in humans leads to T helper cell depletion and immune dysfunction, resulting in immunodeficiency and susceptibility to opportunistic infections. Treating HIV-1 infection with highly active antiretroviral therapy (HAART) has proven effective in reducing viral load and significantly slowing disease progression (Hammer, 2003). SM et al., JAMA, 2008, 300:555-570). However, these treatments may lead to the emergence of HIV strains that are resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases, 2008, 300:555-570). (Diseases 2009, 13:552-559; Smith, RJ et al., Science 2010, 327:697-701). Thus, there is an urgent need to discover new antiretroviral agents that are active against emerging drug-resistant HIV variants.

[0004] U.S. Patent Publication No. 2014 / 0296266A1, published on October 2, 2014, discloses compounds useful for treating Retroviridae viral infections, including infections caused by the HIV virus. U.S. Patent Publication No. 2014 / 0296266A1 discloses, inter alia, compounds of formula I: [ka] (In the formula, A is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms, and the 6-membered monocyclic heteroaryl has one Z at the indicated position. 1 Group, 1 Z 2 group and one or more (e.g., one or two) Z 3 and optionally substituted with a group; R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl or 3- to 12-membered heterocycle may be selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 4 and optionally substituted with a group; R 2 is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or (C-C) carbocycle; R 2 Any phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or (C-C) carbocycle may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 5 and optionally substituted with a group; Each R 3a and R 3bare independently selected from H, halogen, (C1-C3) alkyl and (C1-C3) haloalkyl, or R 3a is selected from H, (C1-C3) alkyl, and (C1-C3) haloalkyl; R 3b is selected from -OH and -CN; Z 1 is selected from 6- to 12-membered aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 1a or Z 1b where appropriate, each Z 1a are independently selected from (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O)2OH, -S(O)2R p1 , -S(O)NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , NO2, -C(O)R n1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O)NR n1 COR p1 Selected from Z1a Any (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12 membered heterocycle may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d and optionally substituted with a group; each Z 1b is independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl; Z 1b Any of the (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl groups may be selected from one or more (e.g., 1, 2, 3, 4 or 5) Z 1c and optionally substituted with a group; each Z 1c are independently selected from (C3-C7) carbocycle, phenyl, 5-6 membered monocyclic heteroaryl, 3-7 membered heterocycle, halogen, -CN, -OR n2 , -OC(O)R p2 , -OC(O)NR q2 R r2 , -SR n2 , -S(O)R p2 , -S(O)2OH, -S(O)2R p2 , -S(O)NR q2 R r2 , -NR q2 R r2 , -NR n2 COR p2 , -NR n2 CO2R p2 , -NR n2 CONR q2 R r2 , -NR n2 S(O)2R p2 , -NR n2 S(O)2OR p2 , -NR n2 S(O2NR q2 R r2 , NO2, -C(O)R n2 , -C(O)OR n2 , -C(O)NR q2 R r2, halophenyl, 5-6 membered haloheteroaryl, 3-7 membered haloheterocycle, and (C1-C8)heteroalkyl; each Z 1d is independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, and (C1-C8) haloalkyl; Each R n1 is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl; R n1 Any (C3-C7) carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d optionally substituted with R n1 Any of the (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl groups may be selected from one or more (e.g., 1, 2, 3, 4 or 5) Z 1c and optionally substituted with a group; Each R p1 is independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl; R p1 Any (C3-C7) carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d optionally substituted with R p1 Any of the (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl groups may be selected from one or more (e.g., 1, 2, 3, 4 or 5) Z 1c and optionally substituted with a group; R q1 and R r1are each independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl; R q1 Or R r1 Any (C3-C7) carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, and phenyl may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 1c Or Z 1d optionally substituted with R q1 Or R r1 Any of the (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl groups may be selected from one or more (e.g., 1, 2, 3, 4 or 5) Z 1c optionally substituted with a group or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocycle, which may be joined by one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d and optionally substituted with a group; Each R n2 is independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, 3- to 7-membered heterocycle, 5- to 6-membered monocyclic heteroaryl, phenyl, halophenyl, 5- to 6-membered monocyclic haloheteroaryl, 3- to 7-membered haloheterocycle, (C1-C8)haloalkyl, and (C1-C8)heteroalkyl; Each R p2 is independently selected from (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C1-C8)haloalkyl, and (C1-C8)heteroalkyl; R q2 and R r2are each independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C1-C8)haloalkyl, and (C1-C8)heteroalkyl; or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C2-C8) alkenyl, (C2-C8) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 and -C(O)NR q3 R r3 Selected from Z 2 Any 6- to 12-membered aryl, 5- to 12-membered C-linked heteroaryl and 3- to 12-membered C-linked heterocycle may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c is optionally substituted with a Z group; 2 Any of the (C2-C8) alkenyl and (C2-C8) alkynyl groups may be selected from one or more (e.g., 1, 2, 3, 4, or 5) Z 2c and optionally substituted with a group; each Z 2a are independently selected from (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O)2OH, -S(O)2R p4 , -S(O)NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2Rp4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 、 NO 2. -C(O)R n4 , -C(O)OR n4 and -C(O)NR q4 R r4 Selected from Z 2a Any (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl and 3-12 membered heterocycle may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c and optionally substituted with a group; each Z 2b is independently selected from (C1-C4)alkyl, (C1-C4)heteroalkyl, and (C1-C4)haloalkyl; each Z 2c are independently halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O)2OH, -S(O)2R p4 , -S(O)NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 Rr4 、 NO2, -C(O)R n4 , -C(O)OR n4 and -C(O)NR q4 R r4 is selected from Each R n3 is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl, and 6-12 membered aryl; R n3 Any (C3-C7) carbocycle, 3- to 12-membered heterocycle, 5- to 12-membered heteroaryl, and 6- to 12-membered aryl may be selected from the group consisting of one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c optionally substituted with R n3 Any of the (C1-C4) alkyl, (C2-C4) alkenyl and (C2-C4) alkynyl groups may be selected from the group consisting of one or more (e.g., one, two, three, four or five) Z 2a and optionally substituted with a group; R q3 and R r3 are each independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl, and 6-12 membered aryl; R q3 Or R r3 Any (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl may be joined by one or more (e.g., 1, 2, 3, 4 or 5) Z 2b Or Z 2c optionally substituted with R q3 Or R r3 Any (C1-C4) alkyl and (C2-C4) alkenyl may be selected from one or more (e.g., 1, 2, 3, 4, or 5) Z 2a optionally substituted with a group or R q3 and R r3together with the nitrogen to which they are attached form a heterocycle or heteroaryl, which heterocycle or heteroaryl may contain one or more (e.g., 1, 2, 3, 4, or 5) Z 2b Or Z 2c and optionally substituted with a group; Each R n4 is independently selected from H, (C1-C4)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)haloalkyl, and (C1-C4)heteroalkyl; Each R p4 is independently selected from (C1-C8)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, and (C1-C4)heteroalkyl; R q4 and R r4 are each independently selected from H, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl, and (C1-C4)heteroalkyl; each Z 3 is independently selected from halogen, (C1-C4)alkyl, -OH, -CN, (C1-C4)heteroalkyl, and (C1-C4)haloalkyl; each Z 4 are independently (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, halogen, -CN, -OR n5 , -OC(O)R p5 , -OC(O)NR q5 R r5 , -SR n5 , -S(O)R p5 , -S(O)2OH, -S(O)2R p5 , -S(O)NR q5 R r5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -NR n5 CONR q5 R r5, -NR n5 S(O)2R p5 , -NR n5 S(O)2OR p5 , -NR n5 S(O)2NR q5 R r5 , NO2, -C(O)R n5 , -C(O)OR n5 and -C(O)NR q5 R r5 Selected from Z 4 Any (C3-C7) carbocyclic ring may have one or more (e.g., 1, 2, 3 , 4 or 5)Z 4a or Z 4b is optionally substituted with a Z group; 4 Any of the (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl groups may be selected from one or more (e.g., 1, 2, 3, 4 or 5) Z 4a and optionally substituted with a group; each Z 4a are independently halogen, -CN, -OR n6 , -OC(O)R p6 , -OC(O)NR q6 R r6 , -SR n6 , -S(O)R p6 , -S(O)2OH, -S(O)2R p6 , -S(O)NR q6 R r6 , -NR q6 R r6 , -NR n6 COR p6 , -NR n6 CO2R p6 , -NR n6 CONR q6 R r6 , -NR n6 S(O)2R p6 , -NR n6 S(O)2OR p6 , -NR n6 S(O)2NR q6 R r6 , NO2, -C(O)R n6 , -C(O)OR n6 and -C(O)NRq6 R r6 is selected from each Z 4b is independently selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C1-C4) haloalkyl; Each R n5 is independently selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl, and (C2-C4)alkynyl; Each R p5 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl; R q5 and R r5 are each independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl; Each R n6 is independently selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl, and (C2-C4)alkynyl; Each R p6 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl; R q6 and R r6 are each independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl; each Z 5 are independently (C1-C6) alkyl, halogen, -CN and -OR n7 is selected from Z 5any (C1-C6)alkyl is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) halogens; Each R n7 are independently selected from H, (C1-C3) alkyl, (C1-C3) haloalkyl, and (C3-C7) carbocycle. or a pharma- ceutically acceptable salt thereof.

[0005] U.S. Patent Publication No. 2014 / 0303164A1, published on October 9, 2014, discloses compounds useful for treating Retroviridae viral infections, including infections caused by the HIV virus. U.S. Patent Publication No. 2014 / 0303164A1 discloses, inter alia, compounds of formula IIId: [ka] (In the formula, A 1 , CH, CZ 3 , or nitrogen, A 2 is CH or nitrogen, R 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 3- to 12-membered heterocycle; R 1 Any 6- to 12-membered aryl, 5- to 12-membered heteroaryl, or 3- to 12-membered heterocycle may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 4 is optionally substituted with a Z group; 4 The groups may be the same or different, Each R 3a and R 3b are independently H or (C1-C3) alkyl; Z 1 is a 6- to 12-membered aryl, a 5- to 14-membered heteroaryl, or a 3- to 14-membered heterocycle; Z 1 Any 6- to 12-membered aryl, 5- to 14-membered heteroaryl, or 3- to 14-membered heterocycle may be joined by one, two, three, four, or five Z 1a or Z 1b where necessary, Z 1a and Z1b The groups may be the same or different, each Z 1a are independently selected from (C3-C7) carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 , -OC(O)R p1 , -OC(O)NR q1 R r1 , -SR n1 , -S(O)R p1 , -S(O)2OH, -S(O)2R p1 , -S(O)NR q1 R r1 , -NR q1 R r1 , -NR n1 COR p1 , -NR n1 CO2R p1 , -NR n1 CONR q1 R r1 , -NR n1 S(O)2R p1 , -NR n1 S(O)2OR p1 , -NR n1 S(O)2NR q1 R r1 , -C(O)R n1 , -C(O)OR n1 , -C(O)NR q1 R r1 and -S(O)NR n1 COR p1 and Z 1a Any (C3-C7) carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle may have 1, 2, 3, 4 or 5 Z 1c or Z 1d is optionally substituted with a Z group; 1c and Z 1d The groups may be the same or different, each Z 1b is independently a (C1-C8)alkyl optionally substituted with 1, 2, 3, 4 or 5 halogens which may be the same or different; each Z 1c are independently halogen, -CN, -OH, -NH2, -C(O)NR q2 R r2or (C1-C8)heteroalkyl; each Z 1d are independently (C1-C8) alkyl or (C1-C8) haloalkyl; Each R n1 are independently H, (C1-C8) alkyl, (C3-C7) carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl; R n1 Any (C3-C7) carbocycle, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a Z group; 1c and Z 1d The groups may be the same or different, R n1 Any (C1-C8) alkyl may have 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a Z group; 1c The groups may be the same or different, Each R p1 are independently (C1-C8) alkyl, (C3-C7) carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl; R p1 Any (C3-C7) carbocycle, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 1c or Z 1d is optionally substituted with a Z group; 1c and Z 1d The groups may be the same or different, R p1 Any (C1-C8) alkyl may have 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a Z group; 1c The groups may be the same or different, Each R q1 and R r1 are independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl; R q1 Or R r1 Any (C3-C7) carbocycle, 3- to 7-membered heterocycle, or 5- to 6-membered monocyclic heteroaryl may be selected from the group consisting of 1, 2, 3, 4, or 5 Z1c Or Z 1d is optionally substituted with a Z group; 1c and Z 1d The groups may be the same or different, R q1 Or R r1 Any (C1-C8) alkyl may have 1, 2, 3, 4 or 5 Z 1c is optionally substituted with a Z group; 1c The groups may be the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered heterocycle, the 5-, 6- or 7-membered heterocycle being bound to 1, 2, 3, 4 or 5 Z 1c Or Z 1d is optionally substituted with a Z group; 1c and Z 1d The groups may be the same or different. Each R q2 and R r2 are independently H, (C1-C8) alkyl, (C3-C7) carbocycle, or R q2 and R r2 together with the nitrogen to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; Z 2 is (C2-C8) alkenyl, (C2-C8) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 and Z 2 Any 6- to 12-membered aryl, 5- to 12-membered C-linked heteroaryl, or 3- to 12-membered C-linked heterocycle may be joined by 1, 2, 3, 4, or 5 Z 2b or Z 2c is optionally substituted with a Z group; 2b and Z 2c The groups may be the same or different, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkynyl may be selected from the group consisting of 1, 2, 3, 4, or 5 Z 2c is optionally substituted with a Z group; 2c The groups may be the same or different, Each R n3 are independently H or (C1-C4) alkyl; Each R q3 and R r3 are independently H or (C1-C4) alkyl; each Z 2b is independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl; each Z 2c are independently oxo, halogen, -CN, -OR n4 , -OC(O)R p4 , -OC(O)NR q4 R r4 , -SR n4 , -S(O)R p4 , -S(O)2OH, -S(O)2R p4 , -S(O)NR q4 R r4 , -NR q4 R r4 , -NR n4 COR p4 , -NR n4 CO2R p4 , -NR n4 CONR q4 R r4 , -NR n4 S(O)2R p4 , -NR n4 S(O)2OR p4 , -NR n4 S(O)2NR q4 R r4 、 -NO2, -C(O)R n4 , -C(O)OR n4 or -C(O)NR q4 R r4 and Each R n4 are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl; Each R p4 are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl; Each R q4 and Rr4 are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl; each Z 3 is independently (C1-C4)heteroalkyl; each Z 4 are independently oxo, (C1-C8) alkyl, (C3-C7) carbocycle, halogen, -CN, -OR n5 , -NR q5 R r5 , -NR n5 COR p5 , -NR n5 CO2R p5 , -C(O)R n5 , -C(O)OR n5 or -C(O)NR q5 R r5 and Z 4 Any (C3-C7) carbocycle or (C1-C8) alkyl may have 1, 2, 3, 4 or 5 Z 4a is optionally substituted with a Z group; 4a The groups may be the same or different, and each Z 4a are independently halogen, -CN, or -OR n6 and Each R n5 , R p5 , R q5 , R r5 , and R n6 are independently H or (C1-C4) alkyl; each Z 5 are independently halogens which may be the same or different; where n is 0, 1, 2, or 3. or a pharma- ceutically acceptable salt thereof. Notwithstanding the above disclosure, there is a need for a potent, stable and improved drug for the treatment of Retroviridae virus infections, including infections caused by the HIV virus. There is a need for compounds that exhibit kinetic and / or pharmacodynamic profiles. There is also interest in the field of HIV therapy and treatment in expanding the pharmacokinetic properties of the regimen provided to patients.Current regimens for treating HIV have advanced enough that patients no longer need to take multiple pills multiple times a day, but still currently require patients to take pills every day for the foreseeable period of their life.Therefore, it would be beneficial to have an HIV therapy that requires patients to take drugs less than once a day (e.g., once every few days, once a week, once every two weeks, once a month, etc.). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] US Patent Application Publication No. 2014 / 0303164 [Patent Document 2] US Patent Application Publication No. 2014 / 0296266 [Non-patent literature]

[0007] [Non-Patent Document 1] Hammer, SM et al., JAMA, 2008, 300:555-570 [Non-Patent Document 2] Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559 [Non-Patent Document 3] Smith, RJ et al., Science 2010, 327:697-701 Summary of the Invention [Means for solving the problem]

[0008] Provided herein are novel compounds that exhibit improved potency, improved metabolic stability, and improved pharmacokinetic and / or pharmacodynamic profiles.

[0009] In some embodiments, the present disclosure provides a compound of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof.

[0010] In some embodiments, the present disclosure provides a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides a compound of formula (IIa): [ka] or a pharma- ceutically acceptable salt thereof.

[0012] In some embodiments, the present disclosure provides a compound of formula (IIb): [ka] or a pharma- ceutically acceptable salt thereof.

[0013] In one embodiment, the present disclosure relates to the use of a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, in the treatment of a disease in a subject in need thereof.

[0014] In one embodiment, the present disclosure relates to the use of a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, in the treatment of a disease in a subject in need thereof.

[0015] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.In certain embodiments, the pharmaceutical composition is in an injectable form.In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0016] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharma- ceutically acceptable salt thereof, and a pharma-ceutically acceptable excipient.In certain embodiments, the pharmaceutical composition is in a parenteral (e.g., injectable) form.In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0017] In certain embodiments, the present disclosure relates to an article of manufacture comprising a unit dosage of a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof.

[0018] In some embodiments, the disclosure relates to an article of manufacture comprising a unit dosage of a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof.

[0019] In certain embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof.

[0020] In some embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof.

[0021] In certain embodiments, the present disclosure relates to a method for preventing HIV infection in a subject, comprising administering to the subject a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject is at risk of contracting the HIV virus, e.g., has one or more risk factors known to be associated with contracting the HIV virus.

[0022] In certain embodiments, the present disclosure relates to a method for preventing HIV infection in a subject, comprising administering to the subject a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject is at risk of contracting the HIV virus, e.g., has one or more risk factors known to be associated with contracting the HIV virus.

[0023] In certain embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0024] In certain embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0025] In certain embodiments, the present disclosure relates to a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for use in medical therapy.

[0026] In certain embodiments, the present disclosure relates to compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in medical therapy.

[0027] In certain embodiments, the present disclosure relates to a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for use in treating or preventing HIV infection in a subject.

[0028] In certain embodiments, the present disclosure relates to a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, for use in treating or preventing HIV infection in a subject.

[0029] In certain embodiments, the present disclosure relates to the use of a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing HIV infection in a subject.

[0030] In certain embodiments, the present disclosure relates to the use of a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing HIV infection in a subject.

[0031] In another embodiment, the present disclosure relates to intermediates useful in the synthesis of compounds of formula (Ia) or (Ib).

[0032] In another embodiment, the present disclosure relates to intermediates useful in the synthesis of compounds of formula (Ia), (Ib), (IIa), and / or (IIb).

[0033] In some embodiments, the pharma- ceutically acceptable salt of the compound of Formula (Ia), (Ib), (IIa), and / or (IIb) is a sodium salt.

[0034] Additional embodiments of the present disclosure are disclosed herein. [Brief description of the drawings]

[0035] [Figure 1] FIG. 1 shows the H NMR of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (400 MHz, methanol-d4).

[0036] [Diagram 2] FIG. 2 shows the H NMR of 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)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (400 MHz, methanol-d4).

[0037] [Diagram 3] FIG. 3 shows the plasma concentration (nM) of Compound 38 after a single subcutaneous (SC) dose in rats.

[0038] [Figure 4] FIG. 4 shows a plot of plasma concentration of Formula Ib at 200 mg / mL in 2% poloxamer 188 in saline over time when dosed subcutaneously in dogs at 6 mg / kg.

[0039] [Diagram 5]FIG. 5 shows a plot of plasma concentration of Formula Ib at 100 mg / mL in 2% poloxamer 188 in saline over time when dosed subcutaneously in dogs at 6 mg / kg.

[0040] [Figure 6] FIG. 6 shows a plot of plasma concentration over time of Formula Ib, sodium salt, at 200 mg / mL in 2% poloxamer 188 in saline, when dosed subcutaneously in dogs at 6 mg / kg.

[0041] [Figure 7] FIG. 7 shows a plot of plasma concentration over time of Formula Ib, free acid form, at 100 mg / mL in NMP when dosed subcutaneously in dogs at 6 mg / kg.

[0042] [Figure 8] FIG. 8 shows a plot of plasma concentration over time of Formula Ib, free acid form, at 200 mg / mL in NMP when dosed subcutaneously in dogs at 6 mg / kg.

[0043] [Figure 9] FIG. 9 shows a plot of plasma concentration over time of Formula Ib, sodium salt, at 200 mg / mL in NMP when dosed subcutaneously in subjects at 6 mg / kg.

[0044] [Figure 10] FIG. 10 shows a plot of plasma concentration of Formula Ib at 200 mg / mL in 10% ethanol, 12% water, and 78% PEG200 over time when dosed subcutaneously in subjects at 6 mg / kg.

[0045] [Figure 11] FIG. 11 shows a plot of plasma concentration over time of the in situ salt of Formula Ib at 200 mg / mL in 10% ethanol, 12% water, and 77% PEG200 when dosed subcutaneously in subjects at 6 mg / kg.

[0046] [Figure 12]FIG. 12 shows a plot of plasma concentration over time of Formula Ib at 200 mg / mL in 10% ethanol, 13% water, and 77% glycofurol containing 1.2 molar equivalents of NaOH to form the Na salt in situ when dosed in subjects at 6 mg / kg.

[0047] [Figure 13] FIG. 13 shows a plot of plasma concentration over time of a fixed 7.5 mg oral dose of Formula Ib in 10% ethanol, 20% Vitamin E TPGS, 70% MIGLYOL 812 in dogs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] The following description is made with the understanding that the disclosure is intended to be illustrative of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only. and should not be construed as limiting the scope of the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0049] 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.

[0050] When a trademark is used herein, it is intended to include the trademarked product and the active pharmaceutical ingredient(s) of the trademarked product, independently.

[0051] 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, etc.

[0052] As used herein, "C max " refers to the maximum observed plasma / serum concentration of a drug.

[0053] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0054] "Pharmaceutically acceptable excipient" includes, without limitation, any adjuvant, carrier, filler, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration as acceptable for use in humans or domestic animals.

[0055] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharma-ceutically acceptable and that possesses (or can be converted into a form which 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, and the like, or with 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, trimethylacetic acid, and the like, and salts formed when an acidic proton present in the parent compound is replaced with a metal ion, for example, either an alkali metal ion (e.g., sodium or potassium), an alkaline earth ion (e.g., calcium or magnesium), or an aluminum ion, or when coordinated with an organic base, for example, diethanolamine, triethanolamine, N-methylglucamine, and the like. Ammonium and substituted or quaternized ammonium salts are also included in this definition. A representative, non-limiting list of pharma- ceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., Vol. 66(I), pp. 1-19 (1977); Remington: The Science and Practice of Pharmacy, edited by R. Hendrickson, 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), page 732, table 38-5, both of which are hereby incorporated by reference herein.

[0056] "Subject(s)" refers 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), and the like.

[0057] As used herein, "treatment" or "treating" is an approach to obtain a beneficial or desired result. For purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and / or attenuation of the extent 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 a disease or condition and / or attenuating the extent of a disease or condition); b) delaying or arresting the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, slowing the worsening or progression of a disease or condition), and / or c) relieving a disease or condition, e.g., causing regression of clinical symptoms, ameliorating the pathology, slowing the progression of a disease, improving quality of life, and / or prolonging life.

[0058] As used herein, "delaying" the onset of a disease or condition means to prolong, hinder, delay, retard, stabilize and / or postpone the onset of a disease or condition. This delay can vary in length of time depending on the history of the disease and / or the subject being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can actually encompass prevention, in that the subject does not develop the disease or condition. For example, a method of "delaying" the onset of AIDS is one that reduces the probability of the onset of the disease within a given time frame and / or reduces the extent of the disease within a given time frame compared to the absence of the method. Such a comparison can be based on clinical studies using a statistically significant number of subjects. For example, the onset of AIDS can be determined by the degree to which a subject's HIV +The condition can be detected using known methods, such as by checking the status and assessing the subject's T cell count or other signs of AIDS onset, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen cervical, axillary or inguinal lymph nodes, or the presence of opportunistic conditions known to be associated with AIDS (e.g., conditions that do not generally appear in subjects with functioning immune systems, but occur in AIDS patients). Onset can also refer to disease progression that may be initially undetectable, and includes emergence, recurrence, and onset.

[0059] As used herein, "prevention" or "preventing" refers to a regimen that prevents the onset of a disease or disorder, such that clinical symptoms of the disease do not develop. Thus, "prevention" refers to the administration of therapy (e.g., administration of a therapeutic agent) to a subject before symptoms of the disease are detectable in the subject (e.g., administration of a therapeutic agent to a subject when the subject is free of detectable infectious agents (e.g., viruses)). The subject may be an individual at risk of developing a disease or disorder, for example, an individual with one or more risk factors known to be associated with the onset or onset of a disease or disorder. Thus, the term "preventing HIV infection" refers to the administration of an anti-HIV therapeutic agent to a subject without detectable HIV infection. It is understood that the subject of an anti-HIV prophylactic therapy may be an individual at risk of contracting the HIV virus. Furthermore, it is understood that prevention may not provide complete protection against the onset of a disease or disorder. In some cases, prevention includes reducing the risk of developing a disease or disorder. Reducing the risk may not provide complete elimination of the risk of developing a disease or disorder.

[0060] As used herein, an "at risk" individual is an individual who is at risk of developing the condition being treated. An "at risk" individual may or may not have a detectable disease or condition, and may or may not exhibit a detectable disease prior to treatment with the methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. Individuals with one or more of these risk factors An individual has a higher probability of developing a disease or condition than an individual who does not have these risk factor(s). For example, an individual at risk for AIDS is an individual who has HIV.

[0061] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit a desired biological or medical response when administered to a subject to treat a disease, including an amount of a compound sufficient to effect such treatment for the disease, or an amount effective to prevent the onset or onset of the disease. The effective amount varies depending on the compound, the disease, and its severity, as well as the age, weight, etc., of the subject to be treated. The effective amount can include a range of amounts. As is understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment result. An effective amount can be considered in the context of administration of one or more therapeutic agents, and a single agent can be considered given in an effective amount when, in conjunction with one or more other agents, a desired or beneficial result can be or is achieved. The appropriate dose of any co-administered compound can be lowered as necessary due to the combined action (e.g., additive or synergistic effect) of the compounds.

[0062] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers in a ratio other than 1:1 is a "scalomic" mixture.

[0063] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0064] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the way they rotate plane polarized light (dextrorotatory or levorotatory) at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and / or hindered rotation about a bond axis and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-. The present disclosure is intended to include all such possible isomers, including racemic mixtures, scalemic mixtures, diastereomeric mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques.

[0065] Unless otherwise expressly defined, the present 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 may 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 and described in the present disclosure as if the amide was explicitly listed alone or together with the imidic acid. When more than two tautomers may exist, the present disclosure includes all such tautomers, even if only a single tautomeric form is represented by chemical name and / or structure.

[0066] The present disclosure also provides prodrugs of the compounds of formula (Ia) or (Ib). A "prodrug" is defined in the pharmaceutical art as a non-biologically active derivative of a drug that, upon administration to the human body, is converted into the biologically active parent drug by following some chemical or enzymatic pathway.

[0067] Additionally, in some embodiments, the present disclosure also provides prodrugs of compounds of formula (Ia), (Ib), (IIa), and / or (IIb).

[0068] The present disclosure also provides for the isotopes of any and all atoms in proportions greater than those naturally occurring, including, but not limited to, deuterium ( 2 It will be understood by one of ordinary skill in the art that this includes any compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) that may be enriched with one or more isotopes, such as H or D.

[0069] Also disclosed are compounds in which 1 to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and thus may be useful for increasing the half-life of the compound when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., vol. 5(12):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 have been replaced by deuterium.

[0070] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, e.g., 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, e.g. 11 C. 18 F, 15 O and 13 Substitution with N may be useful in Positron Emission Topography (PET) experiments to examine substrate receptor occupancy. Isotopically labeled compounds of formula (Ia) or (Ib) can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the examples presented below, using appropriate isotopically labeled reagents in place of previously utilized non-labeled reagents.

[0071] Additionally, in some embodiments, isotopically labeled compounds of Formula (Ia), (Ib), (IIa), and / or (IIb) can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described in the Examples provided below, using appropriate isotopically labeled reagents in place of previously utilized non-labeled reagents.

[0072] The compounds described herein may have chiral and / or geometric isomeric centers (E and Z isomers), and it is understood that all such optical isomers, enantiomers, diastereoisomers, and geometric isomers are encompassed. When compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomeric or enantiomerically enriched form. When chirality is not specified, but exists, it is understood that the embodiment is directed to either the specific diastereomeric or enantiomerically enriched form, or a racemic or scalemic mixture of such compound(s). As used herein, a "scalemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0073] Also provided are pharma- ceutically acceptable hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0074] In a preferred embodiment, the present disclosure relates to the use of a compound of formula (Ia) or (Ib) in the treatment of a Retroviridae viral infection, including an infection caused by the HIV virus, comprising administering a therapeutically effective amount to a subject in need thereof.

[0075] In a preferred embodiment, the present disclosure relates to the use of a compound of formula (Ia), (Ib), (IIa), and / or (IIb) in the treatment of a Retroviridae viral infection, including an infection caused by the HIV virus, comprising administering a therapeutically effective amount to a subject in need thereof.

[0076] Low EC 50 It is a desirable goal to discover compounds having the formula: 50 The EC value refers to the concentration of a compound in the assay that achieves 50% of the maximum efficacy. 50 Compounds with a higher EC 50Similar efficacy is achieved at lower compound concentrations compared to compounds with a lower EC 50 is generally preferred for drug discovery.

[0077] It is a desirable goal to find a compound or its pharma- ceutically acceptable salt with good physical and / or chemical stability. Increasing the overall stability of a compound can lead to increased circulation time in the body. With low decomposition, a stable compound can be administered at a lower dose and still maintain efficacy. Also, with low decomposition, there is less concern about by-products resulting from the decomposition of the compound.

[0078] It is a desirable goal to find a compound or its pharmaceutically acceptable salt with improved pharmacokinetic and / or pharmacodynamic profile and long half-life. It is advantageous for a drug to have moderate or low clearance and long half-life, because this can lead to good bioavailability and high exposure in systemic exposure. The reduction of clearance and increase of half-life time of a compound can reduce the daily dose required for efficacy, thus leading to better efficacy and safety profile. Thus, improved pharmacokinetic and / or pharmacodynamic profile and long half-life can provide better patient compliance.

[0079] It is a desirable goal to find a compound or a pharmacokinetically acceptable salt thereof that has a good pharmacokinetic profile from a sustained release injectable formulation. 50 It is advantageous to have a long acting pharmacokinetic profile, since this can result in a lower dosing frequency, which can provide better patient compliance, which may be desirable for patients with poor or limited access to health care.

[0080] Advantageously, it has been discovered that compounds of formula (Ia) and (Ib) herein provide advantages over the structurally closely related compounds disclosed in U.S. Patent Publication Nos. 2014 / 0296266A1 and 2014 / 0303164A1 (designated herein as Compounds A and B): [ka] [ka]

[0081] Thus, the present disclosure includes, but is not limited to, compounds of formula (Ia) [ka] or a pharma- ceutically acceptable salt thereof, and methods of using the compounds of formula (Ia) for the treatment of Retroviridae viral infections, including infections caused by the HIV virus.

[0082] Thus, the present disclosure includes, but is not limited to, compounds of formula (Ib) [ka] or a pharma- ceutically acceptable salt thereof, and methods of using the compounds of formula (Ib) for the treatment of Retroviridae viral infections, including infections caused by the HIV virus.

[0083] Also disclosed herein are compounds of formula (IIa) and (IIb) that offer advantages over compounds A and B (shown above).

[0084] Thus, the present disclosure includes, but is not limited to, compounds of formula (IIa) [ka] or a pharma- ceutically acceptable salt thereof, and methods of using the compounds of formula (IIa) for the treatment of Retroviridae viral infections, including infections caused by the HIV virus.

[0085] Thus, the present disclosure includes, but is not limited to, compounds of formula (IIb) [ka] or a pharma- ceutically acceptable salt thereof, and methods of using the compounds of formula (IIb) for the treatment of Retroviridae viral infections, including infections caused by the HIV virus.

[0086] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof) are used to prevent HIV infection in a subject. In some embodiments, the compounds disclosed herein are used to prevent HIV infection in a subject at risk of infection. In some embodiments, the compounds disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquiring HIV-1.

[0087] The compounds disclosed herein (e.g., compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof) are believed to be active against the major HIV-1 variants selected by clinical protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and integrase inhibitors (INSTIs). Combination therapy

[0088] In certain embodiments, methods are provided for treating or preventing HIV infection in a human having or at risk of having HIV infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents. In one embodiment, methods are provided for treating HIV infection in a human having or at risk of having HIV infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents.

[0089] In some embodiments, there is provided a method for treating or preventing HIV infection in a human having or at risk of having HIV infection, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents. In one embodiment, a method is provided for treating HIV infection in a human having or at risk of having HIV infection, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents.

[0090] In one embodiment, a pharmaceutical composition is provided that includes a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents, and a pharma- ceutically acceptable excipient.

[0091] In some embodiments, pharmaceutical compositions are provided that include a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharma- ceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents, and a pharma- ceutically acceptable excipient.

[0092] In certain embodiments, the present disclosure provides a method for treating HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0093] In certain embodiments, the present disclosure provides a method for treating HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0094] In certain embodiments, the present disclosure provides a method for treating HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharma- ceutically acceptable salt thereof.

[0095] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with one additional therapeutic agent. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents and / or they can be selected from different classes of therapeutic agents.

[0096] In some embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with one additional therapeutic agent. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or they may be selected from different classes of therapeutic agents. Administration of HIV combination therapy

[0097] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are administered together with one or more additional therapeutic agents. Co-administration of a compound disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein (e.g., compounds of formula (Ia) or (Ib)) and one or more additional therapeutic agents, such that a therapeutically effective amount of a compound disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents are both present in the subject's body. When administered sequentially, the combination can be administered in two or more doses.

[0098] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are administered together with one or more additional therapeutic agents. Co-administration of a compound disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)) and one or more additional therapeutic agents such that a therapeutically effective amount of a compound disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents are both present in the subject's body. When administered sequentially, the combination may be administered in two or more administrations.

[0099] Co-administration includes administration of a unit dosage of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, before or after administration of a unit dosage of one or more additional therapeutic agents. For example, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, can be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. In some embodiments, a unit dosage of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, can be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. The one or more additional therapeutic agents may be administered first, followed within seconds or minutes by administration of a unit dose of the one or more additional therapeutic agents. Alternatively, the one or more additional therapeutic agents may be administered first, followed within seconds or minutes by administration of a unit dose of a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)). In other embodiments, a unit dose of a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) may be administered first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of the one or more additional therapeutic agents. In yet other embodiments, a unit dose of the one or more additional therapeutic agents may be administered first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)).

[0100] In some embodiments, co-administration includes administration of a unit dose of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, before or after administration of a unit dose of one or more additional therapeutic agents. For example, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, can be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by administration of a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)). In other embodiments, a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) is administered first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of one or more additional therapeutic agents. In yet other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (e.g., 1-12 hours) later by administration of a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)).

[0101] For clarity, co-administration of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, with one or more additional therapeutic agents can refer to co-administration with one or more of the therapeutic agents described herein, e.g., the agents listed in paragraphs

[0111] to

[0162] .

[0102] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharma- ceutically acceptable salts thereof, are combined in a single dosage form with one or more additional therapeutic agents for simultaneous administration to a subject. In certain embodiments, such a single dosage form can be administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), and the like. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the single dosage form can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the single dosage form is orally bioavailable and can be administered orally. In certain embodiments, the single dosage form can be a solid dosage form for oral administration.

[0103] In some embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a subject. In certain embodiments, such a single dosage form can be administered by any route appropriate for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the single dosage form can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the single dosage form is orally bioavailable and can be administered orally. In certain embodiments, the single dosage form can be a solid dosage form for oral administration.

[0104] The compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib), or pharma- ceutically acceptable salts thereof), in combination with one or more additional therapeutic agents, can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), and the like. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0105] The compounds disclosed herein (e.g., compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharma- ceutically acceptable salts thereof), in combination with one or more additional therapeutic agents, can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0106] In certain embodiments, the compound of formula (Ia) or (Ib) or its pharma- ceutically acceptable salt is formulated as a tablet that may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet may contain one or more other compounds useful for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0107] In certain embodiments, the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is formulated as a tablet that may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet may contain one or more other compounds useful for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleoside inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0108] In certain embodiments, the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is formulated as a solution formulation that may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet may contain one or more other compounds useful for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleoside inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0109] In certain embodiments, the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is formulated as a suspension that may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet may contain one or more other compounds useful for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleoside inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0110] In certain embodiments, such tablets are suitable for once daily dosing. HIV combination therapy

[0111] In the above embodiments, the additional therapeutic agent is a combination drug for treating HIV, another drug for treating HIV, 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 entry inhibitor, an HIV maturation inhibitor, a latency reversing agent, a compound targeting the HIV capsid, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitor, an IL-13 antagonist, a peptidyl-prolyl cis-trans isomerase A modulator, a protein disulfide isomerase inhibitor, a complement C5a receptor antagonist, a DNA methyltransferase inhibitor, an HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV The anti-HIV agent may be selected from the group consisting of POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0112] In some embodiments, the additional therapeutic agent is a concomitant medication for HIV, another medication for treating HIV, an HIV protease inhibitor, an HIV reverse transcriptase inhibitor, an HIV integrase inhibitor, In particular, the therapeutic agent is selected from the group consisting of HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. HIV Combination Drugs

[0113] Examples of concomitant medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESC OVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETR A® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; cabotegravir and rilpivirine;Cabotegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine; lamivudine + abacavir + zidovudine; lamivudine + abacavir; lamivudine + tenofovir disop lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine; lopinavir + ritonavir + zidovudine + lamivudine; tenofovir + lamivudine; and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride; lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812. Other HIV drugs

[0114] Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkephalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGT V-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. HIV protease inhibitors

[0115] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-310911. HIV reverse transcriptase inhibitors

[0116] Examples of HIV non-nucleoside or non-nucleotidic inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500. Further examples of non-nucleoside reverse transcriptase inhibitors are disclosed in U.S. Patent Publication No. US2016 / 0250215.

[0117] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX®. EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxyl, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fodivudine tidoxyl, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, and KP-1461.

[0118] In some embodiments, examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX®. EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxyl, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fodivudine tidoxyl, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, KP-1461, and 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA). HIV integrase inhibitors

[0119] Examples of HIV integrase inhibitors include elvitegravir, curcumin and derivatives of curcumin, chicoric acid and derivatives of chicoric acid, 3,5-dicaffeoylquinic acid and derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid and derivatives of aurintricarboxylic acid. , caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169 and cabotegravir.

[0120] Examples of HIV non-catalytic, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442. HIV entry inhibitors

[0121] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

[0122] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0123] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and cifuvirtide.

[0124] Examples of CD4 binding inhibitors include ibalizumab and CADA analogs.

[0125] Examples of gp120 inhibitors include Radha-108(receptol)3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0126] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV maturation inhibitors

[0127] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232. Latent Reversal Agent

[0128] Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as Velcade, protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15, JQ1, disulfram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, and GSK-343.

[0129] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0130] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone. Capsid Inhibitors

[0131] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series. Immune-Based Therapies

[0132] Examples of immune-based therapies include Toll-like receptor modulators, e.g., tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha-2b; interferon alpha-n3; These include interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; lintatorimod, the polymer polyethyleneimine (PEI); gepon; lintatorimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, recombinant interleukin-15, RPI-MN, GS-9620, and IR-103. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0133] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatricisib, neratinib, panulisib, perifosine, pictilisib, piralalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonolicisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS -7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0134] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAb®, TandAb®, Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, lacZ antibodies, and the like. Examples of antibodies include anti-ICAM-1 antibodies derived from rabies, DCVax-001, gp140-targeting antibodies, gp41-based antibodies for HIV treatment, human recombinant mAb (PGT-121), ibalizumab, Immuglo, and MB-66.

[0135] Examples of targeting HIV in this manner include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, VRC-HIVMAB080-00-AB, MGD-014 and VRC07. Pharmacokinetic enhancers

[0136] Examples of pharmacokinetic enhancers include cobicistat and ritonavir. Additional Therapeutic Agents

[0137] Examples of additional therapeutic agents include those disclosed in WO2004 / 096286 (Gilead Sciences), WO2006 / 015261 (Gilead Sciences), WO2006 / 110157 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), WO2012 / 003498 (Gilead Sciences), WO2012 / 145728 (Gilead Sciences), WO2013 / 006738 (Gilead Sciences), WO2013 / 159064 (Gilead Sciences), WO2014 / 100323 (Gilead Sciences), US2013 / 0165489 (University of and compounds disclosed in US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences), and WO2013 / 091096 (Boehringer Ingelheim). HIV vaccine

[0138] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, and NAcGM3 / VSSP. ISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV(FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4(Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad 5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines, such as pseudovirion vaccines, CombiVICHvac, LFn-p24B / C fusion vaccines, GTU-based DNA vaccines, HIVgag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, conjugate polypeptide vaccines, dendritic cell vaccines, gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), Ii-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 These include HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin, mutant gp120 polypeptide vaccine, and rAd5 gag-pol env A / B / C vaccine. HIV combination therapy

[0139] In certain embodiments, the compounds disclosed herein (e.g., compounds of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine). ;TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC);DESCOVY® (tenofovir alafenamide and emtricitabine);ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine);GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir);Adefovir;Adefovir dipivoxil;Cobicistat;Emtricitabine;Tenofovir;Tenofovir disoproxil ALUVIA® (KALETRA®; Lopinavir and Ritonavir); COMBIVIR® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir;Fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir; In combination with one, two, three, four or more additional therapeutic agents selected from: fovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0140] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir 1;Tenofovir disoproxil;Tenofovir disoproxil fumarate;Tenofovir alafenamide;Tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine);dolutegravir, abacavir sulfate, and lamivudine;raltegravir;raltegravir and lamivudine;maraviroc;enfuvirtide;ALUVIA® (KALETRA®;lopinavir and ritonavir);COMBIVIR® (zidovudine and lamivudine;AZT+3TC);EP ZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin;Fosamprenavir; Fosamprenavir calcium; Efavirenz; Etravirine; Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine mesylate; Radha-108 (recepto l); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; abacavir sulfate; 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA); and bictegravir, or a pharmaceutically acceptable salt thereof;

[0141] It will be appreciated by those of skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of the compounds listed in those classes.

[0142] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with one or two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with one or two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. and an HIV non-nucleoside inhibitor of reverse transcriptase. In another particular embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In an additional embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0143] In some embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with one or two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another particular embodiment, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0144] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate.

[0145] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, are selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bictegravir (or a pharma- ceutically acceptable salt thereof), or 4'-ethynyl-2-fluorouracil. Combined with d-2'-deoxyadenosine (EFdA).

[0146] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with an HIV integrase inhibitor.

[0147] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate.

[0148] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bictegravir (or a pharmaceutically acceptable salt thereof), or 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

[0149] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0150] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0151] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent that is emtricitabine. In certain embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent that is emtricitabine. In certain embodiments, the compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent that is emtricitabine. In some embodiments, the compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, and the first and second additional therapeutic agents disclosed above are administered simultaneously. Optionally, the compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, and the first and second additional therapeutic agents disclosed above are administered simultaneously. The therapeutic agents are combined in a single dosage form for simultaneous administration to a subject. In other embodiments, the compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, and the first and second additional therapeutic agents disclosed above are administered sequentially.

[0152] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent that is emtricitabine. In certain embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent that is emtricitabine. In certain embodiments, the compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent that is emtricitabine. In some embodiments, the compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents disclosed above are administered simultaneously. Optionally, the compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents disclosed above are combined in a single dosage form for simultaneous administration to a subject. In other embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharma- ceutically acceptable salt thereof, and the first and second additional therapeutic agents disclosed above are administered sequentially.

[0153] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with bictegravir, or a pharma- ceutically acceptable salt thereof.

[0154] The compounds disclosed herein (e.g., any compound of Formula (Ia) or (Ib)) can be combined with one or more additional therapeutic agents, at any dosage of a compound of Formula (Ia) or (Ib) (e.g., 1 mg to 1000 mg of a compound).

[0155] In some embodiments, a compound disclosed herein (e.g., any compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof) can be combined with one or more additional therapeutic agents in any dosage of a compound of Formula (Ia), (Ib), (IIa), and / or (IIb) (e.g., 1 mg to 1000 mg of compound).

[0156] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, In one embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In one particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) can be combined with an agent provided herein at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as each combination of dosages is specifically and individually recited.

[0157] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)) can be combined with agents provided herein in any dosage of the compound (e.g., 1 mg to 1000 mg of compound) in the same manner as each combination of dosages is specifically and individually recited.

[0158] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) may be administered in any dosage amount (e.g., 1 mg to 1000 mg of compound) of the compound as provided herein, as if each combination of dosage amounts were specifically and individually recited. Can be combined with drugs.

[0159] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) can be combined with an agent provided herein at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as each combination of dosages is specifically and individually recited.

[0160] In some embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, is combined with 20-80 mg of bictegravir or a pharma- ceutically acceptable salt thereof. A compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof) can be combined with an agent provided herein at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as each combination of dosage amounts is specifically and individually recited.

[0161] In one embodiment, a kit comprising a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, is provided in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1-3) additional therapeutic agents.

[0162] In some embodiments, kits including a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharma- ceutically acceptable salt thereof, are provided in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1-3) additional therapeutic agents. Pharmaceutical Compositions

[0163] The pharmaceutical compositions disclosed herein comprise a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharma- ceutically acceptable salt thereof, together with one or more pharma- ceutically acceptable excipients and, optionally, other therapeutic agents. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration.

[0164] In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharma- ceutically acceptable salt thereof, in combination with one or more pharma- ceutically acceptable medicaments. Pharmaceutical compositions containing the active ingredient, together with excipients and optionally other therapeutic agents, may be in any form suitable for the intended method of administration.

[0165] Pharmaceutical compositions containing the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharma- ceutically acceptable salts thereof, can be prepared using conventional carriers (e.g., inactive ingredients or excipient materials) that can be selected according to normal practice. Tablets can contain excipients, including glidants, fillers, binders, and the like. Aqueous compositions can be prepared in sterile form and, if intended for delivery by other than oral administration, can generally be isotonic. All compositions can contain excipients, such as those set forth in Rowe et al., Handbook of Pharmaceutical Excipients, 5th Edition, American Pharmacists Association, 1986, as necessary. Excipients can include ascorbic acid and other antioxidants, chelating agents, such as EDTA, carbohydrates, such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

[0166] In some embodiments, pharmaceutical compositions comprising the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharma- ceutically acceptable salts thereof, can be prepared using conventional carriers (e.g., inactive ingredients or excipient materials), which can be selected according to ordinary practice. Tablets can contain excipients, including glidants, fillers, binders, and the like. Aqueous compositions can be prepared in sterile form and, if intended for delivery by other than oral administration, can generally be isotonic. All compositions can contain excipients, such as those set forth in Rowe et al., Handbook of Pharmaceutical Excipients, 5th Edition, American Pharmacists Association, 1986, as appropriate. For example, excipients can include ascorbic acid and other antioxidants, chelating agents, such as EDTA, carbohydrates, such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

[0167] While it is possible for the active ingredient to be administered alone, it may be preferable to present the active ingredient as a pharmaceutical composition. Compositions for both veterinary and human use comprise at least a compound of formula (Ia) or (Ib), 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 (Ib), or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient and a therapeutically effective amount of one or more (e.g., 1, 2, 3 or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents as defined hereinbefore. In one embodiment, the pharmaceutical composition comprises a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient and one other therapeutic ingredient. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the composition and physiologically innocuous to the recipient thereof.

[0168] In some embodiments, while it may be possible to administer the active ingredient alone, it may be preferable to present the active ingredient as a pharmaceutical composition. Compositions for both veterinary and human use comprise at least a compound of formula (Ia), (Ib), (IIa) and / or (IIb), together with one or more acceptable carriers and optionally other therapeutic ingredients. In some embodiments, the pharmaceutical composition comprises a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient and a therapeutically effective amount of one or more (e.g., 1, 2, 3 or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents as previously defined herein ... b), (IIa) and / or (IIb), or a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable excipient and one other therapeutic ingredient. The carrier(s) are "acceptable" in the sense of being compatible with the other ingredients of the composition and physiologically non-toxic to the recipient thereof.

[0169] 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 combining the active ingredient (e.g., a compound of formula (Ia) or (Ib) or a pharmaceutical salt thereof) with one or more inactive ingredients (e.g., carriers, pharmaceutical excipients, etc.). The compositions can be prepared by uniformly and intimately combining the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0170] In some embodiments, 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 combining the active ingredient (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutical salt thereof) with one or more inactive ingredients (e.g., carriers, pharmaceutical excipients, etc.). The compositions can be prepared by uniformly and intimately combining the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. Techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott William and Wilkins, Philadelphia, Pa., 2006.

[0171] Compositions described herein suitable for oral administration may be presented as discrete units (unit dosage forms), including, but not limited to, capsules, cachets or tablets, each containing a predetermined amount of the active ingredient.

[0172] For oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible 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 manufacturing pharmaceutical compositions, and such compositions can contain one or more agents, including sweeteners, flavoring agents, coloring agents and preservatives, to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium 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. The tablets may be uncoated or may be coated by known techniques, including microencapsulation, which delays disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax.

[0173] In some embodiments, disclosed herein are oral dosage forms (eg, tablets) that can be prepared from hot melt extrusion or spray dried dispersion (SDD) techniques.

[0174] In some embodiments, hard capsules are disclosed herein, which are filled with powder, beads or granules containing active ingredient, mixed with non-toxic pharma- ceutically acceptable excipients suitable for manufacturing hard or soft capsules.These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium 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.

[0175] In some embodiments, hard or soft capsules are disclosed herein, which are filled with liquid or semi-solid mixtures containing active ingredient mixed with non-toxic pharma- ceutically acceptable excipients suitable for making hard or soft capsules.These excipients can be, for example, solubilizing oils, such as corn oil, sesame oil, or corn oil; medium-chain triglycerides and related esters, such as derivitized palm kernel oil or coconut oil; self-emulsifying lipid systems (SEDDS or SMEDDS), such as caprylic triglyceride or propylene glycol monocaprylate; viscosity modifiers, such as cetyl alcohol, steryl alcohol, glycerol stearate; and solubilizers and surfactants, such as polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamer, or polysorbate.

[0176] The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous 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 can also be an injectable sterile solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol, or can be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be utilized are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils can be conventionally utilized as a solvent or suspending medium. For this purpose, any bland, fixed oil can be utilized, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be similarly utilized in the preparation of injectables.

[0177] In some embodiments, the sterile injectable preparation disclosed herein may also be a sterile injectable solution or suspension prepared from reconstituted lyophilized powder in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well.

[0178] The preparation suitable for parenteral administration includes aqueous and non-aqueous sterile injections that can contain antioxidants, buffers, bacteriostatic agents and solutes that make the preparation isotonic with the blood of intended recipient; and aqueous and non-aqueous sterile suspensions that can contain suspending agents and thickening agents.In certain embodiments, the suspension is a microsuspension.In certain embodiments, the suspension is a nanosuspension.

[0179] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) include one or more excipients. The excipient should be compatible with the other components of the formulation and physiologically harmless 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 and Quinn), 6th Edition, 2009.

[0180] 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, disclosed herein are parenteral administrations (e.g., SC or IM formulations) comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical salt thereof, and a poloxamer, particularly poloxamer 338. In some embodiments, the amount of poloxamer (e.g., poloxamer 388) in the parenteral administrations 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%.

[0181] 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), poloxamers (e.g., poloxamer 338, 188, or 207). Disclosed herein, in some embodiments, are parenteral administration (e.g., SC or IM formulations) comprising a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical salt thereof, and a poloxamer.

[0182] In certain embodiments, the excipients include N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide, polyethylene glycol, and / or tetraglycol / glycofurol.

[0183] Generally, poloxamers are synthetic non-ionic triblock linear copolymers with a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic polypropylene oxides, in certain cases with a weight ratio of 4:2:4.Thus, in certain embodiments, the compositions disclosed herein comprise a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical 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: [ka] (wherein a and b are integers (e.g., a is 2 to 130 and b is 15 to 67)). Poloxamer 188, for example, is understood to have a molecular weight in the range of about 7680 to about 9510 Daltons (wherein a is about 80 and b is about 27). International Journal of PharmTech 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. Similarly, poloxamer 338 has a molecular weight in the range of about 12700 to about 17400 Daltons (wherein a is about 141 and b is approximately 44).

[0184] Examples of excipients in parenteral formulations (e.g., SC or IM formulations) can also include polyethylene glycol. Generally, polyethylene glycol (PEG) has the general formula H-(O-CH2-CH2) nIn certain embodiments, the PEG may be "capped" with an alkyl group. In these embodiments, the capped PEG has the formula alkyl-(O-CH-CH) n -O-alkyl, (e.g. CH3-(O-CH2-CH2) n -OCH3. The pharmaceutical composition of the present disclosure may include PEG having an average molecular weight of about 100 to about 1000. In some embodiments, the average molecular weight of PEG in the pharmaceutical composition is about 100 to about 800. In some embodiments, the average molecular weight of PEG in the pharmaceutical composition is about 200 to about 600. In some embodiments, the average molecular weight of PEG in the pharmaceutical composition is about 400. In some embodiments, the average molecular weight of PEG in the pharmaceutical composition is about 300. In some embodiments, the average molecular weight of PEG in the pharmaceutical composition is about 200. In some embodiments of the pharmaceutical composition, PEGs of different molecular weights can be combined to obtain a desired property(ies) (e.g., viscosity). Specific examples of PEG include, but are not limited to, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, and the like. PEG100 refers to, for example, polyethylene glycol having an average molecular weight of about 100.

[0185] In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical salt thereof, and saline. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical acceptable salt thereof, saline, and a poloxamer (e.g., poloxamer 338, 188, or 207).

[0186] In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical salt thereof, and saline. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, saline, and a suspending agent. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, saline, and a poloxamer (e.g., poloxamer 338, 188, or 207).

[0187] In some embodiments, a suspension is provided comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical salt thereof, in a poloxamer and saline solution. In some embodiments, the concentration of the poloxamer in the saline solution is about 0.1 to about 20%. In some embodiments, the concentration of the poloxamer in the saline solution is about 0.1 to about 10%. In some embodiments, the concentration of the poloxamer in the saline solution is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. In certain embodiments, the concentration of the poloxamer in the saline solution is about 2%. In certain embodiments, the poloxamer is poloxamer 188. In certain embodiments, the compound is a compound of formula (Ib) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula (Ib) In certain embodiments, the compound is the sodium salt of the compound of formula (Ib).

[0188] In some embodiments, a suspension is provided comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical salt thereof, in a poloxamer and mannitol. In some embodiments, the concentration of the poloxamer in the mannitol is about 0.1 to about 20%. In some embodiments, the concentration of the poloxamer in the mannitol is about 0.1 to about 10%. In some embodiments, the concentration of the poloxamer in the mannitol is about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or about 10%. In certain embodiments, the concentration of the poloxamer in the mannitol is about 2%. In certain embodiments, the poloxamer is poloxamer 188. In certain embodiments, the compound is a compound of formula (Ib) or a pharma- ceutically acceptable salt thereof. In certain embodiments, the compound is a compound of formula (Ib). In certain embodiments, the compound is the sodium salt of the compound of formula (Ib).

[0189] In certain embodiments, the compositions are disclosed as solid dosage forms, including solid injectable dosage forms, for example solid depot forms.

[0190] In certain embodiments, the active ingredient (e.g., a compound of formula Ib) is present as a free acid. In certain embodiments, the active ingredient (e.g., a compound of formula Ib) is present as a sodium salt.

[0191] In certain embodiments, the pharmaceutical composition disclosed herein is a parenteral formulation.In certain embodiments, the formulation is administered subcutaneously to a subject in need thereof.In certain embodiments, the formulation is administered intramuscularly to a subject in need thereof.

[0192] In certain embodiments, the parenteral formulation comprises N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation consists essentially of N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation comprises dimethylsulfoxide.

[0193] In certain embodiments, the parenteral formulation comprises a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutical salt thereof, and water. In certain embodiments, the parenteral formulation comprises a compound of formula (Ib), or a pharmaceutical salt thereof, and water. In certain embodiments, the parenteral formulation further comprises an alcohol. In certain embodiments, the alcohol is ethanol. In certain embodiments, the parenteral formulation further comprises a polyethylene glycol. In certain embodiments, the polyethylene glycol has an average molecular weight of about 200 g / mol. (polyethylene glycol 200). In certain embodiments, the parenteral formulation further comprises an inorganic base. In certain embodiments, the inorganic base is sodium hydroxide. In certain embodiments, the inorganic base is sodium ethoxide. In certain embodiments, the formulation comprises about 0.1 molar equivalents to about 1.5 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 0.5 molar equivalents to about 1.5 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.0 molar equivalent to about 1.2 molar equivalent of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.2 molar equivalent of an inorganic base (e.g., NaOH or NaOEt).

[0194] In certain embodiments, the parenteral formulation consists essentially of a compound of formula (Ib) or a pharmaceutical salt thereof, water, ethanol, and polyethylene glycol 200.

[0195] In certain embodiments, the parenteral formulation consists essentially of a compound of formula (Ib) or a pharmaceutical salt thereof, water, ethanol, polyethylene glycol 200 (polyethylene glycol having an average molecular weight of 200 g / mol), and NaOH. In certain embodiments, the parenteral formulation consists essentially of a compound of formula (Ib) or a pharmaceutical salt thereof, water, ethanol, polyethylene glycol 200, and NaOEt. In certain embodiments, the formulation comprises about 0.1 molar equivalents to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises about 0.5 molar equivalents to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises about 1.0 molar equivalents to about 1.2 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises about 1.2 molar equivalents of NaOH or NaOEt.

[0196] 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 about 5%-20% ethanol, about 5%-20% water, and about 60%-90% PEG200. In certain embodiments, the solution formulation comprises about 10%-15% ethanol, about 10%-15% water, and about 70%-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 further comprises sodium hydroxide or sodium ethoxide. In certain embodiments, the solution formulation further comprises sodium hydroxide. In certain embodiments, the formulation comprises about 0.1 molar equivalents to about 1.5 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 0.5 molar equivalents to about 1.5 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.0 molar equivalents to about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt).

[0197] In some embodiments, a solution formulation is provided containing 200 mg / mL of Formula Ib in about 10% ethanol, about 12% water, and about 77% PEG with about 0.1 to about 1.5 equivalents of NaOH.

[0198] In certain embodiments, oral formulations of compounds of formula (Ia), (Ib), (IIa), and / or (IIb) are provided, which include at least one excipient. The excipient can include ethanol, medium chain triglycerides (e.g., MIGLYOL810, MIGLYOL821, MIGLYOL840, etc.), Vitamin E TPGS, glycerin, and / or pharma-ceutically acceptable oils (e.g., sesame oil, castor oil, safflower oil, vegetable oil, soybean oil, etc.). The oral formulations disclosed herein can include any combination of one or more suitable excipients. The excipients, taken together, can be present in >65% by weight of the total oral formulation, >70% by weight of the total oral formulation, >80% by weight of the total oral formulation, >90% by weight of the total oral formulation, or >95% by weight of the total oral formulation.

[0199] In some embodiments, oral formulations of compounds of formula (Ia), (Ib), (IIa), and / or (IIb) are provided. In certain embodiments, the oral formulations include compounds of formula (Ia), (Ib), (IIa), and / or (IIb), 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 formulations include compounds of formula (Ia), (Ib), (IIa), and / or (IIb), 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), (Ib), (II a) and / or (IIb) in about 10% ethanol, about 20% Vitamin E TPGS, and about 70% MIGLYOL 812. In certain embodiments, the oral formulation is prepared in a hard gelatin capsule.

[0200] The amount of active ingredient that can be combined with the inactive ingredients to produce a dosage form can vary depending on the intended treatment subject and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans can contain about 1 to 1000 mg of active agent formulated with an appropriate, convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material ranges from about 5 to about 95% (weight:weight) of the total composition.

[0201] It should be understood that in addition to the ingredients particularly mentioned above, the compositions of these embodiments may include other agents conventional in the art having regard to the type of composition in question; for example, those suitable for oral administration may include flavoring agents.

[0202] In certain embodiments, the composition comprising the active ingredient disclosed herein (e.g., a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof) in one variant () does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that the composition comprising the compound of formula (Ia) or (Ib) in certain embodiments does not contain an agent that affects (e.g., retards, impedes, or slows down) the metabolism of the compound of formula (Ia) or (Ib) or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of formula (Ia) or (Ib). It is also understood that any of the methods, kits, articles of manufacture, etc. detailed in certain embodiments herein do not contain an agent that affects (e.g., retards, impedes, or slows down) the metabolism of the compound of formula (Ia) or (Ib) or any other active ingredient that is administered separately, sequentially, or simultaneously with the compound of any one of formulas (Ia) or (Ib).

[0203] In some embodiments, a composition comprising an active ingredient disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof) in one variation does not contain an agent that affects the rate at which the active ingredient is metabolized. Thus, it is understood that a composition comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb) in certain embodiments does not contain an agent that affects (e.g., retards, impedes, or slows) the metabolism of a compound of formula (Ia), (Ib), (IIa), and / or (IIb) or any other active ingredient administered separately, sequentially, or simultaneously with a compound of formula (Ia), (Ib), (IIa), and / or (IIb). It is also understood that none of the methods, kits, articles of manufacture, etc. detailed in certain embodiments herein include agents that affect (e.g., retard, impede or slow) the metabolism of the compounds of Formula (Ia), (Ib), (IIa), and / or (IIb) or any other active ingredients administered separately, sequentially or simultaneously with any one of the compounds of Formula (Ia), (Ib), (IIa), and / or (IIb). How to use

[0204] In certain embodiments, methods are disclosed for treating or preventing HIV infection in a subject (e.g., a human), comprising administering to the subject a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof. In some embodiments, methods are disclosed for treating or preventing HIV infection in a subject (e.g., a human), comprising administering to the subject a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof. In certain embodiments, a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is disclosed that inhibits replication of the HIV virus in a subject (e.g., a human), thereby preventing AIDS. Disclosed is a method for treating or delaying the onset of AIDS comprising administering to a subject a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof.

[0205] In some embodiments, disclosed is a method for inhibiting replication of the HIV virus, treating AIDS, or delaying the onset of AIDS in a subject (e.g., a human), comprising administering to the subject a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof. In certain embodiments, a method for preventing HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject is at risk of contracting the HIV virus, e.g., has one or more risk factors known to be associated with contracting the HIV virus.

[0206] In some embodiments, a method for preventing HIV infection in a subject (e.g., a human) is disclosed, comprising administering to the subject a therapeutically effective amount of a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof. In certain embodiments, the subject is at risk of contracting the HIV virus, e.g., has one or more risk factors known to be associated with contracting the HIV virus.

[0207] In certain embodiments, methods are disclosed for treating HIV infection in a subject (e.g., a human), comprising administering to the subject a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, methods are disclosed for treating HIV infection in a subject (e.g., a human), comprising administering to the subject a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof.

[0208] In certain embodiments, a method for treating HIV infection in a subject (e.g., a human) is provided comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, in combination with an HIV protease inhibitor compound, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, an HIV nucleotide inhibitor of reverse transcriptase, or an HIV nucleotide inhibitor of reverse transcriptase. In one embodiment, the method comprises administering to the patient a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents selected from the group consisting of: anti-HIV transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof. In certain embodiments, a method for treating HIV infection in a subject (e.g., a human) is provided comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, in combination with a drug for HIV, another drug for treating HIV, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside or nucleoside inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, a latency reversal agent, a compound targeting the HIV capsid, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, agents, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV Disclosed are methods that include administering in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents selected from the group consisting of POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof.

[0209] In some embodiments, disclosed are methods for treating HIV infection in a subject (e.g., human), comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharma- ceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.In certain embodiments, a method for treating HIV infection in a subject (e.g., a human) is provided comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharma- ceutically acceptable salt thereof, in combination with a drug for HIV, another drug for treating HIV, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside or nucleoside inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV maturation inhibitor, a latency reversal agent, a compound targeting the HIV capsid, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors. In certain embodiments, methods are disclosed that include administering in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents selected from the group consisting of: HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof. In certain embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in the medical therapy of HIV infection (e.g., HIV-1 or HIV virus (e.g., HIV-1) replication or AIDS) or delaying the onset of AIDS in a subject (e.g., a human).

[0210] In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, are disclosed for use in the medical treatment of HIV infection (e.g., HIV-1 or HIV viral (e.g., HIV-1) replication or AIDS) or delaying the onset of AIDS in a subject (e.g., a human). In certain embodiments, compounds of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, are disclosed for use in the manufacture of a medicament for treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in a subject (e.g., a human). One embodiment relates to compounds of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in the therapeutic treatment of AIDS or delaying the onset of AIDS.

[0211] In some embodiments, disclosed are compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in the manufacture of a medicament for treating HIV infection or HIV viral replication or AIDS, or delaying the onset of AIDS, in a subject (e.g., a human). One embodiment relates to compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in the therapeutic treatment of AIDS or delaying the onset of AIDS. In certain embodiments, the use of a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for HIV infection in a subject (e.g., human) is disclosed. In certain embodiments, a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection is disclosed.

[0212] In some embodiments, the use of a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for HIV infection in a subject (e.g., a human) is disclosed. In certain embodiments, a compound of any of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection is disclosed.

[0213] In certain embodiments, in the method of use, administration is to a subject (e.g., a human) in need of treatment. In certain embodiments, in the method of use, administration is to a subject (e.g., a human) at risk of developing AIDS. Compounds of formula (Ia) or (Ib), or pharma- ceutically acceptable derivatives thereof, for use in therapy are provided herein. Disclosed herein are salts of: In one embodiment, the compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, is for use in a method of treating HIV infection or HIV viral replication or AIDS, or delaying the onset of AIDS, in a subject (e.g., a human).

[0214] In some embodiments, disclosed herein are compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in therapy. In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in a method of treating HIV infection or HIV viral replication or AIDS, or delaying the onset of AIDS, in a subject (e.g., human). Also disclosed herein are compounds of formula (Ia) or (Ib), or pharma- ceutically acceptable salts thereof, for use in a method of treating or preventing HIV infection in a subject in need thereof. In certain embodiments, provided herein are compounds of formula (Ia) or (Ib), or pharma- ceutically acceptable salts thereof, for use in a method of treating HIV infection in a subject in need thereof. In certain embodiments, the subject in need thereof is a human being infected with HIV. In certain embodiments, the subject in need thereof is a human who is infected with HIV but does not develop AIDS.In certain embodiments, the subject in need thereof is a subject who is at risk of developing AIDS.In certain embodiments, the subject in need thereof is a human who is infected with HIV and develops AIDS.

[0215] In some embodiments, disclosed herein are compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in a method of treating or preventing HIV infection in a subject in need thereof. In certain embodiments, provided are compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in a method of treating HIV infection in a subject in need thereof. In certain embodiments, the subject in need thereof is a human infected with HIV. In certain embodiments, the subject in need thereof is a human infected with HIV but who has not developed AIDS. In certain embodiments, the subject in need thereof is a subject at risk of developing AIDS. In certain embodiments, the subject in need thereof is a human infected with HIV and has developed AIDS.

[0216] In one embodiment, a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, is provided in combination with one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents as described herein for use in a method of treating or preventing HIV infection in a subject in need thereof. In one embodiment, the additional therapeutic agent is a combination drug for HIV, another drug for treating HIV, 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 entry inhibitor, an HIV maturation inhibitor, a latency reversal agent, a compound targeting the HIV capsid, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitor, an IL-13 antagonist, a peptidyl-prolyl cis-trans isomerase A modulator, a protein disulfide isomerase inhibitor, a complement C5a receptor antagonist, a DNA methyltransferase inhibitor, an HIV vif gene modulator, a Vif dimerization antagonist, an HIV-1 viral infectivity factor inhibitor, a TAT protein inhibitor, an HIV-1 Nef modulator, Hck tyrosine kinase modulator, mixed lineage kinase-3 (MLK-3) inhibitor In some embodiments, the therapeutic agent is selected from the group consisting of an anti-HIV agent, an HIV-1 splicing inhibitor, a Rev protein inhibitor, an integrin antagonist, a nuclear protein inhibitor, a splicing factor modulator, a COMM domain-containing protein 1 modulator, an HIV ribonuclease H inhibitor, a retrocyclin modulator, a CDK-9 inhibitor, a dendritic ICAM-3 binding nonintegrin 1 inhibitor, an HIV GAG protein inhibitor, an HIV POL protein inhibitor, a complement factor H modulator, an ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin dependent kinase inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, and an HIV vaccine, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof.

[0217] In some embodiments, compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharma- ceutically acceptable salts thereof, are provided in combination with one or more (e.g., 1, 2, 3, or 4, or 1 or 2, or 1-3, or 1-4) additional therapeutic agents as described herein for use in a method of treating or preventing HIV infection in a subject in need thereof. In one embodiment, the additional therapeutic agent is a combination drug for HIV, another drug for treating HIV, 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 entry inhibitor, an HIV maturation inhibitor, a latency reversal agent, a compound targeting the HIV capsid, an immune-based therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitor, an IL-13 antagonist, a peptidyl-prolyl cis-trans isomerase A modulator, a protein disulfide isomerase inhibitor, a complement C5a receptor antagonist, a DNA methyltransferase inhibitor, an HIV vif gene modulator, a Vif dimerization antagonist, an HIV-1 viral infectivity factor inhibitor, a TAT protein inhibitor, an HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV The additional therapeutic agent is selected from the group consisting of POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, and combinations thereof. In one embodiment, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating or preventing HIV infection in a subject in need thereof in combination with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent that is emtricitabine. In certain embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating or preventing HIV infection in a subject in need thereof in combination with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent that is emtricitabine.

[0218] In some embodiments, compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are provided for use in a method of treating or preventing HIV infection in a subject in need thereof in combination with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent that is emtricitabine. In certain embodiments, compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are provided for use in a method of treating or preventing HIV infection in a subject in need thereof in combination with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent that is emtricitabine.

[0219] In certain embodiments, the compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is provided for use in preventing HIV infection from taking hold when an individual is exposed to the virus, and / or preventing the virus from establishing a persistent infection, and / or preventing disease symptoms from appearing, and / or preventing the virus from reaching detectable levels in blood, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP).Thus, in certain embodiments, a method is provided for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2).For example, the method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0220] In some embodiments, the compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharma- ceutically acceptable salts thereof, are provided for use in preventing HIV infection from taking hold when an individual is exposed to the virus, and / or preventing the virus from establishing a persistent infection, and / or preventing disease symptoms from appearing, and / or preventing the virus from reaching detectable levels in the blood, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Thus, in certain embodiments, methods are provided for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2). For example, methods for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) are provided. comprises administering a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0221] In certain embodiments, the method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, in combination with safer sex practices. In certain embodiments, the method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering to an individual at risk of infection with HIV. Examples of individuals at high risk of infection with HIV include, without limitation, individuals at risk of sexual transmission of HIV.

[0222] In some embodiments, the method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, in combination with safer sex practices. In certain embodiments, the method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administration to an individual at risk of infection with HIV. Examples of individuals at high risk of infection with HIV include, without limitation, individuals at risk of sexual transmission of HIV.

[0223] In certain embodiments, the reduction in risk of HIV infection is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In certain embodiments, the reduction in risk of HIV infection is at least about 75%. In certain embodiments, the reduction in risk of HIV infection is about 80%, 85%, or 90%.

[0224] In another embodiment, the use of a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection in a human having or at risk of having HIV infection is disclosed.

[0225] In some embodiments, disclosed is the use of a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection in a human having or at risk of having HIV infection.

[0226] Also disclosed herein are compounds of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for use in the therapeutic treatment of AIDS or delaying the onset of AIDS.

[0227] In some embodiments, disclosed herein are compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, for use in the therapeutic treatment of AIDS or delaying the onset of AIDS.

[0228] Also disclosed herein is a compound of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection.

[0229] In some embodiments, a compound of formula (I) is provided for use in the prophylactic or therapeutic treatment of HIV infection. Disclosed herein are compounds of formula (a), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof.

[0230] In certain embodiments, a compound of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, can be used as a research tool (e.g., to test inhibition of HIV reverse transcriptase in a subject or in vitro).

[0231] In some embodiments, the compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, can be used as research tools (e.g., to test inhibition of HIV reverse transcriptase in subjects or in vitro). Route of administration

[0232] The compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, (also referred to herein as the active ingredient) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It is recognized that the preferred route may vary, for example, depending on the condition of the recipient. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0233] In some embodiments, the compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharma- ceutically acceptable salts thereof, (also referred to herein as active ingredients), can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It is recognized that the preferred route may vary, for example, depending on the condition of the recipient. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0234] In some embodiments, the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, may be administered using a syringe suitable for administering the compound. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof.

[0235] In some embodiments, the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, may be administered using an autoinjector that includes a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof. Dosing regimen

[0236] A compound, for example a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof. The salt of can be administered to a subject according to an effective dosing regimen for a desired period or duration, for example, 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. In one variation, the compound is administered on a daily or intermittent schedule. In one variation, the compound is administered on a monthly schedule. In one variation, the compound is administered every two months. In one variation, the compound is administered every three months. In one variation, the compound is administered every four months. In one variation, the compound is administered every five months. In one variation, the compound is administered every six months.

[0237] In some embodiments, the compound, e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, can be administered to a subject according to an effective dosing regimen for a desired period or duration, e.g., at least about one day, at least about one week, at least about one month, at least about two months, at least about three months, at least about four months, at least about six months, or at least about twelve months or longer. In some embodiments, the compound is administered on a daily or intermittent schedule. In some embodiments, the compound is administered on a monthly schedule. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months.

[0238] In some embodiments, the compound, e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, can be administered to the subject for at least about one month, at least about four months, or at least about six months. In some embodiments, the compound (e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof) can be administered subcutaneously to the subject for at least about one month. In some embodiments, the compound (e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof) can be administered subcutaneously or intramuscularly to the subject for at least about four months or at least about six months. In some embodiments, the compound (e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof) can be administered subcutaneously to the subject for at least about one month. In some embodiments, a compound (e.g., a compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof) can be administered subcutaneously or intramuscularly to a subject at least about every three months.

[0239] The amount or frequency of administration of a compound of Formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, may be adjusted during treatment, based on the judgment of the administering physician.

[0240] In some embodiments, the dosage or frequency of administration of the compounds of Formula (Ia), (Ib), (IIa), and / or (IIb), or pharma- ceutically acceptable salts thereof, may be adjusted during treatment, based on the judgment of the administering physician.

[0241] The compound can be administered to a subject (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily. In some embodiments, the compound can be administered to a subject (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once daily. In some embodiments, the compound is administered monthly. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every six months.

[0242] The compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharma- ceutically acceptable salts thereof, can be administered in effective dosages. For example, dosages can be from 1 mg to 1000 mg of compound. In certain embodiments, dosages are about 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140, or 150 mg of compound. In certain embodiments, dosages are about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

[0243] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharma- ceutically acceptable salts thereof, can be administered in an effective dosage. For example, the dosage can be from 1 mg to 1000 mg of the compound. In certain embodiments, the dosage is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140, or 150 mg of the compound. In certain embodiments, the dosage is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

[0244] In some embodiments, the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is administered in a once daily dose. In some embodiments, the compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is administered in a once daily dose of about 1 mg.

[0245] In some embodiments, the compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is administered monthly. In some embodiments, the compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is administered monthly at a dose of about 100 mg.

[0246] In some embodiments, the compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is administered every six months. In some embodiments, the compound of Formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, is administered at a dose of about 600 mg every six months. Kits and Articles of Manufacture

[0247] The present disclosure relates to a kit comprising the compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof.In one embodiment, the kit can comprise one or more additional therapeutic agents as described hereinbefore.The kit can further comprise instructions, for example, for use in inhibiting HIV reverse transcriptase, for example, for use in treating HIV infection or AIDS, or for use as a research tool.The instructions are generally written instructions, but electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.

[0248] In some embodiments, the present disclosure relates to a kit comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharma- ceutically acceptable salt thereof. In one embodiment, the kit can comprise one or more additional therapeutic agents as described hereinabove. The kit can be used to treat, for example, HIV reverse transcriptase inhibition, for example, for use in the treatment of HIV infection or AIDS, or as a research tool, etc. It may further include instructions. The instructions will typically be written instructions, although electronic storage media (e.g., a magnetic diskette or optical disk) containing the instructions are also acceptable.

[0249] The present disclosure also relates to a pharmaceutical kit comprising one or more containers containing a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof. Optionally associated with such container(s) may be a notice in the form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting approval by the governmental agency for manufacture, use, or sale for administration to humans. Each component (if there is more than one component) may be packaged in a separate container, or some components may be combined in one container, if cross-reactivity and shelf life permits. The kit may be in unit dosage form, bulk package (e.g., multi-dose package), or sub-unit dose. The kit may also include multiple unit doses of the compound and instructions, and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., hospital pharmacy and compounding pharmacy).

[0250] In some embodiments, the present disclosure also relates to pharmaceutical kits comprising one or more containers containing a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof. Optionally associated with such container(s) may be a notice in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting approval by the governmental agency for manufacture, use, or sale for administration to humans. Each component (if there is more than one component) may be packaged in a separate container, or some components may be combined in one container, if cross-reactivity and shelf life permits. The kit may be in unit dosage form, bulk package (e.g., multi-dose package), or sub-unit dose. The kit may also include multiple unit doses of the compound and instructions, and may be packaged in an amount sufficient for storage and use in a pharmacy (e.g., hospital pharmacy and compounding pharmacy).

[0251] Also disclosed is an article of manufacture comprising a unit dose of a compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof, in a suitable package for use in the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The article of manufacture may be further sterilized and / or sealed. In some embodiments, disclosed herein is an article of manufacture comprising a unit dose of a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharma- ceutically acceptable salt thereof, in a suitable package for use in the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The article of manufacture may be further sterilized and / or sealed. nomenclature

[0252] The names of the compounds of formula (Ia) and (Ib) of the present disclosure are as generated using ChemBioDraw Ultra 11. [ka] is N-(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-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. [ka] is N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

[0253] The names of the compounds of formula (IIa) and (IIb) of the present disclosure are as generated using ChemBioDraw Ultra 14. [ka] is N-(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-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide. [ka] is 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. Synthesis of Compounds of Formulae (Ia), (Ib), (IIa), and (IIb)

[0254] The present disclosure is also directed to processes and intermediates useful for preparing the subject compounds, or pharma- ceutically acceptable salts thereof.

[0255] Unless otherwise stated, the methods and techniques of the present disclosure are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification.See, for example, Loudon, Organic Chemistry, 5th Edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition, Wiley-Interscience, 2013.

[0256] In certain cases, the processes disclosed herein include forming a salt of a compound of the present disclosure.

[0257] In certain cases, intermediates useful for preparing the compounds of formula (Ia) or (Ib) of the present disclosure are provided. For example, these intermediates include any one or combination of compounds 1-23 or salts thereof. In certain embodiments, the intermediates are selected from compounds 8a, 12, 14, 19, 20, 21, 22, 23, and / or 23b, combinations thereof, or salts thereof.

[0258] In some embodiments, intermediates useful for preparing the compounds of formula (IIa) or (IIb) of the present disclosure are provided. For example, the intermediates include any one or combination of compounds 1, 10, 20, and 25-37, or salts thereof. In some embodiments, the intermediates are selected from compounds 20, 32, 34, 35, 36, and / or 37, combinations thereof, or salts thereof.

[0259] The compounds described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any suitable stationary phase can be used, including normal phase and reverse phase and ionic resin. Most typically, the disclosed compounds are purified through silica gel chromatography and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, LR Snyder and JJ Kirkland (eds.), John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0260] During any of the processes for the preparation of the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This can be achieved by means of conventional protecting groups as described in standard practice, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 4th Edition, Wiley, New York, 2006. The protecting groups can be removed at a convenient subsequent stage using methods known in the art.

[0261] With reference to the exemplary synthetic schemes for these general preparations herein and the specific examples that follow, exemplary chemical entities useful in the methods of the embodiments are now described. Those skilled in the art will recognize that the transformations shown in the schemes below can be carried out in any order compatible with the functionality of the particular pendant groups. Each of the reactions shown in the general schemes is preferably carried out at a temperature from about 0° C. to the reflux temperature of the organic solvent used.

[0262] The compounds disclosed herein can exhibit atropisomerism resulting from steric hindrance affecting the rate of axial rotation around a single bond. The resulting conformers can each be observed as distinct entities by characterization techniques such as NMR and HPLC. The compounds disclosed herein can exist as a mixture of atropisomers. However, detection of atropisomers depends on factors such as temperature, solvent, purification conditions, and time scale of the spectroscopic technique. Interconversion rates at room temperature have half-lives of minutes to hours, hours to days, or days to years. The ratio of atropisomers at equilibrium does not have to be unitary. The characterization data presented herein may not represent equilibrium conditions, depending on the conditions of isolation and characterization, which may include, but are not limited to, handling, solvents used, and temperature. Representative syntheses of compounds of the present disclosure are described in the following schemes and in the specific examples that follow. The following examples are merely illustrative and are not intended to limit the disclosure in any way. EXAMPLES

[0263] Preparation of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (8a) and 2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (8b): Example 1 [ka] Synthesis of lithium 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethane-1-olate (2): A reactor was charged with bicyclo[3.1.0]hexan-3-one (95.6 g, 0.99 mol) and ethyl 2,2,2-trifluoroacetate (113.2 mL, 0.95 mol) and THF (50 mL). The reaction mixture was cooled to 0° C. The internal temperature was maintained at ≦1° C. LiHMDS (lithium bis(trimethylsilyl)amide) (1 L of a 1.0 M solution in THF, 1 mol) was added via an addition funnel at a rate such that the elution rate was 100%. After the addition was complete, hexane (235 mL) was added in a steady stream via the addition funnel and stirred for 15 minutes. The resulting solid was collected by filtration, washed with hexane (3×400 mL), and dried to give the title compound. Synthesis of ethyl 2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (3): The reactor was charged with lithium 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethane-1-olate (177.2 g, 0.89 mol) and EtOH (ethanol) (779 mL). The temperature was brought to 0° C. and maintained at 0° C. HCl in dioxane (4.0 N, 443 mL) was added via an addition funnel, followed by solid ethyl hydrazinoacetate HCl salt (138.4 g, 0.90 mol). The reaction temperature was adjusted to 35° C. After 1 h, the reaction volume was reduced by approximately 40% by distillation under reduced pressure. With vigorous stirring, water (1.3 L) was added and the temperature was adjusted to 15° C. The resulting solid was collected by filtration, washed with water (3×500 mL), hexane (3×400 mL), and dried to give the title compound. MS(m / z)275.1[M+H] + . Synthesis of ethyl 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (4): A reactor was charged with ethyl 2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (291.2 g, 1.06 mol), acetonitrile (1.65 L) and water (825 mL) to which was added N-hydroxyphthalimide (17.4 g, 0.103 mol) and NaClO2 (41.0 g, 0.45 mol, approximately 20% of the total amount added). The reaction mixture was heated to 50° C. and the remaining NaClO2 (163.0 g, 1.80 mol) was added in five portions over 2 hours. After consumption of the starting material, the temperature was adjusted to 20° C. and aqueous sodium bisulfite (40% w / w, 350 mL) was added via an addition funnel. Ethyl acetate (1.75 L) was added and the layers were separated. The aqueous layer was back-extracted with EtOAc (ethyl acetate) (500 mL). The organic layers were combined and washed with saturated aqueous NaHCO3 (500 mL) and 1:1 water / brine (500 mL). The organic layers were concentrated under reduced pressure and co-evaporated with IPAc (isopropyl acetate) (300 mL). The crude solid was crystallized from a mixture of IPAc / heptane. The resulting solid was collected by filtration, washed with heptane, and dried to give the title compound. MS (m / z) 289.0 [M+H] + . Synthesis of 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (5): To a solution of ethyl 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (80.40 g, 278.95 mmol) in 2-MeTHF (2-methyltetrahydrofuran) (167 mL) was added 2 M aqueous sodium hydroxide (167 mL). After stirring at room temperature for 25 min, the reaction mixture was diluted with 2-MeTHF and slowly acidified by dropwise addition of concentrated HCl. The organic layer was isolated and the aqueous layer was extracted with an additional portion of 2-MeTHF. The combined organic layers were washed with saturated aqueous sodium chloride, then dried over sodium sulfate, filtered, and concentrated. The resulting oil was taken up in ethyl acetate. Hexane was added with vigorous stirring until solid formation was observed. The solid was isolated by filtration and dried to give the title compound. MS (m / z) 259.00 [MH] - . 2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropane[3,4 Synthesis of cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolane-1(3bH)-yl)acetic acid (6): To a solution of 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (3.0 g, 11.5 mmol) in DCM (dichloromethane) (25 mL) was added 1,2-ethanedithiol (1.07 mL, 12.68 mmol) followed by boron trifluoride-acetic acid complex (4.0 mL, 28.8 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added water (60 mL) and 2-MeTHF (60 mL). The organic layer was isolated, dried over sodium sulfate, filtered and concentrated. The crude was dissolved in ethyl acetate (2 mL) and the solution was diluted with hexane (12 mL) with vigorous stirring to obtain a solid. The solid was isolated by filtration and dried to obtain the title compound. MS(m / z) 337.12[M+H] + . Synthesis of 2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (7): To a suspension of 1,3-dibromo-5,5-dimethylhydantoin (12.75 g, 44.6 mmol) in DCM (35 mL) was added pyridine hydrogen fluoride (5.0 mL) at 0° C. The suspension was stirred at 0° C. for 10 min. To the suspension was added a solution of 2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)acetic acid (5.00 g, 14.9 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at 0° C. for an additional 15 min. With vigorous stirring, the reaction mixture was poured into saturated aqueous sodium bicarbonate (300 mL). The organic layer was removed and the aqueous layer was acidified to pH ∼1 with concentrated HCl. The aqueous phase was extracted with three portions of MTBE (methyl tert-butyl ether). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Any formed solids were removed by taking up the solids in MTBE (16 mL) and filtering. The solution was then extracted with 2N NaOH (16 mL). With vigorous stirring, the aqueous layer was diluted with water (16 mL) and stirred at room temperature for 15 minutes. The formed solids were removed by filtration. With vigorous stirring, the aqueous layer was acidified to pH approx. 1 by slow dropwise addition of concentrated HCl to give a solid precipitate. The solid was isolated by filtration to give the title compound. MS (m / z) 281.12 [M+H] + . Synthesis of 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (8a) and 2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (8b): 2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid was separated into its component enantiomers, the title compounds, by chiral SFC under the following conditions: Apparatus: Thar350 preparative SFC; Column: ChiralPak IC-10u, 300×50mm I.D; Mobile phase: 35% isopropanol (0.1% NH3·H2O) and CO2; Flow rate: 200mL / min; Column temperature: 38℃; UV detection: 220nm; Sample preparation: Compounds were dissolved in isopropanol to approximately 45mg / mL; Injection: 6.5mL per injection. Analytical SFC [Mobile phase: A for CO2 and B for isopropanol (0.05% DEA); Gradient: B 20%; A; Flow rate: 2.35mL / min; Column: Chiralpak IC-3, 150×4.6mm, 3um; Wavelength: 254nm] 8a: t=3.39min, 8b: t=2.17min. Compound 8a- 1 H NMR (400 MHz, chloroform-d) δ 4.93 (s, 2H), 2.52 - 2.43 (m, 2H), 1.44 - 1.3 8 (m, 1H), 1.15 (m, 1H). Example 2 [ka] Synthesis of 7-bromo-4-chloro-1H-indazol-3-amine (10): To 3-bromo-6-chloro-2-fluorobenzonitrile (13.9 g, 59.3 mmol) in EtOH (ethanol) (60 mL) was added hydrazine monohydrate (5.77 mL). The reaction mixture was heated to 80° C. for 3 h. After cooling to ambient temperature, EtOH (20 mL) was added and stirred. The solid was isolated by filtration, washed with cold EtOH, and dried to give the title compound. MS (m / z) 247.9 [M+H] + . Synthesis of 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (11): A reactor was charged with 7-bromo-4-chloro-1H-indazol-3-amine (397.2 g, 1.6 mol) and Cs2CO3 (1052 g, 3.2 mol) and then diluted with DMF (dimethylformamide) (4000 mL). To this was slowly added 2,2,2-trifluoroethyl trifluoromethanesulfonate (463.2 g, 1.9 mol) via a dropping funnel. Once the addition was complete, the reaction mixture was stirred for 1 h, at which point H2O (16 L) was slowly added. Once the addition was complete, the mixture was stirred at 15° C. for 12 h. The slurry was filtered and the collected solid was suspended in DMF (800 mL). To this was added H2O (4800 mL) and the resulting solid was collected by filtration and dried to give the title compound. MS (m / z) 330.1 [M+H] + . Synthesis of 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (12): A reaction vessel was charged with 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (15.00 g, 45.66 mmol), bis(pinacolato)diboron (17.39 g, 68.49 mmol), potassium propionate (15.36 g, 136.98 mmol), dioxane (90 mL) and DMF (dimethylformamide) (30 mL). Bis(triphenylphosphine)palladium(II) dichloride (0.64 g, 0.91 mmol) was added and the reaction solution was degassed by bubbling argon for 2 minutes. The reaction mixture was heated to 105° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was filtered through a pad of Celite and the silica gel was washed with EtOAc. The filtrate was washed with 5% LiCl solution and brine. The organic layer was separated, dried and concentrated under reduced pressure. The residue was treated with IPAc / heptane (1 / 10) at 60° C., then cooled to ambient temperature and stirred for 15 h. The solid was collected by filtration and dried to yield the title compound. MS (m / z) 376.7 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, 1H), 7.0 6 (d, 1H), 5.55 (s, 2H), 5.45 (q, 2H), 1.32 (s, 12H). Example 3 [ka] Synthesis of 3-methyl-3-(methylsulfonyl)but-1-yne (14): To a stirred suspension of sodium methanesulfinate (18.47 g, 175.5 mmol) and copper(I) chloride (1.45 g, 14.6 mmol) in DMF (dimethylformamide) (50 mL) was added 3-chloro-3-methylbut-1-yne (15.00 g, 146.3 mmol, 16.4 mL) dropwise. The resulting reaction mixture was heated to 40° C. and stirred for 16 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The solution was washed with water and brine. The organic layer was collected, dried over sodium sulfate, and then filtered. The solution was concentrated under vacuum and purified by silica gel chromatography to give the title compound. Mp: 114.8-115.5° C. 1 H NMR (400 MHz, chloroform-d) δ 3.04 (s, 3H), 2.58 (s, 1H), 1.67 (s, 6H). Example 4 [ka] Synthesis of (S)-N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (16): 3,6-Dibromopicolinaldehyde (76.0 g, 0.287 mol) and (S)-2-methylpropane-2-sulfinamide (36.51 g, 0.301 mol) were combined in NMP (N-methyl-2-pyrrolidone) (200 mL). Cs2CO3 (41.94 g, 0.316 mol) was added as a solid in one portion to the reaction mixture. The reaction mixture was stirred for 2 h and then cooled to 5° C. Water (1.3 L) was added to the reaction mixture. The resulting suspension was stirred for 1 h and the solid was isolated by filtration, washed with water (5×100 mL) and dried to give the title compound. MS (m / z) 368.9 [M+H] + . Synthesis of (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (17): A reaction vessel was charged with (S)-N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (65.5 g, 177.95 mmol), followed by DMF (dimethylformamide) (260 mL). The mixture was stirred for 5 minutes until homogenous and the solution was cooled to 8° C. To the reaction mixture was added (3,5-difluorobenzyl)zinc bromide (0.5 M in THF (tetrahydrofuran), 516.04 mL) dropwise over 90 minutes. The mixture was stirred for an additional 2.5 hours. To the reaction mixture was added 5% AcOH (acetic acid) in water (640 mL) over 10 minutes, followed by CPME (cyclopentyl methyl ether) (320 mL) in one portion. The mixture was stirred for 5 minutes, warmed to room temperature, and the layers were separated. The organic layer was washed with 5% AcOH (320 mL), then treated with 0.5 M NaOH (330 mL) and washed with brine. The organic layer was collected, dried over Na2SO4, and filtered. To the crude mixture was added MeOH (methanol) (33 mL). To the stirred mixture was added 3 M HCl in CPME (128 mL) dropwise over 15 min. After stirring for 1 h, the precipitate was removed by filtration. The filtrate was diluted with hexanes (300 mL) and the product was extracted with water (450 mL). The aqueous layer was basified with 8 M NaOH and extracted with CPME (375 mL). The organic layer was washed with brine, dried over Na2SO4, and filtered to give the title compound in solution, which was used directly in the next reaction. MS (m / z) 497.0 [M+H] + . Synthesis of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (18): The resulting solution of (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide was diluted to a volume of 700 mL with CPME, to which acetonitrile (350 mL) was added. To the stirred mixture was added concentrated HCl (37%, 16.4 mL) dropwise over 10 minutes at room temperature. The thick slurry was stirred vigorously for 4 hours. The solid was filtered and washed with 2:1 CPME (cyclopropyl methyl ether):ACN to give the title compound. MS (m / z) 393.3 [M+H] + . Synthesis of tert-butyl (S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (19): A reaction vessel was charged with 2-MeTHF (190 mL), water (190 mL) and (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (46.9 g, 0.11 mol), followed by portionwise addition of NaHCO3 (30.34 g, 0.36 mol). The reaction mixture was cooled to 5° C. and di-tert-butyl dicarbonate (27.47 g, 0.13 mol) was added. The reaction mixture was stirred at 0° C. for 2 h and at ambient temperature for 2 h. The reaction mixture was diluted with water and extracted with MTBE (methyl tert-butyl ether). The organic layer was washed with brine, dried and concentrated. The crude compound was purified by column chromatography on silica to give the title compound. MS (m / z) 492.8 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.85 (d, 1H), 7.42 (d, 1H), 6.90 - 6.72 (m, 3H), 5.33 (dd, 1H), 3.10 (dd, 1H), 2.92 (dd, 1H), 1.36 (s, 9H). Example 5 [ka] Synthesis of tert-butyl (S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (20) A reactor was charged with tert-butyl (S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (50.00 g, 101.8 mmol), 3-methyl-3-methylsulfonyl-but-1-yne (17.86 g, 122.2 mmol), DMF (dimethylformamide) (90 mL) and Et3N (trimethylamine) (42.5 mL, 305.4 mmol). The reaction mixture was heated to 50° C. Bis(triphenylphosphine)palladium(II) dichloride (2.14 g, 3.1 mmol) and copper(I) iodide (0.58 g, 3.1 mmol) were added. After 30 min, the reaction mixture was diluted with MeCN (acetonitrile) (200 mL) and then 7% aqueous NH4Cl (200 mL) was added dropwise. A slurry was formed and allowed to warm to ambient temperature. After 3 hours, the solid was collected by filtration. The cake was washed twice with MeCN / water (1:1, 75 mL) and with MTBE (methyl tert-butyl ether) (75 mL). The solid was dried to give the title compound. MS (m / z) 556 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 8.2 Hz, 1H), 7.29 - 7.15 (m, 1H), 6.70 - 6.55 (m, 2H), 5.79 (d, J = 9.0 Hz , 1H), 5.57 - 5.45 (m, 1H), 3.21 - 3.05 (m, 4H), 2.99 - 2.88 (m, 1H), 1.80 (s, 6H), 1.40* (s, 7H), 1.30* (s, 2H). * denotes the presence of atropisomers in a ratio of 4.6:1. Synthesis of tert-butyl (S)-(1-(3-(3-amino-4-chloro-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)carbamate (21): tert-Butyl (S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (1000.0 mg, 1.79 mmol), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (808.5 mg, 2.15 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65.6 mg, 0.09 mmol), and cesium carbonate (876.7 mg, 2.69 mmol) were placed in a round-bottom flask and placed under argon. Dioxane (10 mL) and water (2 mL) were added and the suspension was degassed by bubbling argon for 60 seconds. After degassing, the reaction flask was fitted with a reflux condenser and heated to 80° C. overnight. The reaction mixture was cooled to room temperature and the aqueous layer was removed. The organic layer was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to give the title compound. MS (m / z) 726.1 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 7.69 - 7.55 (m), 7.55 - 7.42 (m), 7.16 - 7.06 (m), 7.07 - 6.96 (m), 6.89 (d), 6.60 (tt), 6.44 (dd), 6.20 (d), 6.16 (d), 6.08 (s), 5.69 - 5.53 (m), 5.29 (s), 5.26 (d), 4.95 - 4.85 (m), 4.64 (q), 4.59 - 4.46 (m), 4.36 - 4.19 (m), 3.94 - 3.76 (m), 3.64 - 3.54 (m), 3.18 (s), 3.17 (s), 3.01 - 2.84 (m), 2.78 - 2.68 (m), 1.86 - 1.82 (m), 1.38 (s), 1.34 (s), 1.26 (s), 1.23 (s), 1.15 (s). Synthesis of tert-butyl (S)-(1-(3-(4-chloro-3-(N-(methylsulfonyl)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)carbamate (22): tert-Butyl (S)-(1-(3-(3-amino-4-chloro-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)carbamate (37.89 g, 52.18 mmol) was dissolved in methylene chloride (380 mL) with stirring at ambient temperature. To this was added triethylamine (21.82 mL, 156.54 mmol) followed by slow addition of methanesulfonyl chloride (8.08 mL, 104.36 mmol). Upon completion of the reaction, water (200 mL) was added and stirred for 0.5 hours. The organic layer was separated and the aqueous layer was extracted once with methylene chloride. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to a small volume. Hexanes was added. The liquid suspension was decanted. The remaining solid was dried under reduced pressure to give the title compound. MS(m / z): 882.69[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.87 (d), 7.83 (d), 7.76 (s), 7.74 (s), 7 .69 (s), 7.67 (s), 7.65 (s), 7.52 - 7.47 (m), 7.46 (s), 7.37 (d), 7.33 (d), 7.11 - 7.03 (m), 4.79 - 4.55 (m), 4.51 (t), 4.36 (dt), 4.20 - 4.05 (m), 3.64 (s), 3.62 (s), 3.60 (s), 3.59 (s), 3.23 (s), 3.04 (d), 3.01 (d), 2.95 - 2.83 (m), 1.81 (s), 1.34 (s), 1.29 (s), 0.98 (s). Synthesis of (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide (23): To tert-butyl (S)-(1-(3-(4-chloro-3-(N-(methylsulfonyl)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)carbamate (39 g, 44 mmol) dissolved in methylene chloride (120 mL) was added trifluoroacetic acid (80 mL). The reaction mixture was stirred at ambient temperature for 50 min. The reaction mixture was diluted with methylene chloride and poured slowly into ice-cold saturated aqueous NaHCO3. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give the title compound. MS (m / z): 782.84 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.61 (d), 7.54 - 7.44 (m), 7.40 (d), 7.33 (d), 7.20 (d), 6.66 - 6.57 (m), 6.44 (d), 6.33 (d), 6.17 (d), 4.64 (s), 3.68 (s), 3.64 (s), 3.61 (s), 3.55 (s), 3.19 (s), 3.05 (dd), 2.85 - 2.72 (m), 1.86 (s), 1.62 (s). Synthesis of N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (24): (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide (1757 mg, 2.25 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)- 3b,4,4a,5-Tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (666 mg, 2.36 mmol), and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (854 mg, 2.25 mmol) were placed in a round-bottom flask and dissolved in DMF (dimethylformamide) (10.0 mL). To this solution, N,N-diisopropylethylamine (0.80 mL, 4.49 mmol) was added at a rapid dropwise rate. After the addition was complete, the reaction mixture was stirred at room temperature for 15 min to give intermediate 23b, which was not isolated (MS (m / z) 1046.65 [M+H] + To this solution was added 2N aqueous sodium hydroxide solution (5.0 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected and washed with two portions of 5% lithium chloride solution (with two portions of ethyl acetate). Portions of 5% lithium chloride solution n) followed by a wash with brine. The organic layer was isolated, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give the title compound as an amorphous solid. MS(m / z) 968.24[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.87 - 7.57 (m), 7.33 - 7.09 (m), 6.80 - 6.70 (m), 6.54 (d), 6.47 (d), 6.37 - 6.19 (m), 5.02-4.94(m), 4.90 - 4.70 (m), 4.70 - 4.51 (m), 3.94 (dq), 3.32-3.28 (m), 3.23 (d), 3.07 (dd, J = 13.1, 7.6 Hz), 2.93 (dd), 2.68 - 2.35 (m), 1.81 (s), 1.41 (q), 1.12 - 1.00 (m). 19 F NMR (377 MHz, methanol-d4) δ -63.65, -71.78 (t), -72.35 (t), -82.75 (dd), -105.70 (ddd), -111.73 - -113.10 (m). In order to more fully characterize 23b, the compound was isolated. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d), 8.99 (d), 7.96 (d), 7.83 (d), 7.80 (d), 7.76 (d), 7.45 (d), 7.41 (d), 7.31 (d), 7.02 (tt), 6.92 (m), 6.91 (d), 6.48 (m), 4.92 (m) 4.88 (d), 4.79 (d), 4.73 (d), 4.71 (m), 4.69 (m), 4.62 (m), 4.60 (m), 4.38 (dq), 4.12 (dq), 3.68 (s), 3.66 (s), 3.63 (s), 3.58 (s), 3.26 (s), 3.12 (dd), 3.05 (dd), 2.97 (dd), 2.78 (dd), 2.59 (m), 2.53 (m), 1.75 (s), 1.39 (m), 0.98 (m). Preparation of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (32) Example 6 [ka] Synthesis of lithium 2,2-difluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethane-1-olate (25): The title compound was prepared following the method presented for the synthesis of compound 2 utilizing ethyl 2,2-difluoroacetate. 1 H NMR (400 MHz, CDCl3) δ 6.17 (t, J = 53.6 Hz, 1H), 2.78-2.73 (m, 1H), 2.44-2.39 (m, 1H), 2.25-2.24 (m, 1H), 1.70-1.69 (m, 1H), 1.22-1.14 (m, 1H), 0.31-0.27 (m, 1H). Synthesis of sodium 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (26): Me-THF (1.32 L) was added to a 4 L reactor followed by lithium 2,2-difluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethane-1-olate (247 g, 1.32 mol). HCl (4N in dioxane) (0.685 L, 2.74 mol) was added slowly to the mixture while maintaining the internal temperature around 20° C. After addition of ethyl hydrazinoacetate hydrochloride (212.05 g, 1.372 mol), the resulting mixture was stirred at 20° C. for 4 hours. The reaction mixture was heated to 50° C. overnight. 10 N aqueous NaOH (0.548 L, 5.48 mol) was added slowly to the reaction mixture while maintaining the internal temperature at 20° C. After addition, 300 ml of MeTHF was added and the resulting suspension was stirred at 20° C. for 3 hours. The suspension was drained and filtered. The filter cake was washed with hexane (1 L) and dried in a vacuum oven at 56° C. to give the title compound, which was used directly in the next step. MS (m / z) 229.1 [M-Na+H] + . Ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclohexyl Synthesis of cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (27): Ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate from the previous step was charged to a 4 L reactor, followed by EtOH (3.5 L) and concentrated H2SO4 (152 ml. 2.74 mol). The resulting mixture was stirred under reflux for 2 h. EtOH was reduced to 150 ml under vacuum. H2O (500 ml) was added slowly. The solid was collected and washed with H2O and NaHCO3 followed by hexane (500 ml). The solid was dried in an oven at 45 °C to give the title compound. MS (m / z) 257.1 [M+H] + . Synthesis of ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (28): The title compound was prepared following the method presented for the synthesis of compound 4 utilizing ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate. MS (m / z) 271.1 [M+H] + . Synthesis of ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolane]-1(3bH)-yl)acetate (29): To ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (148.5 g, 0.55 mol) in DCM (2.0 L) was added ethane-1,2-dithiol (88.0 g, 0.94 mol) in one portion, followed by BF3·2AcOH (175.8 g, 0.94 mol). The reaction was stirred at room temperature for 12 h. The system was cooled to 0° C. and quenched with saturated aqueous NaHCO3 (1000 ml). The organic layer was separated, washed with brine (500 ml) and dried over Na2SO4. The solvent was removed in vacuum and the residue was purified by silica gel column chromatography to give the title compound. MS(m / z): 347.1 [M+H] + . Synthesis of ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (30): A solution of DBDMH (99 g, 0.35 mol) in DCM (120 mL) was cooled to -8 °C in a Teflon bottle. HF / Py (120 mL) was added dropwise over 30 min. The reaction was stirred at -78 °C for 30 min. A solution of ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolane]-1(3bH)-yl)acetate (40 g, 0.12 mol) in DCM (80 mL) was added dropwise over 15 min at -78 °C. The resulting mixture was stirred for 30 min, then slowly warmed to -30 °C and stirred for 1.5 h. The reaction mixture was slowly poured into aqueous NaHCO3 (500 mL) and extracted with EA (500 mL x 3). The combined organic layers were washed with 10% aqueous Na2S2O3 (500 mL), brine (500 mL) and dried over Na2SO4. The solvent was removed in vacuo to give the crude product, which was further purified by column chromatography to give the title compound. MS (m / z): 293.2 [M+H] + . 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)acetate (31a) and ethyl 2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl ) Isolation of acetate (31b): Ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate was separated into its component enantiomers, the title compounds, by chiral HPLC under the following conditions: Column: ChiralPak AD; Mobile phase: Hex / 3C EtOH=95 / 5; Room temperature; UV detection: 250 nm. Analytical HPLC [Mobile phase: Hex / 3C EtOH=95 / 5; Flow rate: 0.75 mL / min; Column: Chiralpak AD-H, 150×4.6 mm, 5 um; Wavelength: 220 nm] 31a: t=5.30 min, 31b: t=7.00 min. Compound 31a- 1 H NMR (400 MHz, chloroform-d) δ 6.63 (t, J = 54.8 Hz, 1H), 4.83 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 2.48-2.45 (m, 2H), 1.38-1.36 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.13-1.12 (m, 1H). Synthesis of 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (32): To a solution of 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)acetate (26 g, 89.0 mmol) in THF (180 mL), MeOH (90 mL) and water (90 mL) was added LiOH (5.13 g, 213.5 mmol). The mixture was stirred for 4 h. The mixture was concentrated to remove most of the THF and MeOH, and the aqueous was acidified by adjusting the pH to 2-3 with 1N HCl, then extracted with EA (600 mL x 2). The organic phases were separated, combined, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. MS (m / z) 265.0 [M+H]+ . Example 7 [ka] Synthesis of 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine (33): A 2000 mL 4-neck round bottom flask was charged with 7-bromo-4-chloro-1H-indazol-3-amine (130 g, 527.40 mmol, 1.00 equiv), N,N-dimethylformamide (1300 mL), Cs2CO3 (260 g, 797.99 mmol, 1.50 equiv) and stirred for 20 min, followed by the addition of 1,1-difluoro-2-iodoethane (122 g, 635.59 mmol, 1.20 equiv). The resulting mixture was stirred at 65° C. overnight, then cooled to room temperature and quenched by the addition of 3 L water / ice and extracted with 3×1.5 L ethyl acetate. The combined organic layers were washed with 1×1.5 L HO, 1×1.5 L brine, dried over anhydrous sodium sulfate, concentrated under vacuum, and recrystallized from ethanol to give the title compound. MS(m / z) 312.1[M+H] + . Synthesis of 4-chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (34): A 3000 mL 4-neck round bottom flask purged with and maintained under an inert atmosphere of nitrogen was charged with 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine (80 g, 257.63 mmol, 1.00 equiv), 1,4-dioxane (800 mL), N,N-dimethylformamide (800 mL), KOAc (76 g, 774.40 mmol, 3.00 equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (197 g, 775.78 mmol, 3.00 equiv), and Pd(PPh3)2Cl2 (8 g, 11.40 mmol, 0.04 equiv). The mixture was stirred at 110° C. for 4 h, then cooled to room temperature, quenched by addition of 5 L water / ice, and extracted with 2×2 L ethyl acetate. The combined organic layers were washed with 1×1 L H2O, 1×1 L brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied to a silica gel column and eluted with ethyl acetate / petroleum ether (1:10) to give the title compound. MS (m / z): 358 [M+H] + . 1 H-NMR: (DMSO-d6, 300MHz, ppm): δ7.63-7.66 (1H, d), 7.00-7.03 (1H, d), 6.06-6.43 (1H, t), 5.46 (2H, s), 4.90-5.01 (2H, t), 1.34 (12H, s). Example 8 [ka] Synthesis of tert-butyl (S)-(1-(3-(3-amino-4-chloro-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)carbamate (35): tert-Butyl (S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (300 mg, 0.53 mmol), 4-chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (250 mg, 0.7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.016 mmol), and potassium carbonate (186 mg, 1.35 mmol) were placed in a microwave tube, which was placed under argon. Dimethoxyethane (2.5 mL) and water (0.3 mL) were added and the reaction mixture was heated to 130° C. for 7 min in a microwave reactor (Biotage® Initiator+). The reaction mixture was cooled to room temperature and partitioned between EtOAc and 0.1N HCl. The aqueous layer was removed and the organic layer was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give the title compound. MS (m / z) 708.20 [M+H] + ). 1 H NMR (400 MHz, methanol-d4) δ 7.91 - 7.50 (m), 7.28 - 6.89 (m), 6.88 - 6.65 (m), 6.56 (dd), 6.46 - 6.17 (m), 6.08 - 5.60 (m), 4.76 - 4.47 (m), 4.04 - 3.73 (m), 3.73 - 3.41 (m), 3.22 (s), 3.17 - 2.69 (m), 1.80 (s), 1.29 (d), 0.98 (d). Synthesis of tert-butyl (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)carbamate (36): tert-Butyl (S)-(1-(3-(3-amino-4-chloro-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)carbamate (700 mg, 0.99 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol) were dissolved in pyridine (2 mL) with stirring at ambient temperature. To this was added cyclopropane-1-sulfonyl chloride (222 μL, 2.2 mmol). The reaction mixture was stirred at 70° C. until the reaction was complete. Water was added and stirred for 1 h, the resulting precipitate was collected by vacuum filtration, then dissolved in methylene chloride, dried over MgSO4, filtered and concentrated. The residue was purified by silica chromatography to give the title compound. MS(m / z):812.44[M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.93 - 7.58 (m), 7.50 - 7.15 (m), 7.00 (dd), 6.82 - 6.51 (m), 6.47 - 6.29 (m), 6.18 - 5.65 (m), 4.77 - 4.43 (m), 4.31 - 4.08 (m), 3.99 - 3.63 (m), 3.22 (s), 3.18 - 2.71 (m), 1.80 (s), 1.28 (s), 1.20 - 0.76 (m). Synthesis of (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (37): To a solution of tert-butyl (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)carbamate (705 mg, 0.87 mmol) in methylene chloride (5 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred for 1 h and then slowly poured into saturated sodium bicarbonate solution. It was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to give the title compound. MS (m / z): 712.34 [M+H]+. 1 H NMR (400 MHz, methanol-d4) δ 7.93 - 7.58 (m), 7.50 - 7.15 (m), 7.00 (dd), 6.82 - 6.51 (m), 6.47 - 6.29 (m), 6.18 - 5.65 (m), 4.77 - 4.43 (m), 4.31 - 4.08 (m), 3.99 - 3.63 (m), 3.22 (d), 3.18 - 2.71 (m), 1.80 (d), 1.28 (s), 1.20 - 0.76 (m). 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)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane Synthesis of ba[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (38): (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (514 mg, 0.72 mmol), 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluorophenyl) Luoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (191 mg, 0.72 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) were placed in a round-bottom flask and dissolved in DMF (10 mL). n-Methylmorpholine (0.20 mL, 1.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min. Water was added and stirred for 1 h. The resulting precipitate was collected by vacuum filtration, then dissolved in methylene chloride, dried over MgSO4, filtered and concentrated. The residue was purified by RP-HPLC to give the title compound as a TFA salt. MS (m / z) 958.88 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 7.90 - 7.56 (m), 7.30 - 7.07 (m), 6.91 - 6.54 (m), 6.54 - 6.39 (m), 6.37 - 6.21 (m), 6.16 - 5.70 (m), 4.85 - 4.57 (m), 4.34 - 4.12 (m), 3.87 - 3.41 (m), 3.23 (s), 3.17 - 3.02 (m), 3.00 - 2.77 (m), 2.57 - 2.37 (m), 1.81 (s), 1.50 - 0.84 (m). Biological Examples Example A Test A: Antiviral assay in MT4 cells For antiviral assays, 0.4 μL of 189× test concentration of 3-fold serially diluted compounds in DMSO were added in quadruplicate (10 concentrations) to 40 μL of cell growth medium (RPMI1640, 10% FBS, 1% penicillin-streptomycin, 1% L-glutamine, 1% HEPES) in each well of a 384-well plate. A 1 mL aliquot of MT4 cells was pre-infected with 25 μL of cell growth medium (mock infection) or a fresh 1:250 dilution of HIV-IIIb concentrated ABI stock (0.004 moi) for 3 h at 37° C. Infected and uninfected cells were diluted in cell growth medium and 35 μL (2000 cells) was added to each well of the assay plate. The assay plates were then maintained at 37°C in a humidified, 5% CO2 incubator. After 5 days of incubation, 25 μl of 2× concentrated CellTiter-Glo™ Reagent (catalog #G7573, Promega Biosciences, Inc., Madison, WI) was added to each well of the assay plate. Cell lysis was performed by incubating at room temperature for 10 min, and then chemiluminescence was read using an Envision plate reader (PerkinElmer). EC50 was determined as the compound concentration that caused a 50% reduction in luminescent signal, a measure of HIV-1 replication. 50 The value was calculated. Example B Test B: Cytotoxicity assay The same protocol as described in the antiviral assay (Test A) was used to determine the cytotoxicity of compounds and the corresponding CCs. 50 value was determined. Compounds of the present disclosure demonstrate antiviral activity (Test A) as shown in the table below, in comparison to Compound A and Compound B. [Table 1-1] [Table 1-2] Example C Study C. Pharmacokinetic analysis following intravenous administration to Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys Test articles and formulations IV doses of Compounds 24 and 38 were formulated at 0.5 mg / mL in 5% ethanol, 20% PG, 45% PEG300, 30% water (0.01N HCl) at pH 2. Intravenous doses of Compound A and Compound B were formulated at 0.5 mg / mL in a sterile solution of 5% ethanol, 45% PEG400, and 50% water (pH 2.0). All IV formulations were in solution. Animals used Each rat IV dosing group consisted of three male SD rats. At the time of dosing, animals generally weighed between 0.317-0.355 kg. Animals were fasted overnight prior to dose administration and for up to 4 hours after dosing. Each dog IV dosing group consisted of three male naive beagle dogs. At the time of dosing, animals weighed approximately 10-12 kg. Animals were fasted overnight prior to dose administration and for up to 2 hours after dosing. Each IV dosing group of cyno monkeys consisted of three male, naive cyno monkeys. At the time of dosing, animals weighed approximately 3.2-4 kg. Animals were fasted overnight prior to dose administration and for up to 2 hours after dosing. dosage For the IV infusion group, the test compound was administered by intravenous infusion over 30 minutes, with the infusion rate adjusted according to the body weight of each animal to deliver a dose of 1 mg / kg at 2 mL / kg. Sample collection At specified time points after dosing, serial venous blood samples (approximately 0.4 mL for rats and 1.0 mL for dogs, respectively) were collected from each animal. Blood samples were collected in Vacutainer™ tubes (Becton-Disckinson Corp, New Jersey, USA) containing EDTA as an anticoagulant, which were immediately placed on wet ice until centrifugation for plasma. Centrifugation was started within 1 hour of collection. All samples were placed in 96-well tubes and kept at approximately -70°C on dry ice before storage. Determination of Plasma Concentrations of Compound of Formula (I) Plasma concentrations of the test compounds were measured using an LC / MS / MS method. calculation Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. A summary of the pharmacokinetic parameters is shown in the table below. [Table 2] [Table 3] Example D Test D. Metabolic stability in cultured human liver hepatocytes Radiolabeled test compounds were prepared according to methods known in the art, in which tritium had been introduced into the structure in place of one or more hydrogens. Radiolabeled compounds were incubated in pooled cryopreserved hepatocytes at a substrate concentration of 0.25 μM and a radioactivity concentration of 10 uCi / mL. The final hepatocyte concentration was 1 million cells / mL. The hepatocyte / compound reaction mixture was dissolved in InVitroGRO™ KHB buffer (catalog #Z99074, BioreclamationIVT,Inc., Baltimore, MD) at pH 7.4. Incubations were performed in duplicate. A no-cell control and a positive control were included in the incubations. Incubations were performed with gentle shaking in a 37°C incubator in a humid atmosphere of 95% air / 5% CO2 (v / v). After 0, 1, 3, and 6 hours, aliquots (100 mL) were removed and added to 200 mL of quench solution containing 0.1% (v / v) TFA in 5% water / 95% acetonitrile (v / v). Samples were placed on a shaker for 10 minutes followed by centrifugation at 3000 g for 30 minutes. Supernatant samples were analyzed on a Dionex HPLC / PerkinElmer Flow Scintillation Analyzer as described below. Liquid chromatography-radiochromatography A Radiomatic 625TR Flow Scintillation Analyzer coupled to a Dionex / Chromeleon chromatography system. Quantitation was by comparison of radiolabeled metabolites to the parent peak, measured at 37 °C. The column was a Phenomenex Synergi fusion RP (150 × 4.6 mm, 4 mm) maintained at 32 °C. Mobile phase A consisted of 0.1% (v / v) TFA in 99% water / 1% acetonitrile (v / v). Mobile phase B consisted of 0.1% (v / v) TFA in 5% water / 95% acetonitrile (v / v). The flow rate was 1 mL / min using a sample injection volume of 100 mL. The gradient was as follows: mobile phase B was increased linearly from 37 °C to 75% over 47 min, held at 75% for 3 min, returned to 2% and held at 2% for 10 min. Metabolic stability was determined by measuring the relative abundance of metabolites and parent compound over time, and calculating the rate of elimination of the parent compound from this. Stability data was used to calculate predicted human liver clearance according to methods known in the art. Predicted human liver clearance is shown in the table below. [Table 4-1] [Table 4-2] From the above comparative data, the following can be inferred: Compound 24 is more potent in HIV antiviral assays compared to compounds A and B (about 9 and about 16 times more potent, respectively). Compound 24 has a longer terminal half-life in vivo in rats compared to compounds A and B (about 14 and about 9 times longer, respectively). Compound 24 has a lower clearance in vivo in rats compared to compounds A and B (about 10 and about 8.6 times lower, respectively). Compound 24 has a longer terminal half-life in vivo in dogs compared to compounds A and B (about 5 and about 4 times longer, respectively). Compound 24 has a lower clearance in vivo in dogs compared to compounds A and B (about 3 and about 4 times lower, respectively). Compound 24 is more stable in human hepatocytes with a lower predicted liver clearance compared to compounds A and B (about 9 and about 4 times more stable, respectively). The above data demonstrate that compound 24 has improved antiviral efficacy and an improved pharmacokinetic profile (demonstrated by a longer half-life in rats and dogs and lower predicted human clearance) when compared to compounds A and B. In addition, compound 38 is more potent in HIV antiviral assays compared to compounds A and B (about 4 and about 8 times more potent, respectively). Compound 38 has a longer terminal half-life in vivo in rats compared to compounds A and B (about 9.5 and about 6.3 times longer, respectively). Compound 38 has a lower clearance in vivo in rats compared to compounds A and B (about 6.3 and about 5.4 times lower, respectively). Compound 38 has a similar clearance and terminal half-life in vivo in dogs compared to compounds A and B. Compound 38 is more stable in human hepatocytes with a lower predicted liver clearance compared to compounds A and B (about 4.5 and about 2 times more stable, respectively). The above data demonstrate that compound 38 has improved antiviral efficacy and an improved pharmacokinetic profile (as demonstrated by a longer half-life in rats and dogs and a lower predicted human clearance) when compared to compounds A and B. Because the particular pharmacological response observed may vary according to, and depending on, the particular active compound or pharmaceutical carrier selected, whether or not present, as well as the type of formulation and mode of administration utilized, such expected variations or differences in results are contemplated in accordance with the practice of this disclosure. The examples disclosed herein describe the synthesis of the compounds disclosed herein as well as the intermediates used to prepare the compounds.It should be understood that the individual steps described herein can be combined.It should also be understood that separate batches of compounds can be combined and then carried forward in the next synthesis step. Examples of formulations Compound 38 (approximately 30 mg / kg) was formulated as an aqueous suspension in 2% poloxamer 338 in saline (approximately 150 mg / mL). This formulation was then administered as a single subcutaneous (SC) injection to rats to determine the pharmacokinetic (PK) profile. As seen in Figure 3, compound 38 maintains plasma concentrations well above the paEC95 for >10 weeks from a single SC injection. This data demonstrates that compound 38 exhibits sustained release pharmacokinetics. A suspension (200 mg / mL) of compound of formula Ib in 2% poloxamer 188 in saline was prepared. The suspension was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 4 shows a plot of the plasma concentration of compound of formula Ib as a function of time. As the data in Figure 4 shows, compound of formula Ib has measurable plasma concentrations at 70 days, demonstrating sustained release pharmacokinetics. A suspension (100 mg / mL) of the compound of formula Ib in 2% poloxamer 188 in saline was prepared. The suspension was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 5 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 5 shows, the compound of formula Ib has measurable plasma concentrations at 70 days, demonstrating sustained release pharmacokinetics. A suspension of the sodium salt of the compound of formula Ib (200 mg / mL) was prepared in 2% poloxamer 188 in saline. The suspension was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 6 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As Figure 6 shows, the compound of formula Ib has measurable plasma concentrations at 70 days, demonstrating sustained release pharmacokinetics. A solution of the compound of formula Ib in NMP (100 mg / mL) was prepared. The solution was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 7 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 7 shows, the compound of formula Ib has measurable plasma concentrations at 70 days, demonstrating sustained release pharmacokinetics. A solution of the compound of formula Ib in NMP (200 mg / ml) was prepared. The solution was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 8 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 8 shows, the compound of formula Ib has measurable plasma concentrations at 70 days, demonstrating sustained release pharmacokinetics. A solution of the sodium salt of the compound of formula Ib in NMP (200 mg / ml) was prepared. The solution was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 9 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 9 shows, the compound of formula Ib has measurable plasma concentrations at 70 days, demonstrating sustained release pharmacokinetics. A solution formulation (200mg / ml) of the compound of formula Ib was prepared in 10% ethanol, 12% water, and 78% PEG200. The solution was subcutaneously administered to dogs at a dose of 6mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 10 shows the plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 10 shows, the compound of formula Ib has measurable plasma concentrations at 28 days, demonstrating sustained release pharmacokinetics. A solution formulation containing 200 mg / mL of formula Ib in 10% ethanol, 12% water, and 77% PEG with 1.2 molar equivalents of NaOH is provided to form the sodium salt in situ. Subjects are orally dosed with 6 mg / kg of this formulation. A solution (200 mg / ml) of the compound of formula Ib in 10% ethanol, 12% water, and 7% PEG200 with 1.2 molar equivalents of NaOH is prepared to form the sodium salt in situ. The solution is administered subcutaneously to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) profile is determined. Figure 11 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 11 shows, the compound of formula Ib has measurable plasma concentrations at 28 days, demonstrating sustained release pharmacokinetics. A solution formulation (200mg / mL) of the compound of formula Ib was prepared in 10% ethanol, 13% water, and 77% glycofurol containing 1.2 molar equivalents of NaOH to form sodium salt in situ. The solution was administered subcutaneously to dogs at a dose of 6mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 12 shows the plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 12 shows, the compound of formula Ib has measurable plasma concentrations at 28 days, demonstrating sustained release pharmacokinetics. Examples of oral formulations

[0264] An oral formulation containing the compound of formula Ib in 10% ethanol, 20% Vitamin E TPGS, and 70% MIGLYOL 812 was prepared in a hard gelatin capsule. A fixed dose of 7.5 mg of the compound of formula Ib was given orally to dogs to determine the pharmacokinetic (PK) profile. Figure 13 shows the change in plasma concentration of the compound of formula Ib over time. All references, including publications, patents, and patent documents, are incorporated herein by reference as if individually incorporated by reference. This disclosure provides references to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of this disclosure.

[0265] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds of formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof. (Section 2) Compound of formula (Ib) [ka] or a pharma- ceutically acceptable salt thereof. (Section 3) A pharmaceutical composition comprising a therapeutically effective amount of the compound according to item 1 or 2 above, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. (Section 4) The pharmaceutical composition according to item 3, further comprising one, two, three, or four additional therapeutic agents. The additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 The pharmaceutical composition according to item 4, wherein the pharmaceutical composition is selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof. (Section 6) The additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any of these. 5. The pharmaceutical composition according to item 4, wherein the combination is selected from the group consisting of: (Section 7) 7. The pharmaceutical composition according to any one of items 4 to 6, wherein the additional therapeutic agent is selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate. (Section 8) 8. The pharmaceutical composition according to any one of items 4 to 7, wherein the additional therapeutic agent is selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate. (Section 9) A method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the compound according to item 1 or 2 above, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. (Section 10) 10. The method according to claim 9, comprising administering the compound, or a pharma- ceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents. (Section 11) The additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 The method according to claim 10, wherein the therapeutic agent is selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof. (Section 12) 12. The method of claim 10 or 11, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combination thereof. (Section 13) The additional therapeutic agent is abacavir sulfate, tenofovir, tenofovir disoproxil, 13. The method according to any one of items 10 to 12, wherein the active ingredient is selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate. (Section 14) 14. The method according to any one of claims 10 to 13, wherein the additional therapeutic agent is selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate. (Section 15) 3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt thereof, for use in therapy. (Section 16) 3. The compound according to item 1 or 2, or a pharma- ceutical acceptable salt thereof, for use in a method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the compound to a subject in need thereof. (Section 17) 17. The compound for use according to claim 16, wherein the method comprises administering 1, 2, 3 or 4 additional therapeutic agents. (Section 18) The compound for use according to the above clause 17, wherein said additional therapeutic agent is administered simultaneously with said compound of formula (Ia) or (Ib), or a pharma- ceutically acceptable salt thereof. (Section 19) The compound for use according to the above clause 18, wherein said compound of formula (Ia) or (Ib) is combined with said additional therapeutic agent in a single dosage form for simultaneous administration. (Section 20) The compound for use according to the above clause 17, wherein said compound of formula (Ia) or (Ib) is administered and said additional therapeutic agent is administered sequentially. (Section 21) The additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 The compound for use according to the above item 17 is selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof. (Section 22) The compound for use according to the above item 17, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combination thereof. (Section 23) 18. The compound for use according to claim 17, in combination with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. (Section 24) The compound for use according to claim 17, in combination with tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate. (Item 25) The compound for use according to the above item 17, in combination with tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate. (Item 26) 18. The compound for use according to claim 17, in combination with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine. (Section 27) 18. The compound for use according to claim 17, in combination with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent which is emtricitabine. (Section 28) 18. The compound for use according to claim 17, in combination with a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent which is emtricitabine. (Section 29) 7. The pharmaceutical composition according to any one of items 4 to 6, wherein the additional therapeutic agent is 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, or a pharma- ceutically acceptable salt thereof. (Section 30) 13. The method according to any one of claims 10 to 12, comprising administering the compound, or a pharma- ceutically acceptable salt thereof, in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, or a pharma- ceutically acceptable salt thereof. (Section 31) 23. The compound for use according to any one of claims 17 to 22 above, in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, or a pharma- ceutically acceptable salt thereof. (Section 32) Compound of formula (IIa): [ka] or a pharma- ceutically acceptable salt thereof. (Section 33) Compound of formula (IIb) [ka] 33. The compound according to the above item 32, which is: (Section 34) 34. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to the above item 32 or 33, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient. (Section 35) 35. The pharmaceutical composition according to claim 34, further comprising one, two, three or four additional therapeutic agents. (Section 36) The additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, 36. The pharmaceutical composition according to claim 35, wherein the therapeutic agent is selected from the group consisting of an inhibitor, a TAT protein inhibitor, an HIV-1 Nef modulator, an Hck tyrosine kinase modulator, a mixed lineage kinase-3 (MLK-3) inhibitor, an HIV-1 splicing inhibitor, a Rev protein inhibitor, an integrin antagonist, a nuclear protein inhibitor, a splicing factor modulator, a COMM domain-containing protein 1 modulator, an HIV ribonuclease H inhibitor, a retrocyclin modulator, a CDK-9 inhibitor, a dendritic ICAM-3-binding nonintegrin 1 inhibitor, an HIV GAG protein inhibitor, an HIV POL protein inhibitor, a complement factor H modulator, an ubiquitin ligase inhibitor, a deoxycytidine kinase inhibitor, a cyclin-dependent kinase inhibitor, a proprotein convertase PC9 stimulator, an ATP-dependent RNA helicase DDX3X inhibitor, a reverse transcriptase priming complex inhibitor, a G6PD and NADH-oxidase inhibitor, a pharmacokinetic enhancer, an HIV gene therapy, and an HIV vaccine, or any combination thereof. (Section 37) 36. The pharmaceutical composition according to claim 35, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combination thereof. (Section 38) 38. The pharmaceutical composition according to any one of claims 35 to 37, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharma- ceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate. (Section 39) 39. The pharmaceutical composition according to any one of claims 35 to 38, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharma- ceutical acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate. (Section 40) A method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the compound according to item 32 or 33, or a pharma- ceutically acceptable salt thereof, to a subject in need thereof. (Section 41) 41. The method according to claim 40, comprising administering the compound, or a pharma- ceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents. (Section 42) The additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulator, Hck tyrosine kinase 42. The method according to claim 41, wherein the therapeutic agent is selected from the group consisting of kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof. (Section 43) 43. The method according to claim 41 or 42, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combination thereof. (Section 44) 44. The method of any one of claims 41 to 43, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharma- ceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate. (Section 45) 45. The method according to any one of claims 41 to 44, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharma- ceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate. (Section 46) 34. A compound according to claim 32 or 33, or a pharma- ceutically acceptable salt thereof, for use in therapy. (Section 47) 34. The compound according to claim 32 or 33, or a pharma- ceutically acceptable salt thereof, for use in a method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the compound to a subject in need thereof. (Section 48) 48. The compound for use according to claim 47, wherein said method comprises administering 1, 2, 3 or 4 additional therapeutic agents. (Section 49) 49. The compound for use according to claim 48, wherein said additional therapeutic agent is administered simultaneously with said compound of formula (IIa) or (IIb), or a pharma- ceutically acceptable salt thereof. (Section 50) 50. The compound for use according to claim 49, wherein said compound of formula (IIa) or (IIb) is combined with said additional therapeutic agent in a single dosage form for simultaneous administration. (Section 51) 49. The compound for use according to claim 48, wherein said compound of formula (IIa) or (IIb) is administered and said additional therapeutic agent is administered sequentially. (Section 52) The additional therapeutic agent may be a combination drug for HIV, another drug for treating HIV, H IV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 49. The compound for use according to claim 48, selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or any combination thereof. (Section 53) 49. The compound for use according to the above paragraph 48, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitor compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or any combination thereof. (Section 54) 49. The compound for use according to claim 48, in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharma- ceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. (Section 55) 49. The compound for use according to claim 48, in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharma- ceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate. (Section 56) 49. The compound for use according to claim 48, in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharma- ceutically acceptable salt thereof, tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate. (Section 57) a first additional therapeutic agent selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a first additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine. The compound for use according to claim 48, in combination with a second additional therapeutic agent selected from the group consisting of: 49. The compound for use according to claim 48, in combination with a first additional therapeutic agent selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent which is emtricitabine. (Section 59) 49. The compound for use according to claim 48, in combination with a first additional therapeutic agent selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent which is emtricitabine. (Section 60) 40. The pharmaceutical composition according to any one of items 3 to 8, 29, or 34 to 39, which is a parenteral formulation. (Section 61) 61. The parenteral formulation according to claim 60, wherein the parenteral formulation is administered subcutaneously to a subject in need thereof. (Section 62) Item 61. The parenteral formulation according to item 60, wherein the parenteral formulation is administered intramuscularly to a subject in need thereof. (Section 63) 63. A parenteral formulation according to any one of claims 60 to 62, comprising saline. (Section 64) 64. A parenteral formulation according to any one of claims 60 to 63, comprising a poloxamer. (Section 65) 65. The parenteral formulation according to claim 64, wherein the poloxamer is poloxamer 338. (Section 66) [ka] A compound selected from the group consisting of: (Section 67) [ka] A compound selected from the group consisting of: (Section 68) formula: [ka] Compound. (Section 69) 65. The parenteral formulation according to claim 64, wherein the poloxamer is poloxamer 188. (Section 70) 70. The parenteral formulation according to item 69, wherein the concentration of poloxamer 188 in the saline solution is about 1% to about 10%. (Section 71) 71. The parenteral formulation according to item 69 or 70, wherein the concentration of poloxamer 188 in the saline solution is about 1% to about 3%. (Section 72) 72. The parenteral formulation of claim 69, 70 or 71, wherein the concentration of poloxamer 188 in saline is about 2%. (Section 73) 63. A parenteral formulation according to any one of claims 60 to 62, comprising N-methyl-2-pyrrolidone. (Section 74) 63. A parenteral formulation according to any one of paragraphs 60 to 62, consisting essentially of N-methyl-2-pyrrolidone. (Section 75) 63. A parenteral formulation according to any one of paragraphs 60 to 62, comprising dimethylsulfoxide. (Section 76) 63. A parenteral formulation according to any one of paragraphs 60 to 62, consisting essentially of dimethylsulfoxide. (Section 77) 63. A parenteral formulation according to any one of paragraphs 60 to 62, comprising water. (Section 78) 78. A parenteral formulation according to any one of paragraphs 60 to 62 or 77, further comprising alcohol. (Section 79) 79. The parenteral formulation according to claim 78, wherein the alcohol is ethanol. (Section 80) 80. A parenteral formulation according to any one of paragraphs 60 to 62 or 77 to 79, further comprising polyethylene glycol. (Section 81) 81. The parenteral formulation of claim 80, wherein the polyethylene glycol has an average molecular weight of about 200 g / mol. (Section 82) 82. The parenteral formulation of any one of paragraphs 77 to 81, further comprising an inorganic base. (Section 83) 83. The parenteral formulation of claim 82, wherein the inorganic base is sodium hydroxide. (Section 84) About 5% to about 20% ethanol, about 5% to about 20% water, and about 60% to about 90% 84. A parenteral formulation according to any one of claims 60 to 62 and 77 to 83, comprising polyethylene glycol 200. (Section 85) 85. The parenteral formulation according to any one of items 60 to 62 and 77 to 84, comprising about 10% to about 15% ethanol, about 10% to about 15% water, and about 70% to about 80% polyethylene glycol 200. (Section 86) 86. The parenteral formulation according to paragraphs 60 to 62 and 77 to 85, comprising about 10% ethanol, about 12% water, and about 78% polyethylene glycol 200. (Section 87) 40. The pharmaceutical composition according to any one of items 3 to 8, 29, or 34 to 39, which is an oral formulation. (Section 88) 88. A formulation according to any one of clauses 60 to 65 and 69 to 87, wherein the compound is present as a sodium salt.

Claims

[Claim 1] HIV viral infection.

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