Therapeutic compounds useful for the preventive or therapeutic treatment of HIV virus infection.

Abstract

To provide novel compounds for use in the treatment of Retroviridae virus infections, including infections caused by the HIV virus. [Solution] This disclosure relates to compounds of formulas (Ia), (Ib), (IIa), and (IIb) that are useful for treating Retroviridae virus infections, including infections caused by the HIV virus. This disclosure relates to novel compounds. In addition, this disclosure also relates to intermediates for their preparation and pharmaceutical compositions containing the novel compounds.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 377,312 filed on 19 August 2016 and U.S. Provisional Application No. 62 / 457,555 filed on 10 February 2017, the disclosures thereof being invoked by reference in their entirety.

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

[0003] Positive single-stranded RNA viruses, including those belonging to the family Retroviridae, include viruses from the subfamily Orthoretrovirinae and the genera Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, and Spumavirus, which cause many diseases in humans and animals. Among Lentiviruses, HIV-1 infection in humans leads to T helper cell depletion and immune dysfunction, resulting in immunodeficiency and increased susceptibility to opportunistic infections. Treating HIV-1 infection with highly active antiretroviral therapy (HAART) has been proven effective in reducing viral load and significantly delaying disease progression (Hammer, SM et al., JAMA, 2008, Vol. 300: pp. 555-570). However, these treatments may lead to the emergence of HIV strains resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases). Diseases 2009, 13: 552-559; Smith, R. J. et al., Science 2010, 327: 697-701). Thus, there is an urgent need to discover novel anti-retroviral agents that are active against newly 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: [Chemical formula] (wherein, A is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms, and the 6-membered monocyclic heteroaryl is substituted at the indicated position with one Z 1 group, one Z 2 group, and optionally substituted with one or more (e.g., one or two) Z 3 groups, R 1 is a 6- to 12-membered aryl, 5- to 12-membered heteroaryl or 3- to 12-membered heterocycle, and any 6- to 12-membered aryl, 5- to 12-membered heteroaryl or 3- to 12-membered heterocycle of R 1 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 4 groups, R 2 is phenyl, a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl or a (C3-C7) carbocycle, and any phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or (C3-C7) carbocycle of R 2 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 5 groups, each R 3a and R 3bThe elements are independently selected from H, halogens, (C1-C3) alkyl and (C1-C3) haloalkyl, or R 3a R is selected from H, (C1-C3) alkyl and (C1-C3) haloalkyl, 3b It is selected from -OH and -CN, Z 1 Z is selected from 6-12 membered aryl rings, 5-14 membered heteroaryl rings, and 3-14 membered heterorings. 1 Any 6-12 member aryl, 5-14 member heteroaryl, and 3-14 member heteroring of Z 1a or Z 1b It is replaced as needed, each Z 1a These are independently (C3-C7) carbon rings, 6-12 membered aryls, 5-12 membered heteroaryls, 3-12 membered heterorings, halogens, -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)2NR 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)2NR n1 COR p1 Selected from, Z1a Any (C3-C7) carbon ring, 6-12 membered aryl, 5-12 membered heteroaryl, and 3-12 membered heteroring can have one or more (e.g., 1, 2, 3, 4, or 5) Z 1c or Z 1d It is replaced as needed in the base, each Z 1b Z is independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl. 1b Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl are one or more (e.g., 1, 2, 3, 4, or 5) Z 1c It is replaced as needed in the base, each Z 1c These are independently (C3-C7) carbon rings, phenyl, 5-6 member monocyclic heteroaryls, 3-7 member heterocycles, halogens, -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)2NR 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, selected from halophenyl, 5- to 6-membered haloheteroaryl, 3- to 7-membered halocyclic ring 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) carbocyclic ring, 3- to 7-membered heterocyclic ring, 5- to 6-membered monocyclic heteroaryl and phenyl, and any (C3-C7) carbocyclic ring, 3- to 7-membered heterocyclic ring, 5- to 6-membered monocyclic heteroaryl and phenyl of R n1 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d groups, and any (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl of R n1 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c groups, each R p1 is independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic ring, 3- to 7-membered heterocyclic ring, 5- to 6-membered monocyclic heteroaryl and phenyl, and any (C3-C7) carbocyclic ring, 3- to 7-membered heterocyclic ring, 5- to 6-membered monocyclic heteroaryl and phenyl of R p1 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d groups, and any (C1-C8) alkyl, (C2-C8) alkenyl and (C2-C8) alkynyl of R p1 is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c groups, R q1 and R r1Each of these is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbon ring, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl, R q1 Or R r1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 1c Or Z 1d Substitutions are made as needed in the base, R q1 Or R r1 Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 1c Substitutions are made as needed in the base, or R q1 and R r1 These, together with the nitrogen atoms they are bonded to, form a 5, 6, or 7-membered heterocycle, and this 5, 6, or 7-membered heterocycle contains one or more (e.g., 1, 2, 3, 4, or 5) Z atoms. 1c or Z 1d It is replaced as needed in the base, Each R n2 These are independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocyclic, (C1-C8) haloalkyl, and (C1-C8) heteroalkyl. Each R p2 These are independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocyclic, (C1-C8) haloalkyl, and (C1-C8) heteroalkyl. R q2 and R r2Each of these is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocyclic, (C1-C8) haloalkyl and (C1-C8) heteroalkyl, or R q2 and R r2 These, together with the nitrogen atoms to which they are bonded, form a heterocycle of 5, 6, or 7 members. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-bonded heteroaryls, 3-12 membered C-bonded heterocycles, and -C(O)R n3 and -C(O)NR q3 R r3 Selected from, Z 2 Any 6-12 member aryl, 5-12 member C-bonded heteroaryl, and 3-12 member C-bonded heterocycle can have one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c The base is substituted as needed, Z 2 Any (C2-C8) alkenyl and (C2-C8) alkinyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2c It is replaced as needed in the base, each Z 2a These are independently (C3-C7) carbon rings, 6-12 membered aryls, 5-12 membered heteroaryls, 3-12 membered heterorings, halogens, -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)2NR 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) carbon ring, 6-12 membered aryl, 5-12 membered heteroaryl, and 3-12 membered heteroring can have one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c It is replaced as needed in the base, each Z 2b These are independently selected from (C1-C4) alkyl, (C1-C4) heteroalkyl, and (C1-C4) haloalkyl. each Z 2c These are, independently, halogen, -CN, and -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)2NR 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 Selected from, Each R n3 R is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbon ring, 3-12 membered heterocycle, 5-12 membered heteroaryl, and 6-12 membered aryl. n3 Any (C3-C7) carbon ring, 3-12 membered heteroring, 5-12 membered heteroaryl, and 6-12 membered aryl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2b or Z 2c Substitutions are made as needed in the base, R n3 Any (C1-C4) alkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl may have one or more (e.g., 1, 2, 3, 4, or 5) Z 2a It is replaced as needed in the base, R q3 and R r3 Each of these is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbon ring, 3-12 membered heterocycle, 5-12 membered heteroaryl, and 6-12 membered aryl, R q3 Or R r3 Any (C3-C7) carbon ring, 3-12 membered heteroring, 5-12 membered heteroaryl, and 6-12 membered aryl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2b Or Z 2c Substitutions are made as needed in the base, R q3 Or R r3 Any (C1-C4) alkyl and (C2-C4) alkenyl can be one or more (e.g., 1, 2, 3, 4, or 5) Z 2a Substitutions are made as needed in the base, or R q3 and R r3These, together with the nitrogen atoms to which they are bonded, form a heterocycle or heteroaryl, and the heterocycle or heteroaryl has one or more (e.g., 1, 2, 3, 4, or 5) Z atoms. 2b Or Z 2c It is replaced as needed in the base, Each R n4 These are independently selected from H, (C1-C4) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C1-C4) haloalkyl and (C1-C4) heteroalkyl, Each R p4 These are independently selected from (C1-C8) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl and (C1-C4) heteroalkyl. R q4 and R r4 Each of these is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl, and (C1-C4) heteroalkyl. each Z 3 These are independently selected from halogens, (C1-C4) alkyls, -OH, -CN, (C1-C4) heteroalkyls, and (C1-C4) haloalkyls. each Z 4 These are independently (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbon ring, 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)2NR 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) carbon ring may have one or more (e.g., 1, 2, 3) , 4 or 5) Z 4a or Z 4b The base is substituted as needed, Z 4 Any (C1-C8) alkyl, (C2-C8) alkenyl, and (C2-C8) alkynyl are one or more (e.g., 1, 2, 3, 4, or 5) Z 4a It is replaced as needed in the base, each Z 4a These are, independently, halogen, -CN, and -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)2NR 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 Selected from, each Z 4b These are independently selected from (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, and (C1-C4) haloalkyl. Each R n5 These are independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. Each R p5 These are independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. R q5 and R r5 Each of these is independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. Each R n6 These are independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. Each R p6 These are independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. R q6 and R r6 Each of these is independently selected from H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) heteroalkyl, (C2-C4) alkenyl, and (C2-C4) alkynyl. each Z 5 These are independently (C1-C6) alkyl, halogen, -CN and -OR n7 Selected from, Z 5Any (C1-C6) alkyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halogens. Each R n7 (These are independently selected from H, (C1-C3) alkyl, (C1-C3) haloalkyl, and (C3-C7) carbocyclic.) Or relating to its pharmaceutically acceptable salt.

[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, in particular, discloses compounds of formula IIId: [ka] (In the formula, A 1 CH, CZ 3 , or nitrogen, A 2 is CH or nitrogen, R 1 R is a 6-12 member aryl, a 5-12 member heteroaryl, or a 3-12 member heteroring. 1 Any 6-12 member aryl, 5-12 member heteroaryl, or 3-12 member heteroring of the form 1, 2, 3, 4, or 5 Z 4 The base is substituted as needed, Z 4 The base is the same or different, Each R 3a and R 3b These are independently H or (C1-C3) alkyl groups. Z 1 Z is a 6-12 member aryl, a 5-14 member heteroaryl, or a 3-14 member heteroring. 1 Any 6-12 member aryl, 5-14 member heteroaryl, or 3-14 member heteroring of the 1, 2, 3, 4, or 5 Z 1a or Z 1b It is replaced as needed, Z 1a and Z1b The base is the same or different, each Z 1a These are independently (C3-C7) carbon rings, 5-12 membered heteroaryls, 3-12 membered heterocycles, halogens, -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)2NR 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)2NR n1 COR p1 Z 1a Any (C3-C7) carbon ring, 5-12 membered heteroaryl, and 3-12 membered heterocycle can have 1, 2, 3, 4, or 5 Z 1c or Z 1d The base is substituted as needed, Z 1c and Z 1d The base is the same or different, each Z 1b These are (C1-C8) alkyl groups that are independently substituted as needed with the same or different 1, 2, 3, 4, or 5 halogens. each Z 1c These are independently halogen, -CN, -OH, -NH2, and -C(O)NR q2 R r2, or (C1~C8) heteroalkyl, each Z 1d These are independently (C1-C8) alkyl or (C1-C8) haloalkyl, Each R n1 These are independently H, (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R n1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d The base is substituted as needed, Z 1c and Z 1d The bases are the same or different, R n1 Any (C1-C8) alkyl group has 1, 2, 3, 4 or 5 Z 1c The base is substituted as needed, Z 1c The base is the same or different, Each R p1 These are independently (C1-C8) alkyl, (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, and R p1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z 1c or Z 1d The base is substituted as needed, Z 1c and Z 1d The bases are the same or different, R p1 Any (C1-C8) alkyl group has 1, 2, 3, 4 or 5 Z 1c The base is substituted as needed, Z 1c The base is the same or different, Each R q1 and R r1 These are independently H, (C1-C8) alkyl, and (C3-C7) carbon. R is a ring, a 3- to 7-membered heterocyclic ring, or a 5- to 6-membered monocyclic heteroaryl. q1 Or R r1 Any (C3-C7) carbon ring, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl can have 1, 2, 3, 4, or 5 Z1c Or Z 1d The base is substituted as needed, Z 1c and Z 1d The bases are the same or different, R q1 Or R r1 Any (C1-C8) alkyl group has 1, 2, 3, 4 or 5 Z 1c The base is substituted as needed, Z 1c The bases are the same or different, or R q1 and R r1 These, together with the nitrogen atoms they are bonded to, form a 5, 6, or 7-membered heterocycle, and this 5, 6, or 7-membered heterocycle has 1, 2, 3, 4, or 5 Z atoms. 1c Or Z 1d The base is substituted as needed, Z 1c and Z 1d The base is the same or different, Each R q2 and R r2 These are independently H, (C1-C8) alkyl, (C3-C7) carbon ring, or R q2 and R r2 These, together with the nitrogen atoms to which they are bonded, form a heterocycle of 5, 6, or 7 members. Z 2 These include (C2-C8) alkenyls, (C2-C8) alkynyls, 6-12 membered aryls, 5-12 membered C-bonded heteroaryls, 3-12 membered C-bonded heterocycles, and -C(O)R n3 , or -C(O)NR q3 R r3 Z 2 Any 6-12 member aryl, 5-12 member C-bonded heteroaryl, or 3-12 member C-bonded heterocycle can have 1, 2, 3, 4, or 5 Z 2b or Z 2c The base is substituted as needed, Z 2b and Z 2c The base is the same or different, Z 2 Any (C2-C8) alkenyl or (C2-C8) alkinyl has 1, 2, 3, 4, or 5 Z 2c The base is substituted as needed, Z 2c The base is the same or different, Each R n3 These are independently H or (C1-C4) alkyl groups. Each R q3 and R r3 These are independently H or (C1-C4) alkyl groups. each Z 2b These are independently oxo, (C1-C4) alkyl, (C1-C4) heteroalkyl, or (C1-C4) haloalkyl. each Z 2c These are independently oxo, halogen, -CN, and -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)2NR 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 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each R p4 These are independently (C1-C8) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. Each R q4 and Rr4 These are independently H, (C1-C4) alkyl, (C1-C4) haloalkyl, or (C1-C4) heteroalkyl. each Z 3 These are independently (C1-C4) heteroalkyl groups. each Z 4 These are independently oxo, (C1-C8) alkyl, (C3-C7) carbon ring, 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 Z 4 Any (C3-C7) carbon ring or (C1-C8) alkyl group has 1, 2, 3, 4, or 5 Z 4a The base is substituted as needed, Z 4a The bases are the same or different, each Z 4a These are, independently, halogen, -CN, or -OR n6 And, Each R n5 , R p5 , R q5 , R r5 , and R n6 These are independently H or (C1-C4) alkyl groups. each Z 5 These are halogens that are independent of each other and may be the same or different. (n is 0, 1, 2, or 3) Or relating to its pharmaceutically acceptable salt. Despite the above disclosure, there is no drug that is potent, stable, and improved 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. In the field of HIV therapy and treatment, there is also interest in the expanding pharmacokinetic properties of regimens offered to patients. Current regimens for treating HIV have advanced so much that patients no longer need to take multiple pills multiple times a day, but patients still need to take pills daily for the foreseeable duration of their lives. Therefore, it is beneficial to have HIV therapies that require patients to take medication 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] U.S. Patent Application Publication No. 2014 / 0303164 [Patent Document 2] U.S. Patent Application Publication No. 2014 / 0296266 [Non-patent literature]

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

[0008] Novel compounds exhibiting improved potency, improved metabolic stability, and improved pharmacokinetic and / or pharmacodynamic profiles are provided herein.

[0009] In some embodiments, this disclosure relates to compounds of formula (Ia): [ka] Or relating to its pharmaceutically acceptable salt.

[0010] In some embodiments, this disclosure relates to compounds of formula (Ib): [ka] Or relating to its pharmaceutically acceptable salt.

[0011] In some embodiments, the present disclosure relates to a compound of formula (IIa): [ka] Or relating to its pharmaceutically acceptable salt.

[0012] In some embodiments, the present disclosure relates to a compound of formula (IIb): [ka] Or relating to its pharmaceutically acceptable salt.

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

[0014] In one embodiment, the present disclosure relates to the use of compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, in the treatment of a disease in a subject requiring such treatment.

[0015] In certain embodiments, the 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, this disclosure relates to pharmaceutical compositions comprising compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients. 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 disclosure relates to a manufactured article comprising a unit dose of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the disclosure relates to a manufactured article comprising a unit dose of a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof.

[0019] In certain embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject requiring such treatment, comprising administering to the subject a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject requiring such treatment, comprising administering to the subject a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof.

[0021] In certain embodiments, the 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 pharmaceutically acceptable salt thereof. In certain embodiments, the subject is a subject at risk of contracting the HIV virus, for example, a subject having 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 pharmaceutically acceptable salt thereof. In certain embodiments, the subject is at risk of contracting the HIV virus, for example, having 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 requiring such treatment, comprising administering to the subject a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents in a therapeutically effective dose.

[0024] In certain embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject requiring such treatment, comprising administering to the subject 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 a therapeutically effective amount.

[0025] In certain embodiments, the disclosure relates to compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, for use in pharmaceutical therapy.

[0026] In certain embodiments, the disclosure relates to compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, for use in pharmaceutical therapy.

[0027] In certain embodiments, the disclosure relates to compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, for use in the treatment or prevention of HIV infection in a subject.

[0028] In certain embodiments, the disclosure relates to compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, for use in the treatment or prophylaxis of HIV infection in a subject.

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

[0030] In certain embodiments, the disclosure relates to the use of compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for treating or preventing HIV infection in a subject.

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

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

[0033] In some embodiments, the pharmaceutically acceptable salts of the compounds of formula (Ia), (Ib), (IIa), and / or (IIb) are sodium salts.

[0034] Additional embodiments of this disclosure are disclosed herein. [Brief explanation of the drawing]

[0035] [Figure 1] Figure 1 shows the 1H NMR of N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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]pyrazole-1-yl)acetamide (400 MHz, methanol-d4).

[0036] [Figure 2] Figure 2 shows the 1H NMR of N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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]pyrazole-1-yl)acetamide (400 MHz, methanol-d4).

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

[0038] [Figure 4] Figure 4 shows a time-course plot of plasma concentrations of formula Ib in 200 mg / mL of 2% poloxamer 188 in saline after subcutaneous administration of 6 mg / kg to dogs.

[0039] [Figure 5]Figure 5 shows a time-course plot of plasma concentrations of formula Ib in 2% poloxamer 188 in saline solution at a dose of 6 mg / kg subcutaneously administered to dogs.

[0040] [Figure 6] Figure 6 shows a time-course plot of plasma concentrations of sodium salt, formula Ib, equivalent to 200 mg / mL in 2% poloxamer 188 in saline, when administered subcutaneously to dogs at a dose of 6 mg / kg.

[0041] [Figure 7] Figure 7 shows a time-course plot of plasma concentrations of the free acid form (Equation Ib) in NMP at a concentration of 100 mg / mL when administered subcutaneously to dogs at a dose of 6 mg / kg.

[0042] [Figure 8] Figure 8 shows a time-course plot of plasma concentrations of the free acid form (Equation Ib) in NMP at a concentration of 200 mg / mL when administered subcutaneously to dogs at a dose of 6 mg / kg.

[0043] [Figure 9] Figure 9 shows a time-course plot of plasma concentrations of the sodium salt of formula Ib in NMP at a concentration of 200 mg / mL when subcutaneously administered to subjects at a dose of 6 mg / kg.

[0044] [Figure 10] Figure 10 shows a time-course plot of plasma concentrations of formula Ib at 200 mg / mL in 10% ethanol, 12% water, and 78% PEG200 after subcutaneous administration to subjects at a dose of 6 mg / kg.

[0045] [Figure 11] Figure 11 shows a time-course plot of plasma concentrations of the salt of formula Ib, in situ, at 200 mg / mL in 10% ethanol, 12% water, and 77% PEG200, after subcutaneous administration to subjects at a dose of 6 mg / kg.

[0046] [Figure 12]Figure 12 shows a time-course plot of plasma concentrations of formula Ib at 200 mg / mL in 10% ethanol, 13% water, and 77% glycoflore, containing 1.2 molar equivalents of NaOH to form the Na salt in situ, when administered to subjects at 6 mg / kg.

[0047] [Figure 13] Figure 13 shows a time-course plot of plasma concentrations in dogs following a fixed oral dose of 7.5 mg of formula Ib in 10% ethanol, 20% vitamin E TPGS, and 70% miglyol 812. [Modes for carrying out the invention]

[0048] The following statements are made with the understanding that this disclosure is intended to illustrate the claimed subject matter and is not intended to limit the attached claims to any specific embodiment described herein. Titles used throughout this disclosure are provided for convenience only. This should not be construed as limiting the scope of the claims. Embodiments illustrated under any title may be combined with embodiments illustrated under any other title.

[0049] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

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

[0051] As used herein and in the appended claims, the singular forms "a," "an," and "the" include multiple references unless the context explicitly indicates otherwise. Thus, for example, a reference to "the compound" includes multiple such compounds, and a reference to "the assay" includes one or more assays, and so on.

[0052] When used herein, "C max The term "maximum observed plasma / serum concentration" refers to the highest observed concentration of a drug in the plasma / serum.

[0053] "Pharmacologically acceptable" means compounds, salts, compositions, dosage forms and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0054] "Pharmacologically acceptable excipients" include, without limitation, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, colorants, flavor enhancers, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the U.S. Food and Drug Administration as acceptable for use in humans or domesticated animals.

[0055] A "pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses (or can be converted into) the desired pharmacological activity of the parent compound. Examples of such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; or acid addition salts formed 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, and trimethylacetic acid; and salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., sodium or potassium), an alkaline earth ion (e.g., calcium or magnesium), or an aluminum ion, or when an organic base such as diethanolamine, triethanolamine, or N-methylglucamine is coordinated. Ammonium and substituted or quaternized ammonium salts are also included in this definition. A representative, non-restrictive list of pharmaceutically acceptable salts can be found in S.M. Berge et al., J. Pharma Sci., vol. 66(1), pp. 1-19 (1977), and This can be found in Remington: The Science and Practice of Pharmacy, edited by R. Hendrickson, 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), p. 732, Table 38-5, both of which are incorporated herein by reference.

[0056] "Subject(s)" refers to humans, domesticated animals (e.g., dogs and cats), livestock (e.g., cattle, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), etc.

[0057] As used herein, “treatment” or “doing a treatment” means a method for obtaining a beneficial or desired outcome. For the purposes of this disclosure, beneficial or desired outcomes include, but are not limited to, symptom reduction and / or reduction of the scope of symptoms and / or prevention of exacerbation of symptoms associated with a disease or condition. In one embodiment, “treatment” or “doing a treatment” 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 reducing the scope of the disease or condition); b) delaying or stopping the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the exacerbation or progression of a disease or condition); and / or c) alleviating a disease or condition, e.g., causing a regression of clinical symptoms, restoring a condition, delaying disease progression, improving quality of life, and / or prolonging life.

[0058] As used herein, “delaying” the onset of a disease or condition means delaying, interfering with, postponing, delaying, stabilizing, and / or postponing the onset of the disease or condition. The length of this delay may vary depending on the medical history and / or the subject being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can, in practice, encompass prevention in that the subject does not develop the disease or condition. For example, a method of “delaying” the onset of AIDS is a method of reducing the probability of developing the disease within a given time frame and / or reducing the extent of the disease within a given time frame compared to not using the method. Such a comparison may be based on a clinical study using a statistically significant number of subjects. For example, the onset of AIDS is the HIV of a subject. +The condition can be detected using known methods, such as assessing the subject's T cell count or other signs of AIDS onset, e.g., extreme fatigue, weight loss, persistent diarrhea, high fever, swelling of the cervical, axillary, or inguinal lymph nodes, or the presence of opportunistic conditions known to be associated with AIDS (e.g., conditions that do not commonly occur in subjects with a functioning immune system but do occur in AIDS patients). Onset can also refer to disease progression that may initially be undetectable, and includes appearance, relapse, and onset.

[0059] As used herein, “prevention” or “preventing” refers to a regimen that prevents the onset of a disease or disorder so that the clinical symptoms of the disease do not develop. Thus, “prevention” relates to the administration of therapy to a subject (e.g., administration of a therapeutic substance) before signs of the disease become detectable in the subject (e.g., administration of a therapeutic substance to a subject when there is no detectable infectious agent (e.g., virus) in the subject). The subject may be an individual at risk of developing the disease or disorder, e.g., an individual with one or more risk factors known to be associated with the onset or development of the disease or disorder. Thus, the term “preventing HIV infection” refers to the administration of an anti-HIV therapeutic substance to a subject who does not have a detectable HIV infection. It is understood that subjects of anti-HIV prophylactic therapy may be individuals at risk of contracting the HIV virus. Furthermore, it is understood that prevention may not provide complete protection against the onset of the disease or disorder. In some cases, prevention includes reducing the risk of developing the disease or disorder. A reduction in risk may not result in the complete elimination of the risk of developing the disease or disorder.

[0060] As used herein, an individual at risk is an individual that is at risk of developing the condition being treated. An individual at risk may or may not have a detectable disease or condition, and may or may not exhibit a detectable disease prior to treatment by the method described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters known in the art that correlate with the development of a disease or condition. Individuals with these risk factors (multiple risk factors) are more likely to develop a disease or condition than individuals without them. For example, individuals at risk of AIDS are those who have HIV.

[0061] As used herein, the terms “therapeutic effective dose” or “effective dose” refer to an effective amount of a compound, when administered to a subject to treat a disease, that is sufficient to perform such treatment for the disease, thereby eliciting a desired biological or medical response, or an effective amount to prevent the onset or development of the disease. The effective dose varies depending on the compound, the disease, its severity, and the age, weight, etc., of the subject to be treated. The effective dose may include a range of amounts. As understood in the art, the effective dose may be a single or multiple dose, i.e., a single or multiple dose may be required to achieve the desired treatment outcome. The effective dose can be considered in relation to the administration of one or more therapeutic agents, and a monotherapy agent may be considered given in an effective dose if, in combination with one or more other agents, a desirable or beneficial outcome can, or is achieved. The appropriate dose of any co-administered compound may be reduced as necessary due to the combined action of the compounds (e.g., additive or synergistic effect).

[0062] An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. 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 "scalemic" mixture.

[0063] A "diastereoisomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image 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 by either R or S. A resolved compound whose absolute configuration is unknown can be designated as (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Some of the compounds described herein contain one or more asymmetric centers and / or restricted rotation around the bond axis, and thus, enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- from the point of view of absolute stereochemistry can occur. The present disclosure intends to include all such possible isomers, including racemic mixtures, scalemic mixtures, diastereomer mixtures, optically pure forms, and intermediate mixtures. The optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents or can be resolved using conventional techniques.

[0065] Unless otherwise explicitly defined, the present disclosure includes all tautomers of the compounds detailed herein even if only one tautomer is explicitly represented (e.g., by the presentation of one tautomeric form where a pair of two tautomers can exist, both tautomeric forms are intended and described). For example, when a compound containing an amide is referred to (e.g., by structure or chemical name), it is understood that the corresponding imidic acid tautomer is included and described in the present disclosure as if this amide were explicitly listed alone or together with the imidic acid. If more than two tautomers can exist, the present disclosure includes all such tautomers even if only a single tautomeric form is indicated 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 biologically inactive derivative of a drug that is converted into a biologically active parent drug following a chemical or enzymatic pathway upon administration to a human body.

[0067] Furthermore, in some embodiments, the present disclosure also provides prodrugs of the compounds of formula (Ia), (Ib), (IIa), and / or (IIb). <000—0910> The present disclosure also encompasses any compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) that is enriched in one or more isotopes, including but not limited to deuterium ([ 2 H or D), at a ratio higher than the ratio of the naturally occurring isotopes at any atom. 2 It is understood by those skilled in the art that one or more hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms or D (where n is the number of hydrogen atoms in the molecule). As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase resistance to metabolism and thus may be useful for increasing the half-life of a compound when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., Vol. 5(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 are replaced by deuterium.

[0069] Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H,

[0070] respectively. 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 Includes I. Positron-emitting isotopes, for example, 11 C, 18 F, 15 O and 13 Substitution with N may be useful in positron emission tomography (PET) experiments to test substrate receptor occupancy. Isotope-labeled compounds of formula (Ia) or (Ib) can generally be prepared by conventional techniques known to those skilled in the art, or by using appropriate isotope-labeled reagents instead of previously used unlabeled reagents, in a manner similar to that described in the examples presented below.

[0071] Furthermore, in some embodiments, isotope-labeled compounds of formulas (Ia), (Ib), (IIa), and / or (IIb) can generally be prepared by conventional techniques known to those skilled in the art, or by using appropriate isotope-labeled reagents instead of previously used unlabeled reagents, in a manner similar to that described in the examples presented below.

[0072] The compounds described herein may have chiral centers and / or geometric isomer centers (E and Z isomers), and it should be understood that all such optical isomers, enantioisomers, diastereoisomers, and geometric isomers are included. Where a compound is represented in these chiral forms, the embodiments are understood to include, but are not limited to, certain diastereomer or enantiomer-enriched forms. Where chirality is not specified but is present, this embodiment is understood to cover either a certain diastereomer or enantiomer-enriched form, or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture” means a mixture of stereoisomers in a ratio other than 1:1.

[0073] Also provided herein are pharmaceutically acceptable hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein.

[0074] In preferred embodiments, the present disclosure relates to the use of compounds of formula (Ia) or (Ib) in the treatment of Retroviridae virus infections, including infections caused by the HIV virus, which includes administering a therapeutically effective dose to a subject in need thereof.

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

[0076] Low e-commerce 50 The desirable goal is to discover compounds containing or pharmaceutically acceptable salts thereof. 50 The value refers to the concentration of the compound in the assay that achieves 50% of its maximum potency. 50 Compounds having a higher EC 50Compared to compounds with the same properties, it achieves similar efficacy at a lower compound concentration. Therefore, a lower EC 50 This is generally preferable for drug discovery.

[0077] A desirable goal is to discover compounds or pharmaceutically acceptable salts thereof that possess good physical and / or chemical stability. Increased overall stability of a compound can lead to increased circulation time in the body. Low degradability allows stable compounds to be administered at lower doses while still maintaining their potency. Furthermore, low degradability reduces concerns about by-products resulting from the breakdown of the compound.

[0078] A desirable goal is to discover compounds or pharmaceutically acceptable salts thereof with improved pharmacokinetic and / or pharmacodynamic profiles, as well as long half-lives. A drug having moderate or low clearance and a long half-life is advantageous because it can result in good bioavailability and high exposure in systemic exposure. Decreased clearance and increased half-life of a compound can reduce the daily dose required for efficacy, thus resulting in a better efficacy and safety profile. Therefore, an improved pharmacokinetic and / or pharmacodynamic profile, along with a long half-life, can provide better patient compliance.

[0079] A desirable goal is to discover compounds or pharmaceutically acceptable salts thereof with a good pharmacokinetic profile from sustained-release injectable formulations. 50 Furthermore, having a long-acting pharmacokinetic profile is advantageous because it can lead to a lower dosing frequency. A reduced dosing frequency can provide better patient compliance. A reduced dosing frequency may be desirable for patients with limited or difficult access to healthcare.

[0080] Advantageously, compounds of formulas (Ia) and (Ib) herein have been discovered that provide advantages compared to structurally similar compounds (designated herein as Compounds A and B) disclosed in U.S. Patent Publications Nos. 2014 / 0296266 A1 and 2014 / 0303164 A1:

Chem.

Chem.

[0081] Thus, the present disclosure includes, but is not limited to, compounds of formula (Ia)

Chem.

[0082] Thus, the present disclosure includes, but is not limited to, compounds of formula (Ib)

Chem.

[0083] Compounds of formulas (IIa) and (IIb) that provide advantages compared to Compounds A and B (shown above) are also disclosed herein.

[0084] Thus, the present disclosure includes, but is not limited to, compounds of formula (IIa)

Chem.

[0085] Therefore, this disclosure is not limited to the compounds of formula (IIb). [ka] The invention also includes providing pharmaceutically acceptable salts thereof, and methods for using 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 pharmaceutically acceptable salts thereof) are used to prevent HIV infection in subjects. In some embodiments, the compounds disclosed herein are used to prevent HIV infection in subjects at risk of infection. In some embodiments, the compounds disclosed herein are used in pre-exposure prophylaxis (PrEP) to reduce the risk of sexually transmitted HIV-1.

[0087] The compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof) are thought to be active against 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, a method is provided for treating or preventing HIV infection in a person who has or is at risk of having HIV infection, comprising administering to a person 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 one or more additional therapeutic agents (e.g., one, two, three, or four, or one or two, or one to three, or one to four).

[0089] In some embodiments, a method is provided for treating or preventing HIV infection in a person who has or is at risk of having HIV infection, comprising administering to a person a therapeutically effective amount of one or more (e.g., one, two, three, or four, or one or two, or one to three, or one to four) additional therapeutic agents. The present invention provides a method for treating HIV infection in a person who has or is at risk of having HIV infection, comprising administering to a person a therapeutically effective amount of one or more additional therapeutic agents (e.g., one, two, three, or four, or one or two, or one to three, or one to four) of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharmaceutically acceptable salt thereof.

[0090] In one embodiment, a pharmaceutical composition is provided comprising one or more compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)) or pharmaceutically acceptable salts thereof in combination with one or more additional therapeutic agents (e.g., one, two, three, or four, or one or two, or one to three, or one to four) and pharmaceutically acceptable excipients.

[0091] In some embodiments, pharmaceutical compositions are provided comprising one or more compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) or pharmaceutically acceptable salts thereof in combination with one or more additional therapeutic agents (e.g., one, two, three, or four, or one or two, or one to three, or one to four) and pharmaceutically acceptable excipients.

[0092] In certain embodiments, the Disclosure provides a method for treating HIV infection, comprising administering to a subject in need a therapeutically effective amount of one or more additional therapeutic agents appropriate for treating HIV infection, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0093] In certain embodiments, the Disclosure provides a method for treating HIV infection, comprising administering to a subject in need a therapeutically effective amount of one or more additional therapeutic agents appropriate for treating HIV infection, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

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

[0095] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with one additional therapeutic agent. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with four additional therapeutic agents. 1, 2, 3, 4 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.

[0096] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with one additional therapeutic agent. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with four additional therapeutic agents. One, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class, and / or they may be selected from different classes. Implementation 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 the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, with one or more additional therapeutic agents generally means administering the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents simultaneously or sequentially, so that both therapeutically effective amounts of the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents are present in the body of the subject. When administered sequentially, the combination may 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 the compounds 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 means administering the compounds 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 simultaneously or sequentially, so that both therapeutically effective amounts of the compounds 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 present in the body of the subject. When administered sequentially, the combination can be given in two or more doses.

[0099] Co-administration involves administering a unit dose of one or more of the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, before or after the administration of a unit dose of one or more additional therapeutic agents. For example, one or more of the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. In some embodiments, the unit dose of one or more of the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, may be the most In some embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by 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 a unit dose of one of the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)). In other embodiments, a unit dose of one of the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)) is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1 to 12 hours). In yet another embodiment, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of one of the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)) several hours later.

[0100] In some embodiments, co-administration involves administering a unit dose of one or more of the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) or a pharmaceutically acceptable salt thereof, before or after the administration of a unit dose of one or more additional therapeutic agents. For example, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) or a pharmaceutically acceptable salt thereof may be administered within seconds, minutes, or hours following the administration of one or more additional therapeutic agents. In some embodiments, a unit dose of one of the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) or a pharmaceutically acceptable salt thereof is administered first, followed within seconds or minutes by the 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 a unit dose of one of the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)). In other embodiments, a unit dose of one of the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1 to 12 hours). In yet another embodiment, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of one of the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) several hours later (e.g., 1 to 12 hours).

[0101] For the sake of clarity, co-administration of a compound disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharmaceutically acceptable salt thereof, with one or more additional therapeutic agents may mean co-administration with one or more of the thereapeutic agents described herein, for example, those listed in paragraphs

[0111] to

[0162] .

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

[0103] In some embodiments, compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) or pharmaceutically acceptable salts thereof are used. The disclosed compound is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to the subject. In certain embodiments, such a single dosage form can be administered by any route appropriate to the condition being treated. Appropriate routes include oral, rectal, nasal, topical (including oral buccal and sublingual), percutaneous, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). In certain embodiments, the disclosed compound 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 may be a solid dosage form for oral administration.

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

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

[0106] In certain embodiments, the compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is formulated as a tablet which 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 activators, and combinations thereof.

[0107] In certain embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are formulated as tablets which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablets 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 activators, and combinations thereof.

[0108] In certain embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are formulated as solution formulations which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, tablets 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 activators, and combinations thereof.

[0109] In certain embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are formulated as suspensions which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, tablets 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 activators, and combinations thereof.

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

[0111] In the embodiments described above, additional therapeutic agents include: concomitant drugs for treating 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 reversing 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, and HIV vif gene modulator, Vif dimerization antagonist, HIV-1 virus infectivity factor inhibitor, TAT protein inhibitor, HIV-1 Nef modulator, Hck tyrosine kinase modulator, mixed-series kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, Rev protein inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, HIV ribonuclease H inhibitor, retrocycline modulator, CDK-9 inhibitor, dendritic ICAM-3 grabbing nonintegrin 1 inhibitor, HIV GAG protein inhibitor, 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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, HIV vaccines, and combinations thereof.

[0112] In some embodiments, additional therapeutic agents include concomitant drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, and HIV integrase inhibitors. The group consists of HIV integrase inhibitors, HIV non-catalytic (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, as well as "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 (registered trademark) (tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (registered trademark) (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemi fumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofobi Lu and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; 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(registered trademark) (ALUVIA(registered trademark); lopinavir and ritonavir); TRIUMEQ(registered trademark) (dolutegravir, abacavir, and lamivudine); TRIZIVIR(registered trademark) (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 Examples include roxil fumarate; lamivudine + zidovudine + nevirapine; 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] Other drugs used to treat HIV include acemannan, arispolivir, BanLec, deferipron, gamimune, methenkephalin, 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, and HGT. Examples include 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, brekanavir, 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-nucleotide inhibitors of reverse transcriptase include dapivine, delaviridine, delaviridine 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 US2016 / 0250215.

[0117] Examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors 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 Examples include EC (registered trademark) (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, sensabudine, didanosine, erbucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, hodivudine tidoxil, lamivudine, phosphazide, stabudine, zalcitabine, zidovudine, GS-9131, GS-9148, and KP-1461.

[0118] In some embodiments, examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors 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 Examples include EC (registered trademark) (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, sensabudine, didanosine, erbucitabine, festinavir, fosalvudine tidoxyl, CMX-157, dapivine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, hodivudine tidoxyl, lamivudine, phosphazide, stabudine, zalcitabine, zidovudine, GS-9131, GS-9148, KP-1461, and 4'-ethinyl-2-fluoro-2'-deoxyadenosine (EFdA). HIV integrase inhibitors

[0119] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoriate, chicoriate derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, and aurintricarboxylic acid derivatives. Examples include caffeate phenethyl ester, caffeate phenethyl ester derivatives, tylphostin, tylphostin derivatives, quercetin, quercetin derivatives, 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, stilbenisulfonic acid, T-169, and cabotegravir.

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

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

[0122] Examples of CCR5 inhibitors include aplaviroc, bicriviroc, maraviroc, senicriviroc, PRO-140, adaptervir (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 inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvvirtide.

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

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

[0126] Examples of CXCR4 inhibitors include prelixafor, 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 latent reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as Velcade, protein kinase C (PKC) activator, 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 disruption compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamides, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series. Immunity-based therapy

[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 cell 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 in Examples include terferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; lintatrimod, polymer polyethyleneimine (PEI); gepon; lintatrimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normuferon, peginterferon alpha-2a, peginterferon alpha-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, gedatricib, neratinib, panulisib, perifosine, pictilisib, piraralisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonolicib, taselicib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS. Examples include -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, bnAB (broadly neutralizing HIV-1 antibody), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, HIV-targeting antibody recruiting molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-nef single-domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, and other anti-lacto antibodies. Examples include anti-ICAM-1 antibodies derived from D. japonica, DCVax-001, gp140-targeted antibodies, gp41-based antibodies for HIV treatment, human recombinant mAbs (PGT-121), ivalizumab, Immuglo, and MB-66.

[0135] Examples of drugs that target 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 activators

[0136] Examples of pharmacokinetic activators include cobicistat and ritonavir. Additional treatments

[0137] Examples of additional therapeutic agents include 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), and US2013 / 0165489 (University of Examples of compounds disclosed include those in Pennsylvania, US2014 / 0221378 (Japan Tobacco), US2014 / 0221380 (Japan Tobacco), WO2009 / 062285 (Boehringer Ingelheim), WO2010 / 130034 (Boehringer Ingelheim), WO2013 / 006792 (Pharma Resources), 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, combination vaccines, 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 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 adjuvant 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, e.g., pseudovirion vaccine, CombiVICHvac, LFn-p24B / C fusion vaccine, GTU-based DNA vaccine, HIVgag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, 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 Examples include HIV vaccines, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, variant 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 pharmaceutically acceptable salts thereof, are 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 Lu; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemi fumarate; 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); 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; Prolastine; Fosamprenavir;Fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stabudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirudine; delavirudine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir; Combine with one, two, three, four, or more additional therapeutic agents selected from fovir disoproxil fumarate; phosphazides; 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 pharmaceutically acceptable salts thereof are ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate) 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 Lu; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemi fumarate; 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(registered trademark) (LIVEXA(registered trademark); abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR(registered trademark) (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; prolastine;Fosamprenavir; Fosamprenavir calcium efavirenz; Etravirine; Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stabuzin; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine mesylate; Radha-108 (receptor) l); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphatides; lamivudine, nevirapine, and zidovudine; abacavir; abacavir sulfate; 4'-ethinyl-2-fluoro-2'-deoxyadenosine (EFdA); and in combination with one, two, three, four or more additional therapeutic agents selected from bictegravir or its pharmaceutically acceptable salts.

[0141] Those skilled in the art will recognize that the additional therapeutic agents listed above may belong to more than one of the classes listed above. No particular class is intended to limit the functionality of the compounds listed in that class.

[0142] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with one or two reverse transcriptase HIV nucleoside or nucleotide inhibitors. and in combination with HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, and HIV protease inhibitors. In additional embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic activators. In a particular embodiment, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic activator. In another embodiment, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with two reverse transcriptase HIV nucleoside or nucleotide inhibitors.

[0143] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with one or two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In other specific embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitor compounds. In additional embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic activators. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic activator. In other embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0144] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are 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 pharmaceutically acceptable salts thereof are abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bictegravir (or pharmaceutically acceptable salts thereof), or 4'-ethinyl-2-fluorine Combine with 2'-deoxyadenosine (EFdA).

[0146] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with HIV integrase inhibitors.

[0147] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate.

[0148] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bictegravir (or pharmaceutically acceptable salts thereof), or 4'-ethinyl-2-fluoro-2'-deoxyadenosine (EFdA).

[0149] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are 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, as well as a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0150] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are 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, as well as a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0151] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are 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, as well as a second additional therapeutic agent which 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 disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent which is emtricitabine. In some embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and the first and second additional therapeutic agents disclosed above are administered simultaneously. If necessary, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and the first and second additional agents disclosed above are combined. The therapeutic agents are combined within a single dosage form for simultaneous administration to the subject. In other embodiments, the compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, as well as the first and second additional therapeutic agents disclosed above, are administered sequentially.

[0152] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are 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, as well as a second additional therapeutic agent which is emtricitabine. In certain embodiments, the compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are combined with a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, as well as a second additional therapeutic agent which is emtricitabine. In certain embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are 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 which is emtricitabine. In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, and the first and second additional therapeutic agents disclosed above are administered simultaneously. If necessary, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, and the first and second additional therapeutic agents disclosed above are combined in a single dosage form for simultaneous administration to the subject. In other embodiments, compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof, as well as the first and second additional therapeutic agents disclosed above, are administered sequentially.

[0153] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with bictegravir or pharmaceutically acceptable salts 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 in any dosage of the compound of formula (Ia) or (Ib) (e.g., 1 mg to 1000 mg of the compound).

[0155] In some embodiments, the compounds disclosed herein (e.g., any compound of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof) can be combined with one or more additional therapeutic agents in any dosage of the compounds of formula (Ia), (Ib), (IIa), and / or (IIb) (e.g., 1 mg to 1000 mg of the compounds).

[0156] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with 5 to 10, 5 to 15, 5 to 20, 5 to 25, 25 to 30, 20 to 30, 15 to 30, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, The compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are 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) or (Ib)) can be combined with the agents provided herein at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as each dosage combination is specifically and individually enumerated.

[0157] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are 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, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are 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 the agents provided herein at any dosage of the compounds (e.g., 1 mg to 1000 mg of the compounds), just as each combination of dosages is specifically and individually enumerated.

[0158] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with 200–400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are 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, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)), or pharmaceutically acceptable salts thereof, are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)) are provided herein in any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as each combination of dosages is specifically and individually enumerated. It can be combined with medication.

[0159] In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with 200–400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa) and / or (IIb)), or pharmaceutically acceptable salts thereof, are 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, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) can be combined with the agents provided herein at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as each dosage combination is specifically and individually enumerated.

[0160] In some embodiments, the compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, are combined with 20 to 80 mg of bictegravir or pharmaceutically acceptable salts thereof. The compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof) can be combined with the agents provided herein at any dosage of the compound (e.g., 1 mg to 1000 mg of the compound), as each dosage combination is specifically and individually enumerated.

[0161] In one embodiment, a kit comprising a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is provided in combination with one or more additional therapeutic agents (e.g., one, two, three, one or two, or one to three).

[0162] In some embodiments, a kit comprising a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa), and / or (IIb)), or a pharmaceutically acceptable salt thereof, is provided in combination with one or more additional therapeutic agents (e.g., one, two, three, one or two, or one to three). Pharmaceutical composition

[0163] The pharmaceutical compositions disclosed herein comprise one or more pharmaceutically acceptable excipients and, optionally, other therapeutic agents, the compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)) or pharmaceutically acceptable salts thereof. The pharmaceutical compositions 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 include one or more pharmaceutically acceptable compounds (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) or pharmaceutically acceptable salts thereof. It is included with excipients and, if necessary, other therapeutic agents. The pharmaceutical composition containing the active ingredient 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 pharmaceutically acceptable salts thereof, can be prepared using conventional carriers (e.g., inert components or excipient materials) that can be selected according to common practice. Tablets may contain excipients, including flow enhancers, fillers, and binders. Aqueous compositions can be prepared in sterile form and may generally be isotonic if intended for delivery by means other than oral administration. All compositions may optionally contain excipients, e.g., those shown in Rowe et al., Handbook of Pharmaceutical Excipients, 5th edition, American Pharmacists Association, 1986. Examples of excipients include ascorbic acid and other antioxidants, chelating agents, e.g., EDTA, carbohydrates, e.g., dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

[0166] In some embodiments, pharmaceutical compositions containing compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)), or pharmaceutically acceptable salts thereof, can be prepared using conventional carriers (e.g., inert components or excipient materials) that can be selected according to common practice. Tablets may contain excipients, including flow enhancers, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and may generally be isotonic if intended for delivery other than oral administration. All compositions may optionally contain excipients, e.g., those shown in Rowe et al., Handbook of Pharmaceutical Excipients, 5th edition, American Pharmacists Association, 1986. Examples of excipients include ascorbic acid and other antioxidants, chelating agents, e.g., EDTA, carbohydrates, e.g., dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, etc.

[0167] While it is possible to administer the active ingredient alone, it is sometimes preferable to present the active ingredient as a pharmaceutical composition. Compositions for both veterinary and human use contain at least a compound of formula (Ia) or (Ib) together with one or more acceptable carriers and, optionally, other therapeutic components. In one embodiment, the pharmaceutical composition contains a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and 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. In one embodiment, the pharmaceutical composition contains a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and one other therapeutic component. The carrier(s) are “acceptable” in the sense that they are compatible with the other components of the composition and are physiologically harmless to their recipient.

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

[0169] The compositions include those suitable for various routes of administration. The compositions can be conveniently presented in unit dosage forms and can be prepared by any method well known in the art of pharmacy. Such methods involve the step of combining an active ingredient (e.g., a compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt) with one or more inactive ingredients (e.g., a carrier, a pharmaceutical excipient, etc.). The compositions can be prepared by homogeneously and densely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product. The techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams 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 forms and can be prepared by any method well known in the art of pharmaceuticals. Such methods include the step of combining an active ingredient (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or its pharmaceutically acceptable salt) with one or more inactive ingredients (e.g., a carrier, a pharmaceutical excipient, etc.). The compositions can be prepared by homogeneously and densely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, by forming the product. The techniques and formulations are generally described in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams and Wilkins, Philadelphia, Pa., found in 2006.

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

[0172] For oral use, for example, tablets, 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 field of pharmaceutical composition production, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet production are acceptable. These excipients may include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulators and disintegrants 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 coated by known techniques, including microencapsulation, which delays disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a long period. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used alone or in combination with wax.

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

[0174] In some embodiments, rigid capsules are disclosed herein, which are filled with powders, beads, or granules containing an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of rigid or flexible capsules. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulators and disintegrants 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, rigid or flexible capsules are disclosed herein, which are filled with a liquid or semi-solid mixture containing an active ingredient, mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of rigid or flexible capsules. These excipients may be, for example, solubilizing oils, e.g., corn oil, sesame oil, or cod oil; medium-chain triglycerides and related esters, e.g., derivitized palm kernel oil or coconut oil; self-emulsifying lipid systems (SEDDS or SMEDDS), e.g., caprylic triglyceride or propylene glycol monocaprylate; viscosity modifiers, e.g., cetyl alcohol, stearyl alcohol, glycerol stearate; and solubilizers and surfactants, e.g., polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamer, or polysorbate.

[0176] The pharmaceutical compositions of this disclosure may be in the form of sterile injectable preparations, for example, sterile aqueous or oily suspensions for injection. These suspensions can be formulated according to known techniques using appropriate dispersants or wetting agents and suspending agents as described herein. The sterile injectable preparations may also be injectable sterile solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, such as a solution in 1,3-butane-diol, or they may be prepared as lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils can conventionally be used as solvents or suspensions. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid can similarly be used in the preparation of injectable preparations.

[0177] In some embodiments, the sterile injectable preparations disclosed herein may also be sterile injectable solutions or suspensions prepared from reconstituted lyophilized powder in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils can conventionally be used as solvents or suspensions. For this purpose, any non-irritating non-volatile oil, including synthetic monoglycerides or diglycerides, can be used. Furthermore, fatty acids such as oleic acid can similarly be used in the preparation of injectable preparations.

[0178] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable preparations that may contain antioxidants, buffers, bacteriostatic agents, and solutes to be isotonic with the blood of the intended recipient; as well as aqueous and non-aqueous sterile suspensions that may contain suspending agents and thickeners. 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 excipients 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 the Handbook of Pharmaceutical Excipients (edited by 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, parenteral administrations (e.g., SC or IM formulations) containing compounds of formulas (Ia), (Ib), (IIa), and / or (IIb), or their pharmaceutically active salts, as well as poloxamers, particularly poloxamer 338, are disclosed herein. In some embodiments, the amount of poloxamer (e.g., poloxamer 388) in the parenteral administrations disclosed herein is less than about 5%, for example, 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) and poloxamers (e.g., poloxamer 338, 188, or 207). In some embodiments, parenteral administrations (e.g., SC or IM formulations) comprising compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or their pharmaceutically active salts, as well as poloxamers, are disclosed herein.

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

[0183] Generally, poloxamers are synthetic nonionic triblocks of linear copolymers having a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic polypropylene oxides, with a weight ratio of 4:2:4 in certain cases. Therefore, in certain embodiments, the compositions disclosed herein include compounds of formulas (Ia), (Ib), (IIa), and / or (IIb), or their pharmaceutically active salts, as well as block copolymers comprising 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] (Here, a and b are integers (for example, a is between 2 and 130, and b is between 15 and 67)). Poloxamer 188 is understood, for example, to have a molecular weight in the range of approximately 7680 to 9510 daltons (where a is approximately 80 and b is approximately 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 approximately 8400 daltons. Similarly, poloxamer 338 has a molecular weight in the range of approximately 12700 to 17400 Da (where a is approximately 141, b is approximately 44.

[0184] Examples of excipients in parenteral formulations (e.g., SC or IM formulations) may also include polyethylene glycol. Generally, polyethylene glycol (PEG) has the general formula H-(O-CH2-CH2) nIt is a polyether having an -OH group. In certain embodiments, PEG may be "capped" with an alkyl group. In those embodiments, the capped PEG is of the formula alkyl-(O-CH2-CH2) n -O-alkyl, (e.g., CH3-(O-CH2-CH2)) n -OCH3. The pharmaceutical compositions of this disclosure may contain 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, desired properties (multiple) (e.g., viscosity) can be obtained by combining PEGs of different molecular weights. Specific examples of PEG, but not limited to these, include PEG100, PEG200, PEG300, PEG400, PEG500, and PEG600. PEG100 refers, for example, to 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 compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, saline solution, and 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 compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, and saline solution. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, saline solution, and a suspending agent. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, saline solution, and poloxamer (e.g., poloxamer 338, 188, or 207).

[0187] In some embodiments, suspensions are provided containing a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, in poloxamer and saline. In some embodiments, the concentration of poloxamer in saline is about 0.1 to about 20%. In some embodiments, the concentration of poloxamer in saline is about 0.1 to about 10%. In some embodiments, the concentration of poloxamer in saline 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 a particular embodiment, the concentration of poloxamer in saline is about 2%. In a particular embodiment, poloxamer is poloxamer 188. In a particular embodiment, the compound is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof. In a particular embodiment, the compound is formula (Ib) It is a compound of the formula (Ib). In certain embodiments, the compound is the sodium salt of the compound of formula (Ib).

[0188] In some embodiments, suspensions are provided containing compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, in poloxamer and mannitol. In some embodiments, the concentration of poloxamer in mannitol is about 0.1 to about 20%. In some embodiments, the concentration of poloxamer in mannitol is about 0.1 to about 10%. In some embodiments, the concentration of poloxamer in 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 poloxamer in mannitol is about 2%. In certain embodiments, poloxamer is poloxamer 188. In certain embodiments, the compound is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is the compound of formula (Ib). In certain embodiments, the compound is the sodium salt of the compound of formula (Ib).

[0189] In certain embodiments, the composition is disclosed as a solid injection dosage form, such as a solid depot form.

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

[0191] In certain embodiments, the pharmaceutical compositions disclosed herein are parenteral formulations. In certain embodiments, the formulation is administered subcutaneously to subjects requiring it. In certain embodiments, the formulation is administered intramuscularly to subjects requiring it.

[0192] In certain embodiments, the parenteral formulation comprises N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation is essentially derived from N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation comprises dimethyl sulfoxide.

[0193] In certain embodiments, the parenteral formulation comprises a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, and water. In certain embodiments, the parenteral formulation comprises a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, and water. In certain embodiments, the parenteral formulation further comprises an alcohol. In certain embodiments, the alcohol is ethanol. In certain embodiments, the parenteral formulation further comprises 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 contains about 0.1 molar equivalents to about 1.5 molar equivalents of the inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation contains about 0.5 molar equivalents to about 1.5 molar equivalents of the inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation contains about 1.0 to about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt).

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

[0195] In certain embodiments, the parenteral formulation consists essentially of the compound of formula (Ib) or its pharmaceutically acceptable salt, 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 the compound of formula (Ib) or its pharmaceutically acceptable salt, water, ethanol, polyethylene glycol 200, and NaOEt. In certain embodiments, the formulation contains about 0.1 to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation contains about 0.5 to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation contains about 1.0 to about 1.2 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation contains 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% to 20% ethanol, about 5% to 20% water, and about 60% to 90% PEG200. In certain embodiments, the solution formulation comprises about 10% to 15% ethanol, about 10% to 15% water, and about 70% to 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 contains about 0.1 to about 1.5 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation contains about 0.5 to about 1.5 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation contains about 1.0 to about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation contains 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 along with about 0.1 to about 1.5 equivalents of NaOH in about 10% ethanol, about 12% water, and about 77% PEG.

[0198] In certain embodiments, oral formulations of compounds of formula (Ia), (Ib), (IIa), and / or (IIb) are provided, comprising at least one excipient. The excipients may include ethanol, medium-chain triglycerides (e.g., MIGLYOL810, MIGLYOL821, MIGLYOL840, etc.), vitamin E TPGS, glycerin, and / or pharmaceutically acceptable oils (e.g., sesame oil, castor oil, safflower oil, vegetable oil, soybean oil, etc.). The oral formulations disclosed herein may include one or more suitable excipients in any combination. The excipients together may be present in an amount of >65% by weight, >70% by weight, >80% by weight, >90% by weight, 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 formulation comprises a compound 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 formulation comprises a compound 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 Includes 812. In certain embodiments, the oral formulation is of formula (Ia), (Ib), (II a), and / or (IIb), the compounds are contained in about 10% ethanol, about 20% vitamin E TPGS, and about 70% MIGLYOL 812. In certain embodiments, the oral formulation is prepared in hard gelatin capsules.

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

[0201] In particular, it should be understood that, in addition to the components described above, the compositions of these embodiments may also contain other agents conventional in the art, taking into consideration the type of composition in question, such as flavoring agents if suitable for oral administration.

[0202] In certain embodiments, a composition containing one variant of the active ingredient disclosed herein (e.g., a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof) does not contain any agent that affects the rate at which the active ingredient is metabolized. Therefore, it is understood that a composition containing a compound of formula (Ia) or (Ib) in a particular embodiment does not contain any agent that affects (e.g., slows, interferes with, or delays) the metabolism of any other active ingredient administered separately, sequentially, or simultaneously with the compound of formula (Ia) or (Ib). It is also understood that none of the methods, kits, manufactured articles, etc., detailed in certain embodiments herein contain any agent that affects (e.g., slows, interferes with, or delays) the metabolism of any other active ingredient administered separately, sequentially, or simultaneously with the compound of formula (Ia) or (Ib), or either one of the compounds of formula (Ia) or (Ib).

[0203] In some embodiments, a composition comprising one variant of the active ingredient disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof) does not contain any agent that affects the rate at which the active ingredient is metabolized. Therefore, it is understood that a composition comprising a compound of formula (Ia), (Ib), (IIa), and / or (IIb) in a particular embodiment does not contain any agent that affects (e.g., slows, interferes with, or delays) the metabolism of any other active ingredient administered separately, sequentially, or simultaneously with a compound of formula (Ia), (Ib), (IIa), and / or (IIb), either sequentially or simultaneously. It is also understood that none of the methods, kits, manufactured articles, etc., detailed in certain embodiments herein contain any compound of formula (Ia), (Ib), (IIa), and / or (IIb) or any agent that affects (e.g., delays, interferes with, or slows down) the metabolism of any other active ingredient 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, a method is disclosed for treating or preventing HIV infection in a subject (e.g., a human), comprising administering a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, a method is disclosed for treating or preventing HIV infection in a subject (e.g., a human), comprising administering a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, in a subject (e.g., a human), the replication of the HIV virus is inhibited, AIDS Disclosed are methods for treating or delaying the onset of AIDS, comprising administering a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, to a subject.

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

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

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

[0208] In certain embodiments, a method for treating HIV infection in a subject (e.g., a human) involves administering to the subject in need a therapeutically effective amount of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, such as an HIV protease inhibitor, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside inhibitor of reverse transcriptase, or an HIV nucleotide inhibitor of reverse transcriptase. Disclosed is a method comprising administering in combination with one or more additional therapeutic agents (e.g., one, two, three, or four, or one or two, or one to three, or one to four) selected from the group consisting of HIV transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic activators, and other drugs for treating HIV, as well as combinations thereof, in a therapeutically effective amount. In certain embodiments, a method for treating HIV infection in a subject (e.g., a human) is provided to a subject requiring it, comprising a therapeutically effective amount of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, a concomitant drug 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. 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 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV Disclosed is a method comprising administering in combination with one or more additional therapeutic agents (e.g., one, two, three, or four, or one or two, or one to three, or one to four) 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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof, in a therapeutically effective amount.

[0209] In some embodiments, a method is disclosed for treating HIV infection in a subject (e.g., a human), comprising administering to a subject in need a therapeutically effective amount of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, or four, or one or two, or one to three, or one to four) additional therapeutic agents selected from the group consisting of HIV protease inhibitors, 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 activators, 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 to a subject requiring the treatment of HIV by administering a therapeutically effective amount of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, a combination drug 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 modulators, Hck tyrosine kinase modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding nonintegrin 1 inhibitors, HIV GAG protein inhibitors. Disclosed are methods comprising administering in combination with one or more additional therapeutic agents (e.g., one, two, three, or four, or one or two, or one to three, or one to four) 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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof, in a therapeutic amount. In certain embodiments, compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, are disclosed for use in a subject (e.g., human) to treat HIV infection (e.g., HIV-1 or replication of the HIV virus (e.g., HIV-1) or to delay the onset of AIDS.

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

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

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

[0213] In certain embodiments, the method of use involves administration to a subject (e.g., a human) in need of treatment. In certain embodiments, the method of use involves administration to a subject (e.g., a human) at risk of developing AIDS. Compounds of formula (Ia) or (Ib), or pharmaceutically acceptable compounds, for use in therapy. Salts of the formula are disclosed herein. In one embodiment, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is intended for use in a subject (e.g., human) in a method of treating HIV infection or HIV virus replication or AIDS, or delaying the onset of AIDS.

[0214] In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, for use in therapy are disclosed herein. In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are for use in a subject (e.g., a human) to treat HIV infection or HIV virus replication or AIDS, or to delay the onset of AIDS. Compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, for use in a subject requiring such treatment or prevention of HIV infection are also disclosed herein. In certain embodiments, compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, are provided for use in a subject requiring such treatment or prevention of HIV infection. In certain embodiments, the subject requiring such treatment is a human infected with HIV. In certain embodiments, the subjects requiring it are individuals who are infected with HIV but have not developed AIDS. In certain embodiments, the subjects requiring it are individuals who are at risk of developing AIDS. In certain embodiments, the subjects requiring it are individuals who are infected with HIV and have developed AIDS.

[0215] In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are disclosed herein for use in methods of treating or preventing HIV infection in subjects requiring such treatment. In certain embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are provided for use in methods of treating HIV infection in subjects requiring such treatment. In certain embodiments, the subjects requiring such treatment are human beings infected with HIV. In certain embodiments, the subjects requiring such treatment are human beings infected with HIV but who have not developed AIDS. In certain embodiments, the subjects requiring such treatment are subjects at risk of developing AIDS. In certain embodiments, the subjects requiring such treatment are human beings infected with HIV and who have developed AIDS.

[0216] In one embodiment, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV infection in a subject requiring such treatment, 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 described herein. In one embodiment, the additional therapeutic agent is a combination drug 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 dimerizing antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulator, Hck tyrosine kinase modulator, mixed series kinase-3 (MLK-3) inhibitor The following are selected from the group consisting of harmful agents, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, 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 activators, and other drugs for treating HIV, as well as combinations thereof.

[0217] In some embodiments, compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically 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 described herein for use in methods of treating or preventing HIV infection in subjects requiring such treatment or prevention. In one embodiment, the additional therapeutic agent is a combination drug 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 dimerizing antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulator, Hck tyrosine kinase modulator, mixed-series kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, Rev protein inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, HIV ribonuclease H inhibitor, retrocyclin modulator, CDK-9 inhibitor, dendritic ICAM-3-binding nonintegrin 1 inhibitor, HIV GAG protein inhibitor, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide-based inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic activators, and other drugs for treating HIV, or 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 requiring it, 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. In a particular 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 requiring it, 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.

[0218] In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are provided for use 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, in a method for treating or preventing HIV infection in subjects requiring it. In certain embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are provided for use 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, in a method for treating or preventing HIV infection in subjects requiring it.

[0219] In certain embodiments, compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, are provided for use, for example, pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), to prevent HIV infection from becoming established and / or to prevent the virus from establishing a persistent infection and / or to prevent the onset of disease symptoms and / or to prevent the virus from reaching detectable levels in the blood when an individual has been exposed to the virus. 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, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) includes administering compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) includes 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) includes 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, compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof, are provided for use, for example, pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), to prevent HIV infection from becoming established and / or to prevent the virus from establishing a persistent infection, and / or to prevent the onset of disease symptoms, and / or to prevent the virus from reaching detectable levels in the blood, if an individual has been exposed to the virus. Thus, in certain embodiments, methods for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) are provided. For example, methods for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) This includes 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) includes 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) includes 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, a method for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) includes administering a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with safer sexual activity. In certain embodiments, a method for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) includes administration to an individual at risk of HIV infection. Examples of individuals at high risk of HIV infection include, without limitation, individuals at risk of HIV sexual transmission.

[0222] In some embodiments, a method for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) includes administering compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, in combination with safer sexual activity. In certain embodiments, a method for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) includes administration to individuals at risk of HIV infection. Examples of individuals at high risk of HIV infection include, without limitation, individuals at risk of HIV sexual transmission.

[0223] In certain embodiments, the reduction in the risk of HIV infection is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In certain embodiments, the reduction in the risk of HIV infection is at least about 75%. In certain embodiments, the reduction in the 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 pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection in a person who has or is at risk of having HIV infection is disclosed.

[0225] In some embodiments, the use of compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, is disclosed for the manufacture of pharmaceuticals for the treatment of HIV infection in humans who have or are at risk of having HIV infection.

[0226] Compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, for use in the therapeutic treatment of AIDS or in delaying the onset of AIDS are also disclosed herein.

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

[0228] Compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, for use in the prophylactic or therapeutic treatment of HIV infection are also disclosed herein.

[0229] In some embodiments, formula (I) is used for prophylactic or therapeutic treatment of HIV infection. Compounds of (a), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are disclosed herein.

[0230] In certain embodiments, compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, can be used as research tools (for example, to test the inhibition of HIV reverse transcriptase in subjects or in vitro).

[0231] In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically 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] Compounds of formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof (also referred to herein as the active ingredient), can be administered by any route appropriate to the condition being treated. Appropriate routes include oral, rectal, nasal, topical (including oral buccal and sublingual), percutaneous, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be recognized that the preferred route may vary, for example, depending on the recipient's condition. 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, compounds of formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof (also referred to herein as active ingredients) can be administered by any route appropriate to the condition being treated. Appropriate routes include oral, rectal, nasal, topical (including oral buccal and sublingual), percutaneous, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It should be recognized that preferred routes may vary, for example, depending on the recipient's condition. 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, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts 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 compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof.

[0235] In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, may be administered using an automated injector containing 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 compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof. Administration regimen

[0236] Compounds, for example, compounds of formula (Ia) or (Ib), or pharmaceutically acceptable compounds The salt of the compound may be administered to the subject 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, according to an effective dosing regimen. In one variant, the compound is administered on a daily or intermittent schedule. In one variant, the compound is administered on a monthly schedule. In one variant, the compound is administered every 2 months. In one variant, the compound is administered every 3 months. In one variant, the compound is administered every 4 months. In one variant, the compound is administered every 5 months. In one variant, the compound is administered every 6 months.

[0237] In some embodiments, a compound, for example, a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, can be administered to a subject 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, according to an effective dosing regimen. In some embodiments, the compound is administered daily or intermittently. In some embodiments, the compound is administered monthly. In some embodiments, the compound is administered every 2 months. In some embodiments, the compound is administered every 3 months. In some embodiments, the compound is administered every 4 months. In some embodiments, the compound is administered every 5 months. In some embodiments, the compound is administered every 6 months.

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

[0239] The dosage or frequency of administration of the compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, may be adjusted between treatments at the discretion of the administering physician.

[0240] In some embodiments, the dosage or frequency of administration of compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, may be adjusted between treatments at the discretion of the administering physician.

[0241] The compound can be administered to a subject (e.g., a human) in an effective dose. 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 dose. 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 pharmaceutically acceptable salts thereof, can be administered in effective doses. For example, doses can range from 1 mg to 1000 mg of the compound. In certain embodiments, doses are approximately 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, doses are approximately 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 pharmaceutically acceptable salts thereof, can be administered in effective doses. For example, doses can range from 1 mg to 1000 mg of the compound. In certain embodiments, doses are approximately 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, doses are approximately 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 compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are administered in a once daily dose. In some embodiments, the compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are administered in a once daily dose of approximately 1 mg.

[0245] In some embodiments, the compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are administered monthly. In some embodiments, the compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are administered monthly in doses of approximately 100 mg.

[0246] In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are administered every six months. In some embodiments, compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof, are administered in doses of approximately 600 mg every six months. Kits and manufactured articles

[0247] This disclosure relates to a kit comprising a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. In one embodiment, the kit may include one or more additional therapeutic agents described herein. The kit may further include instructions for use, for example, in the inhibition of HIV reverse transcriptase, for example, in the treatment of HIV infection or AIDS, or for use as a research tool. Instructions are generally written instructions, but an electronic storage medium (e.g., a magnetic diskette or optical disk) containing the instructions is also acceptable.

[0248] In some embodiments, this disclosure relates to a kit comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof. In one embodiment, the kit may include one or more additional therapeutic agents previously described herein. The kit may be used, for example, in the inhibition of HIV reverse transcriptase, for example, in the treatment of HIV infection or AIDS, or for use as a research tool, etc. Instructions may further be included. Instructions are generally written instructions, but electronic storage media containing instructions (e.g., magnetic diskettes or optical disks) are also acceptable.

[0249] This disclosure also relates to a pharmaceutical kit comprising one or more containers containing a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. Accompanying such container(s) as may be a notice in the form prescribed by the government agency regulating the manufacture, use, or sale of the medicinal product, which reflects the government agency's approval for manufacture, use, or sale for human administration. Each component(s) (if there are more than one component) may be packaged in a separate container, or some components may be combined in a single container, where cross-reactivity and shelf life are acceptable. The kit may be in unit dosage forms, bulk packages (e.g., multi-dose packages), or subunit doses. The kit may also contain multiple unit doses of the compound and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., hospital pharmacies and dispensing pharmacies).

[0250] In some embodiments, the disclosure also relates to a pharmaceutical kit comprising one or more containers containing compounds of formula (Ia), (Ib), (IIa), and / or (IIb), or pharmaceutically acceptable salts thereof. Accompanying such containers may, as required, be a notice in the form prescribed by the government agency regulating the manufacture, use, or sale of the medicinal product, which reflects the government agency's approval for manufacture, use, or sale for human administration. Each component (if there is more than one component) may be packaged in a separate container, or some components may be combined in a single container, where cross-reactivity and shelf life are acceptable. The kit may be in unit dosage forms, bulk packages (e.g., multi-dose packages), or subunit doses. The kit may also contain multiple unit doses of the compound and instructions for use, and may be packaged in quantities sufficient for storage and use in a pharmacy (e.g., hospital pharmacies and dispensing pharmacies).

[0251] Also disclosed herein are manufactured articles containing a unit dose of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in appropriate packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The manufactured articles may be further sterilized and / or sealed. In some embodiments herein, manufactured articles containing a unit dose of a compound of formula (Ia), (Ib), (IIa), and / or (IIb), or a pharmaceutically acceptable salt thereof, in appropriate packaging for use in the methods described herein are disclosed herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc. The manufactured articles may be further sterilized and / or sealed. nomenclature

[0252] The names of the compounds of formulas (Ia) and (Ib) in this disclosure are as generated using ChemBioDraw Ultra 11. [ka] This is N-(1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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]pyrazole-1-yl)acetamide. [ka] This is N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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]pyrazole-1-yl)acetamide.

[0253] The names of the compounds of formulas (IIa) and (IIb) in this disclosure are as generated using ChemBioDraw Ultra 14. [ka] This is N-(1-(3-(4-chloro-3-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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]pyrazole-1-yl)acetamide. [ka] This is N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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]pyrazole-1-yl)acetamide. Synthesis of compounds of formulas (Ia), (Ib), (IIa), and (IIb)

[0254] This disclosure also covers processes and intermediates useful for preparing the subject compound or pharmaceutically acceptable salts thereof.

[0255] Unless otherwise stated, the methods and techniques of this disclosure are generally carried out in accordance with the prior art methods well known and described in the 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; and Smith, *March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure*, 7th edition, Wiley-Interscience, 2013.

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

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

[0258] In some embodiments, intermediates useful for preparing compounds of formula (IIa) or (IIb) of the present disclosure are provided. For example, these intermediates comprise one or a combination of compounds 1, 10, 20, and 25-37 or their salts. 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 chromatographic means known in the art, including, for example, high-performance liquid chromatography (HPLC), preparative thin-layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion-exchange chromatography. Any suitable stationary phase, including normal-phase and reverse-phase chromatography as well as ionic resins, can be used. Most typically, the disclosed compounds are purified via silica gel chromatography and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd edition, edited by L.R. Snyder and J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, edited by E. Stahl, Springer-Verlag, New York, 1969.

[0260] During any of the processes for preparing the compound of the subject, it may be necessary and / or desirable to protect any sensitive or reactive groups of the molecules involved. This can be achieved by conventional protecting group means, e.g., as described in standard practice, e.g., TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 4th edition, Wiley, New York, 2006. Protecting groups can be removed at a convenient subsequent step using methods known from the art.

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

[0262] The compounds disclosed herein may exhibit atropisomerism arising from steric hindrance affecting the axial rotational velocity around single bonds. The resulting conformational isomers can be observed as distinct entities by characterization techniques such as NMR and HPLC. The compounds disclosed herein may exist as mixtures of atropisomers. However, the detection of atropisomers depends on factors such as temperature, solvent, purification conditions, and the time scale of the spectroscopic analysis technique. Interconversion rates at room temperature have half-lives ranging from minutes to hours, hours to days, or days to years. The ratio of atropisomers at equilibrium does not have to be single. The characterization data presented herein, but not limited to these, may not represent equilibrium states depending on isolation and characterization conditions, which may include handling, solvents used, and temperature. Typical synthesis methods of the compounds of this disclosure are described in the following scheme and in the specific examples that follow. The following examples are illustrative and are not intended to limit this disclosure. [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]pyrazole-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]pyrazole-1-yl)acetic acid (8b): (Example 1) [ka] Synthesis of lithium 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hexane-2-ylidene)ethane-1-oleate (2): Bicyclo[3.1.0]hexane-3-one (95.6 g, 0.99 mol), 2,2,2-trifluoroethyl acetate (113.2 mL, 0.95 mol), and THF (50 mL) were added to the reactor. The reaction mixture was cooled to 0°C. The internal temperature was maintained at ≤1°C. LiHMDS (lithium bis(trimethylsilyl)amide) (1.0 M solution in 1 L of THF, 1 mol) was added via a dropping funnel at a steady rate. After the addition was complete, hexane (235 mL) was added via a dropping funnel in a steady flow and stirred for 15 minutes. The resulting solid was collected by filtration, washed with hexane (3 × 400 mL), and dried to obtain the title compound. Synthesis of ethyl 2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate (3): Lithium 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hexane-2-ylidene)ethane-1-oleate (177.2 g, 0.89 mol) and EtOH (ethanol) (779 mL) were added to the reactor. The temperature was set to 0°C and maintained at 0°C. HCl in dioxane (4.0 N, 443 mL) was added via a dropping funnel, followed by solid ethyl hydrazinoethyl HCl salt (138.4 g, 0.90 mol). The reaction temperature was adjusted to 35°C. After 1 hour, the reaction volume was reduced by approximately 40% under reduced pressure by distillation. Water (1.3 L) was added with vigorous stirring, and the temperature was adjusted to 15°C. The resulting solid was collected by filtration, washed with water (3 × 500 mL) and hexane (3 × 400 mL), and dried to obtain 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]pyrazole-1-yl)acetate (4): Ethyl 2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (291.2 g, 1.06 mol), acetonitrile (1.65 L), and water (825 mL) were added to the reactor. To this, N-hydroxyphthalimide (17.4 g, 0.103 mol) and NaClO2 (41.0 g, 0.45 mol, approximately 20% of the total amount added) were 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 the consumption of the starting materials, the temperature was adjusted to 20°C, and aqueous sodium bisulfite (40% w / w, 350 mL) was added via a dropping funnel. Ethyl acetate (1.75 L) was added, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (500 mL). The organic layers were combined and washed with saturated aqueous solution NaHCO3 (500 mL) and 1:1 water / brine (500 mL). The organic layers were concentrated under reduced pressure and co-evaporated with isopropyl acetate (IPAc) (300 mL). The crude solid was crystallized from an IPAc / heptane mixture. The resulting solid was collected by filtration, washed with heptane, and dried to obtain 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]pyrazole-1-yl)acetic acid (5): Ethyl 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (80.40 g, 278.95 mmol) was dissolved in 2-MeTHF (2-methyltetrahydrofuran) (167 mL), to which 2 M aqueous sodium hydroxide (167 mL) was added. After stirring at room temperature for 25 minutes, the reaction mixture was diluted with 2-MeTHF and slowly acidified by the dropwise addition of concentrated HCl. The organic layer was isolated, and the aqueous layer was extracted with additional 2-MeTHF. The combined organic layers were washed with saturated aqueous sodium chloride, then dehydrated with sodium sulfate, filtered, and concentrated. The resulting oil was placed in ethyl acetate. Hexane was added with vigorous stirring until solid formation was observed. The solid was isolated by filtration and dried to obtain the title compound. MS (m / z) 259.00 [MH] - . 2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4 Synthesis of cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolane]-1(3bH)-yl)acetic acid (6): 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid (3.0 g, 11.5 mmol) was dissolved in dichloromethane (DCM) (25 mL), to which 1,2-ethanedithiol (1.07 mL, 12.68 mmol) was added, followed by the addition of boron trifluoride-acetic acid complex (4.0 mL, 28.8 mmol). The reaction mixture was stirred overnight at room temperature. Water (60 mL) and 2-MeTHF (60 mL) were added to the reaction mixture. The organic layer was isolated, dehydrated with sodium sulfate, filtered, and concentrated. The crude product was dissolved in ethyl acetate (2 mL), and the solution was diluted with hexane (12 mL) while vigorously 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]pyrazole-1-yl)acetic acid (7): A suspension of 1,3-dibromo-5,5-dimethylhydantoin (12.75 g, 44.6 mmol) in DCM (35 mL) was mixed with pyridine hydrofluoric acid (5.0 mL) at 0°C. The suspension was stirred at 0°C for 10 minutes. To the suspension, a solution of 2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolan]-1(3bH)-yl)acetic acid (5.00 g, 14.9 mmol) was added dropwise. After the addition was complete, the reaction mixture was stirred at 0°C for a further 15 minutes. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate (300 mL) while stirring vigorously. The organic layer was removed, and the aqueous layer was acidified to pH approximately 1 with concentrated HCl. The aqueous phase was extracted with three portions of MTBE (methyl tert-butyl ether). The combined organic layers were dehydrated with sodium sulfate, filtered, and concentrated. The resulting solid was placed in MTBE (16 mL) and filtered to remove any additional solids. The solution was then extracted with 2N NaOH (16 mL). The aqueous layer was diluted with water (16 mL) while vigorously stirring and stirred at room temperature for 15 minutes. The resulting solid was removed by filtration. A solid precipitate was obtained by acidifying the aqueous layer to approximately pH 1 by slowly adding concentrated HCl dropwise while vigorously stirring. The title compound was obtained by isolating the solid by filtration. 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]pyrazole-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]pyrazole-1-yl)acetic acid (8b): 2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetic acid was separated into its constituent enantiomer, the title compound, 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: 200 mL / min; Column temperature: 38°C; UV detection: 220 nm; Sample preparation: Compound dissolved in isopropanol until approximately 45 mg / mL; Injection: 6.5 mL per injection. Analytical SFC [Mobile phase: A for CO2 and B for isopropanol (0.05% DEA); Gradient: B 20%; A; Flow rate: 2.35 mL / min; Column: Chiralpak IC-3, 150×4.6 mm, 3 μm; Wavelength: 254 nm] 8a: t=3.39 min, 8b: t=2.17 min. Compound 8a- 1 ¹H 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-indazole-3-amine (10): Hydrazine monohydrate (5.77 mL) was added to 3-bromo-6-chloro-2-fluorobenzonitrile (13.9 g, 59.3 mmol) in ethanol (60 mL). The reaction mixture was heated at 80 °C for 3 hours. After cooling to ambient temperature, 20 mL of ethanol (EtOH) was added and the mixture was stirred. The solid was isolated by filtration, washed with cold ethanol (EtOH), and dried to obtain the title compound. MS (m / z) 247.9 [M+H] + . Synthesis of 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine (11): 7-bromo-4-chloro-1H-indazole-3-amine (397.2 g, 1.6 mol) and Cs2CO3 (1052 g, 3.2 mol) were added to a reactor and then diluted with DMF (dimethylformamide) (4000 mL). 2,2,2-trifluoroethyltrifluoromethanesulfonate (463.2 g, 1.9 mol) was slowly added via a dropping funnel. After the addition was complete, the reaction mixture was stirred for 1 hour, during which time H2O (16 L) was slowly added. After the addition was complete, the mixture was stirred at 15°C for 12 hours. The slurry was filtered, and the collected solid was suspended in DMF (800 mL). H2O (4800 mL) was added, and the resulting solid was collected by filtration and dried to obtain 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-indazole-3-amine (12): 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine (15.00 g, 45.66 mmol), bis(pinacolato)diborone (17.39 g, 68.49 mmol), potassium propionate (15.36 g, 136.98 mmol), dioxane (90 mL), and DMF (dimethylformamide) (30 mL) were added to the reaction vessel. Bis(triphenylphosphine)palladium(II) dichloride (0.64 g, 0.91 mmol) was added, and the reaction solution was degassed by bubbling with argon for 2 minutes. The reaction mixture was heated at 105°C for 4 hours. After cooling to ambient temperature, the reaction mixture was filtered through a Celite pad and washed with silica gel using ethyl acetate. 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 hours. The solid was collected by filtration and dried to produce 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)buta-1-yine (14): 3-chloro-3-methylbuta-1-yine (15.00 g, 146.3 mmol, 16.4 mL) was added dropwise 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). The resulting reaction mixture was heated to 40 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with water and brine. The organic layer was collected, dehydrated with sodium sulfate, and then filtered. The solution was concentrated under vacuum and purified by silica gel chromatography to obtain the title compound. Mp: 114.8~115.5 °C. 1 ¹H 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-dibromopyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (16): 3,6-Dibromopicoline aldehyde (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 to the reaction mixture as a solid all at once. The reaction mixture was stirred for 2 hours and then cooled to 5°C. Water (1.3 L) was added to the reaction mixture. The resulting suspension was stirred for 1 hour, the solid was isolated by filtration, washed with water (5 × 100 mL), and dried to obtain the title compound. MS (m / z) 368.9 [M + H] + . Synthesis of (S)-N-((S)-1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (17): (S)-N-((3,6-dibromopyridine-2-yl)methylene)-2-methylpropane-2-sulfinamide (65.5 g, 177.95 mmol) was added to the reaction vessel, followed by DMF (dimethylformamide) (260 mL). The mixture was stirred for 5 minutes until homogeneous, and the solution was cooled to 8°C. Zinc (3,5-difluorobenzyl)bromide (0.5 M in THF (tetrahydrofuran), 516.04 mL) was added dropwise to the reaction mixture over 90 minutes. The mixture was stirred for a further 2.5 hours. 5% AcOH (acetic acid) in water (640 mL) was added to the reaction mixture over 10 minutes, followed by CPME (cyclopentyl methyl ether) (320 mL) all at once. 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, dehydrated with Na₂SO₄, and filtered. MeOH (methanol) (33 mL) was added to the crude mixture. 3 M HCl in CPME (128 mL) was added dropwise to the stirred mixture over 15 minutes. After stirring for 1 hour, the precipitate was removed by filtration. The filtrate was diluted with hexane (300 mL), and the product was extracted with water (450 mL). The aqueous layer was basicized with 8 M NaOH and extracted with CPME (375 mL). The title compound was obtained in solution by washing the organic layer with brine, dehydrating with Na₂SO₄, and filtering, and this was used directly in the next reaction. MS (m / z) 497.0 [M + H] + . Synthesis of (S)-1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethane-1-amine (18): The solution of (S)-N-((S)-1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide was diluted to 700 mL in CPME, and acetonitrile (350 mL) was added. Concentrated HCl (37%, 16.4 mL) was added dropwise to the stirred mixture at room temperature for 10 minutes. The thick slurry was vigorously stirred for 4 hours. The solid was filtered and washed with CPME (cyclopropyl methyl ether):ACN in a 2:1 ratio to obtain the title compound. MS (m / z) 393.3 [M+H] + . Synthesis of tert-butyl(S)-(1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (19): In a reaction vessel, 190 mL of 2-MeTHF, 190 mL of water, and 46.9 g (0.11 mol) of (S)-1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethane-1-amine were added, followed by the gradual addition of 30.34 g (0.36 mol) of NaHCO3. The reaction mixture was cooled to 5°C, and 27.47 g (0.13 mol) of di-tert-butyl dicarbonate was added. The reaction mixture was stirred at 0°C for 2 hours, and then stirred at ambient temperature for 2 hours. 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 silica column chromatography to obtain the title compound. MS (m / z) 492.8 [M+H] + . 1 ¹H 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)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (20) 50.00 g, 101.8 mmol) tert-butyl(S)-(1-(3,6-dibromopyridine-2-yl)-2-(3,5-difluorophenyl)ethyl) carbamate, 17.86 g, 122.2 mmol 3-methyl-3-methylsulfonyl buta-1-yin, 90 mL DMF (dimethylformamide), and 42.5 mL, 305.4 mmol Et3N (trimethylamine) were added to the reactor. The reaction mixture was heated to 50°C. 2.14 g, 3.1 mmol bis(triphenylphosphine)palladium(II) dichloride and 0.58 g, 3.1 mmol copper(I) iodide were added. After 30 minutes, the reaction mixture was diluted with 200 mL MeCN (acetonitrile), and then 200 mL of 7% aqueous NH4Cl was added dropwise. A slurry was formed and adjusted 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 then with MTBE (methyl tert-butyl ether) (75 mL). The title compound was obtained by drying the solid. MS (m / z) 556 [M+H] + . 1 ¹H 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). * indicates 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-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (21): tert-butyl(S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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-indazole-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 with argon for 60 seconds. After degassing, a reflux condenser was attached to the reaction flask, and it was heated overnight at 80°C. 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 obtain the title compound. MS (m / z) 726.1 [M+H] + . 1¹H 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)methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (22): tert-butyl(S)-(1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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. Triethylamine (21.82 mL, 156.54 mmol) was added, followed by the slow addition of methanesulfonyl chloride (8.08 mL, 104.36 mmol). Once the reaction was complete, water (200 mL) was added and the mixture was 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, dehydrated with MgSO4, filtered, and concentrated to a small volume. Hexane was added. The liquid suspension was decanted. The title compound was obtained by drying the remaining solid under reduced pressure. MS(m / z): 882.69[M+H] + . 1 ¹H 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)buta-1-in-1-yl)pyridine-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)-N-(methylsulfonyl)methanesulfonamide (23): 39 g, 44 mmol of tert-butyl(S)-(1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (39 g, 44 mmol) was dissolved in methylene chloride (120 mL), to which trifluoroacetic acid (80 mL) was added. The reaction mixture was stirred at ambient temperature for 50 minutes. The reaction mixture was diluted with methylene chloride and slowly poured into ice-cold saturated aqueous solution NaHCO3. The organic layer was separated, washed with water and brine, dehydrated with MgSO4, filtered, and concentrated to dryness to obtain the title compound. MS(m / z):782.84[M+H] + . 1 1H 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-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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]pyrazole-1-yl)acetamide (24): (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-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]pyrazole-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 minutes to obtain intermediate 23b, which was not isolated (MS (m / z) 1046.65 [M+H]). + ). To this solution, 5.0 mL of 2N sodium hydroxide aqueous solution was added. 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 diluted with two portions of 5% lithium chloride solution (with two Portions of 5% lithium chloride solution n) The mixture was washed, followed by washing with brine. The organic layer was isolated, dehydrated with sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain the title compound as an amorphous solid. MS (m / z) 968.24 [M+H] + . 1 1H 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). To more completely 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]pyrazole-1-yl)acetic acid (32) (Example 6) [ka] Synthesis of lithium 2,2-difluoro-1-(3-oxobicyclo[3.1.0]hexane-2-ylidene)ethane-1-oleate (25): The title compound was prepared using 2,2-difluoroethyl acetate according to the method presented for the synthesis of compound 2. 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]pyrazole-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]hexane-2-ylidene)ethane-1-oleate (247 g, 1.32 mol). While maintaining the internal temperature at around 20°C, HCl (4N in dioxane) (0.685 L, 2.74 mol) was slowly added to the mixture. After the addition of ethyl hydrazinohydrochloride (212.05 g, 1.372 mol), the resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was heated overnight at 50°C. 10N aqueous NaOH (0.548 L, 5.48 mol) was slowly added to the reaction mixture, and the internal temperature was maintained at 20°C. After the 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 filtered cake was washed with hexane (1 L) and dried in a vacuum oven at 56°C to obtain the title compound, which was then used directly in the next step. MS(m / z)229.1[M-Na+H] + . Ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H- Synthesis of clopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetate (27): Ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate from the previous step was added to a 4 L reactor, followed by the addition of EtOH (3.5 L) and concentrated H2SO4 (152 ml, 2.74 mol). The resulting mixture was stirred under reflux for 2 hours. The EtOH was reduced to 150 ml under vacuum. H2O (500 ml) was slowly added. The solid was collected and washed with H2O and NaHCO3, followed by washing with hexane (500 ml). The solid was dried in an oven at 45°C to obtain 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]pyrazole-1-yl) acetate (28): The title compound was prepared using ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate according to the method presented for the synthesis of compound 4. 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]dithiolan]-1(3bH)-yl)acetate (29): Ethane-1,2-dithiol (88.0 g, 0.94 mol) was added in one batch to ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (148.5 g, 0.55 mol) in DCM (2.0 L), followed by BF3·2AcOH (175.8 g, 0.94 mol). The reaction mixture was stirred at room temperature for 12 hours. The system was cooled to 0°C and quenched with saturated aqueous solution NaHCO3 (1000 ml). The organic layer was separated, washed with brine (500 ml), and dehydrated with Na2SO4. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography to obtain 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]pyrazole-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 minutes. The reaction mixture was stirred at -78°C for 30 minutes. A solution of ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolan]-1(3bH)-yl) acetate (40 g, 0.12 mol) in DCM (80 mL) was added dropwise over 15 minutes at -78°C. The resulting mixture was stirred for 30 minutes, then slowly warmed to -30°C and stirred for 1.5 hours. 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) and brine (500 mL), and dehydrated with Na2SO4. The crude product was obtained by removing the solvent under vacuum, and this was further purified by column chromatography to obtain 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]pyrazole-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]pyrazole-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]pyrazole-1-yl) acetate was separated into its constituent enantiomer, the title compound, 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 μm; Wavelength: 220 nm] 31a: t=5.30 min, 31b: t=7.00 min. Compound 31a- 1 ¹H 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]pyrazole-1-yl)acetic acid (32): Ethyl 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-1-yl) acetate (26 g, 89.0 mmol) was dissolved in THF (180 mL), MeOH (90 mL), and water (90 mL), to which LiOH (5.13 g, 213.5 mmol) was added. The mixture was stirred for 4 hours. The mixture was concentrated to remove most of the THF and MeOH, and the aqueous solution 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, dehydrated with Na2SO4, filtered, and concentrated under vacuum to obtain the title compound. MS (m / z) 265.0 [M+H]+ . (Example 7) [ka] Synthesis of 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-3-amine (33): In a 2000 mL four-necked round-bottom flask, 7-bromo-4-chloro-1H-indazole-3-amine (130 g, 527.40 mmol, 1.00 equivalent), N,N-dimethylformamide (1300 mL), and Cs2CO3 (260 g, 797.99 mmol, 1.50 equivalent) were added and stirred for 20 minutes. Subsequently, 1,1-difluoro-2-iodoethane (122 g, 635.59 mmol, 1.20 equivalent) was added. The resulting mixture was stirred overnight at 65°C, then cooled to room temperature, quenched by adding 3 L of water / ice, and extracted with 3 × 1.5 L of ethyl acetate. The combined organic layers were washed with 1 × 1.5 L of H2O and 1 × 1.5 L of brine, dehydrated with anhydrous sodium sulfate, concentrated under vacuum, and recrystallized from ethanol to obtain 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-indazole-3-amine (34): A 3000 mL four-necked round-bottom flask, purged with an inert nitrogen atmosphere and maintained, was filled with 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-3-amine (80 g, 257.63 mmol, 1.00 equivalent), 1,4-dioxane (800 mL), N,N-dimethylformamide (800 mL), KOAc (76 g, 774.40 mmol, 3.00 equivalent), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (197 g, 775.78 mmol, 3.00 equivalent), and Pd(PPh3)2Cl2 (8 g, 11.40 mmol, 0.04 equivalent). The mixture was stirred at 110°C for 4 hours, then cooled to room temperature, quenched by adding 5 L of water / ice, and extracted with 2 × 2 L of ethyl acetate. The combined organic layer was washed with 1 × 1 L of H₂O and 1 × 1 L of brine, dehydrated with 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 obtain 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-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (35): tert-butyl(S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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-indazole-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 and subjected to argon. Dimethoxyethane (2.5 mL) and water (0.3 mL) were added, and the reaction mixture was heated to 130°C for 7 minutes in a microwave reactor (Biotage® Initiator+). The reaction mixture was cooled to room temperature and partitioned between HCl and 0.1N HCl. The aqueous layer was removed, and the organic layer was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography to obtain 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-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (36): tert-butyl(S)-(1-(3-(3-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-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. Cyclopropane-1-sulfonyl chloride (222 μL, 2.2 mmol) was added. The reaction mixture was stirred at 70°C until the reaction was complete. Water was added and the mixture was stirred for 1 hour. The resulting precipitate was collected by vacuum filtration, then dissolved in methylene chloride, dehydrated with MgSO4, filtered, and concentrated. The residue was purified by silica chromatography to obtain the title compound. MS (m / z): 812.44 [M+H] + . 1 ¹H 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)buta-1-in-1-yl)pyridine-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-3-yl)cyclopropanesulfonamide (37): To a solution of tert-butyl(S)-(1-(3-(4-chloro-3-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (705 mg, 0.87 mmol) in methylene chloride (5 mL), trifluoroacetic acid (3 mL) was added. The reaction mixture was stirred for 1 hour, then slowly poured into a saturated sodium bicarbonate solution. This was extracted with ethyl acetate. The organic layer was separated, washed with brine, dehydrated with MgSO4, filtered, and concentrated to obtain the title compound. MS (m / z): 712.34 [M+H]+. 1 ¹H 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-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazole-7-yl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cycloprop Synthesis of pa[3,4]cyclopenta[1,2-c]pyrazole-1-yl)acetamide (38): (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)buta-1-in-1-yl)pyridine-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazole-3-yl)cyclopropanesulfonamide (514 mg, 0.72 mmol), 2-((3bS,4aR)-3-(difluoromethyl)-5,5-diph Luoro-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-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 minutes. Water was added and the mixture was stirred for 1 hour. The resulting precipitate was collected by vacuum filtration, then dissolved in methylene chloride, dehydrated with MgSO4, filtered, and concentrated. The residue was purified by RP-HPLC to obtain the title compound as the 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 the antiviral assay, 0.4 μL of the compound at the 189X test concentration, 3-fold serially diluted in DMSO, was added in four consecutive lines 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 (10 concentrations). 1 mL aliquots of MT4 cells were pre-infected at 37°C for 3 hours with 25 μL of cell growth medium (pseudoinfection) or fresh 1:250 dilution of HIV-IIIb enriched ABI stock (0.004 moi). Infected and uninfected cells were diluted in cell growth medium, and 35 μL (2000 cells) was added to each well of an assay plate. The assay plate was 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 incubation at room temperature for 10 minutes, and then chemiluminescence was read using an Envision plate reader (PerkinElmer). The EC25 was defined as the compound concentration that caused a 50% reduction in the luminescence signal, which is a measure of HIV-1 replication. 50 The value was calculated. Example B Test B: Cytotoxicity assay Except for using uninfected cells, the same protocol as described in the antiviral assay (Test A) was used to analyze the cytotoxicity of the compound and the corresponding CC. 50 The value was determined. The compounds disclosed herein demonstrate antiviral activity (Test A) as shown in the table below, compared to compounds A and B. [Table 1-1] [Table 1-2] Example C Study C. Pharmacokinetic analysis after intravenous administration to Sprague Dolly rats, Beagle dogs, and cynomolgus monkeys. Test samples and formulations IV doses of compounds 24 and 38 were formulated at 0.5 mg / mL in 5% ethanol, 20% PG, 45% PEG300, and 30% pH2 (0.01N HCl) water. Intravenous infusion doses of compounds A and B were formulated at 0.5 mg / mL in a sterile solution of 5% ethanol, 45% PEG400, and 50% water (pH2.0). All IV formulations were in solution form. Animals used Each rat IV dose group consisted of three male SD rats. At the time of administration, the animals were weighed between 0.317 and 0.355 kg. The animals were fasted overnight before dose administration and for up to 4 hours after administration. Each dog IV dose group consisted of three male, previously unexperimented Beagle dogs. At the time of administration, the animals were weighed between 10 and 12 kg. The animals were fasted overnight before dose administration and for up to 2 hours after administration. Each IV-dose group of cynomolgus monkeys consisted of three male cynomolgus monkeys that had not been previously used in experiments. At the time of administration, the animals were weighed to approximately 3.2–4 kg. The animals were fasted overnight before dose administration and for up to two hours after administration. dosage In the IV infusion group, the test compound was administered intravenously over a 30-minute period. The infusion rate was adjusted according to each animal's body weight to ensure that a dose of 1 mg / kg was delivered at 2 mL / kg. Sample collection At identified time points after drug administration, a series of 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, and immediately placed on wet ice until centrifugation for plasma. Centrifugation was initiated within 1 hour of collection. All samples were placed in 96-well tubes and maintained at approximately -70°C on dry ice before storage. Determination of plasma concentrations of the compound of formula (I). The plasma concentrations of the test compound were measured using LC / MS / MS methods. calculation Non-compartmental pharmacokinetic analysis was performed on plasma concentration-time data. A summary of the pharmacokinetic parameters is shown in the table below. [Table 2] [Table 3] Example D Experiment D. Metabolic stability in cultured human liver cells. Radiolabeled test compounds were prepared in which tritium was introduced into the structure in place of one or more hydrogen atoms, according to methods known in the art. 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. Two incubation cycles were performed. Cell-free controls and positive controls were included in the incubation. Incubation was carried out in a 37°C incubator under a high humidity atmosphere of 95% air / 5% CO2 (v / v) with gentle shaking. After 0, 1, 3, and 6 hours, aliquots (100 mL) were taken and added to 200 mL of quench solution containing 0.1% (v / v) TFA in 5% water / 95% acetonitrile (v / v). The sample was placed in a shaker for 10 minutes, followed by centrifugation at 3000g for 30 minutes. The supernatant sample was analyzed using a Dionex HPLC / PerkinElmer Flow Scintillation Analyzer as described below. Liquid chromatography - Radiochromatography Radiomatic 625TR Flow Scintillation Analyzer connected to a Dionex / Chromeleon chromatography system Quantification was performed by comparing the radiolabeled metabolites measured with the parent peak. 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). A sample injection volume of 100 mL was used and the flow rate was 1 mL / min. The gradient was as follows: Mobile phase B was linearly increased from 0% to 75% over 47 minutes, maintained at 75% for 3 minutes, returned to 2%, and maintained at 2% for 10 minutes. Metabolic stability was determined by measuring the time-dependent changes in the relative abundances of metabolites and parent compounds, and then calculating the elimination rate of the parent compound. Using the stability data, predicted human liver clearance values ​​were calculated according to methods known in the art. The predicted human liver clearance values ​​are shown in the table below. [Table 4-1] [Table 4-2] From the above comparative data, we can infer the following: Compound 24 is more potent in HIV antiviral assays compared to compounds A and B (approximately 9 and 16 times potent, respectively). Compound 24 has a longer terminal half-life in vivo in rats compared to compounds A and B (approximately 14 and 9 times longer, respectively). Compound 24 has a lower clearance in vivo in rats compared to compounds A and B (approximately 10 and 8.6 times lower, respectively). Compound 24 has a longer terminal half-life in vivo in dogs compared to compounds A and B (approximately 5 and 4 times longer, respectively). Compound 24 has a lower clearance in vivo in dogs compared to compounds A and B (approximately 3 and 4 times lower, respectively). Compound 24 is more stable in human hepatocytes with a lower predicted hepatic clearance compared to compounds A and B (approximately 9 and 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 and lower predicted human clearance in rats and dogs) compared to compounds A and B. Furthermore, compound 38 is more potent in HIV antiviral assays compared to compounds A and B (approximately 4 and 8 times more potent, respectively). Compound 38 has a longer terminal half-life in vivo in rats compared to compounds A and B (approximately 9.5 and 6.3 times longer, respectively). Compound 38 has a lower clearance in vivo in rats compared to compounds A and B (approximately 6.3 and 5.4 times lower, respectively). Compound 38 has 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 hepatic clearance compared to compounds A and B (approximately 4.5 and 2 times more stable, respectively). The above data demonstrate that compound 38 has improved antiviral efficacy and an improved pharmacokinetic profile (which is demonstrated by a longer half-life and lower predicted human clearance in rats and dogs) compared to compounds A and B. The specific pharmacological responses observed may vary depending on the presence of a selected specific active compound or pharmaceutical carrier, as well as the type of formulation and mode of administration used; therefore, such expected variations or differences in the results are assumed in accordance with the practices of this disclosure. The examples disclosed herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare those 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 advanced in subsequent synthesis steps. Examples of formulations Compound 38 (approximately 30 mg / kg) was formulated as an aqueous suspension in 2% poloxamer 338 saline (approximately 150 mg / mL). This formulation was then administered to rats as a single subcutaneous (SC) injection, and the pharmacokinetic (PK) profile was determined. As shown in Figure 3, compound 38 maintained plasma concentrations well above paEC95 for >10 weeks after a single SC injection. This data demonstrates that compound 38 exhibits sustained-release pharmacokinetics. A suspension of the compound of formula Ib (200 mg / mL) was prepared in 2% poloxamer 188 saline. 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 the compound of formula Ib as a function of time. As the data in Figure 4 show, the compound of formula Ib has a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 70. A suspension of the compound of formula Ib (100 mg / mL) was prepared in 2% poloxamer 188 saline. 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 show, the compound of formula Ib has a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 70. A suspension (200 mg / mL) of the sodium salt of compound Ib in 2% poloxamer 188 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 6 shows a plot of the plasma concentration of compound Ib as a function of time. As shown in Figure 6, compound Ib has a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 70. A solution of the compound of formula Ib (100 mg / mL) was prepared in NMP. 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 a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 70. A solution of the compound of formula Ib (200 mg / ml) was prepared in NMP. 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 a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 70. A solution (200 mg / ml) of the sodium salt of compound Ib in NMP 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 compound Ib as a function of time. As the data in Figure 9 shows, compound Ib has a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 70. A solution formulation (200 mg / ml) of the compound of formula Ib was prepared in 10% ethanol, 12% water, and 78% PEG200. The solution was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 10 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 10 show, the compound of formula Ib has a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 28. To form a sodium salt in situ, 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. Subjects were orally administered 6 mg / kg of this formulation. To form a sodium salt in situ, 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, was prepared. The solution was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was 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 show, the compound of formula Ib has a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 28. To form the sodium salt in situ, a solution formulation (200 mg / mL) of the compound of formula Ib was prepared in 10% ethanol, 13% water, and 77% glycoflor, containing 1.2 molar equivalents of NaOH. The solution was administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) profile was determined. Figure 12 shows a plot of the plasma concentration of the compound of formula Ib as a function of time. As the data in Figure 12 show, the compound of formula Ib has a measurable plasma concentration demonstrating sustained-release pharmacokinetics on day 28. Examples of oral formulations

[0264] Oral formulations containing the compound of formula Ib in 10% ethanol, 20% vitamin E TPGS, and 70% MIGLYOL 812 were prepared in hard gelatin capsules. A fixed dose of 7.5 mg of the compound of formula Ib was administered orally to dogs, and the pharmacokinetic (PK) profile was determined. Figure 13 shows the changes 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 they were individually incorporated by reference. This disclosure provides references to various embodiments and techniques. However, it should be understood that many variations and modifications are possible 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) Compound of formula (Ia): [ka] Or a pharmaceutically acceptable salt thereof. (Section 2) Compound of formula (Ib) [ka] The compounds described in item 1 above, or their pharmaceutically acceptable salts. (Section 3) A pharmaceutical composition comprising a therapeutically effective amount of the compound described in item 1 or 2 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Section 4) The pharmaceutical composition according to item 3 above, further comprising 1, 2, 3, or 4 additional therapeutic agents. (Item 5) The aforementioned additional therapeutic agents include: 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 dimerizing antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 The pharmaceutical composition described in item 4 above, selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. (Section 6) The aforementioned additional therapeutic agents include HIV protease inhibitors, 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 activators, and other drugs for treating HIV, or any of these. A pharmaceutical composition according to item 4 above, selected from the group consisting of combinations of the above. (Section 7) The pharmaceutical composition according to items 4 to 6 above, 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) The pharmaceutical composition according to items 4 to 7 above, 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 described in item 1 or 2 above, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. (Section 10) The method according to item 9, comprising administering the compound, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents. (Section 11) The aforementioned additional therapeutic agents include: 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 dimerizing antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 The method according to item 10 above, selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. (Section 12) The method according to item 10 or 11, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, 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 activators, and other drugs for treating HIV, or any combination thereof. (Section 13) The aforementioned additional therapeutic agents include abacavir sulfate, tenofovir, tenofovir disoproxil, and The method according to items 10 to 12 above, selected from the group consisting of nofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate. (Section 14) The method according to items 10 to 13 above, wherein the additional therapeutic agent is selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate. (Section 15) The compounds described in item 1 or 2 above, or pharmaceutically acceptable salts thereof, for use in therapy. (Section 16) A compound described in item 1 or 2 above, or a pharmaceutically acceptable salt thereof, for use in a method of 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) The compound for use according to item 16, wherein the method comprises administering one, two, three, or four additional therapeutic agents. (Section 18) The compound for use as described in item 17 above, wherein the additional therapeutic agent is administered simultaneously with the compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. (Section 19) The compound for use according to item 18 above, wherein the compound of formula (Ia) or (Ib) is combined with the additional therapeutic agent in a single dosage form for co-administration. (Section 20) The compound for use according to item 17 above, wherein the compound of formula (Ia) or (Ib) is administered, and the additional therapeutic agent is administered sequentially. (Section 21) The aforementioned additional therapeutic agents include: 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 dimerizing antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Compounds for use as described in item 17 above, selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. (Section 22) The additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, 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 activators, and other drugs for treating HIV, or any combination thereof, for use as described in item 17 above. (Section 23) Compounds for use as described in item 17 above, in combination with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. (Section 24) Compounds for use as described in item 17 above, in combination with tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate. (Item 25) Compounds for use as described in item 17 above, in combination with tenofovir disoproxil, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate. (Item 26) Compounds for use as described in item 17 above, 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) A compound for use as described in item 17 above, 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) Compounds for use as described in item 17 above, 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) The pharmaceutical composition according to items 4 to 6 above, wherein the additional therapeutic agent is 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir, or a pharmaceutically acceptable salt thereof. (Section 30) The method according to items 10 to 12, comprising administering the compound, or a pharmaceutically acceptable salt thereof, in combination with 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir, or a pharmaceutically acceptable salt thereof. (Section 31) Compounds for use as described in sections 17 to 22 above, in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, or a pharmaceutically acceptable salt thereof. (Section 32) Compound of formula (IIa): [ka] Or a pharmaceutically acceptable salt thereof. (Section 33) Compound of formula (IIb) [ka] The compounds described in item 32 above, or their pharmaceutically acceptable salts. (Section 34) A pharmaceutical composition comprising a therapeutically effective amount of the compound described in item 32 or 33 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. (Section 35) The pharmaceutical composition according to item 34 above, further comprising 1, 2, 3, or 4 additional therapeutic agents. (Section 36) The aforementioned additional therapeutic agents include 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 dimerizing antagonists, and HIV-1 virus infectivity factor inhibitors. A pharmaceutical composition according to item 35 above, selected from the group consisting of harmful agents, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. (Section 37) The pharmaceutical composition according to item 35, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, 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 activators, and other drugs for treating HIV, or any combination thereof. (Section 38) The pharmaceutical composition according to items 35 to 37, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate. (Section 39) The pharmaceutical composition according to items 35 to 38, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir or pharmaceutically acceptable salts 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 described in item 32 or 33 above, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. (Section 41) The method according to item 40, comprising administering the compound, or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents. (Section 42) The aforementioned additional therapeutic agents include: 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 dimerizing antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulator, Hck tyrosine The method according to item 41 above, selected from the group consisting of enzyme modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. (Section 43) The method according to item 41 or 42, wherein the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, 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 activators, and other drugs for treating HIV, or any combination thereof. (Section 44) The method according to items 41 to 43, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate. (Section 45) The method according to items 41 to 44, wherein the additional therapeutic agent is selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir or pharmaceutically acceptable salts thereof, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate. (Section 46) Compounds described in paragraph 32 or 33 above, or pharmaceutically acceptable salts thereof, for use in therapeutic purposes. (Section 47) A compound described in item 32 or 33 above, or a pharmaceutically acceptable salt thereof, for use in a method of 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) The compound for use according to item 47, wherein the method comprises administering one, two, three, or four additional therapeutic agents. (Section 49) The compound for use as described in item 48 above, wherein the additional therapeutic agent is administered simultaneously with the compound of formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof. (Section 50) The compound for use according to item 49, wherein the compound of formula (IIa) or (IIb) is combined with the additional therapeutic agent in a single dosage form for co-administration. (Section 51) The compound for use according to item 48 above, wherein the compound of formula (IIa) or (IIb) is administered, and the additional therapeutic agent is administered sequentially. (Section 52) The aforementioned additional therapeutic agents are concomitant drugs for HIV, other drugs for treating HIV, H IV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, 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 dimerizing antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Compounds for use as described in item 48 above, selected from the group consisting of Nef modulators, Hck tyrosine kinase modulators, mixed-series kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 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 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic activators, HIV gene therapies, and HIV vaccines, or any combination thereof. (Section 53) The additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, 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 activators, and other drugs for treating HIV, or any combination thereof, for use as described in item 48 above. (Section 54) Compounds for use as described in item 48 above, in combination with 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir or pharmaceutically acceptable salts thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. (Section 55) Compounds for use as described in item 48 above, in combination with 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate. (Section 56) Compounds for use as described in item 48 above, in combination with 4'-ethinyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir disoproxil, tenofovir disoproxil hemi-fumarate, or tenofovir disoproxil fumarate. (Section 57) A first additional therapeutic agent selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, as well as a selection from the group consisting of emtricitabine and lamivudine. A compound for use as described in item 48 above, in combination with a second additional therapeutic agent selected. (Item 58) Compounds for use as described in item 48 above, in combination with a first additional therapeutic agent selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent which is emtricitabine. (Section 59) Compounds for use as described in item 48 above, in combination with a first additional therapeutic agent selected from the group consisting of 4'-ethinyl-2-fluoro-2'-deoxyadenosine, tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent which is emtricitabine. (Section 60) A parenteral preparation, the pharmaceutical composition described in any one of the above items 3 to 8, 29, or 34 to 39. (Section 61) The parenteral preparation according to item 60, wherein the parenteral preparation is administered subcutaneously to a subject who requires it. (Section 62) The parenteral preparation according to item 60, wherein the parenteral preparation is administered intramuscularly to a subject requiring it. (Section 63) A parenteral preparation according to any one of items 60 to 62 above, comprising saline solution. (Section 64) A parenteral preparation containing poloxamer, as described in any one of items 60 to 63 above. (Section 65) The parenteral formulation according to item 64 above, wherein the poloxamer is poloxamer 338. (Section 66) [ka] A compound selected from the group consisting of the following. (Section 67) [ka] A compound selected from the group consisting of the following. (Section 68) formula: [ka] A compound of [unclear]. (Section 69) The parenteral formulation according to item 64 above, wherein the poloxamer is poloxamer 188. (Section 70) The parenteral preparation described in item 69 above, wherein the concentration of poloxamer 188 in saline solution is approximately 1% to approximately 10%. (Section 71) The parenteral preparation described in item 69 or 70 above, wherein the concentration of poloxamer 188 in saline solution is approximately 1% to approximately 3%. (Section 72) The parenteral preparation described in paragraphs 69, 70, or 71 above, wherein the concentration of poloxamer 188 in saline solution is approximately 2%. (Section 73) A parenteral preparation according to any one of items 60 to 62 above, comprising N-methyl-2-pyrrolidone. (Section 74) A parenteral preparation according to any one of the above paragraphs 60 to 62, comprising essentially N-methyl-2-pyrrolidone. (Section 75) A parenteral preparation according to any one of items 60 to 62 above, comprising dimethyl sulfoxide. (Section 76) A parenteral preparation according to any one of items 60 to 62 above, comprising essentially dimethyl sulfoxide. (Section 77) A parenteral preparation containing water, as described in any one of items 60 to 62 above. (Section 78) A parenteral preparation according to any one of items 60 to 62 or 77 above, further comprising alcohol. (Section 79) The parenteral preparation according to item 78 above, wherein the alcohol is ethanol. (Section 80) A parenteral formulation according to any one of items 60 to 62 or 77 to 79, further comprising polyethylene glycol. (Section 81) The parenteral formulation according to item 80, wherein the polyethylene glycol has an average molecular weight of about 200 g / mol. (Section 82) A parenteral preparation according to any one of items 77 to 81 above, further comprising an inorganic base. (Section 83) The parenteral preparation according to item 82, wherein the inorganic base is sodium hydroxide. (Section 84) Approximately 5% to 20% ethanol, approximately 5% to 20% water, and approximately 60% to 90% Parenteral formulations according to items 60 to 62 and 77 to 83, comprising polyethylene glycol 200. (Section 85) Parenteral formulations according to paragraphs 60 to 62 and 77 to 84, comprising approximately 10% to 15% ethanol, approximately 10% to 15% water, and approximately 70% to 80% polyethylene glycol 200. (Section 86) A parenteral formulation according to items 60 to 62 and 77 to 85, comprising approximately 10% ethanol, approximately 12% water, and approximately 78% polyethylene glycol 200. (Section 87) A pharmaceutical composition according to any one of the above items 3 to 8, 29, or 34 to 39, which is an oral preparation. (Section 88) The preparation according to any one of the above items 60 to 65 and 69 to 87, wherein the compound is present as a sodium salt.

Claims

[Claim 1] An urgent need to discover a novel antiretroviral agent.

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