Therapeutic compounds for prophylactic or therapeutic treatment of HIV virus infections

Abstract

The present invention relates to compounds of formulae (Ia), (Ib), (IIa) and (IIb), which are useful in the treatment of retroviral viral infections, including infections caused by HIV. # imgabs0 #

Description

[0001] This application is a divisional application of an invention patent application with an application date of August 17, 2017, application number 202010662665.4, and invention name “Therapeutic compounds for the preventive or therapeutic treatment of HIV virus infection”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional Application Serial No. 62 / 377,312, filed on August 19, 2016, and U.S. Provisional Application Serial No. 62 / 457,555, filed on February 10, 2017, the disclosures of which are incorporated herein by reference in their entireties. Technical Field

[0004] The present disclosure relates to novel compounds for treating retroviral viral infections, including infections caused by HIV virus, intermediates for their preparation and pharmaceutical compositions containing the novel compounds. Background Art

[0005] The positive single-stranded RNA virus including retroviridae includes forward and reverse transcription (Orthor etrovirinae) subfamily and Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus, Spumavirus, which cause many human and animal diseases. Among slow viruses, HIV-1 infection causes exhaustion and immune dysfunction of T helper cells in humans, causing immunodeficiency and susceptibility to opportunistic infections. It has been proven that treatment of HIV-1 infection with highly effective antiretroviral therapy (HAART) is effective in reducing viral load and significantly delaying disease progression (Hammer, SM, et al.; JAMA 2008, 300: 555-570). However, these treatments may lead to the emergence of HIV strains resistant to current therapies (Taiwo, B., International Journal of Infectious Diseases 2009, 13:552-559; Smith, RJ, et al., Science 2010, 327:697-701). Therefore, there is an urgent need to discover new antiretroviral agents that are effective against emerging drug-resistant HIV variants.

[0006] US Patent Publication No. 2014 / 0296266A1, published on October 2, 2014, discloses compounds useful for treating retroviral viral infections, including infections caused by HIV virus. US Patent Publication No. 2014 / 0296266A1 relates in particular to compounds of Formula I:

[0007]

[0008] in:

[0009] A is a 6-membered monocyclic heteroaryl having one or two nitrogen atoms, wherein the 6-membered monocyclic heteroaryl is replaced by one Z at the indicated position. 1 The group is substituted by a Z 2 group, and optionally one or more (eg, 1 or 2) Z 3 Group substitution;

[0010] R 1 is a 6-12 membered aryl, a 5-12 membered heteroaryl or a 3-12 membered heterocycle, wherein R 1 Any 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclic ring of is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 4 Group substitution;

[0011] R 2 is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl or (C3-C7) carbocyclic ring, wherein R 2 Any phenyl, 5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl or (C3-C7) carbocyclic ring is optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) Z 5 Group substitution;

[0012] Each R 3a and R 3b is independently selected from H, halogen, (C1-C3) alkyl and (C1-C3) haloalkyl, or R 3a is selected from H, (C1-C3) alkyl and (C1-C3) haloalkyl, R 3b Selected from -OH and -CN;

[0013] Z 1 is selected from 6-12 membered aryl, 5-14 membered heteroaryl and 3-14 membered heterocyclic ring, wherein Z 1 Any 6-12 membered aryl, 5-14 membered heteroaryl and 3-14 membered heterocyclic ring of 1a or Z 1b replace;

[0014] Each Z 1a independently selected from (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n1 、-OC(O)R p1 、-OC(O)NR q1 R r1 、-SR n1 、-S(O)R p1 、-S(O)2OH、-S(O)2R p1 、-S(O)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 , where Z 1a Any (C3-C7) carbocyclic, 6-12-membered aryl, 5-12-membered heteroaryl, and 3-12-membered heterocyclic ring of 1c or Z 1d Group substitution;

[0015] Each Z 1b is independently selected from (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)alkynyl, wherein Z 1b Any (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)alkynyl of 1c Group substitution;

[0016] Each Z 1cindependently selected from (C3-C7) carbocycle, phenyl, 5-6 membered monocyclic-heteroaryl, 3-7 membered heterocycle, halogen, -CN, -OR n2 、-OC(O)R p2 、-OC(O)NR q2 R r2 、-SR n2 、-S(O)R p2 、-S(O)2OH、-S(O)2R p2 、-S(O)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 , halogenated phenyl, 5-6 membered halogenated heteroaryl, 3-7 membered halogenated heterocycle and (C1-C8) heteroalkyl;

[0017] Each Z 1d independently selected from (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl and (C1-C8)haloalkyl;

[0018] Each R n1 is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein R n1 Any (C3-C7) carbocyclic ring, 3-7 membered heterocyclic ring, 5-6 membered monocyclic-heteroaryl and phenyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d Group substitution, where R n1 Any (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)alkynyl of 1c Group substitution;

[0019] Each R p1 is independently selected from (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein R p1 Any (C3-C7) carbocyclic ring, 3-7 membered heterocyclic ring, 5-6 membered monocyclic-heteroaryl and phenyl group is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d Group substitution, where R p1 Any (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)alkynyl of 1c Group substitution;

[0020] Each R q1 and R r1 is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl and phenyl, wherein R q1 or R r1 Any (C3-C7) carbocyclic, 3-7 heterocyclic, 5-6 membered monocyclic-heteroaryl and phenyl group is optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d Group substitution, where R q1 or R r1 Any (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)alkynyl of 1c Group substitution, or R q1 and R r1 and the nitrogen atom to which it is attached form a 5-, 6- or 7-membered heterocyclic ring, wherein the 5-, 6- or 7-membered heterocyclic ring is optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) Z 1c or Z 1d Group substitution;

[0021] Each R n2 independently selected from H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic-halogenated heteroaryl, 3-7 membered haloheterocycle, (C1-C8)haloalkyl, and (C1-C8)heteroalkyl;

[0022] Each R p2independently selected from (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic-halogenated heteroaryl, 3-7 membered haloheterocycle, (C1-C8)haloalkyl and (C1-C8)heteroalkyl;

[0023] Each R q2 and R r2 R is independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic-heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic-halogenated heteroaryl, 3-7 membered haloheterocycle, (C1-C8) haloalkyl and (C1-C8) heteroalkyl, or R q2 and R r2 and the nitrogen atom to which it is attached form a 5-membered, 6-membered or 7-membered heterocyclic ring;

[0024] Z 2 is selected from (C2-C8)alkenyl, (C2-C8)alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C(O)R n3 and -C(O)NR q3 R r3 , where Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl, and 3-12 membered C-linked heterocycle of 2b or Z 2c Group substitution, where Z 2 Any (C2-C8)alkenyl and (C2-C8)alkynyl groups are optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) Z 2c Group substitution;

[0025] Each Z 2a independently selected from (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR n4 、-OC(O)R p4 、-OC(O)NR q4 R r4 、-SR n4 、-S(O)R p4 、-S(O)2OH、-S(O)2R p4 、-S(O)2NR q4 R r4 、-NR q4 R r4 、-NR n4COR 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 and -C(O)NR q4 R r4 , where Z 2a Any (C3-C7) carbocyclic, 6-12-membered aryl, 5-12-membered heteroaryl, and 3-12-membered heterocyclic ring of 2b or Z 2c Group substitution;

[0026] Each Z 2b independently selected from (C1-C4)alkyl, (C1-C4)heteroalkyl and (C1-C4)haloalkyl;

[0027] Each Z 2c independently selected from halogen, -CN, -OR n4 、-OC(O)R p4 、-OC(O)NR q4 R r4 、-SR n4 、-S(O)R p4 、-S(O)2OH、-S(O)2R p4 、-S(O)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 and -C(O)NR q4 R r4 ;

[0028] Each R n3 is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl, wherein R n3 Any (C3-C7) carbocyclic, 3-12 membered heterocyclic, 5-12 membered heteroaryl and 6-12 membered aryl of 2b or Z 2c Group substitution; wherein R n3 Any (C1-C4)alkyl, (C2-C4)alkenyl and (C2-C4)alkynyl of 2a Group substitution;

[0029] Each R q3 and R r3 is independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl, wherein R q3 or R r3 Any (C3-C7) carbocyclic, 3-12 membered heterocyclic, 5-12 membered heteroaryl and 6-12 membered aryl of 2b or Z 2c Group substitution, where R q3 or R r3 Any (C1-C4) alkyl and (C2-C4) alkenyl groups are optionally replaced by one or more (e.g., 1, 2, 3, 4 or 5) Z 2a Group substitution, or R q3 and R r3 and the nitrogen atom to which it is attached form a heterocyclic or heteroaryl group, wherein the heterocyclic or heteroaryl group is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) Z 2b or Z 2c Group substitution;

[0030] Each R n4 independently selected from H, (C1-C4)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)haloalkyl and (C1-C4)heteroalkyl;

[0031] Each R p4independently selected from (C1-C8)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl and (C1-C4)heteroalkyl;

[0032] Each R q4 and R r4 independently selected from H, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C1-C4)haloalkyl and (C1-C4)heteroalkyl;

[0033] Each Z 3 independently selected from halogen, (C1-C4)alkyl, -OH, -CN, (C1-C4)heteroalkyl and (C1-C4)haloalkyl;

[0034] Each Z 4 independently selected from (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)carbocycle, halogen, -CN, -OR n5 、-OC(O)R p5 、-OC(O)NR q5 R r5 、-SR n5 、-S(O)R p5 、-S(O)2OH、-S(O)2R p5 、-S(O)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 , where Z 4 Any (C3-C7) carbocyclic ring of 4a or Z 4b Group substitution, where Z 4Any (C1-C8)alkyl, (C2-C8)alkenyl and (C2-C8)alkynyl of 4a Group substitution;

[0035] Each Z 4a independently selected from halogen, -CN, -OR n6 、-OC(O)R p6 、-OC(O)NR q6 R r6 、-SR n6 、-S(O)R p6 、-S(O)2OH、-S(O)2R p6 、-S(O)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)NR q6 R r6 ;

[0036] Each Z 4b independently selected from (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl and (C1-C4)haloalkyl;

[0037] Each R n5 independently selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0038] Each R p5 independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0039] Each R q5 and R r5independently selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0040] Each R n6 independently selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0041] Each R p6 independently selected from (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0042] Each R q6 and R r6 independently selected from H, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)heteroalkyl, (C2-C4)alkenyl and (C2-C4)alkynyl;

[0043] Each Z 5 independently selected from (C1-C6)alkyl, halogen, -CN and -OR n7 ,

[0044] Where Z 5 Any (C1-C6)alkyl of is optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) halogen;

[0045] Each R n7 independently selected from H, (C1-C3)alkyl, (C1-C3)haloalkyl and (C3-C7)carbocycle;

[0046] or a pharmaceutically acceptable salt thereof.

[0047] US Patent Publication No. 2014 / 0303164A1, published on October 9, 2014, discloses compounds useful for treating retroviral viral infections, including infections caused by HIV virus. US Patent Publication No. 2014 / 0303164A1 is particularly directed to compounds of Formula IIId:

[0048]

[0049] in

[0050] A 1 H, -Z 3 or nitrogen;

[0051] A 2 is CH or nitrogen;

[0052] R 1 is a 6-12 membered aryl group, a 5-12 membered heteroaryl group or a 3-12 membered heterocyclic ring, wherein R 1 Any 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocyclic ring of 4 Group substitution, where Z 4 The groups are the same or different;

[0053] Each R 3a and R 3b are independently H or (C1-C3) alkyl;

[0054] Z 1 is a 6-12 membered aryl, a 5-14 membered heteroaryl or a 3-14 membered heterocyclic ring, wherein Z 1 Any 6-12 membered aryl, 5-14 membered heteroaryl or 3-14 membered heterocyclic ring of 1a or Z 1b Substitution, where Z 1a and Z 1b The groups are the same or different;

[0055] Each Z 1a are independently (C3-C7) carbocyclic, 5-12 membered heteroaryl, 3-12 membered heterocyclic, halogen, -CN, -OR n1 、-OC(O)R p1 、-OC(O)NR q1 R r1 、-SR n1 、-S(O)R p1 、-S(O)2OH、-S(O)2R p1 、-S(O)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 Rr1 and -S(O)2NR n1 COR p1 , where Z 1a Any (C3-C7) carbocyclic ring, 5-12 membered heteroaryl ring and 3-12 membered heterocyclic ring of 1c or Z 1d Group substitution, where Z 1c and Z 1d The groups are the same or different;

[0056] Each Z 1b is independently (C1-C8)alkyl optionally substituted by 1, 2, 3, 4 or 5 halogens, each Z 1b are the same or different;

[0057] Each Z 1c are independently halogen, -CN, -OH, -NH2, -C(O)NR q2 R r2 or (C1-C8) heteroalkyl;

[0058] Each Z 1d are independently (C1-C8)alkyl or (C1-C8)haloalkyl;

[0059] Each R n1 are independently H, (C1-C8) alkyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic or 5-6 membered monocyclic heteroaryl, wherein R n1 Any (C3-C7) carbocyclic, 3-7 membered heterocyclic or 5-6 membered monocyclic-heteroaryl radical of 1c or Z 1d Group substitution, where Z 1c and Z 1d The groups are the same or different, and wherein R n1 Any (C1-C8) alkyl group is optionally replaced by 1, 2, 3, 4 or 5 Z 1c Group substitution, where Z 1c The groups are the same or different;

[0060] Each R p1 are independently (C1-C8) alkyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic or 5-6 membered monocyclic heteroaryl, wherein R p1 Any (C3-C7) carbocyclic, 3-7 membered heterocyclic or 5-6 membered monocyclic-heteroaryl radical of 1c or Z 1d Group substitution, where Z 1c and Z 1d The groups are the same or different, and wherein Rp1 Any (C1-C8) alkyl group is optionally replaced by 1, 2, 3, 4 or 5 Z 1c Group substitution, where Z 1c The groups are the same or different;

[0061] Each R q1 and R r1 are independently H, (C1-C8) alkyl, (C3-C7) carbocyclic, 3-7 membered heterocyclic, or 5-6 membered monocyclic-heteroaryl, wherein R q1 or R r1 Any (C3-C7) carbocyclic, 3-7 membered heterocyclic or 5-6 membered monocyclic-heteroaryl radical of 1c or Z 1d Group substitution, where Z 1c and Z 1d The groups are the same or different, and wherein R q1 or R r1 Any (C1-C8) alkyl group is optionally replaced by 1, 2, 3, 4 or 5 Z 1c Group substitution, where Z 1c The groups are the same or different, or R q1 and R r1 and the nitrogen atom to which it is attached form a 5-, 6- or 7-membered heterocyclic ring, wherein the 5-, 6- or 7-membered heterocyclic ring is optionally substituted by 1, 2, 3, 4 or 5 Z 1c or Z 1d Group substitution, where Z 1c and Z 1d The groups are the same or different;

[0062] Each R q2 and R r2 are independently H, (C1-C8) alkyl, (C3-C7) carbocycle, or R q2 and R r2 and the nitrogen atom to which it is attached form a 5-membered, 6-membered or 7-membered heterocyclic ring;

[0063] Z 2 is (C2-C8)alkenyl, (C2-C8)alkynyl, 6-12-membered aryl, 5-12-membered C-linked heteroaryl, 3-12-membered C-linked heterocycle, -C(O)R n3 or -C(O)NR q3 R r3 , where Z 2 Any 6-12 membered aryl, 5-12 membered C-linked heteroaryl or 3-12 membered C-linked heterocycle of 2b or Z 2c Group substitution, where Z2b and Z 2c The groups are the same or different, and wherein Z 2 Any (C2-C8)alkenyl or (C2-C8)alkynyl group of 2c Group substitution, where Z 2c The groups are the same or different;

[0064] Each R n3 are independently H or (C1-C4) alkyl;

[0065] Each R q3 and R r3 are independently H or (C1-C4) alkyl;

[0066] Each Z 2b are independently oxo, (C1-C4)alkyl, (C1-C4)heteroalkyl or (C1-C4)haloalkyl;

[0067] Each Z 2c are independently oxy, halogen, -CN, -OR n4 、-OC(O)R p4 、-OC(O)NR q4 R r4 、-SR n4 、-S(O)R p4 、-S(O)2OH、-S(O)2R p4 、-S(O)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 ;

[0068] Each R n4are independently H, (C1-C4)alkyl, (C1-C4)haloalkyl or (C1-C4)heteroalkyl;

[0069] Each R p4 are independently (C1-C8)alkyl, (C1-C4)haloalkyl or (C1-C4)heteroalkyl;

[0070] Each R q4 and R r4 are independently H, (C1-C4)alkyl, (C1-C4)haloalkyl or (C1-C4)heteroalkyl;

[0071] Each Z 3 are independently (C1-C4)heteroalkyl;

[0072] Each Z 4 are independently oxy, (C1-C8) alkyl, (C3-C7) carbocycle, halogen, -CN, -OR n5 、-NR q5 R r5 、-NR n5 COR p5 、-NR n5 CO2R p5 、-C(O)R n5 、-C(O)OR n5 or -C(O)NR q5 R r5 , where Z 4 Any (C3-C7) carbocyclic ring or (C1-C8) alkyl group is optionally replaced by 1, 2, 3, 4 or 5 Z 4a Group substitution, where Z 4a The groups are the same or different;

[0073] Each Z 4a are independently halogen, -CN or -OR n6 ;

[0074] Each R n5 , R p5 , R q5 , R r5 and R n6 are independently H or (C1-C4) alkyl;

[0075] Each Z 5 are independently halogen, each Z 5 can be the same or different; and

[0076] N is 0, 1, 2 or 3;

[0077] or a pharmaceutically acceptable salt thereof.

[0078] Despite the foregoing disclosure, there remains a need for compounds that are effective and stable and exhibit improved pharmacokinetic and / or pharmacodynamic properties for treating retroviral viral infections, including infections caused by HIV virus.

[0079] Also of interest in the field of HIV treatment and therapy is the pharmacokinetic properties of regimens that extend the regimens offered to patients. Although many advances have been made in current regimens for treating HIV, patients no longer need to take multiple pills multiple times a day, today's patients still need to take pills daily for the foreseeable life span. Therefore, it would be beneficial to have an HIV therapy that requires patients to take medication less frequently than once a day (e.g., once every two days, once a week, once every other week, once a month, etc.).

[0080] Provided herein are novel compounds that exhibit improved potency, improved metabolic stability, and improved pharmacokinetic and / or pharmacodynamic profiles. Summary of the invention

[0081] In some embodiments, the present invention relates to compounds of formula (Ia):

[0082]

[0083] or a pharmaceutically acceptable salt thereof.

[0084] In some embodiments, the present invention relates to compounds of formula (Ib):

[0085]

[0086] or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the present invention relates to compounds of formula (IIa):

[0088]

[0089] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the present invention relates to compounds of formula (IIb):

[0091]

[0092] or a pharmaceutically acceptable salt thereof.

[0093] In one embodiment, the invention relates to the use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for treating a disease in a subject in need thereof.

[0094] In one embodiment, the invention relates to the use of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for treating a disease in a subject in need thereof.

[0095] In certain embodiments, the present invention 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.

[0096] In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is in parenteral (e.g., injectable) form. In certain embodiments, the pharmaceutical composition is suitable for oral administration.

[0097] In certain embodiments, the invention relates to a preparation comprising a unit dose of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the present invention relates to a preparation comprising a unit dose of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof.

[0099] In certain embodiments, the invention relates to a method of treating or preventing HIV infection in an individual in need thereof, comprising administering to the individual a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the invention relates to a method of treating or preventing HIV infection in an individual in need thereof, comprising administering to the individual a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments, the invention relates to a method for preventing HIV infection in an individual, the method comprising administering to the individual a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual is at risk of HIV infection, such as an individual with one or more risk factors known to be associated with HIV infection.

[0102] In certain embodiments, the invention relates to a method for preventing HIV infection in an individual, the method comprising administering to the individual a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual is at risk of HIV infection, such as an individual with one or more risk factors known to be associated with HIV infection.

[0103] In certain embodiments, the invention relates to a method of treating or preventing HIV infection in an individual in need thereof, comprising administering to the individual a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0104] In certain embodiments, the present invention relates to a method of treating or preventing HIV infection in an individual in need thereof, comprising administering to the individual a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents.

[0105] In certain embodiments, the present invention relates to a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0106] In certain embodiments, the present invention relates to compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof, for use in medical therapy.

[0107] In certain embodiments, the present invention relates to a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for use in treating or preventing HIV infection in an individual.

[0108] In certain embodiments, the present invention relates to compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof, for use in treating or preventing HIV infection in an individual.

[0109] In certain embodiments, the present invention relates to the use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing HIV infection in an individual.

[0110] In certain embodiments, the present invention relates to the use of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating or preventing HIV infection in an individual.

[0111] In another embodiment, the invention relates to intermediates useful in the synthesis of compounds of formula (Ia) or (Ib).

[0112] In another embodiment, the present invention relates to intermediates useful in the synthesis of compounds of formula (Ia), (Ib), (IIa) and / or (IIb).

[0113] In some embodiments, the pharmaceutically acceptable salt of the compound of Formula (Ia), (Ib), (IIa) and / or (IIb) is a sodium salt.

[0114] Other embodiments of the invention are disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0115] Figure 1 N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide is shown. 1 H NMR (400 MHz, methanol-d4).

[0116] Figure 2 N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide is shown. 1 H NMR (400 MHz, methanol-d4).

[0117] Figure 3 Shown are plasma concentrations (nM) of compound 38 after a single subcutaneous (SC) dose in rats.

[0118] Figure 4 Shown is a graph of plasma concentration of 200 mg / mL of Formula Ib in 2% poloxamer 188 saline over time when dosed at 6 mg / kg subcutaneously in dogs.

[0119] Figure 5 Shown is a graph of plasma concentrations of 100 mg / mL of Formula Ib in 2% poloxamer 188 saline over time when dosed subcutaneously at 6 mg / kg in dogs.

[0120] Figure 6 Shown is a graph of plasma concentrations over time of 200 mg / mL of the sodium salt of Formula Ib in 2% poloxamer 188 saline when dosed subcutaneously in dogs at 6 mg / kg.

[0121] Figure 7 Shown is a graph of plasma concentrations of 100 mg / mL free acid form of Formula Ib in NMP over time when dosed subcutaneously at 6 mg / kg in dogs.

[0122] Figure 8 Shown is a graph of the plasma concentration of 200 mg / mL free acid form of Formula Ib in NMP over time when dosed subcutaneously at 6 mg / kg in dogs.

[0123] Fig. 9 Shown is a graph of plasma concentrations over time of 200 mg / mL of the sodium salt of Formula Ib in NMP when administered subcutaneously at 6 mg / kg in a subject.

[0124] Fig.10 Shown is a graph of plasma concentration of 200 mg / mL of Formula Ib in 10% ethanol, 12% water, and 78% PEG200 over time when administered subcutaneously at 6 mg / kg in subjects.

[0125] Fig.11 Shown is a graph of plasma concentration over time of 200 mg / mL of Formula Ib (in situ salt) in 10% ethanol, 12% water, and 77% PEG200 when administered subcutaneously at 6 mg / kg in subjects.

[0126] Fig.12 Shown is a graph of plasma concentration over time of 200 mg / mL of Formula Ib forming an in situ Na salt with 1.2 molar equivalents of NaOH in 10% ethanol, 13% water, and 77% glycofurol when dosed subcutaneously at 6 mg / kg in a subject.

[0127] Fig.13 Shown is a graph of plasma concentration over time for a fixed 7.5 mg oral dose of Formula Ib in 10% ethanol, 20% Vitamin E TPGS, 70% MI GLYOL 812 in dogs. DETAILED DESCRIPTION

[0128] The following description is completed with the recognition that the present invention should be considered as an example of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments shown. The titles used throughout the present invention are provided for convenience and should not be interpreted as limiting the claims in any way. The embodiments shown under any title can be combined with the embodiments shown under any other title.

[0129] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.

[0130] When a trade name is used herein, it is intended to independently include the trade name product as well as the active pharmaceutical ingredient or ingredients of the brand name product.

[0131] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, reference to "the assay" includes reference to one or more assays, and so forth.

[0132] As used herein, the term “C 最大 ” refers to the maximum observed plasma / serum concentration of the drug.

[0133] "Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0134] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0135] "Pharmaceutically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound (or can be converted into a form having the desired pharmacological activity of the parent compound). Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; 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, trimethylacetic acid, etc., and when the 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 metal ion (e.g., calcium or magnesium) or an aluminum ion; or salts formed when coordinated with an organic base such as diethanolamine, triethanolamine, N-methylglucamine, etc. This definition also includes ammonium salts and substituted or quaternized ammonium salts. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in SM Berge et al., J. Pharma Sci., 66 (1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), page 732, Table 38-5, both publications are hereby incorporated by reference into the text.

[0136] "Subject" refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cows, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), and the like.

[0137] As used herein, "treatment" is a method for obtaining a beneficial or desired result. For the purposes of the present invention, a beneficial or desired result includes, but is not limited to, relieving symptoms and / or reducing the extent of symptoms and / or preventing the worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition, and / or reducing the extent of a disease or condition); b) slowing down or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, delaying the worsening or progression of a disease or condition); and / or c) alleviating a disease or condition, such as causing regression of clinical symptoms, improving the disease state, delaying disease progression, improving quality of life, and / or prolonging survival.

[0138] As used herein, "delaying" the development of a disease or condition means postponing, hindering, slowing down, delaying, stabilizing and / or stalling the development of a disease or condition. The delay may be of varying lengths of time, depending on the history of the disease and / or the individual being treated. It will be apparent to those skilled in the art that a sufficient or significant delay may actually encompass prevention, since the individual does not develop the disease or condition. For example, a method of "delaying" the development of AIDS is a method of reducing the probability of disease development and / or reducing the extent of the disease within a given time frame compared to not using the method. Such comparisons may be based on clinical studies using a statistically significant number of individuals. For example, the development of AIDS may be detected using known methods, such as confirming an individual's HIV + The individual's T cell count or other signs of AIDS progression are assessed for status and assessment, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits, or groin, or the presence of opportunistic conditions known to be associated with AIDS (e.g., conditions that are not normally present in individuals with a functioning immune system but are present in AIDS patients). Progression can also refer to disease progression that may not be detected initially, and includes onset, relapse, and flare-up.

[0139] As used herein, "prevention" refers to a scheme that prevents the onset of a disease or illness so that the clinical symptoms of the disease do not occur. Therefore, "prevention" involves administering treatment (e.g., administering a therapeutic substance) to the individual before signs of disease can be detected in the individual (e.g., administering a therapeutic substance to the individual in the absence of a detectable pathogen (e.g., a virus) in the individual). The individual can be an individual with a risk of developing a disease or illness, such as an individual with one or more known risk factors associated with the development or onset of a disease or illness. Therefore, the term "prevention of HIV infection" refers to administering anti-HIV therapeutic substances to individuals who do not have detectable HIV infection. It should be understood that the individual who carries out anti-HIV preventive treatment can be an individual with a risk of contracting HIV virus. In addition, it should be understood that prevention may not result in being completely free from the onset of a disease or illness. In some cases, prevention includes reducing the risk of developing a disease or illness. Reducing risk may not result in completely eliminating the risk of developing a disease or illness.

[0140] As used herein, an "at risk" individual is one who is at risk of developing a condition to be treated. An "at risk" individual may or may not have a detectable disease or condition, and may or may not have exhibited a detectable disease prior to the treatment methods described herein. "At risk" means that the individual has one or more so-called risk factors, which are measurable parameters associated with the development of a disease or condition and are known in the art. Individuals with one or more of these risk factors have a higher likelihood of developing the disease or condition than individuals without these risk factors. For example, individuals at risk for AIDS are those with HIV.

[0141] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount that effectively induces a desired biological or medical response, including an amount of a compound that is sufficient to make the treatment of the disease effective when administered to an individual to treat the disease, or refers to an amount that effectively protects against infection or onset of the disease. The effective amount will vary according to the compound, the disease and its severity, and the age, weight, etc. of the individual to be treated. The effective amount may include a range of amounts. As understood in the art, an effective amount may be in the form of one or more doses, that is, a single dose or multiple doses may be required to achieve the desired therapeutic result. An effective amount may be considered in the case of administering one or more therapeutic agents, and if combined with one or more other agents, an effective amount of a single agent may be considered, so that the desired or beneficial result may or can be achieved. Due to the combined effect of the compounds (e.g., additive or synergistic), the appropriate dose of any co-administered compound may be optionally reduced.

[0142] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers that is not in a 1:1 ratio is a "scalemic" mixture.

[0143] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0144] Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be determined by R or S. Resolved compounds whose absolute configuration is unknown can be referred to as (+) or (-) according to the direction (right-handed or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and / or are hindered in rotation around a bond axis, and thus may produce enantiomers, diastereomers, and other stereoisomeric forms that may be defined as (R)- or (S)- in terms of absolute stereochemistry. The present invention is intended to include all such possible isomers, including racemic mixtures, partially racemic mixtures, diastereomeric mixtures, optically pure forms, and intermediate mixtures. Optically active (R)-isomers and (S)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0145] Unless otherwise expressly defined, the present invention includes all tautomers of the compounds detailed herein, even if only one tautomer is expressly shown (e.g., where a pair of tautomers may exist, both tautomeric forms are intended to be described by presenting one tautomeric form). For example, if an amide-containing compound is referred to (e.g., by structure or chemical name), it is understood that the present invention includes the corresponding imidic acid tautomer and that it will be described as if the amide alone or both the amide and the imidic acid were expressly described. When more than two tautomers may exist, the present invention includes all such tautomers, even if only one tautomeric form is shown by chemical name and / or structure.

[0146] The present invention also provides prodrugs of compounds of formula (Ia) or (Ib). "Prodrug" is defined in the pharmaceutical field as a biologically inactive derivative of a drug that is converted into a biologically active parent drug according to some chemical or enzymatic pathway after administration to the human body.

[0147] In addition, in some embodiments, the present invention also provides prodrugs of compounds of Formula (Ia), (Ib), (IIa) and / or (IIb).

[0148] It will be understood by those skilled in the art that the present invention also includes any compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) that may be enriched in one or more isotopes at a level above the naturally occurring isotopic ratio in any or all atoms, such as, but not limited to, deuterium ( 2 H or D).

[0149] The present invention also discloses compounds in which 1 to n hydrogen atoms connected to the carbon atom can be replaced by deuterium atoms or D, wherein n is the number of hydrogen atoms in the molecule. As known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. These compounds can increase resistance to metabolism, and therefore can be used to increase the half-life of the compound when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5 (12): 524-527 (1984). These compounds are synthesized by methods well known in the art, for example, by using raw materials in which one or more hydrogen atoms have been replaced by deuterium.

[0150] Examples of isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 36 Cl, 123 I, and 125 I. Using positron emitting isotopes (e.g. 11 C, 18 F, 15 O and 13 Substitution by N) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula (Ia) or (Ib) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples listed below, using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0151] Additionally, in some embodiments, isotopically-labeled compounds of Formula (Ia), (Ib), (IIa) and / or (IIb) can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples listed below, using an appropriate isotopically-labeled reagent in place of the unlabeled reagent previously employed.

[0152] The compounds described herein may have chiral centers and / or geometric isomer centers (E-isomers and Z-isomers), and it is understood that the invention includes all such optical isomers, enantiomeric isomers, diastereomeric isomers, and geometric isomers. When a compound is represented in its chiral form, it is understood that the embodiment includes, but is not limited to, a specific diastereoisomer- or enantiomer-enriched form. When chirality is not specified but is present, it is understood that the embodiment relates to a specific diastereoisomer- or enantiomer-enriched form; or a racemic or partially racemic mixture of these compounds. As used herein, a "partially racemic mixture" is a mixture of stereoisomers in a ratio other than 1:1.

[0153] The present invention also provides pharmaceutically acceptable hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.

[0154] In a preferred embodiment, the present invention relates to the use of a compound of formula (Ia) or (Ib) in the treatment of retroviral viral infections, including infections caused by HIV virus, comprising administering a therapeutically effective amount to an individual in need thereof.

[0155] In a preferred embodiment, the present invention relates to the use of compounds of formula (Ia), (Ib), (IIa) and / or (IIb) in the treatment of retroviral viral infections, including infections caused by HIV virus, wherein the treatment comprises administering a therapeutically effective amount to an individual in need thereof.

[0156] The ideal goal is to find 50 A compound or a pharmaceutically acceptable salt thereof. 50 Values ​​refer to the concentration of compound that achieves 50% of the maximal efficacy in the test. 50 Compounds with lower EC 50 Compounds with similar efficacy achieved at lower compound concentrations. Therefore, for drug development, lower EC 50 Usually preferred.

[0157] The ideal goal is to find a compound or a pharmaceutically acceptable salt thereof with good physical and / or chemical stability. An increase in the overall stability of the compound can increase the circulation time in the body. Due to less degradation, stable compounds can be administered at lower doses while still maintaining efficacy. In addition, due to less degradation, there is less concern about byproducts from compound degradation.

[0158] The ideal goal is to find a compound or a pharmaceutically acceptable salt thereof with improved pharmacokinetic and / or pharmacodynamic properties and a long half-life. It is advantageous for a drug to have a moderate or low clearance rate and a long half-life because this can lead to good bioavailability and high exposure in systemic exposure. Reducing the clearance rate of a compound and increasing the half-life of a compound can reduce the daily dose required to achieve efficacy, thereby providing better efficacy and safety. Therefore, improved pharmacokinetic and / or pharmacodynamic properties and a long half-life can provide better patient compliance.

[0159] The ideal goal is to find compounds or pharmaceutically acceptable salts thereof with good pharmacokinetic properties from sustained-release injectable formulations. 50 Long-acting pharmacokinetics are advantageous because they can lead to low dosing frequencies. Reducing dosing frequencies can provide better patient compliance. For patients with limited or difficult access to health care, it is desirable to reduce dosing frequencies.

[0160] Advantageously, the present invention has found that compounds of formula (Ia) and (Ib) have advantages over structurally similar compounds disclosed in U.S. Patent Publications 2014 / 0296266A1 and 2014 / 0303164A1 (referred to herein as Compounds A and B):

[0161]

[0162] Therefore, the present invention includes but is not limited to providing compounds of formula (Ia):

[0163]

[0164] or a pharmaceutically acceptable salt thereof, and methods of using the compounds of formula (Ia) to treat retroviral viral infections, including infections caused by HIV virus.

[0165] Therefore, the present invention includes but is not limited to providing compounds of formula (Ib):

[0166]

[0167] or a pharmaceutically acceptable salt thereof, and methods of using the compounds of formula (Ib) to treat retroviral viral infections, including infections caused by HIV virus.

[0168] Also disclosed herein are compounds of formula (IIa) and (IIb) which have advantages over compounds A and B (shown above).

[0169] Therefore, the present invention includes but is not limited to providing compounds of formula (IIa):

[0170]

[0171] or a pharmaceutically acceptable salt thereof, and methods of using the compounds of formula (IIa) to treat retroviral viral infections, including infections caused by HIV virus.

[0172] Therefore, the present invention includes but is not limited to providing a compound of formula (IIb):

[0173]

[0174] or a pharmaceutically acceptable salt thereof, and methods of using the compounds of formula (IIb) to treat retroviral viral infections, including infections caused by HIV virus.

[0175] 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 individuals. In some embodiments, the compounds disclosed herein are used to prevent HIV infection in individuals at risk of infection. In some embodiments, the compounds disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of acquiring HIV-1 through sexual intercourse.

[0176] It is believed that the compounds disclosed herein (e.g., compounds of Formula (Ia), (Ib), (IIa) and / or (IIb) or pharmaceutically acceptable salts thereof) are effective against the major HIV-1 mutants selected by clinical protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRT I) and integrase inhibitors (INSTI).

[0177] Combination therapy

[0178] In certain embodiments, methods of treating or preventing HIV infection in a human suffering from or at risk of HIV infection are provided, the methods comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof, and 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. In one embodiment, methods of treating HIV infection in a human suffering from or at risk of HIV infection are provided, the methods comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof, and 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.

[0179] In some embodiments, methods of treating or preventing HIV infection in a human suffering from or at risk of HIV infection are provided, the methods comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof, and 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. In one embodiment, methods of treating HIV infection in a human suffering from or at risk of HIV infection are provided, the methods comprising administering to the human a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof, and 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.

[0180] In one embodiment, a pharmaceutical composition is provided, comprising a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof, and 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 and a pharmaceutically acceptable excipient.

[0181] In some embodiments, a pharmaceutical composition is provided, comprising a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof, and 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 and a pharmaceutically acceptable excipient.

[0182] In certain embodiments, the present invention provides a method of treating HIV infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0183] In certain embodiments, the present invention provides a method for treating HIV infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0184] In certain embodiments, the present invention provides a method for treating HIV infection, comprising administering to an individual in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof.

[0185] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with one additional therapeutic agent. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents.

[0186] In some embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with one additional therapeutic agent. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0187] Administration of HIV combination therapy

[0188] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is administered together with one or more additional therapeutic agents. Co-administration of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) and one or more additional therapeutic agents such that a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents are present in the body of the individual. When administered sequentially, the combination may be administered in two or more administrations.

[0189] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is administered together with one or more additional therapeutic agents. Co-administration of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) and one or more additional therapeutic agents such that a therapeutically effective amount of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents are both present in the body of the individual. When administered sequentially, the combination may be administered in two or more administrations.

[0190] Co-administration includes administering a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof before or after administering a unit dose of one or more additional therapeutic agents. For example, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof can be administered within seconds, minutes, or hours of administering one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is administered first, followed by administering a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administering a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) is administered first, followed by administering a unit dose of one or more additional therapeutic agents a few hours (e.g., 1-12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein (eg, a compound of Formula (Ia) or (Ib)) several hours (eg, 1-12 hours) later.

[0191] In some embodiments, co-administration includes administering a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof before or after administering a unit dose of one or more additional therapeutic agents. For example, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof can be administered within seconds, minutes, or hours of administering one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) is administered first, followed by a unit dose of one or more additional therapeutic agents a few hours (e.g., 1-12 hours) later. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) a few hours (e.g., 1-12 hours) later.

[0192] For the avoidance of doubt, co-administration of a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof with one or more additional therapeutic agents may refer to co-administration with one or more therapeutic agents described herein (e.g., those listed in paragraphs

[00111] to

[00162] ).

[0193] In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to an individual. In certain embodiments, this single dosage form can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the single dosage form can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the single dosage form is orally bioavailable and can be administered orally. In certain embodiments, the single dosage form can be a solid dosage form for oral administration.

[0194] 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 more additional therapeutic agents in a single dosage form for simultaneous administration to an individual. In certain embodiments, such a single dosage form can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the single dosage form can be administered intravenously, subcutaneously or intramuscularly. In certain embodiments, the single dosage form is orally bioavailable and can be administered orally. In certain embodiments, the single dosage form can be a solid dosage form for oral administration.

[0195] The compounds disclosed herein (e.g., compounds of formula (Ia) or (Ib)) or pharmaceutically acceptable salts thereof and one or more additional therapeutic agents can be administered in combination by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. 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.

[0196] 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 can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. 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.

[0197] In certain embodiments, the compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is formulated into a tablet, which may optionally contain one or more other compounds for treating HIV. In certain embodiments, the tablet may contain one or more other compounds for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0198] In certain embodiments, the compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is formulated into a tablet, which may optionally contain one or more other compounds for treating HIV. In certain embodiments, the tablet may contain one or more other compounds for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0199] In certain embodiments, the compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is formulated into a solution formulation, which may optionally contain one or more other compounds for treating HIV. In certain embodiments, the tablet may contain one or more other compounds for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0200] In certain embodiments, the compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is formulated into a suspension, which may optionally contain one or more other compounds for treating HIV. In certain embodiments, the tablet may contain one or more other compounds for treating HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0201] In certain embodiments, such tablets are suitable for once-daily administration.

[0202] HIV combination therapy

[0203] In the above embodiments, the additional therapeutic agent can be an anti-HIV agent selected from the following: a combination drug for treating HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0204] In some embodiments, the additional therapeutic agent is selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0205] HIV combination drugs

[0206] Examples of combination drugs include (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; (zidovudine and lamivudine; AZT+3TC); ( abacavir sulfate and lamivudine; ABC+3TC); ( lopinavir and ritonavir); (dolutegravir, abacavir, and lamivudine); (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 dolutegravir and tenofovir disoproxil; dolutegravir + lamivudine; lamivudine + abacavir + zidovudine; lamivudine + abacavir; lamivudine + tenofovir disoproxil fumarate; lamivudine + zidovudine + nevirapine; lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine; lopinavir + ritonavir + zidovudine + lamivudine; tenofovir + lamivudine; tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride; lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812.

[0207] Other HIV medicines

[0208] Examples of other drugs used to treat HIV include acetomorph, alisporivir, BanLe c, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGT V-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-00 7. SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

[0209] HIV protease inhibitors

[0210] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and TMC-310911.

[0211] HIV reverse transcriptase inhibitors

[0212] Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM- 1500. Other examples of non-nucleoside reverse transcriptase inhibitors are disclosed in US Patent Publication US2016 / 0250215.

[0213] Examples of HIV reverse transcriptase nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azithromycin, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (didanosine, DDL), abacavir, abacavir sulfate, alovudine, aprecitabine, censavudine, didanosine, efcitabine, festinavir, fisalvudinetidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148 and KP-1461.

[0214] In some embodiments, examples of HIV reverse transcriptase nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azithromycin, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (didanosine, ddl), abacavir, abacavir sulfate, alovudine, aprecitabine, censavudine, didanosine, efavirenz, festinavir, fosivudine ester, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine ester, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148 and KP-1461, and 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

[0215] HIV integrase inhibitors

[0216] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AV X-15567, diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, and cabotegravir.

[0217] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442.

[0218] HIV entry inhibitors

[0219] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CC R5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[0220] Examples of CCR5 inhibitors include apuvirod, vicovirod, maraviroc, cenikvirod, PRO-140, adaptavir (RAP-101), nifevirod (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0221] Examples of gp41 inhibitors include abovirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0222] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0223] Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostamsavir tromethamine, IQP-0831, and BMS-663068.

[0224] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0225] HIV maturation inhibitors

[0226] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

[0227] Latency reversal agents

[0228] Examples of latency reversing agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as bortezomib (velcade), protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberoylanilide hydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15, JQ1, disulfiram, amphotericin B, ubiquitin inhibitors such as ragozola analogs, and GSK-343.

[0229] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0230] Examples of PKC activators include indole lactams, prostratin, ingenol B, and DAG-lactone.

[0231] Capsid inhibitors

[0232] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301 and AVI-CAN1-15 series.

[0233] Immune-based therapies

[0234] Examples of immune-based therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (PD-1) modulators; programmed death-ligand 1 (PD-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; quinine (hydroxychloroquine); interleukins (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-N3; pegylated interferon alpha; Interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, normferon, peginterferon alpha-2a, peginterferon alpha-2b, recombinant interleukin-15, RPI-MN, GS-9620, and IR-103.

[0235] Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0236] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQ R-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

[0237] HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins

[0238] Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include DA Fab derivatives, bn ABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360 and those targeting HIV gp120 or gp41, antibodies targeting HIV-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, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant monoclonal antibodies (PGT-121), ibalizumab, Immu glo, MB-66.

[0239] Examples of those antibodies that target HIV in this manner include bavirimab, 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.

[0240] Pharmacokinetic enhancers

[0241] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0242] Additional therapeutic agents

[0243] Examples of additional therapeutic agents include compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO2014 / 100323 (Gilead Sciences), US2013 / 0165489 (University of Pennsylvania), US2014 / 0221378 (Japan Tobacco), US2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences) and WO 2013 / 091096 (Boehringer Ingelheim).

[0244] HIV vaccine

[0245] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVA C HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mR NA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSPISA-51, poly-ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]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, GOV X-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGa g), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, Co mbiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugated peptide 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, multi-branched Env vaccine, MVA vaccine, Pennvax-GP, pp71 defective HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActiveHIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 peptide vaccine, rAd5 gag-pol env A / B / C vaccine. .

[0246] HIV combination therapy

[0247] In a specific embodiment, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvir; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); TRI (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; pr olastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosph azid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0248] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from: (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); ( rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (tenofovir alafenamide, emtricitabine, and rilpivirine); (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvir; ( lopinavir and ritonavir); (zidovudine and lamivudine; AZ T+3TC); ( abacavir sulfate and lamivudine; ABC+3TC); (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; Zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine and zidovudine; abacavir; abacavir sulfate; 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA); and bictegravir or a pharmaceutically acceptable salt thereof.

[0249] It will be appreciated by those skilled in the art that the additional therapeutic agents listed above may be included in more than one of the categories listed above. The specific categories are not intended to limit the functionality of those compounds listed in those categories.

[0250] In one specific embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with one or two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In one specific embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a compound that inhibits HIV protease. In another embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with at least one of a nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

[0251] In some embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with one or two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In a specific embodiment, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a compound that inhibits HIV protease. In additional embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with at least one of a nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

[0252] In a specific embodiment, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate.

[0253] In some embodiments, a compound disclosed herein (e.g., a compound of (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bictegravir (or a pharmaceutically acceptable salt thereof), or 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

[0254] In some embodiments, a compound disclosed herein (eg, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with an HIV integrase inhibitor.

[0255] In a specific embodiment, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate.

[0256] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, bictegravir (or a pharmaceutically acceptable salt thereof), or 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).

[0257] In a specific embodiment, a compound disclosed herein (e.g., a compound of Formula (Ia) or Formula (Ib)) or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0258] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0259] In a specific embodiment, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In a specific embodiment, a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In a specific embodiment, the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt is combined with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In some embodiments, the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt is administered simultaneously with the first additional therapeutic agent and the second additional therapeutic agent as disclosed above. Optionally, the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt is combined with the first additional therapeutic agent and the second additional therapeutic agent as disclosed above in a single dosage form to be applied to an individual simultaneously. In other embodiments, the compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt, and the first additional therapeutic agent and the second additional therapeutic agent as disclosed above are sequentially administered.

[0260] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In a specific embodiment, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In a specific embodiment, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is administered simultaneously with the first additional therapeutic agent and the second additional therapeutic agent as disclosed above. Optionally, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is combined with the first additional therapeutic agent and the second additional therapeutic agent as disclosed above in a single dosage form for simultaneous administration to an individual. In other embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and the first additional therapeutic agent and the second additional therapeutic agent as disclosed above are administered sequentially.

[0261] In some embodiments, a compound disclosed herein (eg, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is combined with bictegravir or a pharmaceutically acceptable salt thereof.

[0262] The compounds disclosed herein (e.g., any compound of Formula (Ia) or (Ib)) can be combined with one or more additional therapeutic agents at any dose (e.g., 1 mg to 1000 mg of compound) of the compound of Formula (Ia) or (Ib).

[0263] In some embodiments, the compounds disclosed herein (e.g., any compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) can be combined with one or more additional therapeutic agents at any dose (e.g., 1 mg to 1000 mg of compound) of the compound of Formula (Ia), (Ib), (IIa) and / or (IIb).

[0264] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 1000 mg of the compound), as if each dose combination is specifically and individually listed.

[0265] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30 or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of Formula (Ia), (Ib), (IIa) and / or (IIb)) can be combined with the agents provided herein at any dose of the compound (e.g., 1 mg to 1000 mg of the compound), as if each dose combination is specifically and individually listed.

[0266] In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400 or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 1000 mg of the compound), as if each dose combination was specifically and individually listed.

[0267] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400 or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 1000 mg of the compound), as if each dose combination was specifically and individually listed.

[0268] In some embodiments, a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with 20-80 mg of bictegravir or a pharmaceutically acceptable salt thereof. A compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 1000 mg of the compound), as if each dose combination was specifically and individually listed.

[0269] In one embodiment, a kit is provided comprising a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0270] In some embodiments, a kit is provided comprising a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0271] Pharmaceutical composition

[0272] The pharmaceutical compositions disclosed herein comprise a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical composition containing the active ingredient may be in any form suitable for the desired method of administration.

[0273] In some embodiments, the pharmaceutical compositions disclosed herein comprise a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical composition containing the active ingredient may be in any form suitable for the desired method of administration.

[0274] Pharmaceutical compositions containing a compound disclosed herein (e.g., a compound of Formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof can be prepared with conventional carriers (e.g., inactive ingredients or excipient materials), which can be selected as usual. Tablets can contain excipients, including glidants, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and, when intended for delivery by means other than oral administration, can generally be isotonic. All compositions can optionally contain excipients, such as those described in Rowe et al, Handbook of Pharmaceutical Excipients, 5 th edition, American Pharmacists Association, 1986. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

[0275] In some embodiments, pharmaceutical compositions containing a compound disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof can be prepared with conventional carriers (e.g., inactive ingredients or excipient materials), which can be selected as usual. Tablets can contain excipients, including glidants, fillers, binders, etc. Aqueous compositions can be prepared in sterile form and, when intended for delivery by means other than oral administration, can generally be isotonic. All compositions can optionally contain excipients, such as Rowe et al, Handbook of Pharmaceutical Excipients, 5 th edition, American Pharmacists Association, 1986. For example, excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.

[0276] Although the active ingredient can be administered alone, it is preferred that the active ingredient is presented in the form of a pharmaceutical composition. Compositions for veterinary and human use comprise at least a compound of formula (Ia) or (Ib), and one or more acceptable carriers and optional other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient and 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 as defined above. In one embodiment, the pharmaceutical composition comprises a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient and one other therapeutic ingredient. A carrier is "acceptable" in the sense that it is compatible with the other ingredients of the composition and is physiologically harmless to its recipient.

[0277] In some embodiments, although the active ingredient can be administered alone, it is preferred that the active ingredient is present in the form of a pharmaceutical composition. Compositions for veterinary and human use comprise at least a compound of formula (Ia), (Ib), (IIa) and / or (IIb), and one or more acceptable carriers and optional other therapeutic ingredients. In some embodiments, the pharmaceutical composition comprises a compound 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., one, two, three or four, or one or two, or one to three, or one to four) additional therapeutic agents as defined above. In some embodiments, the pharmaceutical composition comprises a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient and one other therapeutic ingredient. A carrier is "acceptable" in the sense that it is compatible with the other ingredients of the composition and is physiologically harmless to its recipient.

[0278] The composition includes compositions suitable for various routes of administration. The composition can be conveniently present in the form of a unit dosage form and can be prepared by any method well known in the pharmaceutical field. Such methods include the step of combining an active ingredient (e.g., a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof) with one or more inactive ingredients (e.g., a carrier, a pharmaceutical excipient, etc.). The composition can be prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then (if necessary) forming the product. Technology and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0279] In some embodiments, the composition includes compositions suitable for various routes of administration. The composition can be conveniently present in the form of a unit dosage form and can be prepared by any method well known in the pharmaceutical field. Such methods include the step of combining an active ingredient (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) with one or more inactive ingredients (e.g., a carrier, a pharmaceutical excipient, etc.). The composition can be prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then (if necessary) forming the product. Technology and formulations can generally be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

[0280] Compositions described herein suitable for oral administration may be presented as discrete units (unit dosage forms) including, but not limited to, capsules, cachets or tablets, each containing a predetermined amount of the active ingredient.

[0281] For example, when used for oral use, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents to provide a palatable preparation, including sweeteners, flavoring agents, coloring agents and preservatives. Tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, cross-linked carboxymethylcellulose sodium, povidone, calcium phosphate or sodium phosphate; granulating agents and disintegrants, such as corn starch or alginic acid; binders, such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0282] In some embodiments, disclosed herein are oral dosage forms (eg, tablets) that can be prepared by hot melt extrusion or spray drying dispersion (SDD) techniques.

[0283] In some embodiments, disclosed herein are hard capsules filled with powders, beads or granules containing active ingredients mixed with non-toxic pharmaceutically acceptable excipients suitable for making hard or soft capsules. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, cross-linked carboxymethyl cellulose sodium, povidone, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.

[0284] In some embodiments, disclosed herein are hard or soft capsules filled with a liquid or semisolid mixture containing an active ingredient mixed with a nontoxic pharmaceutically acceptable excipient suitable for making a hard or soft capsule. These excipients can be, for example, solubilizing oils such as maize oil, sesame oil or corn oil; medium chain triglycerides and related esters such as derived palm kernel oil or coconut oil; self-emulsifying lipid systems (SEDDS or SMEDDS) such as caprylic triglyceride or propylene glycol monocaprylate; viscosity modifiers such as hexadecanol, sterols, stearyl glyceride; and solubilizers and surfactants such as polyethylene glycol, propylene glycol, glycerol, ethanol, polyethoxylated castor oil, poloxamer or polysorbate.

[0285] The pharmaceutical composition of the present invention can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned herein. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. The acceptable carriers and solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can generally be used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0286] In some embodiments, the sterile injectable preparation disclosed herein can also be a sterile injectable solution or suspension, which is prepared by reconstructing a lyophilized powder in a nontoxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Among them, acceptable carriers and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can generally be used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections.

[0287] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient; aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. In certain embodiments, the suspension is a microsuspension. In certain embodiments, the suspension is a nanosuspension.

[0288] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) will include one or more excipients. The excipient should be compatible with the other ingredients of the formulation and physiologically harmless to its recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey & Quinn), 6th edition, 2009.

[0289] Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (e.g., polysorbate 20 or 80) and poloxamers (e.g., poloxamer 338, 188, or 207). In some embodiments, disclosed herein are parenteral administrations (e.g., SC or IM formulations) comprising a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and a poloxamer, particularly poloxamer 338. In some embodiments, the amount of poloxamer (e.g., poloxamer 388) in the parenteral administrations disclosed herein is less than about 5%, e.g., less than about 3%, about 2%, about 1%, or about 0.5%.

[0290] Examples of solubilizing excipients in parenteral formulations (e.g., SC or IM formulations) include, but are not limited to, polysorbates (e.g., polysorbate 20 or 80), poloxamers (e.g., poloxamer 338, 188, or 207). In some embodiments, disclosed herein are parenteral administrations (e.g., SC or IM formulations) comprising a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and a poloxamer.

[0291] In certain embodiments, excipients include N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide, polyethylene glycol, and / or glycofurol.

[0292] Typically, poloxamers are synthetic nonionic triblock linear copolymers having a central hydrophobic chain of polyoxypropylene adjacent to two hydrophilic polyoxypropylenes (in some cases having a weight ratio of 4:2:4). Thus, in certain embodiments, the compositions disclosed herein comprise a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and a block copolymer consisting of one polyoxypropylene portion and two hydrophilic polyoxypropylene portions. In certain embodiments, the ratio of the polyoxypropylene portion to the two hydrophilic polyoxypropylene portions is 4:2:4 (hydrophilic polyoxypropylene: polyoxypropylene: hydrophilic polyoxypropylene). Poloxamers are generally understood to have the following structure: Wherein a and b are integers (e.g., a is 2-130 and b is 15-67). For example, it is believed that the molecular weight range of poloxamer 188 is about 7680 to about 9510 Daltons (wherein a is about 80 and b is about 27). International Journal of PharmTech Research, Vol. 1, No. 2, pp 299-303, April-June 2009. In some cases, the average molecular weight of poloxamer 188 is about 8400 Daltons. Similarly, the molecular weight range of poloxamer 338 is about 12700 to about 17400 Da (wherein a is about 141 and b is about 44).

[0293] Examples of excipients in parenteral formulations (e.g., SC or IM formulations) may also include polyethylene glycol. Typically, polyethylene glycol (PEG) is a polyol having the general formula H-(O-CH2-CH2) n In certain embodiments, the PEG can be "end-capped" with an alkyl group. In those embodiments, the end-capped PEG has the formula alkyl-(O-CH2-CH2) n -O-alkyl (e.g. CH3-(O-CH2-CH2) n -OCH3). The pharmaceutical composition of the present invention may include PEG having an average molecular weight of about 100 to about 1000. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 100 to about 800. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 200 to about 600. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 400. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 300. In some embodiments, the average molecular weight of the PEG in the pharmaceutical composition is about 200. In some embodiments of the pharmaceutical composition, PEGs of different molecular weights may be combined to obtain one or more desired properties (e.g., viscosity). Specific examples of PEG include, but are not limited to, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, etc. For example, PEG 100 refers to polyethylene glycol having an average molecular weight of about 100.

[0294] In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, and saline. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, saline and a poloxamer (e.g., poloxamer 338, 188 or 207).

[0295] In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, and saline. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, saline and a suspending agent. In some embodiments, the parenteral formulations disclosed herein (e.g., SC or IM formulations) are aqueous suspensions comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, saline and a poloxamer (e.g., poloxamer 338, 188 or 207).

[0296] In some embodiments, a suspension of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof contained in a poloxamer and saline is provided. In some embodiments, the concentration of the poloxamer in saline is from about 0.1 to about 20%. In some embodiments, the concentration of the poloxamer in saline is from about 0.1 to about 10%. In some embodiments, the concentration of the 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 certain embodiments, the concentration of the poloxamer in saline is about 2%. In certain embodiments, the 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 a compound of formula (Ib). In certain embodiments, the compound is the sodium salt of the compound of Formula (Ib).

[0297] In some embodiments, a suspension of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof contained in poloxamer and mannitol is provided. In some embodiments, the concentration of poloxamer in mannitol is from about 0.1 to about 20%. In some embodiments, the concentration of poloxamer in mannitol is from about 0.1 to about 10%. In some embodiments, the concentration of poloxamer in mannitol is about 0.1%, 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, the 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 a compound of formula (Ib). In certain embodiments, the compound is a sodium salt of a compound of formula (Ib).

[0298] In certain embodiments, the compositions are disclosed as solid dosage forms, including solid injectable dosage forms, such as solid depot forms.

[0299] In certain embodiments, the active ingredient (eg, a compound of Formula Ib) is present in the form of a free acid. In certain embodiments, the active ingredient (eg, a compound of Formula Ib) is present in the form of a sodium salt.

[0300] In certain embodiments, the pharmaceutical compositions disclosed herein are parenteral formulations. In certain embodiments, the formulation is administered subcutaneously to an individual in need thereof. In certain embodiments, the formulation is administered intramuscularly to an individual in need thereof.

[0301] In certain embodiments, the parenteral formulation comprises N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation consists essentially of N-methyl-2-pyrrolidone. In certain embodiments, the parenteral formulation comprises dimethyl sulfoxide.

[0302] 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 alcohol. In certain embodiments, the alcohol is ethanol. In certain embodiments, the parenteral formulation further comprises polyethylene glycol. In certain embodiments, the average molecular weight of polyethylene glycol is about 200g / mol (polyethylene glycol 200). In certain embodiments, the parenteral formulation further comprises an inorganic base. In certain embodiments, the inorganic base is sodium hydroxide. In certain embodiments, the inorganic base is sodium ethoxide. In certain embodiments, the formulation comprises an inorganic base (e.g., NaOH or NaOEt) in an amount of about 0.1 molar equivalents to about 1.5 molar equivalents. In certain embodiments, the formulation comprises an inorganic base (e.g., NaOH or NaO Et) in an amount of about 0.5 molar equivalents to about 1.5 molar equivalents. In certain embodiments, the formulation comprises about 1.0 molar equivalents to about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt).

[0303] In certain embodiments, the parenteral formulation consists essentially of a compound of Formula (Ib) or a pharmaceutically acceptable salt thereof, water, ethanol, and polyethylene glycol 200.

[0304] In certain embodiments, the parenteral formulation consists essentially of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, water, ethanol, polyethylene glycol 200 (polyethylene glycol with an average molecular weight of 200 g / mol) and sodium hydroxide. In certain embodiments, the parenteral formulation consists essentially of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, water, ethanol, polyethylene glycol 200 and NaOEt. In certain embodiments, the formulation comprises about 0.1 molar equivalents to about 1.5 molar equivalents of NaOH or NaO Et. In certain embodiments, the formulation comprises about 0.5 molar equivalents to about 1.5 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises about 1.0 molar equivalents to about 1.2 molar equivalents of NaOH or NaOEt. In certain embodiments, the formulation comprises about 1.2 molar equivalents of NaOH or NaOEt.

[0305] In certain embodiments, parenteral preparations are solution preparations comprising a mixture of ethanol, water and polyethylene glycol. In certain embodiments, parenteral preparations are solution preparations comprising a mixture of ethanol, water and PEG 200. In certain embodiments, solution preparations comprise about 5%-20% ethanol, about 5% to 20% water and about 60% to 90% PEG200. In certain embodiments, solution preparations comprise about 10%-15% ethanol, about 10% to 15% water and about 70% to 80% PEG 200. In certain embodiments, solution preparations comprise about 10% ethanol, about 12% water and about 78% PEG 200. In certain embodiments, solution preparations also comprise an inorganic base. In certain embodiments, solution preparations also comprise sodium hydroxide or sodium ethoxide. In certain embodiments, solution preparations also comprise sodium hydroxide. In certain embodiments, preparations comprise an inorganic base (e.g., NaOH or NaOEt) of about 0.1 molar equivalents to about 1.5 molar equivalents. In certain embodiments, the formulation comprises from about 0.5 molar equivalents to about 1.5 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises from about 1.0 molar equivalents to about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt). In certain embodiments, the formulation comprises about 1.2 molar equivalents of an inorganic base (e.g., NaOH or NaOEt).

[0306] In some embodiments, a solution formulation is provided containing 200 mg / mL of Formula Ib in about 10% ethanol, about 12% water, and about 77% PEG and about 0.1 to about 1.5 equivalents of NaOH.

[0307] In certain embodiments, an oral formulation of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) comprising at least one excipient is provided. Excipients may include ethanol, medium chain triglycerides (e.g., MIGLYOL810, MIGLYOL821, MIGLYOL 840, etc.), vitamin E TPGS, glycerol and / or a pharmaceutically acceptable oil (e.g., sesame oil, castor oil, safflower oil, vegetable oil, soybean oil, etc.). The oral formulation disclosed herein may include any combination of one or more suitable excipients. The excipients taken together may be present in an amount of>65% of the total weight of the oral formulation,>70% of the total weight of the oral formulation,>80% of the total weight of the oral formulation,>90% of the total weight of the oral formulation,>95% of the total weight of the oral formulation.

[0308] 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 812. In certain embodiments, the oral formulation comprises a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) in about 10% ethanol, about 20% Vitamin E TPGS, and about 70% MIGLYOL 812. In certain embodiments, oral formulations are prepared in the form of hard gelatin capsules.

[0309] The amount of active ingredients that can be combined with inactive ingredients to generate a dosage form can vary depending on the individual to be treated and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to a human may contain about 1 to 1000 mg of active material, formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material is about 5 to about 95% (weight: weight) of the total composition.

[0310] It should be understood that in addition to the ingredients particularly mentioned above, the compositions of the embodiments may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0311] In certain embodiments, a composition comprising an active ingredient disclosed herein (e.g., a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof) in one variation does not contain an agent that affects the metabolic rate of the active ingredient. Thus, it should be understood that a composition comprising a compound of Formula (Ia) or (Ib) in certain embodiments does not contain an agent that affects (e.g., slows, hinders, or delays) the metabolism of a compound of Formula (Ia) or (Ib) or any other active ingredient that is administered alone, sequentially, or simultaneously with a compound of Formula (Ia) or (Ib). It should also be understood that any method, kit, article, etc. described in detail herein in certain embodiments does not contain an agent that affects (e.g., slows, hinders, or delays) the metabolism of a compound of Formula (Ia) or (Ib) or any other active ingredient that is administered alone, sequentially, or simultaneously with a compound of Formula (Ia) or (Ib).

[0312] In some embodiments, a composition comprising an active ingredient disclosed herein (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) in one variation does not contain an agent that affects the metabolic rate of the active ingredient. Thus, it should be understood that a composition comprising a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) in certain embodiments does not contain an agent that affects (e.g., slows, hinders or delays) the metabolism of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or any other active ingredient administered alone, sequentially or simultaneously with a compound of Formula (Ia), (Ib), (IIa) and / or (IIb). It is also understood that in certain embodiments any of the methods, kits, articles of manufacture, etc. described herein do not contain agents that affect (e.g., slow, hinder or delay) the metabolism of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or any other active ingredient administered alone, sequentially or simultaneously with a compound of Formula (Ia), (Ib), (IIa) and / or (IIb).

[0313] How to use

[0314] In certain embodiments, disclosed are methods of treating or preventing HIV infection in an individual (eg, a human), the method comprising administering to the individual a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0315] In some embodiments, disclosed are methods for treating or preventing HIV infection in an individual (e.g., a human), the method comprising administering to the individual a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof.

[0316] In certain embodiments, disclosed are methods for inhibiting HIV viral replication, treating AIDS, or delaying the onset of AIDS in an individual (e.g., a human), the method comprising administering to the individual a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, disclosed are methods for inhibiting HIV viral replication, treating AIDS, or delaying the onset of AIDS in an individual (e.g., a human), the method comprising administering to the individual a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof.

[0318] In certain embodiments, a method for preventing HIV infection in an individual (e.g., a human) is disclosed, the method comprising administering to the individual a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual is at risk of HIV infection, such as an individual with one or more risk factors known to be associated with HIV infection.

[0319] In some embodiments, a method for preventing HIV infection in an individual (e.g., a human) is disclosed, the method comprising administering to the individual 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 individual is at risk of HIV infection, such as an individual with one or more risk factors known to be associated with HIV infection.

[0320] In certain embodiments, disclosed are methods for treating HIV infection in an individual (eg, a human), the method comprising administering to the individual a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, disclosed are methods for treating HIV infection in an individual (eg, a human), the method comprising administering to the individual a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof.

[0322] In certain embodiments, methods for treating HIV infection in an individual (e.g., a human) are disclosed, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from the following: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, other drugs used to treat HIV, and combinations thereof.In certain embodiments, a method of treating HIV infection in an individual (e.g., a human) is disclosed, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, or four; or one or two; or one to three; or one to four) additional therapeutic agents selected from the following: a combination drug for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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, HIVvif gene modulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, CO MM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIVGA G protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

[0323] In some embodiments, disclosed are methods for treating HIV infection in an individual (e.g., a human), comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) in combination, or a pharmaceutically acceptable salt thereof, and 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 selected from the following: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, other drugs used to treat HIV, and combinations thereof.In certain embodiments, a method of treating HIV infection in an individual (e.g., a human) is disclosed, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof in combination with 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 selected from the following: a combination drug for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICA M-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof. In certain embodiments, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is disclosed for use in medical therapy of HIV infection (e.g., HIV-1 or HIV virus (e.g., HIV-1) replication or AIDS or delaying the onset of AIDS in an individual (e.g., human)).

[0324] In some embodiments, compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof, are disclosed for use in the medical treatment of HIV infection (e.g., HIV-1 or replication of HIV virus (e.g., HIV-1) or AIDS or delaying the onset of AIDS in an individual (e.g., a human)).

[0325] In certain embodiments, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is disclosed for use in the preparation of a medicament for treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in an individual (e.g., a human). One embodiment relates to a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of HIV infection or AIDS or for the therapeutic treatment or delaying the onset of AIDS.

[0326] In some embodiments, compounds of Formula (Ia), (Ib), (IIa) and / or (IIb) or pharmaceutically acceptable salts thereof are disclosed for use in the preparation of a medicament for treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in an individual (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 the therapeutic treatment or delaying the onset of AIDS.

[0327] In certain embodiments, disclosed is the use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for HIV infection in an individual (e.g., a human). In certain embodiments, disclosed is the use of either compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of HIV infection.

[0328] In some embodiments, disclosed is the use of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for HIV infection in an individual (e.g., a human). In certain embodiments, disclosed is any compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of HIV infection.

[0329] In certain embodiments, in the methods of use, the administration is to an individual (eg, a human) in need of treatment. In certain embodiments, in the methods of use, the administration is to an individual (eg, a human) at risk of developing AIDS.

[0330] Disclosed herein are compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof for use in therapy. In one embodiment, the compounds of formula (Ia) or (Ib) or pharmaceutically acceptable salts thereof are used in a method of treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in an individual (e.g., a human).

[0331] In some embodiments, disclosed herein are compounds of Formula (Ia), (Ib), (IIa) and / or (IIb) or pharmaceutically acceptable salts thereof for use in therapy. In some embodiments, compounds of Formula (Ia), (Ib), (IIa) and / or (IIb) or pharmaceutically acceptable salts thereof are used in a method of treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in an individual (e.g., a human).

[0332] Also disclosed herein is 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 an individual in need thereof. In certain embodiments, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof is provided for use in a method of treating HIV infection in an individual in need thereof. In certain embodiments, the individual in need thereof is a person who has been infected with HIV. In certain embodiments, the individual in need thereof is a person who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk of developing AIDS. In certain embodiments, the individual in need thereof is a person who has been infected with HIV and has developed AIDS.

[0333] In some embodiments, disclosed herein are compounds of Formula (Ia), (Ib), (IIa) and / or (IIb) or pharmaceutically acceptable salts thereof for use in methods of treating or preventing HIV infection in an individual in need thereof. 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 an individual in need thereof. In certain embodiments, the individual in need thereof is a person who has been infected with HIV. In certain embodiments, the individual in need thereof is a person who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk of developing AIDS. In certain embodiments, the individual in need thereof is a person who has been infected with HIV and has developed AIDS.

[0334] In one embodiment, provided is a method of treating or preventing HIV infection in an individual in need thereof in combination with a compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and 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 as described herein. In one embodiment, the additional therapeutic agent is selected from a combination drug for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIVGA G protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cell cycle protein-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, other drugs used to treat HIV, and combinations thereof.

[0335] In some embodiments, provided are compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts 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 as described herein for use in a method of treating or preventing HIV infection in an individual in need thereof. In one embodiment, the additional therapeutic agent is selected from a combination drug for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cell cycle protein-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof. In one embodiment, the additional therapeutic agent is selected from compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, other drugs used to treat HIV, and combinations thereof.

[0336] In one embodiment, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is provided in combination with a first additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent for use in a method of treating or preventing HIV infection in an individual in need thereof, wherein the second additional therapeutic agent is emtricitabine. In a specific embodiment, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is provided in combination with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate and a second additional therapeutic agent for use in treating or preventing HIV infection in an individual in need thereof, wherein the second additional therapeutic agent is emtricitabine.

[0337] In some embodiments, provided is a method of treating or preventing HIV infection in an individual in need thereof in combination with a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and a first additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine. In a specific embodiment, provided is a method of treating or preventing HIV infection in an individual in need thereof in combination with a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0338] In a specific embodiment, there is provided a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for preventing HIV infection and / or preventing the virus from establishing a permanent infection and / or preventing the appearance of symptoms of the disease and / or preventing the virus from reaching a detectable level in the blood when the individual is exposed to the virus, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Therefore, in certain embodiments, there is provided a method 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 a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) includes administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0339] In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is provided for preventing HIV infection and / or preventing the virus from establishing a permanent infection and / or preventing the appearance of symptoms of the disease and / or preventing the virus from reaching a detectable level in the blood when the individual is exposed to the virus, for example, for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Therefore, in certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) is provided. For example, 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 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, and one or more additional therapeutic agents. In certain embodiments, a method for reducing the risk of infection with HIV (e.g., HIV-1 and / or HIV-2) comprises administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0340] In certain embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, and combining it with safer sex. In certain embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering to an individual at risk of HIV infection. Examples of individuals with a high risk of HIV infection include, but are not limited to, individuals at risk of sexually transmitted HIV.

[0341] In some embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof, combined with safer sex. In certain embodiments, methods for reducing the risk of HIV infection (e.g., HIV-1 and / or HIV-2) include administering to an individual at risk of HIV infection. Examples of individuals at high risk of HIV infection include, but are not limited to, individuals at risk of sexually transmitting HIV.

[0342] In certain embodiments, the reduction in risk of HIV infection is at least about 40%, 50%, 60%, 70%, 80%, 90% or 95%. In certain embodiments, the reduction in risk of HIV infection is at least about 75%. In certain embodiments, the reduction in risk of HIV infection is about 80%, 85% or 90%.

[0343] In another embodiment, disclosed is the use of a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV infection in a human suffering from or at risk of developing HIV infection.

[0344] In some embodiments, disclosed is the use of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV infection in a human suffering from or at risk of developing HIV infection.

[0345] Also disclosed herein is a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for use in therapeutically treating or delaying the onset of AIDS.

[0346] In some embodiments, disclosed herein are compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof, for use in therapeutically treating or delaying the onset of AIDS.

[0347] Also disclosed herein is a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of HIV infection.

[0348] In some embodiments, disclosed herein are 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.

[0349] In certain embodiments, the compounds of Formula (Ia) or (Ib), or pharmaceutically acceptable salts thereof, can be used as research tools (eg, for studying inhibition of HIV reverse transcriptase in a subject or in vitro).

[0350] In some embodiments, the compounds of Formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof, can be used as research tools (eg, for studying inhibition of HIV reverse transcriptase in a subject or in vitro).

[0351] Route of administration

[0352] The compound of formula (Ia) or (Ib) or its pharmaceutically acceptable salt (also referred to herein as active ingredient) can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It should be understood that the preferred route can vary depending on, for example, the condition of the recipient. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0353] In some embodiments, the compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof (also referred to herein as active ingredient) can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. It should be understood that the preferred route may vary depending on, for example, the condition of the recipient. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0354] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof can 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 a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof.

[0355] In some embodiments, a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof can be administered using an automatic 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 a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof.

[0356] Dosage regimen

[0357] The compound (e.g., a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof) can be applied to an individual for a desired period of time or continued administration according to an effective dosing regimen, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered in a daily regimen or an intermittent regimen. In one variation, the compound is administered in a monthly regimen. In one variation, the compound is administered once every two months. In one variation, the compound is administered once every three months. In one variation, the compound is administered once every four months. In one variation, the compound is administered once every five months. In one variation, the compound is administered once every six months.

[0358] In some embodiments, the compound (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) can be administered to an individual for a desired period of time or continued administration, such as 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 in a once-daily regimen or an intermittent regimen. In some embodiments, the compound is administered in a monthly regimen. In some embodiments, the compound is administered once every two months. In some embodiments, the compound is administered once every three months. In some embodiments, the compound is administered once every four months. In some embodiments, the compound is administered once every five months. In some embodiments, the compound is administered once every six months.

[0359] In some embodiments, the compound (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) can be administered to an individual for at least about 1 month, at least about 4 months, or at least about 6 months. In some embodiments, the compound (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) can be administered subcutaneously to an individual for at least about 1 month. In some embodiments, the compound (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) can be administered subcutaneously or intramuscularly to an individual for at least about 4 months, or at least about 6 months. In some embodiments, the compound (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) can be administered subcutaneously to an individual for at least about 1 month. In some embodiments, a compound (e.g., a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof) can be administered to a subject subcutaneously or intramuscularly at least about once every 3 months.

[0360] The dosage or frequency of administration of the compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof may be adjusted during the course of treatment based on the judgment of the administering physician.

[0361] In some embodiments, the dosage or frequency of administration of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof may be adjusted during treatment based on the judgment of the administering physician.

[0362] The compound can be administered to an individual (eg, a human) in an effective amount. In certain embodiments, the compound is administered once a day.

[0363] In some embodiments, the compound can be administered to an individual (e.g., human) in a therapeutically effective amount. In some embodiments, the compound is administered once a day. In some embodiments, the compound is administered once a month. In some embodiments, the compound is administered once every three months. In some embodiments, the compound is administered once every four months. In some embodiments, the compound is administered once every six months.

[0364] The compounds disclosed herein (e.g., compounds of Formula (Ia) or (Ib)) or pharmaceutically acceptable salts thereof can be administered in an effective dose. For example, the dose can be 1 mg to 1000 mg of compound. In certain embodiments, the dose is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140, or 150 mg of compound. In certain embodiments, the dose is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

[0365] 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 at an effective dose. For example, the dose can be 1 mg to 1000 mg of compound. In certain embodiments, the dose is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105, 110, 120, 130, 140, or 150 mg of compound. In certain embodiments, the dose is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

[0366] In some embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is administered at a dose once daily. In some embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg once daily.

[0367] In some embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is administered once a month. In some embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is administered once a month at a dose of about 100 mg.

[0368] In some embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is administered once every 6 months. In some embodiments, the compound of Formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is administered once every 6 months at a dose of about 600 mg.

[0369] Kits and Products

[0370] The present invention relates to a kit comprising a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In one embodiment, the kit may comprise one or more additional therapeutic agents as described above. The kit may further comprise instructions for use, such as for inhibiting HIV reverse transcriptase, such as for treating HIV infection or AIDS or as a research tool. Although electronic storage media (such as magnetic disks or optical disks) containing instructions are also acceptable, instructions for use are generally written instructions.

[0371] In some embodiments, the present invention 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 comprise one or more additional therapeutic agents as described above. The kit may further include instructions for use, such as for inhibiting HIV reverse transcriptase, such as for treating HIV infection or AIDS or as a research tool. Although electronic storage media (such as magnetic disks or optical disks) comprising instructions are also acceptable, instructions for use are typically written instructions.

[0372] The present invention further relates to a pharmaceutical kit comprising one or more containers, the container comprising a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. Optionally connected to the container may be a notice in a form specified by a government agency, which specifies the manufacture, use or specification of the drug, the notice reflecting the specifications authorized by the agency to manufacture, use or be used for administration to a person. Each component (if there is more than one component) can be packaged in a separate container, or some components can be combined in one container where cross-reactivity and shelf life permit. The kit can be a unit dosage form, a bulk package (e.g., a multi-dose package) or a subunit dose. The kit can also include a plurality of unit doses of the compound and instructions for use, and the amount of the package is sufficient to be stored and used in a pharmacy (e.g., a hospital pharmacy and a dispensing pharmacy).

[0373] In some embodiments, the present invention also relates to a pharmaceutical kit comprising one or more containers, wherein the container comprises formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof. Optionally connected to the container may be a notice in a form prescribed by a government agency, which specifies the manufacture, use or specifications of the drug, and the notice reflects the specifications authorized by the agency to manufacture, use or be administered to a person. Each component (if there is more than one component) can be packaged in a separate container, or some components can be combined in one container where cross-reactivity and shelf life permit. The kit can be a unit dosage form, a bulk package (e.g., a multi-dose package) or a subunit dose. The kit can also include multiple unit doses of the compound and instructions for use, and the amount of the package is sufficient for storage and use in a pharmacy (e.g., a hospital pharmacy and a dispensing pharmacy).

[0374] Also disclosed are articles of manufacture comprising a unit dose of a compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, cans, flexible packaging, etc. The articles of manufacture may be further sterilized and / or sealed.

[0375] In some embodiments, disclosed herein are articles comprising a unit dose of a compound of Formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, cans, flexible packaging, etc. The article may be further sterilized and / or sealed.

[0376] Nomenclature

[0377] The names of the compounds of formula (Ia) and (Ib) of the present invention were generated using ChemBioDraw Ultra 11.

[0378]

[0379] It is N-(1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetamide.

[0380]

[0381] It is N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetamide.

[0382] The names of the compounds of formula (IIa) and (IIb) of the present invention were generated using ChemBioDraw Ultra 14.

[0383]

[0384] It is N-(1-(3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetamide.

[0385]

[0386] It is N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamido)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

[0387] Synthesis of compounds of formula (Ia), (Ib), (IIa) and (IIb)

[0388] The present invention also relates to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

[0389] Unless otherwise indicated, the methods and techniques of the present invention are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, 5 thedition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7 th edition, Wiley-Interscience, 2013.

[0390] In some cases, the methods disclosed herein include the step of forming a salt of a compound of the invention.

[0391] In some cases, intermediates that can be used to prepare compounds of formula (Ia) or (Ib) of the present invention are provided. For example, those intermediates include any one or a combination 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 a salt thereof.

[0392] In some embodiments, intermediates that can be used to prepare compounds of formula (IIa) or (IIb) of the present invention are provided. For example, those intermediates include any one of compounds 1, 10, 20 and 25-37 or their salts or their combination. In some embodiments, the intermediate is selected from compounds 20, 32, 34, 35, 36 and / or 37, their combination or their salt.

[0393] The compounds described herein can be purified by any method known in the art, including chromatography, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. Most commonly, the disclosed compounds are purified by silica gel and / or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2 nd ed., ed. LRSnyder and JJKirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

[0394] During any of the processes for the preparation of the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules of interest. This can be accomplished using conventional protecting groups as described in standard texts, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 4 th ed., Wiley, New York 2006. The protecting groups may be removed at an appropriate subsequent stage using methods known in the art.

[0395] Exemplary chemical entities that can be used for the methods in the embodiments will now be described by reference to the illustrative synthetic schemes and subsequent specific examples used herein for general preparation. 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 specific side groups. Each reaction described in the general scheme is preferably carried out at about 0° C. to the reflux temperature of the organic solvent used.

[0396] The compounds disclosed herein may exhibit atropisomerism caused by steric hindrance affecting the axial rotation rate around a single bond. Through characterization techniques such as NMR and HPLC, it can be observed that the resulting conformational isomers are each different entities. The compounds disclosed herein may exist as a mixture of atropisomers. However, the detection of atropisomers depends on factors such as temperature, solvent, purification conditions and the time scale of spectral techniques. The half-life of the mutual conversion rate at room temperature is from minutes to hours, hours to days, or days to years. The ratio of atropisomers may be inconsistent under equilibrium conditions. Depending on the conditions of separation and characterization, the characterization data provided herein may not represent equilibrium conditions, and the conditions may include but are not limited to treatment, solvents used and temperature.

[0397] For the purpose of example only, the present invention includes but is not limited to the following technical solutions:

[0398] Technical solution 1. Compound of formula (Ia):

[0399]

[0400] or a pharmaceutically acceptable salt thereof.

[0401] Technical Solution 2. The compound according to Technical Solution 1, which is a compound of formula (Ib):

[0402] or a pharmaceutically acceptable salt thereof.

[0403] Technical Solution 3. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in Technical Solution 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0404] Technical Solution 4. The pharmaceutical composition according to Technical Solution 3 further comprises one, two, three or four additional therapeutic agents.

[0405] Technical solution 5. A pharmaceutical composition according to technical solution 4, wherein the additional therapeutic agent is selected from: a combination drug for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1Ne f modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICA M-3 capture 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 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccine, or any combination thereof.

[0406] Technical Solution 6. A pharmaceutical composition according to Technical Solution 4, wherein the additional therapeutic agent is selected from: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or any combination thereof.

[0407] Technical solution 7. A pharmaceutical composition according to technical solutions 4-6, wherein the additional therapeutic agent is selected from: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate.

[0408] Technical solution 8. The pharmaceutical composition according to technical solutions 4-7, wherein the additional therapeutic agent is selected from: tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

[0409] Technical Solution 9. A method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the compound described in Technical Solution 1 or 2 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0410] Technical Solution 10. The method according to Technical Solution 9, wherein the method comprises administering the compound or a pharmaceutically acceptable salt thereof in combination with one, two, three or four additional therapeutic agents.

[0411] Technical solution 11. A method according to technical solution 10, wherein the additional therapeutic agent is selected from: a combination of drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cell cycle protein-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

[0412] Technical Solution 12. A method according to Technical Solution 10 or 11, wherein the additional therapeutic agent is selected from: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or any combination thereof.

[0413] Technical solution 13. A method according to technical solutions 10-12, wherein the additional therapeutic agent is selected from: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate.

[0414] Technical solution 14. The method according to technical solutions 10-13, wherein the additional therapeutic agent is selected from: tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

[0415] Technical Solution 15. Use of the compound described in Technical Solution 1 or 2 or a pharmaceutically acceptable salt thereof for treatment.

[0416] Technical Solution 16. Use of the compound described in Technical Solution 1 or 2 or a pharmaceutically acceptable salt thereof for treating or preventing human immunodeficiency virus (HIV) infection, the method comprising administering a therapeutically effective amount of the compound to an individual in need thereof.

[0417] Technical solution 17. The use of the compound according to Technical solution 16, wherein the method comprises administering one, two, three or four additional therapeutic agents.

[0418] Technical Solution 18. The use of the compound according to Technical Solution 17, wherein the additional therapeutic agent is administered simultaneously with the compound of Formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

[0419] Technical solution 19. The use of the compound according to Technical solution 18, wherein the compound of formula (Ia) or (Ib) and the additional therapeutic agent are administered simultaneously in a single dosage form.

[0420] Technical Solution 20. The use of the compound according to Technical Solution 17, wherein the compound of formula (Ia) or (Ib) and the additional therapeutic agent are administered sequentially.

[0421] Technical solution 21. The use of a compound according to technical solution 17, wherein the additional therapeutic agent is selected from: a combination drug for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic IC AM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cell cycle protein-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

[0422] Technical Solution 22. The use of a compound according to Technical Solution 17, wherein the additional therapeutic agent is selected from: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or any combination thereof.

[0423] Technical solution 23. The use of the compound according to Technical Solution 17, wherein the compound is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate.

[0424] Technical solution 24. The use of the compound according to Technical Solution 17, wherein the compound is combined with tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate.

[0425] Technical Solution 25. The use of the compound according to Technical Solution 17, wherein the compound is combined with tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate.

[0426] Technical solution 26. The use of the compound according to Technical Solution 17, wherein the compound is combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0427] Technical solution 27. The use of the compound according to Technical Solution 17, wherein the compound is combined with a first additional therapeutic agent selected from tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0428] Technical Solution 28. The use of the compound according to Technical Solution 17, wherein the compound is combined with a first additional therapeutic agent selected from tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0429] Technical Solution 29. A pharmaceutical composition according to Technical Solutions 4-6, wherein the additional therapeutic agent is 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof.

[0430] Technical Solution 30. The method according to Technical Solutions 10-12, wherein the method comprises administering the compound or a pharmaceutically acceptable salt thereof in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof.

[0431] Technical solution 31. The use of the compound according to Technical Solutions 17-22, wherein the compound is administered in combination with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof.

[0432] Technical solution 32. Compound of formula (IIa):

[0433]

[0434] or a pharmaceutically acceptable salt thereof.

[0435] Technical solution 33. The compound according to technical solution 32, which is a compound of formula (IIb):

[0436] or a pharmaceutically acceptable salt thereof.

[0437] Technical solution 34. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in Technical Solution 32 or 33 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0438] Technical Solution 35. A pharmaceutical composition according to Technical Solution 34, which further comprises one, two, three or four additional therapeutic agents.

[0439] Technical solution 36. A pharmaceutical composition according to technical solution 35, wherein the additional therapeutic agent is selected from: a combination drug for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infectious factor inhibitors, TAT protein inhibitors, HIV-1Ne f modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICA M-3 capture 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 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccine, or any combination thereof.

[0440] Technical solution 37. A pharmaceutical composition according to technical solution 35, wherein the additional therapeutic agent is selected from: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or any combination thereof.

[0441] Technical solution 38. A pharmaceutical composition according to technical solutions 35-37, wherein the additional therapeutic agent is selected from: 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate.

[0442] Technical solution 39. A pharmaceutical composition according to technical solutions 35-38, wherein the additional therapeutic agent is selected from: 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

[0443] Technical solution 40. A method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of a compound as described in Technical Solution 32 or 33 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0444] Technical Solution 41. A method according to Technical Solution 40, wherein the method comprises administering the compound or a pharmaceutically acceptable salt thereof in combination with one, two, three or four additional therapeutic agents.

[0445] Technical solution 42. A method according to technical solution 41, wherein the additional therapeutic agent is selected from: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cell cycle protein-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

[0446] Technical solution 43. A method according to technical solution 41 or 42, wherein the additional therapeutic agent is selected from: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or any combination thereof.

[0447] Technical solution 44. A method according to technical solutions 41-43, wherein the additional therapeutic agent is selected from: 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate.

[0448] Technical solution 45. A method according to technical solutions 41-44, wherein the additional therapeutic agent is selected from: 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

[0449] Technical Solution 46. Use of the compound described in Technical Solution 32 or 33 or a pharmaceutically acceptable salt thereof for treatment.

[0450] Technical Solution 47. Use of the compound described in Technical Solution 32 or 33 or a pharmaceutically acceptable salt thereof for treating or preventing human immunodeficiency virus (HIV) infection, the method comprising administering a therapeutically effective amount of the compound to an individual in need thereof.

[0451] Technical Solution 48. The use of a compound according to Technical Solution 47, wherein the method comprises administering one, two, three or four additional therapeutic agents.

[0452] Technical Solution 49. The use of the compound according to Technical Solution 48, wherein the additional therapeutic agent is administered simultaneously with the compound of Formula (IIa) or (IIb) or a pharmaceutically acceptable salt thereof.

[0453] Technical solution 50. The use of the compound according to Technical Solution 49, wherein the compound of formula (IIa) or (IIb) and the additional therapeutic agent are administered simultaneously in a single dosage form.

[0454] Technical Solution 51. The use of the compound according to Technical Solution 48, wherein the compound of formula (IIa) or (IIb) and the additional therapeutic agent are administered sequentially.

[0455] Technical solution 52. The use of a compound according to technical solution 48, wherein the additional therapeutic agent is selected from: a combination drug for HIV, other drugs for treating HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic IC AM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cell cycle protein-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

[0456] Technical solution 53. The use of a compound according to technical solution 48, wherein the additional therapeutic agent is selected from: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or any combination thereof.

[0457] Technical solution 54. The use of the compound according to Technical Solution 48, wherein the compound is combined with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate.

[0458] Technical solution 55. The use of the compound according to Technical Solution 48, wherein the compound is combined with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate.

[0459] Technical Solution 56. The use of the compound according to Technical Solution 48, wherein the compound is combined with 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate.

[0460] Technical solution 57. The use of the compound according to technical solution 48, wherein the compound is combined with a first additional therapeutic agent selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0461] Technical solution 58. The use of the compound according to technical solution 48, wherein the compound is combined with a first additional therapeutic agent selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0462] Technical Solution 59. The use of the compound according to Technical Solution 48, wherein the compound is combined with a first additional therapeutic agent selected from 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0463] Technical Solution 60. A pharmaceutical composition according to any one of Technical Solutions 3-8, 29 or 34-39, wherein the composition is a parenteral preparation.

[0464] Technical Solution 61. A parenteral preparation according to Technical Solution 60, wherein the preparation is administered subcutaneously to an individual in need.

[0465] Technical Solution 62. A parenteral preparation according to Technical Solution 60, wherein the preparation is administered intramuscularly to an individual in need.

[0466] Technical Solution 63. A parenteral preparation according to any one of Technical Solutions 60-62, wherein the preparation comprises saline.

[0467] Technical Solution 64. A parenteral preparation according to any one of Technical Solutions 60-63, wherein the preparation comprises poloxamer.

[0468] Technical Solution 65. An extragastric preparation according to Technical Solution 64, wherein the poloxamer is poloxamer 338.

[0469] Technical solution 66. A compound selected from:

[0470]

[0471] Technical solution 67. A compound selected from:

[0472]

[0473] Technical solution 68. A compound of the following formula:

[0474]

[0475] Technical Solution 69. An extragastric preparation according to Technical Solution 64, wherein the poloxamer is poloxamer 188.

[0476] Technical solution 70. The parenteral preparation according to Technical Solution 69, wherein the concentration of poloxamer 188 in saline is about 1% to about 10%.

[0477] Technical solution 71. A parenteral preparation according to technical solution 69 or 70, wherein the concentration of poloxamer 188 in saline is about 1% to about 3%.

[0478] Technical solution 72. A parenteral preparation according to Technical Solution 69, 70 or 71, wherein the concentration of poloxamer 188 in saline is about 2%.

[0479] Technical Solution 73. A parenteral preparation according to any one of Technical Solutions 60-62, wherein the preparation contains N-methyl-2-pyrrolidone.

[0480] Technical Solution 74. A parenteral preparation according to any one of Technical Solutions 60-62, wherein the preparation is essentially composed of N-methyl-2-pyrrolidone.

[0481] Technical Solution 75. A parenteral preparation according to any one of Technical Solutions 60-62, wherein the preparation contains dimethyl sulfoxide.

[0482] Technical Solution 76. A parenteral preparation according to any one of Technical Solutions 60-62, wherein the preparation is essentially composed of dimethyl sulfoxide.

[0483] Technical Solution 77. A parenteral preparation according to any one of Technical Solutions 60-62, wherein the preparation comprises water.

[0484] Technical Solution 78. A parenteral preparation according to any one of Technical Solutions 60-62 or 77, wherein the preparation further comprises alcohol.

[0485] Technical Solution 79. An extragastric preparation according to Technical Solution 78, wherein the alcohol is ethanol.

[0486] Technical Solution 80. A parenteral preparation according to any one of Technical Solutions 60-62 or 77-79, wherein the preparation further comprises polyethylene glycol.

[0487] Technical Solution 81. A parenteral preparation according to Technical Solution 80, wherein the average molecular weight of the polyethylene glycol is about 200 g / mol.

[0488] Technical Solution 82. The parenteral preparation according to any one of Technical Solutions 77-81, which also contains an inorganic base.

[0489] Technical Solution 83. An extra-gastric preparation according to Technical Solution 82, wherein the inorganic base is sodium hydroxide.

[0490] Technical solution 84. The parenteral preparation according to technical solutions 60-62 and 77-83, wherein the preparation comprises about 5% to about 20% ethanol, about 5% to about 20% water and about 60% to about 90% polyethylene glycol 200.

[0491] Technical solution 85. The parenteral preparation according to technical solutions 60-62 and 77-84, wherein the preparation comprises about 10% to about 15% ethanol, about 10% to about 15% water and about 70% to about 80% polyethylene glycol 200.

[0492] Technical Solution 86. A parenteral preparation according to Technical Solutions 60-62 and 77-85, wherein the preparation comprises about 10% ethanol, about 12% water and about 78% polyethylene glycol 200.

[0493] Technical Solution 87. A pharmaceutical composition according to any one of Technical Solutions 3-8, 29 or 34-39, wherein the composition is an oral preparation.

[0494] Technical Solution 88. A preparation according to any one of Technical Solutions 60-65 and 69-87, wherein the compound is present in the form of a sodium salt.

[0495] The schemes below and the specific examples that follow describe representative syntheses of compounds of the invention.The following examples are illustrative only and are not intended to limit the invention in any way.

[0496] 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1, 2-c]pyrazol-1-yl)acetic acid (8a) and 2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- Preparation of cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetic acid (8b):

[0497] Example 1

[0498] Preparation of compounds 8a and 8b

[0499]

[0500] Synthesis of 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethane-1-ol lithium (2):

[0501] Bicyclo[3.1.0]hexan-3-one (95.6 g, 0.99 mol) and ethyl 2,2,2-trifluoroacetate (113.2 mL, 0.95 mol) and THF (50 mL) were added to the reactor. The reaction mixture was cooled to 0 ° C. LiHMDS (bis(trimethylsilyl)lithium amide) (1 L 1.0 M solution in THF, 1 mol) was added through a feed funnel at a rate to maintain an internal temperature of ≤1 ° C. After addition, hexane (235 mL) was added through a feed funnel at a steady flow rate and stirred for 15 minutes. The obtained solid was collected by filtration, and the obtained solid was washed with hexane (3×400 mL) and dried to obtain the title compound.

[0502] 2-(3-(Trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid Synthesis of ethyl ester (3):

[0503] Lithium 2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hex-2-ylidene)ethane-1-olate (177.2 g, 0.89 mol) and EtOH (ethanol) (779 mL) were added to the reactor. The temperature was brought to and maintained at 0°C. A solution of HCl in dioxane (4.0 N, 443 mL) was added via an addition funnel followed by solid ethyl hydrazinoacetate HCl salt (138.4 g, 0.90 mol). The reaction temperature was adjusted to 35°C. After 1 hour, the reaction volume was reduced by about 40% by distillation under reduced pressure. 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), hexane (3×400 mL) and dried to give the title compound. MS (m / z) 275.1 [M+H] + .

[0504] 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole-1- Synthesis of ethyl acetate (4):

[0505] To the reactor was added ethyl 2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (291.2 g, 1.06 mol), acetonitrile (1.65 L) and water (825 mL) to which was added N-hydroxyphthalimide (17.4 g, 0.103 mol) and NaClO2 (41.0 g, 0.45 mol, about 20% of the total added amount). 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 starting material was consumed, the temperature was adjusted to 20°C and aqueous sodium bisulfite solution (40% w / w, 350 mL) was added via an addition funnel. Ethyl acetate (1.75 L) was added and the layers were separated. The aqueous layer was back extracted with EtOAc (ethyl acetate) (500 mL). The organic layers were combined and washed with saturated NaHCO3 aqueous solution (500 mL) and 1:1 water / brine (500 mL). The organic layer was concentrated under reduced pressure and co-evaporated with IPAc (isopropyl acetate) (300 mL). The crude solid was crystallized from a mixture of IPAc / heptane. The resulting solid was collected by filtration, washed with heptane and dried to give the title compound. MS (m / z) 289.0 [M+H] + .

[0506] 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole-1- Synthesis of acetic acid (5):

[0507] To a solution of ethyl 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (80.40 g, 278.95 mmol) in 2-MeTHF (2-methyltetrahydrofuran) (167 mL) was added 2M aqueous sodium hydroxide solution (167 mL). After stirring at room temperature for 25 minutes, the reaction mixture was diluted with 2-MeTHF and slowly acidified by dropwise addition of concentrated HCl. The organic layer was separated and the aqueous layer was extracted with another portion of 2-MeTHF. The combined organic layers were washed with saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. The resulting oil was added to ethyl acetate. Hexane was added under vigorous stirring until solid formation was observed. The solid was separated by filtration and dried to obtain the title compound. MS (m / z) 259.00 [MH] - .

[0508] 2-(3-(Trifluoromethyl)-4,4a-dihydrospiro[cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiopentane Synthesis of 1-(3-(4-(4-cyclo)-1-(3bH)-yl)acetic acid (6):

[0509] To a solution of 2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (3.0 g, 11.5 mmol) in DCM (dichloromethane) (25 mL) was added 1,2-ethanedithiol (1.07 mL, 12.68 mmol) followed by boron trifluoride-acetic acid complex (4.0 mL, 28.8 mmol). The reaction mixture was stirred at room temperature overnight. Water (60 mL) and 2-MeTHF (60 mL) were added to the reaction mixture. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in ethyl acetate (2 mL) and the solution was diluted with hexane (12 mL) under vigorous stirring to obtain a solid. The solid was separated by filtration and dried to obtain the title compound. MS (m / z) 337.12 [M+H] + .

[0510] 2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole- Synthesis of 1-methyl)acetic acid (7):

[0511] To a suspension of 1,3-dibromo-5,5-dimethylhydantoin (12.75 g, 44.6 mmol) in DCM (35 mL) was added hydrofluoric acid pyridine (5.0 mL) at 0°C. The suspension was stirred at 0°C for 10 minutes. A solution of 2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolane]-1(3bH)-yl)acetic acid (5.00 g, 14.9 mmol) was added dropwise to the suspension. After the addition was complete, the reaction mixture was stirred at 0°C for another 15 minutes. The reaction mixture was poured into a saturated aqueous sodium bicarbonate solution (300 mL) with vigorous stirring. The organic layer was removed and the aqueous layer was acidified to pH about 1 with concentrated HCl. The aqueous phase was extracted with three portions of MTBE (methyl tert-butyl ether). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting solid was placed in MTBE (16 mL) and filtered to remove any resulting solid. The solution was then extracted with 2N NaOH (16 mL). The aqueous layer was diluted with water (16 mL) under vigorous stirring and stirred at room temperature for 15 minutes. The resulting solid was removed by filtration. The aqueous layer was acidified to pH about 1 by slowly dropping concentrated HCl under vigorous stirring to obtain a solid precipitate. The solid was separated by filtration to obtain the title compound. MS (m / z) 281.12 [M+H] + .

[0512] 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1, 2-c]pyrazol-1-yl)acetic acid (8a) and 2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H- Synthesis of cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetic acid (8b):

[0513] 2-(5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid was separated into its constituent enantiomers (i.e., the title compound) by chiral SFC under the following conditions: Instrument: Thar 350 preparative SFC; Column: ChiralPak IC-10u, 300×50mmI.D.; Mobile phase: 35% isopropanol (0.1% NH3·H2O) and CO2; Flow rate: 200mL / min; Column temperature: 38°C; UV detection: 220nm; Sample preparation: Dissolve the compound in isopropanol to about 45mg / mL; Injection: 6.5mL per injection. Analytical SFC [mobile phase: A is CO2, B is isopropanol (0.05% DEA); gradient: B 20%; A; flow rate: 2.35 mL / min; column: Chiralpak IC-3, 150×4.6 mm, 3 um; wavelength: 254 nm] 8a: t=3.39 min, 8b: t=2.17 min.

[0514] Compound 8a- 1H NMR (400 MHz, CHLOROFORM-d) δ 4.93 (s, 2H), 2.52–2.43 (m, 2H), 1.44–1.38 (m, 1H), 1.15 (m, 1H).

[0515] Example 2

[0516] Preparation of compound 12

[0517]

[0518] Synthesis of 7-bromo-4-chloro-1H-indazol-3-amine (10):

[0519] To a solution of 3-bromo-6-chloro-2-fluorobenzonitrile (13.9 g, 59.3 mmol) in EtOH (ethanol) (60 mL) was added hydrazine monohydrate (5.77 mL). The reaction mixture was heated to 80 ° C and maintained for 3 hours. After cooling to ambient temperature, EtOH (20 mL) was added to enable stirring. The solid was isolated by filtration, washed with cold EtOH and dried to give the title compound. MS (m / z) 247.9 [M+H] + .

[0520] Synthesis of 7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (11):

[0521] 7-Bromo-4-chloro-1H-indazole-3-amine (397.2 g, 1.6 mol) and Cs2CO3 (1052 g, 3.2 mol) were added to the reactor, and then diluted with DMF (dimethylformamide) (4000 mL). 2,2,2-trifluoroethyl trifluoromethanesulfonate (463.2 g, 1.9 mol) was slowly added thereto through an addition funnel. After the addition, the reaction mixture was stirred for 1 hour, and H2O (16 L) was slowly added while stirring. After the addition, 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 thereto, and the resulting solid was collected by filtration and dried to obtain the title compound. MS (m / z) 330.1 [M+H] + .

[0522] 4-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)- Synthesis of 1H-indazole-3-amine (12):

[0523] 7-Bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine (15.00 g, 45.66 mmol), bis(pinacolato)diboron (17.39 g, 68.49 mmol), potassium propionate (15.36 g, 136.98 mmol), dioxane (90 mL) and DMF (dimethylformamide) (30 mL) 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 argon for 2 minutes. The reaction mixture was heated to 105 °C and maintained for 4 hours. After cooling to ambient temperature, the reaction mixture was filtered through a celite pad and silica gel and washed with EtOAc. The filtrate was washed with 5% LiCl solution and brine. The organic layer was separated and 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 give the title compound. MS (m / z) 376.7 [M+H] +1 H NMR (400MHz, DMSO-d6) δ7.69(d,1H),7.06(d,1H),5.55(s,2H),5.45(q,2H),1.32(s,12H).

[0524] Example 3

[0525] Preparation of compound 14

[0526]

[0527] Synthesis of 3-methyl-3-(methylsulfonyl)but-1-yne (14):

[0528] 3-Chloro-3-methylbut-1-yne (15.00 g, 146.3 mmol, 16.4 mL) was added dropwise to a stirred suspension of sodium methanesulfonate (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 EtOAc. The solution was washed with water and brine. The organic layer was collected and dried with sodium sulfate and then filtered. The solution was concentrated in vacuo and purified by silica gel chromatography to obtain the title compound. Mp: 114.8–115.5 ° C. 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.04 (s, 3H), 2.58 (s, 1H), 1.67 (s, 6H).

[0529] Example 4

[0530] Preparation of compound 19

[0531]

[0532] Synthesis of (S)-N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfenamide (16)

[0533] 3,6-Dibromopyridinecarboxaldehyde (76.0 g, 0.287 mol) and (S)-2-methylpropane-2-sulfenamide (36.51 g, 0.301 mol) were mixed in NMP (N-methyl-2-pyrrolidone) (200 mL). Cs2CO3 (41.94 g, 0.316 mol) was added as a solid to the reaction mixture. 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 separated by filtration, and the solid was washed with water (5×100 mL) and dried to obtain the title compound. MS (m / z) 368.9 [M+H] + .

[0534] (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2- Synthesis of sulfenamide (17):

[0535] To the reaction vessel was added (S)-N-((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (65.5 g, 177.95 mmol) followed by DMF (dimethylformamide) (260 mL). The mixture was stirred for 5 minutes until homogeneous and the solution was cooled to 8°C. (3,5-difluorobenzyl)zinc 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 an additional 2.5 hours. A 5% AcOH (acetic acid) solution in water (640 mL) was added to the reaction mixture over 10 minutes followed by a single addition of CPME (cyclopentyl methyl ether) (320 mL). 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) and then treated with 0.5 M NaOH (330 mL) and washed with brine. The organic layer was collected, dried over Na2SO4 and filtered. MeOH (methanol) (33 mL) was added to the crude mixture. A solution of 3M HCl in CPME (128 mL) was added dropwise to the stirring 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 alkalized with 8M NaOH and extracted with CPME (375 mL). The organic layer was washed with brine, dried over Na2SO4 and filtered to obtain a solution of the title compound, which was used directly in the next step reaction. MS (m / z) 497.0 [M+H] + .

[0536] Synthesis of (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (18):

[0537] The resulting (S)-N-((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfenamide solution was diluted with CPME to a volume of 700 mL, to which acetonitrile (350 mL) was added. Concentrated HCl (37%, 16.4 mL) was added dropwise to the stirring mixture at room temperature over 10 minutes. The concentrated slurry was stirred vigorously for 4 hours. The solid was filtered off and washed with 2:1 CPME (cyclopropyl methyl ether): ACN to give the title compound. MS (m / z) 393.3 [M+H] + .

[0538] (S)-tert-Butyl (1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (19) synthesis:

[0539] 2-MeTHF (190 mL), water (190 mL) and (S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine (46.9 g, 0.11 mol) were added to the reaction vessel, followed by the addition of NaHCO3 (30.34 g, 0.36 mol) in portions. The reaction mixture was cooled to 5 °C and di-tert-butyl dicarbonate (27.47 g, 0.13 mol) was added. The reaction mixture was stirred at 0 °C for 2 hours and 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 gel column chromatography to give the title compound. MS (m / z) 492.8 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.85(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).

[0540] Example 5

[0541] Preparation of Formula (Ib) (Compound 24)

[0542]

[0543] (S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5- Synthesis of tert-butyl (difluorophenyl)ethyl)carbamate (20):

[0544] Add (S)-tert-butyl (1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (50.00 g, 101.8 mmol), 3-methyl-3-methylsulfonyl-but-1-yne (17.86 g, 122.2 mmol), DMF (dimethylformamide) (90 mL) and Et3N (trimethylamine) (42.5 mL, 305.4 mmol) to the reactor. Heat the reaction mixture to 50°C.

[0545] Bis(triphenylphosphine)palladium(II)dichloride (2.14 g, 3.1 mmol) and cuprous(I)iodide (0.58 g, 3.1 mmol) were added. After 30 minutes, the reaction mixture was diluted with MeCN(acetonitrile) (200 mL) and then 7% NH4Cl aqueous solution (200 mL) was added dropwise. A slurry was formed and adjusted to ambient temperature. After 3 hours, the solid was collected by filtration. The filter cake was washed twice with MeCN / water (1:1, 75 mL) and washed with MTBE (methyl tert-butyl ether) (75 mL). The solid was dried to obtain the title compound. MS (m / z) 556 [M+H] + . 1 H NMR (400 MHz, CHLOROFORM-d) δ7.84 (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.

[0546] (S)-(1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3- Tert-butyl (methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (21) synthesis:

[0547] A round-bottom flask was charged with tert-butyl (S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (1000.0 mg, 1.79 mmol), 4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (808.5 mg, 2.15 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65.6 mg, 0.09 mmol) and cesium carbonate (876.7 mg, 2.69 mmol) and placed under argon. Dioxane (10 mL) and water (2 mL) were added and the suspension was degassed by bubbling argon for 60 seconds. After degassing, the reaction flask was equipped with a reflux condenser and heated to 80°C overnight. The reaction mixture was cooled to room temperature and the aqueous layer was removed. The organic layer was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography to obtain the title compound. MS (m / z) 726.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ7.69–7.55 (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).

[0548] (S)-(1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H- Indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5

[0549] Synthesis of tert-butyl (2-difluorophenyl)ethyl)carbamate (22):

[0550] (S)-tert-butyl (1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (37.89 g, 52.18 mmol) was dissolved in dichloromethane (380 mL) at ambient temperature with stirring. Triethylamine (21.82 mL, 156.54 mmol) was added thereto, followed by the slow addition of methanesulfonyl chloride (8.08 mL, 104.36 mmol). When the reaction was complete, water (200 mL) was added and stirred for 0.5 hours. The organic layer was separated and the aqueous layer was extracted once with dichloromethane. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to a small volume. Hexane was added. The liquid suspension was decanted. The remaining solid was dried under reduced pressure to give the title compound. MS (m / z): 882.69 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.87(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).

[0551] (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)butane- 1-(1-alkyne-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methane Synthesis of sulfonamide (23):

[0552] Trifluoroacetic acid (80 mL) was added to (S)-(1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamic acid tert-butyl ester (39 g, 44 mmol) dissolved in dichloromethane (120 mL). The reaction mixture was stirred at ambient temperature for 50 minutes. The reaction mixture was diluted with dichloromethane and slowly poured into an ice-cold saturated aqueous NaHCO3 solution. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give the title compound. MS (m / z): 782.84 [M+H]+ . 1 H NMR (400 MHz, chloroform-d) δ7.61(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).

[0553] N-((S)-1-(3-(4-chloro-3-(methylsulfonamide)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6- (3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS, 4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)ethyl Synthesis of amide (24):

[0554] (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide (1757 mg, 2.25 mmol), 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl) )-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (666 mg, 2.36 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate) (854 mg, 2.25 mmol) were added to a round-bottom flask and dissolved in DMF (dimethylformamide) (10.0 mL). N,N-diisopropylethylamine (0.80 mL, 4.49 mmol) was quickly added dropwise to the solution. After the addition was complete, the reaction mixture was stirred at room temperature for 15 minutes to give the unisolated intermediate 23b (MS (m / z) 1046.65 [M+H] + ). To the solution was added 2N aqueous sodium hydroxide solution (5.0 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was collected and washed with two portions of 5% lithium chloride solution and then with brine. The organic layer was separated, dried over 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] + . 1HNMR(400MHz, methanol-d4)δ7.87–7.57(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=13.1,7.6Hz),2.93(dd),2.68–2.35(m),1.81(s),1.41(q),1.12–1.00(m). 19 FNMR (377 MHz, methanol-d4) δ–63.65,–71.78 (t),–72.35 (t),–82.75 (dd),–105.70 (ddd),–111.73––113.10 (m).

[0555] To more fully characterize 23b, this compound was isolated. 1 H NMR(400MHz,DMSO-d6)δ9.20(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),3.2 6(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).

[0556] 2-((3bS,4aR)-3-(Difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1, Preparation of 2-c]pyrazol-1-yl)acetic acid (32)

[0557] Example 6

[0558] Preparation of compound 32

[0559]

[0560] Synthesis of 2,2-difluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethane-1-ol lithium (25):

[0561] The title compound was prepared according to the method used for the synthesis of compound 2 using ethyl 2,2-difluoroacetate. 1H NMR(400MHz, CDCl3)δ6.17(t,J=53.6Hz,1H),2.78-2.73(m,1H),2.44-2.39(m,1 H),2.25-2.24(m,1H),1.70-1.69(m,1H),1.22-1.14(m,1H),0.31-0.27(m,1H).

[0562] 2-(3-(Difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid Synthesis of sodium (26):

[0563] Me-THF (1.32 L) was added to a 4 L reactor, followed by lithium 2,2-difluoro-1-(3-oxobicyclo[3.1.0]hex-2-ylidene)ethane-1-olate (247 g, 1.32 mol). HCl (4N in dioxane) (0.685 L, 2.74 mol) was slowly added to the mixture, maintaining the internal temperature at about 20°C. After the addition of ethyl hydrazinoacetate hydrochloride (212.05 g, 1.372 mol), the resulting mixture was stirred at 20°C for 4 hours. The reaction mixture was heated to 50°C overnight. 10N NaOH aqueous solution (0.548 L, 5.48 mol) was slowly added to the reaction mixture, maintaining the internal temperature at 20°C. After the addition was complete, 300 ml of MeTHF was added and the resulting suspension was stirred at 20°C for 3 hours. The suspension was drained and filtered. The filter cake was washed with hexanes (1 L) and dried in a vacuum oven at 56 °C to afford the title compound, which was used directly in the next step. MS (m / z) 229.1 [M-Na+H] + .

[0564] 2-(3-(Difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid Synthesis of ethyl ester (27):

[0565] The ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate from the previous step was added to a 4 L reactor followed by EtOH (3.5 L) and concentrated H2SO4 (152 ml, 2.74 mol). The resulting mixture was stirred at reflux for 2 hours. The EtOH was reduced to 150 ml under vacuum. H2O (500 ml) was added slowly. The solid was collected and washed with H2O and NaHCO3, followed by hexanes (500 ml). The solid was dried in an oven at 45 °C to give the title compound. MS (m / z) 257.1 [M+H] + .

[0566] 2-(3-(Difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole-1- Synthesis of ethyl acetate (28):

[0567] The title compound was prepared using ethyl 2-(3-(difluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate according to the method used to synthesize compound 4. MS (m / z) 271.1 [M+H] + .

[0568] 2-(3-(Difluoromethyl)-4,4a-dihydrospiro[cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiopentane Synthesis of ethyl 1-(3-(4-(4-cyclohexyl)-1-yl)acetate (29):

[0569] To a solution of ethyl 2-(3-(difluoromethyl)-5-oxo-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (148.5 g, 0.55 mol) in DCM (2.0 L) was added ethane-1,2-dithiol (88.0 g, 0.94 mol) in one portion, followed by BF3·2AcOH (175.8 g, 0.94 mol). The reaction was stirred at room temperature for 12 hours. The system was cooled to 0°C and quenched with saturated aqueous NaHCO3 solution (1000 ml). The organic layer was separated, washed with brine (500 ml) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the title compound. MS (m / z): 347.1 [M+H] + .

[0570] 2-(3-(Difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole- Synthesis of ethyl acetate (30):

[0571] 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 was stirred at -78 °C for 30 minutes. A solution of ethyl 2-(3-(difluoromethyl)-4,4a-dihydrospiro[cyclopropyl[3,4]cyclopenta[1,2-c]pyrazole-5,2'-[1,3]dithiolane]-1(3bH)-yl)acetate (40 g, 0.12 mol) in DCM (80 mL) was added dropwise over 15 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 a NaHCO3 aqueous solution (500 mL) and extracted with EA (500 mL×3). The combined organic layers were washed with 10% aqueous Na2S2O3 solution (500 mL), brine (500 mL), and dried over Na2SO4. The solvent was removed in vacuo to give a crude product, which was further purified by column chromatography to give the title compound. MS (m / z): 293.2 [M+H] + .

[0572] 2-((3bS,4aR)-3-(Difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1, 2-((3bR,4aS)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrafluoroethylene)-1-( ... Isolation of ethyl 1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)acetate (31b):

[0573] Ethyl 2-(3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate was separated into its constituent enantiomers (i.e., 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 um; wavelength: 220 nm] 31a: t=5.30 min, 31b: t=7.00 min.

[0574] Compound 31a- 1 H NMR (400 MHz, CHLOROFORM-d) δ 6.63 (t, J = 54.8 Hz, 1H), 4.83 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 2.48-2.45 (m, 2H), 1.38-1.36 (m, 1H), 1.28 (t, J = 7.2 Hz, 3H), 1.13-1.12 (m, 1H).

[0575] 2-((3bS,4aR)-3-(Difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1, Synthesis of 2-c]pyrazol-1-yl)acetic acid (32):

[0576] To a solution of ethyl 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate (26 g, 89.0 mmol) in THF (180 mL), MeOH (90 mL) and water (90 mL) was added LiOH (5.13 g, 213.5 mmol). The mixture was stirred for 4 hours. The mixture was concentrated to remove most of the THF and MeOH, and the aqueous layer was acidified with 1N HCl to adjust the pH to 2-3, and then extracted with EA (600 mL×2). The organic phases were separated and combined, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. MS (m / z) 265.0 [M+H] + .

[0577] Example 7

[0578] Preparation of compound 34

[0579]

[0580] Synthesis of 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine (33):

[0581] 7-Bromo-4-chloro-1H-indazol-3-amine (130 g, 527.40 mmol, 1.00 equiv), N,N-dimethylformamide (1300 mL) and Cs2CO3 (260 g, 797.99 mmol, 1.50 equiv) were added to a 2000 mL 4-necked round-bottom flask, stirred for 20 minutes, and then 1,1-difluoro-2-iodoethane (122 g, 635.59 mmol, 1.20 equiv) was added. The resulting mixture was stirred at 65 ° C overnight, 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, 1×1.5 L of brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and recrystallized from ethanol to obtain the title compound. MS (m / z) 312.1 [M+H] + .

[0582] 4-Chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Synthesis of indazole-3-amine (34):

[0583] To a 3000 mL four-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added 7-bromo-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-amine (80 g, 257.63 mmol, 1.00 equiv), 1,4-dioxane (800 mL), N,N-dimethylformamide (800 mL), KOAc (76 g, 774.40 mmol, 3.00 equiv), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (197 g, 775.78 mmol, 3.00 equiv) and Pd(PPh3)2Cl2 (8 g, 11.40 mmol, 0.04 equiv). The mixture was stirred at 110°C for 4 hours, then cooled to room temperature, quenched by adding 5L of water / ice, and extracted with 2×2L of ethyl acetate. The combined organic layers were washed with 1×1L of H2O, 1×1L of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was added to a silica gel column and eluted with ethyl acetate / petroleum ether (1:10) to give the title compound. MS (m / z): 358 [M+H] + . 1 H-NMR: (DMSO-d6, 300MHz, ppm): δ7.63-7.66(1H,d),7.00-7.03(1H,d),6.06-6.43(1H,t),5.46(2H,s),4.90-5.01(2H,t),1.34(12H,s).

[0584] Example 8

[0585] Preparation of Formula (IIb) (Compound 38)

[0586]

[0587] (S)-(1-(3-(3-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methyl Synthesis of tert-butyl (3,5-difluorophenyl)ethyl)carbamate (35) become:

[0588] (S)-tert-butyl (1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (300 mg, 0.53 mmol), 4-chloro-1-(2,2-difluoroethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-amine (250 mg, 0.7 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14 mg, 0.016 mmol) and potassium carbonate (186 mg, 1.35 mmol) were placed in a microwave tube and placed under argon. Dimethoxyethane (2.5 mL) and water (0.3 mL) were added, and the reaction mixture was heated in a microwave reactor ( Initiator+) was heated to 130°C for 7 minutes. The reaction mixture was cooled to room temperature and partitioned between EtOAc and 0.1N HCl. The aqueous layer was removed and the organic layer was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give the title compound. MS (m / z) 708.20 [M+H] + ). 1 H NMR (400MHz, methanol-d4) δ7.91–7.50(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).

[0589] (S)-(1-(3-(4-chloro-3-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3- methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)

[0590] Synthesis of tert-butyl carbamate (36):

[0591] At ambient temperature and stirring, (S)-tert-butyl (1-(3-(3-amino-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (700 mg, 0.99 mmol) and 4-dimethylaminopyridine (24 mg, 0.2 mmol) were dissolved in pyridine (2 mL). Cyclopropane-1-sulfonyl chloride (222 μL, 2.2 mmol) was added thereto. The reaction mixture was stirred at 70 ° C until the reaction was complete. Water was added and stirred for 1 hour, and the resulting precipitate was collected by vacuum filtration, then dissolved in dichloromethane, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound. MS (m / z): 812.44 [M+H] + . 1 H NMR(400MH z, methanol-d4)δ7.93–7.58(m),7.50–7.15(m),7.00(dd),6.82–6.51(m),6.47–6.29(m),6.18–5.65(m),4.7 7–4.43(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).

[0592] (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)butane- Synthesis of 1-(1-alkyn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (37) become:

[0593] To a solution of (S)-tert-butyl(1-(3-(4-chloro-3-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (705 mg, 0.87 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3 mL). The reaction mixture was stirred for 1 hour and then slowly poured into a saturated sodium bicarbonate solution. Extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to give the title compound. MS (m / z): 712.34 [M+H]+.

[0594] 1H NMR (400MHz, methanol-d4) δ7.93-7.58(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).

[0595] N-((S)-1-(3-(4-chloro-3-(cyclopropanesulfonamide)-1-(2,2-difluoroethyl)-1H-indazol-7-yl)-6- (3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS, 4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopentyl[1,2-c]pyrazol-1-yl)ethyl Synthesis of amide (38):

[0596] (S)-N-(7-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (514 mg, 0.72 mmol), 2-((3bS,4aR)-3-(difluoromethyl)-5,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2-difluoroethyl)-1H-indazol-3-yl)cyclopropanesulfonamide (514 mg, 0.72 mmol), Fluoro-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)-acetic acid (191 mg, 0.72 mmol), 1-hydroxybenzotriazole (49 mg, 0.36 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) were added to 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 stirred for 1 hour. The resulting precipitate was collected by vacuum filtration and then dissolved in dichloromethane, dried over MgSO4, filtered and concentrated. The residue was purified by RP-HPLC to give the title compound as a TFA salt. MS (m / z) 958.88 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.90–7.56(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).

[0597] Biological Examples

[0598] Example A

[0599] Test A: Antiviral assay in MT4 cells

[0600] For antiviral assays, 0.4 μL of 3-fold serial dilutions of compounds at 189X test concentration in DMSO were added 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) in quadruplicate.

[0601] 1 mL aliquots of MT4 cells were pre-infected with 25 μL of cell growth medium (mock infected) or fresh 1:250 dilution of HIV-IIIb concentrated ABI stock (0.004 moi) for 3 hours at 37° C. Infected and uninfected cells were diluted in cell growth medium and 35 μL (2000 cells) were added to each well of the assay plate.

[0602] The assay plate was then kept in a humidified 5% CO2 incubator at 37°C. After 5 days of incubation, 25 μl of 2X concentrated CellTiter-Glo™ reagent (Catalog No. 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 chemiluminescence was read using an Envision plate reader (PerkinElmer). EC 50 Values ​​were calculated as the compound concentration that reduced the luminescent signal, a measure of HIV-1 replication, by 50%.

[0603] Example B

[0604] Test B: Cytotoxicity assay

[0605] Compound cytotoxicity and the corresponding CC were determined using the same protocol as described in the antiviral assay (Test A). 50 Values, except that uninfected cells were used.

[0606] Compared with Compound A and Compound B, the compounds of the present invention showed antiviral activities as shown in the following table (Test A).

[0607]

[0608]

[0609] Example C

[0610] Test C: Pharmacokinetic analysis after intravenous administration in Sprague-Dawley rats and beagle dogs and cynomolgus monkeys Analysis

[0611] Test Articles and Formulations

[0612] Compound 24 and 38 IV administrations were formulated at a concentration of 0.5 mg / mL in 5% ethanol, 20% PG, 45% PEG300, 30% pH 2 (0.01 N HCl) water. Compound A and Compound B intravenous infusions were formulated at a concentration of 0.5 mg / mL in a sterile solution of 5% ethanol, 45% PEG 400 and 50% water (pH 2.0). All IV formulations were in solution.

[0613] Animals used

[0614] Each rat IV dosing group consisted of 3 male SD rats. At the time of dosing, the body weight of the animals was generally between 0.317 and 0.355 kg. The animals were fasted overnight before dosing until 4 hours after dosing. Each dog IV dosing group consisted of 3 male juvenile beagles. At the time of dosing, the animals weighed approximately 10-12 kg. The animals were fasted overnight before dosing until 2 hours after dosing.

[0615] Each cynomolgus monkey (cyno) IV dosing group consisted of 3 male juvenile cynomolgus monkeys. At the time of dosing, the animals weighed approximately 3.2-4 kg. The animals were fasted overnight before dosing until 2 hours after dosing.

[0616] Drug administration

[0617] For the IV infusion group, test compounds were administered by intravenous infusion over 30 minutes. The infusion rate was adjusted to 2 mL / kg to deliver a dose of 1 mg / kg based on the body weight of each animal.

[0618] Sample collection

[0619] Serial venous blood samples (approximately 0.4 mL per rat and 1.0 mL per dog) were taken from each animal at designated time points after dosing. Blood samples were collected into a Vacutainer containing EDTA as an anticoagulant. TM Tubes (Becton-Disckinson Corp, New Jersey, USA) were placed immediately on wet ice and centrifuged to obtain plasma. Centrifugation was started within 1 hour after collection. All samples were placed in 96-well tubes and kept on dry ice and then stored at approximately -70°C.

[0620] Determination of the concentration of the compound of formula (I) in plasma

[0621] The concentrations of test compounds in plasma were measured using LC / MS / MS method.

[0622] calculate

[0623] Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. A summary of the pharmacokinetic parameters is shown in the table below.

[0624]

[0625]

[0626]

[0627] Example D

[0628] Test D: Metabolic stability in cultured human liver hepatocytes

[0629] Radiolabeled test compounds are prepared according to methods known in the art wherein tritium is introduced into the structure in place of one or more hydrogens.

[0630] Radiolabeled compounds were incubated in pooled cryopreserved hepatocytes at a substrate concentration of 0.25 μM and a radioactivity concentration of 10 μCi / mL. The final hepatocyte concentration was 1 million cells / mL. The hepatocyte / compound reaction mixture was dissolved in InVitroGRO 5% PBS, pH 7.4. TM KHB buffer (Catalog No. Z99074, Bioreclamation IVT, Inc., Baltimore, MD). Incubations were performed in duplicate. A cell-free control and a positive control were included in the incubations. Incubations were performed in a humidified atmosphere of 95% air / 5% CO2 (v / v) in a 37°C incubator with gentle shaking. Aliquots (100 mL) were removed after 0, 1, 3, and 6 hours and added to 200 mL of a quenching solution containing 0.1% (v / v) TFA in 5% water / 95% acetonitrile (v / v). The samples were placed on an oscillator for 10 minutes and then centrifuged at 3000 g for 30 minutes. Supernatant samples were analyzed on a Dionex HPLC / PerkinElmer Flow Scintillation Analyzer as described below.

[0631] Liquid chromatography-radiation chromatography

[0632] Quantification was performed by comparing the radiolabeled metabolite peak and the parent peak measured on a Radiomatic 625TR FlowScintillation Analyzer connected to a Dionex / Chromeleon chromatography system. The column was a Phenomenex Synergi fusionRP (150×4.6 mm, 4 mm) maintained at 32 degrees Celsius. Mobile phase A consisted of 0.1% (vv) 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 with a flow rate of 1 mL / min. The gradient was as follows: mobile phase B was linearly increased to 75% in 47 minutes, maintained at 75% for 3 minutes, changed back to 2%, and maintained at 2% for 10 minutes.

[0633] Metabolic stability is determined by measuring the relative abundance of metabolites to the parent over time and calculating the disappearance rate of the parent compound therefrom. The stability data are used to calculate predicted human liver clearance according to methods known in the art. The predicted human liver clearance is shown in the table below.

[0634]

[0635] Based on the above comparison data, the following can be deduced:

[0636] Relative to compounds A and B, compound 24 is more effective in HIV antiviral tests (about 9 times and about 16 times more effective, respectively). Relative to compounds A and B, compound 24 has a longer terminal half-life in vivo in rats (about 14 times and about 9 times longer, respectively). Relative to compounds A and B, compound 24 has a lower in vivo clearance rate in rats (about 10 times and about 8.6 times lower, respectively). Relative to compounds A and B, compound 24 has a longer terminal half-life in vivo in dogs (about 5 times and about 4 times longer, respectively). Relative to compounds A and B, compound 24 has a lower in vivo clearance rate in dogs (about 3 times and about 4 times lower, respectively). Compared to compounds A and B, compound 24 is more stable in human hepatocytes and has a lower predicted liver clearance rate (about 9 times and about 4 times more stable, respectively).

[0637] The above data demonstrate that compound 24 has improved antiviral efficacy and improved pharmacokinetic properties compared to compounds A and B (demonstrated by longer half-life in rats and dogs and lower predicted human clearance).

[0638] In addition, relative to compounds A and B, compound 38 is more effective in HIV antiviral tests (about 4 times and about 8 times more effective, respectively). Relative to compounds A and B, compound 38 has a longer terminal half-life in vivo in rats (about 9.5 times and about 6.3 times longer, respectively). Relative to compounds A and B, compound 38 has a lower in vivo clearance rate in rats (about 6.3 times and about 5.4 times lower, respectively). Compared with compounds A and B, compound 38 has similar in vivo clearance and terminal half-life in dogs. Relative to compounds A and B, compound 38 is more stable in human hepatocytes and has a lower predicted liver clearance rate (about 4.5 times and about 2 times more stable, respectively).

[0639] The above data demonstrate that compound 38 has improved antiviral efficacy and improved pharmacokinetic properties compared to compounds A and B (demonstrated by longer half-life in rats and dogs and lower predicted human clearance).

[0640] The specific pharmacological reactions observed may vary according to and depending on the specific active compound selected or the presence or absence of a pharmaceutical carrier, as well as the type of formulation and route of administration employed, and such expected variations or differences in results are contemplated according to the practice of the present invention.

[0641] The embodiments disclosed herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. It should be understood that the various steps described herein can be combined. It should also be understood that the compounds of each batch can be combined and then used in the next synthesis step.

[0642] Formulation Examples

[0643] Compound 38 (about 30 mg / kg) was formulated as an aqueous suspension in a 2% poloxamer 338 saline solution (about 150 mg / mL). The formulation was then administered to rats as a single subcutaneous (SC) injection and the pharmacokinetic (PK) properties were determined. Figure 3 As seen in Figure 2, compound 38 maintained plasma concentrations well above paEC95 for more than 10 weeks starting from a single SC injection. This data suggests that compound 38 exhibits extended-release pharmacokinetics.

[0644] A suspension of the compound of formula Ib in 2% poloxamer 188 in saline (200 mg / mL) was prepared. The suspension was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Figure 4 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Figure 4 As shown in the data in, the compound of Formula Ib had measurable plasma concentrations at Day 70, indicating extended release pharmacokinetics.

[0645] A suspension of the compound of formula Ib in 2% poloxamer 188 in saline (100 mg / mL) was prepared. The suspension was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Figure 5 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Figure 5 As shown in the data in, the compound of Formula Ib had measurable plasma concentrations at Day 70, indicating extended release pharmacokinetics.

[0646] A suspension of the sodium salt of the compound of formula Ib in 2% poloxamer 188 in saline (200 mg / mL) was prepared. The suspension was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Figure 6 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Figure 6 As shown, the compound of Formula Ib had measurable plasma concentrations at day 70, indicating extended release pharmacokinetics.

[0647] A solution of the compound of formula Ib in NMP (100 mg / mL) was prepared. The solution was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Figure 7 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Figure 7 As shown in the data in, the compound of Formula Ib had measurable plasma concentrations at Day 70, indicating extended release pharmacokinetics.

[0648] A solution of the compound of formula Ib in NMP (200 mg / mL) was prepared. The solution was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Figure 8 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Figure 8 As shown in the data in, the compound of Formula Ib had measurable plasma concentrations at Day 70, indicating extended release pharmacokinetics.

[0649] A solution of the sodium salt of the compound of formula Ib in NMP (200 mg / mL) was prepared. This solution was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Fig. 9 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Fig. 9 As shown in the data in, the compound of Formula Ib had measurable plasma concentrations at Day 70, indicating extended release pharmacokinetics.

[0650] A solution formulation of the compound of formula Ib in 10% ethanol, 12% water and 78% PEG 200 (200 mg / ml) was prepared. The solution was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Fig.10 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Fig.10 As shown in the data, the compound of Formula Ib had measurable plasma concentrations at day 28, indicating extended release pharmacokinetics.

[0651] A solution formulation containing 200 mg / mL of Formula Ib and 1.2 molar equivalents of NaOH to form the sodium salt in situ in 10% ethanol, 12% water, and 77% PEG is provided. The formulation is orally administered to a subject at 6 mg / kg. A solution of the compound of Formula Ib in 10% ethanol, 12% water, 7% PEG 200 (200 mg / ml) and 1.2 molar equivalents of NaOH is prepared to form the sodium salt in situ. The solution is administered subcutaneously to dogs at a dose of 6 mg / kg, and the pharmacokinetic (PK) properties are determined. Fig.11 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Fig.11 As shown in the data, the compound of Formula Ib had measurable plasma concentrations at day 28, indicating extended release pharmacokinetics.

[0652] A solution formulation of the compound of formula Ib in 10% ethanol, 13% water and 77% glycofurol (200 mg / mL) and 1.2 molar equivalents of NaOH was prepared to form the sodium salt in situ. The solution was subcutaneously administered to dogs at a dose of 6 mg / kg and the pharmacokinetic (PK) properties were determined. Fig.12 A graph showing the plasma concentration of the compound of Formula Ib as a function of time is shown. Fig.12 As shown in the data, the compound of Formula Ib had measurable plasma concentrations at day 28, indicating extended release pharmacokinetics.

[0653] Oral Formulation Example

[0654] An oral formulation was prepared containing the compound of Formula Ib in 10% ethanol, 20% Vitamin E TPGS and 70% MIGLYOL 812 in a hard gelatin capsule. A fixed 7.5 mg dose of the compound of Formula Ib was orally administered to dogs and the pharmacokinetic (PK) properties were determined. Fig.13 The plasma concentration of the compound of formula Ib is shown over time.

[0655] All references, including publications, patents and patent documents, are incorporated herein by reference as if individually incorporated herein by reference. The present invention provides references for various embodiments and techniques. However, it should be understood that many changes and modifications can be made while remaining within the spirit and scope of the present disclosure.

Claims

1. Compounds of formula (Ia): or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, which is a compound of formula (Ib): or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

4. The pharmaceutical composition of claim 3, further comprising one, two, three or four additional therapeutic agents.

5. The pharmaceutical composition of claim 4, wherein the additional therapeutic agent is selected from the group consisting of: combination drugs for HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversal agents, compounds targeting 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 regulators, Vif dimerization antagonists, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef regulators, Hck tyrosine kinase regulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nuclear protein inhibitors, splicing factor regulators, COMM domain-containing protein 1 regulators, HIV ribonuclease H inhibitors, retrocyclin regulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cell cycle protein-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, or any combination thereof.

6. The pharmaceutical composition of claim 4, wherein the additional therapeutic agent is selected from the group consisting of: compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs used to treat HIV, or any combination thereof.

7. The pharmaceutical composition of claims 4-6, wherein the additional therapeutic agent is selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate.

8. The pharmaceutical composition according to claims 4-7, wherein the additional therapeutic agent is selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate.

9. A method for treating or preventing human immunodeficiency virus (HIV) infection, comprising administering a therapeutically effective amount of the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

10. The method of claim 9, wherein the method comprises administering the compound or a pharmaceutically acceptable salt thereof in combination with one, two, three or four additional therapeutic agents.

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