EA036921B1 - Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection - Google Patents

Abstract

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

Description

Region

The present invention relates to novel compounds for use in the treatment of infections caused by viruses of the Retroviridae family, including infections caused by the HIV virus. The present invention also relates to intermediates for preparing such a compound and to pharmaceutical compositions containing said novel compound.

State of the art

The positive single-stranded RNA viruses that make up the Retroviridae family include the subfamilies Orthoretrovirinae and the genus Alpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus, Epsilonretrovirus, Lentivirus and Spumavirus, which cause diseases in humans and animals. Infection with the Lentivirus virus HIV-1 in humans results in the depletion of helper T cells and impaired immune function, which leads to immunodeficiency and vulnerability of the body to opportunistic infections. Treatment of HIV-1 virus infections with highly active antiretroviral therapy (HAART) has been shown to be effective in lowering viral load and significantly reducing the rate of disease progression (Hammer, S.M. et al., JAMA 2008, 300: 555-570). However, these treatments may be responsible for the emergence of HIV strains resistant to existing therapeutic agents (Taiwo, B., International Journal of Infectious Diseases 2009, 13: 552-559; Smith, RJ et al., Science 2010, 327: 697-701) ... Accordingly, there is an urgent need to identify new antiretroviral agents that are active against emerging drug-resistant HIV variants.

US Patent Application 2014/0296266A1, published Oct. 2, 2014, discloses compounds that can be used to treat Retroviridae virus infection, including HIV virus infection. US patent application No. 2014/0296266A1 relates, among other objects, to compounds of formula I

R ¹ R ²

I wherein A is a 6-membered monocyclic heteroaryl with one or two nitrogen atoms, said 6-membered monocyclic heteroaryl being substituted with one Z ¹ group at the position shown, with one Z ² group and optionally substituted with one or more (e.g. 1 or 2) groups Z ³ ;

R ¹ is 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle, with any 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle in R ¹ optionally contains, as substituents, one or more (eg, 1, 2, 3, 4 or 5) Z ⁴ groups;

R ² is phenyl, 5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl, or (C ₃ -C ₇ ) carbocycle, any phenyl, 5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl, or (C ₃ -C ₇ ) the carbocycle in R ^{2 is} optionally substituted with one or more (eg 1, 2, 3, 4 or 5) Z ⁵ groups;

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-C ₃ ) alkyl and (C ₁ -C ₃ ) haloalkyl, and R ^{3b is} selected from —OH and —CN;

Z ^{1 is} selected from 6-12 membered aryl, 5-14 membered heteroaryl and 3-14 membered heterocycle, with any 6-12 membered aryl, 5-14 membered heteroaryl and 3-14 membered heterocycle in Z ¹ optionally contains, as substituents, one or more (eg 1, 2, 3, 4, or 5) Z ^1a or Z ^1b ;

each Z ^{1a is} independently selected from (C3-C7) carbocycle, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR ⁿ¹ , —OC (O) ^Rp1 , -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 , and any (C ₃ -C ₇ ) carbocycle, 6-12-membered aryl, 5-12-membered heteroaryl and 3-12-membered heterocycle in Z ^1a optionally contains one or more (for example, 1, 2, 3, 4 or 5) groups as substituents Z ^1c or Z ^1d ;

each Z ^{1b is} independently selected from (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl, and any (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl in Z ^1b optionally be substituted with one or more (eg 1, 2, 3, 4 or 5) Z ^1c groups;

each Z ^{1c is} independently selected from (C ₃ -C ₇ ) carbocycle, phenyl, 5-6 membered monocyclic re-1 036921 theroaryl, 3-7 membered heterocycle, halogen, —CN, —OR ¹ ′ ² . -OC (O) Rp ² , -OC (O) NR ^q2 R ^r2 , -SR ⁿ² , -S (O) Rp ² ,

-S (O) ₂ OH, -S (O) ₂ Rp ² , -S (O) 2NR ^q2 R ^r2 , -NR ^q2 R ^r2 , -NR ⁿ² CORp ² , -NR ⁿ² CO2Rp ² , -NR ⁿ² CONR ^q2 R ^r2 , -NR ⁿ² S (O) ₂ Rp ² ,

-NR ⁿ² S (O) 2ORp ² , -NR ⁿ² S (O2NR ^q2 R ^r2 , NO ₂ , -C (O) R ⁿ² , -C (O) OR ⁿ² , -C (O) NR ^q2 R ^r2 , halophenyl , 5-6 membered haloheteroaryl, 3-7 membered haloheterocycle, and (C ₁ -C ₈ ) heteroalkyl;

each Z ^{1d is} independently selected from (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, and (C ₁ -C ₈ ) haloalkyl;

each R ^{n1 is} independently selected from H, (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl and phenyl, and any (C3-C7) carbocycle, 3-7-membered heterocycle, 5-6-membered monocyclic heteroaryl and phenyl in R ⁿ¹ optionally contains one or more substituents (for example, 1, 2, 3, 4 or 5) groups Z ^1c or Z ^1d , and wherein any (C1-C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl in R ⁿ¹ optionally contains one or more (eg, 1, 2, 3, 4 or 5) Z ^1c groups;

each R ^{p1 is} independently selected from (C1-C8) alkyl, (C2-C8) alkenyl, (C2-C8) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, and phenyl , and any (C3-C7) carbocycle, 3-7-membered heterocycle, 5-6-membered monocyclic-heteroaryl and phenyl in R ^p1 optionally contains one or more substituents (for example, 1, 2, 3, 4 or 5) groups Z ^1c or Z ^1d , and wherein any (C1-C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl in R ^p1 optionally contains one or more (for example, 1, 2, 3, 4 or 5) groups Z ^1c ;

each of 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, and any (C3-C7) carbocycle, 3-7-membered heterocycle, 5-6-membered monocyclic heteroaryl and phenyl in R ^q1 or R ^r1 optionally contains one or more substituents (for example, 1, 2, 3, 4 or 5) groups Z ^1c or Z ^1d , and any (C1-C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl in R ^q1 or R ^{r1 is} optionally substituted with one or more (e.g. 1, 2, 3, 4 or 5) groups Z ^1c , or R ^q1 and R ^r1 together with the nitrogen atom to which they are attached form 5-, 6- or a 7-membered heterocycle, said 5-, 6- or 7-membered heterocycle optionally substituted with one or more (eg, 1, 2, 3, 4 or 5) Z ^1c or Z ^1d groups;

each R ^{n2 is} independently selected from H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5 -6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C ₁ -C ₈ ) haloalkyl and (C ₁ -C ₈ ) heteroalkyl;

each R ^{p2 is} independently selected from (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 -membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C ₁ -C ₈ ) haloalkyl and (C ₁ -C ₈ ) heteroalkyl;

R ^q2 and R ^{r2 are} each independently selected from H, (C ₁ -C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl, (C ₂ -C ₈ ) alkynyl, (C3-C7) carbocycle, 3-7 membered heterocycle, 5-6 membered monocyclic heteroaryl, phenyl, halophenyl, 5-6 membered monocyclic haloheteroaryl, 3-7 membered haloheterocycle, (C ₁ -C ₈ ) haloalkyl and (C ₁ -C ₈ ) heteroalkyl or R ^q2 and R ^r2 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocycle;

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 , and any 6-12 membered aryl, 5-12 membered C-linked heteroaryl and 3-12-membered C-linked heterocycle in Z ² optionally contains as substituents one or more (e.g., 1, 2, 3, 4 or 5) groups, Z ^2b and Z ^2c, and wherein any (C2-C ₈₎ alkenyl and (C ₂ -C ₈₎ alkynyl consisting of Z ² optionally contains as a substituent one or more (eg 1, 2, 3, 4 or 5) Z ^2c groups;

each Z ^{2a is} 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 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 , and any (C3-C7) carbocycle, 6-12-membered aryl, The 5-12 membered heteroaryl and the 3-12 membered heterocycle in Z ^{2a are} optionally substituted with one or more (eg, 1, 2, 3, 4 or 5) Z ^2b or Z ^2c groups;

each Z ^{2b is} independently selected from (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) heteroalkyl, and (C ₁ -C ₄ ) haloalkyl;

each Z ^{2c is} 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 ;

each Rn ^{3 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, any (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl in R ⁿ³ optionally contains one or more substituents (for example, 1, 2, 3, 4 or 5) groups Z ^2b or Z ^2c , and any (C1-C4) alkyl, (C ₂ -C ₄ ) alkenyl and (C ₂ -C ₄ ) alkynyl in Rn ³ optionally

- 2 036921 contains, as substituents, one or more (eg 1, 2, 3, 4 or 5) groups Z ^2a ;

R ^q3 and R ^{r3 are} each independently selected from H, (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl, and 6-12 membered aryl , wherein any (C3-C7) carbocycle, 3-12 membered heterocycle, 5-12 membered heteroaryl and 6-12 membered aryl in R ^q3 or R ^r3 optionally be substituted with one or more (e.g., 1, 2, 3, 4 or 5) groups Z ^2b or Z ^2c , and wherein any (C1 -C4) alkyl and (C ₂ -C ₄ ) alkenyl in R ^q3 or R ^r3 optionally contains one or more ( for example, 1, 2, 3, 4 or 5) groups Z ^2a , or R ^q3 and R ^r3 together with the nitrogen atom to which they are attached form a heterocycle or heteroaryl, said heterocycle or heteroaryl optionally being substituted by one or more (for example, 1, 2, 3, 4 or 5) groups Z ^2b or Z ^2c ;

R ⁿ⁴ each independently selected from H, (C1-C ₄₎ alkyl, (C ₂ -C ₈₎ alkenyl, (C ₂ -C ₈₎ alkynyl, (C1-C ₄₎ -haloalkyl and (C1-C ₄₎ heteroalkyl;

each R ^p4 is independently selected from (C1-C ₈₎ alkyl, (C ₂ -C ₄₎ alkenyl, (C ₂ -C ₄₎ alkynyl, (C1-C ₄₎ -haloalkyl and (C1-C ₄₎ heteroalkyl;

R ^q4 and R ^{r4 are} each independently selected from H, (C1-C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl, (C ₂ -C ₄ ) alkynyl, (C1-C ₄ ) haloalkyl and (C ₁ -C ₄ ) heteroalkyl;

each Z ³ is independently selected from halo, (C1-C ₄₎ alkyl, -OH, -CN, (C1- C ₄₎ heteroalkyl and (C1 -C ₄₎ haloalkyl;

each Z ^{4 is} 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) ORn5 and ^{-C (O) NR q5 R r5} , wherein each (C3-C7) carbocyclic ring composed of ⁴ Z optionally is substituted with one or more (for example 1, 2, 3, 4 or 5) groups Z ^4a or Z ^4b , and any (C1-C ₈ ) alkyl, (C ₂ -C ₈ ) alkenyl and (C ₂ -C ₈ ) alkynyl in Z ⁴ optionally contains, as substituents, one or more (for example, 1, 2, 3, 4 or 5) Z ^4a groups;

each Z ^{4a is} 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 ;

each Z ^{4b is} independently selected from (C1-C ₄ ) alkyl, (C ₂ -C ₄ ) alkenyl, (C ₂ -C ₄ ) alkynyl, and (Ci -C ₄ ) haloalkyl;

each R ^{n5 is} independently selected from H, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) heteroalkyl, (C ₂ -C ₄ ) alkenyl, and (C ₂ -C ₄₎ ) alkynyl;

each Rp ^{5 is} independently selected from (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) heteroalkyl, (C ₂ -C ₄ ) alkenyl and (C ₂ -C ₄ ) alkynyl ;

R ^q5 and R ^r5 are each independently selected from H, (C ₁ -C ₄₎ alkyl, (C ₁ -C ₄₎ haloalkyl, (C ₁ -C ₄₎ heteroalkyl, (C ₂ -C ₄₎ alkenyl and (C ₂ -C ₄ ) alkynyl;

each R ^{n6 is} independently selected from H, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) heteroalkyl, (C ₂ -C ₄ ) alkenyl, and (C ₂ -C ₄₎ ) alkynyl;

each Rp ^{6 is} independently selected from (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) heteroalkyl, (C ₂ -C ₄ ) alkenyl and (C ₂ -C ₄ ) alkynyl ;

R ^q6 and R ^{r6 are} each independently selected from H, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, (C ₁ -C ₄ ) heteroalkyl, (C ₂ -C ₄ ) alkenyl, and (C ₂ -C ₄ ) alkynyl;

Z ⁵ each independently selected from (C1-C6) alkyl, halogen, -CN and -OR ^n7, wherein any (C1-C ₆₎ alkyl in Z ⁵ composition optionally contains as a substituent one or more (e.g., 1, 2, 3, 4 or 5) halogens; and each R ^{n7 is} independently selected from H, (C ₁ -C ₃ ) alkyl, (C ₁ -C ₃ ) haloalkyl, and (C ₃ -C ₇ ) carbocycle;

or a pharmaceutically acceptable salt thereof.

US patent application 2014 / 0303164A1, published October 9, 2014, discloses compounds that can be used in the treatment of Retroviridae virus infection, including HIV virus infection. U.S. Patent Application 2014 / 0303164A1 relates, inter alia, to compounds of formula IIId

- 3 036921 where A ¹ represents CH, CZ ³ or nitrogen;

A ² represents CH or nitrogen;

R ¹ is 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle, with any 6-12 membered aryl, 5-12 membered heteroaryl or 3-12 membered heterocycle in R ¹ optionally contains 1, 2, 3, 4 or 5 Z ⁴ groups as substituents, said Z ⁴ groups being the same or different;

each R ^3a and R ^{3b is} independently H or (C ₁ -C ₃ ) alkyl;

Z ¹ is 6-12 membered aryl, 5-14 membered heteroaryl or 3-14 membered heterocycle, any 6-12 membered aryl, 5-14 membered heteroaryl or 3-14 membered heterocycle in Z ¹ optionally contains, as substituents, 1, 2, 3, 4 or 5 groups Z ^1a or Z ^1b , said groups Z ^1a and Z ^1b being the same or different;

each Z ^{1a is} independently (C3-C7) carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, -CN, -OR ⁿ¹ , -OC (O) R ^p1 , -OC (O) NR ^q1 R ^r1 , -SR ⁿ¹ , -S (O) R ^p1 , -S (O) 2OH, -S (O) ₂ R ^p1 , -S (O) 2NR ^q1 R ^r1 , -NR ^q1 R ^r1 , -NR ⁿ¹ COR ^p1 , -NR ⁿ¹ CO2R ^p1 , -NR ⁿ¹ CONR ^q1 R ^r1 , -NR ⁿ¹ S (O) 2R ^p1 , -NR ⁿ¹ S (O) 2OR ^p1 , -NR ⁿ¹ S (O) 2NR ^q1 R ^r1 , -C (O) R ⁿ¹ , -C (O) OR ⁿ¹ , -C (O) NR ^q1 R ^r1 and -S (O) 2NR ⁿ¹ COR ^p1 , with any (C3-C ₇ ) carbocycle, 5-12 membered heteroaryl and the 3-12 membered heterocycle in Z ^1a optionally contains 1, 2, 3, 4 or 5 Z ^1c or Z ^1d groups as substituents, and the Z ^1c and Z ^1d groups may be the same or different;

each Z ^{1b is} independently (C ₁ -C ₈ ) alkyl optionally substituted with 1, 2, 3, 4 or 5 halogens, which may be the same or different;

each Z ^1c is independently halogen, -CN, -OH, -NH2, -C (O) NR q2 R r2 or (C1 -C ₈₎ heteroalkyl;

each Z ^1d independently represents (C ₁ -C ₈ ) alkyl or (C ₁ -C ₈ ) haloalkyl;

each R ^{n1 is} independently H, (C1-C8) alkyl, (C3-C7) carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, with any (C3-C7) carbocycle, 3-7- a heterocycle or 5-6-membered monocyclic heteroaryl in R ⁿ¹ optionally contains 1, 2, 3, 4 or 5 groups Z ^1c or Z ^1d as substituents, wherein said groups Z ^1c and Z ^1d may be the same or different, and wherein any (C1 -C ₈₎ alkyl in R ⁿ¹ composition optionally is substituted 1, 2, 3, 4 or 5 groups Z ^1c, Z ^1c which groups may be the same or different;

each R ^{p1 is} independently (C1-C8) alkyl, (C3-C7) carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic heteroaryl, any (C3-C7) carbocycle, 3-7 membered heterocycle or 5-6-membered monocyclic-heteroaryl in R ^p1 optionally contains 1, 2, 3, 4 or 5 groups Z ^1c or Z ^1d as substituents, wherein said groups Z ^1c and Z ^1d may be the same or different, and when any (C1 -C8) alkyl in R ^p1 optionally contains as substituents 1, 2, 3, 4 or 5 Z ^1c groups, said Z ^1c groups being the same or different;

each R ^q1 and R ^{r1 is} independently H, (C1-C8) alkyl, (C3-C7) carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any (C3-C7) carbocycle, 3-7-membered heterocycle or 5-6-membered monocyclic-heteroaryl in R ^q1 or R ^r1 optionally contains 1, 2, 3, 4 or 5 groups Z ^1c or Z ^1d as substituents, and said groups Z ^1c and Z ^1d can be the same or different, and wherein any (C1-C ₈₎ alkyl is composed R ^q1 or R ^r1 optionally substituted 1, 2, 3, 4 or 5 groups Z ^1c, wherein said group Z ^1c may be the same or different, or R ^q1 and R ^r1 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocycle, wherein said 5-, 6- or 7-membered heterocycle optionally contains 1, 2 as substituents , 3, 4 or 5 groups Z ^1c or Z ^1d , and the groups Z ^1c and Z ^1d may be the same or different;

each R ^q2 and R ^{r2 is} independently H, (C ₁ -C ₈ ) alkyl, (C ₃ -C ₇ ) carbocycle, or R ^q2 and R ^r2 together with the nitrogen atom to which they are attached form 5-, 6 - or a 7-membered heterocycle;

Z ² is (C2-C8) alkenyl, (C2-C8) alkynyl, 6-12 membered aryl, 5-12 membered C-linked heteroaryl, 3-12 membered C-linked heterocycle, -C (O) R ⁿ³ or -C (O) NR ^q3 R ^r3 , and any 6-12 membered aryl, 5-12 membered C-linked heteroaryl or 3-12-membered C-linked heterocycle in Z ^{2 is} optionally substituted 1, 2, 3, 4 or 5 groups Z ^2b and Z ^2c, wherein group Z ^2b and Z ^2c may be the same or different, and wherein any (C2-C ₈₎ alkenyl or (C ₂ C ₈₎ alkynyl consisting of Z ² optionally contains, as substituents, 1, 2, 3, 4 or 5 Z ^2c groups, where the Z ^2c groups may be the same or different;

each R ^{3 is} independently H or (C1 -C ₄ ) alkyl;

each R ^q3 and R ^{r3 is} independently H or (C ₁ -C ₄ ) alkyl;

each Z ^{2b is} independently oxo, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) heteroalkyl, or (C ₁ -C ₄ ) haloalkyl;

each Z ^{2c is} independently oxo, halogen, -CN, -OR ⁿ⁴ , -OC (O) R ^p4 , -OC (O) NR ^q4 R ^r4 , -SR ⁿ⁴ , -S (O) R ^p4 , -S ( O) 2OH, -S (O) 2R ^p4 , -S (O) 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 ;

- 4 036921 R ⁿ⁴ each independently represents H, _(C1-C4) alkyl, _(C1-C4) haloalkyl or (C1 -C ₄₎ heteroalkyl;

each R ^{p4 is} independently (C ₁ -C ₈ ) alkyl, (C ₁ -C ₄ ) haloalkyl, or (C1 -C ₄ ) heteroalkyl;

each R ^q4 and R ^{r4 is} independently H, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) haloalkyl, or (C1 -C ₄ ) heteroalkyl;

each Z ^{3 is} independently (C ₁ -C ₄ ) heteroalkyl;

Z ⁴ each independently represents oxo, (C1-C8) alkyl, (C3-C7) carbocyclic ring, ^{halogen, -CN, -OR n5, -NR q5} R r5, -NR n5 COR p5, -NR n5 CO2R p5, - ^{C (O) R n5, -C} (O) oR n5 or ^{-C (O) NR q5 R r5} , wherein each (C3-C ₇₎ carbocycle or (C ₁ -C ₈₎ alkyl, Z ⁴ consisting of optionally contains as substituents 1, 2, 3, 4 or 5 of the Z ^4a groups, said Z ^4a groups being the same or different;

each Z ^{4a is} independently halogen, —CN, or —OR ⁿ⁶ ;

each R ⁿ⁵ , R ^p5 ; R ^q5, R ^r5 and R ⁿ⁶ independently represents H or (C1-C ₄₎ alkyl;

each Z ⁵ independently represents halogen, which may be the same or different; n is 0, 1, 2, or 3;

or a pharmaceutically acceptable salt thereof.

Notwithstanding the data described above, there is a need for compounds that are effective and stable, and show improved pharmacokinetic and / or pharmacodynamic profiles for the treatment of Retroviridae infections, including HIV virus infections.

Also in the field of HIV therapeutics and HIV treatment, it is of interest to expand the pharmacokinetic properties of regimens offered to patients. Although current HIV treatment regimens are progressive enough to prevent patients from taking multiple pills multiple times a day, patients today still have to take one pill every day for the entire projected life span. Accordingly, it would be beneficial to have HIV treatments that require medication to be taken less frequently than once a day (for example, once every two days, once a week, once every few weeks, once a month, etc.) .).

The following are novel compounds showing improved potency, improved metabolic stability, and improved pharmacokinetic and / or pharmacodynamic profiles.

Short description

In some embodiments, the present invention relates to a compound of formula (Ia)

(la) or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention relates to a compound of formula (Ib)

(lb) or a pharmaceutically acceptable salt thereof.

- 5 036921

In some embodiments, the present invention relates to a compound of formula (IIa)

o (Pa) or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention relates to a compound of formula (IIb)

(IIb) or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention relates to the use of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in the treatment of a disease in a subject in need thereof. In one embodiment, 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 treatment of a disease in a subject in need thereof. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is in a form suitable for injection. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the present invention provides 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 some embodiments, the pharmaceutical composition is in a parenteral form (eg, suitable for injection). In some embodiments, the pharmaceutical composition is suitable for oral administration.

In some embodiments, the present invention relates to an article of manufacture containing a single dosage of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention relates to an article of manufacture comprising a unit dosage of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method for treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method of treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof.

In some embodiments, the present invention provides a method for preventing HIV infection in a subject, comprising administering to the subject a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is at risk for HIV infection, as in the case of a subject having one or more known risk factors associated with HIV virus infection.

In some embodiments, the present invention provides a method for preventing HIV infection in a subject, comprising administering to the subject a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is at risk of contracting HIV, as in the case of a subject having one or more known facts

- 6,036,921 risk factors associated with HIV infection.

In some embodiments, the present invention relates to a method for treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more other therapeutic agents. In some embodiments, the present invention provides a method for treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more other therapeutic agents.

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

In some embodiments, the present invention relates to a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in medical therapy.

In some embodiments, the present invention relates to a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of HIV infection in a patient.

In some embodiments, the present invention relates to a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of HIV infection in a patient.

In some embodiments, the present invention relates to the use of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject.

In some 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, for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject.

In another embodiment, the present invention relates to intermediates that can be used to synthesize a compound of formula (Ia) or (Ib).

In another embodiment, the present invention relates to intermediates that can be used to synthesize a compound of Formula (Ia), (Ib), (IIa) and / or (IIb).

In some embodiments, a pharmaceutically acceptable salt of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) is a sodium salt.

Additional embodiments of the disclosed subject matter are disclosed herein.

Brief Description of Drawings

FIG. 1 shows ¹ H-NMR (400 MHz, methanol-d ₄ ) N - ((S) -1- (3- (4-chloro-3- (methylsulfonamido) -1 (2,2,2-trifluoroethyl) -Sh -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-1Hcyclopropa [3,4] cyclopenta [1.2-c | πyrαzol-1-yl) acetamide.

FIG. 2 shows ¹ H-NMR (400 MHz, methanol-d ₄ ) N - ((S) -1- (3- (4-chloro-3 (cyclopropanesulfonamido) -1 - (2,2-difluoroethyl) -1H-indazole) -7-yl) -6- (3-methyl-3 - (methylsulfonyl) but-1in-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2 - ((3bS , 4aR) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5tetrahydro-1H-cycloπropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetamide.

FIG. 3 shows the concentration (nM) of compound 38 after a single subcutaneous (SC) administration in rats.

FIG. 4 shows a plot of plasma concentration versus time for 200 mg / ml of formula (Ib) in 2% Poloxamer 188 in saline when administered subcutaneously to dogs at 6 mg / kg.

FIG. 5 shows a plot of plasma concentration versus time for 100 mg / ml of formula (Ib) in 2% Poloxamer 188 in saline when administered subcutaneously to dogs at 6 mg / kg.

FIG. 6 shows a plot of plasma concentration versus time for 200 mg / ml of formula (Ib) as sodium salt in 2% Poloxamer 188 in saline when administered subcutaneously to dogs at 6 mg / kg.

FIG. 7 shows a plot of plasma concentration versus time for 100 mg / ml of formula (Ib) free acid in NMP when administered subcutaneously to dogs at 6 mg / kg.

FIG. 8 shows a plot of plasma concentration versus time for 200 mg / ml of formula (Ib) free acid in NMP when administered subcutaneously to dogs at 6 mg / kg.

FIG. 9 is a plot of plasma concentration versus time for 200 mg / ml of formula (Ib) in sodium salt form in NMP when administered subcutaneously to a subject at 6 mg / kg.

FIG. 10 shows a graph of plasma concentration versus time for 200 mg / ml of formula (Ib) in 10% ethanol, 12% water and 78% PEG 200 when administered subcutaneously to subjects at 6 mg / kg.

FIG. 11 shows a plot of plasma concentration versus time for 200 mg / ml of formula (Ib) as in situ formed salt in 10% ethanol, 12% water and 77% PEG 200 when administered subcutaneously to subjects at 6 mg / kg.

- 7 036921

FIG. 12 shows a plot of plasma concentration versus time for 200 mg / ml of formula (Ib) in 10% ethanol, 13% water and 77% glycofurol with 1.2 mol eq. NaOH to form in situ Na salt when administered subcutaneously to subjects at a dose of 6 mg / kg.

FIG. 13 shows a plot of plasma concentration versus time for a fixed 7.5 mg oral dose of formula (Ib) in 10% ethanol, 20% vitamin E TPGS, 70% MIGLYOL 812 in dogs.

Detailed description

The following description has been written with the understanding that the present invention is to be construed as an example of the claimed subject matter and that the accompanying claims are not intended to be limited to the specific illustrated embodiments. The headings used in this specification are for convenience only and should not be construed as limiting the claims in any way. The implementations after any heading may be combined with the implementations after any other heading. Unless otherwise indicated, all technical and scientific terms used in this description have the meanings usually attributed to them by one of ordinary skill in the art.

When used herein, trade names are intended to independently include the product bearing that trade name and the active pharmaceutical ingredient (s) of the product bearing the said trade name.

As used herein and in the appended claims, the singular includes the plural of the same term, unless the context clearly requires otherwise. Accordingly, for example, indication of a compound includes a plurality of such compounds, and indication of an assay includes an indication of one or more assays, etc. In this text, the term Cmax refers to the maximum observed plasma / serum drug concentration.

Pharmaceutically acceptable refers to compounds, salts, compositions, dosage forms, and other materials useful in preparing a pharmaceutical composition suitable for pharmaceutical use in veterinary medicine or in humans.

Pharmaceutically acceptable excipient includes, without limitation, any adjuvant, carrier, excipient, lubricant, sweetener, diluent, preservative, pigment / colorant, palatability enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic an agent, diluent, or emulsifier that has been approved by the FDA as acceptable for use in humans or pets.

Pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and that has (or can be converted to a form that has) the desired pharmacological activity of the parent compound. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or 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, ptoluenesulfonic acid, and salts formed when an acidic proton present in a compound is replaced by a metal ion, such as an alkali metal ion (such as sodium or potassium), an alkali metal ion (such as calcium or magnesium) or an aluminum ion, or is coordinated with an organic base such as diethanolamine, triethanolamine, N-methylglucamine and the like. Also included in this definition are the ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutical salts can be found in S.M. Berge et al., J. Pharma Sci., 66 (1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, ed. R. Hendrickson, 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005) at p. 732, tab. 38-5; both of these sources are incorporated herein by reference.

The subject and subjects refer to humans, pets (eg, dogs and cats), farm animals (eg, cattle, sheep, goats and pigs), laboratory animals (eg, mice, rats, hamsters, guinea pigs, rabbits, dogs and monkeys), etc.

As used herein, a treatment or treatment process is an approach to obtaining beneficial or desired results. For the purposes of the present disclosure, beneficial or desirable results include, but are not limited to, amelioration of a symptom and / or a decrease in the severity of a symptom and / or prevention of worsening of a symptom associated with a disease or condition. In one embodiment, the treatment or treatment process includes one or more of the following: a) suppressing the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and / or reducing the extent of the disease or condition), b) slowing down or arresting the development of one or more symptoms associated with a disease or condition (eg, stabilization of a disease or condition, delaying worsening or progression of a disease or condition), and / or c) ameliorating the disease or condition, such as providing regression of clinical symptoms, a decrease in the severity of a disease state, a delay in the progression of the disease, an increase in the quality of life, and / or an increase in the period of survival. In the present text, the delay in the development of a disease or condition means to delay, obstruct, slow down, delay, stabilize and / or delay the development of a disease or condition. This delay can be of varying duration depending on the history of the disease and / or the subject being treated. As will be apparent to one of ordinary skill in the art, a sufficient or significant delay may, in practice, involve prevention, in which case the subject does not develop a disease or condition. For example, a method that delays the development of AIDS is a method that reduces the likelihood of developing a disease at a given time interval and / or reduces the severity of a disease at a given time interval, as compared to a situation in which this method is not applied. Such comparisons can be based on clinical studies in a significant number of subjects. For example, the development of AIDS can be detected using known methods, such as checking the HIV + status of the subject and assessing the number of T cells in the subject or other indicators of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes on neck, armpits, or groin, or the presence of an opportunistic condition known to be AIDS-related (for example, a condition not commonly seen in subjects with functioning immune systems, but occurring in patients with LSP). Development can also refer to the progression of a disease, which may be undetectable at the beginning and includes onset, relapse, and onset. In this text, the prevention or prevention process refers to a scheme that protects against the occurrence of a disease or disorder in such a way that clinical symptoms of the disease do not develop. Accordingly, prevention refers to the application of therapy (eg, administration of a therapeutic agent) to a subject prior to the occurrence of detectable signs of disease in the subject (eg, administration of a therapeutic agent to a subject in the absence of a detectable infectious agent (eg, a virus) in the subject). The subject can be an individual at risk of developing a disease or disorder, as in the case of an individual having one or more known risk factors associated with the development or occurrence of the disease or disorder. Accordingly, the term prevention of HIV infection refers to the administration to a subject who does not have detectable HIV infection of an anti-HIV therapeutic agent. It is understood that the subject for the use of preventive therapy against HIV may be an individual at risk of infection with the HIV virus. Further, it is understood that prevention does not necessarily result in complete protection against the onset of the disease or disorder. In some cases, prevention includes reducing the risk of developing a disease or disorder. Reducing the risk may not completely eliminate the risk of developing the disease or disorder. In the present text, an at-risk individual is an individual at risk of developing the disease being treated. An at-risk individual may or may not have a detectable disease or condition, and a detectable disease may or may not appear in him or her prior to treatment by the methods described herein. At risk means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. An individual with one or more of these risk factors is more likely to develop a disease or condition than an individual without (or without) that risk factor. For example, individuals at risk of developing AIDS are individuals with HIV.

As used herein, the term therapeutically effective amount or effective amount refers to an amount that is effective in providing a desired biological or medical response, including an amount of a compound that, when administered to a subject to treat a disease, is sufficient to provide that treatment for a disease, or an amount that is effective for protection against the onset or onset of the disease. The effective amount will vary depending on the compound, the disease and its severity, as well as the severity and age, weight, etc. the subject being treated. An effective amount can include a range of amounts. It is understood in the art that an effective amount may be in one or more doses, i. E. a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount can be considered in the context of administering one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if, in combination with one or more other agents, the desired or beneficial result can be achieved or achieved. Appropriate dosages of any co-administered compounds can optionally be reduced by the combined action (eg, additive or synergistic effects) of the compounds.

Enantiomers are a pair of stereoisomers that are not superimposed mirror images of each other. A 1: 1 mixture of a pair of enantiomers is a racemic 9 036921 mixture. A mixture of enantiomers in a ratio other than 1: 1 is a scalemic mixture.

Diastereoisomers are stereoisomers that contain at least two asymmetric atoms, but which are not mirror images of each other.

The absolute stereochemistry is given in accordance with the Cahn-Ingold-Prelog R-S system. If the compound is a pure enantiomer, the stereochemistry of each carbon atom can be designated as R or S. Separated compounds, the absolute configuration of which is unknown, can be designated as (+) or (-) depending on the direction (right or levogyrate), in which they rotate the plane of polarized light at the sodium D-line wavelength. Some of the compounds described herein contain one or more asymmetric centers and / or are characterized by difficult rotation around the bond axis and, accordingly, can give rise to enantiomers, diastereomers and other stereoisomeric forms, which in terms of absolute stereoisomerism can be designated as (R) - or (S) -. The present invention is intended to include all such isomers, including racemic mixtures, scalemic mixtures, mixtures of diastereoisomers, optically pure forms, and intermediate mixtures. The optically active (R) - and (S) -isomers can be prepared using synthons or chiral reagents, or separated using conventional techniques. Unless expressly stated otherwise, the present invention includes all tautomers of the compounds of the present invention described herein, even if only one tautomer is explicitly indicated (e.g., reference to one tautomeric form is intended to include both tautomeric forms in cases where a pair of two tautomeric forms). For example, when referring to a compound containing an amide (for example, via structure or chemical name), it is meant that the present invention also includes an imido acid tautomer and describes the compound in the same way as if the amide were explicitly stated separately or together with imidic acid. In cases where more than two tautomers may exist, the present invention includes all such tautomers even if the chemical name and / or structure reflects only one tautomer.

The present invention also provides prodrugs of a compound of formula (Ia) or (Ib). In the pharmaceutical field, a prodrug is defined as a biologically inactive derivative of a drug that, after being administered to a human body, is converted to a biologically active parent compound by some chemical or enzymatic mechanism.

In addition, some embodiments of the present disclosure also provide prodrugs of compounds of formula (Ia), (Ib), (IIa) and / or (IIb). For a person skilled in the art it is clear that the present invention also includes any compound disclosed in this text (for example, a compound of formula (Ia) or (Ib)), which can be enriched to a state exceeding the natural isotope ratios, for one or all atoms one or more isotopes such as, but not limited to, deuterium ( ² H or D). Also disclosed are compounds in which 1 to n hydrogen atoms attached to any carbon atom can be replaced with a deuterium atom or D, where n is the number of carbon atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds can increase resistance to metabolism and, accordingly, can be useful for increasing the half-life of the compounds when administered to a mammal. See, for example, Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, Trends Pharmacol. Sci., 5 (12): 524-527 (1984). Such compounds are synthesized using means known in the art using starting materials in which one or more hydrogen atoms have been replaced with deuterium.

Examples of isotopes that may be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ⁿ 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, respectively. Substitutions with positron-emitting isotopes such as ⁿ C, ¹⁸ F, ¹⁵ O, and ¹³ N may be useful for positron emission tomography (PET) studies of substrate receptor occupancy. Isotopically labeled compounds of formula (Ia) or (Ib) can generally be prepared using conventional techniques known to those skilled in the art, or by methods analogous to those described in the Examples section below, using isotopically labeled reagents instead of the unlabeled reagent used previously. In addition, in some embodiments, isotopically labeled compounds of formula (Ia), (Ib), (IIa) and / or (IIb) can generally be prepared using conventional techniques known to one of ordinary skill in the art or using methods analogous to those described in the examples. below, using a suitable isotopically labeled reagent in place of the unlabeled reagent used in the original method.

The compounds described herein may contain chiral centers and / or centers of geometric isomerism (E and Z isomers); it is also understood that all such optical, enantiomeric, diastereoisomeric, and geometric isomers are included. Where the compounds are in chiral form, such an embodiment is intended to include, but is not limited to, specific diastereoisomerically or enantiomerically enriched forms. In cases where chiral

- 10 036921 ness not specified, but present, such an embodiment is intended to refer to any particular diastereomerically or enantiomerically enriched form or racemic or scalemic mixture of such compound (s). In the present text, a scalemic mixture is a mixture of stereoisomers in a ratio other than 1: 1. Also provided are pharmaceutically acceptable hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein.

In one preferred embodiment, the present invention relates to the use of a compound of formula (Ia) or (Ib) in the treatment of Retroviridae virus infection, including HIV virus infection, comprising administering a therapeutically effective amount to a subject in need thereof. In one preferred embodiment, the present invention relates to the use of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) in the treatment of Retroviridae virus infection, including HIV infection, comprising administering a therapeutically effective amount to a subject in need thereof ... An attractive challenge is to find a compound, or a pharmaceutically acceptable salt thereof, that has a low EC50. EC50 refers to the concentration of a compound in the test that provides 50% of maximum efficacy. A compound with a lower EC ₅₀ achieves similar efficacy at a lower compound concentration compared to a compound with a higher EC ₅₀ . Accordingly, in drug development, a lower EC _{50 is} generally preferred.

An attractive challenge is to find a compound, or a pharmaceutically acceptable salt thereof, that has good physical and / or chemical stability. Increasing the overall stability of the compound can provide an increase in circulation time in the body. Due to its lower degradation, the stable compound can be administered at lower doses and still remain effective. Lower degradation also reduces problems associated with compound degradation by-products.

An attractive challenge is to find a compound, or a pharmaceutically acceptable salt thereof, that has an improved pharmacokinetic and / or pharmacodynamic profile and a long half-life. It is desirable that the drug has moderate to low clearance and a long half-life, as this can give good bioavailability and high exposure on systemic exposure. A decrease in clearance and an increase in half-life can provide a decrease in the daily dose required for efficacy, and thus provide an improved safety profile. Thus, an improved pharmacokinetic and / or pharmacodynamic profile and a long half-life can provide improved patient compliance. An attractive challenge is to find a compound, or a pharmaceutically acceptable salt thereof, which has a good pharmacokinetic profile in an injectable sustained release formulation. It is preferred that the drug has a low EC50 and long-acting pharmacokinetic parameters, as this can provide a low frequency of administration. Reducing the frequency of administration can provide improved patient compliance. Reducing the frequency of administration may be desirable for patients with difficult or limited access to medical care.

In a preferred embodiment, a compound of formula (Ia) and (Ib) according to this document is found which provides advantages over structurally related compounds (referred to herein as compounds A and B) disclosed in US patent publications 2014/0296266A1 and 2014 / 0303164A1:

- 11 036921

Accordingly, the present disclosure includes, but is not limited to, providing a compound of formula (Ia)

or a pharmaceutically acceptable salt thereof and methods of using a compound of formula (Ia) for the treatment of infections caused by Retroviridae viruses, including infections caused by HIV virus.

Accordingly, the present disclosure includes, but is not limited to, providing a compound of formula (Ib)

or a pharmaceutically acceptable salt thereof and methods of using a compound of Formula (Ib) for the treatment of infections caused by Retroviridae viruses, including infections caused by the HIV virus.

Also disclosed herein is a compound of formulas (IIa) and (IIb) that provides advantages over Compounds A and B (shown above).

Accordingly, the present disclosure includes, but is not limited to, providing a compound of formula (IIa)

- 12 036921

(PA) or a pharmaceutically acceptable salt thereof; and methods of using a compound of formula (IIa) for the treatment of infections caused by Retroviridae viruses, including infections caused by the HIV virus.

Accordingly, the present disclosure includes, but is not limited to, providing a compound of formula (IIb)

// o (IIb) or a pharmaceutically acceptable salt thereof and methods of using a compound of formula (IIb) for the treatment of infections caused by Retroviridae viruses, including infections caused by the HIV virus.

In some embodiments, the Compounds disclosed herein (eg, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or pharmaceutically acceptable salts thereof) are used to prevent HIV infection in a subject. In some embodiments, the compounds disclosed herein are used to prevent HIV infection in a subject at risk of infection. In some embodiments, the compounds disclosed herein are used for pre-exposure prophylaxis (PrEP) to reduce the risk of sexual transmission of the HIV-1 virus.

The compounds disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof) are believed to have activity against most HIV-1 mutants formed in selection for clinically used protease inhibitors (PI, PI), nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and integrase inhibitors (INSTI).

Combined therapy.

In some embodiments, there is provided a method of treating or preventing HIV infection in a person with this infection or at risk of infection, comprising administering to the person a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salts in combination with a therapeutically effective amount (eg, one, two, three or four, or one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, there is provided a method of treating or preventing HIV infection in a person with this infection or at risk of infection, comprising administering to the person a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salts, in combination with a therapeutically effective amount (e.g., one, two, three, or four, or one or two, or one to three, or one to four) additional therapeutic agents.

In some embodiments, a method of treating or preventing HIV infection in a person with this infection or at risk of infection is provided, comprising administering to the person 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 (eg, one, two, three or four, or one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, there is provided a method of treating or preventing HIV infection in a person with this infection or at risk of infection, comprising administering to the person a therapeutically effective amount of a compound disclosed herein (e.g., compounds of formula (Ia), (Ib) , (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount (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, pharmaceutical compositions are provided comprising a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, in combination with one or more (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. In some embodiments, pharmaceutical compositions are provided comprising 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 one or more (for example, 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.

In some embodiments, the present invention provides a method of treating HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective the amount of one or more other therapeutic agents that are suitable for the treatment of HIV infection.

In some embodiments, the present invention provides a method of treating HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more other therapeutic agents that are suitable for the treatment of HIV infection.

In some embodiments, the present invention provides a method of treating HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound disclosed herein (eg, 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 some embodiments, a compound disclosed herein (eg, a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with one additional therapeutic agent. In some embodiments, a compound disclosed herein (eg, a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with two therapeutic agents. In other embodiments, a compound disclosed herein (eg, 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 (eg, a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. Said one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from one class of therapeutic agents and / or they can be selected from different classes of therapeutic agents. 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 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 additional therapeutic agent. 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 two 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 (eg, a compound of formula (Ia), (Ib), (IIa), and / or (IIb)) or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. These one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from one class of therapeutic agents and / or they can be selected from different classes of therapeutic agents.

The use of combination therapy for HIV.

In some embodiments, a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof is administered with one or more

- 14,036921 other 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 other 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 other therapeutic agents, wherein 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 said one or more other therapeutic agents are simultaneously present in the patient's body. In the case of sequential administration, the combination can be administered in two or more administrations.

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 administered with one or more other 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 other 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 other therapeutic agents, wherein a therapeutically effective amount of a compound disclosed herein document, (for example, compounds of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof and said one or more other therapeutic agents are simultaneously present in the body of the subject. In the case of sequential administration, the combination can be administered in two or more administrations. Co-administration includes the administration of single doses of compounds disclosed herein (eg, a compound of formula (Ia) or (Ib)) or pharmaceutically acceptable salts thereof before or after administration of single doses of one or more additional therapeutic agents. For example, administration of a compound disclosed herein (eg, a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, can be accomplished within seconds, minutes, or hours of administration of one or more other therapeutic agents. In some embodiments, a single 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 a single dose of one or more other therapeutic agents over seconds or minutes ... Alternatively, a single dose of one or more other therapeutic agents is administered first, followed by a single dose of a compound disclosed herein (eg, a compound of formula (Ia) or (Ib)) within seconds or minutes. In other embodiments, a single dose of a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)) is administered first, and then, after an interval of several hours (e.g., 1-12 hours), a single dose of one or more than other therapeutic agents. In other embodiments, a single dose of one or more other therapeutic agents is administered first, and then, after an interval of several hours (e.g., 1-12 hours), a single dose of a compound disclosed herein is administered (e.g., a compound of formula (Ia) or (Ib)).

In some embodiments, co-administration includes administration of single doses of compounds disclosed herein (e.g., compounds of formula (Ia), (Ib), (IIa), and / or (IIb)) or pharmaceutically acceptable salts thereof before or after administration of single dosages of one or more other therapeutic agents. For example, a compound disclosed herein (for example, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) or a pharmaceutically acceptable salt thereof can be administered within seconds, minutes, or hours from the administration of one or more than other therapeutic agents. In some embodiments, a single 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 within seconds or minutes, a single dose of one or more other therapeutic agents is administered. Alternatively, a single dose of one or more other therapeutic agents is administered first, followed by a single dose of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) in within seconds or minutes. In other embodiments, a single dose of a compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) is administered first, and then after an interval of several hours (e.g. 1-12 h), a single dose of one or more other therapeutic agents is administered. In other embodiments, a single dose of one or more other therapeutic agents is administered first, and then, after an interval of several hours (e.g., 1-12 hours), a single dose of a compound disclosed herein is administered (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)).

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 other therapeutic agents may refer to co-administration with one or more of the therapeutic agents described herein, for example the agents listed above.

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In some 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 other therapeutic agents in a single dosage form for simultaneous administration to a subject. In some embodiments, such a single dosage form can be administered by any route appropriate for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In some embodiments, the disclosed compounds can be administered parenterally. In some embodiments, a single dosage form can be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the unit dosage form is orally bioavailable and can be administered orally. In some embodiments, the unit dosage form may be a solid oral dosage form.

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 more other therapeutic agents in a single dosage form for simultaneous administration to the subject. In some embodiments, such a single dosage form can be administered by any route appropriate for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In some embodiments, the disclosed compounds can be administered parenterally. In some embodiments, a single dosage form can be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the unit dosage form is orally bioavailable and can be administered orally. In some embodiments, the unit dosage form may be a solid oral dosage form.

A compound disclosed herein (eg, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof) in combination with one or more other therapeutic agents can be administered by any route appropriate for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In some embodiments, the disclosed compounds can be administered parenterally. In some embodiments, the disclosed compounds may be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the disclosed compounds are orally bioavailable and can be orally administered.

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 one or more other therapeutic agents can be administered by any suitable route for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. In some embodiments, the disclosed compounds can be administered parenterally. In some embodiments, the disclosed compounds may be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the disclosed compounds are orally bioavailable and can be orally administered.

In some embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is in the form of a tablet, which may optionally contain one or more other compounds that can be used to treat HIV. In some embodiments, the tablet may contain one or more other compounds that can be used to treat HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors, non-catalytic site binding (or allosteric), pharmacokinetic augmentation agents, and combinations thereof. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is in the form of a tablet, which may optionally contain one or more other compounds that can be used to treat HIV. In some embodiments, the tablet may contain one or more other compounds that can be used to treat HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors, non-catalytic site-binding (or allosteric), pharmacokinetic enhancers, and combinations thereof.

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In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is in the form of a solution, which may optionally contain one or more other compounds that can be used to treat HIV. In some embodiments, the tablet may contain one or more other compounds that can be used to treat HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors that do not bind to the catalytic site (or allosteric), pharmacokinetic enhancers, and combinations thereof.

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is in the form of a suspension, which may optionally contain one or more compounds that can be used to treat HIV. In some embodiments, the tablet may contain one or more other compounds that can be used to treat HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors, non-catalytic site-binding (or allosteric), pharmacokinetic enhancers, and combinations thereof.

In some embodiments, such tablets are suitable for once daily administration.

Combination HIV therapy.

In the embodiments described above, the additional therapeutic agent may be an anti-HIV agent selected from the group consisting of combination drugs for the treatment of 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, inhibitors of HIV integrase, non-catalytic binding (or allosteric) inhibitors of HIV integrase, inhibitors of HIV penetration into cells, inhibitors of HIV maturation, agents reversing latency, compounds targeting the HIV capsid, immunotherapeutic agents, inhibitors phosphainositol-3 kinase (PI3K), antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, inhibitors of HIV matrix protein p17, antagonists of IL-13, modulators of peptidyl prolylcis / trans isomerase A, inhibitors of protein disulfide isomerase, antagonists complement receptor C5a, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed line kinase-3 (MLK-3) inhibitors ), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, ICAM-3-binding nonintegrin 1 inhibitors dendritic cells, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, DDH inhibitors of ATP-dependent RX3-transitase inhibitors, DDH inhibitors oxidase and G6PD, substances that improve their pharmacokinetics, HIV gene therapy agents, HIV vaccines, and their combinations. In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic binding (or allosteric) inhibitors HIV integrase, HIV penetration inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immunotherapeutic agents, PI3K inhibitors, HIV antibodies and bispecific antibodies and antibody-like therapeutic proteins, and combinations thereof.

Combined drugs for the treatment of HIV.

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); duranavir, 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, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lami

- 17 036921 woodin; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC + AZT + 3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; duranavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; cabotergravir and rilpivirine; cabotergravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirin, lamivudine, 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; and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride; lopinavir, ritonavir, zidovudine, and lamivudine; Vacc-4x and Romidepsin; and APH-0812.

Other medicines for HIV.

Examples of other drugs for the treatment of HIV include acemannan, alisporovir, Banlek, deferiprone, Gamimune, methenkephalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, H1 viral, SB-728-T, 1,5-dicaffelloylquinic acid, rHIV7 -shl-TAR-CCR5RZ, gene therapy agent AAV-eCD4-Ig, gene therapy agent MazF, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH- 116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200 , SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

HIV protease inhibitors.

Examples of HIV protease inhibitors include amprenavir, atazanavir, brekanavir, duranavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir typran, mesylate, ritonavir, saquinavir typran, mesylate, ritonavir, saquinavir typran, mesylate, ritonavir, saquinavir typran, mesilatine, PP-17G-65 ), T-169, BL-008 and TMC-310911.

HIV reverse transcriptase inhibitors.

Examples of non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors include dapivirine, delaverdine, delaverdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, AIC-292, KM-023, and VM-1500. Other inhibitors of non-nucleoside reverse transcriptase inhibitors are disclosed in US Patent Publication No. US2016 / 0250215. Examples of nucleoside or nucleotide HIV reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azuvidine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide, disiirafovilovil , ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirin, etravidine, tenofovirine, tenofovir-5753 phosphazide, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148 and KP-1461.

In some embodiments, examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include adefovir, adefovir dipivoxil, azuvidine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide disisyfirafovilovil EX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirin, distilledirin, OCR-57 tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, KP-1461, and 4'-ethynyl-2-fluoro-2'deoxyadenosine (EFdA).

HIV integrase inhibitors.

Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicuffeloylquinic acid, 3,5-dicaffeloylquinic acid derivatives, aurine carboxylic acid, aurin carboxylic acid derivatives, caffeic acid phenethyl ester caffeic acid ester, tyrphostine, tyrphostine derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, diketoquinoline-4-1 derivatives, LEDGF integrase inhibitor, ledgins, M-522, M-532 -310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169 and cabotegravir. Examples of non-catalytic site binding or allosteric HIV integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.

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Inhibitors of HIV penetration into the cell.

Examples of inhibitors of HIV entry into a cell (fusion) include senicrivirok, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplavirok, vikrivirok, aravirok, senicrivirok, PRO-140, adaptavir (RAP-101), nifevirok (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, C25P polypeptide , TD-0680 and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, biomedical enfuvirtide, biosimilar enfuvirtide, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-12, and PIE trimer sifuvirtide.

Examples of inhibitors of binding to CD4 include ibalizumab and CADA analogs.

Examples of gp120 inhibitors include Radha-108 (Receptol) 3B3-PE38, BanLec, bentonite nanopreparation, fostemsavir tromethamine, IQP-0831, and BMS-663068.

Examples of CXCR4 inhibitors include plerixaphor, ALT-1188, N15 peptide, and vMIP (Haimipu).

HIV maturation inhibitors.

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

Agents that reverse latency.

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

Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG lactones.

Capsid inhibitors.

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid degrading compounds, inhibitors of the HIV nucleocapsid p7 protein (NCp7) such as azidocarbonamide, and HIV p24 capsid protein inhibitors, verii AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15.

Immunotherapeutic agents.

Examples of immunotherapeutic agents include toll-like receptors such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13, programmed cell death protein 1 modulators (Pd-1 modulators) programmed cell death ligand 1 (Pd-L1), IL-15 agonists, DermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), ribavirin, polyethyleneimine polymer (PEI), Gepon, rintatolimod, IL-12, WF-10, VGV-1, MOR22, MOR22 -936559, CYT-107, interleukin-15 / Fc fusion protein, normferon (1 Normferon ™), peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, RPI-MN, GS-9620 and IR-103.

Phosphatidylinositol kinase (PI3K) inhibitors.

Examples of PI3K inhibitors include idealisib, alpelisib, buparlisib, carboxyamidotriazole orotat, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosin, pictilisib, pilaralisib, pylaralisib, amertiisibalisib, piquertizibasib9 , 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, PQR-309, RG-7666, RP-6530, RV1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

Antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins.

Examples of antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bnABs (broad spectrum antibodies to HIV-1), BMS-936559, TMB-360 and agents targeting HIV gp120 or gp41, anti-HIV recruitment molecules, anti-CD63 monoclonal antibodies, anti-GB type C virus antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-nef single-domain antibodies, anti-Rev antibodies, anti-CD18 antibodies from camelids, α anti-ICAM-1 antibodies from camelids, DCVax-001, antibodies targeting gp140, anti-HIV therapeutic antibodies based on gp41, recombinant human MATs (PGT-121), ibalizumab, Immuglo (Immuglo), MB-66

Examples of agents targeting HIV in this way include bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5 + C2G12 + C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, 10E, 7B , VRC-07-523, VRC-HIVMAB080-00-AB, MGD-014 and VRC07.

Substances that improve pharmacokinetics,

Examples of a pharmacokinetic enhancer include cobicistat and ritonavir.

Additional therapeutic agents.

Examples of additional therapeutic agents include compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead

- 19 036921

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), WO 2014 / 100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim ), WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).

HIV vaccines.

Examples of HIV vaccines include peptide vaccines, recombinant protein subunit vaccines, live vector vaccines, DNA vaccines, avian CD4 vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144 ), vaccine based on monomeric gp120 HIV-1 subtype C, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC- 3S, adenovirus-5 recombinant vaccine with DNA from different taxa (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA- 51, vaccines with poly-ICLC adjuvant, TatImmune, GTU-multiHIV (FIT-06), gp1405V2.TVl + MF-59, rVSVINHIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35 -Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1 , Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYMV201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, vaccine Ad26.Mod.HIV, 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 vaccine, CombiVICHvac, LFn-p24 B / C hybrid vaccine, DNA GTU vaccine, HIV gag / pol / nef / env DNA vaccine, HIV TAT vaccine, conjugated polypeptide vaccines, dendritic cell vaccines, gag DNA vaccines, GI-2010, vaccine containing gp41 of the HIV-1 virus, the vaccine against HIV (with the RFA adjuvant), hybrid peptide vaccines containing the I i-key / epitope MHC II, ITV-2, ITV-3, ITV-4, LIPO-5, vaccines based on Env of different subtypes (multi-fold), Ankara MVA virus vaccine, Pennvax-GP, vaccine containing pp71-deficient HCMV carrying HIV gag, recombinant peptide vaccine (HIV infection), NCI, vaccine containing HIV rgp160, HIV RNActive vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapy eutic HIV vaccine, UBI vaccine containing HIV gp120, Vacc-4x + romidepsin, polypeptide vaccine containing gp120 variant, rAd5 gag-pol env A / B / C vaccine.

Combination HIV therapy.

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 ATRIPLA® ( efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; aravirok; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC + AZT + 3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; duranavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; duranavir; lamivudine; prolastine; 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; delaverdine; delaverdine mesylate; Radha-108 (recipe); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir and abacavir sulfate.

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 ATRIPLA® (efavirenz, tenofovir disoproxil fumarate and emtricitabine); COMPLERA® (EVIPLERA; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); TRUVADA® (tenofovir diso

- 20 036921 proxyl fumarate and emtricitabine; TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; araviroka; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC + AZT + 3TC); rilpivirin; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; duranavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; duranavir; lamivudine; prolastina; 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; delaverdine; delaverdine mesylate; Radha-108 (recipe); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; abacavir sulfate; 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) and bictegravir or a pharmaceutically acceptable salt thereof.

One of ordinary skill in the art will understand that the additional therapeutic agents listed above may belong to more than one of the classes listed above. Specific classes are not intended to limit the functionality of the connections provided within those classes. In one specific embodiment, a compound disclosed herein (eg, 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 particular 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 HIV reverse transcriptase inhibitor and a non-nucleoside HIV reverse transcriptase inhibitor. 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 HIV reverse transcriptase inhibitor and an HIV reverse transcriptase inhibiting compound. In a further 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 HIV reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a pharmacokinetic enhancing agent. In some 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 nucleoside HIV reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancing agent In another an embodiment, a compound disclosed herein (eg, 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.

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 reverse transcriptase inhibitors HIV. In one 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 HIV reverse transcriptase inhibitor and a non-nucleoside HIV reverse transcriptase inhibitor. 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 HIV reverse transcriptase inhibitor, and a compound that inhibits HIV reverse transcriptase. In an additional 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 HIV reverse transcriptase inhibitor, non-nucleoside an inhibitor of HIV reverse transcriptase; and a substance that improves pharmacokinetics. 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 at least one nucleoside HIV reverse transcriptase inhibitor , an integrase inhibitor and a pharmacokinetic-improving agent. 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, combined

- 21 036921 yu with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

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, alafen tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate.

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 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-fluoroadene-2'-desiccine.

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 an HIV integrase inhibitor.

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 firafumifumifenatom ... 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).

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 pharmaceutical agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

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 pharmaceutical agent selected from the group, consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of latrimicivine and emmycivudabine. 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 pharmaceutical agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate , tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, said second additional therapeutic agent being emtricitabine. In a specific embodiment, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is combined with a first additional pharmaceutical agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, said 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 pharmaceutical agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, said the second additional therapeutic agent is emtricitabine. In some embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and said first and second additional therapeutic agents as disclosed above are administered simultaneously. Optionally, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and said first and second additional therapeutic agents as disclosed above, are combined in a single dosage form for simultaneous administration to a subject. In other embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and said first and second additional therapeutic agents as disclosed above are administered sequentially.

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 pharmaceutical agent selected from the group, consisting of tenofovir

22 036921 tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, said second additional therapeutic agent being 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 pharmaceutical agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, said second additional therapeutic agent being 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 pharmaceutical agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, tenofovir disoproxil, and a second additional therapeutic agent, said second additional therapeutic agent being emtricitabine. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and said first and second additional therapeutic agents as disclosed above are administered simultaneously. Optionally, a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof and said first and second additional therapeutic agents as disclosed above are combined in a single dosage form for simultaneous administration to a subject. In other embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, and said first and second additional therapeutic agents as disclosed above are administered sequentially.

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.

A compound disclosed herein (for example, any compound of formula (Ia) or (Ib)) can be combined with one or more other therapeutic agents at any dosage value of a compound of formula (Ia) or (Ib) (for example, from 1 to 1000 mg of compound).

In some embodiments, a compound disclosed herein (e.g., any compound of formula (Ia), (Ib), (IIa), and / or (IIb)) or a pharmaceutically acceptable salt thereof may be combined with one or more other therapeutic agents at any dosage value of the compound of formula (Ia), (Ib), (IIa) and / or (IIb) (for example, from 1 to 1000 mg of the compound). In some 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 tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg emtricitabine. In some 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 mg, 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg emtricitabine. In some 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 tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide, and 200 mg emtricitabine. In some 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 (eg, a compound of formula (Ia) or (Ib)) can be combined with agents provided herein at any compound dosage level (eg, from 1 mg to 1000 mg of a compound), as if each combination of dosages was given separately explicitly.

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 tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg emtricitabine. 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 5-10, 5-15, 5 -20, 5-25, 25-30, 20-30, 15-30 or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg emtricitabine. 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 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg emtricitabine. In some 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 (for example, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) can be combined with agents provided herein

- 23 036921 at any compound dosage level (eg, from 1 to 1000 mg of a compound), as if each dosage combination were given separately explicitly. In some 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 tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil, and 200 mg emtricitabine. In some 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, 200350, 250-350, 250-400, 350 -400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. In some 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 (eg, a compound of formula (Ia) or (Ib)) can be combined with agents provided herein at any compound dosage level (eg, from 1 mg to 1000 mg of a compound), as if each combination of dosages was given separately explicitly.

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 tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. 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 200-250, 200-300, 200 -350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. 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 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. A compound disclosed herein (e.g., a compound of formula (Ia), (Ib), (IIa) and / or (IIb)) can be combined with agents disclosed herein at any compound dosage level (e.g., from 1 to 1000 mg of compound) as if each dosage combination were explicitly stated separately. 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. A compound disclosed herein (for example, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof) can be combined with the agents provided herein at any compound dosage level (for example, from 1 to 1000 mg of the compound) as if each combination of dosages were given separately explicitly.

In one embodiment, kits are provided containing a compound disclosed herein (e.g., a compound of formula (Ia) or (Ib)), or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one, or two or one to three) additional therapeutic agents.

In some embodiments, kits are provided containing 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 one or more ( for example, for example, one, two, three, one or two, or one to three) additional therapeutic agents.

Pharmaceutical compositions.

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, together with one or more pharmaceutically acceptable excipients, and optionally one or more other therapeutic agents. Pharmaceutical compositions containing the active ingredient can be presented in any form suitable for the intended route of administration. 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, together with one or more pharmaceutically acceptable excipients, and optionally one or more other therapeutic agents. Pharmaceutical compositions containing the active ingredient can be presented in any form suitable for the intended route of administration.

Pharmaceutical compositions containing a compound disclosed herein (for example, a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof can be prepared using conventional carriers (for example, an inactive ingredient or auxiliary material), which can be selected in accordance with normal practice. The tablets may contain excipients, including lubricants, fillers, binders, and the like. Aquatic

- 24,036921 compositions can be made in sterile form, and when intended for delivery by a route other than oral, usually can be isotonic. All compositions may additionally contain adjuvants such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 5th ed., American Pharmacists Association, 1986. Excipients may contain ascorbic acid and other antioxidants, chelating agents such as EDTA , hydrocarbons such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid and the like.

In some embodiments, pharmaceutical compositions are provided 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 using conventional carriers (eg, inactive ingredient or auxiliary material), which can be selected in accordance with normal practice. The tablets may contain excipients, including lubricants, fillers, binders, and the like. The aqueous compositions can be made in sterile form and, when intended for delivery, by a route other than oral administration, can usually be isotonic. All compositions may additionally contain adjuvants such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, 5th ed., American Pharmacists Association, 1986. Excipients may contain ascorbic acid and other antioxidants, chelating agents such as EDTA , hydrocarbons such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid and the like.

While the active ingredients can be administered separately, it may be preferred if they are in the form of pharmaceutical compositions. Compositions for both veterinary and human use contain at least one compound of formula (Ia) or (Ib), together with one or more acceptable carriers and optionally other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (Ia) or (Ib), or a 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 hereinabove. 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. Carriers (carrier) are acceptable in the sense that they are compatible with other ingredients of the composition and physiologically harmless.

In some embodiments, although the active ingredients can be administered separately, it may be preferred if they are in the form of pharmaceutical compositions. Compositions for both veterinary and human use contain at least one compound of formula (Ia), (Ib), (IIa) and / or (IIb), together with one or more acceptable carriers and optionally other therapeutic ingredients. In some embodiments, the pharmaceutical composition comprises a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a 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 defined above in this document. 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. Carriers (carrier) are acceptable in the sense that they are compatible with the other ingredients of the composition and physiologically harmless to the recipient of the composition.

Compositions include compositions suitable for various routes of administration. The compositions can be presented in a convenient dosage form and can be prepared by any of the methods well known in the pharmaceutical art. Such methods include the step of combining an active ingredient (eg, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof) with one or more inactive ingredients (eg, a carrier, a pharmaceutical auxiliary, etc.). The compositions can be prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, followed by shaping the product (if necessary). Manufacturing techniques are generally described in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Wiliams and Wilkins, Philadelphia, NY. Philadelphia, USA, 2006.

In some embodiments, the compositions include compositions suitable for various routes of administration. The compositions can be presented in a convenient dosage form and can be prepared by any of the methods well known in the pharmaceutical art. 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, an auxiliary pharmaceutical agent and etc.). The compositions can be prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, followed by shaping the product (if necessary). Manufacturing techniques are generally described in Remington: The Science and Practice of

Pharmacy, 21st ed., Lippincott Wiliams and Wilkins, Philadelphia, pc. Philadelphia, USA, 2006.

The compositions described herein suitable for oral administration may be presented as discrete units (dosage form), including, but not limited to, capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient.

In the case of oral administration, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions for oral administration can be prepared according to any method known in the art for making pharmaceutical compositions, and such compositions can contain one or more agents, including sweeteners, flavoring agents, colors and preservatives, which provide an edible preparation. Tablets containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient suitable for tabletting are acceptable. These adjuvants can be, for example, inert diluents such as sodium or calcium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate, granulating agents and disintegrating agents such as corn starch or alginic acid, binders such such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic, and lubricants such as magnesium stearate, stearic acid or talc. The tablets can be uncoated or can be coated using any of the known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract to provide sustained action over an extended period. For example, a retarding material such as glyceryl monostearate can be used alone or in combination with a wax. In some embodiments, oral dosage forms (eg, tablets) are disclosed herein that can be prepared by hot melt extrusion or spray dried dispersion (SDD).

In some embodiments, provided herein are hard capsules filled with powder, particles, or granules containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient, which are suitable for the manufacture of hard or soft capsules. These adjuvants can be, for example, inert diluents such as sodium or calcium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, sodium or calcium 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.

In some embodiments, disclosed herein are hard or soft capsules filled with liquid or semi-liquid mixtures containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient that is suitable for making hard or soft capsules. These adjuvants can be, for example, solubilizing oils such as maize oil, sesame oil, or corn oil; medium chain triglycerides and corresponding esters such as derivatized palm kernel oil or coconut oil; self-emulsifying lipid systems (SEDDS or SMEDDS) such as caprylic acid triglyceride or propylene glycol monocaprylate; viscosity modifiers such as cetyl alcohol, steril alcohol, glycerol stearate; and solubilizers and surfactants such as polyethylene glycol, propylene glycol, glycerin, ethanol, polyethoxylated castor oil, poloxamers or polysorbates.

The pharmaceutical compositions of the present invention may be in the form of an injectable (injectable) preparation, such as an aqueous or oily injection suspension. The suspension can be made in accordance with known technology using suitable dispersing or wetting agents and suspending agents, which are mentioned herein. Sterile injectable preparations can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as preparations in the form of a solution in 1,3-butane diol, or prepared in the form of a lyophilized powder. Acceptable bases and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. Additionally, in accordance with common practice, you can use sterile, non-volatile oils as a solvent or suspending medium. Any aseptic, non-volatile oil, including synthetic mono- or diglycerides, is suitable for this purpose. Additionally, fatty acids such as oleic acid can be similarly used in the preparation of injectables. In some embodiments, a sterile injectable preparation disclosed herein may also be an injection solution or suspension prepared from reconstituted lyophilized powder in a non-toxic parenteral acceptable diluent or solvent, for example, in the form of a solution in 1, 3-butane diole. Acceptable bases and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. Additionally, in accordance with common practice, you can use sterile, non-volatile oils as a solvent or suspending medium. Any aseptic, non-volatile oil, including synthetic mono- or diglycerides, is suitable for this purpose. Additionally, fatty acids such as oleic acid can be similarly used in the preparation of injectables.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bacteriostatics, and solutes that render the formulation isotonic to the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. In some embodiments, the suspension is a microsuspension. In some embodiments, the suspension is a nanosuspension.

In some embodiments, formulations suitable for parenteral administration (eg, intramuscular (IM, BM) and subcutaneous (SC, SC) administration) will include one or more excipients. The excipients must be compatible with the other ingredients of the composition and are physiologically harmless to their recipients. 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 (ed. Rowe, Sheskey & Quinn), 6th ed. 2009. Examples of solubilizing excipients in a parenteral formulation (eg, subcutaneous or intramuscular formulation) include, but are not limited to, polysorbates (such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338, 188, or 207). In some embodiments, parenteral administration (e.g., subcutaneous or intramuscular formulation) is disclosed that includes 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 (eg, poloxamer 388) in parenteral administration disclosed herein is less than about 5%, eg, less than about 3%, about 2%, about 1%, or about 0.5%. Examples of solubilizing excipients in a parenteral formulation (eg, subcutaneous or intramuscular formulation) include, but are not limited to, polysorbates (such as polysorbate 20 or 80), poloxamers (such as poloxamer 338, 188, or 207). In some embodiments, parenteral administration (eg, a subcutaneous or intramuscular formulation) is disclosed that comprises a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof and a poloxamer.

In some embodiments, adjuvants include N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide, polyethylene glycol, and / or tetralikol / glycofurol.

In general, poloxamers are synthetic non-ionic linear triblock copolymers having a hydrophobic polyoxypropylene central chain flanked by two hydrophilic polypropylene oxides, in some embodiments in a 4: 2: 4 weight ratio. Accordingly, in some 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 segment and two hydrophilic polypropylene oxide segments. In some embodiments, the ratio of polyoxypropylene segment to two hydrophilic polypropylene oxide segments is 4: 2: 4 (hydrophilic propylene oxide: polyoxypropylene: hydrophilic propylene oxide). It is generally known that poloxamers have the following structure:

where a and b are integers (for example, a is 2-130 and b is 15-67).

For example, it is understood that poloxamer 188 has a molecular weight in the range of about 7680 to about 9510 Da (where a is about 80 and b is about 27). International Journal of PharmTech Research, Vol. 1, No. 2, p. 299-303, April-June 2009. In some cases, poloxamer 188 has an average molecular weight of about 8400 Da. Likewise, poloxamer 338 has a molecular weight in the range of about 12,700 to about 17,400 Da (where a is about 141 and b is about 44).

Examples of excipients in the formulation for parenteral administration (eg, formulation for subcutaneous or intramuscular administration) may also include polyethylene glycol. In general, polyethylene glycol (PEG, PEG) is a polyester of the general formula H- (O — CH ₂ —CH ₂ ) _n —OH. In some embodiments, the PEG may be capped with an alkyl group. In such embodiments, the capped PEG has the formula α-alkyl- (O-CH ₂ - (CH ₂ ) _n -O-α-alkyl (e.g.

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CH ₃ - (O-CH ₂ -CH ₂ ) n-OCH ₃ . Pharmaceutical compositions 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 from about 100 to about 800. In some embodiments, the weight average molecular weight of the PEG in the pharmaceutical composition is is from 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 can be combined to obtain the desired property or properties (e.g. measures, viscosity). Specific examples of PEG include, but are not limited to, PEG 100, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, etc. PEG 100, for example, refers to a polyethylene glycol with an average molecular weight of about 100. In some embodiments, a parenteral formulation (eg, subcutaneous or intramuscular formulation) disclosed herein is an aqueous suspension. In some embodiments, a parenteral formulation (e.g., a subcutaneous or intramuscular formulation) disclosed herein is an aqueous suspension that contains a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt and saline thereof. In some embodiments, a parenteral formulation (e.g., a subcutaneous or intramuscular formulation) disclosed herein is an aqueous suspension that contains a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt, saline solution and poloxamer (such as poloxamer 338, 188, or 207).

In some embodiments, a parenteral formulation (eg, a subcutaneous or intramuscular formulation) disclosed herein is an aqueous suspension. In some embodiments, a parenteral formulation (e.g., a subcutaneous or intramuscular formulation) disclosed herein is an aqueous suspension that contains a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt and saline thereof. In some embodiments, a parenteral formulation (e.g., a subcutaneous or intramuscular formulation) disclosed herein is an aqueous suspension that contains a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt, saline and suspending agent thereof. In some embodiments, a parenteral formulation (e.g., a subcutaneous or intramuscular formulation) disclosed herein is an aqueous suspension that contains a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt, saline solution and poloxamer thereof (such as poloxamer 338, 188 or 207).

In some embodiments, a suspension is provided comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in a poloxamer and saline solution. In some embodiments, the concentration of poloxamer in the saline is from about 0.1% to about 20%. In some embodiments, the concentration of the poloxamer in the saline is from about 0.1 to about 10%. In some embodiments, the concentration of poloxamer in the saline solution is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or about 10% ... In some embodiments, the concentration of the poloxamer in the saline is about 2%. In some embodiments, the poloxamer is poloxamer 188. In some embodiments, the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ib). In some embodiments, the compound is the sodium salt of a compound of formula (Ib). In some embodiments, a suspension is provided comprising a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in poloxamer and mannitol. In some embodiments, the concentration of poloxamer in the mannitol is from about 0.1% to about 20%. In some embodiments, the concentration of poloxamer in the 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 some embodiments, the concentration of the poloxamer in the mannitol is about 2%. In some embodiments, the poloxamer is poloxamer 188. In some embodiments, the compound is a compound of formula (Ib), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (Ib). In some embodiments, the compound is the sodium salt of a compound of formula (Ib). In some embodiments, a solid dosage form composition is disclosed, including a solid injectable dosage form, such as a solid depot form.

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

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

In some embodiments, the parenteral formulation comprises N-methyl-2pyrrolidone. In some embodiments, the parenteral formulation consists essentially of N-methyl-2-pyrrolidone. In some embodiments, the parenteral composition comprises dimethyl sulfoxide.

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

In some embodiments, the parenteral formulation consists essentially of a compound of formula (Ib), or a pharmaceutically acceptable salt thereof, water, ethanol, and polyethylene glycol 200.

In some embodiments, the parenteral formulation consists essentially of a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, water, ethanol, polyethylene glycol 200 (a polyethylene glycol with an average molecular weight of 200 g / mol), and NaOH. In some 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 some embodiments, the composition comprises from about 0.1. up to about 1.5 mol.eq. NaOH or NaOEt. In some embodiments, the composition comprises from about 0.5 to about 1.5 molar equivalents. NaOH or NaOEt. In some embodiments, the composition comprises from about 1.0 to about 1.2 molar equivalents. NaOH or NaOEt. In some embodiments, the composition contains about 1.2 mol. Equiv. NaOH or NaOEt. In some embodiments, the parenteral formulation is a solution formulation containing a mixture of ethanol, water, and polyethylene glycol. In some embodiments, the parenteral formulation is a solution formulation containing a mixture of ethanol, water, and PEG 200. In some embodiments, the solution formulation contains about 5-20% ethanol, about 5-20% water, and about 60 to 90% PEG 200. In some embodiments, the solution formulation contains about 10-15% ethanol, about 1015% water, and about 70 to 80% PEG 200. In some embodiments, the solution formulation contains about 10% ethanol , about 12% water, and about 78% PEG 200. In some embodiments, the solution formulation further comprises an inorganic base. In some embodiments, the solution formulation further comprises sodium hydroxide or sodium ethoxide. In some embodiments, the solution formulation further comprises sodium hydroxide. In some embodiments, the composition comprises from about 0.1 to about 1.5 molar equivalents. an inorganic base (for example, NaOH or NaOEt). In some embodiments, the composition comprises from about 0.5 to about 1.5 molar equivalents. an inorganic base (for example, NaOH or NaOEt). In some embodiments, the composition comprises from about 1.0 to about 1.2 molar equivalents. an inorganic base (for example, NaOH or NaOEt).

In some embodiments, the composition contains about 1.2 mol. Equiv. an inorganic base (for example, NaOH or NaOEt).

In some embodiments, formulations are provided in the form of solutions containing 200 mg / ml of formula (Ib) with about 0.1-1.5 equiv. in NaOH to about 10% ethanol, about 12% water and about 77% PEG.

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In some embodiments, a composition for oral administration of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) is provided, containing at least one excipient. Excipients may include ethanol, medium chain triglycerides (e.g. MIGLYOL 810 (Migliol 810), MIGLYOL 821, MIGLYOL 840, etc.), vitamin E TPGS, (da-tocopheryl polyethylene glycol), glycerin and / or pharmaceutically acceptable oils (e.g. sesame oil, castor oil, safflower oil, vegetable oil, soybean oil, etc.). Oral formulations disclosed herein may contain any combination of one or more excipients. Excipients collectively can constitute> 65% by weight of the total oral formulation,> 70% by weight of the total oral formulation,> 80% by weight of the total oral formulation,> 90% by weight of the total formulation for oral administration or> 95% by weight of the total formulation for oral administration.

In some embodiments, an orally administered composition of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) is provided. In some embodiments, an oral composition 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 from about 50 to about 85% MIGLYOL 812.

In some embodiments, an oral composition 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 from about 60 to about 77% MIGLYOL 812. In some embodiments, an oral composition comprises a compound of formula (Ia), (Ib), (IIa), and / or (IIb), about 10% ethanol, about 20% Vitamin E TPGS, and about 70% MIGLYOL 812. In some embodiments, the oral composition is formulated in hard gelatin capsules.

The amount of active ingredient that can be combined with inactive ingredients to obtain a dosage form may vary depending on the intended subject of treatment and the particular route of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain from about 1 mg to about 1000 mg of active material combined with a suitable and convenient amount of carrier material (eg, inactive ingredient or excipient). In some embodiments, the carrier material ranges from about 5% to about 95% of the total composition (w / w). It should be understood that in addition to the ingredients specifically mentioned above, the compositions according to these embodiments may include other agents commonly used in the art depending on the type of particular composition, for example, compositions suitable for oral administration may include flavorings.

In some embodiments, a composition comprising an active ingredient disclosed herein (eg, a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof), in one embodiment, does not contain agents that affect the rate at which the active ingredient is metabolized. Accordingly, it is understood that compositions containing a compound of formula (Ia) or (Ib), in some embodiments, do not contain agents that could affect (e.g., slow down, hinder or delay) the metabolism of a compound of formula (Ia) or (Ib) or any other active ingredient, administered separately, sequentially or simultaneously with compound (Ia) or (Ib). It is also clear that any of the methods, kits, articles, and the like, detailed in these documents, in some implementations does not contain agents that could affect (for example, slow down, hinder or delay) the metabolism of compound (Ia) or (Ib) or some other active ingredient, administered separately, sequentially or simultaneously with a compound of any formula (Ia) or (Ib).

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) does not contain agents that affect the rate with which the active ingredient is metabolized. Accordingly, it is understood that compositions containing a compound of formula (Ia), (Ib), (IIa) and / or (IIb), in some embodiments, do not contain agents that could affect (e.g., slow, obstruct, or delay) metabolism of a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of formula (Ia), (Ib), (IIa) and / or (IIb). It is also clear that any of the methods, kits, articles, and the like, detailed in these documents, in some embodiments does not contain agents that could affect (e.g., slow down, hinder, or delay) the metabolism of a compound of formula (Ia ), (Ib), (IIa) and / or (IIb) or any other active ingredient administered separately, sequentially or simultaneously with a compound of any formula (Ia), (Ib), (IIa) and / or (IIb) ...

Application methods.

In some embodiments, a method of treating or preventing HIV infection in a subject (eg, a human) is disclosed comprising administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to the subject.

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In some embodiments, a method of treating or preventing HIV infection in a subject (eg, a human) is disclosed comprising administering a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, to the subject.

In some embodiments, a method of inhibiting HIV virus replication, treating AIDS, or delaying the onset of AIDS in a subject (eg, a human) is disclosed, comprising administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to the subject.

In some embodiments, a method is disclosed for inhibiting HIV virus replication, treating AIDS, or delaying the onset of AIDS in a subject (e.g., a human), comprising administering a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt to this subject.

In some embodiments, a method of preventing HIV infection in a subject (eg, a human) is disclosed comprising administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the subject is at risk for HIV infection, as in the case of a subject having one or more known risk factors associated with HIV virus infection.

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

In some embodiments, a method of treating HIV infection in a subject (eg, a human) is disclosed comprising administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, a method of treating HIV infection in a subject (eg, a human) is provided, comprising administering a compound of formula (Ia), (Ib) (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, to the subject.

In some embodiments, a method of treating HIV infection in a subject (e.g., a human) is disclosed comprising administering to a subject in need of 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 (e.g., one, two, three, or four, or one or two, or one to three, or one to four) additional therapeutic agents selected from the group consisting of compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide inhibitors of reverse HIV 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, substances that improve their pharmacokinetics for HIV, and others combinations. In some embodiments, a method of treating HIV infection in a subject (e.g., a human) is disclosed comprising administering to a subject in need of 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 (e.g., one, two, three or four, or one or two, or one to three, or one to four) additional therapeutic agents selected from the group consisting of combination medicines for HIV, other medicines for HIV, HIV protease inhibitors , non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase that do not bind to the catalytic site (or allosteric) inhibitors of HIV integrase, inhibitors of HIV penetration into the cell, inhibitors of HIV maturation, agents that reverse connections, natse HIV capsid, immunotherapeutic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV matrix protein p17 inhibitors, IL-13 antagonists, modulators of peptidyl-prolyl-cis-trans isomerase A , disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulator inhibitors, Vif dimerization inhibitors, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV1 Nef protein modulators, modulators of tyrosine kinase Hck kinase 3 (MLK-3), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, modulators of COMM domain-containing protein 1, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, ICAM- inhibitors 3-binding nonintegrin 1 dendritic cells, inhibitors of HIV GAG protein, inhibits HIV POL protein pores, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, ATP-dependent RNA-helicase inhibitors DDX3X, inhibitors of priming 6 HA and HA D-oxidase inhibitors improving pharmacokinetics, HIV gene therapy and HIV vaccines, or any combination thereof.

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In some embodiments, a method of treating HIV infection in a subject (e.g., a human) is disclosed comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salts in combination with a therapeutically effective amount (e.g. one, two, three or four, or one or two, or one to three, or one to four) additional therapeutic agents selected from the group consisting of 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, inhibitors of CCR, polymeric inhibitors and other medicines for HIV, as well as their combinations. In some embodiments, a method of treating HIV infection in a subject (e.g., a human) is disclosed comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salts in combination with a therapeutically effective amount (e.g., one, two, three or four, or one or two, or one to three, or one to four) additional therapeutic agents selected from the group consisting of combination drugs for HIV , other drugs for 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 that do not bind to the catalytic site (or allosteric) inhibitors of HIV integrase, inhibitors of HIV entry into the cell, HIV maturation inhibitors, latency reversing agents, compounds targeting the HIV capsid, immunotherapeutic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV matrix protein p17 inhibitors, IL-13 antagonists, peptidyl-prolyl-cis-trans modulators isomerase A, disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulator inhibitors, Vif dimerization inhibitors, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef protein modulators, HIV-1 tyrosine kinase inhibitors mixed line kinase-3 (MLK-3), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors , inhibitors of ICAM-3-binding nonintegrin 1 of dendritic cells, protein inhibitors HIV GAG, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, ATP-dependent RNA-helicase DDX3X3X inhibitors, and inhibitors of PRX3XD HAD complex inhibitors -oxidases, substances that improve pharmacokinetics, HIV gene therapy and HIV vaccines, or any combination thereof.

In some embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is disclosed for use in medical therapy for HIV infection (eg, HIV-1) or HIV virus replication (eg, HIV-1) or AIDS, or delayed onset AIDS in a subject (for example, a human)).

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is disclosed for use in medical therapy of HIV infection (e.g., HIV-1 or HIV virus replication (e.g. HIV-1) or AIDS or delaying the onset of AIDS in a subject (eg, human)).

In some embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is disclosed for use in the manufacture of a medicament for treating HIV infection or HIV virus or AIDS virus replication, or delaying the onset of AIDS in a subject (eg, 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 use in therapeutic treatment or for delaying the onset of AIDS.

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is disclosed for use in the manufacture of a medicament for treating HIV infection or HIV or AIDS virus replication, or delaying onset AIDS in a subject (eg human). One embodiment relates to a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in therapeutic treatment or for delaying started AIDS.

In some embodiments, the use of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for HIV infection in a subject (eg, human) is disclosed. In some embodiments, a compound of any formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is disclosed for use in a prophylactic or

- 32 036921 for the treatment of HIV infection.

In some embodiments, the use of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for HIV infection in a subject (eg, a human) is disclosed. In some embodiments, a compound of any formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection is disclosed.

In some embodiments, the methods of use are administered to a subject (eg, a human) in need of treatment. In some embodiments, the methods of use are administered to a subject (eg, human) at risk of developing AIDS. Provided herein is a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, is for use in a method of treating HIV infection or HIV viral replication or AIDS, or delaying the onset of AIDS in a subject (eg, human).

In some embodiments, disclosed herein is a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in therapy. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is for use in a method of treating HIV infection or HIV or AIDS virus replication or delaying the onset of AIDS in a subject ( for example, a person). 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 a subject in need thereof. In some 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 a subject in need thereof. In some embodiments, a subject in need thereof is a human infected with HIV. In some embodiments, a subject in need thereof is a human infected with HIV who has not yet developed AIDS. In some embodiments, a subject in need thereof is a subject at risk of developing AIDS. In some embodiments, a subject in need thereof is an HIV-infected person who has already developed AIDS.

In some embodiments, disclosed herein is a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV infection in a subject in need thereof. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof is provided for use in a method of treating HIV infection in a person in need thereof. In some embodiments, a subject in need thereof is a human infected with HIV. In some embodiments, a subject in need thereof is a human infected with HIV who has not yet developed AIDS. In some embodiments, a subject in need thereof is a subject at risk of developing AIDS. In some embodiments, a subject in need thereof is an HIV-infected person who has already developed AIDS.

In one embodiment, there is provided a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one two, three, or four, or one or two, or one to three, or one to four) additional therapeutic agents described herein for use in a method of treating or preventing HIV infection in a person in need thereof. In one embodiment, said additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic site-binding (or allosteric) inhibitors of HIV integrase, inhibitors of HIV entry into the cell, inhibitors of HIV maturation, agents that reverse the latency state, compounds targeting the HIV capsid, immunotherapeutic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, modulators of peptidyl-prolyl-cis-trans isomerase A, disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulator inhibitors, Vif dimerization inhibitors, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef protein modulators, Hck tyrosine kinase modulators, mixed line kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors , Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, ICAM-3-binding nonintegrin 1 inhibitors of dendritic cells, HIV GAG protein inhibitors , HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclic inhibitors

- 33 036921 lin-dependent kinase, PC9 proprotein convertase stimulants, DDX3X ATP-dependent RNA helicase inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADPH oxidase inhibitors, substances that improve pharmacokinetics combinations, HIV vaccines or their gene therapy and their HIV gene therapy and HIV gene therapy. In one embodiment, said additional therapeutic agents are 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, inhibitors of HIV integrase 41 , CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other HIV drugs, and combinations thereof.

In some embodiments, there is provided a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one two, three, or four, or one or two, or one to three, or one to four) additional therapeutic agents described herein for use in a method of treating or preventing HIV infection in a subject in need thereof. In one embodiment, said additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic site-binding (or allosteric) inhibitors of HIV integrase, inhibitors of HIV entry into the cell, inhibitors of HIV maturation, agents that reverse the latency state, compounds targeting the HIV capsid, immunotherapeutic agents, phosphatidylinositol-3 kinase (PI3K) inhibitors, antibodies to HIV , bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl-cistrans isomerase A modulators, disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulator inhibitors, Vif dimerization inhibitors, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef protein modulators, ISK tyrosine kinase modulators, mixed line kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors , Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, ICAM-3-binding nonintegrin 1 inhibitors of dendritic cells, HIV GAG protein inhibitors , HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, ATP-dependent RNA-helicase DDX3X inhibitors, HAD-HAD oxidase inhibitors and inhibitors, and inhibitors of priming HAD complex inhibitors , improving pharmacokinetics, means of gene therapy of viral H and HIV vaccines or any combination thereof. In one embodiment, said additional therapeutic agents are 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, inhibitors of HIV integrase 41 , CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other HIV drugs, and combinations thereof.

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

In some embodiments, there is provided a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with a first additional pharmaceutical agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, said second additional therapeutic agent being emtricitabine, for use in a method of treating or preventing HIV infection in a subject in need thereof. In a specific embodiment, a compound of formula (Ia), (Ib), (IIa) and / or (IIb) is provided, or

34 036921 a pharmaceutically acceptable salt thereof in combination with a first additional pharmaceutical agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate, tenofovir disoproxil, and a second additional therapeutic agent, said second additional therapeutic agent being emtricitabine , for use in a method of treating or preventing HIV infection in a subject in need thereof. In a specific embodiment, there is provided a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in preventing infection when an individual is in contact with a virus and / or to prevent the establishment of permanent infection by the virus and / or to prevent the onset of symptoms disease and / or to prevent the achievement of detectable levels of virus in the blood, for example, for pre-exposure (pre-exposure) prophylaxis (PrEP, PrEP, PrEP) or post-exposure (post-exposure) prophylaxis (PEP, PEP, PEP). Accordingly, in some embodiments, methods are provided for reducing the risk of contracting HIV (eg, HIV-1 and / or HIV-2). For example, methods of reducing the risk of contracting HIV (eg, HIV-1 and / or HIV-2) include administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. In some embodiments, methods of reducing the risk of contracting HIV (eg, HIV-1 and / or HIV-2) comprise administering a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents. In some embodiments, methods of reducing the risk of contracting HIV (e.g., HIV-1 and / or HIV-2) comprise 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 ...

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, is provided for use to prevent infection when an individual is exposed to a virus and / or to prevent persistent infection with the virus, and / or to prevent the onset of symptoms of the disease, and / or to prevent the achievement of detectable levels of the virus in the blood, for example, for pre-exposure (pre-exposure) prophylaxis (PrEP, PrEP, PrEP) or post-exposure (post-exposure) prophylaxis (PEP, PEP, PKP). Accordingly, in some embodiments, methods are provided for reducing the risk of contracting HIV (eg, HIV-1 and / or HIV-2). For example, methods of reducing the risk of contracting HIV (eg, HIV-1 and / or HIV-2) include administering a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof. In some embodiments, methods of reducing the risk of contracting HIV (e.g., HIV-1 and / or HIV-2) comprise administering a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with one or more other therapeutic agents. In some embodiments, methods of reducing the risk of contracting HIV (e.g., HIV-1 and / or HIV-2) comprise 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.

In some embodiments, methods of reducing the risk of contracting HIV (eg, HIV-1 and / or HIV-2) comprise administering a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, in combination with safer sexual behavior. In some embodiments, methods of reducing the risk of HIV infection (eg, 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 sexual transmission of HIV.

In some embodiments, methods of reducing the risk of contracting HIV (e.g., HIV-1 and / or HIV-2) comprise administering a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, in combination with safer sexual behavior. In some embodiments, methods of reducing the risk of HIV infection (eg, 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 sexual transmission of HIV.

In some embodiments, the reduction in risk of contracting HIV is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the risk reduction for HIV infection is at least about 75%. In some embodiments, the risk reduction for HIV infection is about 80%, 85%, or 90%.

In another embodiment, there is disclosed the use of a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection in a person with infection or risk of infection.

In some embodiments, the use of a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HIV infection in a person with infection or at risk of infection is disclosed.

Also disclosed herein is a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, for use in therapeutic treatment or for delaying the onset of AIDS.

- 35 036921

In some embodiments, disclosed herein is a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in therapeutic treatment or for delaying the onset of AIDS. 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.

In some embodiments, provided herein is a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection.

In some embodiments, a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, can be used as a research tool (eg, to study inhibition of HIV reverse transcriptase in a subject or in vitro).

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, can be used as a research tool (e.g., to study inhibition of HIV reverse transcriptase in a subject or in vitro).

Routes of administration.

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

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

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.

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, may be administered using a self-injection device 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.

Introduction mode.

A compound such as a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, can be administered to a subject in accordance with an effective administration regimen over a desired period of time or duration, such as at least about one day, at least about one week at least about one 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 embodiment, the compound is administered on a daily or interval dosing schedule. In one embodiment, the compound is administered on a monthly dosing schedule. In one embodiment, the compound is administered every two months. In one embodiment, the compound is administered every three months. In one embodiment, the compound is administered every four months. In one embodiment, the compound is administered every five months. In one embodiment, the compound is administered every 6 months.

In some embodiments, a compound such as a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, can be administered to a subject in accordance with an effective administration regimen over a desired period of time or as long as as at least about 1 day, at least about 1 week, at least about 1 month, at least

- 36,036921 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 some embodiments, the compound is administered on a daily or interval schedule. In some embodiments, the compound is administered on a monthly dosing schedule. In some embodiments, the compound is administered every 2 months. In some embodiments, the compound is administered every 3 months. In some embodiments, the compound is administered every 4 months. In some embodiments, the compound is administered every 5 months. In some embodiments, the compound is administered every 6 months.

In some embodiments, a compound, such as a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof, can be administered to a subject for at least about 1 month, at least about 4 months, or at least about 6 months. 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 subcutaneously to a subject 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 subcutaneously or intramuscularly to a subject for at least about 4 months, or at least about 6 months. In some embodiments, a compound (eg, a compound of formula (Ia), (Ib), (IIa) and / or (IIb), or a pharmaceutically acceptable salt thereof) can be administered subcutaneously to a subject for at least about 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 subcutaneously or intramuscularly to a subject at least about every 3 months.

The dosage or frequency of administration of a 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. 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 throughout the course of treatment based on the judgment of the administering physician.

The compound can be administered to a subject (eg, a human) in an effective amount. In some embodiments, the compound is administered once a day. In some embodiments, the compound can be administered to a subject (eg, human) in a therapeutically effective amount. In some embodiments, the compound is administered once a day. In some embodiments, the compound is administered monthly. In some embodiments, the compound is administered every 3 months. In some embodiments, the compound is administered every 4 months. In some embodiments, the compound is administered every 6 months.

A compound disclosed herein (eg, a compound of formula (Ia) or (Ib)) or a pharmaceutically acceptable salt thereof can be administered at a dosage amount that is effective. For example, the dosage amount can be from 1 mg to 1000 mg of the compound. In some 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 the compound. In some 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.

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 can be administered at a dosage amount that is effective. For example, the dosage may be from 1 mg to 1000 mg of the compound. In some 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 the compound. In some 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.

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered in a once-daily dose. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered in a once daily dosage of about 1 mg.

In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered monthly. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered monthly at a dosage of about 100 mg. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered every 6 months. In some embodiments, a compound of formula (Ia), (Ib), (IIa) and / or (IIb)), or a pharmaceutically acceptable salt thereof, is administered every 6 months at a dose of about 600 mg.

Sets and products.

The present disclosure relates to a kit containing a compound of formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. In one embodiment, the kit may include one or more of the other therapeutic agents described hereinabove. The kit may further contain instructions for use, for example, for use in inhibiting reverse

- 37 036921 HIV transcriptase, for example, for use in the treatment of HIV infection or AIDS or as a research tool. Instructions for use are usually written instructions, although electronic storage media (such as a magnetic diskette or optical disc) are also acceptable.

In some embodiments, the present invention also provides 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 contain one or more of the other therapeutic agents described hereinabove. The kit may further contain instructions for use, for example, for use in inhibiting HIV reverse transcriptase, for example, for use in the treatment of HIV infection or AIDS, or as a research tool. Instructions for use are usually written instructions, although electronic storage media (such as a magnetic diskette or optical disc) are also acceptable. The present invention also relates to a pharmaceutical kit containing one or more containers containing a compound of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof. Optionally, such container (s) may be accompanied by a notice in the form prescribed by a government pharmaceutical authority, reflecting the approval of that authority for manufacture, use or sale for human use. Each component (if more than one component is present) can be packed in a separate container or some components can be combined in one container if this is acceptable in terms of cross-reactivity and shelf life. The kits can be presented in the form of dosage forms, packages without dividing into doses (for example, in multi-dose packages) or in doses less than the standard). The kits can also include multiple unit doses of the compounds and instructions for use, and can be packaged in quantities sufficient for storage and use in pharmacies (eg, hospital pharmacies or prescription pharmacies).

The present disclosure also relates to a pharmaceutical kit containing one or more containers containing a compound of formula (Ia), (Ib), (IIa) and / or (IIb) or a pharmaceutically acceptable salt thereof. Optionally, such container (s) may be accompanied by a notice in the form prescribed by a government pharmaceutical authority, reflecting the approval of that authority for manufacture, use or sale for human use. Each component (if more than one component is present) can be packed in a separate container or some components can be combined in one container if this is acceptable in terms of cross-reactivity and shelf life. The kits can be presented in the form of dosage forms, packages without dividing into doses (for example, in multi-dose packages or in doses less than the standard). The kits can also include multiple unit doses of the compounds and instructions for use, and can be packaged in quantities sufficient for storage and use in pharmacies (eg, hospital pharmacies or prescription pharmacies).

Also disclosed is an article of manufacture comprising a dosage unit 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, bottles, vessels, ampoules, bottles, cans, flexible packaging, and the like. The product can also be sterilized and / or sealed.

In some embodiments, articles of manufacture are disclosed comprising a dosage unit 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, bottles, vessels, ampoules, bottles, cans, flexible packaging, and the like. The product can also be sterilized and / or sealed.

Nomenclature.

The names of compounds of formulas (Ia) and (Ib) according to the present invention were generated using ChemBioDraw Ultra 11.

- 38 036921 is N- (1- (3- (4-chloro-3- (methylsulfonamido) -1- (2,2,2-trifluoroethyl) -1H-indazol-7yl) -6- (3-methyl- 3- (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2- (5,5difluoro-3- (trifluoromethyl) -3b, 4 , 4а, 5-tetrahydro-III-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1yl) acetamide.

represents N - ((S) -1- (3- (4-chloro-3- (methylsulfonamido) -1- (2,2,2-trifluoroethyl) -1H-indazol7-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-III-cyclopropa [3,4] cyclopenta [1,2c] pyrazol-1-yl) acetamide.

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

represents N- (1- (3- (4-chloro-3- (cyclopropanesulfonamido) -1- (2,2-difluoroethyl) -1H-ind azol-7-yl) -6- (3-methyl-3 - (methylsulfonyl) but-1-in-1 -yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2- (3 (difluoromethyl) -5,5-difluoro-3b, 4, 4a, 5-tetrahydro-III-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1yl) acetamide.

represents N - ((S) -1- (3- (4-chloro-3- (cyclopropanesulfonamido) -1- (2,2-difluoroethyl) -1Hindazol-7-yl) -6- (3-methyl-3 - (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2 ((3bS, 4αR) -3- (difluoromethyl) -5,5 -difluoro-3b, 4,4a, 5-tetrahydro-III-cyclopropa [3,4] cyclopenta [1,2c] pyrαzol-1-yl) acetamide.

Synthesis of compounds of formula (Ia), (Ib), (IIa) and (IIb).

The present invention also relates to methods and intermediates that can be used to prepare the disclosed compounds or pharmaceutically acceptable salts thereof. Unless otherwise indicated, the methods and techniques of the present invention are generally carried out in accordance with conventional techniques well known and described in various general and more specific references and discussed herein. See, for example, Loudon, Organic Chemistry, 5th ed., New York, USA: Oxford University Press, 2009, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed., Wiley- Interscience, 2013. In some cases, the methods disclosed herein include the step of salt formation of a compound of the present invention. In some embodiments, intermediates are provided that can be used in the preparation of compounds of formula (Ia) or (Ib) of the present invention. For example, these intermediates include any one or a combination of compounds 1-23 or salts thereof. In some embodiments, intermediate compounds are selected from compounds 8a, 12,

- 39 036921

14, 19, 20, 21, 22, 23 and / or 23b, combinations thereof or salts thereof.

In some embodiments, intermediates are provided that can be used in the preparation of compounds of formula (IIa) or (IIb). For example, these intermediates include any one or a combination of compounds 1, 10, 20, and 25-37, or salts thereof. In some embodiments, intermediates are selected from compounds 20, 32, 34, 35, 36, and / or 37, combinations thereof, or salts thereof.

The compounds described herein can be purified by any means known in the art, including chromatographic agents such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, supercritical fluid chromatography (SFC), and ion exchange chromatography. Any stationary phase can be used, including normal and reverse phases, and ionic resins. Most often, the disclosed compounds are purified by chromatography on silica gel and / or alumina. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., Ed. L.R. Snyder, J.J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the methods for preparing the disclosed compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved. This can be done using conventional protecting groups, as described in classic works such as T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 4th ed., Wiley, NY, 2006. Protective groups can be removed at a convenient subsequent step using methods known in the art.

Examples of chemical compounds that can be used in the methods according to the embodiments will be described below by way of representative synthetic schemes for general preparation and the specific examples that follow. The person skilled in the art will understand that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular side groups. Each of the reactions shown in the general schemes are preferably carried out at a temperature from about 0 ° C to the reflux temperature of the organic solvent used.

The compounds disclosed herein can exhibit atropisomerism due to steric hindrances affecting the rate of axial rotation around a single bond. Each of the resulting conformational isomers can be observed as a separate object when studied by methods such as NMR and HPLC. The compounds disclosed herein can exist as a mixture of atropisomers. However, the detection of atropisomers depends on factors such as temperature, solvent, purification conditions, and time parameters of the spectroscopic technique. The rate of mutual transformations at room temperature is characterized by a half-life of minutes to hours, hours to days, or days to years. The equilibrium ratio of atropisomers can be different. The characterization data presented herein may not be at equilibrium depending on isolation and test conditions, which may include, but are not limited to, handling, solvents used, and temperature. Representative examples of the synthesis of compounds according to the present invention are shown in the schemes below, and in the following specific examples. The examples below are purely illustrative and are not intended to limit the present disclosure in any way.

Preparation of 2 - ((3bS, 4aR) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole- 1-yl) acetic acid (a) and 2 - ((3bR, 4aS) -5,5-difluoro-3- (trifluoromethyl) 3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [ 1,2-c] pyrazol-1-yl) acetic acid (8b).

- 40 036921

Example 1.

Preparation of compounds 8a and 8b:

five

8a 8b

Synthesis of lithium 2,2,2-trifluoro-1- (3-oxobicyclo [3.1.0] hexan-2-ylidene) ethan-1-olate (2).

The reactor was loaded with bicyclo [3.1.0] hexan-3-one (95.6 g, 0.99 mol) and ethyl 2,2,2-trifluoroacetate (113.2 ml, 0.95 mol) and THF (50 ml). The reaction mixture was cooled to 0 ° C. LiHMDS (lithium bis (trimethylsilyl) amide) (1 L of 1.0 M solution in THF, 1 mol) was added through the addition funnel at such a rate to maintain the internal temperature <1 ° C. After the addition was complete, hexanes (235 mL) was added in an even stream through the addition funnel and stirred for 15 minutes. The resulting solids were collected by filtration, washed with hexanes (3x400 ml) and dried to give the title compound.

Synthesis of ethyl 2- (3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate (3).

The reactor was loaded with 2,2,2-trifluoro-1- (3-oxobicyclo [3.1.0] hexan-2-ylidene) ethan-1-lithium olate (177.2 g, 0.89 mol) and EtOH (ethanol) (779 ml) ... The temperature was brought to 0 ° C and maintained at this level. HCl in dioxane (4.0N, 443 mL) was added via an addition funnel, followed by the addition of solid ethyl hydrazinoacetate in the form of an HCl salt (138.4 g, 0.90 mol). The temperature of the reaction mixture was brought to 35 ° C. After 1 h, the volume of the reaction mixture was reduced by ~ 40% by distillation under reduced pressure. Water (1.3 L) was added with vigorous stirring and the temperature was brought to 15 ° C. The resulting solids were collected by filtration, washed with water (3x500 ml), hexanes (3x400 ml) and dried to give the title compound.

MS (m / z): 275.1 [M + H] +.

Synthesis of ethyl 2- (5-oxo-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2с] pyrazol-1-yl) acetate (4) ...

The reactor was charged with ethyl 2- (3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrαzol-1-yl) acetate (291.2 g , 1.06 mol), acetonitrile (1.65 L) and water (825 ml), to which were added N-hydroxyphthalimide (17.4 g, 0.103 mol) and NaClO2 (41.0 g, 0.45 mol, ~ 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 h. After consumption of the starting material, the temperature was brought to 20 ° C and aqueous sodium bisulfite (40% w / w, 350 ml) through the addition funnel. Added

- 41 036921 ethyl acetate (1.75 L) and separated the layers. The aqueous layer was back extracted with ethyl acetate (ethyl acetate) (500 ml). The organic layers were combined and washed with saturated aqueous NaHCO ₃ (500 ml) and 1: 1 water / brine (500 ml). The organic layer was concentrated under reduced pressure and coevaporated with IPAc (isopropyl acetate) (300 ml). The crude solid was crystallized from IPAc / heptane. The resulting solids were collected by filtration, washed with heptane and dried to give the title compound.

MS (m / z): 289.0 [M + H] ⁺ .

Synthesis of 2- (5-oxo-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetic acid (5 ).

To a solution of ethyl 2- (5-oxo-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate ( 80.40 g, 278.95 mmol) in 2-Me-THF (2-methyltetrahydrofuran) (167 ml) was added 2 M aqueous sodium hydroxide (167 ml). After stirring for 25 min at room temperature, the reaction mixture was diluted with 2-methyltetrahydrofuran and slowly acidified by adding dropwise concentrated HCl. The organic layer was isolated and the aqueous layer was extracted with additional 2-Me-THF. The combined organic layers were washed with saturated aqueous sodium chloride, then dried over sodium sulfate, filtered and concentrated. The resulting oil was diluted in ethyl acetate. Hexanes were added with vigorous stirring until a solid was visible. The solid was isolated by filtration and dried to give the title compound.

MS (m / z): 259.00 [MH] ^- .

Synthesis of 2- (3- (trifluoromethyl) -4,4a-dihydrospiro [cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-5,2 '[1,3] dithiolane] -1 (3bH) -yl ) acetic acid (6).

To a solution of 2- (5-oxo-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2c] pyrazol-1-yl) acetic acid (3.0 g , 11.5 mmol) in DCM (dichloromethane) (25 ml), 1,2-ethanedithiol (1.07 ml, 12.68 mmol) was added, followed by the 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-Me-THF (60 ml) were added to the reaction mixture. The organic layer was isolated, dried over sodium sulfate, filtered and concentrated. The crude product was dissolved in ethyl acetate (2 ml) and the solution was diluted with hexanes (12 ml) with vigorous stirring to give a solid. This solid was isolated by filtration and dried to give the title compound.

MS (m / z): 337.12 [M + H] +.

Synthesis of 2- (5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2 ^ pyrazole-Tyl-acetic acid (7).

Pyridine hydrofluoride (5.0 ml) was added to a suspension of 1,3-dibromo-5,5-dimethylhydantoin (12.75 g, 44.6 mmol) in DCM (35 ml) at 0 ° C. The suspension was stirred at 0 ° C for 10 min. A solution of 2- (3- (trifluoromethyl) -4,4a-dihydrospiro [cyclopropa [3,4] cyclopenta [1,2-c] pyrazole5,2 '- [1,3] dithiolane] -1 (3bH) -yl) acetic acid (5.00 g, 14.9 mmol) dropwise. Upon completion of the addition, the reaction mixture was stirred at 0 ° C for an additional 15 min. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (300 ml) with vigorous stirring. The organic layer was removed and the aqueous layer was acidified to pH ~ 1 with concentrated HCl. The aqueous phase was extracted with three portions of MTBE (methyl tert-butyl ether). The combined organic layers were dried with sodium sulfate, filtered and concentrated. The resulting solid was diluted in MTBE (16 ml) and filtered to completely remove the resulting solid. The solution was then extracted with 2 N NaOH (16 ml). The aqueous layer was diluted with water (16 ml) with vigorous stirring and stirred at room temperature for 15 minutes. The resulting solid was removed by filtration. The aqueous layer was acidified by slowly, dropwise, adding concentrated HCl to pH ~ 1 with vigorous stirring to obtain a solid residue. The solid was isolated by filtration to give the title compound.

MS (m / z): 281.12 [M + H] +.

Synthesis of 2 - ((3bS, 4aR) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole- 1-yl) acetic acid (8a) and 2 - ((3bR, 4aS) -5,5-difluoro-3- (trifluoromethyl) -3b, 4,4a, 5tetrahydro-1H-cyclopropa [3,4] cyclopenta [1 , 2-c] pyrazol-1-yl) acetic acid (8b).

2- (5,5-Difluoro-3- (trifluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetic acid was separated the enantiomeric components indicated in the title by chiral SFC under the following conditions: instrument: Thar 350 for preparative SFC; Column: ChiralPak IC-10 μm, 300x50 mm (I.D.); Mobile phase: 35% isopropanol (0.1% NH3-H2O) and CO2; flow rate: 200 ml / min; column temperature: 38 ° C; UV detection: 220 nm; sample preparation: the compound was dissolved in isopropanol to ~ 45 mg / ml; injection: 6.5 ml per injection. Analytical SFC [mobile phase: A for CO ₂ and B for isopropanol (0.05% diethanolamine); gradient: B 20%;

- 42 036921

A; flow rate: 2.35 ml / min; column: Chiralpak IC-3, 150x4.6 mm, 3 μm; wavelength: 254 nm] 8a:

t = 3.39 min, 8b: t = 2.17 min.

Compound 8a - ¹ H-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).

Example 2.

Getting connection 12

Pd (PPh ₃ ) ₂ CI ₂ potassium propionate DMF, dioxane

Synthesis of 7-bromo-4-chloro-1H-indazol-3-amine (10).

To 3-bromo-6-chloro-2-fluorobenzonitrile (13.9 g, 59.3 mmol) in EtOH (ethanol) (60 ml) was added hydrazine monohydrate (5.77 ml). The reaction mixture was heated to 80 ° C for 3 h. After cooling to ambient temperature, EtOH (20 ml) was added and left stirring. The solids were collected by filtration, washed with cold EtOH and dried to give the title compound.

MS (m / z): 247.9 [M + H] +.

Synthesis of 7-bromo-4-chloro-1- (2,2,2-trifluoroethyl) -1H-indazol-3-amine (11).

The reactor was charged with 7-bromo-4-chloro-1H-indazol-3-amine (397.2 g, 1.6 mol) and Cs ₂ CO ₃ (1052 g, 3.2 mol), then diluted with DMF (dimethylformamide) (4000 ml). To this, 2,2,2-trifluoroethyl trifluoromethanesulfonate (463.2 g, 1.9 mol) was slowly added via an addition funnel. After the addition was complete, the reaction mixture was allowed to stir for 1 h, after which H ₂ O (16 L) was slowly added. After the addition was complete, the mixture was left stirring for 12 hours at 15 ° C. The suspension was filtered and the collected solids were suspended in DMF (800 ml). To this was added H ₂ O (4800 ml) and the resulting solids were collected by filtration and dried to give the title compound.

MS (m / z): 330.1 [M + H] ⁺ .

Synthesis of 4-chloro-7- (4,4,5,5-tertramethyl-1,3,2-dioxaborolan-2-yl) -1- (2,2,2-trifluoroethyl) -III-indazol3-amine (12 ).

The reaction vessel was charged with 7-bromo-4-chloro-1- (2,2,2-trifluoroethyl) -1H-indazol-3-amine (15.00 g, 45.66 mmol), bis- (pinacolato) dibor (17.39 g, 68.49 mmol), potassium propionate (15.36 g, 136.98 mmol), dioxane (90 ml) and DMF (dimethylformamide) (30 ml). Bis- (triphenylphosphine) palladium (P) dichloride (0.64 g, 0.91 mmol) was added and the reaction solution was degassed by bubbling argon for 2 min. The reaction mixture was heated to 105 ° C for 4 h. After cooling to ambient temperature, the reaction mixture was filtered through a pad of celite and silica gel, rinsing with ethyl acetate. The filtrate was washed with 5% LiCl solution and brine. The organic layers were separated, dried and concentrated under reduced pressure. The residue was treated with IPAc / heptane (1/10) at 60 ° C, then cooled to ambient temperature and stirred for 15 s. The solids were collected by filtration and dried to give the title compound.

MS (m / z): 376.7 [M + H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ 7.69 (d, 1H), 7.06 (d, 1H), 5.55 (s, 2H), 5.45 (q, 2H), 1.32 (s, 12H).

Example 3.

Getting connection 14

Cl CuCI, DMF _{0 <} S _x

ABOUT

14

Synthesis of 3-methyl-3- (methylsulfonyl) but-1-yne (14).

To a stirred suspension of sodium methanesulfinate (18.47 g, 175.5 mmol) and copper (I) chloride (1.45 g, 14.6 mmol) in DMF (dimethylformamide) (50 ml) was added 3-chloro-3-methylbut-1-yne (15.00 d, 146.3 mmol, 16.4 ml). The resulting reaction mixture was heated to 40 ° C and stirred in

- 43 036921 for 16 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solution was washed with water and brine. The organic layer was collected and dried over sodium sulfate, then filtered. The solution was concentrated in vacuo and purified by silica gel chromatography to give the title compound.

Mp: 114.8-115.5 ° C.

¹ H-NMR (400 MHz, chloroform-d) δ 3.04 (s, 3H), 2.58 (s, 1H), 1.67 (s, 6H).

Example 4.

Getting connection 19

Synthesis of (S) -N - ((3,6-dibromopyridin-2-yl) methylene) -2-methylpropane-2-sulfinamide (16).

3,6-Dibromopicolinaldehyde (76.0 g, 0.287 mol) and (S) -2-methylpropane-2-sulfinamide (36.51 g, 0.301 mol) were combined in NMP (N-methyl-2-pyrrolidone) (200 ml). Solid Cs ₂ CO ₃ (41.94 g, 0.316 mol) was added to the reaction mixture in one portion. The reaction mixture was stirred for 2 h, then cooled to 5 ° C. Water (1.3 L) was added to the reaction mixture. The resulting slurry was stirred for 1 hour, the solids were collected by filtration, washed with water (5x100 ml) and dried to give the title compound.

MS (m / z): 368.9 [M + H] +.

Synthesis of (S) -N - ((S) -1- (3,6-dibromopyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2-methylpropane-2sulfinamide (17).

A reaction vessel was charged with (S) -N - ((3,6-dibromopyridin-2-yl) methylene) -2-methylpropane-2sulfinamide (65.5 g, 177.95 mmol) followed by DMF (dimethylformamide) (260 mL). This mixture was stirred for 5 min 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 min. This mixture was stirred for an additional 2.5 h.% AcOH (acetic acid) in water (640 ml) was added to the reaction mixture over 10 min, followed by one portion of CPME (cyclopentyl methyl ether) (320 ml). The mixture was stirred for 5 min, warmed to room temperature and the layers were separated. The organic layer was washed with 5% AcOH (320 ml), then treated with 0.5 M NaOH (330 ml) and washed with brine. The organic layer was collected, dried with Na ₂ SO ₄ and filtered. MeOH (methanol) (33 ml) was added to the crude mixture. To the stirred mixture was added dropwise 3M HCl in CPME (128 ml) over 15 min. 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 podslushivaet 8 molar NaOH and was extracted with cyclopentylmethyl ether (375 ml). The organic layer was washed with brine, dried with Na ₂ SO ₄ and filtered to give the title compound in solution which was used directly in the next reaction.

MS (m / z): 497.0 [M + H] ⁺ .

Synthesis of (S) -1 - (3,6-dibromopyridin-2-yl) -2- (3,5-difluorophenyl) ethan-1-amine (18).

The resulting solution of (S) -N - ((S) -1- (3,6-dibromopyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2-methylpropane-2-sulfinamide was diluted with cyclopentylmethyl ether to volume of 700 ml, and added to this acetonitrile (350 ml). Concentrated HCl (37%, 16.4 mL) was added to the stirred mixture dropwise over 10 min at room temperature. The thick slurry was stirred vigorously for 4 hours. The solids were filtered and washed with 2: 1 CPME (cyclopropyl methyl ether): acetonitrile to give the title compound.

MS (m / z): 393.3 [M + H] ⁺ .

- 44 036921

Synthesis of tert-butyl- (S) - (1- (3,6-dibromopyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (19).

The reaction vessel was charged with 2-Me-THF (190 ml), water (190 ml) and (S) -1- (3,6-gu6poMnupuguH-2yl) -2- (3,5-difluorophenyl) ethan-1-amine (46.9 g, 0.11 mol), and then NaHCO ₃ (30.34 g, 0.36 mol) was added 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 h and at ambient temperature for 2 h. The reaction mixture was diluted with water and extracted with MTBE (methyl tert-butyl ether). The organic layers were 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 (400 MHz, Methanol-d ₄ ) δ 7.85 (d, 1H), 7.42 (d, 1H), 6.90-6.72 (m, 3H), 5.33 (dd, 1H), 3.10 (dd, 1H) , 2.92 (dd, 1H), 1.36 (s, 9H).

Example 5.

Preparation of formula (Ib) (compound 24)

Synthesis of tert-butyl- (S) - (1- (3-brom-6- (3-methyl-3- (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2 (3, 5-difluorophenyl) ethyl) carbamate (20).

The reactor was charged with tert-butyl- (S) - (1- (3,6-dibromypiridin-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 Et ₃ N (trimethylamine) (42.5 ml, 305.4 mmol). The reaction mixture was heated to 50 ° C. bis- (Triphenylphosphine) palladium (P) dichloride (2.14 g, 3.1 mmol) and copper (I) iodide (0.58 g, 3.1 mmol) was added. After 30 min, the reaction mixture was diluted with acetonitrile (MeCN) (200 ml) and then 7% aqueous NH ₄ Cl (200 ml) was added dropwise. A slurry formed, the temperature of which was brought to ambient temperature. After 3 hours, the solids were collected by filtration. The filter cake was washed twice with MeCN / water (1: 1, 75 ml) and MTBE (methyl tert-butyl ether) (75 ml). The solid was dried to give the title compound.

MS (m / z): 556 [M + H] ⁺ .

¹ H-NMR (400 MHz, chloroform-d) δ 7.84 (d, J = 8.2 Hz, 1H), 7.29-7.15 (m, 1H), 6.70-6.55 (m, 2H), 5.79 (d, J = 9.0 Hz, 1H), 5.57-5.45 (m, 1H), 3.21-3.05 (m, 4H), 2.99-2.88 (m, 1H), 1.80 (s, 6H), 1.40 * (s, 7H), 1.30 * ( s,

- 45 036921

2H). * denotes the presence of atropisomers in the ratio 4.6: 1.

Synthesis of tert-butyl (S) - (1- (3- (3-αmino-4-chloro-1- (2,2,2-trifluoroethyl) -1H-indazol-7-yl) -6- (3-methyl -3 (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (21).

tert-Butyl- (S) - (1 - (3-bromo-6- (3-methyl-3 - (methylsulfonyl) but-1 -in-1-yl) pyridin-2-yl) -2- (3, 5difluorophenyl) ethyl) carbamate (1000.0 mg, 1.79 mmol), 4-chloro-7- (4,4,5,5-tertramethyl-1,3,2-dioxaborolan2-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) was loaded into a round bottom flask and placed under argon atmosphere. Dioxane (10 ml) and water (2 ml) were added and the suspension was degassed by bubbling argon for 60 s. 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 give the title compound.

MS (m / z): 726.1 [M + H] ⁺ .

¹ H-NMR (400 MHz, chloroform-d) δ 7.69-7.55 (m), 7.55-7.42 (m), 7.16-7.06 (m), 7.07-6.96 (m), 6.89 (d), 6.60 (tt) , 6.44 (dd), 6.20 (d), 6.16 (d), 6.08 (s), 5.69-5.53 (m), 5.29 (s), 5.26 (d), 4.95-4.85 (m), 4.64 (q), 4.594.46 (m), 4.36-4.19 (m), 3.94-3.76 (m), 3.64-3.54 (m), 3.18 (s), 3.17 (s), 3.01-2.84 (m), 2.78-2.68 (m ), 1.86-1.82 (m), 1.38 (s), 1.34 (s), 1.26 (s), 1.23 (s), 1.15 (s).

Synthesis of tert-butyl (S) - (1- (3- (4-chloro-3- (N- (methylsulfonyl) methylsulfonαmido) -1- (2,2,2trifluoroethyl) -1Н-indazol-7-yl) -6 - (3-methyl-3 - (methylsulfonyl) but-1-in-1-yl) pyridin-2-yl) -2- (3,5 difluorophenyl) ethyl) carbamate (22).

tert-Butyl (S) - (1- (3- (3-amino-4-chloro-1- (2,2,2-trifluoroethyl) -1H-indazol-7-yl) -6- (3-methyl- 3 (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (37.89 g, 52.18 mmol) was dissolved in methylene chloride (380 ml) with stirring at ambient temperature. To this was added triethylamine (21.82 ml, 156.54 mmol) followed by 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 h. The organic layer was separated and the aqueous layer was extracted once with methylene chloride. The combined organic layers were washed with water and brine, dried with MgSO ₄ , filtered and concentrated to low volume. Hexanes were added. The liquid suspension was decanted. The remaining solid was dried under reduced pressure to give the title compound.

MS (m / z): 882.69 [M + H] +.

¹ H-NMR (400 MHz, Methanol ^) δ 7.87 (d), 7.83 (d), 7.76 (s), 7.74 (s), 7.69 (s), 7.67 (s), 7.65 (s), 7.52 7.47 ( m), 7.46 (s), 7.37 (d), 7.33 (d), 7.11-7.03 (m), 4.79-4.55 (m), 4.51 (t), 4.36 (dt), 4.20-4.05 (m), 3.64 (s), 3.62 (s), 3.60 (s), 3.59 (s), 3.23 (s), 3.04 (d), 3.01 (d), 2.95-2.83 (m), 1.81 (s), 1.34 (s) , 1.29 (s), 0.98 (s).

Synthesis of (S) -N- (7- (2- (1-amino-2- (3,5-difluorophenyl) ethyl) -6- (3-methyl-3 - (methylsulfonyl) but-1 -in-1 yl ) pyridin-3-yl) -4-chloro-1 - (2,2,2-trifluoroethyl) -1Н-indazol-3-yl) -N- (methylsulfonyl) methanesulfonamide (23).

K tert-butyl- (S) - (1 - (3 - (4-chloro-3 - (N- (methylsulfonyl) methylsulfonamido) -1 - (2,2,2-trifluoroethyl) 1H-indazol-7-yl) -6- (3-methyl-3- (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (39 g, 44 mmol), dissolved in methylene chloride (120 ml), was added trifluoroacetic acid (80 ml). The reaction mixture was stirred at ambient temperature for 50 minutes. The reaction mixture was diluted with methylene chloride and slowly poured into ice-cold saturated NaHCO ₃ solution. The organic layer was separated, washed with water and brine, dried with MgSO ₄ , filtered and concentrated to dryness to give the title compound.

MS (m / z): 782.84 [M + H] ⁺ .

1H-NMR (400 MHz, chloroform-d) δ 7.61 (d), 7.54-7.44 (m), 7.40 (d), 7.33 (d), 7.20 (d), 6.66-6.57 (m), 6.44 (d) , 6.33 (d), 6.17 (d), 4.64 (s), 3.68 (s), 3.64 (s), 3.61 (s), 3.55 (s), 3.19 (s), 3.05 (dd), 2.85-2.72 ( m), 1.86 (s), 1.62 (s).

Synthesis of N - ((S) -1- (3- (4-chloro-3- (methylsulfonamido) -1- (2,2,2-trifluoroethyl) -1H-indazol-7-yl) -6- (3methyl- 3- (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2 - ((3bS, 4aR) -5,5difluoro-3- ( trifluoromethyl) -3b, 4,4α, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1yl) acetamide (24).

(S) -N- (7- (2- (1-amino-2- (3,5-difluorophenyl) ethyl) -6- (3-methyl-3- (methylsulfonyl) but-1-yn-1yl) pyridine -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, 4,4α, 5-tetrahydro-1Hcyclopropa [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-triαzolo [4,5-b] pyridinium 3-oxide hexafluorophosphate) (854 mg, 2.25 mmol) were loaded into a round bottom flask and dissolved in DMF (dimethylformamide) (10.0 ml). N, N-diisopropylethylamine (0.80 mL, 4.49 mmol) was added dropwise quickly to the solution. Upon completion of the addition, the reaction mixture was stirred at room temperature for 15 min to give intermediate 23b, which was not isolated (MS (m / z): 1046.65 [M + H] +). To the solution was added 2N. water. sodium hydroxide solution (5.0 ml). This 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 isolated, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to give the title compound as an amorphous solid.

MS (m / z): 968.24 [M + H] ⁺ .

¹ H-NMR (400 MHz, methanol-d ₄ ) δ 7.87-7.57 (m), 7.33-7.09 (m), 6.80-6.70 (m), 6.54 (d), 6.47 (d), 6.376.19 (m ), 5.02-4.94 (m), 4.90-4.70 (m), 4.70 4.51 (m), 3.94 (dq), 3.32-3.28 (m), 3.23 (d), 3.07 (dd, J = 13.1, 7.6 Hz) , 2.93 (dd), 2.68-2.35 (m), 1.81 (s), 1.41 (q), 1.12-1.00 (m).

¹⁹ B-NMR (377 MHz, Methanol-d ₄ ) δ -63.65, -71.78 (t), -72.35 (t), -82.75 (dd), -105.70 (ddd), -111.73 - 113.10 (m).

In order to more fully characterize 23b, this compound was isolated.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.20 (d), 8.99 (d), 7.96 (d), 7.83 (d), 7.80 (d), 7.76 (d), 7.45 (d), 7.41 ( d), 7.31 (d), 7.02 (tt), 6.92 (m), 6.91 (d), 6.48 (m), 4.92 (m) 4.88 (d), 4.79 (d), 4.73 (d), 4.71 (m ), 4.69 (m), 4.62 (m), 4.60 (m), 4.38 (dq), 4.12 (dq), 3.68 (s), 3.66 (s), 3.63 (s), 3.58 (s), 3.26 (s ), 3.12 (dd), 3.05 (dd), 2.97 (dd), 2.78 (dd), 2.59 (m), 2.53 (m), 1.75 (s), 1.39 (m), 0.98 (m).

Preparation of 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole- 1-yl) acetic acid (32).

Example 6.

Getting connection 32

25 26

28

30 31a 31b

31a 32

Synthesis of lithium 2,2-difluoro-1- (3-oxobicyclo [3.1.0] hexan-2-ylidene) ethan-1-olate (25).

The title compound was prepared according to the method outlined for the synthesis of compound 2 using ethyl 2,2-difluoroacetate.

1H-NMR (400 MHz, CDCl ₃ ) δ 6.17 (t, J = 53.6 Hz, 1H), 2.78-2.73 (m, 1H), 2.44-2.39 (m, 1H), 2.25-2.24 (m, 1H), 1.70-1.69 (m, 1H), 1.22-1.14 (m, 1H), 0.31-0.27 (m, 1H).

Synthesis of 2- (3- (difluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1yl) sodium acetate (26).

Me-THF (1.32 L) was added to a 4 L reactor, after which 2,2-difluoro-1- (3oxobicyclo [3.1.0] hexane-2-ylidene) ethan-1-lithium olate (247 g, 1.32 mol ). To this mixture was slowly added HCl (4N in dioxane) (0.685 L, 2.74 mol) while maintaining the internal temperature at about 20 ° C. After adding ethyl hydrazinoacetate hydrochloride (212.05 g, 1.372 mol), the resulting mixture was stirred at 20 ° C for 4 h. The reaction mixture was heated to 50 ° C overnight. To the reaction mixture was slowly added 10N HCl. aqueous NaOH (0.548 L, 5.48 mol) and maintained the internal temperature at 20 ° C. Then 300 ml of Me-THF was added and the resulting suspension was stirred at 20 ° C for 3 hours. The suspension was separated from the liquid and filtered. The filter cake was washed with hexane

47036921 (1 L) and dried in a vacuum oven at 56 ° C to give the title compound which was used directly in the next step.

MS (m / z): 229.1 [M-Na + H] +.

Synthesis of ethyl 2- (3- (difluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate (27).

Ethyl 2- (3- (difluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-1yl) acetate from the previous stage was loaded into a reactor with a volume of 4 L, after which EtOH (3.5 L) and concentrated H ₂ SO ₄ (152 ml, 2.74 mol) were added. The resulting mixture was stirred under reflux for 2 hours. The amount of EtOH was reduced to 150 ml in vacuo. H2O (500 ml) was added slowly. The solids were collected and washed with water and NaHCO ₃ and then with hexane (500 ml). The solid was dried in an oven at 45 ° C to give the title compound.

MS (m / z): 257.1 [M + H] ⁺ .

Synthesis of ethyl 2- (3- (difluoromethyl) -5-oxo-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2c] pyrazol-1-yl) acetate (28) ...

The title compound was prepared according to the method outlined for the synthesis of compound 4 using ethyl 2- (3- (difluoromethyl) -3b, 4,4a, 5-tetrahydro-1H-cycloπroπa [3,4] cyclopenta [1 , 2-c] pyrazol-1-yl) acetate.

MS (m / z): 271.1 [M + H] +.

Synthesis of ethyl 2- (3- (difluoromethyl) -4,4a-dihydrospiro [cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-5,2 '[1,3] dithiolane] -1 (3bH) - yl) acetate (29).

To ethyl 2- (3- (difluoromethyl) -5-oxo-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate ( 148.5 g, 0.55 mol) in DCM (2.0 L) was added ethane-1,2-dithiol (88.0 g, 0.94 mol) in one portion, followed by BF ₃ -2AcOH (175.8 g, 0.94 mol). The reaction mixture was stirred at room temperature for 12 hours. The system was cooled to 0 ° C and neutralized with saturated aqueous NaHCO ₃ (1000 ml). The organic layer was separated, washed with brine (500 ml) and dried with Na2SO4. The solvents were 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] +.

Synthesis of ethyl 2- (3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate (30).

A solution of DBDMH (99 g, 0.35 mol) in DCM (120 ml) was cooled to -8 ° C in a Teflon vial. HF / Py (120 ml) was added dropwise over a period of 30 minutes. The reaction mixture was stirred at -78 ° C for 30 min. A solution of ethyl 2- (3- (difluoromethyl) -4,4-dihydrospiro [cyclopropa [3,4] cyclopenta [1,2-c] pyrazole-5,2 '- [1,3] dithiolane] -1 ( 3bH) -yl) acetate (40 g, .12 mol) in DCM (80 ml) over a 15 min period at -78 ° C. The resulting mixture was stirred for 30 min, then slowly heated to -30 ° C and stirred for 1.5 h. The reaction mixture was slowly poured into water. NaHCO3 (500 ml) and extracted with ethyl acetate (3x500 ml). The combined organic layer was washed with 10% aqueous Na2S2O3 (500 ml), brine (500 ml) and dried with Na2SO4. The solvents were removed in vacuo to give the crude product, which was then purified by column chromatography to give the title compound.

MS (m / z): 293.2 [M + H] +.

A solution of ethyl 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate (31a) and ethyl-2 - ((3bR, 4aS) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetate (31b).

Ethyl 2- (3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2c] pyrazol-1-yl) acetate was separated into the constituents of the title enantiomers are 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, 150x4.6 mm, 5 μm; wavelength: 220 nm] 31a: t = 5.30 min, 31b: t = 7.00 min.

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

Synthesis of 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazole- 1-yl) acetic acid (32).

To a solution of ethyl 2 - ((3bS, 4aR) -3- (difluoromethyl) -5,5-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c ] pyrazol-1-yl) acetate (26 g, 89.0 mmol) in THF (180 ml), MeOH (90 ml) and water (90 ml) was added LiOH (5.13 g, 213.5 mmol). The mixture was stirred for 4 hours. The mixture was concentrated to remove most of the THF and MeOH, the aqueous phase was acidified with 1N HCl to pH 2-3, then extracted with ethyl acetate (600 mlx2). The organic phase was separated and combined, dried with Na ₂ SO ₄ , filtered and concentrated in vacuo to give as indicated in

- 48 036921 header connection.

MS (m / z): 265.0 [M + H] ⁺ .

Example 7.

Getting connection 34

Synthesis of 7-bromo-4-chloro-1- (2,2-difluoroethyl) -1H-indazol-3-amine (33).

7-bromo-4-chloro-1Н-indazol-3-amine (130 g, 527.40 mmol, 1.00 eq.), N, N-dimethylformamide (1300 ml), Cs ₂ CO was placed in a 2000 ml 4-necked round-bottom flask. ₃ (260 g, 797.99 mmol, 1.50 eq.) With stirring for 20 min, after which 1,1-difluoro-2-iodoethane (122 g, 635.59 mmol, 1.20 eq.) Was added. The resulting mixture was stirred overnight at 65 ° C, then cooled to room temperature, neutralized by the addition of 3 L of water / ice mixture, extracted with 3x1.5 L of ethyl acetate. The combined organic layer was washed with 1x1.5 L H2O, 1x1.5 L brine, dried with anhydrous sodium sulfate, concentrated in vacuo, and recrystallized from ethanol to give the title compound.

MS (m / z): 312.1 [M + H] ⁺ .

Synthesis of 4-chloro-1- (2,2-difluoroethyl) -7- (4,4,5,5-tertramethyl-1,3,2-dioxaborolan-2-yl) -1H-indazole-3amine (34).

In a 3000 ml 4-necked round-bottom flask, purged with nitrogen and maintained in a neutral atmosphere of nitrogen, was placed 7-bromo-4-chloro-1- (2,2-difluoroethyl) -1H-indazol-3-amine (80 g, 257.63 mmol, 1.00 eq.), 1,4-dioxane (800 ml), N, N-dimethylformamide, (800 ml), KOAc (76 g, 774.40 mmol, 3.00 eq.), 4,4,5,5-tertramethyl -2- (tertramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (197 g, 775.78 mmol, 3.00 eq.) And Pd (PPh ₃ ) ₂ Cl ₂ (8 g, 11.40 mmol, 0.04 eq.). The mixture was stirred for 4 h at 110 ° C, then cooled to room temperature, neutralized by adding 5 L of water / ice mixture, extracted with 2x2 L of ethyl acetate. The combined organic layer was washed with 1x1 L of water, 1x1 L of brine, dried with anhydrous sodium sulfate, and concentrated in vacuo. The residue was loaded onto a silica gel column, loaded onto a silica gel column eluting with ethyl acetate / petroleum ether (1:10) to give the title compound.

MS (m / z): 358 [M + H] ⁺ .

¹ H-NMR (DMSO-d6, 300 MHz, ppm): 57.63-7.66 (1H, d), 7.00-7.03 (1H, d), 6.06-6.43 (1H, t), 5.46 (2H, s), 4.90 -5.01 (2H, t), 1.34 (12H, s).

Example 8.

Preparation of formula (IIb) (compound 38)

Synthesis of tert-butyl- (S) - (1- (3- (3-amino-4-chloro-1- (2,2-difluoroethyl) -1H-indazol-7-yl) -6- (3-methyl- 3 (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (35).

tert-Butyl- (S) - (1- (3-bromo-6- (3-methyl-3- (methylsulfonyl) but-1-yn-1-yl) pyrudin-2-yl) -2- (3, 5difluorophenyl) ethyl) carbamate (300 mg, 0.53 mmol), 4-chloro-1- (2,2-difluoroethyl) -7- (4,4,5,5-tertramethyl1,3,2-dioxaborolan-2-yl) -1H-indazol-3-amine (250 mg, 0.7 mmol), [1,1'-bis- (diphenylphosphino) ferrocene] dichloropalladium (P) (14 mg, 0.016 mmol) and potassium carbonate (186 mg, 1.35 mmol) loaded into a microwave tube and placed under an argon atmosphere. Dimethoxyethane (2.5 ml) and water (0.3 ml) were added and the reaction mixture was heated to 130 ° C in a microwave reactor (Biotage®

- 49 036921

Initiator +) for 7 minutes. The reaction mixture was cooled to room temperature and partitioned between

EtOAc and 0.1N. HCl. The aqueous layer was removed, 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] +).

Ή-NMR (400 MHz, Methanol-d ₄ ) δ 7.91-7.50 (m), 7.28-6.89 (m), 6.88-6.65 (m), 6.56 (dd), 6.46-6.17 (m), 6.08-5.60 ( m), 4.76-4.47 (m), 4.04-3.73 (m), 3.73-3.41 (m), 3.22 (s), 3.17-2.69 (m), 1.80 (s), 1.29 (d), 0.98 (d) ...

Synthesis of tert-butyl- (S) - (1 - (3 - (4-chloro-3 - (cyclopropanesulfonamido) -1 - (2,2-difluoroethyl) -III-ind azol-7-yl) -6- (3 -methyl-3- (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (36).

tert-Butyl (S) - (1 - (3 - (3-amino-4-chloro-1 - (2,2-difluoroethyl) -Sh-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) dissolved in pyridine (2 ml) with stirring at ambient temperature. To this was added cyclopropane-1-sulfonyl chloride (222 μL, 2.2 mmol). The reaction mixture was stirred at 70 ° C until the reaction was complete. Water was added and stirred for 1 h and the resulting precipitate was collected by vacuum filtration, then dissolved in methylene chloride, dried with MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography to give the title compound.

MS (m / z): 812.44 [M + H] ⁺ .

Ή-NMR (400 MHz, Methanol-d ₄ ) δ 7.93-7.58 (m), 7.50-7.15 (m), 7.00 (dd), 6.82-6.51 (m), 6.47-6.29 (m), 6.18-5.65 ( m), 4.77-4.43 (m), 4.31-4.08 (m), 3.99-3.63 (m), 3.22 (s), 3.18-2.71 (m), 1.80 (s), 1.28 (s), 1.20-0.76 ( m).

Synthesis of (S) -N- (7- (2- (1-amino-2- (3,5-difluorophenyl) ethyl) -6- (3-methyl-3 - (methylsulfonyl) but-1-yn-1 yl ) pyridin-3-yl) -4-chloro-1 - (2,2-difluoroethyl) -1H-indazol-3-yl) cyclopropanesulfonamide (37).

To a solution of m-butyl- (S) - (1 - (3 - (4-chloro-3 - (cyclopropanesulfonamido) -1 - (2,2-difluoroethyl) -Sh-ind azol-7-yl) -6- ( 3-methyl-3- (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) carbamate (705 mg, 0.87 mmol) in methylene chloride (5 ml ) trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred for 1 hour, then slowly poured into saturated sodium bicarbonate solution. It was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried with MgSO ₄ , filtered and concentrated to give the title compound.

MS (m / z): 712.34 [M + H] +.

Ή-NMR (400 MHz, Methanol-d ₄ ) δ 7.93-7.58 (m), 7.50-7.15 (m), 7.00 (dd), 6.82-6.51 (m), 6.47-6.29 (m), 6.18-5.65 ( m), 4.77-4.43 (m), 4.31-4.08 (m), 3.99-3.63 (m), 3.22 (d), 3.18-2.71 (m), 1.80 (d), 1.28 (s), 1.20-0.76 ( m).

Synthesis of N - ((S) -1- (3- (4-chloro-3- (cyclopropanesulfonamido) -1- (2,2-difluoroethyl) -1H-indazol-7-yl) -6 (3-methyl-3 - (methylsulfonyl) but-1-yn-1-yl) pyridin-2-yl) -2- (3,5-difluorophenyl) ethyl) -2 - ((3bS, 4aR) -5,5difluoro-3- (trifluoromethyl ) -3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1yl) acetamide (38).

(S) -N- (7- (2- (1-amino-2- (3,5-difluorophenyl) ethyl) -6- (3-methyl-3 - (methylsulfonyl) but-1-in-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-difluoro-3b, 4,4a, 5-tetrahydro-1H-cyclopropa [3,4] cyclopenta [1,2-c] pyrazol-1-yl) acetic acid (191 mg, 0.72 mmol) , 1-hydroxybenzotriazole (49 mg, 0.36 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (180 mg, 0.94 mmol) were loaded into 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 h. The precipitate formed was collected by vacuum filtration, then dissolved in methylene chloride, dried with MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC to give the title compound as a TFA salt.

MS (m / z): 958.88 [M + H] ⁺ .

Ή-NMR (400 MHz, Methanol-d ₄ ) δ 7.90-7.56 (m), 7.30-7.07 (m), 6.91-6.54 (m), 6.54-6.39 (m), 6.37-6.21 (m), 6.16- 5.70 (m), 4.85-4.57 (m), 4.34-4.12 (m), 3.87 -3.41 (m), 3.23 (s), 3.17 -3.02 (m), 3.00-2.77 (m), 2.572.37 (m ), 1.81 (s), 1.50-0.84 (m).

Biological examples

Example A.

Test A. Study of antiviral activity on MT4 cells.

To study the antiviral activity, 0.4 μl of 189X of the tested concentration 3-fold serially diluted in DMSO was added to 40 μl of cell growth medium (RPMI 1640, 10% PBS, 1% penicillin-streptomycin, 1% L-glutamine, 1% HEPES) in each well of a 384-well plate (10 concentrations) in four replicates.

- 50 036921

Aliquots of 1 ml MT4 cells were pre-infected for 3 h at 37 ° C using 25 μl of cell growth medium (simulated infection) or a fresh 1: 250 dilution of HIV-IIIb stock solution (ABI) (at multiplicity of infection (moi ) 0.004).

Infected and uninfected cells were diluted in cell growth medium and 35 μl (2000 cells) was added to each well of assay plates.

The assay plates were kept in a humidified incubator at 5% CO ₂ and at 37 ° C.

After 5 incubations, 25 μl of 2X Concentrated CellTiter-Glo ™ Reagent (Cat # G7573, Promega Biosciences, Inc., Madison, WI, USA) was added to each well of the assay plate, cells were lysed by incubation at room temperature for 10 min. and then read the chemiluminescence using an Envision plate reader (PerkinElmer). EC50 values were calculated as the concentration of compound that causes a 50% reduction in the luminescence signal, which is a measure of HIV-1 replication.

Example B.

Test B. Study of cytotoxicity.

The cytotoxicity of the compound and the corresponding CC ₅₀ values were determined using the protocol described for the antiviral activity test (Test A), except that uninfected cells were used.

As shown in the table below, the compound of the present invention exhibits antiviral activity (Test A) compared to Compound A and Compound B.

Compound ECso (nM) CC50 (nM) Compound 24 0.185 30068 Compound 38 0.399 55218 Compound A 1.715 21839 Compound B 2.991 14491

Example C.

Test C. Analysis of pharmacokinetics after intravenous administration in rats, beagle dogs and Javanese macaques.

The investigated products and composition.

Compounds 24 and 38 for intravenous administration were prepared in 5% ethanol, 20% PG, 45% PEG 300, 30% water at pH 2 (0.01N HCl) in an amount of 0.5 mg / ml. Doses of Compound A and Compound B for intravenous infusion were prepared in a sterile solution containing% ethanol, 45% PEG 400, and 50% water (pH 2.0) in an amount of 0.5 mg / ml. All intravenous formulations were in the form of a solution.

Used animals.

Each group of intravenous rats consisted of 3 male Sprague-Dawley rats. At the time of administration, the weight of the rats was in general from 0.317 to 0.355 kg.

Animals were fasted overnight before administration and until 4 hours after administration.

Each IV dog group consisted of 3 male beagle dogs not previously used in experiments. At the time of administration, the weight of the animals was ~ 10-12 kg. Animals were fasted overnight before administration and until 2 hours after administration.

Each group of cynomolgus monkeys for intravenous administration consisted of 3 male cynomolgus monkeys not previously used in experiments. At the time of administration, the weight of the animals was ~ 3.2-4 kg. Animals were fasted overnight before administration and until 2 hours after administration.

Introduction.

For the intravenous infusion group, the test compound was administered by intravenous infusion over 30 minutes. The infusion rate was adjusted according to the body weight of each animal so as to deliver a dose of 1 mg / kg at 2 ml / kg.

Collection of samples.

Serial blood samples (approximately 0.4 ml each for rats and 1.0 ml for dogs) were taken at the indicated time points after administration to each animal.

Blood samples were collected in Vacutainer ™ tubes (Becton-Disckinson Corp, New Jersey, USA) containing EDTA as an anticoagulant and immediately placed on wet ice prior to centrifugation to obtain plasma. Centrifugation was started within 1 hour after collection. All samples were placed in 96-well tubes and kept on dry ice until stored at approximately -70 ° C.

Determination of plasma concentrations of a compound of formula (I).

The LC / MS / MS method was also used to measure the concentration of test compounds in plasma.

- 51 036921

Calculations.

Non-compartmental analysis of pharmacokinetics was performed based on the results of determining the plasma concentration over time. The summary pharmacokinetic parameters are shown in the tables below.

Connection e CL in rats (l / h / kg) Vss in rats (l / kg) tl / 2 U cr iss (h) CLu dogs (l / h / kg) Vss in dogs (l / kg) tl / 2 Have dogs ak (h) CLu macaques (l / h / kg) Vss in macaques (l / kg) tl / 2 Poppy k (l) Compound 24 0.05 1.8 28 0.07 1.6 22 0.24 2.7 12 Compound 38 0.08 1.8 19 0.33 1.77 7 0.21 2.1 9.5 Compound A 0.50 1.0 2 0.25 0.8 4 0.45 1.18 2.3 Compound IN 0.43 1.4 3 0.28 1.3 6 0.42 1.59 3.4 CL: observed clearance; Vss: volume of distribution at steady state; ti / ₂ : final half-life

Compound Stakh in rats AUCmf (μM-h) in dogs Stakh in dogs AUCmf (μM-h) in dogs Javan. Stakh Javan. AUCmf (μM-h) Compound 24 1.8 19 2.2 14.8 1.3 4.5 Compound 38 2.4 thirteen 1.6 3.3 1.3 4.9 Compound A 1.4 2.7 2.1 five 1.8 2.6 Compound B 1.1 2.7 1.4 4.3 1.4 2.9 AUCinf: Area under the curve t = 0 to infinity; Stax: maximum plasma concentration

Example D.

Test D. Metabolic stability in culture of human liver hepatocytes Radiolabeled test compounds, in the structure of which instead of one or more hydrogen atoms introduced tritium, were obtained by methods known in this field.

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 concentration of hepatocytes was 1 million cells / ml. The hepatocyte / compound reaction mixture was dissolved in InVitroGRO ™ KHB buffer (cat # Z99074, Bioreclamation IVT, Inc., Baltimore, MD) at pH 7.4. The incubation was carried out in duplicate. Cell-free control and positive control were included in all incubations. Incubations were carried out with gentle shaking at an incubator temperature of 37 ° C and an atmospheric humidity of 95% / 5% CO ₂ (v / v). Aliquots (100 ml) were taken after 0, 1, 3, and 6 h and added to 200 ml of neutralizing solution, which contained 0.1% (v / v) TFA in a 5% water / 95% acetonitrile (v / v) mixture. ). The samples were placed in a shaker for 10 min, after which they were centrifuged at 3000g for 30 min. Supernatant samples were analyzed on a Dionex HPLC / PerkinElmer Flow Scintillation Analyzer as described below.

Liquid chromatography - radiochromatography.

Quantitative analysis was carried out by comparing the peaks of radiolabeled metabolites and starting compounds determined on a Radiomatic 625TR Flow Scintillation Analyzer connected to a Dionex / Chromeleon chromatographic system. A Phenomenex Synergi fusion RP column (150x4.6 mm, 4 mm) was used, which was maintained at 32 ° C. Mobile phase A consisted of 0.1% (v / v) TFA in a 99% water / 1% acetonitrile (v / v) mixture. Mobile phase B consisted of 0.1% (v / v) TFA in a 5% water / 95% acetonitrile (v / v) mixture. The flow rate was 1 ml / min with a used injection volume of 100 ml. The following gradient was used: Mobile phase B was ramped up to 75% over 47 minutes, held at 75% for 3 minutes, changed back to 2%, held at 2% for 10 minutes.

- 52 036921

Metabolic stability was determined by measuring the relative content of metabolites and parent compound as a function of time and calculating, based on these data, the rate of disappearance of the parent compound. The stability data were used to calculate the expected hepatic clearance values according to methods known in the art.

The values for the expected hepatic clearance in humans are shown in the table below.

Predicted human hepatic clearance (l / h / kg) Compound 24 0.01 Compound 38 0.02 Compound A 0.09 Compound B 0.04

The following conclusions can be drawn from the above comparative data.

Compound 24 is more effective in the test of antiviral activity against HIV compared to compounds A and B (about 9 and about 16, respectively, more effective). Compound 24 has a longer terminal half-life in vivo in rats compared to compounds A and B (about 14 and about 9 times longer, respectively). Compound 24 has a lower in vivo clearance in rats compared to compounds A and B (approximately 10 and approximately 8.6 times lower, respectively). Compound 24 has a longer terminal half-life in vivo in dogs compared to compounds A and B (about 5 and about 4 times longer, respectively). Compound 24 has a lower in vivo clearance in dogs than Compounds A and B (about 3 and about 4 times lower, respectively). Compound 24 is more stable in human hepatocytes and has a lower predicted hepatic clearance compared to compounds A and B (about 9 and about 4 times more stable, respectively).

The above data demonstrate that Compound 24 has improved antiviral activity and pharmacokinetic profile (as indicated by a longer half-life in rats and dogs and a lower predicted clearance in humans) compared to Compounds A and B.

In addition, compound 38 is more effective in antiviral activity against HIV test than compounds A and B (about 4 and about 8 times more effective, respectively). Compound 38 has a longer terminal half-life in vivo in rats compared to compounds A and B (about 9.5 and about 6.3 times longer, respectively). Compound 38 is characterized by a lower in vivo clearance in rats compared to compounds A and B (approximately 6.3 and approximately 5.4 times lower, respectively). Compound 38 has in vivo clearance and terminal half-lives in dogs close to those of compounds A and B. Compound 38 is more stable in human hepatocytes and has a lower predicted hepatic clearance compared to compounds A and B (about 4.5 and about 2 times more stable, respectively).

The above data demonstrate that Compound 38 has increased antiviral activity and an improved pharmacokinetic profile (as indicated by a longer half-life in rats and dogs and a lower predicted clearance in humans) compared to Compounds A and B.

The specific pharmacological responses observed can vary according to and depending on the particular active compound selected and whether pharmaceutical carriers are present, as well as the types of dosage form and route of administration employed, and the practice of the present invention provides for such expected variations or differences in results.

The examples disclosed herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare such compounds. It is understood that the individual steps described in this document can be combined. It is also contemplated that individual batches of a compound can be combined and then used further in the next step of the synthesis.

An example of obtaining formulations (preparations).

Compound 38 (about 30 mg / kg) was formulated as an aqueous suspension in 2% Poloxamer 338 in saline (about 150 mg / ml). This formulation was then administered as a single subcutaneous (SC, PC) injection to rats and the pharmacokinetic profile (PK) was determined. As can be seen in FIG. 3, Compound 38 maintains plasma concentration values well above paEC95 for> 10 weeks after a single subcutaneous injection. These data indicate that Compound 38 exhibits sustained release pharmacokinetic properties.

- 53 036921

A suspension of the compound of formula (Ib) was prepared in 2% poloxamer 188 in saline (200 mg / ml). The suspension was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 4 is a graph showing the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 4, the compound of formula (Ib) retains measurable plasma concentrations at day 70, demonstrating sustained release pharmacokinetic properties.

A suspension of the compound of formula (Ib) was prepared in 2% poloxamer 188 in saline (100 mg / ml). The suspension was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 5 shows a graph of the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 5, the compound of formula (Ib) retains measurable plasma concentrations at day 70, demonstrating sustained release pharmacokinetic properties.

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 administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 6 is a graph showing the plasma concentration of a compound of formula (Ib) as a function of time. As FIG. 6, the compound of formula (Ib) retains measurable plasma concentrations at day 70, demonstrating sustained release pharmacokinetic properties.

A solution of the compound of formula (Ib) in NMP (N-methylpyrrolidone) (100 mg / ml) was prepared. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 7 is a graph showing the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 7, the compound of formula (Ib) retains measurable plasma concentrations at day 70, demonstrating sustained release pharmacokinetic properties.

A solution of the compound of formula (Ib) in NMP (200 mg / ml) was prepared. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 8 shows a graph of the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 8, the compound of formula (Ib) retains measurable plasma concentrations at day 70, demonstrating sustained release pharmacokinetic properties.

A solution of the sodium salt of the compound of formula (Ib) in NMP (200 mg / ml) was prepared. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 9 is a graph showing the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 9, the compound of formula (Ib) retains measurable plasma concentrations at day 70, demonstrating sustained release pharmacokinetic properties.

The compound of formula (Ib) was prepared in 1 mixture of 10% ethanol, 12% water and 78% PEG 200 (200 mg / ml) in the form of a solution. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 10 shows a graph of the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 10, the compound of formula (Ib) retains measurable plasma concentrations on day 28, demonstrating sustained release pharmacokinetic properties.

A composition was prepared containing 200 mg / ml of formula (Ib) with 1.2 mol.eq. NaOH to produce in situ sodium salt in a mixture of 10% ethanol, 12% water and 77% PEG, in solution form. This formulation was administered orally to the subjects at a dose of 6 mg / kg. A solution of the compound of formula (Ib) was prepared in a mixture of 10% ethanol, 12% water and 7% PEG 200 (200 mg / ml) with 1.2 molar equiv. NaOH to form in situ sodium salt. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 11 is a graph showing the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 11, the compound of formula (Ib) retains measurable plasma concentrations on day 28, demonstrating sustained release pharmacokinetic properties.

The composition of the compound of formula (Ib) was prepared in a mixture of 10% ethanol, 13% water and 77% glycofurol (200 mg / ml) with 1.2 mol.eq. NaOH to form in situ sodium salt in solution form. The solution was administered to dogs subcutaneously at a dose of 6 mg / kg and the pharmacokinetic (PK) profile was determined. FIG. 12 shows a graph of the plasma concentration of a compound of formula (Ib) as a function of time. As seen from the data shown in FIG. 12, a compound of Formula Ib, retains measurable plasma concentrations at day 28, demonstrating sustained release pharmacokinetic properties.

An example of a composition (preparation) for oral administration.

An oral formulation was prepared containing the compound of formula (Ib) in 10% ethanol, 20% Vitamin E TPGS, and 70% Migliol 812 (MIGLYOL) in hard gelatin capsules. Dogs were given a fixed 7.5 mg dose of a compound of formula (Ib) orally and the pharmacokinetic (PK) profile was determined. FIG. 13 shows the change in plasma concentration over time for a compound of formula (Ib).

All sources cited, including publications, patents, and patent documents, are incorporated herein by reference, as if each were separately incorporated by reference. Various implementations and techniques are indicated throughout the present disclosure. Nonetheless,

- 54 036921 it should be understood that many changes and modifications can be made without departing from the spirit and scope of this disclosure.

Claims (17)

1. Compound of formula (Ia) or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, which is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof 3. A compound of formula (IIa) or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 3, which is a compound of formula (IIb) or a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition containing a therapeutically effective amount of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. - 55 036921 6. A pharmaceutical composition according to claim 5, further comprising one, two, three or four additional therapeutic agents, said additional therapeutic agents being selected from the group consisting of combination drugs for HIV, other drugs for HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase that do not bind to a catalytic site (or allosteric), inhibitors of HIV integrase, inhibitors of HIV penetration into the cell, inhibitors of HIV maturation, agents that reverse compounds targeting the HIV capsid, immunotherapeutic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV matrix protein p17 inhibitors, IL-13 antagonists, peptidyl-prolyl-cis-trans modulators isomer Pase A, protein disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulator inhibitors, Vif dimerization inhibitors, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 kinase Nef kinase inhibitors, HIV-1 kinase inhibitors, tyrosinase inhibitors line-3 (MLK-3), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, modulators of splicing factors, modulators of COMM domain containing protein 1, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, inhibitors ICAM-3-binding nonintegrin 1 of dendritic cells, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, stimulants of proprotein convertase ATP3 ATP3, inhibitors of PX3 ATP3 proprotein convertase inhibitors inhibitors of the priming complex o fraternal transcriptase, G6PD and NADPH oxidase inhibitors, ritonavir, cobicistat, HIV gene therapy and HIV vaccines, or any combination thereof; while, optionally, additional therapeutic agents are 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, inhibitors of HIV integrase, inhibitors of HIV g41 CXCR4, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, ritonavir, cobicistat and other HIV drugs, or any combination thereof. 7. A pharmaceutical composition according to claim 6, characterized in that: i) said pharmaceutical composition comprises a therapeutically effective amount of a compound according to claim 1 or 2, said additional therapeutic agents being selected from the group consisting of GS-9131, GS-9148, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, 4'-ethynyl-2-fluoro-2'-deoxyadenosine and bictegravir or their pharmaceutically acceptable salts, which optionally consists of additional therapeutic agents, a lafenofenamide tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate; or ii) said pharmaceutical composition comprises a therapeutically effective amount of a compound according to claim 3 or 4, said additional therapeutic agents being selected from the group consisting of GS-9131, GS-9148, 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, tenofovir alafenamide fumarana, optional from the therapeutic group of etomifovir 4 α-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate. 8. A pharmaceutical composition according to any one of claims 5-7, characterized in that said composition is presented in a composition for oral administration or in a composition for parenteral administration, optionally, the composition for parenteral administration is administered subcutaneously or intramuscularly to a subject in need thereof. 9. A pharmaceutical composition according to claim 8, characterized in that said composition for parenteral administration contains: i) saline and optionally further comprises poloxamer, where optionally said poloxamer is poloxamer 338 or poloxamer 188, optionally, if said poloxamer is poloxamer 188, then the concentration of poloxamer 188 in saline is 1 to 10%, optionally 1 to 3%, optionally about 2%; or ii) N-methyl-2-pyrrolidone, optionally said composition consisting essentially of N-methyl-2-pyrrolidone; or iii) dimethyl sulfoxide, where optionally said composition consists essentially of dimethyl sulfoxide; or - 56 036921 iv) water and / or alcohol, where optionally said alcohol is ethanol and / or polyethylene glycol, where optionally the average molecular weight of the polyethylene glycol is about 200 g / mol, and / or an inorganic base, where optionally said the inorganic base is sodium hydroxide. 10. A pharmaceutical composition according to claim 9, wherein said composition iv) for parenteral administration comprises 5 to 20% ethanol, 5 to 20% water and 60 to 90% polyethylene glycol 200, and optionally contains 10 to 15% ethanol, from 10 to 15% water and 70 to 80% polyethylene glycol 200; optionally containing about 10% ethanol, about 12% water, and about 78% polyethylene glycol 200. 11. A pharmaceutical composition according to any one of claims 8 to 10, characterized in that said compound is present in the form of a sodium salt. 12. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in therapy. 13. Use of a therapeutically effective amount of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of human immunodeficiency virus (HIV) infection. 14. Use according to claim 13, further comprising administering one, two, three or four additional therapeutic agents, optionally: i) additional therapeutic agents are administered simultaneously with a compound of formula (Ia), (Ib), (IIa) or (IIb) or a pharmaceutically acceptable salt thereof, optionally a compound of formula (Ia), (Ib), (IIa) or (IIb) ) is used in combination with additional therapeutic agents in a single dosage form for simultaneous administration; or ii) sequentially administering a compound of formula (Ia), (Ib), (IIa) or (IIb) and administering additional therapeutic agents. 15. Use according to claim 14, wherein said compound is a compound according to claim 1 or 2, and wherein said additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase, non-catalytic binding (or allosteric) inhibitors of HIV integrase, inhibitors of HIV penetration into the cell, inhibitors of HIV maturation, agents that reverse the latent targeting HIV capsid, immunotherapeutic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV matrix protein p17 inhibitors, IL-13 antagonists, peptidyl-prolyl-cis-trans isomerase modulators A, inhibitors of proteinisul fidisomerase, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulator inhibitors, Vif dimerization inhibitors, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef protein modulators, Hck tyrosine kinase modulators, mixed line 3 (MLK-3), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, modulators of COMM domain-containing protein 1, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, ICAM- inhibitors 3-binding non-integrin 1 dendritic cells, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulants DDX, RNKel-ATP3 inhibitors , inhibitors of the priming complex of reverse transcriptase, inhibiting G6PD and NADPH oxidase inhibitors, ritonavir, cobicistat, HIV gene therapy and HIV vaccines, or any combination thereof, optionally additional therapeutic agents selected from the group consisting of compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide reverse transcriptase inhibitors HIV transcriptase, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, ritonavir, cobicistat or other drugs thereof for HIV this optionally said compound is used in combination with: i) abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide or tenofovir alafenamide hemifumarate; or ii) 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, or pharmaceutically acceptable salts thereof; or iii) tenofovir alafenamide, tenofovir alafenamide fumarate, or tenofovir alafenamide hemifumarate; or iv) tenofovir disoproxil, tenofovir disoproxil hemifumarate, or tenofovir disoproxil fumarate; or - 57 036921 v) a first therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of lamicivudabine and emiricivudabine; or vi) a first additional therapeutic agent selected from the group consisting of tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, said second additional therapeutic agent being emtricitabine; or vii) a first additional therapeutic agent selected from the group consisting of tenofovir disoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, said second additional therapeutic agent being emtricitabine. 16. Use according to claim 14, wherein said compound is a compound according to claim 3 or 4, and wherein said additional therapeutic agents are selected from the group consisting of combination drugs for HIV, other drugs for HIV, inhibitors HIV proteases, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors that do not bind to the catalytic site (or allosteric) HIV integrase inhibitors, inhibitors of HIV penetration into the cell, inhibitors of HIV maturation, inhibitors of HIV maturation, condition, compounds targeting HIV capsid, immunotherapeutic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV matrix protein inhibitors p17, IL-13 antagonists, peptidyl-prolyl-cis modulators -trans isomerase A, inhibitor in protein disulfide isomerase, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulator inhibitors, Vif dimerization inhibitors, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef protein modulators, modulators of tyrosine kinase Hck kinase inhibitors -3 (MLK-3), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, ICAM inhibitors -3-binding nonintegrin 1 of dendritic cells, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, DDX-dependent proprotein convertase PCX3 stimulants, RNA-ATF3 inhibitors , inhibitors of the reverse transcriptase priming complex Iptase, G6PD and NADPH oxidase inhibitors, ritonavir, cobicistat, HIV gene therapy and HIV vaccines, or any combinations thereof, optionally additional therapeutic agents selected from the group consisting of compounds that inhibit HIV protease, non-nucleoside inhibitors of HIV reverse transcriptase, non-nucleotide HIV reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, inhibitors of capsid polymerization, ritonavir and any other drugs for HIV , while optionally said compound is used in combination with: i) 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulphate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafamifenatom alenofiram; or ii) 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir alafenamide, tenofovir alafenamide fumarate or tenofovir alafenamide hemifumarate; or iii) 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate; or iv) a first additional therapeutic agent selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide, and hemifumum therapeutics an agent selected from the group consisting of emtricitabine and lamivudine; or v) a first additional therapeutic agent selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir alafenamide fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, the second additional therapeutic agent being is emtricitabine; or vi) a first additional therapeutic agent selected from the group consisting of - 58 036921 4'-ethynyl-2-fluoro-2'-deoxyadenosine, tenofovir disoproxil fumarate, tenofovir disoproxil and tenofovir disoproxil hemifumarate, and a second additional therapeutic agent, the second additional therapeutic agent being emtricitabine. 17. A compound selected from the group consisting of: 14 13 12 11 10 9 8 7 6 5 4 3 2 1 -0 -1 ppm